CN1741994A

CN1741994A - 3-aminopyrrolidine derivatives as modulators of chemokine receptors

Info

Publication number: CN1741994A
Application number: CN 200380109198
Authority: CN
Inventors: 薛楚标; B·梅特卡尔夫; 冯皓; 曹敢峰; 黄太生; 郑长胜; D·J·罗宾逊; A·Q·韩
Original assignee: Incyte Corp
Current assignee: Incyte Corp
Priority date: 2002-11-27
Filing date: 2003-11-26
Publication date: 2006-03-01
Also published as: UA87449C2; ZA200504322B

Abstract

The present invention relates to 3-aminopyrrolidine derivatives of the formula I: (wherein R1, R2, R3, R4, R5, R6, R7, R8, X, Y and X are as defined herein) which are useful as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of chemokine receptors and more specifically as a modulator of the CCR2 and/or CCR5 receptor. The compounds and compositions of the invention may bind to chemokine receptors, e.g., the CCR2 and/or CCR5 chemokine receptors, and are useful for treating diseases associated with chemokine, e.g., CCR2 and/or CCR5, activity, such as atherosclerosis, restenosis, lupus, organ transplant rejection and rheumatoid arthritis.

Description

3-amino-pyrrolidine derivatives as chemokine receptor modulators

The application requires to enjoy the sequence number of U.S. Provisional Application formerly 60/429 that we proposed respectively on November 27th, 2002 and on April 18th, 2003,605 and 60/463,976 right of priority and for various purposes will be attached to herein at the full content of these applications by reference.

Invention field

The present invention relates to the conditioning agent of Chemokine Receptors, for example antagonist and they are as the purposes of medicament.The invention still further relates to the new compound and the medical approaches of treatment inflammation and other imbalance (particularly relevant imbalance such as rheumatoid arthritis, lupus, graft versus host disease (GVH disease) and/or transplant rejection) with lymphocyte or monocytosis.More particularly, the present invention relates to 3-amino-pyrrolidine derivatives and as the purposes of chemokine receptor modulators.

More particularly, the present invention relates to new anti-inflammatory and immunomodulatory bioactive compounds and pharmaceutical composition thereof, can work, suppress MCP-1 (MCP-1) thus by antagonism CCR2 acceptor (being also referred to as the MCP-1 acceptor).New compound is the 3-amino-pyrrolidine derivatives.The invention still further relates to the purposes of new compound in composition, they the preparation method, be used for their intermediate of preparation and they are as the purposes of therapeutical agent.

Chemokine conditioning agent/antagonist of the present invention can effectively be used as disease such as arteriosclerosis, asthma, pulmonary fibrosis, myocarditis, ulcerative colitis, psoriasis, asthma, ulcerative colitis, ephritis (ephrosis), multiple sclerosis, lupus, systemic lupus erythematous, hepatitis, pancreatitis, sarcoidosis, organ transplantation, Crohn disease, endometriosis, congestive heart failure, viral meningitis, cerebral infarction, neuropathy, (wherein the infiltration of the tissue of blood leucocyte (as monocyte and lymphocyte) is in the initiation of disease for mucocutaneous lymphnode syndrome and pyemia, development or kept main effect) therapeutical agent and/or preventive.

The present invention also provides immunomodulatory bioactive compounds and the pharmaceutical composition thereof that works by the antagonizing CCR 5 acceptor.

Background of invention

White corpuscle is by the blood vessel migration and be sent to it seems it is the key factor of the disease-resistant inflammatory reaction of initiation standard in the diseased tissue.This process (being also referred to as leukocytic additional process) also relates to outbreak and the progress and the debilitating autoimmune disorder of life-threatening inflammation.Therefore, the pathology of these diseases are derived from the attack of health immunity system to healthy tissues.Therefore, prevention and the blocking leukocyte target tissue that adds to inflammation and have an autoimmune disorder is therapeutic interventional high efficiency method.

The different white corpuscle classifications that participate in cell immune response comprise monocyte, lymphocyte, neutrophilic granulocyte, eosinocyte and basophilic leukocyte.In most of the cases, lymphocyte is the white corpuscle that causes, cooperates and keep chronic inflammatory reaction, and a therefore normally most important class stops the cell that enters the inflammatory position.Lymphocyte attracts monocyte to tissue site, and these M:Ls are the reason that causes the actual tissue infringement in most of inflammatory disease together.Known lymphocyte and/or monocyte infiltration can cause chronic widely autoimmune disorder, also can cause the organ-graft refection.These diseases include but not limited to rheumatoid arthritis, chronic contact dermatitis, enteritis, lupus, systemic lupus erythematous, multiple sclerosis, arteriosclerosis, psoriasis, sarcoidosis, the spontaneous lung fibrosis, dermatomyositis, skin pemphigoid and relative disease (pemphigus vulgaris for example, pemphigus foliaceus, pemphigus erythematosus), glomerulonephritis, vasculitis (vasculitides), hepatitis, diabetes, disease between allograft rejection and graft and place body.

White corpuscle leaves blood vessel and accumulates in the inflammatory position, and diseases induced process has at least three steps, is described as (1) and rolls migration [Springer, T.A., the Nature 346:425-433 (1990) that endothelium is passed in ring, (2) activation/secure attachment and (3); Lawrence and Springer, Cell65:859-873 (1991); Butcher, E.C., Cell 67:1033-1036 (1991)].Second step can mediate at molecular level by the chemoattractant acceptor.Then, the chemoattractant acceptor leukocyte surface with combine by the chemoattractant cytokine of emiocytosis at the undermined and position of infecting.But the receptors bind activated leukocyte strengthens the adhesion that the fixed member of endothelial migration is passed in mediation, and promotes the Direct Transfer of cell to chemoattractant cytokine source.

Chemoattracting cytoking (white corpuscle chemoattractant/incitant) is also referred to as chemokine, also can be called intercrines and SIS cytokine, it is class inflammatory/immunomodulatory polypeptide factor, molecular weight is 6-15kDa, can discharge by various cells, scavenger cell as the inflammatory position, monocyte, eosinocyte, neutrophilic granulocyte, fibroblast, vascular endothelial cell, smooth muscle cell and mast cell are (at Luster, New Eng.J Med., 338,436-445 (1998) and Rollins, Blood, 90,909-928 has summary in (1997)).Equally, Oppenheim, J.J. etc. be at Annu.Rev.Immunol., 9:617-648 (1991); Schall and Bacon be at Curr.Opin.Immunol., 6:865-873 (1994); Baggiolini, M. etc. are at Adv.Immunol., and 55:97-179 has described chemokine in (1994).Chemokine has the ability that stimulates direct cell migration, and this process is called chemotaxis.Each chemokine comprises the disulfide linkage (internal disulfide bonds) of four cysteine residues (C) and two inside.Chemokine can be direct neighbors based on the cysteine residues of two amino end groups or be separated by an amino acid and be divided into two subtribes of CC family and CXC family respectively.It is relevant that two subtribes of these differences and tissue become the gene cluster of separating.In each gene cluster, the general sequence similarity that shows of chemokine is 25 to 60%.CXC chemokine (as interleukin-8 (IL-8), neutrophilic granulocyte-activator-2 (NAP-2) and melanoma growth-stimulating activated protein (MGSA)) mainly tends to neutrophilic granulocyte and T lymphocyte, and the CC chemokine (then tends to other cell type (scavenger cell, T lymphocyte, eosinocyte, dentritic cell and basophilic leukocyte) as RANTES, MIP-1 α, MIP-1 β, MCP (MCP-1, MCP-2, MCP-3, MCP-4 and MCP-5) and eotaxins (1 and-2).These do not belong to the chemokine of two kinds of main chemokine subtribes chemokine lymphotoxin-1, lymphotoxin-2 (all being the C chemokine) and fractalkine (CXXXC chemokine) yet.

MCP-1 (being also referred to as MCAF (abbreviation of macrophage chemotactic factor and incitant)) or JE) by the CC chemokine of monocyte/macrophage, smooth muscle cell, fibroblast, vascular endothelial cell manufacturing and can cause monocytic cell migration and cell adhesion (referring to as Valente A.J. etc., Biochemistry, 1988,27,4162; Matsushima, K. etc., J.Exp.Med., 1989,169,1485; Yoshimura, T. etc., J.Immunol., 1989,142,1956; Rollins, B.J. etc., Proc.Natl.Acad.Sci.USA, 1988,85,3738; Rollins, B.J. etc., Blood, 1991,78,1112; Jiang, Y. etc., J.Immunol., 1992,148,2423; Vaddi, K. etc., J.Immunol., 1994,153,4721), the memory T lymphocyte is (referring to as Carr.M.W. etc., Proc.Natl.Acad.Sci.USA, 1994,91,3652), the T lymphocyte (referring to as Loetscher, P. etc., FASEB J., 1994,8,1055) and natural killer cell (referring to as Loetscher, P. etc., J.Immunol., 1996,156,322; Allavena, P. etc., Eur.J.Immunol., 1994,24,3233) and by the histamine release of basophilic leukocyte mediation (referring to as Alam., R. etc., J.Clin.Invest., 1992,89,723; Bischoff, S.C. etc., J.Exp.Med., 1992,175,1271; Kuna, P. etc., J.Exp.Med., 1992,175,489).In addition, reported the height expression of MCP-1 in the gathering of monocyte/macrophage and/or T cell is considered to the disease that disease causes or progress is very important, described disease for example arteriosclerosis (referring to as Hayes, I.M. etc., Arterioscler.Thromb.Vasc.Biol., 1998,18,397; Takeya, M. etc., Hum.Pathol., 1993,24,534; Yla-Herttuala, S. etc., Proc.Natl.Acad.Sci.USA, 1991,88,5252; Nelken, N.A. etc., J.Clin.Invest., 1991,88,1121), rheumatoid arthritis is (referring to as Koch.A.E.. etc., J.Clin.Invest., 1992,90,772; Akahoshi, T. etc., Arthritis Rheum., 1993,36,762; Robinson, E. etc., Clin.Exp.Immunol., 101,398), ephritis is (referring to as Noris.M. etc., Lab.Invest., 1995,73,804; Wada, T. etc., Kidney Int., 1996,49,761; Gesualdo, L. etc., Kidney Int., 1997,51,155), ephrosis is (referring to as S aitoh, A. etc., J.Cli.Lab.Anal., 1998,12,1; Yokoyama, H. etc., J.Leukoc.Biol., 1998,63,493), pulmonary fibrosis, lung sarcoidosis are (referring to as Sugiyama, Y. etc., Internal Medicine, 1997,36,856), asthma (referring to as Karina, M. etc., J.Invest, Allergol.Clin.Immunol., 1997,7,254; Stephene, T.H. etc., Am.J.Respir.Crit.Care Med., 1997,156,1377; Sousa, A.R. etc., Am.J.Respir CellMol.Biol., 1994,10,142), multiple sclerosis is (referring to for example McManus, C. etc., J.Neuroimmunol, 1998,86,20), psoriasis is (referring to for example Gillitzer, R. etc., J.Inverst.Dermatol, 1993,202,127), enteritis (referring to as Grimm, M.C. etc., J.Leukoc.Biol., 1996,59,804; Reineckr, H.C. etc., Gastroenterology, 1995,106,40), myocarditis (referring to as Seino, Y. etc., Cytokine, 1995,7,301), endometriosis (referring to as Jolicoeur, C. etc., Am.J.Pathol., 1998,152,125), the intraperitoneal adhesion is (referring to as Zeyneloglu, H.B. etc., Human Reproduction, 1998,13,1194), congestive heart failure (referring to as Aurust, P. etc., Circulation, 1998,97,1136), chronic hepatopathy (referring to as Marra, F. etc., Am.J.Pathol., 1998,152,423), viral meningitis is (referring to as Lahrtz, F. etc., Eur.J.Immunol., 1997,27,2484), mucocutaneous lymphnode syndrome (referring to as Wong, M. etc., J.Rheumatol., 1997,24,1179) and pyemia (referring to as Salkowaki, C.A. etc., Infect.Immun., 1998,66,3569).In addition, also reported anti--MCP-1 antibody to class rheumatoid arthritis animal model show to suppress effect or result of treatment (referring to as Schimmer, R.C. etc., J.Immunol., 1998,160,1466; Schrier, D.J. etc., J.Leukoc.Biol., 1998,63,359; Ogata, H. etc., J.Pathol., 1997,182,106), multiple sclerosis (referring to as Karpus, W.J. etc., J.Leukoc.Biol., 1997,62,681), ephritis (referring to as Lloyd, C.M. etc., J.Exp.Med., 1997,185,1371; Wada, T. etc., FASEB J.1996,10,1418), asthma (referring to as Gonzalo, J.A. etc., J.Exp.Med., 1998,188,157; Lukacs, N.W. etc., J.Immunol., 1997,158,4398), atherosclerosis is (referring to as Guzman, L.A. etc., Circulation, 1993,88 (suppl.), I-371), delayed-type hypersensitivity (referring to as Rand, M.L. etc., Am.J.Pathol., 1996,148,855), pulmonary hypertension is (referring to as Kimura.H. etc., Lab.Invest., 1998,78,571) and the intraperitoneal adhesion (referring to as Zeyneloglu.H.B. etc., Am.J.Obstet.Gynecol., 1998,179,438).It is reported the peptide antagonists of MCP-1, i.e. MCP-1 (9-76) also can suppress sacroiliitis (referring to as Gong in mouse model, J.H. at J.Exp., the 4th edition, 1997,186,131), simultaneously to the mouse that lacks MCP-1 studies show that MCP-1 very important to replenishing in the monocytic body (referring to as Lu, B. etc., J.Exp.Med., 1998,187,601; Gu, L. etc., Moll.Cell, 1998,2,275).

The document of publishing shows that chemokine such as MCP-1 and MIP-1 α can lure monocyte and lymphocyte on focus and mediate its activity, therefore be considered to monocyte and the closely-related disease of lymphocyte (as arteriosclerosis, restenosis, rheumatoid arthritis, psoriasis, asthma, ulcerative colitis, ephritis (ephrosis), multiple sclerosis, pulmonary fibrosis, myocarditis, hepatitis, pancreatitis, sarcoidosis, Crohn disease, endometriosis, congestive heart failure, viral meningitis, cerebral infarction, neuropathy, mucocutaneous lymphnode syndrome and pyemia) initiation, the development and keep closely related (for example, see Rovin, B.H. etc., Am.J.Kidney.Dis., 1998,31,1065; Lloyd, C. etc., Curr.Opin.Nephrol.Hypertens., 1998,7,281; Conti, P. etc., Allergy and Asthma Proc., 1998,19,121; Ransohoff, R.M. etc., Trends Neurosci., 1998,21,154; MacDermott, R.P. etc., Inflammatory Bowel Diseases, 1998,4,54).

The chemokine that adheres to specific cells-surface receptor belongs to G-albumen coupling seven-transmembrane territory albumen (Horuk is at Trends Pharm.Sci., 15,159-165 (1994) summarizes), is called as " Chemokine Receptors ".When in conjunction with their cognate ligand, the signal of Chemokine Receptors in associating trimerization G albumen transition cell, therefore except that other response, cause also that intracellular calcium concentration increases sharply, cell shape changes, the threshing of the expression increase of adhesive cell molecule, cell and promote cell migration.

The gene of clones coding specific chemokines acceptor, and known these acceptors is the G-albumen coupling seven transmembrane domain receptor that is present in the various lymphocyte populations.Up to now, identify five kinds of CXC Chemokine Receptors (CXCR1-CXCR5) and eight kinds of CXC Chemokine Receptors (CXCR1-CXCR8) at least.For example IL-8 is the part of CXCR1 and CXCR2, and MIP-1 α is the part of CCR1 and CCR5, and MCP-1 be CCR2A and CCR2B part (with reference to following example: Holmes, W.E. etc., Science 1991,253,1278-1280; Murphy P.M. etc., Science, 253,1280-1283; Neote, K. etc., Cell, 1993,72,415-425; Charo, I.F. etc., Proc.Natl.Acad.Sci.USA, 1994,91,2752-2756; Yamagami, S. etc., Biochem.Biophys.Res.Commum., 1994,202,1156-1162; Combadier, C. etc., The Journal of Biological Chemistry, 1995,270,16491-16494, Power, C.A. etc., J.Biol.Chem., 1995,270,19495-19500; Samson, M. etc., Biochemistry, 1996,35,3362-3367; Murphy, P.M., Annual Review of Immunology, 1994,12,592-633).It is reported, in the mouse that lacks CCR-1, can suppress pneumonia and granuroma formation and (see Gao, J.-L. etc., J.Exp.Med., 1997,185,1959; Gerard, C. etc., J.Clin.Invest., 1997,100,2022), and in the mouse that lacks CCR-2, reduced replenishing with the formation of atherosclerotic lesions of scavenger cell and (seen Boring, L. etc., Nature, 1998,394,894; Kuziel, W.A. etc., Proc.Natl.Acad.Sci., USA, 1997,94,12053; Kurihara, T. etc., J.Exp.Med., 1997,186,1757; Boring, L. etc., J.Clin.Invest., 1997,100,2552).

Therefore, but chemokine inhibiting such as MCP-1 and/or MIP-1 α are attached to the medicine on their acceptor, chemokine receptor anagonists for example, can effectively be used as chemokine inhibiting such as MCP-1 and/or MIP-1 α medicament, but prior art there is not the report about the 3-amino-pyrrolidine derivatives with this drug effect to the effect of target cell.A kind of fabulous drug design method has been represented in the evaluation of the compound of the function of mediation CCR2 and/or CCR5, is used for the treatment of with CCR2 and/or CCR5 with research and development and activates relevant inflammation and disease, for example rheumatoid arthritis, lupus and other inflammation.The invention provides the chemokine receptor modulators and the antagonist of long-term needs.

Goal of the invention

According to aforesaid idea, a free-revving engine of the present invention provides the chemokine receptor anagonists and the chemokine receptor modulators of treatment rheumatoid arthritis.

Another main purpose of the present invention provides chemokine receptor anagonists and medicament purposes thereof.

Other purpose of the present invention provides chemokine receptor modulators and medicament purposes thereof.

A present invention also purpose provides the 3-amino-pyrrolidine derivatives.

Another object of the present invention relates to the new compound and the medical approaches for the treatment of inflammation.

Other purpose of the present invention provides novel anti-inflammatory and immunomodulatory bioactivation compound and the pharmaceutical composition thereof that works through antagonism CCR2 acceptor.

The present invention also purpose provides the 3-amino-pyrrolidine derivatives and as the purposes of chemokine receptor modulators.

The present invention goes back the purposes that a purpose provides 3-amino-pyrrolidine derivatives and treatment and prevention of arterial sclerosis and restenosis.

The present invention also purpose provides the 3-amino-pyrrolidine derivatives and as the purposes of CCR5 receptor modulators.

Another main purpose of the present invention provides 3-amino-pyrrolidine bioactivation compound and the pharmaceutical composition thereof that works through the antagonizing CCR 5 acceptor.

Other purpose of the present invention and embodiment hereinafter will be discussed.But, though be important to note that many other embodiments of the present invention not in this manual, yet still in the spirit and scope of the present invention and/or claims.

Summary of the invention

The present invention provides the compound of formula I in the embodiment widely at it:

Its enantiomorph, diastereomer, the mixture that is rich in enantiomorph, racemic mixture, prodrug, crystallized form, noncrystalline form, amorphous form, solvate, metabolite and pharmacy acceptable salt, wherein:

X is selected from aryl, single replacement or polysubstituted aryl, heterocycle heteroaryl, single replacement or polysubstituted heteroaryl, carbocyclic ring, the single replacement or polysubstituted carbocyclic ring (CR ₉R ₁₀) _n, n=0-5 wherein;

Y is a key, or be selected from oxygen, sulphur, nitrogen, amido linkage, thioamides key, sulphonamide, ketone ,-CHOH-,-the CHO-alkyl-, oxime or urea;

Z is selected from has 0-3 R ₁₁Substituent carbocyclic ring, aromatic ring, heterocycle or hetero-aromatic ring group, wherein R ₁₁Be independently selected from: halogen; alkyl; thiazolinyl; alkynyl; alkoxyl group; alkoxyalkyl; alkyl-thio-alkyl; alkylthio; single-; two-or tri haloalkyl; single-; two-or three halogenated alkoxies; nitro; amino; single-or two-substituted-amino; single-or two-substituted-amino alkyl; carboxyl; esterifying carboxyl group; formamyl (carboxamido); single-or two-replacement sulfamyl (sulfoamide); alkyl-carbonyl; the cyclic alkyl alkylsulfonyl; aryl sulfonyl; heteroarylsulfonyl; alkyl-carbonyl; the cyclic alkyl carbonyl; aryl carbonyl; the heteroaryl carbonyl; thiocarbamoyl; cyano group and R _11a-aryl or R _11a-heteroaryl, wherein R _11aFor H, halogen, OH, amino, list-or two-substituted-amino, list-, two-or tri haloalkyl, alkoxyl group, list-, two-or three halogenated alkoxies, formamyl, sulfamyl, carboxylamine base (carbamete), urea or cyano group;

R ₁Be independently selected from: carbocyclic ring, heterocycle, aryl, heteroaryl, arylalkyl, heteroarylalkyl, aryl alkenyl, heteroaryl thiazolinyl, aromatic yl polysulfide yl, heteroaryl alkynyl, aromatic yl aminocarbonyl, heteroaryl amino carbonyl, aryl-amino-carbonyl, heteroaryl amino formyl radical, aryl-ureido, heteroaryl urea groups, aryloxy, heteroaryloxy, alkoxy aryl, heteroaryl alkoxyl group, arylamino or heteroaryl amino, and wherein said carbocyclic ring, heterocycle, aryl, arylalkyl, heteroaryl or heteroarylalkyl can be by 0-3 R _1aSubstituting group replaces, wherein R _1aBe independently selected from: halogen; alkyl; thiazolinyl; alkynyl; alkoxyl group; alkoxyalkyl; alkyl-thio-alkyl; hydroxyalkyl; single-; two-or tri haloalkyl; single-; two-or three halogenated alkoxies; nitro; amino; single-or two-substituted-amino; single-or two-substituted-amino alkyl; aminocarboxyl; single-or two-substituted aminocarbonyl; cyclic aminocarbonyl; amino-sulfonyl; single-or two-substituted-amino alkylsulfonyl; alkyl-carbonyl; the cyclic alkyl carbonyl; the aryl carbonyl base; the heteroaryl carbonyl; alkyl sulphonyl; the cyclic alkyl alkylsulfonyl; aryl sulfonyl; heteroarylsulfonyl; carboxylic acid; the esterification carboxylic acid; alkyl-carbonyl-amino; the cyclic alkyl carbonylamino; aryl-carbonylamino; the heteroaryl carbonylamino; cyano group; arylalkyl; heteroarylalkyl; aryloxy alkyl; the heteroaryloxy alkyl; the aryl alkylthio; the heteroaryl alkylthio; the carboxylamine base; single-or two-substituted-amino formyloxy; R _1b-aryl or R _1b-heteroaryl, wherein R _1bFor H, halogen, OH, amino, list-or two-substituted-amino, list-, two-or tri haloalkyl, alkoxyl group, list-, two-or three halogenated alkoxies, hydroxyalkyl, alkoxyalkyl, aminoalkyl group, list-or two-substituted-amino alkyl, formamyl, sulfamyl, carboxylamine base, urea or cyano group;

R ₂Be independently selected from: H, amino, list-or two-substituted-amino, OH, carboxyl, esterifying carboxyl group, formamyl, the single substituted-amino formyl radical of N-and N, N-disubstituted amido formyl radical, cyano group, alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group, alkoxyl group, alkylthio, list-, two-or tri haloalkyl, halogen, aryl or heteroaryl;

Optional R ₁And R ₂Bonding forms volution each other;

R ₃, R ₄, R ₅And R ₆Be independently selected from: H, amino, OH, alkyl, haloalkyl, dihalo alkyl, tri haloalkyl, thiazolinyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyl group and alkylthio;

Optional R ₁And R ₃But forming, cyclisation has 0-3 R _aSubstituent carbocyclic ring or heterocycle, wherein R _aBe selected from halogen, alkyl, alkoxyl group, alkylthio, list-, two-or tri haloalkyl, list-, two-or three halogenated alkoxies, nitro, amino, carboxyl, esterifying carboxyl group, formamyl, thiocarbamoyl, cyano group, singly replace, two replace or polysubstituted aryl and heterocycles, optionally comprise 0-3 R _bSubstituting group, wherein R _bSubstituting group be selected from halogen, alkyl, alkoxyl group, alkylthio, list-, two-or tri haloalkyl, list-, two-or three halogenated alkoxies, nitro, amino, carboxyl, esterifying carboxyl group, formamyl, thiocarbamoyl and cyano group;

Optional R ₃And R ₄Or R ₅And R ₆Cyclisation forms the bridged bicyclic system of band ethylidene bridged bond;

Optional R ₃And R ₆Cyclisation forms band methylene radical or ethylidene or is selected from the heteroatomic bridged bicyclic system of N, O and S;

R ₇And R ₈Be independently selected from hydrogen, C ₁-C ₈Alkyl and optional by oxygen or sulphur interval, alkoxyl group, list-, two-or tri haloalkyl, list-, two-or three halogenated alkoxies, alkoxyalkyl, aryloxy, heteroaryloxy, alkoxy aryl, heteroaryl alkoxyl group, aryloxy alkyl, heteroaryloxy alkyl, alkoxy aryl alkyl or heteroaryl alkoxyalkyl;

Optional R ₇And R ₈But cyclisation forms spiral shell carbocyclic ring or spiroheterocyclic;

R ₉And R ₁₀Be independently selected from H, OH, amino, alkoxyl group, list-or disubstituted amido, alkyl, thiazolinyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, carbocyclic ring or heterocycle;

Optional R ₉And R ₁₀But cyclisation forms carbocyclic ring or heterocycle; And

r＝0-3。

The present invention also provides the compound of formula II:

Wherein, X, Y, Z and R ₁, R ₂, R ₃, R ₄, R ₅, R ₆, R ₇And R ₈In relevant preferred embodiment, be described in detail; For enough simple, each substituting group is defined as the corresponding substituent more preferably subclass of formula I compound.

The present invention also relates to the compound of formula III:

Wherein, R ₁, R ₂, R ₃, R ₄, R ₅, R ₆, R ₇, R ₈Be described in detail in relevant preferred embodiment with m; For enough simple, each substituting group is defined as the corresponding substituent more preferably subclass of formula I compound.

The present invention also relates to comprise the anti-inflammatory of above-mentioned formula I, II and III and/or the pharmaceutical composition of immunomodulatory compounds, can work, suppress MCP-1 (MCP-1) thus by antagonism CCR2 acceptor (being also referred to as the MCP-1 acceptor).

The present invention also relates to comprise the anti-inflammatory of above-mentioned formula I, II and III and/or the pharmaceutical composition of immunomodulatory compounds, can work, suppress MCP-1 (MCP-1) thus by antagonizing CCR 5 acceptor (being also referred to as the MCP-1 acceptor).

The present invention also relates to formula I, II and III compound, wherein said compound has the function of CCR2 chemokine receptor modulators, can be used for prevention or treatment inflammation illness and disease for example rheumatoid arthritis, anaphylactia, psoriasis, allergic dermatitis, lupus and asthma.

The present invention also relates to formula I, II and III compound, wherein said compound has the function of CCR5 chemokine receptor modulators, can be used for prevention or treatment inflammation illness and disease for example rheumatoid arthritis, anaphylactia, psoriasis, allergic dermatitis, lupus and asthma.

The invention still further relates in mammalian body the method for regulating chemokine receptor activity, described method comprises the formula I, the II that give significant quantity and the compound of III.

The present invention also provides the pharmaceutical composition that comprises the compound that is selected from formula I, II and III and these compounds and composition to relate to the purposes of the disease of CCR2 Chemokine Receptors in prevention or treatment.

The present invention also provides the pharmaceutical composition that comprises the compound that is selected from formula I, II and III and these compounds and composition to relate to the purposes of the disease of CCR5 Chemokine Receptors in prevention or treatment.

The present invention also provides treatment to suffer from the mammiferous method of inflammation, rheumatoid arthritis, lupus, systemic lupus erythematous, arteriosclerosis, restenosis, immunity imbalance and transplant rejection, described method comprises the pharmaceutical composition that gives these Mammals treatment significant quantities, and described composition comprises acceptable vehicle, diluent or carrier on formula I, II and III compound and the bound drug.

The description of preferred embodiment

The present invention relates to have the compound of following chemical structure I and II:

Z is selected from has 0-3 R ₁₁Substituent carbocyclic ring, aromatic ring, heterocycle or hetero-aromatic ring group, wherein R ₁₁Be independently selected from: halogen; alkyl; thiazolinyl; alkynyl; alkoxyl group; alkoxyalkyl; alkyl-thio-alkyl; alkylthio; single-; two-or tri haloalkyl; single-; two-or three halogenated alkoxies; nitro; amino; single-or two-substituted-amino; single-or two-substituted-amino alkyl; carboxyl; esterifying carboxyl group; formamyl; list or disubstituted amido formyl radical; the carboxylamine base; list or disubstituted amido formyloxy; sulfamyl; single-or two-replacement sulfamyl; alkyl-carbonyl; the cyclic alkyl alkylsulfonyl; aryl sulfonyl; heteroarylsulfonyl; alkyl-carbonyl; the cyclic alkyl carbonyl; aryl carbonyl; the heteroaryl carbonyl; thiocarbamoyl; cyano group and R _11a-aryl or R _11a-heteroaryl, wherein R _11aFor H, halogen, OH, amino, list-or two-substituted-amino, list-, two-or tri haloalkyl, alkoxyl group, list-, two-or three halogenated alkoxies, formamyl, sulfamyl, carboxylamine base, urea or cyano group;

R ₁Be independently selected from: carbocyclic ring; heterocycle; aryl; heteroaryl; arylalkyl; heteroarylalkyl; aryl alkenyl; the heteroaryl thiazolinyl; aromatic yl polysulfide yl; the heteroaryl alkynyl; aromatic yl aminocarbonyl; the heteroaryl amino carbonyl; aryl-amino-carbonyl; the heteroaryl amino formyl radical; aryl-ureido; the heteroaryl urea groups; aryloxy; heteroaryloxy; alkoxy aryl; the heteroaryl alkoxyl group; arylamino or heteroaryl amino and wherein said carbocyclic ring; heterocycle; aryl; arylalkyl; heteroaryl or heteroarylalkyl can be by 0-3 R _1aSubstituting group replaces, wherein R _1aBe independently selected from: halogen; alkyl; thiazolinyl; alkynyl; alkoxyl group; alkoxyalkyl; alkyl-thio-alkyl; hydroxyalkyl; single-; two-or tri haloalkyl; single-; two-or three halogenated alkoxies; nitro; amino; single-or two-substituted-amino; single-or two-substituted-amino alkyl; aminocarboxyl; single-or two-substituted aminocarbonyl; cyclic aminocarbonyl; amino-sulfonyl; single-or two-substituted-amino alkylsulfonyl; alkyl-carbonyl; the cyclic alkyl carbonyl; the aryl carbonyl base; the heteroaryl carbonyl; alkyl sulphonyl; the cyclic alkyl alkylsulfonyl; aryl sulfonyl; heteroarylsulfonyl; carboxylic acid; the esterification carboxylic acid; alkyl-carbonyl-amino; the cyclic alkyl carbonylamino; aryl-carbonylamino; the heteroaryl carbonylamino; cyano group; arylalkyl; heteroarylalkyl; aryloxy alkyl; the heteroaryloxy alkyl; the aryl alkylthio; the heteroaryl alkylthio; the carboxylamine base; single-or two-substituted-amino formyloxy; R _1b-aryl or R _1b-heteroaryl, wherein R _1bFor H, halogen, OH, amino, list-or two-substituted-amino, list-, two-or tri haloalkyl, alkoxyl group, list-, two-or three halogenated alkoxies, hydroxyalkyl, alkoxyalkyl, aminoalkyl group, list-or two-substituted-amino alkyl, formamyl, sulfamyl, carboxylamine base, urea or cyano group;

Optional R ₁And R ₂Bonding forms volution each other;

R ₃, R ₄, R ₅And R ₆Be independently selected from: H, amino, OH, alkyl, haloalkyl, dihalo alkyl, tri haloalkyl, thiazolinyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyl group, list, two or three halogenated alkoxy and alkylthios;

r＝0-3。

The invention still further relates to the compound of formula III:

R ₁Be independently selected from: carbocyclic ring; heterocycle; aryl; heteroaryl; arylalkyl; heteroarylalkyl; aryl alkenyl; the heteroaryl thiazolinyl; aromatic yl polysulfide yl; the heteroaryl alkynyl; aromatic yl aminocarbonyl; the heteroaryl amino carbonyl; aryl-amino-carbonyl; the heteroaryl amino formyl radical; aryl-ureido; the heteroaryl urea groups; aryloxy; heteroaryloxy; alkoxy aryl; the heteroaryl alkoxyl group; arylamino or heteroaryl amino and wherein said carbocyclic ring; heterocycle; aryl; arylalkyl; heteroaryl or heteroarylalkyl can be by 0-3 R _1aSubstituting group replaces, wherein R _1aBe independently selected from: halogen; alkyl; thiazolinyl; alkynyl; alkoxyl group; alkoxyalkyl; alkyl-thio-alkyl; hydroxyalkyl; single-; two-or tri haloalkyl; single-; two-or three halogenated alkoxies; nitro; amino; single-or two-substituted-amino; single-or two-substituted-amino alkyl; aminocarboxyl; single-or two-substituted aminocarbonyl; cyclic aminocarbonyl; amino-sulfonyl; single-or two-substituted-amino alkylsulfonyl; alkyl-carbonyl; the cyclic alkyl carbonyl; aryl carbonyl; the heteroaryl carbonyl; alkyl sulphonyl; the cyclic alkyl alkylsulfonyl; aryl sulfonyl; heteroarylsulfonyl; carboxylic acid; the esterification carboxylic acid; alkyl-carbonyl-amino; the cyclic alkyl carbonylamino; aryl-carbonylamino; the heteroaryl carbonylamino; cyano group; arylalkyl; heteroarylalkyl; aryloxy alkyl; the heteroaryloxy alkyl; the aryl alkylthio; the heteroaryl alkylthio; the carboxylamine base; single-or two-substituted-amino formyloxy; R _1b-aryl or R _1b-heteroaryl, R _1bFor H, halogen, OH, amino, list-or two-substituted-amino, list-, two-or tri haloalkyl, alkoxyl group, list-, two-or three halogenated alkoxies, hydroxyalkyl, alkoxyalkyl, aminoalkyl group, list-or two-substituted-amino alkyl, formamyl, sulfamyl, carboxylamine base, urea or cyano group;

Optional R ₁And R ₂Bonding forms volution each other;

And m=0-5.

Definition as mentioned, for the compound of formula I and II, X is selected from aryl, single replacement or polysubstituted aryl, heterocycle, heteroaryl, single replacement or polysubstituted heteroaryl, carbocyclic ring, the single replacement or polysubstituted carbocyclic ring (CR ₉R ₁₀) _n, n=0-5 wherein.Term aryl will comprise aromatic carbocyclic group such as phenyl, xenyl, indenyl, naphthyl and aromatic ring and heterocyclic condensed ring group such as 2-benzothienyl, 3-benzothienyl, 2-benzofuryl, 3-benzofuryl, 2-indyl, 3-indyl, 2-quinolyl, 3-quinolyl, 2-[4-morpholinodithio base, 2-benzoxazolyl, 2-benzimidazolyl-, 1-isoquinolyl, 4-quinolyl, 1-pseudoindoyl, 3-pseudoindoyl and acridyl.The term heterocycle will comprise aromatics and non-aromatic ring, for example comprise 3 to 20, preferred 4 to 10 annular atomses, and one of them is heteroatoms such as oxygen, sulphur, phosphorus or nitrogen.The example of these groups comprises furyl, thienyl, pyrryl, pyrrolidyl, imidazolyl, triazolyl, thiazolyl, tetrazyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, quinolyl, isoquinolyl, quinoxalinyl, benzothiazolyl, benzoxazolyl, benzothienyl or benzofuryl.Other example comprises non-aromatic heterocyclic, and they are non-aromatic carbocyclic, comprises one or more heteroatomss for example nitrogen, oxygen or sulphur in the ring.Described ring can have five, six, seven or eight annular atomses.Example comprises 2-tetrahydrofuran base, 3-tetrahydrofuran base, 2-tetrahydro-thienyl, 3-tetramethylene sulfide, 2-morpholinyl, morpholinyl, 4-morpholinyl, 2-thio-morpholinyl, 3-thio-morpholinyl, 4-thio-morpholinyl, 1-pyrrolidyl, 2-pyrrolidyl, 3-pyrrolidyl, 1-piperazinyl, 2-piperazinyl, piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl and 4-thiazolidyl.When the implication of X and Z was identical, their definition was also identical.In addition, when described heteroaryl or heterocyclic radical were nitrogen heterocyclic ring, the nitrogen deformable was with N → O ^-Form (N oxide compound) exist and this oxide compound is also included within the scope of the present invention.When being sulfur heterocyclic ring, this oxysulfide is also included within the scope of the present invention.

The substituting group of aryl of the present invention, aralkyl, heteroaryl, heteroaralkyl and heterocyclic group is selected from halogen, alkyl, alkoxyl group, single halogenated alkoxy, dihalo alcoxyl base, three halogenated alkoxies, alkylthio and single haloalkyl, dihalo alkyl, tri haloalkyl, nitro, amino, carboxyl, esterifying carboxyl group, formamyl, thiocarbamoyl and cyano group.More particularly, described substituting group also can be selected from trifluoromethyl, C _1-4Alkyl, halogen, trifluoromethoxy, fluorine methoxyl group, difluoro-methoxy, C _1-5Alkoxyl group, C _1-5Alkyloyl, C _1-5Alkanoyloxy, C _1-5Alkylamino, two (C _1-5Alkyl)-amino, C _1-5Alkanoylamino, nitro, carboxyl, formamyl, C _1-5Alkoxy carbonyl, sulfydryl, C _1-5Sulfoamido, carbamyl C _1-5Alkyl, N-(C _1-5Alkyl) carbamyl C _1-5Alkyl, N-(C _1-5Alkyl) ₂Carbamyl-C _1-5Alkyl, hydroxyl C _1-5Alkyl or C _1-5Alkoxy C _1-4Alkyl.

Except as otherwise noted, otherwise term halogen or halogen, or itself is as another substituent part, expression fluorine, chlorine, bromine, iodine atom.Similarly, term such as haloalkyl will comprise single haloalkyl and multi-haloalkyl.As halo (C ₁-C ₄) alkyl represents to comprise trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl etc.

When using when independent use or as suffix, the term alkyl comprises straight chain and branched structure such as primary alkyl, secondary alkyl and tertiary alkyl.These groups can comprise up to 15, preferably up to 8 and more preferably up to 4 carbon atoms.Similarly, term thiazolinyl and alkynyl refer to unsaturated straight chain or branched structure, comprise 2 to 12, preferred 2 to 6 carbon atoms.Circular part such as cycloalkyl, cycloalkenyl group and cycloalkyne are similar in essence but contain at least 3 carbon atoms.The example of saturated hydrocarbyl comprises the homologue and the isomer of methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl, isobutyl-, sec-butyl, cyclohexyl, (cyclohexyl) methyl, cyclopropyl methyl, following group, for example n-pentyl, n-hexyl, n-heptyl, n-octyl etc.The example of unsaturated alkyl comprises vinyl, 2-propenyl, crot(on)yl, 2-isopentene group, 2-(butadienyl), 2,4-(pentadienyl), 3-(1, the 4-pentadienyl), ethynyl, 1-and 3-proyl, 3-butynyl and more high-grade homologue and isomer.In the present invention, cycloalkyl also will comprise adamantyl and other bridged bond compound.Described term alkoxyl group, alkylamino and alkylthio (or thio alkoxy) use its conventional sense, and refer to respectively to be connected to alkyl on the molecule remainder by Sauerstoffatom, amino or sulphur atom.Therefore, term such as alkoxyl group comprise the moieties as defined above that is connected with suitable functional group with alkylthio.

Other suitable substituents that can use in many carbocyclic rings of the present invention (for example cyclic aliphatic, aromatics, non-aromatic heterocyclic or benzyl) comprises, for example-OH, halogen (Br ,-Cl ,-I and-F) ,-O (aromatic group of phenyl, aromatics or the replacement of the benzyl of aliphatic series, the aliphatic series that replaces, benzyl, replacement, phenyl, replacement) ,-CN ,-NO ₂,-COOH ,-NH ₂,-NH (aromatic group of the phenyl of the benzyl of the aliphatic group of aliphatic group, replacement, benzyl, replacement, phenyl, replacement, aromatics or replacement) ,-NH (aromatic group of the phenyl of the benzyl of the aliphatic group of aliphatic group, replacement, benzyl, replacement, phenyl, replacement, aromatics or replacement) ₂,-COO (aromatic group of the phenyl of the benzyl of the aliphatic group of aliphatic group, replacement, benzyl, replacement, phenyl, replacement, aromatics or replacement) ,-CONH ₂,-CONH (aromatic group of the phenyl of the benzyl of the aliphatic group of aliphatic group, replacement, benzyl, replacement, phenyl, replacement, aromatics or replacement) ,-SH ,-S (aromatic group of the phenyl of the benzyl of the aliphatic group of aliphatic group, replacement, benzyl, replacement, phenyl, replacement, aromatics or replacement) and-NH-C=NH)-NH ₂Non-aromatic heterocyclic, benzyl or the aryl that replaces also can be with the aliphatic group of aliphatic group or replacement as substituting group.Alkyl that replaces or aliphatic group also can be with the aromatic group of benzyl, aromatics or the replacement of non-aromatic heterocyclic, benzyl, replacement as substituting groups.The non-aromatic heterocyclic that replaces also can have=O ,=S ,=NH or=N (aromatic group of aliphatic series, aromatics or replacement) is as substituting group.The non-aromatic heterocyclic of the aliphatic series that replaces, the aromatics of replacement, replacement or the benzyl of replacement can have the substituting group more than.

As R ₁The carbocyclic ring substituting group of definition will comprise the cycloalkyl and the dicyclo of 3-10 carbon atom and encircle the bridged bond system more, as norborneol alkyl, adamantyl and dicyclo [2.2.2] octyl group.As R ₁The group that the carbocyclic ring substituting group of definition also can be further meets above X definition with heterocycle or hetero-aromatic ring such as pyridyl, pyrrolidyl and all replaces.

R ₁Substituent object lesson comprises phenyl; pyridine-2-base; the 4-aminomethyl phenyl; 3-methyl-phenyl; the 2-aminomethyl phenyl; the 4-bromophenyl; the 3-bromophenyl; the 4-chloro-phenyl-; 3-chloro-phenyl; the 4-trifluoromethyl; the 3-trifluoromethyl; the 2-trifluoromethyl; the 2-p-methoxy-phenyl; the 3-pyridyl; the 4-pyridyl; 2-methoxyl group-5-pyridyl; 2-oxyethyl group-5-pyridyl; 3; the 4-methylenedioxyphenyl; the 4-fluorophenyl; 3-Trifluoromethyl-1 H-pyrazol-1-yl; the 3-fluorophenyl; the 4-p-methoxy-phenyl; the 3-p-methoxy-phenyl; pyridin-4-yl; pyridin-3-yl; 5-picoline-2-base; 6-picoline-2-base; quinolyl-4; 3-methyl isophthalic acid H-pyrazol-1-yl; 3; 5-dimethyl-1H-pyrazol-1-yl; the 4-trifluoromethyl; the 3-trifluoromethyl; 3; the 4-methylenedioxyphenyl; the 4-cyano-phenyl; 4-(amino-carbonyl) phenyl; 1-pyridine oxide-4-base; pyridine-2-base; pyridin-3-yl; pyridin-4-yl; 4-picoline-2-base; 5-picoline-2-base; 6-picoline-2-base; 6-methoxypyridine-2-base; 6-methoxypyridine-3-base; 6-picoline-3-base; 6-ethylpyridine-3-base; 6-isopropyl pyridine-3-base; 6-cyclopropyl pyridin-3-yl; 1-pyridine oxide-3-base; 1-pyridine oxide-2-base; the 3-cyano-phenyl; 3-(amino-carbonyl) phenyl; 4-(morpholine-4-base carbonyl-)-phenyl; 5-(morpholine-4-base carbonyl) pyridine-2-base; 6-(morpholine-4-base carbonyl) pyridin-3-yl; 4-(4-methylpiperazine-1-base-carbonyl) phenyl; 6-(azetidine-1-yl) pyridin-3-yl; 5-cyanopyridine-2-base; 6-cyanopyridine-3-base; 5-(methoxyl group-methyl) pyridine-2-base; 5-(1-hydroxyl-1-first and second bases) pyridine-2-base; the 5-dimethylamino methyl; 4-B aminocarbonyl-phenyl; 4-isopropyl amino-carbonyl phenyl; uncle's 4-fourth aminocarbonyl-phenyl; 4-dimethylamino carbonyl phenyl; 4-(azetidine-1-yl) carbonyl phenyl; 4-(pyridine-1-yl) carbonyl phenyl; 4-(morpholine-4-yl) carbonyl phenyl; 4-(dimethyl-aminocarboxyl)-2-aminomethyl phenyl; 2-methyl-4-(methylamino--carbonyl) phenyl; 3-methyl-4-(methylamino carbonyl) phenyl; 4-(dimethylamino carbonyl)-3-aminomethyl phenyl; 3-methyl-4-(pyridine-1-base carbonyl) phenyl; 4-(dimethylamino carbonyl)-3-fluorophenyl; 4-[(2; 2; the 2-trifluoroethyl) aminocarboxyl] phenyl; 3-fluoro-4-amino-carbonyl-phenyl; 4-ethyl-aminocarboxyl-3-fluorophenyl; 3-amino-carbonyl phenyl; 3-dimethyl-aminocarbonyl-phenyl; 5-dimethylamino carbonyl-2-p-methoxy-phenyl; 2-methoxyl group-5-methyl-aminocarbonyl-phenyl; 3-(methylamino carbonylamino) phenyl; 6-(morpholine-4-yl)-pyridin-3-yl; 6-Dimethylamino pyridine-3-base; 6-sec.-propyl aminopyridine-3-base; 6-(tetramethyleneimine-1-yl)-pyridin-3-yl; 6-cyclopropyl aminopyridine-3-base; 6-ethoxy pyridine-3-base; 6-(2-fluorine oxyethyl group) pyridin-3-yl; 6-(2; the 2-difluoroethoxy) pyridin-3-yl; 6-(2; 2; the 2-trifluoro ethoxy) pyridin-3-yl; the 4-iodophenyl; 5-(tetramethyleneimine-1-base carbonyl)-2-pyridyl; 5-(morpholine-4-base-carbonyl)-2-pyridyl; 5-dimethylamino carbonyl-2-pyridyl; 4-dimethylamino carbonyl-aminophenyl; 6-(1-hydroxyl-1-methylethyl) pyridin-3-yl; 4-(1-hydroxyl-1-methylethyl)-phenyl; 4-(methoxymethyl) phenyl; 3-fluoro-4-(methoxymethyl) phenyl; 4-(dimethylamino) phenyl; 4-(dimethylamino)-3-fluorophenyl; 1H-indazole-5-base; 1-methyl isophthalic acid H-indazole-5-base; 2-methyl isophthalic acid H-indazole-5-base; 1; the 3-thiazol-2-yl; 5-ethyl-1; the 3-thiazol-2-yl; 5-(methyl-aminocarboxyl)-1; the 3-thiazol-2-yl; 1; 3-thiazole-5-base; 2-(methoxycarbonyl amino)-1; 3-thiazole-5-base; 2-sec.-propyl-1; 3-thiazole-5-base; 5-(pyridin-3-yl)-1; the 3-thiazol-2-yl; 5-(morpholine-4-base carbonyl)-1; the 3-thiazol-2-yl; 5-aminocarboxyl-1; the 3-thiazol-2-yl; 5-dimethylamino carbonyl-1; the 3-thiazol-2-yl; 5-(tetramethyleneimine-1-base carbonyl)-1; the 3-thiazol-2-yl; 5-allyl group-1; the 3-thiazol-2-yl; 5-propyl group-1; the 3-thiazol-2-yl; 5-B aminocarbonyl-1; the 3-thiazol-2-yl; 5-phenyl-1; the 3-thiazol-2-yl; the 5-methyl isophthalic acid; the 3-thiazol-2-yl; 5-methylol-1; the 3-thiazol-2-yl; 5-(1-hydroxyl-1-methylethyl)-1; the 3-thiazol-2-yl; 5-methoxyl group-methyl isophthalic acid; the 3-thiazol-2-yl; 5-(2-pyridyl)-1; the 3-thiazol-2-yl; 2-(tetramethyleneimine-1-yl)-1; 3-thiazole-4-base; 2-(morpholine-4-yl)-1; 3-thiazole-4-base; the 2-methyl isophthalic acid; 3-thiazole-5-base; 2-(1-hydroxyl-1 methylethyl)-1; 3-thiazole-5-base; 2-(tetramethyleneimine-1-yl)-1; 3-thiazole-5-base; 2-oxyethyl group-1; 3-thiazole-5-base; 2-ethyl-1; 3-thiazole-5-base; 2-(tetramethyleneimine-1-ylmethyl)-1,3-thiazoles-5-base; 2-(morpholine-4-yl)-1,3-thiazoles-5-base; 2-methoxyl group-methyl isophthalic acid; 3-thiazole-5-base; 2-isobutyl--1; 3-thiazole-5-base; 2-B aminocarbonyl-1,3-thiazoles-5-base; 2-(tetramethyleneimine-1-base carbonyl)-1,3-thiazoles-5-base; 2-(morpholine-4-base carbonyl)-1; 3-thiazole-5-base; 2-(3-pyridyl)-1; 3-thiazole-5-base; 2-(2-pyridyl)-1,3-thiazoles-5-base; the 4-methyl isophthalic acid, the 3-thiazol-2-yl; 1; 3-benzo-thiazol-2-yl; pyrimidine-5-base; pyrimidine-2-base; pyridazine-4-base; pyridazine-3-base; pyrazine-2-base; 2-methoxyl group-pyrimidine-5-base; 2-oxyethyl group-pyrimidine-5-base; 2-(2-fluorine oxyethyl group) pyrimidine-5-base; 2-methylpyrimidine-5-base; 2-ethyl-pyrimidine-5-base; 2-sec.-propyl pyrimidine-5-base; 2-cyclopropyl pyrimidine-5-base; pyrimidine-4-base; 4-(pyrimidine-5-yl) phenyl; 4-(1; 3-oxazole-2-yl) phenyl; 4-(1H-imidazoles-1-yl) phenyl; 4-(morpholine-4-yl) phenyl; 5-(pyrazine-2-yl) pyridine-2-base; 4-(1-methyl isophthalic acid H-imidazoles-1-yl) phenyl; 4-(4,6-dimethyl pyrimidine-5-yl) phenyl; 6-bromopyridine-3-base; 5-bromopyridine-2-base; 4 '-(methylsulfonyl) biphenyl-4-base; 3 '-(methylsulfonyl) biphenyl-4-base; 3 '-(methoxyl group-carbonyl)-biphenyl-4-base; 4-(2,3-dihydro-1; 4-benzo dioxine-6-yl) phenyl; 4 '-(dimethyl-amino)-biphenyl-4-base; 4-(pyridin-3-yl) phenyl; 4-(1H-pyrazoles-4-yl) phenyl; 4-(3; 3 '-dipyridyl-6-base; 4-(3,4 '-dipyridyl-6-base; 5-(3-acetylphenyl) pyridine-2-base; 5-[3-(dimethyl-amino) phenyl] pyridine-2-base; 5-[3-(trifluoromethyl) phenyl] pyridine-2-base; 5-[4-(methylsulfonyl) phenyl] pyridine-2-base; 5-(4-methoxyl group-phenyl) pyridine-2-base; 5-(3-methoxyl group-phenyl) pyridine-2-base; 5-[3-(aminocarboxyl) phenyl] pyridine-2-base; 5-(4-fluoro-phenyl) pyridine-2-base; 5-(3, the 4-difluorophenyl) pyridine-2-base; 5-(3; 5-dimethyl isoxazole-4-yl) pyridine-2-base; 5-(1-methyl isophthalic acid H-pyrazoles-4-yl) pyridine-2-base; 5-(1H-pyrazoles-4-yl) pyridine-2-base; 5-(1-cumarone-2-yl) pyridine-2-base; 5-(1; 3-benzodioxole base) pyridine-2-base; 5-(2-formyl radical-phenyl) pyridine-2-base; 4-(2 '-formyl biphenyl-4-base; 5-(1,3-oxazole-2-yl) pyridine-2-base; 6-(1,3-oxazole-2-yl) pyridin-3-yl; 4-(1; the 3-thiazol-2-yl) phenyl; 5-(1; the 3-thiazol-2-yl) pyridine-2-base; 6-(1,3-thiazoles-2-yl) pyridin-3-yl; 6-(1H-imidazoles-1-yl) pyridin-3-yl; 5-(1H-imidazoles-1-yl) pyridine-2-base; 6-phenylpyridine-3-base; 5-(pyrimidine-5-yl) pyridine-2-base; 5-(pyrimidine-2-base) pyridine-2-base; 5-(3-aminocarbonyl-phenyl) pyridine-2-base; 4-(1-methyl isophthalic acid H-imidazol-4 yl) phenyl; 4-(1H-imidazol-4 yl) phenyl; 5-[2-(methylol) phenyl] pyridine-2-base; 2 '-(methylol) biphenyl-4-base; the 5-{2-[(dimethylamino) methyl] phenyl } pyridine-2-base; 2 '-[(dimethylamino) methyl] biphenyl-4-base; 5-Calmazine-2-base; 5-two fluoro-methyl-pyrazines-2-base; 5-methyl-pyrazine-2-base; 2-methylpyrimidine-5-base; 2-methyl fluoride-pyrimidine-5-base; 2-difluoromethyl pyrimidine-5-base; 2-trifluoromethyl pyrimidine-5-base; 2-cyclopropyl pyrimidine-5-base; isothiazole-5-base; 3-methyl isothiazole-5-base; 3-methyl fluoride-isothiazole-5-base; 4-(dimethylamino-carbonyl) phenyl; 4-(methylamino-carbonyl) phenyl; 4-(morpholine-4-base carbonyl) phenyl; 4-(piperidines-1-base carbonyl) phenyl; 3-fluoro-4-(tetramethyleneimine-1-base carbonyl) phenyl; 5-(tetramethyleneimine-1-base carbonyl) pyridine-2-base; 5-(dimethylamino carbonyl) pyridine-2-base; 5-(morpholine-4-base carbonyl) pyridine-2-base; quinolyl-4; 6-methoxypyridine-3-base; 6-(morpholine-4-yl) pyridin-3-yl; 4-(dimethyl-amino methyl) phenyl; 5-(dimethylamino methyl) pyridine-2-base; 5-(dimethylamino carbonyl)-pyridine-2-base; 4-[hydroxyl (pyridin-3-yl) methyl] phenyl; 6-[(hydroxyl-(pyridin-3-yl) methyl] pyridin-3-yl; 6-(dimethylamino carbonyl)-pyridin-3-yl; 4-(4-hydroxy piperidine-1-base carbonyl) phenyl; 4-(4-methoxyl group piperidines-1-base carbonyl) phenyl; 5-(4-methoxyl group piperidines-1-base carbonyl)-pyridine-2-base; 6-(4-methoxyl group piperidines-1-base carbonyl) pyridin-3-yl; phenoxy group; benzyloxy; the 3-thienyl; 5-(methoxyl group-methyl)-1,3-thiazoles-2-base; 5-(morpholine-4-base carbonyl)-1; the 3-thiazol-2-yl; 2-sec.-propyl-1; 3-thiazole-5-base; 2-(methoxymethyl)-1,3-thiazoles-5-base; 5-(methoxymethyl)-1,3-thiazoles-2-base; 4-(pyrimidine-2-base) phenyl; 4-(pyrimidine-4-yl) phenyl and 5-(methoxymethyl) pyridine-2-base.

But the term cyclisation forms the R of the bridged bicyclic system with ethylidene bridged bond ₃And R ₄Or R ₅And R ₆To comprise dicyclo [2.2.2] octyl group system and all isomeric forms, adamantyl and all isomeric forms thereof thereof, and optional can make the stable substituting group of molecule (as C with heterocycle, heteroaryl, hydroxyl, amino, halogen and those ₁-C ₅All substituting groups of-alkoxyl group, halogen, haloalkyl and above-mentioned definition) replace.

Term R ₃And R ₆Have methylene radical or be selected from N, O and the heteroatomic bridged bicyclic system of S but cyclisation forms, will comprise as the norborneol alkyl and also have above-mentioned heteroatomic all stable bridge joint systems.They also can be chosen wantonly with heterocycle, heteroaryl, hydroxyl, amino, halogen and can make the stable substituting group of molecule (as C ₁-C ₅All substituting groups of-alkoxyl group, halogen, haloalkyl and above-mentioned definition) replace.

Work as R ₇And R ₈When being independently selected from alkoxyl group such as OR, R can be selected from H, fourth-2-alkynes-1-base, benzyl, pyridine-2-ylmethyl, pyridin-3-yl methyl, propoxy-and oxyethyl group.

Unless stated otherwise, otherwise the compound that above-mentioned formula provides comprises pharmacy acceptable salt, prodrug, diastereomer, racemic mixture, crystallized form, non--crystallized form, amorphous form and solvate.

According to the concrete substituting group on compound described herein, the term pharmacy acceptable salt comprises the salt by the active compound of nontoxic relatively acid or alkali preparation.When compound of the present invention comprises than tart functional group, can by with these compound direct reaction of required alkali of capacity and neutral form or in suitable inert solvent reaction obtain base addition salt.The example of pharmaceutically acceptable base addition salt comprises sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salt.When compound of the present invention comprises the functional group of alkalescence, can be by directly or in suitable inert solvent, react and obtain acid salt with the neutral form of required acid of capacity and this compound.The example of pharmaceutically acceptable acid salt comprises the salt that is derived from mineral acid example hydrochloric acid, Hydrogen bromide, nitric acid, carbonic acid, phosphoric acid, part neutral phosphoric acid, sulfuric acid, part neutral sulfuric acid, hydroiodic acid HI or phosphorous acid etc. and is derived from the salt of relative non-toxic organic acid as acetate, propionic acid, isopropylformic acid, toxilic acid, propanedioic acid, phenylformic acid, Succinic Acid, wood acid, FUMARIC ACID TECH GRADE, amygdalic acid, phthalic acid, Phenylsulfonic acid, right-toluenesulphonic acids, citric acid, tartrate, methylsulfonic acid etc.Also comprise the salt of amino acid such as arginine etc. and the salt of organic acid such as glucuronic acid or galacturonic acid etc.Some specific compound of the present invention can comprise alkalescence and acidic functionality simultaneously, makes described compound be convertible into alkali or acid salt.

The compound of neutral form of the present invention can be by making described salt and alkali or acid-respons, and isolate parent compound in a usual manner and regain.The parent form of compound is different with some physical properties of various salt forms, and as the solubleness in polar solvent, yet described salt is consistent with compound parent form for the purposes of the present disclosure.

As mentioned above, some compound of the present invention has chirality or unsymmetrical carbon (optical center) or two key; Racemoid, diastereomer, geometrical isomer and single optical isomer, these all are included in the scope of the present invention.

Some compound of formula I, II or III can non-solvent compound form and solvate form thereof, comprises that hydrate forms exists.Usually, solvate form thereof and non-solvent compound form are equal to and all are included in the scope of the present invention.Some compound of the present invention can polymorphic form or amorphous form existence.Generally speaking, all physical form all are identical concerning the purposes of the present invention's expection and all will be included in the scope of the invention.

Except that salt form, the present invention also provides the compound of prodrug form.The prodrug of compound described herein is to be easy to experience chemical transformation so that those compounds of The compounds of this invention to be provided under physiological condition.In addition, prodrug can convert The compounds of this invention in vivo by chemistry or biochemical method.For example, when prodrug being placed in skin patch storage tank (transdermal patch reservoir), suitable enzyme or chemical reagent can convert it to The compounds of this invention lentamente.

The compounds of this invention can prepare with many methods that the organic synthesis those skilled in the art know.The method that various 3-amino-pyrrolidine intermediates can be described from commercial source or operational version 1-6 obtains.Trans-3-amino-4-hydroxy tetramethyleneimine-1-formic acid tertiary butyl ester 1-4 can 2, and 5-dihydro-1H-pyrroles-1-formic acid tertiary butyl ester 1-1 is feedstock production (scheme 1).With oxygenant as-chlorine peroxybenzoic acid (mCPBA) oxidation 1-1, then with benzylamine or sodiumazide open loop so that trans-3-benzylamino-4-hydroxyl pyrrolidine-1-formic acid tertiary butyl ester or trans-3-nitrine-4-hydroxyl pyrrolidine-1-formic acid tertiary butyl ester 1-3 to be provided.With catalyzer such as palladium on carbon or load on palladium hydroxide hydrogenation on the carbon with preparation compound 1-4.

Scheme 1

The method of describing in trans 3-amino-4-hydroxy tetramethyleneimine-1-formic acid benzyl ester 2-3 available solutions 2 is synthetic.3-pyrroline-1-formic acid benzyl ester 2-1 is followed with the ammonium hydroxide open loop so that compound 2-3 to be provided with oxygenant such as mCPBA epoxidation.

Scheme 2

Can alkyl be introduced on the 4-hydroxyl of tetramethyleneimine by the method that operational version 3 is described.The reaction of intermediate 1-3 and N-(benzyloxy carbonyl oxygen base) succinimide (CbzOSu) can generate 3-1.Use sodium hydride, with after the hydroxy alkylated, use palladium catalyst such as palladium hydroxide to remove benzyl and Cbz group by hydrogenation, the 3-alkoxyl group pyrrolidin derivatives of production 3-3 with alkylogen.

Scheme 3

Perhaps, the method for alkylation available solutions 4 descriptions of the 4-hydroxyl position of tetramethyleneimine is finished.After with the Boc of intermediate 2-3 protection, then with sodium hydride do alkali with it with the alkylogen alkylation with generation intermediate 4-2.Can provide formula 4-3 as HCl at dioxane or TFA processing 4-2 with acid.

Scheme 4

It is synthetic that the volution pyrrolidin derivatives can be used on the order of describing in the scheme 5 suc as formula the compound of 5-6.After intermediate 1-4 being carried out Cbz protection, then with oxygenant such as sulfur trioxide pyridine complex with its oxidation with preparation ketone 5-2.Allyl group bromination magnesium is added to ketone 5-2 to be gone up so that tertiary alcohol 5-3 to be provided.Use 9-BBN/H ₂O ₂Processing is transformed into alcohol with the alkene among the 5-3.After handling the alcohol of gained, reaction mixture is obtained closed loop product 5-5 through backflow with methylsulfonyl chloride.Remove Cbz by hydrogenation, obtain compound 5-6.

Scheme 5

But the 3-amino-pyrrolidine derivatives that the 5-alkyl replaces synthesizes suc as formula the order of describing in the compound operational version 6 of 6-5.Compound 6-1 can be synthetic according to the method for document description (T.Rosen etc., J.Med.Chem.1988,31,1598-1611), then 6-1 and phenylformic acid are carried out the Mitsunobu coupling, obtain ester 6-2.Use K ₂CO ₃/ MeOH ester hydrolysis is to produce pure 6-3.Described alcohol and methylsulfonyl chloride reaction are then handled the methanesulfonates of gained with preparation triazo-compound 6-4 with sodiumazide under heating up.Use catalyzer such as Pd-C that the azido-among the 6-4 is transformed into amino compound with production 6-5 by hydrogenation.

Scheme 6

But the order of describing among the operational version 7-19 is synthesized various cyclohexanone derivatives.The compound of formula 7-2 can add to 1 by aryl magnesium halide or aryl halide/BuLi, and 4-cyclohexanedione 7-1 goes up and prepares.Perhaps, can be added to 1 by aryl magnesium halide, aryl halide/BuLi or heteroaryl H/ tetramethyl piperidine lithium, 4-cyclohexanedione list condensed ethandiol 7-3, then the ketal 7-4 with the acid treatment gained synthesizes 7-2.

Scheme 7

The 4-aryl cyclohexanone derivative of formula 8-3 and 8-5 can be synthetic according to the method that shows in the scheme 8.Intermediate 7-4 is handled, then with catalyzer such as Pd-C or PtO with dehydrogenating agent such as thionyl chloride/pyridine ₂The alkene of reduction gained.It is fluorine-based can changing hydroxyl with DAST processing intermediate 7-4 processing.By the ketal among 8-2 and the 8-4 being removed, obtain the ketone of formula 8-3 and 8-5 with acid treatment.

Scheme 8

Perhaps, but the method for describing in the compound operational version 9 of formula 8-3 preparation.With hexanaphthene-1, list-protection of 4-glycol 9-1 is then with its methylsulfonic acid generation methanesulfonates 9-3 with t-butyldimethylsilyl (TBDMS).Can generate intermediate 9-4 with heteroaryl such as pyrazoles, imidazoles, triazole or tetrazolium displacement methanesulfonates.Remove the TBDMS group with TBAF, then it is obtained the compound of formula 8-3 through the Swern oxidation.

Scheme 9

Pyrazoles, imidazoles, triazole or tetrazolium that Ar=replaces

Perhaps, the compound of formula 8-3 can be synthetic according to scheme 10.Generate pure 10-1 with reductive agent such as sodium borohydride reduction ketone 7-3, can 10-1 be transformed into methanesulfonates 10-2 by handling with methylsulfonyl chloride.Can generate intermediate 10-3 with heterocycle such as pyrazoles, imidazoles, triazole or tetrazolium displacement methanesulfonates 10-2, wherein processing is transformed into compound 8-3 with 10-3 as HCl with acid.

Scheme 10

Pyrazoles, imidazoles, triazole or tetrazolium that Ar=replaces

The method that the compound available solutions 11 of 4-hydroxyl-4-(pyrimidine-2-base) pimelinketone 11-4 shows is synthetic.With LDA/ (Bu) ₃SnH handles 2-chloropyrimide 11-1 to generate stannyl pyrimidine derivatives 11-2, can be by handling 11-2 with n-Butyl Lithium, and then with 1,4-cyclohexanedione list condensed ethandiol 7-3 quencher is reacted so that ketal intermediate 11-3 to be provided.Go protection to obtain ketone 11-4 ketal with acid as HCl.

Scheme 11

But the method that the volution cyclohexanone derivative operational version 12 of formula 12-3 is described is synthetic.Handle 2-bromobenzyl alcohol 12-1 that R replaces and the solution of gained is joined 1 with n-Butyl Lithium, among the 4-cyclohexanedione list condensed ethandiol 7-3, generate adducts 12-2.Use TFA/CH ₂Cl ₂Handling 12-2 can cause closed loop and remove ketal simultaneously to obtain spirocyclic ketone 12-3.

Scheme 12

The spirocyclic ketone of formula 13-6 and 13-8 can be obtained by the method that scheme 13 is described.Make after the ketone among spent glycol/TMSCl protection 13-1, available reductive agent such as lithium aluminium hydride are reduced into glycol 13-3 with diester 13-2.The glycol of gained is transformed into two methanesulfonates 13-4, and wherein 13-4 can react to generate volution indenes intermediate 13-5 with LHMDS and indene derivative.Hydrogenation 13-5 can produce volution indan derivative 13-7.As HCl ketal 13-5 and 13-7 are gone protection with acid, obtain corresponding ketone 13-6 and 13-8.

Scheme 13

Scheme 14 has been described compound synthetic of formula 14-4.Handle the 4-cyano group bromobenzene that R-replaces with n-Butyl Lithium, then with 1,4-cyclohexanedione list condensed ethandiol 7-3 quencher is with preparation intermediate 14-1.After basic hydrolysis cyano group, with coupling agent such as BOP with the carboxylic acid of gained and amine coupling to obtain acid amides 14-3.The ketone of formula 14-4 can be provided with acid treatment ketal 14-3.

Scheme 14

The compound of formula 15-4 can be as preparation as described in the scheme 15.Can be by handling hydroxy intermediate 14-1 dehydration so that alkene intermediate 15-1 to be provided with thionyl chloride/pyridine.With the cyan-hydrolysis of alkali with 15-1, then with amine with the carboxylic acid coupling of gained so that amide intermediate 15-3 to be provided.The compound of formula 15-4 can be by then obtaining with acid treatment with catalyzer such as Pd-C hydrogenation.

Scheme 15

Introducing substituting group on 4 aryl of pimelinketone or heteroaryl can begin to finish from ketal intermediate 16-1, and wherein X is a bromine or iodine.Handle 16-1 with butyllithium, then with electrophilic reagent such as alkylogen, aldehyde, ketone, isocyanic ester, chloro-formic ester or carbonic ether quencher, make the Suzuki coupling of 16-1 and boric acid or make 16-1 and aryl ZnX (X=halogen ion) reacts the aryl derivatives 16-2 that can prepare the R-replacement.Perhaps, the compound of formula 16-2 can be a boric acid ester by changing 16-1, then allows the boric acid ester of gained and RX (X=Br, I) carry out the Suzuki coupling and generates.16-2 obtains ketone 16-4 with the acid treatment ketal.

Scheme 16

When the Ar of 16-4 is the thiazole residue, can introduce the R substituting group according to the method that scheme 17-19 describes.The order of describing in 1,3-thiazoles-2-radical derivative available solutions 17 that the 5-R-of formula 17-5 replaces obtains.Handle 1,3-thiazoles then with 1 with n-Butyl Lithium, 4-cyclohexanedione list condensed ethandiol 7-3 quencher and produce intermediate 17-2.With 5 lithiumations (lithiation) of thiazole, then can generate intermediate 17-4 with electrophilic reagent such as alkylogen, isocyanic ester, carbonic acid gas, aldehydes or ketones quencher.By ketal being transformed into ketone 17-5 with acid treatment.

Scheme 17

1,3-thiazoles-5-radical derivative that the 2-R-of formula 18-3 replaces synthetic comprises the lithiumation with 18-1, then with 1, and the quencher of 4-cyclohexanedione list condensed ethandiol, and the ketal of gained is transformed into ketone.

Scheme 18

Perhaps, can obtain the compound of formula 18-3 according to the method that scheme 19 is described.Thiazole 19-1 lithiumation with the protection of 2-trimethyl silyl then produces intermediate 19-2 with the 7-3 quencher.After removing trimethyl silyl, the 19-3 lithiumation then with electrophilic reagent such as alkylogen, aldehyde, ketone, isocyanic ester, chloro-formic ester or carbonic ether quencher, is generated the thiazole derivative 19-4 that 5-R-replaces with TBAF.By obtaining ketone 18-3 with acid treatment 19-4.

Scheme 19

The product compound of formula I can be shown in scheme 20, by 3-amino-pyrrolidine intermediate and the combination of pimelinketone intermediate are obtained.With 3-amino-pyrrolidine derivatives 20-1 and the coupling of formula 20-2 carboxylic acid, obtain acid amides 20-3 with coupling agent such as BOP, chloro-formic ester or EDC.After with acid or hydrogenation the protecting group on the tetramethyleneimine nitrogen (P) being removed, with the tetramethyleneimine 20-4 of gained and the ketone reduction amination of formula 20-5, obtain the target compound of formula 20-6 with reductive agent such as sodium triacetoxy borohydride or catalytic hydrogenation.Perhaps, the compound useful catalyst of formula 20-6 such as Pd-C or Pd (OH) 2 carry out reduction amination with the ketone of 20-3 (P=Cbz, Bn) and formula 20-5 and obtain through hydrogenation.

Scheme 20

Perhaps, the method for product compound available solutions 21 descriptions of various formula I is synthetic.With reductive agent such as sodium triacetoxy borohydride with 3-tert-butoxycarbonyl amino-pyrrolidine 21-2 and ketone 21-1 (M.Povarny etc., Tetrahedron Lett.1984,25,1311-1312) reduction amination obtains intermediate 21-3.Handling 21-3 with acid in the aqueous solution can be transformed into ketal ketone and remove the Boc group simultaneously.The amine of gained and the reaction of two carbonic acid, two-tertiary butyl ester can obtain the keto-amine intermediate 21-4 of Boc protection.Aryl MgX or ArX/BuLi added on the ketone 21-4 can produce pure 21-5.Remove Boc with acid as the solution of 4N HCl in dioxane, follow the target compound that the carboxylic acid coupling of the amine 21-6 of gained and formula 20-2 is obtained formula 21-7 with coupling agent such as BOP.

Scheme 21

Perhaps, the method for product compound available solutions 22 descriptions of various formula I is synthetic.With aryl MgX or ArX/BuLi add to ketone 21-1 (M.Povarny etc., Tetrahedron Lett.1984,25, can produce pure 22-1 on 1311-1312).In the aqueous solution, handle and ketal can be transformed into ketone as HCl with acid.With reductive agent such as sodium triacetoxy borohydride the ketal 22-2 and the tetramethyleneimine intermediate 20-4 of gained also answered amination reaction, obtain the target compound of formula 22-3.

Scheme 22

Perhaps, can be according to the compound of scheme 23 synthetic various formula I.With 5-norbornylene-2-alcohol (23-1) (G.T.Wang etc., J.Org.Chem.2001,66,2052-2056 carries out the Swern oxidation, then aryl MgX or ArX/BuLi are added to and to produce tertiary alcohol 23-3 (C.J.Collins, B.M.Benjamin, J.Am.Chem.Soc.1967 on the ketone 23-2,89,1652-1661).By the conversion of olefines among the 23-3 can be become with borine/hydrogen peroxide treatment pure 23-4 (C.J.Collins, B.M.Benjamin, J.Org.Chem.1972,37,4358-4366).Described alcohol is carried out the Swern oxidation can provide ketone 23-5, wherein ketone 23-5 and pyrrolidin derivatives 20-4 can be carried out reduction amination with reductive agent such as sodium triacetoxy borohydride, obtains the target compound of formula 23-6.

Scheme 23

Perhaps, can be according to the compound of scheme 24 synthetic various formula I.With trans-4-Trans-4-Amino Cyclohexanol 24-1 and the reaction of two carbonic acid, two-tertiary butyl ester, obtain trans-4-tert-butoxycarbonyl Trans-4-Amino Cyclohexanol 24-2, wherein 24-2 can produce ketone 24-3 through the Swern oxidation.Ketone 24-3 and pyrrolidin derivatives 20-4 can be obtained intermediate formula 24-4 through reduction amination with reductive agent such as sodium triacetoxy borohydride.Remove Boc with acid as the solution of 4N HCl in dioxane, follow the target compound that the amine 24-5 of gained and aryl acyl chlorides or aryl carboxylic acid alkylation is obtained formula 24-6 with coupling agent such as BOP.

Scheme 24

The compound that perhaps, can synthesize various formula I according to the order of scheme 25.Ketone intermediate 7-2 reduction can be obtained cis glycol 25-1 with reductive agent such as lithium aluminum hydride or sodium borohydride.Can carry out the selectivity methylsulfonic acidization by handling 25-1, obtain list-methanesulfonates 25-2 with 1 normal methane sulfonyl chloride.With 3-amino-pyrrolidine derivatives 21-2 displacement methanesulfonates, can obtain anti-form-1,4-disubstituted cyclohexane derivatives 25-3.Remove the Boc group with acid, then the carboxylic acid coupling of the amine of gained and formula 20-2 is obtained the product compound of formula 25-5.

Scheme 25

Perhaps, can be as the compound of synthetic various formula I as described in the scheme 26-27.Can obtain intermediate 26-2 (scheme 26) through three kinds of methods.Method 1 comprises the Mitsunobu coupling of succinimide 26-1 and pure 25-1, and wherein 26-1 can be by handling the D-l-asparagine with thionyl chloride/methyl alcohol (esterification), then prepares with alkali such as NaOH cyclisation.Method 2 is included in alkali such as CsF exists down with succinimide 26-1 displacement methanesulfonates intermediate 25-2.In method 3, methanesulfonates 25-2 can be reduced into amine (26-4) with the nitrine intermediate 26-3 of gained with sodiumazide displacement and by hydrogenation.After the ring-opening reaction of D-aspartic anhydride 26-5 and 26-4, then use the carbonyl dimidazoles closed loop, obtain intermediate 26-2.

Scheme 26

The method that provides with scheme 27 can be transformed into intermediate 26-2 final product 27-3.After by hydrogenation the Cbz group of 26-2 being removed, then the succinimide of 27-1 can be reduced into tetramethyleneimine through hydrogenation deallocation position by handling with borine.The amine 27-2 and the carboxylic acid coupling of gained can be obtained the product compound of formula 27-3 with coupling agent such as BOP, chloro-formic ester or EDC.

Scheme 27

Perhaps, the product compound of the method synthesis type I shown in the available solutions 28.When the Ar residue on the cyclohexyl of 28-1 has iodo, described iodo can be transformed into boric acid ester.At PdCl ₂(dppf) existence obtains the compound of the R replacement of formula 28-2 down with the boric acid ester and ArX (X=Br, the I) coupling of gained.Perhaps, the compound of formula 28-2 can obtain by the Suzuki coupling of boric acid and 28-1.

Scheme 28

Perhaps, can obtain the intermediate of formula 25-4 according to scheme 29.When the D-aspartic acid dimethyl ester 29-1 with reductive agent such as LAH reduction N-Cbz protection follows the glycol of handling gained with methylsulfonyl chloride, obtain two methanesulfonates 29-2.In the presence of NaI and proton sponge, handle amine intermediate 26-4 with two methanesulfonates 29-2, obtain pyrrolidin derivatives 29-3.Use catalyzer such as Pd-C the Cbz group of 29-3 to be removed, obtain the intermediate of formula 25-4 by hydrogenation.

Scheme 29

Perhaps, the compound of the method synthesis type I shown in the available solutions 30.With the ketone derivatives reduction amination of pyrrolidin derivatives 30-1 and formula 30-2, obtain intermediate 30-3 with reductive agent such as sodium triacetoxy borohydride.After removing protecting group P (P=Boc or Cbz),, obtain the compound of formula 30-5 then with the carboxylic acid of formula 20-2 and the amine coupling of gained.

Compound of the present invention can be the MCP-1 receptor modulators, antagonist for example, and can suppress combining of MCP-1 and its acceptor.Be astoundingly, described compound T cell capable of blocking is in external migration, and to the obvious effect that is supplemented with of the inflammatory cells of the multiple model of inflammatory disease.Therefore, the compound of formula I can be used as the therapeutical agent of inflammatory disease, wherein inflammatory disease is particularly assembled diseases associated with lymphocyte and/or monocyte, as sacroiliitis, rheumatoid arthritis, multiple sclerosis, neuropathic pain, arteriosclerosis and transplant rejection.In addition, these compounds can be used for handling the super quick imbalance of supersensitivity such as asthma and allergic rhinitis (feature is that basophilic leukocyte activates and eosinocyte replenishes), and are used for the treatment of restenosis and chronic or acute immune disorder.

As the context of the invention is used, the adjusting of chemokine receptor activity will comprise that active antagonism, excitement, part antagonism and/or the part relevant with concrete Chemokine Receptors (preferred CCR2 acceptor) are exciting.Term composition used herein will comprise the product of the appointment composition that contains specified volume, and any mix products that directly or indirectly is derived from the appointment composition of specified volume.Must be compatible with other composition of preparation and nontoxic with pharmaceutically acceptable carrier, thinner or the vehicle represented to recipient itself.

The compound of formula I of the present invention and composition thereof can be used for regulating chemokine receptor activity, particularly CCR2.Therefore, compound of the present invention suppresses the compound of Mammals proteic at least one function of for example human CCR2 of CCR2 albumen or character for those.This inhibit feature of compound can be by in conjunction with method of testing (for example, part in conjunction with or promotor in conjunction with), the signal testing method (for example, activate Mammals G albumen, induction is quick and the concentration of the kytoplasm free ca of instantaneous increase) and/or cellular response function (for example, the inflammatory mediator that stimulates chemotaxis, exocytosis or discharge) illustrated by white corpuscle.

Illustrate the present invention with the following examples, but be not intended to limit it.

Embodiment

Hereinafter reagent of Shi Yonging and solvent can be from commercial source, and (Milwaukee, Wis USA) obtain as Aldrich ChemicalCo..Mass spectral result represents with the ratio of quality and electric charge, then reports according to the relative abundance of each ion (in bracket).In table, single m/e value reporting be comprise the M+H of common atom isotope (perhaps, as shown, M-H) ion.The molecular formula that isotopic pattern is expected down corresponding to all situations.

Embodiment 1

Steps A

6-oxa--3-azabicyclo [3.1.0] hexane-3-t-butyl formate.To 3-chlorine peroxybenzoic acid (13.0g, 75.3mmol) the CH of cooling in ice bath ₂Cl ₂(50ml) drip 2 in the solution, 5-pyrrolin t-butyl formate (5g, CH 29.5mmol) ₂Cl ₂(50ml) solution.Stirring described mixture 30 minutes and stirring are at room temperature spent the night in ice bath.Leach described solid.Use Na ₂S ₂O ₃, NaHCO ₃With the described thing twice that leaches of salt water washing, use MgSO ₄Dry and concentrated.Hexane solution wash-out on silica gel chromatographic column with 20%EtOAc obtains the required oily compound of 4.75g.MS calculated value (M+H) ⁺186, actual value 186.

Step B

(3S, 4S)-3-(benzylamino)-4-hydroxyl pyrrolidine-1-t-butyl formate.With the epoxide of steps A (4.6g, 24.9mmol) and benzylamine (5.2g, ethanolic soln 48.6mmol) stir down at 85 ℃ and spend the night.Removing desolvates obtains solid by under reduced pressure concentrating.Wash described solid with 50%EtOAc/ hexane mixed solvent, obtain the required compound of 6.2g.MS calculated value (M+H) ⁺293, actual value 293.

Step C

(3S, 4S)-3-amino-4-hydroxy tetramethyleneimine-1-t-butyl formate.Under the hydrogen of 55psi, with the intermediate of step B (5.4g, 18.5mmol), Pd (OH) ₂Methyl alcohol (200ml) solution stirring of/C (0.3g) is spent the night.Catalyzer filtered and concentrate and obtain the required product solid of 3.7g leaching thing.MS calculated value (M+H) ⁺203, actual value 203.

Step D

(3S, 4S)-3-hydroxyl-4-[({[3-(trifluoromethyl) benzoyl] amino } ethanoyl)-amino] tetramethyleneimine-1-t-butyl formate.To 3-(trifluoromethyl) Benzoyl chloride of cooling in ice bath (21g, drip in toluene 98.7mmol) (400ml) solution glycine methyl ester hydrochloride (11.5g, 94mmol) and the solution of triethylamine (100ml) in water (210ml) and THF (65ml).After at room temperature stirring 8 hours, isolate two-phase.Use the EtOAc aqueous layer extracted.Use NaHCO ₃With the organic phase that the salt water washing merges, use MgSO ₄Dry and concentrated.Residuum is dissolved among MeOH (150ml) and the THF (300ml).To wherein adding 2N NaOH (300ml) solution.Described mixture at room temperature stirred spend the night,, use the EtOAc extracting twice with concentrated hydrochloric acid (pH=2) acidifying.With salt water washing organic phase, use MgSO ₄Dry and concentrated.Crystallization obtains required (3-trifluoromethyl benzamido) the acetic acid product solid of 18g from the EtOAc/ hexane.MS calculated value (M+H) ⁺248, actual value 248.

To with the ice bath refrigerative by the carboxylic acid that above obtains (3.2g, 13mmol) and the amino alcohol that obtains of step C (2.02g adds NEt in DMF 10mmol) (15mL) solution ₃(4.2mL, 30mmol), then add BOP (5.8g, 13mmol).Mixture at room temperature stirred spend the night.Salt solution (100ml) is added in the mixture.Extract described solution twice with EtOAc.Use NaHCO ₃With salt water washing organic phase, use MgSO ₄Dry and concentrated.At first use 20%MeOH/EtOAc wash-out on silica gel chromatographic column then, obtain the required product solid of 3.7g with the 70%EtOAc/ hexane.MS calculated value (M+H) ⁺432, actual value 332 (M+H-Boc) ⁺

Step e

N-(2-{[(3S, 4S)-4-hydroxyl pyrrolidine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide.(3.7g 8.6mmol) is dissolved in CH with the product of step D ₂Cl ₂(10ml) and among the TFA (10ml).After at room temperature stirring 40 minutes, remove volatile matter, obtain required oily product by under reduced pressure concentrating.MS calculated value (M+H) ⁺332, actual value 446 (M+H+TFA) ⁺

Step F

N-(2-{[(3S, 4S)-1-cyclohexyl-4-hydroxyl pyrrolidine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide.To the intermediate of step e (444mg, 1mmol) and pimelinketone (196mg adds NEt in THF 2mmol) (5ml) solution ₃(0.42ml 3mmol), then adds Na (OAc) ₃BH (424mg, 2mmol).At room temperature stir described mixture overnight and pour in the NaCl solution.Extract described solution twice with EtOAc.Use NaHCO ₃With the EtOAc layer that the salt water washing merges, use MgSO ₄Dry and concentrated.Obtain the required product of 324mg with silica gel purification.MS calculated value (M+H) ⁺414, actual value 414.

Embodiment 2

N-(2-{[(3S, 4S)-4-(fourth-2-alkynes-1-base oxygen base)-1-cyclohexyl tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide.To with the compound of ice bath refrigerative embodiment 1 (41mg, add in THF 0.1mmol) (3ml) solution NaH (16mg, 0.4mmol), then add the 2-butyne bromine (9.6 μ L, 0.11mmol).In ice bath, stir after 3 hours, add saturated NH ₄Cl solution then adds EtOAc.Separate the EtOAc layer, the salt water washing is through MgSO ₄Dry and concentrated.Obtain the powder of titled reference compound with the reversed-phase HPLC purifying.MS calculated value (M+H) ⁺466, actual value 466.

Embodiment 3

N-(2-{[(3S, 4S)-4-(benzyloxy)-1-cyclohexyl tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide.The method of describing according to embodiment 2 prepares titled reference compound with the benzyl bromine with the alkylation of embodiment 1.MS calculated value (M+H) ⁺504, actual value 504.

Embodiment 4

N-(2-{[(3S, 4S)-1-cyclohexyl-4-(pyridine-2-ylmethoxy)-tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide.Prepare titled reference compound with similar embodiment 3 methods.MS calculated value (M+H) ⁺505, actual value 505.

Embodiment 5

N-(2-{[(3S, 4S)-1-cyclohexyl-4-(pyridin-3-yl methoxyl group) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide.Prepare titled reference compound with similar embodiment 3 methods.MS calculated value (M+H) ⁺505, actual value 505.

Embodiment 6

Steps A

4-hydroxy-4-phenyl pimelinketone.To using ice bath refrigerative 1,4-cyclohexanedione (6.72g, THF (20ml, 20mmol) solution of the phenyl-magnesium-bromide of adding 1M in THF 60mmol) (100ml) solution.At room temperature stir described mixture 3 hours and used NH ₄The quencher of Cl solution.The solution of gained extracts three times with EtOAc.With the organic phase that the salt water washing merges, use MgSO ₄Dry and concentrated.With 1: 1 EtOAc/ hexane wash-out purifying on silicagel column, obtain the titled reference compound of 0.83g (22%).MS calculated value (M+H) ⁺190, actual value 173 (M+H-H ₂O) ⁺

Step B

N-(2-{[(3S, 4S)-4-hydroxyl-1-(4-hydroxy-4-phenyl cyclohexyl) tetramethyleneimine-3-yl] amino-2-oxoethyl }-3-(trifluoromethyl) benzamide.To the ketone of steps A (198mg, 1.1mmol) and the tetramethyleneimine intermediate of embodiment 1 step e (331mg adds Na (OAc) in THF solution 1mmol) ₃BH (424mg, 2mmol).At room temperature stir described mixture overnight and pour in the NaCl solution.The solution of gained extracts three times with EtOAc.Use NaHCO ₃With the EtOAc layer that the salt water washing merges, use MgSO ₄Dry and concentrated.Purifying on silica gel obtains 150mg and moves isomer (trans-isomer(ide), MS calculated value (M+H) faster ⁺506, actual value 506) and 130mg move slower isomer (cis-isomeride, MS calculated value (M+H) ⁺506, actual value 506).

Embodiment 7

Steps A

8-pyridine-2-base-1,4-dioxo spiro ring [4.5] decane-8-alcohol.To (14g adds the butyl lithium solution (36ml) of 2.5M in anhydrous diethyl ether 88.6mmol) (300ml) solution at-78 ℃ of following refrigerative 2-bromopyridines.After interpolation finishes, continue down to stir 1 hour at-78 ℃.To wherein slowly adding 1,4-cyclohexanedione list condensed ethandiol (15g, anhydrous diethyl ether 96mmol) (300ml) solution.Add finish after, allow mixture be warmed to 0 ℃ and continue to stir 1 hour.By adding water (100ml) the solution quencher reactant of ammonium chloride (4.5g).Isolate organic phase and with dichloromethane extraction water 4 times.Use MgSO ₄The dry organic phase that merges and concentrated.By the EtOAc crystallization, obtain the required product of 7g.Methyl alcohol/EtOAc with 10% is the wash-out mother liquor on silicagel column, obtains the required product of 3g.MS calculated value (M+H) ⁺236, actual value 236.0.

Step B

4-hydroxyl-4-pyridine-2-basic ring hexanone.Above-mentioned product is dissolved in the HCl aqueous solution (30ml) of THF (30ml) and 3N.Under 50 ℃, stirred the mixture 3 hours.After being cooled to room temperature, under agitation add NaHCO ₃Till not having bubble to produce.Isolate organic phase and with THF aqueous layer extracted three times.Use MgSO ₄The dry organic phase that merges and concentrated.Grinding residues in EtOAc.

Step C

N-(2-{[(3S, 4S)-4-hydroxyl-1-(4-hydroxyl-4-pyridine-2-basic ring hexyl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide.Can use and the similar method of the description of embodiment 6 the ketone reductive amination of using the pyrrolidin derivatives that makes by embodiment 1 step e to make by step B.MS calculated value (M+H) ⁺507, actual value 507.

Following compounds can prepare according to embodiment 6 and 7 methods of describing.

Embodiment #	R	MS(M+H) ⁺
Embodiment #	R	MS(M+H) ⁺	8	The 4-aminomethyl phenyl	520
9	The 3-aminomethyl phenyl	520	8	The 4-aminomethyl phenyl	520
9	The 3-aminomethyl phenyl	520	10	The 2-aminomethyl phenyl	520
11	The 4-bromophenyl	584	10	The 2-aminomethyl phenyl	520
11	The 4-bromophenyl	584	12	The 3-bromophenyl	584
13	The 4-chloro-phenyl-	539	12	The 3-bromophenyl	584
13	The 4-chloro-phenyl-	539	14	The 3-chloro-phenyl-	539
15	The 4-trifluoromethyl	574	14	The 3-chloro-phenyl-	539
15	The 4-trifluoromethyl	574	16	The 3-trifluoromethyl	574
17	The 2-trifluoromethyl	574	16	The 3-trifluoromethyl	574
17	The 2-trifluoromethyl	574	18	The 4-p-methoxy-phenyl	536
19	The 3-p-methoxy-phenyl	536	18	The 4-p-methoxy-phenyl	536
19	The 3-p-methoxy-phenyl	536	20	The 2-p-methoxy-phenyl	536
21	Pyridin-3-yl	507	20	The 2-p-methoxy-phenyl	536
21	Pyridin-3-yl	507	22	Pyridin-4-yl	507
23	6-methoxypyridine-3-base	537	22	Pyridin-4-yl	507
23	6-methoxypyridine-3-base	537	24	6-ethoxy pyridine-3-base	551

25

3, the 4-methylenedioxyphenyl

550

Embodiment 26

N-(2-{[(3S, 4S)-1-(4-cyano group-4-benzyl ring hexyl)-4-hydroxyl pyrrolidine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide.The similar method of description of use and embodiment 6 uses the intermediate that is made by embodiment 1 step e with 4-cyano group-4-benzyl ring hexanone reductive amination, obtains titled reference compound.MS calculated value (M+H) ⁺515, actual value 515.

Embodiment 27

Steps A

8-(4-fluorophenyl)-1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-7-alkene.Under 10 ℃, to 1,4-cyclohexanedione list condensed ethandiol (8.1g, and the THF solution of the 4-fluorophenyl magnesium bromide of adding 1M in THF 50mmol) (20ml) solution (65ml, 65mmol).Before with the saturated ammonium chloride solution quencher, at room temperature stirred the mixture 2 hours.Described solution extracts 3 times with EtOAc.With the organic phase that the salt water washing merges, use MgSO ₄Dry and concentrated.With toluene (80ml) absorption of residual excess.Right to wherein adding-toluenesulphonic acids monohydrate (80mg).Described mixture stirs under refluxing and dewatered 2 hours with the Dean-Stark water trap simultaneously.The saturated NaHCO of the solution of gained ₃With the salt water washing, use MgSO ₄Dry and concentrated.With 5%, 10% use then 15% EtOAc the hexane solution wash-out and on silica gel purifying, obtain titled reference compound solid (8.8g, 75%).MS calculated value (M+H) ⁺235, actual value 235.

Step B

8-(4-fluorophenyl)-1,4-dioxo spiro ring [4.5] decane.(8.8g 37.6mmol) is dissolved in the toluene and adds PtO with the intermediate of steps A ₂(0.5g).Stir the mixture overnight of gained in nitrogen atmosphere (pressure is under the normal atmosphere).Leach catalyzer and under reduced pressure remove filtrate.With 5% being elutriant with the hexane solution of 10% EtOAc then, carry out quick silica gel column chromatography, obtain oily titled reference compound (8.6g, 98%).MS calculated value (M+H) ⁺237, actual value 237.

Step C

4-(4-fluorophenyl) pimelinketone.(8.6g 36.5mmol) is dissolved in the H of toluene (40ml), THF (20ml) and 10% with the intermediate of step B ₂SO ₄Water (25ml) solution in, under refluxing, stir and spend the night.After being cooled to room temperature, isolate organic layer, use the salt water washing, use MgSO ₄Dry and concentrated.With 5% being elutriant with the hexane solution of 10% EtOAc then, carry out quick silica gel column chromatography, obtain oily titled reference compound (6.0g, 86%).MS calculated value (M+H) ⁺193, actual value 193.

Step D

N-[2-((3S, 4S)-1-[4-(4-fluorophenyl) cyclohexyl]-4-hydroxyl pyrrolidine-3-yl } amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide.Can use and the similar method of the description of embodiment 6 intermediate that makes by embodiment 1 step e ketone reductive amination, obtain titled reference compound step C.MS calculated value (M+H) ⁺508, actual value 508.

Embodiment 28

Steps A

2-(1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-7-alkene-8-yl) pyridine.(2g 8.5mmol) is dissolved in the pyridine (40ml) and with described solution ice bath cooling the ketal that embodiment 7, steps A are obtained.To wherein adding SOCl ₂(3.1ml, 42.5mmol).Allowing solution be warmed to room temperature and continue to stir spends the night.Then add water with the reactant quencher by adding ice.The solution of gained extracts 3 times with EtOAc.Use MgSO ₄The dry EtOAc layer that merges and concentrated.EtOAc/ hexane solution with 0 to 55% is an elutriant, carries out quick silica gel column chromatography, obtains the 1.54g titled reference compound.MS calculated value (M+H) ⁺218, actual value 218.

Step B

2-(1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-yl) pyridine.(1.54g 7.1mmol) is dissolved in the methyl alcohol (40ml) and adds Pd/C (160mg) with the alkene that above obtains.The hydrogenation 3 hours under 53psi of described system.Leach catalyzer and concentrated filtrate obtains titled reference compound.MS calculated value (M+H) ⁺220, actual value 220.

Step C

4-pyridin-3-yl pimelinketone.According to the method that embodiment 7, step B describe, handle with aqueous hydrochloric acid, above-mentioned ketal is transformed into ketone.MS calculated value (M+H) ⁺176, actual value 176.

Step D

N-(2-{[(3S, 4S)-4-hydroxyl-1-(4-pyridine-2-basic ring hexyl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide.Can use the ketone reductive amination of using the intermediate that makes by embodiment 1 step e above to obtain with the similar method of the description of embodiment 6, obtain titled reference compound.MS calculated value (M+H) ⁺490, actual value 490.

Embodiment 29

Steps A

The 4-{[tertiary butyl (dimethyl) silyl] the oxygen base } hexalin.To cooling in ice bath 1, the 4-cyclohexanediol (5g, 43mmol), imidazoles (2.92g, 43mmol) and NEt ₃CH (7ml) ₂Cl ₂(100ml) add in the solution tert-butyldimethylsilyl chloride (6.47g, 43mmol).At room temperature stir described mixture overnight.Add water and isolate organic phase.Use the EtOAc aqueous layer extracted.Use MgSO ₄The dry organic phase that merges and concentrated.With 3: 1 EtOAc/ hexane solutions was elutriant, carried out quick silica gel column chromatography, obtained titled reference compound (4.2g, 42%).MS calculated value (M+H) ⁺231, actual value 231.

Step B

The methylsulfonic acid 4-{[tertiary butyl (dimethyl) silyl] the oxygen base } cyclohexyl ester.The CH of the silyl intermediate that in ice bath, by steps A, obtains to cooling ₂Cl ₂(40ml) add NEt in the solution ₃(6ml), then add methylsulfonyl chloride (1.8ml).After at room temperature stirring 2 hours, the described solution of dilute with water.Isolate organic phase and use the EtOAc aqueous layer extracted.Use MgSO ₄The dry organic phase that merges and concentrated.With 2: 1 EtOAc/ hexane solutions was elutriant, carried out quick silica gel column chromatography, obtained oily titled reference compound (4.6g, 82%).MS calculated value (M+H) ⁺309, actual value 309.

Step C

1-(the 4-{[tertiary butyl (dimethyl) silyl] the oxygen base } cyclohexyl)-3-(trifluoromethyl)-1H-pyrazoles.(1.0g adds NaH (0.3g, 60% mineral oil solution) in DMF 7.35mmol) (10ml) solution to the 3-Trifluoromethyl-1 H-pyrazoles of cooling in ice bath.Stir described mixture after 10 minutes, add methanesulfonates (1.13g, DMF 3.68mmol) (5ml) solution of step B.At room temperature continue to stir 1 hour, under 100 ℃, spend the night then.After being cooled to room temperature, described solution poured in the frozen water and with EtOAc extraction three times.With the extract that the salt water washing merges, use MgSO ₄Dry and concentrated.With 5: 1 EtOAc/ hexane solutions wash-out purifying on silica gel, obtain oily titled reference compound (0.56g, 44%).MS calculated value (M+H) ⁺349, actual value 349.

Step D

4-[3-(trifluoromethyl)-1H-pyrazol-1-yl] hexalin.(0.56g 1.6mmol) is dissolved in CH with the intermediate of step C ₂Cl ₂(10ml) and add the CH of the TBAF of 1M ₂Cl ₂(5ml) solution.After at room temperature stirring 2 hours, use CH ₂Cl ₂Dilute described solution.With the solution of salt water washing gained, use MgSO ₄Dry and concentrated.With 2: 1 EtOAc/ hexane solutions wash-out purifying on silica gel, obtain oily titled reference compound (0.27g, 71%).MS calculated value (M+H) ⁺235, actual value 235.

Step e

4-[3-(trifluoromethyl)-1H-pyrazol-1-yl] pimelinketone.To the cooling under-78 ℃ oxalyl chloride (0.25ml, add in THF 2.88mmol) (10ml) solution DMSO (0.3ml, 4.23mmol).Stir described mixture after 20 minutes, (0.27g, THF 1.15mmol) (2ml) solution then adds NEt to the alcohol of adding step D ₃(1ml, 7.1mmol).After at room temperature stirring 2 hours, dilute described solution with EtOAc.With the solution of salt water washing gained, use MgSO ₄Dry and concentrated.With 2: 1 EtOAc/ hexane solutions wash-out purifying on silica gel, obtain oily titled reference compound (0.22g, 82%).MS calculated value (M+H) ⁺233, actual value 233.

Step F

N-{2-[((3S, 4S)-4-hydroxyl-1-{4-[3-(trifluoromethyl)-1H-pyrazol-1-yl] cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide.Can use and the similar method of the description of embodiment 6, use the tetramethyleneimine intermediate that makes by embodiment 1 step e, obtain titled reference compound the ketone reductive amination that step e obtains.MS calculated value (M+H) ⁺548, actual value 548.

Following compounds can prepare according to the method that embodiment 27-29 describes.

Embodiment #	R	MS(M+H) ⁺
Embodiment #	R	MS(M+H) ⁺	30	The 3-fluorophenyl	508
31	The 4-fluorophenyl	523	30	The 3-fluorophenyl	508
31	The 4-fluorophenyl	523	32	The 3-chloro-phenyl-	523
33	The 4-bromophenyl	568	32	The 3-chloro-phenyl-	523
33	The 4-bromophenyl	568	34	The 3-bromophenyl	568
35	The 4-aminomethyl phenyl	504	34	The 3-bromophenyl	568
35	The 4-aminomethyl phenyl	504	36	The 3-aminomethyl phenyl	504
37	The 2-aminomethyl phenyl	504	36	The 3-aminomethyl phenyl	504
37	The 2-aminomethyl phenyl	504	38	The 4-p-methoxy-phenyl	520
39	The 3-p-methoxy-phenyl	520	38	The 4-p-methoxy-phenyl	520
39	The 3-p-methoxy-phenyl	520	40	Pyridin-4-yl	490
41	Pyridin-3-yl	490	40	Pyridin-4-yl	490
41	Pyridin-3-yl	490	42	5-picoline-2-base	504
43	6-picoline-2-base	504	42	5-picoline-2-base	504
43	6-picoline-2-base	504	44	Quinolyl-4	540
45	3-methyl isophthalic acid H-pyrazol-1-yl	494	44	Quinolyl-4	540
45	3-methyl isophthalic acid H-pyrazol-1-yl	494	46	3,5-dimethyl-1H-pyrazol-1-yl	508

47	The 4-trifluoromethyl	558
47	The 4-trifluoromethyl	558	48	The 3-trifluoromethyl	558
49	3, the 4-methylenedioxyphenyl	534	48	The 3-trifluoromethyl	558

Embodiment 50

Steps A

8-[2-(methylol) phenyl]-1,4-dioxo spiro ring [4.5] decane-8-alcohol.To 2-bromobenzyl alcohol (3.0g, in 16mmol) THF (40ml) the solution hexane solution (14.1ml) of the n-Butyl Lithium of adding 2.5M of cooling under-78 ℃.Stir described mixture 1 hour down and cool back-78 ℃ at-4 ℃.In 15 minutes, to wherein adding 1,4-cyclohexanedione list condensed ethandiol (2.5g, THF 16mmol) (10ml).Continue down to stir 30 minutes and stirred 1 hour down at-78 ℃ at-4 ℃.Add aqueous ammonium chloride solution quencher reaction.With the solution of EtOAc extraction gained 3 times.With the extract that the salt water washing merges, use MgSO ₄Dry and concentrated.Methyl alcohol/CH with 5% ₂Cl ₂Solution is the wash-out purifying on silica gel, obtains titled reference compound.MS calculated value (M+H) ⁺265, actual value 287 (M+Na) ⁺

Step B

3H, 4 ' H-volution [2-cumarone-1,1 '-hexanaphthene]-4 '-ketone.Described ketal is dissolved in 80% TFA/CH ₂Cl ₂After at room temperature stirring 3.5 hours, concentrate described solution.Absorb residuum with EtOAc.With the solution of 1N NaOH and salt water washing gained, use MgSO ₄Dry and concentrated.

Step C

N-(2-{[(3S, 4S)-4-hydroxyl-1-(3H-volution [2-cumarone-1,1 '-hexanaphthene]-4 '-yl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide.Can use and the similar method of the description of embodiment 6, use the intermediate that makes by embodiment 1 step e, obtain titled reference compound ketone and reductive amination that step B obtains.MS calculated value (M+H) ⁺518, actual value 518.

Embodiment 51

Steps A

2,2 '-(1,3-dioxolane-2,2 '-two bases) two acetic acid dimethyl esters.Under the room temperature, add 12ml (96mmol) TMSCl in the solution in the 50ml methylene dichloride to 4.2g (24mmol) 3-keto-glutaric acid dimethyl ester and 2.7ml (48mmol) ethylene glycol.Stirred described mixture 3 days down at 50 ℃.With the saturated described reaction of sodium bicarbonate aqueous solution quencher.Use the extracted with diethyl ether water layer.With the organic layer that the salt water washing merges, use Na ₂SO ₄Drying, vapourisation under reduced pressure.Obtain required product 2,2 '-(1,3-dioxolane-2,2 ' two bases) two acetic acid dimethyl esters (2.6g, 12mmol, productive rate: 50%): MS (m/e): 219 (M+1) with silica gel chromatography ⁺

Step B

2,2 '-(1,3-dioxolane-2,2 '-two bases) di-alcohol.Under 0 ℃, to 2, add the LAH of 1.4g (36mmol) in anhydrous THF (100ml) solution of 2 '-(1,3-dioxolane-2,2 '-two bases) two acetic acid dimethyl esters.Then with reaction mixture refluxed 1h, with 15% aqueous sodium hydroxide solution (3ml) and water (3ml) quencher.Stir described mixture overnight, through the Celite diatomite filtration.Residuum THF (100ml * 2) washed twice.The organic phase that evaporation merges.Use the silica gel chromatography purifying, obtain 1.3g (8.0mmol, productive rate: 2,2 '-(1,3-dioxolane-2,2 '-two bases) di-alcohol 66%).MS(m/e)：163(M+1) ⁺。

Step C

1,3-dioxolane-2,2-two basic two ethane-2,1-two basic two methanesulfonates.Under the room temperature, to 2,2 '-(1,3-dioxolane-2,2-two bases) di-alcohol (1.3g, add in methylene dichloride 8.0mmol) (100ml) solution triethylamine (3.4ml, 24mmol).Described solution is cooled to-40 ℃, drip then methylsulfonyl chloride (1.65ml, 20mmol).After 30 minutes, progressively be warmed to 0 ℃ at-40 ℃ of stirred reaction mixtures then.With the saturated described reaction of sodium bicarbonate aqueous solution quencher.Use the dichloromethane extraction water layer.With the organic extract that the salt water washing merges, use Na ₂SO ₄Dry and evaporation obtains crude product 1,3-dioxolane-2,2-two basic two ethane-2,1-two basic two methanesulfonates: MS (m/e): 319 (M+1) ⁺

Step D

Two volutions-[1,3-dioxolane-2,1 '-hexanaphthene-4 ', 1 "-indenes].(0.5g, THF 4.3mmol) (10ml) solution adds THF (8.6ml, 8.6mmol) solution of the LHMDS of 1M to refrigerative indenes in ice bath.Stir after 30 minutes, add THF (5mL) solution of above-mentioned thick two methanesulfonates.At room temperature stir described mixture overnight and add the cold water quencher.The solution of gained EtOAc extracting twice.Use MgSO ₄The dry extract that merges and concentrated.With 1: 5 EtOAc/ hexane solution wash-out purifying on silica gel, obtain 250mg (26%) titled reference compound.MS calculated value (M+H) ⁺243, actual value 243.

Step e

4H-volution-[hexanaphthene-1,1 '-indenes] 4-ketone.Ketal (0.24g, adding 1N hydrochloric acid (3ml) solution in THF 1mmol) (3ml) solution to step D.At room temperature stir and spend the night, with the described solution of solution dilution of EtOAc and saturated sodium bicarbonate.Separate described organic layer and with twice of EtOAc aqueous layer extracted.Use MgSO ₄The dry organic phase that merges and concentrated.With 1: 5 EtOAc/ hexane solution wash-out purifying on silica gel, obtain 170mg (86%) titled reference compound.MS calculated value (M+H) ⁺199, actual value 199.

Step F

N-(2-{[(3S, 4S)-4-hydroxyl-1-volution [hexanaphthene-1,1 '-indenes]-4-base tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide.Can use with the similar method of the description of embodiment 6 and use the tetramethyleneimine intermediate that makes by embodiment 1 step e, obtain titled reference compound the ketone reductive amination that step e obtains.MS calculated value (M+H) ⁺514, actual value 514.

Embodiment 52

N-(2-{[(3S, 4S)-1-(2 ', 3 '-dihydro volution [hexanaphthene-1,1 '-indenes]-4-yl)-4-hydroxyl pyrrolidine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide.Do the compound of catalyzer hydrogenation embodiment 52 with Pd/C, obtain titled reference compound.MS calculated value (M+H) ⁺516, actual value 516.

Embodiment 53

Steps A

(3S, 4S)-the 3-{[(benzyloxy) carbonyl] amino }-4-hydroxyl pyrrolidine-1-t-butyl formate.In THF (40ml) solution of the amine (6.9mmol) that 1.4g embodiment 1 step C obtains, add 2.1gCbzSu (84mmol) and then add Et ₃N (1.1ml, 7.6mmol).At room temperature stirring described reactant down spends the night.Under vacuum, remove and desolvate.Absorb residuum with EtOAc/ water.Isolate two-phase and with twice of EtOAc aqueous phase extracted.Use Na ₂SO ₄The dry organic phase that merges concentrates under vacuum.With hexane/EtOAc of 2: 1 wash-out on silica gel column chromatography, obtain the titled reference compound of 1.6g (68%).MS actual value: 237.2 (M-Boc+1) ⁺, 336.9 (M+1) ⁺, 359.2 (M+Na) ⁺

Step B

(3S)-and the 3-{[(benzyloxy) carbonyl] amino }-4-oxo-pyrrolidine-1-t-butyl formate.To under-78 ℃, in THF (10ml) solution of 0.7ml oxalyl chloride, adding the anhydrous DMSO of 1.5ml.Stir after 5 minutes, add anhydrous THF (20ml) solution of the alcohol intermediate of 1.6g steps A, then add the 2.3ml triethylamine.Remove cooling bath.Reaction stirred 0.5h at room temperature then.EtOAc/ water quencher reaction mixture with 50/50ml.With twice of EtOAc aqueous phase extracted.Use Na ₂SO ₄The dry organic phase that merges and concentrated under vacuum.With 2: 1 hexanes/EtOAc wash-out, carry out the silica gel chromatography purifying, obtain the 1.44g titled reference compound.MS(M+H) ⁺：335。

Step C

(4S)-and 3-allyl group-4-{[(benzyloxy) carbonyl] amino }-3-hydroxyl pyrrolidine-1-t-butyl formate.Under 0 ℃, in THF (20ml) solution of the ketone of 1.44g step B, add 6.2ml allyl group bromination magnesium.Color becomes black at once.After at room temperature stirring is spent the night, with the EtOAc/ water quencher reaction mixture of 50/50ml.With twice of EtOAc aqueous phase extracted.Use Na ₂SO ₄The dry organic phase that merges and concentrated under vacuum.With 3: 1～2: 1 hexanes/EtOAc wash-out, carry out the silica gel chromatography purifying and obtain the 0.85g titled reference compound.MS(M+H) ⁺：377。

Step D

(4S)-and the 4-{[(benzyloxy) carbonyl] amino }-3-hydroxyl-3-(3-hydroxypropyl) tetramethyleneimine-1-t-butyl formate.In anhydrous THF (20ml) solution of the allyl alcohol of 0.85g step C, add 15ml0.5N 9-BBN.Stirred described reactant 2 days.Add entry (0.5ml) and then add the hydrogen peroxide of 1ml 30% and the NaOAc/ water of 1ml.Stir after 1 hour, separate organic phase.With in the hydrochloric acid and the aqueous solution and use the EtOAc extracting twice.Use Na ₂SO ₄The dry extract that merges.Under vacuum, remove and desolvate.With pure EtOAc/ wash-out on silica gel column chromatography, obtain the 0.80g titled reference compound.MS(M+H) ⁺395。

Step e

(9S)-and the 9-{[(benzyloxy) carbonyl] amino }-1-oxa--7-azaspiro [4.4] nonane-7-t-butyl formate.Under 0 ℃, in methylene dichloride (15ml) solution of the glycol of 0.80g step D, add 0.2ml methylsulfonyl chloride and 0.8ml triethylamine.Stir after 1 hour, allow mixture flow through night next time at 60 ℃.Under vacuum, remove and desolvate.Absorb residuum and separate two-phase with EtOAc/ water.With twice of EtOAc aqueous phase extracted.Use Na ₂SO ₄The dry organic phase that merges.Under vacuum, remove and desolvate.The EtOAc wash-out of the EtOAc/ hexane to 100% with 15% carries out the silica gel chromatography purifying and obtains the 0.32g titled reference compound.MS(M+H) ⁺：377。

Step F

(9S)-9-amino-1-oxa--7-azaspiro [4.4] nonane-7-t-butyl formate.The sample (0.3g) that above obtains is dissolved in the 10ml methyl alcohol.Add 0.2g Pd/C.Allow mixture at 1atmH ₂(air bag air feed) stirring down spends the night and filters.Under vacuum, remove and desolvate, obtain the 0.22g crude product.With 2: 1 EtOAc/ methanol-eluted fractions, carry out the silica gel chromatography purifying, obtain 0.13g (64%) titled reference compound.MS actual value: 143.1 (M-Boc+1).

Step G

(9S)-and 9-[({[3-(trifluoromethyl) benzoyl] amino } ethanoyl) amino]-1-oxa--7-azaspiro [4.4] nonane-7-t-butyl formate.In ice bath, to the amine of step F (0.13g, 0.54mmol) and 3-(trifluoromethyl benzamido) acetate (0.133g adds bop reagent (0.238g in DMF 0.54mmol) (7ml) solution, 0.54mmol) then add triethylamine (0.5ml, 3.5mmol).At room temperature reaction stirred is spent the night.Under 60 ℃ and perfect vacuum, remove and desolvate.Absorb residuum with the EtOAc/ sodium bicarbonate aqueous solution.Separate two-phase and with twice of EtOAc aqueous phase extracted.Use Na ₂SO ₄The dry organic phase that merges and concentrated under vacuum.Using the EtOAc wash-out, carry out the silica gel chromatography purifying and obtain 0.18g (70%) titled reference compound, is the mixture of two kinds of diastereomers.MS(M+H) ⁺：472。

Step H

N-{2-[(9S)-1-oxa--7-azaspiro [4.4] ninth of the ten Heavenly Stems-the 9-base is amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide.The intermediate (0.18g) of step G is mixed with hydrochloric acid/dioxane of 5ml 4N.Concentrate with solution stirring 2 hours and under vacuum.MS(M+H) ⁺372。

Step I

N-(2-{[(9S)-7-(4-hydroxy-4-phenyl cyclohexyl)-1-oxa--7-azaspiro [4.4] ninth of the ten Heavenly Stems-9-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide.To the amine of step H (90mg, 0.243mmol) and 4-hydroxy-4-phenyl-pimelinketone (43mg, add in THF 0.226mmol) (5ml) solution sodium triacetoxy borohydride reagent (129mg, 0.61mmol) then add triethylamine (0.29ml, 2mmol).At room temperature reaction stirred is spent the night.Under vacuum, remove and desolvate.Absorb residuum with the EtOAc/ sodium bicarbonate aqueous solution.Separate two-phase and with twice of EtOAc aqueous layer extracted.Use Na ₂SO ₄The dry organic phase that merges and concentrated.Use the preparation HPLC purifying, obtain two kinds of isomer.MS：546.4(M+1) ⁺。

Embodiment 54

Steps A

(3S, 4S)-3-{ benzyl [(benzyloxy) carbonyl] amino }-4-hydroxyl pyrrolidine-1-t-butyl formate.The intermediate that obtains to embodiment 1 step B (3.2g, 11mmol) and N-(benzyloxycarbonyloxy base) succinimide (4.23g adds NEt in DMF 11mmol) (20ml) solution ₃(4.6ml, 33mmol.At room temperature stirring described reactant down spends the night and dilute with water.With the solution of EtOAc extraction gained three times., the extract that the water washing of usefulness salt merges three times is used MgSO ₄Dry and concentrated.EtOAc/ hexane wash-out on silica gel column chromatography with 30% obtains oily titled reference compound (2.5g, 53%).MS calculated value (M+H) ⁺427, actual value 449 (M+Na) ⁺

Step B

(3S, 4S)-3-{ benzyl [(benzyloxy) carbonyl] amino }-4-oxyethyl group tetramethyleneimine-1-t-butyl formate.To the cooling in ice bath above-mentioned intermediate (1g, add in THF 2.3mmol) (6ml) solution NaH (184mg, 4.6mmol).After stirring the mixture 30 minutes, and the adding iodic ether (0.96ml, 12mmol).Allow mixture at room temperature stir then to spend the night and use the aqueous ammonium chloride solution quencher.With the solution of EtOAc extraction gained three times.With the extract that the salt water washing merges, use Na ₂SO ₄The dry organic phase that merges and concentrated.The hexane solution of EtOAc with 10% is the wash-out purifying on silica gel, obtains oily titled reference compound (0.9g, 90%).MS (M+H) ⁺455, actual value 478 (M+Na) ⁺

Step C

(3S, 4S)-3-amino-4-oxyethyl group tetramethyleneimine-1-t-butyl formate.(2.0g 4.5mmol) is dissolved in the methyl alcohol with above-mentioned intermediate.To wherein adding the Pd (OH) that loads on the gac ₂(0.2g).Mixture stirred under 55psi spend the night.Catalyzer is leached and concentrates described filtrate.MS (M+H) ⁺231, actual value 231.

Step D

(3S, 4S)-3-oxyethyl group-4-[({[3-(trifluoromethyl) benzyloxy] amino } ethanoyl) amino] tetramethyleneimine-1-t-butyl formate.(1.0g, 4.43mmol) (1.09g, (1.96g 4.43mmol) then adds NEt to add BOP in DMF 4.43mmol) (20ml) solution with (3-trifluoromethyl benzyloxy amino) acetate to the amine of cooling in ice bath ₃(5ml).Allow mixture at room temperature stir to spend the night and under reduced pressure concentrate.Absorb residuum with EtOAc.With the solution of sodium bicarbonate and salt water washing gained, use MgSO ₄Dry and concentrated.With 2: 1 EtOAc/ hexane solutions wash-out purifying on silica gel, obtain solid titled reference compound (1.8g, 88%).MS (M+H) ⁺460, actual value 460.

Step e

N-(2-{[(3S, 4S)-4-oxyethyl group tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide.Above-mentioned intermediate is dissolved in dioxane (20ml) solution of 4N HCl.At room temperature stirred 2 hours, and removed and desolvate, obtain solid.MS (M+H) ⁺360, actual value 360.

Step F

N-(2-{[(3S, 4S)-4-oxyethyl group-1-(4-hydroxy-4-phenyl cyclohexyl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide.Can use the amine reductive amination of using the ketone that makes by embodiment 6 steps A above to obtain with the similar method of the description of embodiment 6, obtain titled reference compound.MS calculated value (M+H) ⁺534, actual value 534.

Embodiment 55

Steps A

4-(8-hydroxyl-1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-yl) benzonitrile.At liquid nitrogen-Et ₂During O bathed, in argon gas atmosphere, (10g, 0.055mol) solution in anhydrous THF of 260ml and 70ml anhydrous hexane was cooled to-100 ℃ with 4-bromobenzyl nitrile.Drip n-Butyl Lithium (34.3ml, 0.055mol, the hexane solution of 1.6M), temperature is no more than-95 ℃ in making.Restir is 10 minutes between-100 ℃ to-95 ℃, drips 1 then, and (8.75g, the 0.055mol) solution in the anhydrous THF of 55ml keep temperature to be lower than-95 ℃ to 4-cyclohexanedione list condensed ethandiol carefully.Between-100 ℃ to-95 ℃, stirred 10 minutes, and be warmed to 20 ℃ and pour (400ml) in the frozen water into then.Isolate organic layer, use Et ₂Twice of O (200ml) aqueous layer extracted.Use MgSO ₄Dry organic extract that merges and evaporation obtain the 14.1g white crystal.Grind the white crystals that obtains 9.9g (70% productive rate) with ether: ¹HNMR (CDCl ₃) δ 1.6-2.2 (8H, m, hexanaphthene), 3.97 (4H, s, ketals), 7.63 (4H, s, Ar) MS:260 (M+1) ⁺

Step B

4-(1-hydroxyl-4-oxo cyclohexyl) benzonitrile.At room temperature, (520mg 2.0mmol) is dissolved in the mixed solvent of 10ml THF and 10ml1N aqueous hydrochloric acid benzonitrile with 4-(8-hydroxyl-1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-yl).Then 60 ℃ of stirred reaction mixtures 1 hour.Solution is cooled to room temperature, and regulating PH with saturated sodium bicarbonate solution is 7～8.Isolate organic layer, use twice of EtOAc (20ml * 2) aqueous layer extracted.Use MgSO ₄Dry organic extract that merges and evaporation obtain the oily residuum.With 40% ethyl acetate-hexane solution is elutriant, carries out silica gel chromatography purifying (flash chromatography level), obtains the required product of 410mg (95%): ¹HNMR (CDCl ₃) δ 7.7 (2H, d, J=11.0Hz), 7.42 (2H, d, J=10.7Hz), 4.10 (H, s), 2.79-2.74 (2H, m), 2.63-2.49 (2H, m), 1.95-1.89 (2H, m), 1.67-1.59 (2H, m); MS:216 (M+1) ⁺

Step C

N-[2-((3S, 4S)-1-[4-(4-cyano-phenyl)-4-hydroxy-cyclohexyl]-4-oxyethyl group tetramethyleneimine-3-yl } amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide.Make reductive agent with sodium triacetoxy borohydride, use the intermediate general ketone reductive amination above that makes by embodiment 54 step e, obtain titled reference compound.MS：559(M+H) ⁺。

Embodiment 56

Steps A

4-(8-hydroxyl-1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-yl) phenylformic acid.In steam bath, (7.5g, 0.029mol) mixture heating up in 190ml 2-methyl cellosolve and 190ml 2.5N sodium hydroxide solution is 15 hours for benzonitrile with 4-(8-hydroxyl-1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-yl).With the cold described solution of ice bath, regulating PH with concentrated hydrochloric acid is 7～8 and evaporate to dryness.Adding entry (375ml) and regulating PH with hydrochloric acid is 2.Leach the brown solid and wash the 4-that obtains 7.6g (productive rate is 94%) (8-hydroxyl-1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-yl) phenylformic acid with water: ¹HNMR (CDCl ₃) δ 1.6-2.3 (8H, m, hexanaphthene), 4.00 (4H, s, ketals), 7.60 (2H, s, Ar) 8.00 (2H, s, Ar); MS:279 (M+1) ⁺

Step B

4-(8-hydroxyl-1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-yl)-N-methyl-benzamide.At room temperature, with 4-(8-hydroxyl-1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-yl) phenylformic acid (560mg, 2mmol), methylamine (1.2ml, the THF solution of 2.0M), bop reagent (1.07g, 2.4mmol) and 0.8ml (6mmol) triethylamine be dissolved among the 15ml DMF.At room temperature stirred reaction mixture spends the night then.As elutriant, directly carry out silica gel chromatography purifying (flash chromatography level) with 50% ethyl acetate-hexane solution, obtain the required product of 410mg (70%): ¹HNMR (CDCl ₃) δ 7.76 (2H, d, J=11.2Hz), 7.56 (2H, d, J=10.9Hz), 5.10 (H, s), 3.90 (4H, s), 3.37 (3H, m), 2.80-2.75 (2H, m), 2.60-2.45 (2H, m), 1.95-1.90 (2H, m), 1.63-1.52 (2H, m); MS:292 (M+1) ⁺

Step C

4-(1-hydroxyl-4-oxo cyclohexyl)-N-methyl-benzamide.At room temperature, (8-hydroxyl-1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-yl)-(410mg 1.4mmol) is dissolved in the mixed solvent of 7ml THF and 7ml 1N aqueous hydrochloric acid N-methyl-benzamide with 4-.Then 60 ℃ of stirred reaction mixtures 1 hour.Solution is cooled to room temperature, and regulating PH with saturated sodium bicarbonate solution is 7～8.Isolate organic layer, use twice of EA (20ml * 2) aqueous layer extracted.Use MgSO ₄Dry organic extract that merges and evaporation obtain the oily residuum.As elutriant, carry out silica gel chromatography purifying (flash chromatography level) with 40% ethyl acetate-hexane solution, obtain the required product of 410mg (90%): ¹HNMR (CDCl ₃) δ 7.78 (2H, d, J=11.2Hz), 7.51 (2H, d, J=10.9Hz), 4.10 (H, s), 3.37 (3H, m), 2.79-2.74 (2H, m), 2.63-2.49 (2H, m), 1.95-1.89 (2H, m), 1.67-1.59 (2H, m); MS:248M+1) ⁺

Step D

N-(2-{[(3S, 4S)-4-oxyethyl group-1-(4-hydroxyl-4-{4-[(methylamino) carbonyl] phenyl } cyclohexyl)-tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide.Make reductive agent with sodium triacetoxy borohydride, use the intermediate general ketone reductive amination above that makes by embodiment 54 step e, obtain titled reference compound.MS：591(M+H) ⁺。

Embodiment 57

Steps A

8-(1-pyridine oxide-4-yl)-1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-alcohol.To 2.35g (10mmol) 8-pyridin-4-yl-1, add 2.6g (15mmol) mCPBA in methylene dichloride (20ml) solution in 4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-alcohol (the method preparation of describing according to embodiment 7).Stirred reaction mixture 1.5 hours at room temperature then.Directly carry out the silica gel chromatography purifying, obtain titled reference compound (2.45g, 98%).

Step B

4-hydroxyl-4-(1-pyridine oxide-4-yl) pimelinketone.With the guard method of going of routine, by 8-(1-pyridine oxide-4-yl)-1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-synthetic titled reference compound of 8-alcohol.

Step C

N-[2-((3S, 4S)-4-oxyethyl group-1-[4-hydroxyl-4-(1-pyridine oxide-4-yl) cyclohexyl] tetramethyleneimine-3-yl } amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide.Can use conventional reductive amination method to obtain titled reference compound.MS：(M+H) ⁺551。

With the synthetic following compound of the method for similar embodiment 54-57.

Embodiment 54-57

Embodiment #	R ¹	R ²	MS(M+H) ⁺
Embodiment #	R ¹	R ²	MS(M+H) ⁺	58	OH	The 4-aminomethyl phenyl	548
59	OH	The 4-p-methoxy-phenyl	564	58	OH	The 4-aminomethyl phenyl	548
59	OH	The 4-p-methoxy-phenyl	564	60	OH	The 3-p-methoxy-phenyl	564
61	OH	The 4-fluorophenyl	552	60	OH	The 3-p-methoxy-phenyl	564
61	OH	The 4-fluorophenyl	552	62	OH	The 3-fluorophenyl	552
63	OH	The 4-chloro-phenyl-	568	62	OH	The 3-fluorophenyl	552
63	OH	The 4-chloro-phenyl-	568	64	OH	3, the 4-methylenedioxyphenyl	578
65	OH	Pyridine-2-base	535	64	OH	3, the 4-methylenedioxyphenyl	578
65	OH	Pyridine-2-base	535	66	OH	Pyridin-3-yl	535
67	OH	Pyridin-4-yl	535	66	OH	Pyridin-3-yl	535
67	OH	Pyridin-4-yl	535	68	OH	4-picoline-2-base	549
69	OH	5-picoline-2-base	549	68	OH	4-picoline-2-base	549
69	OH	5-picoline-2-base	549	70	OH	6-picoline-2-base	549
71	OH	6-methoxypyridine-3-base	565	70	OH	6-picoline-2-base	549
71	OH	6-methoxypyridine-3-base	565	72	OH	1-pyridine oxide-3-base	551

73	OH	1-pyridine oxide-2-base	551
73	OH	1-pyridine oxide-2-base	551	74	OH	Quinolyl-4	585
75	OH	The 3-cyano-phenyl	559	74	OH	Quinolyl-4	585
75	OH	The 3-cyano-phenyl	559	76	OH	3-(amino-carbonyl) phenyl	591
77	H	Pyridin-3-yl	519	76	OH	3-(amino-carbonyl) phenyl	591
77	H	Pyridin-3-yl	519	78	H	Pyridin-4-yl	519
79	H	Pyridine-2-base	519	78	H	Pyridin-4-yl	519
79	H	Pyridine-2-base	519	80	H	1-pyridine oxide-2-base	535
81	H	1-pyridine oxide-3-base	535	80	H	1-pyridine oxide-2-base	535
81	H	1-pyridine oxide-3-base	535	82	H	1-pyridine oxide-4-base	535
83	H	6-methoxypyridine-3-base	549	82	H	1-pyridine oxide-4-base	535
83	H	6-methoxypyridine-3-base	549	84	H	4-(morpholine-4-base carbonyl) phenyl	631
85	H	5-(morpholine-4-base carbonyl) pyridine-2-base	632	84	H	4-(morpholine-4-base carbonyl) phenyl	631
85	H	5-(morpholine-4-base carbonyl) pyridine-2-base	632	86	H	6-(morpholine-4-base carbonyl) pyridin-3-yl	632
87	H	4-(4-methylpiperazine-1-base carbonyl) phenyl	644	86	H	6-(morpholine-4-base carbonyl) pyridin-3-yl	632
87	H	4-(4-methylpiperazine-1-base carbonyl) phenyl	644	88	H	3-methyl isophthalic acid H-pyrazol-1-yl	522
89	H	3-Trifluoromethyl-1 H-pyrazol-1-yl	576	88	H	3-methyl isophthalic acid H-pyrazol-1-yl	522

Embodiment 90

N-(2-{[(3S, 4S)-4-oxyethyl group-1-(3H-volution [2-cumarone-1,1 '-hexanaphthene]-4 '-yl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide.Can use with the similar method of the description of embodiment 54 and obtain titled reference compound.MS:(M+H) ⁺546, actual value 546.

Embodiment 91

N-(2-{[(3S, 4S)-4-oxyethyl group-1-volution [hexanaphthene-1,1 '-indenes]-4-base tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide.Can use with the similar method of the description of embodiment 52 and obtain titled reference compound.MS:(M+H) ⁺542, actual value 542.

Embodiment 92

N-(2-{[(3S, 4S)-1-(2 ', 3 '-dihydro volution [hexanaphthene-1,1 '-indenes]-4-yl)-4-oxyethyl group tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide.Can use with the similar method of the description of embodiment 54 and obtain titled reference compound.MS:(M+H) ⁺544, actual value 544.

Embodiment 93

Steps A

6-oxa--3-azabicyclo [3.1.0] hexane-3-benzyl formate.In methylene dichloride (700ml) solution of 30g (133mmol) 3-tetramethyleneimine-1-benzyl formate, add 57.2g (200ml) mCPBA.Stir down at room temperature that described reactant spends the night and with the quencher of 250ml20% aqueous solution of sodium bisulfite.Isolate organic layer, and with twice of methylene dichloride (100ml * 2) aqueous layer extracted.With the extract twice that saturated sodium bicarbonate aqueous solution (250ml * 2), salt water washing merge, use Na ₂SO ₄Drying, vapourisation under reduced pressure.As elutriant, carry out the silica gel chromatography purifying with 40% ethyl acetate-hexane solution, obtain (24g, 83%) required product.MS(M+H) ⁺220。

Step B

(3S, 4S)-3-amino-4-hydroxy tetramethyleneimine-1-benzyl formate.In the 6-of 20.7g (94.4mmol) oxa--3-azabicyclo [3.1.0] hexane-solution of 3-benzyl formate in 80ml methyl alcohol, add 80ml ammonium hydroxide.Spend the night at 60 ℃ of stirred reaction mixtures.Reaction mixture under reduced pressure concentrated obtain the oily residuum (22.3g 94.4mmol), can be directly used in next step N-Boc-protective reaction.MS(M+H) ⁺237。

Step C

(3S, 4S)-the 3-[(tert-butoxycarbonyl) amino]-4-hydroxyl pyrrolidine-1-benzyl formate.At 0 ℃, in the THF (200ml) of the above-mentioned amino alcohol of 22.3g (94.4mmol) solution, add 26.8g (123mmol) two dimethyl dicarbonate butyl esters and 17.1ml (123mmol) triethylamine.At room temperature stirring described reactant down spends the night.With 100ml vinyl acetic monomer and 100ml aqueous solution quencher reactant.Isolate organic phase, and with twice of vinyl acetic monomer (100ml * 2) aqueous layer extracted.With the extract twice that saturated sodium bicarbonate aqueous solution (250ml * 2), salt water washing merge, use Na ₂SO ₄Drying, vapourisation under reduced pressure.As elutriant, carry out the silica gel chromatography purifying with 70% ethyl acetate-hexane solution, obtain (27.3g, 86%) required product.MS(M+H) ⁺337。

Step D

(3S, 4S)-3-(allyl group oxygen base)-4-[(tert-butoxycarbonyl) amino]-4-hydroxyl pyrrolidine-1-benzyl formate.At 0 ℃, to 26g (77mmol) 3-[(tert-butoxycarbonyl) amino]-add 5g (211mmol) sodium hydride in THF (120ml) solution of 4-hydroxyl pyrrolidine-1-benzyl formate.Stir described reaction-ure mixture 1 hour down at 0 ℃, add 10ml (115mmol) allyl bromide 98 then.Allowing reaction mixture be warmed to room temperature continues then at room temperature to react and spends the night.Add entry (50ml) quencher reactant.Isolate organic phase, and with twice of vinyl acetic monomer (100ml * 2) aqueous layer extracted.With the extract twice that the salt water washing merges, use Na ₂SO ₄Drying, vapourisation under reduced pressure.As elutriant, carry out the silica gel chromatography purifying with 25% ethyl acetate-hexane solution, obtain (21.3g, 73%) required product.MS(M+H) ⁺377。

Step e

(3S, 4S)-3-(allyl group oxygen base)-4-amino-pyrrolidine-1-benzyl formate.To 21.3g (56.6mmol) 3-(allyl group oxygen base)-4-[(tert-butoxycarbonyl) amino]-add the dioxane solution of the HCl of 250ml 4N in THF (125ml) solution of tetramethyleneimine-1-benzyl formate.At room temperature stirred described reactant 2 hours, and under reduced pressure concentrated and obtain the oily residuum.Again dissolve this residuum with the 200ml saturated sodium bicarbonate solution.With mixture pH regulator to 7～8, use vinyl acetic monomer (100ml * 2) extracting twice then.With the extract that the salt water washing merges, use Na ₂SO ₄Drying, vapourisation under reduced pressure obtain the oily residuum.With 5% methyl alcohol-ethyl acetate is elutriant, carries out the silica gel chromatography purifying, obtains (10.5g, 68%) titled reference compound.MS(M+H) ⁺277。

Step F

(3S, 4S)-3-(allyl group oxygen base)-4-[({[3-(trifluoromethyl) benzoyl] amino } ethanoyl) amino] tetramethyleneimine-1-benzyl formate.At room temperature, in DMF (150ml) solution of 10g (36mmol) 3-(allyl group oxygen base)-4-amino-pyrrolidine-1-benzyl formate, add 12g (105mmol) N-methylmorpholine, 19g (44mmol) bop reagent and 10g (39mmol) aminobenzoic acid derivative.At room temperature stirring described reaction-ure mixture spends the night.With 50% ethyl acetate-hexane is elutriant, directly carries out the silica gel chromatography purifying, obtains (14.5g, 79.8%) titled reference compound.MS(M+H) ⁺506。

Step G

N-(2-oxo-2-{[(3S, 4S)-(4-propoxy-tetramethyleneimine-3-yl)] amino } ethyl)-3-(trifluoromethyl) benzamide hydrochloride salt.To 3.7g 3-(allyl group oxygen base)-4-[({[3-(trifluoromethyl) benzoyl] amino } ethanoyl) amino] add 3.6ml 6N aqueous hydrochloric acid and 171mgPd/C (10%, be adsorbed on the carbon) in methyl alcohol (35ml) solution of tetramethyleneimine-1-benzyl formate.Stirring described reaction-ure mixture under room temperature and hydrogen (40psi) spends the night.Described mixture obtains (1.73g, 58%) titled reference compound through Celite diatomite filtration and under reduced pressure concentrated.MS(M+H) ⁺374。

Step H

N-[2-((3S, 4S)-1-[4-hydroxyl-4-(1-pyridine oxide-4-yl) cyclohexyl]-4-propoxy-tetramethyleneimine-3-yl } amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide.According to the typical method of reductive amination, use N-(2-oxo-2-{[4-propoxy-tetramethyleneimine-3-yl] amino } ethyl)-3-(trifluoromethyl) benzamide hydrochloride salt and the synthetic this compound of 4-hydroxyl-4-(1-pyridine oxide-4-yl) pimelinketone.MS(m/e)：565(M+H) ⁺。

According to the synthetic following compound of the method for embodiment 93.

Embodiment #	R ¹	R ²	MS(M+H) ⁺
Embodiment #	R ¹	R ²	MS(M+H) ⁺	94	OH	Phenyl	548
95	OH	The 4-p-methoxy-phenyl	578	94	OH	Phenyl	548
95	OH	The 4-p-methoxy-phenyl	578	96	OH	3, the 4-methylenedioxyphenyl	592
97	OH	Pyridine-2-base	549	96	OH	3, the 4-methylenedioxyphenyl	592
97	OH	Pyridine-2-base	549	98	OH	Pyridin-3-yl	549
99	OH	Pyridin-4-yl	549	98	OH	Pyridin-3-yl	549
99	OH	Pyridin-4-yl	549	100	OH	Quinolyl-4	599
101	OH	6-methoxypyridine-3-base	579	100	OH	Quinolyl-4	599
101	OH	6-methoxypyridine-3-base	579	102	OH	4-picoline-2-base	563
103	OH	5-picoline-2-base	563	102	OH	4-picoline-2-base	563
103	OH	5-picoline-2-base	563	104	OH	6-picoline-2-base	563
105	OH	6-methoxypyridine-2-base	579	104	OH	6-picoline-2-base	563

106	OH	1-pyridine oxide-3-base	565
106	OH	1-pyridine oxide-3-base	565	107	H	Pyridin-3-yl	533
108	H	Pyridin-4-yl	533	107	H	Pyridin-3-yl	533
108	H	Pyridin-4-yl	533	109	H	3,5-dimethyl-1H-pyrazol-1-yl	550
110	H	3-methyl isophthalic acid H-pyrazol-1-yl	536	109	H	3,5-dimethyl-1H-pyrazol-1-yl	550
110	H	3-methyl isophthalic acid H-pyrazol-1-yl	536	111	H	1-pyridine oxide-3-base	549

Embodiment 112

N-(2-oxo-2-{[(3S, 4S)-4-propoxy--1-(3H-volution [2-cumarone-1,1 '-hexanaphthene]-4 '-yl) tetramethyleneimine-3-yl] amino } ethyl)-3-(trifluoromethyl) benzamide.Use obtains titled reference compound with the similar method of description of embodiment 93.MS: calculated value (M+H) ⁺560, actual value 560.

Embodiment 113

N-(2-oxo-2-{[(3S, 4S)-4-propoxy--1-volution [hexanaphthene-1,1 '-indenes]-4-base tetramethyleneimine-3-yl] amino } ethyl)-3-(trifluoromethyl) benzamide.Use obtains titled reference compound with the similar method of description of embodiment 93.MS: calculated value (M+H) ⁺556, actual value 556.

Embodiment 114

Steps A

(3-trifluoromethyl-benzamido) acetate.In 0 ℃, 30 minutes, to Padil (15.014g, 0.20mol) slow 3-trifluoromethyl-Benzoyl chloride (41.714g, MeCN 0.20mol) (75ml) solution of adding in the solution in MeCN (400ml) and 2M NaOH (250ml) of quick stirring.Under 0 ℃, stirred muddy yellow solution 30 minutes.To PH=3, then remove MeCN with 3M hydrochloric acid acidizing reaction mixture with rotary evaporation.The mixture of using ethyl acetate (400ml * 3) extraction to obtain then.The dry organic layer that merges filters and concentrates, and obtains faint yellow solid (48.53g), grinds with toluene (500ml).After the filtration, solid product is colourless until filtrate with the cold toluene washing.It's weekend is past drying under high vacuum, obtains white powder product: 44.60g (90%).MS(M+H) ⁺＝248.1。 ¹HNMR(CDCl ₃-d ₆)δ12.70(br s，1H)，9.17(m，1H)，8.20(dd，2H)，7.94(dd，1H)，7.78(m，1H)，3.97(d，2H)。

Step B

N-(2-{[(3R)-benzyl-pyrrole alkane-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide.Under-10 to-15 ℃ and nitrogen, by syringe to (3-trifluoromethyl-benzamido) acetate (4.2g, 17mmol) and NMM (2.8ml, 25.5mmol) in the solution of anhydrous THF (30ml), add isopropyl chlorocarbonate (2.4ml, 17.85mmol).Reaction mixture is the pulverize redness gradually.After 15 minutes, (3.0g, the drips of solution of THF 17mmol) (15ml) is added in the above-mentioned mixed acid anhydride, keeps temperature of reaction＜-10 ℃ with (3R)-1-benzyl-pyrrole alkane-3-amine in 20 minutes.Reaction mixture becomes scarlet.After 1 hour, allow reaction mixture be warmed to room temperature, and water (25ml) quencher, with vinyl acetic monomer * 3 extractions, drying, filtration and the concentrated orange solids that obtains.Add MeCN and concentrate and remove vinyl acetic monomer.Add MeCN (15-20ml) then and obtain slurry, through ice bath cooling and stirred 30 minutes.After the filtration, colourless until filtrate with cold MeCN (10-15mL) washing.Dried overnight under high vacuum obtains faint yellow solid product: 5.0g (73%).MS(M+H) ⁺＝406.2。 ¹HNMR(CDCl ₃)δ8.16(s，1H)，8.00(dd，1H)，7.78(dd，1H)，7.57(m，1H)，7.25(m，6H)，7.06(m，1H)，6.39(m，1H)，4.48(m，1H)，4.04(d，2H)，3.62(d，2H)，2.86(m，1H)，2.63(m，1H)，2.57(m，1H)，2.36(m，2H)。

Step C

N-((R)-tetramethyleneimine-3-base carbamoyl methyl)-3-trifluoromethyl-benzamide.(14.0g, Parr 34.5mmol) shake and add palladium hydroxide (2.8g, 20% weight) in the bottle to the compound that the step B that is dissolved in methyl alcohol (50ml) is housed.The described suspended substance of vibration spends the night under room temperature and hydrogen (55psi).Leach mixture and concentrated with Celite diatomite, obtain the white solid titled reference compound; Productive rate 10.5g, 97%. ¹HNMR(CDCl ₃)δ9.06(t，1H)，8.20(m，3H)，7.94(d，1H)，7.75(t，1H)，4.23(m，1H)，3.89(d，2H)，3.00-3.22(m，4H)，2.82(m，1H)，2.05(m，1H)，1.73(m，1H)；MS m/z＝316.3(M+H) ⁺。

Step D

8-(6-methoxyl group-pyridin-3-yl)-1,4-two oxa-s-volution [4.5] last of the ten Heavenly stems-8-alcohol.In the exsiccant three-necked bottle, (12.6g 67.2mmol) is dissolved in anhydrous THF (130ml) and at N with 5-bromo-2-methoxypyridine ₂Under be cooled to-78 ℃.Drip hexane (28.2ml, 70.4mmol) solution and stirred described mixtures 50 minutes down of 2.5M n-Butyl Lithium at-78 ℃.Slowly in pyridine mixtures, add 1,4-cyclohexanedione list condensed ethandiol (10.0g, 64.0mmol) solution in anhydrous THF (25ml).Stirred described mixture 80 minutes down at-78 ℃.With this reactant of saturated ammonium chloride solution quencher and with dichloromethane extraction (3 *).Dry extract (the MgSO that merges ₄), filter and concentrate and obtain yellow oil.With 10% methanol/dichloroethane is elutriant, carries out purification by flash chromatography, and obtaining titled reference compound is yellow solid; Output 16.5g, 62.2mmol, 97%. ¹HNMR(CDCl ₃)δ8.26(s，1H)，7.72(d，1H)，6.69(d，1H)，3.96(t，4H)，3.91(s，3H)，2.21(s，1H)，2.08(m，4H)，1.82(m，2H)，1.66(m，2H)；MS m/z＝266.1(M+H) ⁺。

Step e

4-hydroxyl-4-(6-methoxyl group-pyridin-3-yl)-pimelinketone.(11.5g adds 3N HCl (75ml) and at room temperature stirs and spend the night in THF 43.3mmol) (100ml) solution to the ketal of step D.The pH that adds 3N sodium hydroxide solution regulator solution is to～11.After removing most of THF by rotary evaporation, with dichloromethane extraction (3 *) water.Dry extract (the MgSO that merges ₄), filter and concentrate and obtain yellow oil solid state titled reference compound.Output 8.2g, 37.1mmol, 86%. ¹HNMR(CDCl ₃)δ8.26(s，1H)，7.75(d，1H)，6.73(d，1H)，3.91(s，3H)，2.91(m，2H)，2.78(m，1H)，2.32(m，2H)，2.21(m，4H)；MS m/z＝222.1。

Step F

N-((3R)-1-[4-hydroxyl-4-(6-methoxyl group-pyridin-3-yl)-cyclohexyl]-tetramethyleneimine-3-base carbamyl }-methyl)-3-trifluoromethyl-benzamide.To N-((3R)-tetramethyleneimine-3-base carbamoyl methyl)-3-trifluoromethyl-benzamide (5.0g, 15.9mmol) dry methylene chloride (1.01) solution in add the ketone (4.56g of step e, 20.6mmol), then add sodium triacetoxy borohydride (6.72g, 31.7mmol).At room temperature stirring described reactant down spends the night.Add 1N sodium hydroxide solution (250ml) the described reactant of neutralization and with dichloromethane extraction (3 *).Dry extract (the MgSO that merges ₄), filter and concentrate and obtain viscous solid.With 1% ammonium hydroxide/15% methyl alcohol/vinyl acetic monomer is elutriant, carries out purification by flash chromatography, and the isomer that needing to obtain is a white solid; Output (only being the lower isomer of polarity) 3.68g, 7.1mmol, 45%. ¹HNMR(CDCl ₃)δ8.28(s，1H)，8.09(s，1H)，7.97(d，1H)，7.75(dd，2H)，7.55(m，2H)，6.90(d，1H)，6.72(d，1H)，4.44(m，1H)，4.12(s，2H)，3.92(s，3H)，2.87(m，1H)，2.65(m，2H)，2.27(m，4H)，2.11(bs，1H)，1.93(m，2H)，1.64(m，5H)；MS m/z＝521.2(M+H) ⁺。

Embodiment 115

Steps A

Cis-1-pyridine-2-basic ring hexane-1, the 4-glycol.Add THF (150ml) among the LAH in the four-necked bottle that is contained in 1L (50ml, the THF solution of 1.0M), in 1.5 hours, drip 4-hydroxyl-4-pyridine-2-basic ring hexanone (10.0g, THF 52.3mmol) (100ml) solution then.Temperature of reaction is always about 30 ℃.Whether finish and HPLC shows the ratio 1: 9 of trans and cis glycol with HPLC analysis and judgement reaction.By slowly adding entry (8ml) and 15% sodium hydroxide (2ml) quencher reactant, and with Celite diatomite filtration mixture.Concentrated filtrate obtains oily matter (10.1g), with 1%TEA/5%IPA/ hexane (400ml), uses 1%TEA/15%IPA/10%tBME/ hexane (6L) wash-out then, carries out silica gel (350g) chromatogram purification.With suitable elution fraction merging and concentrated under vacuum, obtain cis-1-pyridine-2-basic ring hexane-1,4-glycol (6.3g, 63%) is white solid.LCMS：194.3(M+H，100％)。 ¹HNMR(CDCl ₃)δ8.54(dd，1H)，7.72(dd，1H)，7.68(dd，1H)，7.39(d，1H)，5.09(bs，1H)，3.82-3.76(m，1H)，2.56-2.49(m，1H)，2.01-1.98(m，2H)，1.96-1.84(m，2H)，1.80-1.75(m，2H)，1.64-1.58(m，2H)。

Step B

Methylsulfonic acid cis-4-hydroxyl-4-pyridine-2-basic ring polyhexamethylene.Under 0 ℃, to the alcohol of steps A (6.3g, 32.6mmol) and TEA (13.6ml, add in THF 97.8mmol) (100ml) solution methylsulfonyl chloride (3.78ml, 48.9mmol).Stir after 1.5 hours, judge with lcms analysis whether reaction is finished.By adding 20% saleratus (40ml) quencher reactant and extracting with ethyl acetate (300ml).With 10% saleratus, salt brine solution washing organic layer, concentrate with dried over sodium sulfate and under vacuum.Under 70 ℃, residuum can be in toluene (100ml) crystallization and at the air drying solid, obtain solid crystal (5.25g, 59.4%).LCMS：272.3(M+H ⁺，100％)； ¹HNMR(CDCl ₃)δ8.54(d，1H)，7.76(dd，1H)，7.35(dd，1H)，7.26(dd，1H)，5.20(bs，1H)，4.86-4.77(m，1H)，3.06(s，3H)，2.30-2.10(m，4H)，1.96-1.88(m，2H)，1.80-1.78(m，2H)。

Step C

[(3R)-and 1-(trans-the 4-hydroxyl-the 4-pyridine-2-basic ring hexyl) tetramethyleneimine-3-yl] t-butyl carbamate.Weighing methylsulfonic acid 4-hydroxyl-4-pyridine-2-basic ring polyhexamethylene (0.245g, 0.9mmol) and (3R)-(1.6g's tetramethyleneimine-3-aminocarbamic acid tert-butyl ester 8.59mmol) packs in the microwave oven test tube.Clean reaction mixture put into 71 ℃ microwave oven 15 minutes.Vinyl acetic monomer/methyl alcohol (100/0 to 10/90) with 1% ammonium hydroxide is elutriant, carries out the silica gel chromatography purifying, obtain [(3R)-and 1-(4-hydroxyl-4-pyridine-2-basic ring hexyl) tetramethyleneimine-3-yl] t-butyl carbamate.LC/MS：362.2(M+H，100％)。 ¹HNMR(CDCl ₃)δ8.52(m，1H)，7.70(m，1H)，7.43(d，1H)，7.19(m，1H)，4.86(bs，2H)，4.20(bs，1H)，2.82(m，1H)，2.68(s，1H)，2.56(m，1H)，2.40(m，1H)，2.31(s，1H)，2.27-2.17(m，3H)，2.04-1.98(m，2H)，1.78-1.74(m，3H)，1.61(m，2H)，1.46(s，9H)。

Step D

Trans-4-[(3R)-3-amino-pyrrolidine-1-yl]-1-pyridine-2-basic ring hexanol.At room temperature, (50mg adds 1 of 4.0M hydrochloric acid, 4-dioxane (3ml) in 0.14mmol) to [(3R)-1-(4-hydroxyl-4-pyridine-2-basic ring hexyl) tetramethyleneimine-3-yl] t-butyl carbamate.Stir after 5 minutes, be settled out product.Add methyl alcohol (0.6ml) in mixture, described solution becomes clearly substantially, has some gelatinoids simultaneously.Judge with HPLC and LCMS and to finish after being reflected at two and one-half-hours.Concentrate the mixture of gained, obtain 4-[(3R)-3-amino-pyrrolidine-1-yl]-1-pyridine-2-basic ring hexanol hydrochloride (72mg, 99%).LC/MS：262.1(M+H ⁺，100％)。

Step e

N-(2-{[(3R)-1-(4-hydroxyl-4-pyridine-2-basic ring hexyl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide.At room temperature, to 4-[(3R)-3-amino-pyrrolidine-1-yl]-1-pyridine-2-basic ring hexanol (69mg, 0.26mmol) anhydrous THF (5ml) solution in add TEA (0.10ml) and another kind (3-trifluoromethyl-benzamido)-acetate (60mg, 0.24mmol), N-(3-dimethylaminopropyl)-N '-ethyl carbon imide hydrochloride (50mg, 0.26mmol) THF (5.0ml) solution, add DMF (0.07ml) and extra TEA (0.05ml) then, be mixed with solution.At room temperature reaction stirred is spent the night and is added the described reactant of entry (25ml) quencher and with ethyl acetate extraction (4 * 35ml).The extract, the filtration that merge with dried over sodium sulfate also under reduced pressure remove and desolvate.Vinyl acetic monomer/methyl alcohol (100/0 to 10/90) with 1% ammonium hydroxide is elutriant, and residuum is carried out the silica gel chromatography purifying, then uses HPLC purifying, the CH of the TFA with 0.05% ₃CN solution/water wash-out obtains N-(2-{[(3R)-1-(4-hydroxyl-4-pyridine-2-basic ring hexyl) tetramethyleneimine-3-yl of tfa salt form] amino }-the 2-oxoethyl)-two (trifluoroacetate) (68mg, 57%) of 3-(trifluoromethyl) benzamide.LRMS：491(M+H，100％)。 ¹HNMR(CD ₃OD)δ8.20(s，1H)，8.12(d，1H)，7.85(d，1H)，7.67(t，1H)，6.96(s，2H)，4.37(m，1H)，4.01(s，2HH)，2.88(m，1H)，2.77(m，1H)，2.61(m，1H)，2.52(m，2H)，2.44(q，1H)，2.21(m，2H)，1.96(m，2H)，1.65(m，3H)，1.40(m，2H)。

Embodiment 116

Steps A

2-azetidine-1-base-5-bromopyridine.Stir azetidine hydrochloride (590mg, 6.3mmol), 5-bromo-2-fluorine pyridine (1.11g, 6.3mmol), Cs ₂CO ₃(4.1g 12.6mmol) heated 20 hours down with the mixture of anhydrous DMSO (7ml) and at 95 ℃.Reaction mixture and filtration.Use the water treatment solid, use ethyl acetate extraction 3 times.Dry organic layer, the filtration that merges obtains 1.15 gram (86%) required products, is faint yellow solid.MS(M+H ⁺)＝213.0/215.0。 ¹HNMR(CDCl ₃)δ8.18(d，1H)，7.50(dd，1H)，6.18(d，1H)，4.03(t，4H)，2.40(q，2H)。

Step B

8-(6-azetidine-1-yl pyridines-3-yl)-1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-alcohol.(64mg 0.30mmol) is dissolved among the anhydrous THF (1.5ml) and is cooled to-78 ℃, then adds n-Butyl Lithium (0.196ml, the hexane solution of 1.6M) with 2-azetidine-1-base-5-bromopyridine.After 30 minutes, at stable stirring and-78 ℃ of droppings 1 down, 4-cyclohexanedione list condensed ethandiol (44.6mg, anhydrous THF (0.2mL) solution 0.286mmol).After one hour, with ammonium chloride (aqueous solution) quencher reactant and slowly be warming up to room temperature.With dichloromethane extraction water layer three times, drying, filter and concentrate and obtain crude product, with flash column chromatography purifying (100% ethyl acetate), obtain 35mg (43%) white solid.MS(M+H ⁺)＝291.1。

Step C

4-(6-azetidine-1-yl pyridines-3-yl)-4-hydroxy-cyclohexanone.With 8-(6-azetidine-1-yl pyridines-3-yl)-1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-alcohol (35mg) is dissolved among the THF (1.2ml), at room temperature adds the hydrochloric acid (0.8ml) of 3M then.The solution of gained at room temperature stirred 2 hours, and the sodium hydroxide with 6N alkalizes to PH=10 in ice bath then.With dichloromethane extraction water layer three times.The dry organic layer that merges filters and rotary evaporation obtains 28mg (97%) white product, is not further purified.MS(M+H ⁺)＝247.0。

Step D

N-(2-{ (3R)-1-[4-(6-azetidine-1-yl pyridines-3-yl)-4-hydroxy-cyclohexyl] tetramethyleneimine-3-yl } amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide.Under room temperature and nitrogen, to 4-(6-azetidine-1-yl pyridines-3-yl)-4-hydroxy-cyclohexanone (115mg, 0.467mmol) and N-((R)-tetramethyleneimine-3-base carbamoyl methyl)-3-(trifluoromethyl) benzamide (140.4mg, 0.445mmol) anhydrous methylene chloride (19ml) solution in once add sodium triacetoxy borohydride (198mg, 0.934mmol).Reaction stirred is spent the night (16 hours) and is handled with yellow soda ash (aqueous solution) under nitrogen, with dichloromethane extraction 3 times, drying, filtration and the concentrated crude product that obtains, with column chromatography purifying (20: 80: 0.5 methanol/ethyl acetate/ammonium hydroxide), obtain the required isomer products of 60mg (25%) (spot), be white solid on TLC top.MS(M+H ⁺)＝546.1。 ¹HNMR(CD ₃OD)δ8.24(m，2H)，8.17(m，2H)，7.88(m，2H)，7.74(m，2H)，6.56(d，1H)，4.36(m，2H)，4.27(m，3H)，4.06(m，3H)，3.86(m，1H)，3.48(m，2H)，3.20(m，1H)，2.69(m，1H)，2.60(m，2H)，2.35-2.30(m，4H)，2.20-1.97(m，4H)，1.73(m，2H)。

Embodiment 117

Steps A

6-bromine cigarette nitrile (nicotinonitrile).(13.8g 100mmol) heated 32 hours down at 145 ℃ in phosphorus tribromide (150ml) with 6-chlorine cigarette nitrile.After the cooling, enriched mixture under vacuum.In resistates, add phosphorus tribromide (150ml), and mixture heated 32 hours in addition down at 145 ℃.After the cooling, enriched mixture and adding ice-water mixture (500ml) under vacuum.Add the sodium bicarbonate neutralise mixt, and (3 * 250ml) extract described product with ethyl acetate.The organic phase that merges with the salt water washing and use dried over mgso.Under vacuum, remove and desolvate,, obtain 14.9g (81%) 6-bromine cigarette nitrile white solid with chromatogram purification residuum (hexane-ethyl acetate): ¹HNMR (400Hz, CDCl ₃) δ 7.66 (d, J=11.0Hz, 2H), 7.80 (dd, J=3.1,11.0Hz, 1H), 8.67 (d, J=3.1Hz, 1H); MS m/z 183.0,185.0 (M+H) ⁺

Step B

6-(8-hydroxyl-1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-yl) cigarette nitrile.Under liquid nitrogen-ether was bathed, (2g, 0.011mol) solution in anhydrous THF of 50ml and 15ml anhydrous hexane was cooled to-100 ℃ under argon gas with 6-bromine cigarette nitrile.Drip n-Butyl Lithium (7.5ml, 0.011mol, the hexane solution of 1.6M) rapidly, temperature is no more than-95 ℃ in making.-100 ℃ to-95 ℃ restir orange solutions 10 minutes, in 10 minutes, drip 1 then, (1.8g, the 0.011mol) solution in anhydrous THF (55ml) carefully keep temperature to be no more than-95 ℃ to 4-cyclohexanedione list condensed ethandiol.-100 ℃ to-95 ℃ following stirred reaction mixtures 10 minutes, be warmed to 20 ℃ and pour in the frozen water (400ml) then.Isolate organic layer, with twice of water layer of extracted with diethyl ether (200ml).Use MgSO ₄Dry organic extract that merges and evaporation obtain 2.8g white crystal solid.Obtain 1.9g (productive rate 67%) white crystal: MS:261 (M+H) with the ether grinding ⁺

Step C

6-(1-hydroxyl-4-oxo cyclohexyl) cigarette nitrile.With the protection method of going of 4-(1-hydroxyl-4-oxo cyclohexyl) cyanobenzene of identical routine, by 6-(8-hydroxyl-1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-yl) the synthetic titled reference compound of cigarette nitrile.

Step D

N-[2-((3R)-and 1-[4-(5-cyanopyridine-2-yl)-4-hydroxy-cyclohexyl] tetramethyleneimine-3-yl } amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide.With the synthetic titled reference compound of the reductive amination method of similar embodiment 114.MS(M+H) ⁺516。

Embodiment 118

Steps A

8-(6-fluorine pyridin-3-yl)-1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-alcohol.Under nitrogen, (2g, 0.011mol) solution in the 50ml anhydrous diethyl ether is cooled to-78 ℃ with 5-bromo-2-fluorine pyridine.Dropping n-Butyl Lithium (7.5ml, 0.011mol, the hexane solution of 1.6M) and TMEDA (2.5g, 0.022mmol).-78 ℃ of following restir orange solutions 1 hour, in 10 minutes, drip 1 then, 4-cyclohexanedione list condensed ethandiol (1.8g, 0.011mol) solution in anhydrous THF (20ml).Stirred reaction mixture 1 hour is warmed to 20 ℃ and pour in the frozen water (400ml) then.Isolate organic layer, with twice of water layer of ethyl acetate extraction (20ml * 2).Use MgSO ₄Dry organic extract that merges and evaporation obtain the 2g white solid.The silica gel chromatography purifying obtains 1.7g (productive rate 67%) white crystal: MS:254 (M+H) ⁺

Step B

5-(8-hydroxyl-1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-yl) pyridine-2-formonitrile HCN.To 1.7g 8-(6-fluorine pyridin-3-yl)-1, add in 4-dioxo spiro ring [4.5] last of the ten Heavenly stems-solution of 8-alcohol (6.6mmol) in 20mlDMF KCN (430g, 6.6mmol) and 18-hat-6 ethers (1.8g, 6.6mmol).Reaction mixture refluxed two days.Direct chromatogram purification on silica gel obtains 5-(8-hydroxyl-1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-yl) pyridine-2-formonitrile HCN (620mg, 36%): MS (m/e): 261 (M+H) ⁺

Step C

5-(1-hydroxyl-4-oxo cyclohexyl) pyridine-2-formonitrile HCN.Routine with identical 4-(1-hydroxyl-4-oxo cyclohexyl) cyanobenzene is gone protection method, by the synthetic titled reference compound of 5-(8-hydroxyl-1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-yl) pyridine-2-formonitrile HCN.

Step D

N-[2-((3R)-and 1-[4-(6-cyanopyridine-3-yl)-4-hydroxy-cyclohexyl] tetramethyleneimine-3-yl } amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide.With the synthetic titled reference compound of the reductive amination method of similar embodiment 114.MS516(M+H) ⁺。

Embodiment 119

Steps A

2-bromo-5-bromo methyl cycloheptapyridine.(5.00g, 29.1mmol) (5.22g 29.3mmol) is dissolved in tetracol phenixin (40ml) with N-bromine succinimide with 2-bromo-5-picoline under nitrogen.(0.35g, the backflow mixture is 4 hours 1.4mmol) and under heating to add benzoyl peroxide.Mixture is cooled to room temperature, filters, with sodium bicarbonate/water washing.Mixture is adsorbed on the silica gel, is gradient eluent with hexane to 10% ethyl acetate/hexane then, carries out chromatogram purification.Merge pure component and concentrated, obtain required monobromination product, be faint yellow solid, 3.60g (49%).LC/MS (positively charged ion) m/z=249.8,251.8,253.8 (M+H) ⁺

Step B

2-bromo-5-(methoxymethyl) pyridine.(3.58g 14.3mmol) is dissolved in methyl alcohol (20ml) with 2-bromo-5-brooethyl-pyridine under nitrogen.Add sodium methylate (0.89g, 15.7mmol, 95%) and at room temperature stir the mixture.After 3 hours, the methyl alcohol rotary evaporation fallen and residuum is dissolved in methylene dichloride and washes with water.Organic extract is adsorbed on the silica gel, is gradient eluent from hexane to 20% ethyl acetate/hexane then, carries out chromatogram purification.Merge pure component and concentrated, obtain titled reference compound, be colorless oil, 2.62g (90%).LC/MS (positively charged ion) m/z=202.0,204.0 (M+H) ⁺

Step C

4-hydroxyl-4-[5-(methoxymethyl) pyridine-2-yl] pimelinketone.(2.61g 12.9mmol) is dissolved among the anhydrous THF (40ml) and is cooled to-78 ℃ with 2-bromo-5-(methoxymethyl) pyridine under nitrogen.In 10 minutes, drip n-Butyl Lithium (6.20ml, 15.5mmol, the hexane solution of 2.5M) and form dark solution.After 15 minutes, in 2 minutes, drip 1,4-dioxo spiro ring [4,5] last of the ten Heavenly stems-8-ketone (2.21g, 14.1mmol) solution in THF.In 3 hours, gradually mixture is warmed to room temperature.Transform fully with TLC (50% ethyl acetate/hexane) and LC/MS proof.(14ml 6.0M) and at room temperature stirred the mixture 3 hours, then with sodium bicarbonate/water neutralization to add aqueous hydrochloric acid.Be adsorbed on the separation of the enterprising circumstances in which people get things ready for a trip spectrum of silica gel with ethyl acetate extraction mixture 3 times and with the extract that merges.With hexane to 40% ethyl acetate/hexane classification wash-out.Merge pure component and concentrated, obtain titled reference compound, be faint yellow solid, 1.00g (33%).LC/MS (positively charged ion) m/z=236.1 (M+H) ⁺

Step D

N-{2-[((3R)-and 1-[is trans-4-hydroxyl-4-[5-(methoxymethyl) pyridine-2-yl] and cyclohexyl] tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide.N-{2-oxo-2-[(3R)-tetramethyleneimine-3-base is amino] ethyl }-3-(trifluoromethyl) benzamide hydrochloride salt (100mg, 0.284mmol) and 4-hydroxyl-4-[5-(methoxymethyl) pyridine-2-yl] (67.0mg 0.284mmol) is dissolved in the 2-propyl alcohol (15ml) pimelinketone.Add triethylamine (80 μ l, 0.57mmol) and sodium triacetoxy borohydride (120mg 0.57mmol) and at room temperature stirs the mixture and spends the night.Mixture is adsorbed on the enterprising circumstances in which people get things ready for a trip spectrum of silica gel separates, with methylene dichloride to 10% ethanol/methylene/0.5% ammonium hydroxide wash-out.Merge each elution fraction and obtain pure higher R _fThe isomer of value is white solid (90mg, 59%) and pure low R _fThe isomer of value is white solid (39mg, 26%).Higher R _fThe product of value: LC/MS (positively charged ion) m/z=535.2 (M+H) ⁺Low R _fThe product of value: LC/MS (positively charged ion) m/z=535.2 (M+H) ⁺

Embodiment 120

Steps A

2-(6-bromopyridine-3-yl) propane-2-alcohol.With 2,5-dibromo pyridine 3.05g (12.5mmol) is dissolved in 20ml THF and the 120ml anhydrous diethyl ether and is cooled to-78 ℃.By syringe in 30 minutes slowly Dropwise 5 .0ml n-butyllithium solution (2.5M, 12.5mmol).Stir described mixture down after 30 minutes at-78 ℃, and adding acetone (2ml, 20mmol).Reaction mixture was warmed to room temperature in two hours, add 10ml water quencher reactant then.Extract mixture 2 times with EtOAc.The dry extract that merges and concentrated.Behind 20% ethyl acetate isohexane solution crystallization, obtain 1.3g white crystal (productive rate 48%).MS：215.0，217.0(M ⁺+1)。

Step B

8-[5-(1-hydroxyl-1-methylethyl) pyridine-2-yl]-1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-alcohol.(1.08g 5mmol) is dissolved in 10ml THF and the 50ml anhydrous diethyl ether with 2-(6-bromopyridine-3-yl) propane-2-alcohol.After being cooled to-78 ℃, by syringe in 10 minutes, slowly drip the 4.20ml n-butyllithium solution (2.5M, 11mmol).Stir described mixture down after 30 minutes at-78 ℃, add 1, and 4-cyclohexanedione list condensed ethandiol (0.80g, 5mmol).Reaction mixture was warmed to room temperature in two hours, add 5ml water quencher reactant then.Extract mixture 2 times with EtOAc.The dry extract that merges and concentrated.Behind the ethyl acetate isohexane solution crystallization with 40-70%, obtain 0.48g white crystal (productive rate 42%).MS：294.1(M ⁺+1)

Step C

4-hydroxyl-4-[5-(1-hydroxyl-1-methylethyl) methyl] pyridine-2-yl } pimelinketone.With 8-[5-(1-hydroxyl-1-methylethyl) pyridine-2-yl]-1, (0.18g 29mmol) is dissolved in THF (10ml) and the 10ml 2N hydrochloric acid 4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8 alcohol.Stir after 2 hours, with saturated sodium bicarbonate aqueous solution neutralization reaction mixture to PH～8～9 and with ethyl acetate extraction 2 times.With the dry and concentrated 0.15g white solid (productive rate 98%) that obtains of the extract that merges.MS：250.2(M ⁺+1)。

Step D

N-{2-[((3R)-and 1-{4-hydroxyl-4-[5-(1-hydroxyl-1-methylethyl) pyridine-2-yl] cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide.Can use the similar approach of describing with embodiment 114 to prepare titled reference compound by the ketone that step C obtains.MS549(M+H) ⁺。

Embodiment 121

Steps A

6-bromo-pyridine-3-formaldehyde.With 2,5-dibromo pyridine 9.48g (40mmol) is dissolved in 60ml THF and the 150ml anhydrous diethyl ether.After being cooled to-78 ℃, by syringe in 30 minutes, slowly drip the 16ml n-butyllithium solution (2.5M, 40mmol).Stir described mixture down after 30 minutes at-78 ℃, add N, and dinethylformamide (3.5g, 48mmol).Reaction mixture was warmed to room temperature in two hours, add 10ml water quencher reactant then.Extract mixture 2 times with EtOAc.The dry extract that merges and concentrated.Behind the ethyl acetate isohexane solution crystallization with 30-40%, obtain 2.80g white crystal (productive rate 28%).MS：186.0，188.0(M ⁺+1)。

Step B

1-(6-bromopyridine-3-yl)-N, N-dimethyl methylamine.To tetraisopropoxy titanium (6.4g, 22mmol) and the methyl alcohol of 2.0M dimethylamine (22ml 44mmol) adds 6-bromopyridine-3-formaldehyde (2.10g, 11mmol) solution in 20ml methyl alcohol in the solution.After at room temperature stirring 5 hours, add sodium borohydride (0.43g, 11mmol) and stir the mixture and spend the night.Add 10ml water quencher reactant and with EtOAc extraction 2 times.The dry extract that merges and concentrated.Methanol ethyl acetate solution and 0.5% ammonium hydroxide with 20-40% are elutriant, carry out the flash column chromatography purifying, obtain 1.15g oily matter (productive rate 47%).MS：214.0，216.0(M ⁺+1)

Step C

The 8-{5-[(dimethylamino) methyl] pyridine-2-yl }-1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8 alcohol.With 1-(6-bromopyridine-3-yl)-N, (1.15g 5.4mmol) is dissolved in 30ml THF and the 80ml anhydrous diethyl ether N-dimethyl methylamine.After being cooled to-78 ℃, by syringe in 10 minutes, slowly drip the 2.60ml n-butyllithium solution (2.5M, 6.40mmol).Stir described mixture down after 30 minutes at-78 ℃, add 1, and 4-cyclohexanedione list condensed ethandiol (1.01g, 6.4mmol).Reaction mixture was warmed to room temperature in two hours, add 10ml water quencher reactant then.Extract mixture 2 times with EtOAc.The dry extract that merges and concentrated.Methanol ethyl acetate solution and 0.5% ammonium hydroxide with 20-40% are elutriant, carry out the flash column chromatography purifying, obtain 0.85g oily matter (productive rate 54%).MS：293.2.0(M ⁺+1)。

Step D

The 4-{5-[(dimethylamino) methyl] pyridine-2-yl }-the 4-hydroxy-cyclohexanone.With the 8-{5-[(dimethylamino) methyl] pyridine-2-yl }-1, (0.85g 2.9mmol) is dissolved in THF (10ml) and the 10ml 2N hydrochloric acid 4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8 alcohol.Stir after 2 hours, with saturated sodium bicarbonate aqueous solution neutralization reaction mixture to PH～8～9 and with ethyl acetate extraction 2 times.With the dry and concentrated 0.37g white solid (productive rate 51%) that obtains of the extract that merges.MS：249.2(M ⁺+1)。

Step e

N-(2-{[(3R)-1-(4-{5-[(dimethylamino) methyl] pyridine-2-yl }-the 4-hydroxy-cyclohexyl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide.Can use the similar approach of describing with embodiment 114 to prepare titled reference compound by the ketone that step D obtains.MS548(M+H) ⁺。

Synthesize following embodiment similarly according to the method that embodiment 114-121 describes.

Embodiment #	R	MS(M+H) ⁺
Embodiment #	R	MS(M+H) ⁺	122	Pyridin-3-yl	491
123	Pyridin-4-yl	491	122	Pyridin-3-yl	491
123	Pyridin-4-yl	491	124	6-picoline-2-base	505
125	5-picoline-2-base	505	124	6-picoline-2-base	505
125	5-picoline-2-base	505	126	4-picoline-2-base	505
127	1-pyridine oxide-3-base	507	126	4-picoline-2-base	505
127	1-pyridine oxide-3-base	507	128	1-pyridine oxide-4-base	507
129	1-pyridine oxide-2-base	507	128	1-pyridine oxide-4-base	507
129	1-pyridine oxide-2-base	507	130	6-methoxypyridine-2-base	521

131	Quinolyl-4	541
131	Quinolyl-4	541	132	4-benzonitrile base	515
133	3-benzonitrile base	515	132	4-benzonitrile base	515
133	3-benzonitrile base	515	134	4-(amino-carbonyl) phenyl	547
135	4-(B aminocarbonyl) phenyl	561	134	4-(amino-carbonyl) phenyl	547
135	4-(B aminocarbonyl) phenyl	561	136	4-(sec.-propyl aminocarboxyl) phenyl	575
137	4-(tertiary butyl aminocarboxyl) phenyl	589	136	4-(sec.-propyl aminocarboxyl) phenyl	575
137	4-(tertiary butyl aminocarboxyl) phenyl	589	138	4-(dimethylamino carbonyl) phenyl	561
139	4-[(azetidine-1-yl) carbonyl] phenyl	573	138	4-(dimethylamino carbonyl) phenyl	561
139	4-[(azetidine-1-yl) carbonyl] phenyl	573	140	4-[(tetramethyleneimine-1-yl) carbonyl] phenyl	587
141	4-[(morpholine-1-yl) carbonyl] phenyl	603	140	4-[(tetramethyleneimine-1-yl) carbonyl] phenyl	587
141	4-[(morpholine-1-yl) carbonyl] phenyl	603	142	4-(dimethylamino carbonyl)-2-aminomethyl phenyl	575
143	2-methyl-4-(amino-carbonyl) phenyl	561	142	4-(dimethylamino carbonyl)-2-aminomethyl phenyl	575
143	2-methyl-4-(amino-carbonyl) phenyl	561	144	3-methyl-4-(amino-carbonyl) phenyl	561
145	4-(dimethylamino carbonyl)-3-aminomethyl phenyl	575	144	3-methyl-4-(amino-carbonyl) phenyl	561
145	4-(dimethylamino carbonyl)-3-aminomethyl phenyl	575	146	3-methyl-4-(tetramethyleneimine-1-base carbonyl) phenyl	601
147	4-(dimethylamino carbonyl)-3-fluorophenyl	579	146	3-methyl-4-(tetramethyleneimine-1-base carbonyl) phenyl	601
147	4-(dimethylamino carbonyl)-3-fluorophenyl	579	148	4-[(2,2, the 2-trifluoroethyl) aminocarboxyl] phenyl	615
149	3-fluoro-4-(methylamino carbonyl) phenyl	565	148	4-[(2,2, the 2-trifluoroethyl) aminocarboxyl] phenyl	615
149	3-fluoro-4-(methylamino carbonyl) phenyl	565	150	4-(ethylamino carbonyl)-3-fluorophenyl	579
151	3-(amino-carbonyl) phenyl	547	150	4-(ethylamino carbonyl)-3-fluorophenyl	579
151	3-(amino-carbonyl) phenyl	547	152	3-(dimethylamino carbonyl) phenyl	561
153	5-(dimethylamino carbonyl)-2-p-methoxy-phenyl	591	152	3-(dimethylamino carbonyl) phenyl	561
153	5-(dimethylamino carbonyl)-2-p-methoxy-phenyl	591	154	2-methoxyl group-5-(methylamino carbonyl) phenyl	577
155	3-(amino-carbonyl amino) phenyl	562	154	2-methoxyl group-5-(methylamino carbonyl) phenyl	577
155	3-(amino-carbonyl amino) phenyl	562	156	6-(morpholine-4-yl) pyridin-3-yl	576
157	6-Dimethylamino pyridine-3-base	534	156	6-(morpholine-4-yl) pyridin-3-yl	576

158	6-sec.-propyl aminopyridine-3-base	549
158	6-sec.-propyl aminopyridine-3-base	549	159	6-(tetramethyleneimine-1-yl) pyridin-3-yl	560
160	6-cyclopropyl aminopyridine-3-base	546	159	6-(tetramethyleneimine-1-yl) pyridin-3-yl	560
160	6-cyclopropyl aminopyridine-3-base	546	161	6-ethoxy pyridine-3-base	535
162	6-(2-fluorine oxyethyl group) pyridin-3-yl	553	161	6-ethoxy pyridine-3-base	535
162	6-(2-fluorine oxyethyl group) pyridin-3-yl	553	163	6-(2, the 2-difluoroethoxy) pyridin-3-yl	571
164	6-(2,2, the 2-trifluoro ethoxy) pyridin-3-yl	589	163	6-(2, the 2-difluoroethoxy) pyridin-3-yl	571
164	6-(2,2, the 2-trifluoro ethoxy) pyridin-3-yl	589	165	Phenyl	490
166	The 4-aminomethyl phenyl	504	165	Phenyl	490
166	The 4-aminomethyl phenyl	504	167	The 4-fluorophenyl	508
168	The 3-fluorophenyl	508	167	The 4-fluorophenyl	508
168	The 3-fluorophenyl	508	169	The 4-bromophenyl	568
170	The 4-iodophenyl	616	169	The 4-bromophenyl	568
170	The 4-iodophenyl	616	171	5-(tetramethyleneimine-1-base carbonyl)-2-pyridyl	588
172	5-(morpholine-4-base carbonyl)-2-pyridyl	604	171	5-(tetramethyleneimine-1-base carbonyl)-2-pyridyl	588
172	5-(morpholine-4-base carbonyl)-2-pyridyl	604	173	5-dimethylamino carbonyl-2-pyridyl	562
174	4-methylamino carbonylamino phenyl	562	173	5-dimethylamino carbonyl-2-pyridyl	562
174	4-methylamino carbonylamino phenyl	562	175	6-(1-hydroxyl-1-methylethyl) pyridin-3-yl	549
176	4-(1-hydroxyl-1-methylethyl) phenyl	548	175	6-(1-hydroxyl-1-methylethyl) pyridin-3-yl	549
176	4-(1-hydroxyl-1-methylethyl) phenyl	548	177	4-(methoxymethyl) phenyl	534
178	3-fluoro-4-(methoxymethyl) phenyl	552	177	4-(methoxymethyl) phenyl	534
178	3-fluoro-4-(methoxymethyl) phenyl	552	179	4-(dimethylaminomethyl) phenyl	547
180	4-(dimethylaminomethyl)-3-fluorophenyl	565	179	4-(dimethylaminomethyl) phenyl	547
180	4-(dimethylaminomethyl)-3-fluorophenyl	565	181	1H-indazole-5-base	530
182	1-methyl isophthalic acid H-indazole-5-base	544	181	1H-indazole-5-base	530
182	1-methyl isophthalic acid H-indazole-5-base	544	183	1-methyl isophthalic acid H-indazole-5-base	544

Embodiment 184

Steps A

4-(1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-7-alkene-8-yl) benzonitrile.At room temperature, in 4-(8-hydroxyl-1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems--the 8-yl) solution of benzonitrile (7.8g) in the 100ml methylene dichloride, add triethylamine (21ml).Solution is cooled to-40 ℃, drips benzene sulfonyl chloride (4.7ml) then.-40 ℃ of reaction stirred 30 minutes, be warmed to room temperature then gradually and continue to stir and spend the night.With saturated sodium bicarbonate aqueous solution quencher reactant.With methylene dichloride (aqueous layer extracted.Organic extract with the salt water washing merges also evaporates with dried over sodium sulfate.Residuum column chromatography purifying (hexane/ethyl acetate=5/l), obtain 5.2g white solid product (71% productive rate): ¹HNMR (CDCl ₃) δ 7.62-7.55 (2H, m), 7.50-7.45 (2H, m), 6.17-6.13 (H, m), 4.02 (4H, s), 2.68-2.62 (2H, m), 2.53-2.47 (2H, m), 1.96-1.92 (2H, m); MS:242 (M+1) ⁺

Step B

4-(1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-7-alkene-8-yl) phenylformic acid.In steam bath, (5.2g, 0.021mol) mixture heating up in 190ml 2-methyl cellosolve and 190ml 2.5N sodium hydroxide solution is 15 hours for benzonitrile with 4-(1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-7-alkene-8-yl).With the cold described solution of ice bath, regulating PH with concentrated hydrochloric acid is 7～8 and evaporate to dryness.Adding entry (375ml) and regulating PH with hydrochloric acid is 2.Leach the brown solid and wash the 4-that obtains 5.3g (productive rate is 94%) (1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-7-alkene-8-yl) phenylformic acid with water: ¹HNMR (CDCl ₃) δ 8.06-8.01 (2H, m), 7.53-7.46 (2H, m), 6.18-6.14 (1H, m), 4.03 (4H, s), 2.73-2.67 (2H, m), 2.52-2.49 (2H, m), 2.00-1.93 (2H, m); MS:260 (M+1) ⁺

Step C

4-(1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-yl) phenylformic acid.In being dissolved in solution in the 30ml methyl alcohol, 5.3g 4-(1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-7-alkene-8-yl) phenylformic acid adds 2.3gPd/C (10wt%).Allow suspended substance at H ₂(air bag air feed) stirred 1 hour down and with the filtration of Celite Celite pad, be concentrated into dried obtain required product (5.2g, output: 97%), white solid: ¹HNMR (CDCl ₃) δ 8.06-8.01 (2H, m), 7.58-7.53 (2H, m), 4.02 (4H, s), 2.73-2.67 (2H, m), 2.70-2.61 (1H, m), 1.93-1.64 (8H, m); MS:262 (M+1) ⁺

Step D

4-(1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-yl)-N, the N-dimethyl benzamide.At room temperature, with 546mg (2mmol) 4-(1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-yl) phenylformic acid, N, N dimethylamine (1.2ml, 2.0MTHF solution), bop reagent (1.07g, 2.4mmol) and triethylamine (0.8ml 6mmol) is dissolved in 15ml DMF.At room temperature reaction stirred is spent the night.Carry out direct silica gel chromatography (flash chromatography level) purifying,, obtain the required product of 466mg (80%) with 50%EtOAc-hexane wash-out, 4-(1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-yl)-N, the N-dimethyl benzamide: ¹HNMR (CDCl ₃) δ 7.39 (2H, d, J=11.6Hz), 7.29 (2H, d, J=10.6Hz), 3.93 (4H, s), 3.17-2.99 (7H, m), 2.55-2.49 (4H, m), 2.13-2.10 (2H, m), 2.00-1.90 (2H, m); MS:289 (M+1) ⁺

Step e

N, N-dimethyl-4-(4-oxo cyclohexyl) benzamide.At room temperature, with 4-(1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-yl)-N, (466mg 1.6mmol) is dissolved in the mixed solvent of 8ml THF and 8ml 1N aqueous hydrochloric acid the N-dimethyl benzamide.Then 60 ℃ of stirred reaction mixtures 1 hour.Solution is cooled to room temperature, and regulating PH with saturated sodium bicarbonate solution is 7～8.Isolate organic layer, use twice of EtOAc (20ml * 2) aqueous layer extracted.Use MgSO ₄Dry organic extract that merges and evaporation obtain the oily residuum.With 40% ethyl acetate-hexane is elutriant, carries out silica gel (flash chromatography level) chromatogram purification, obtains the required product N of 360mg (90%), N-dimethyl-4-(4-oxo cyclohexyl) benzamide. ¹HNMR(CDCl ₃)δ7.39(2H，d，J＝11.60Hz)，7.29(2H，d，J＝10.6Hz)，3.15-2.99(7H，m)，2.56-2.49(4H，m)，2.15-2.10(2H，m)，2.01-1.94(2H，m)；MS：245(M+1) ⁺。

Step F

N, and N-dimethyl-4-(4-{ (3R)-3-[({[3-(trifluoromethyl) benzoyl] amino } ethanoyl) amino] tetramethyleneimine-1-yl } cyclohexyl) benzamide.With N, N-dimethyl-4-(4-oxo cyclohexyl) benzamide (100mg, 0.4mmol) and the N-{2-oxo-2-[(3R)-tetramethyleneimine-1-base is amino] ethyl }-(126mg 0.4mmol) is dissolved in the 10ml methylene dichloride 3-(trifluoromethyl) benzamide.In solution, add sodium triacetoxy borohydride (170mg, 0.8mmol).At room temperature reaction stirred is 2 hours.Carry out direct silica gel chromatography purifying, obtain final product 45mg (point on TLC top and first peak of HPLC), productive rate: 22%.MS：545(M+1) ⁺。

With the synthetic the following example of similar method.

Embodiment #	R	MS(M+H) ⁺
Embodiment #	R	MS(M+H) ⁺	185	4-(methylamino carbonyl) phenyl	531

186	4-(morpholine-4-base carbonyl) phenyl	587
186	4-(morpholine-4-base carbonyl) phenyl	587	187	4-(piperidines-1-base carbonyl) phenyl	585
188	3-fluoro-4-(tetramethyleneimine-1-base carbonyl) phenyl	589	187	4-(piperidines-1-base carbonyl) phenyl	585
188	3-fluoro-4-(tetramethyleneimine-1-base carbonyl) phenyl	589	189	5-(tetramethyleneimine-1-base carbonyl) pyridine-2-base	572
190	5-(dimethylamino carbonyl) pyridine-2-base	546	189	5-(tetramethyleneimine-1-base carbonyl) pyridine-2-base	572
190	5-(dimethylamino carbonyl) pyridine-2-base	546	191	5-(morpholine-4-base carbonyl) pyridine-2-base	588
192	Pyridine-2-base	475	191	5-(morpholine-4-base carbonyl) pyridine-2-base	588
192	Pyridine-2-base	475	193	Pyridin-3-yl	475
194	Pyridin-4-yl	475	193	Pyridin-3-yl	475
194	Pyridin-4-yl	475	195	1-pyridine oxide-2-base	491
196	1-pyridine oxide-3-base	491	195	1-pyridine oxide-2-base	491
196	1-pyridine oxide-3-base	491	197	1-pyridine oxide-4-base	491
198	Quinolyl-4	525	197	1-pyridine oxide-4-base	491
198	Quinolyl-4	525	199	6-methoxypyridine-3-base	505
200	6-(morpholine-4-yl) pyridin-3-yl	560	199	6-methoxypyridine-3-base	505
200	6-(morpholine-4-yl) pyridin-3-yl	560	201	4-(dimethylaminomethyl) phenyl	531
202	5-(dimethylaminomethyl) pyridine-2-base	532	201	4-(dimethylaminomethyl) phenyl	531
202	5-(dimethylaminomethyl) pyridine-2-base	532	203	5-(dimethylamino carbonyl) pyridine-2-base	546
204	4-[hydroxyl (pyridin-3-yl) methyl] phenyl	581	203	5-(dimethylamino carbonyl) pyridine-2-base	546
204	4-[hydroxyl (pyridin-3-yl) methyl] phenyl	581	205	6-[hydroxyl (pyridin-3-yl) methyl] pyridin-3-yl	582
206	6-(dimethylamino carbonyl) pyridin-3-yl	546	205	6-[hydroxyl (pyridin-3-yl) methyl] pyridin-3-yl	582
206	6-(dimethylamino carbonyl) pyridin-3-yl	546	207	4-(4-hydroxy piperidine-1-base carbonyl) phenyl	601
208	4-(4-methoxyl group piperidines-1-base carbonyl) phenyl	615	207	4-(4-hydroxy piperidine-1-base carbonyl) phenyl	601
208	4-(4-methoxyl group piperidines-1-base carbonyl) phenyl	615	209	5-(4-methoxyl group piperidines-1-base carbonyl) pyridine-2-base	616
210	6-(4-methoxyl group piperidines-1-base carbonyl) pyridin-3-yl	616	209		616

Embodiment 211

Steps A

1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-alcohol.To 1,4-cyclohexanedione list condensed ethandiol (5.0g, add in methanol 32mmol) (20ml, 1: the 1) solution sodium borohydride (1.21g, 32mmol).Described mixture at room temperature stirs and spends the night.Remove methyl alcohol by rotary evaporation.With ethyl acetate extraction (3 *) water layer.Dry organic layer (the MgSO that merges ₄), concentrate and to obtain oily matter, under high vacuum, places and spend the night, obtain 5.12g 1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-pure oily matter of 8-.MS (EI) calculated value (M+H) ⁺=159.1; Actual value: 159.2.

Step B

8-phenoxy group-1,4-dioxo spiro ring [4.5] decane.To 1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-alcohol (1.05g, 6.63mmol), phenol (0.75g, 7.95mmol), triphenylphosphine (1.91g, 7.29mmol) methylene dichloride (20ml) solution in add the azoformic acid diisopropyl ester (1.57ml, 7.95mmol).After stirring under room temperature and the nitrogen is spent the night, concentrated reaction mixture.Residuum is an elutriant with 10: 90 hexane-ethyl acetate, carries out purification by flash chromatography, obtains 1.09g 8-phenoxy group-1,4-dioxo spiro ring [4.5] decane.MS (EI) calculated value (M+H) ⁺=235.1; Actual value: 235.0.

Step C

4-phenoxy group pimelinketone.With 8-phenoxy group-1, (1.05g, THF/3N hydrochloric acid 4.48mmol) (20ml, 1: 1) solution at room temperature stirs and spends the night 4-dioxo spiro ring [4.5] decane.With ethyl acetate extraction (3 *) aqueous solution.Dry organic layer (the MgSO that merges ₄), concentrate and obtain 4-phenoxy group pimelinketone oily matter.MS (EI) calculated value M+H=191.1; Actual value: 191.0.

Step D

N-(the 2-oxo-2-{[(3R)-1-(4-phenoxy group cyclohexyl) tetramethyleneimine-3-yl] amino } ethyl)-3-(trifluoromethyl) benzamide.To 4-phenoxy group pimelinketone (0.091g, 0.475mmol) and N-[2-oxo-2-({ 2-oxo-2-[(3R)-tetramethyleneimine-3-base is amino] ethyl } amino) ethyl]-add in the solution of 3-(trifluoromethyl) benzamide in 2% ethanol/dichloromethane (10ml) sodium triacetoxy borohydride (0.134g, 0.634mmol).Described mixture washs with the ethyl acetate diluted reaction mixture and with saturated sodium carbonate after stirring under room temperature and the nitrogen is spent the night.With ethyl acetate extraction (3 *) water layer.Dry organic layer (the MgSO that merges ₄), concentrate and (ethyl acetate is to ethyl acetate: methyl alcohol: triethylamine=9: 1: 0.1), obtain the 0.12g titled reference compound with purification by flash chromatography.MS (EI) calculated value (M+H) ⁺=490.2; Actual value: 490.0.

Embodiment 212

Steps A

8-(benzyloxy)-1,4-dioxo spiro ring [4.5] decane.Under 0 ℃, to 1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-alcohol (1.18g, 7.46mmol) and NaH (0.358g, add in DMF 8.96mmol) (5ml) solution benzyl bromine (1.06ml, 8.95mmol).After stirring is spent the night under nitrogen, add entry and ethyl acetate.Water layer ethyl acetate extraction 3 times.Use MgSO ₄The dry organic layer that merges concentrates and is elutriant with 10% EtOAc/ hexane, carries out purification by flash chromatography, obtains the 1.524g titled reference compound.MS (EI) calculated value: (M+1) ⁺=249.1; Actual value: 249.2. ¹HNMR(300MHz，CDCl ₃)δ(ppm)7.35(5H，m)，4.52(2H，s)，3.95(4H，m)，3.5(1H，m)，1.95-1.50(8H，m)。

Step B

4-(benzyloxy) pimelinketone.Method according to embodiment 211 step C prepares titled reference compound by steps A.MS (EI) calculated value: (M+1) ⁺205.1; Actual value: 205.0.

Step C

N-[2-((3R)-and 1-[4-(benzyloxy) cyclohexyl] tetramethyleneimine-3-yl } amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide.According to the method for embodiment 211 step D, B prepares titled reference compound by step.MS (EI) calculated value: (M+1) ⁺=504.2; Actual value: 504.4.

Embodiment 213

Steps A

4,4-phenylbenzene-pimelinketone.Add 4 in Parr hydrogenation bottle, methyl alcohol (20ml) solution of 4-phenylbenzene-2-tetrahydrobenzene-1-ketone (0.91g, 3.66) then adds 10%Pd/C (0.2g).Hydrogenated mixture spends the night under the hydrogen of 50psi.Use methanol wash after leaching catalyzer, concentrated filtrate obtains 0.90g 4 under vacuum, 4-phenylbenzene-pimelinketone.MS (EI) calculated value: (M+1) ⁺=251.1; Actual value: 251.1.

Step B

N-(2-{[(3R)-1-(4,4-phenylbenzene cyclohexyl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide.Method according to embodiment 211 step D prepares titled reference compound by steps A.MS (EI) calculated value: (M+H) ⁺=550.3; Actual value: 550.5.

Embodiment 214

Steps A

[(3R)-and 1-(trans-the 2-hydroxy-cyclohexyl) tetramethyleneimine-3-yl] t-butyl carbamate.In the test tube of sealing, add cyclohexene oxide (2.34ml, 23.2mmol), (3R)-tetramethyleneimine-3-aminocarbamic acid tert-butyl ester (2.16mmol) and methyl alcohol (2ml).Seal this mixture, heat down and stir and spend the night at 60 ℃.Concentrated reaction mixture obtains 3.29g[(3R)-1-(2-hydroxy-cyclohexyl) tetramethyleneimine-3-yl] t-butyl carbamate.MS (EI) calculated value: (M+H) ⁺=285.2; Actual value: 285.1.

Step B

(3R)-and 1-[is trans-2-(benzyloxy) cyclohexyl] and tetramethyleneimine-3-yl } t-butyl carbamate.At 0 ℃, to [(3R)-1-(trans-the 2-hydroxy-cyclohexyl) tetramethyleneimine-3-yl] t-butyl carbamate (0.70g, 2.46mmol) and 60%NaH (0.108g, 2.71mmol) add in the mixture in DMF (5mL) the benzyl bromine (0.79g, 2.71mmol).After stirring is spent the night under nitrogen, add entry and ethyl acetate.Water layer ethyl acetate extraction 3 times.Use MgSO ₄The dry organic layer that merges concentrates and is elutriant with methyl alcohol/EtOAc of EtOAc to 10%, carries out purification by flash chromatography, obtains the 0.60g titled reference compound.MS (EI) calculated value: (M+H) ⁺=375.3; Actual value: 375.4.

Step C

(3R)-and 1-[is trans-2-(benzyloxy) cyclohexyl] and tetramethyleneimine-3-amine.At room temperature, incite somebody to action (3R)-1-[-2-(trans benzyloxy) cyclohexyl] tetramethyleneimine-3-yl } (0.60g, 1.602mmol) mixture in 4N hydrochloric acid/dioxane (10ml) stirred 1 hour t-butyl carbamate.Concentrated solution obtains the 0.55g titled reference compound, is dihydrochloride.MS (EI) calculated value: (M+1) ⁺=275.2; Actual value: 275.3.

Step D

N-(2-((3R)-and 1-[is trans-2-(benzyloxy) cyclohexyl] and tetramethyleneimine-3-yl } amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide.To (3R)-1-[trans-2-(benzyloxy) cyclohexyl] tetramethyleneimine-3-amine dihydrochloride (0.14g, 0.45mmol) and (3-trifluoromethyl-benzamido)-acetate (0.111g, 0.45mmol) add triethylamine (0.188ml in the mixture in methylene dichloride (5mL), 1.35mmol), then add EDC (0.0863g, 0.45mmol) and HOBt (0.069g, 0.45mmol).At room temperature stir the mixture and spend the night.Then with the ethyl acetate diluted reaction mixture and with saturated sodium carbonate and salt water washing.Use MgSO ₄Dry organic layer concentrates and is elutriant with methyl alcohol/EtOAc of EtOAc to 10%, carries out purification by flash chromatography, obtains the 0.186g titled reference compound.MS (EI) calculated value: M+1=504.2; Actual value: 504.4.

Embodiment 215

Steps A

[(3R)-and 1-(cis-2-azido-cyclohexyl) tetramethyleneimine-3-yl] t-butyl carbamate.At 0 ℃, to [(3R)-1-(2-hydroxy-cyclohexyl) tetramethyleneimine-3-yl] t-butyl carbamate (3.29g, 11.60mmol) and add in the mixture of triethylamine (3.23ml, 23.71) in methylene dichloride (20mL) MsCl (1.08ml, 12.86mmol).After stirring is spent the night under nitrogen, add entry and ethyl acetate.Water layer ethyl acetate extraction 3 times.Use MgSO ₄The dry organic layer that merges also concentrates.Residuum and sodiumazide in 20ml DMF and under 80 ℃ and nitrogen, stir and spend the night.Then with the ethyl acetate diluted reaction mixture and wash with water 3 times.Use MgSO ₄Dry organic layer and the concentrated 2.87g titled reference compound that obtains.MS (EI) calculated value: (M+1) ⁺=310.2; Actual value: 310.1.

Step B

(3R)-1-(cis-2-azido-cyclohexyl) tetramethyleneimine-3-amine.At room temperature, incite somebody to action [(3R)-and 1-(cis-2-azido-cyclohexyl) tetramethyleneimine-3-yl] (0.57g, 1.842mmol) mixture in 4N hydrochloric acid/dioxane (10ml) stirred 1 hour t-butyl carbamate.Concentrated solution obtains the 0.48g titled reference compound, is hydrochloride.MS (EI) calculated value: (M+H) ⁺=210.2; Actual value: 210.2.

Step C

N-(2-{[(3R)-1-(cis-2-azido-cyclohexyl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide.To (3R)-1-(cis-2-azido-cyclohexyl) tetramethyleneimine-3-amine (0.453g that stirs, 1.842mm0l) and (3-trifluoromethyl-benzamido)-acetate (0.478g, 1.934mmol) add triethylamine (0.57ml in the mixture in methylene dichloride (15mL), 4.06mmol), then add EDC (0.389g, 2.03mmol) and HOBt (0.287g, 2.13mmol).At room temperature stirred the mixture 3 hours.Then with the ethyl acetate diluted reaction mixture and with saturated sodium carbonate and salt water washing.Use MgSO ₄Dry organic layer concentrates and is elutriant with methyl alcohol/EtOAc of EtOAc to 10%, carries out purification by flash chromatography, obtains the 0.745g titled reference compound.MS (EI) calculated value: (M+H) ⁺=439.3; Actual value: 439.4.

Step D

N-(2-{[(3R)-1-(cis-2-aminocyclohexyl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide.In Parr hydrogenation bottle, add N-(2-{[(3R)-1-(cis-2-azido-cyclohexyl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide (0.745g, 1.70mmol) methyl alcohol (20ml) solution, then add 10%Pd/C (0.15g).Hydrogenated mixture spends the night under the hydrogen of 50psi.Use methanol wash after leaching catalyzer, concentrated filtrate obtains 0.70g N-(2-{[(3R)-1-(cis-2-aminocyclohexyl) tetramethyleneimine-3-yl under vacuum] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide.MS (EI) calculated value: (M+H) ⁺=413.2; Actual value: 413.3.

Step e

N-[2-((3R)-and 1-[cis-2-(benzamido) cyclohexyl] tetramethyleneimine-3-yl } amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide.To N-(2-{[(3R)-1-(cis-2-aminocyclohexyl) tetramethyleneimine-3-yl that stirs] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide (0.48g, 0.6mmol) and phenylformic acid (0.088g, 0.72mmol) add triethylamine (0.25ml in the mixture in methylene dichloride (5mL), 1.8mmol), then add EDC (0.138g, 0.72mmol) and HOBt (0.097g, 0.72mmol).At room temperature stirred the mixture 3 hours.Then with the ethyl acetate diluted reaction mixture and with saturated sodium carbonate and salt water washing.Use MgSO ₄Dry organic layer concentrates and is elutriant with methyl alcohol/EtOAc of EtOAc to 10%, carries out purification by flash chromatography, obtains the 0.13g titled reference compound.MS (EI) calculated value: (M+H) ⁺=517.2; Actual value: 517.3.

Embodiment 216

The N-{2-oxo-2-[((3R)-1-{ cis-2-[(phenyl acetyl) amino]-cyclohexyl } tetramethyleneimine-3-yl) amino] ethyl }-3-(trifluoromethyl) benzamide.Method according to embodiment 215 prepares titled reference compound.MS (EI) calculated value: (M+H) ⁺=531.3; Actual value: 531.3.

Embodiment 217

N-[2-((3R)-and 1-[cis-2-(benzylamino) cyclohexyl] tetramethyleneimine-3-yl } amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide.To phenyl aldehyde (0.061ml, 0.6mmol) and N-(2-{[(3R)-1-(cis-2-aminocyclohexyl) tetramethyleneimine-3-yl] amino-the 2-oxoethyl)-3-(trifluoromethyl) benzamide (0.278g, 0.60mmol) add in the mixture in methylene dichloride (10mL) sodium triacetoxy borohydride (0.128g, 0.60mmol).Stir the mixture under room temperature and the nitrogen spend the night after, wash with the ethyl acetate diluted reaction mixture and with saturated sodium carbonate.With EtOAc aqueous layer extracted (3 *).Use MgSO ₄The dry organic layer that merges concentrates and with EtOAc to EtOAc: methyl alcohol: triethylamine=9: 1: 0.5 is an elutriant, carries out purification by flash chromatography, obtains the 0.21g titled reference compound.MS (EI) calculated value: (M+H) ⁺=503.3; Actual value: 503.4.

Embodiment 218

Steps A

8-(1,3-thiazoles-2-yl)-1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-alcohol.Under-78 ℃, nitrogen protection and stirring, ((1.0g is in THF 11.75mmol) (10ml) solution 12.92mmol) to add thiazole for 8.1ml, the hexane solution of 1.6M with n-butyllithium solution.Stirring is after 1 hour down at-78 ℃, and with 1, (1.84g, THF 11.75mmol) (10ml) solution are added in the lithiated compound and at-78 ℃ through syringe and stirred 3 hours down 4-cyclohexanedione list condensed ethandiol.Add water (5ml), and allow mixture be warmed to room temperature, use ethyl acetate extraction 3 times.Use MgSO ₄The dry organic layer that merges filters, and concentrates under the vacuum and through chromatogram purification, obtains 2.531g8-(1,3-thiazoles-2-yl)-1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-alcohol, productive rate 89%.MS (EI) calculated value (M+H) ⁺242.1, actual value 242.2.

Step B

4-hydroxyl-4-(1,3-thiazoles-2-yl) pimelinketone.Under 50 ℃, with 8-(1,3-thiazoles-2-yl)-1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-(1.0g, 4.14mmol) solution stirring in the HCl (1: 1) of 20mlTHF/3N is 1 hour for 8-alcohol.After being cooled to room temperature, use Na ₂CO ₃Treating mixture is to PH=8 and with ethyl acetate extraction three times.With the organic layer that the saturated nacl aqueous solution washing merges, use MgSO ₄Dry and concentrated 0.82g 4-hydroxyl-4-(1,3-thiazoles-2-yl) pimelinketone, the productive rate 99% of obtaining.MS (EI) calculated value: (M+H) ⁺=198.1; Actual value: 198.2

Step C

N-[2-((3R)-and 1-[4-hydroxyl-4-(1,3-thiazoles-2-yl) cyclohexyl] tetramethyleneimine-3-yl } amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide.To 4-hydroxyl-4-(1, the 3-thiazol-2-yl) pimelinketone (0.075g, 0.38mmol) and N-[2-oxo-2-(2-oxo-2-(3R) tetramethyleneimine-3-base is amino] and ethyl } amino) ethyl]-3-(trifluoromethyl) benzamide (0.10g, 0.317mmol) add in the mixture in 2% ethanol/dichloromethane (10mL) sodium triacetoxy borohydride (0.134g, 0.634mmol).Stir the mixture under room temperature and the nitrogen spend the night after, wash with the ethyl acetate diluted reaction mixture and with saturated sodium carbonate.With EtOAc aqueous layer extracted (3 *).Use MgSO ₄The dry organic layer that merges, concentrating and using 5% methyl alcohol/EtOAc/ triethylamine (1: 9: 0.5) with EtOAc then to methyl alcohol/EtOAc (1: 9) is elutriant, carries out purification by flash chromatography, obtains the 0.141g titled reference compound, productive rate is 90%.MS (EI) calculated value: (M+H) ⁺=497.2; Actual value: 497.3.

Embodiment 219

Steps A

8-(5-ethyl-1,3-thiazoles-2-yl)-1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-alcohol.Under-78 ℃, nitrogen protection and stirring, (5.70ml, the hexane solution of 1.6M 9.12mmol) add 8-(1,3-thiazoles-2-yl)-1, and 4-dioxo spiro ring [4.5] last of the ten Heavenly stems-(1.00g is in THF 4.14mmol) (10ml) solution for 8-alcohol with n-butyllithium solution.Stirring is after 1 hour down at-78 ℃, and (0.736ml 9.12mmol) is added in the lithiated compound through syringe with iodic ether under-78 ℃.Allow mixture slowly be warmed to room temperature and stirring is spent the night.Add entry and ethyl acetate.With ethyl acetate extraction water 3 times (3 *).With the organic layer that saturated NaCl washing merges, use MgSO ₄Drying concentrates and with 20% ethyl acetate/hexane wash-out, carries out purification by flash chromatography, obtains the 0.79g titled reference compound, productive rate 71%.MS calculated value (M+H) ⁺270.1, actual value 270.1.

Step B

4-(5-ethyl-1,3-thiazoles-2-yl)-4-hydroxy-cyclohexanone.According to the method for embodiment 218 step B, prepare titled reference compound by the ketal of steps A.MS (EI) calculated value: (M+H) ⁺=226.1; Actual value: 226.2.

Step C

N-[2-((3R)-and 1-[4-(5-ethyl-1,3-thiazoles-2-yl)-4-hydroxy-cyclohexyl] tetramethyleneimine-3-yl } amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide.According to embodiment 218 methods, prepare titled reference compound by the ketone of step B.MS (EI) calculated value: (M+H) ⁺=525.2; Actual value: 525.2.

Embodiment 220

Steps A

2-(8-hydroxyl-1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-yl)-1,3-thiazoles-4-formic acid.Under-78 ℃, nitrogen protection and stirring, with n-butyllithium solution (17.1ml, the hexane solution of 1.6M; 27.35mmol) adding 8-(1; the 3-thiazol-2-yl)-1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-(3.00g is in THF 12.43mmol) (50ml) solution for 8-alcohol.-78 ℃ down stir 1 hour after, (10g 227mmol) is added in the lithiated compound and at-78 ℃ and stirred 2 hours down with dry ice.Add entry and allow mixture be warmed to room temperature.Then with 1N hydrochloric acid treating mixture to pH be 3 to 4 and with ethyl acetate extraction 3 times.With the organic layer that the saturated nacl aqueous solution washing merges, use MgSO ₄Drying concentrates and with ethyl acetate to 1% ethanol/eluent ethyl acetate chromatogram, obtains 3.23g2-(8-hydroxyl-1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-yl)-1,3-thiazoles-4-formic acid.MS calculated value (M+H) ⁺286.1; Actual value: 286.0.

Step B

2-(8-hydroxyl-1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-yl)-1,3-thiazoles-4-methane amide.To 2-(the 8-hydroxyl-1 that stirs, 4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-yl)-1,3-thiazole-4-formic acid (0.30g, 1.05mmol) and methylamine (the THF solution of 2M, 2ml 4mmol) add triethylamine (0.5ml in the mixture in methylene dichloride (10mL), 3.6mmol), then add EDC (0.242g, 1.262mmol) and HOBt (0.193g, 1.26mmol).At room temperature stir the mixture and spend the night.Then with the ethyl acetate diluted reaction mixture and with saturated sodium carbonate and salt water washing.Use MgSO ₄Dry organic layer concentrates and is elutriant with 50%EtOAc to EtOAc, carries out purification by flash chromatography, obtains the 0.16g titled reference compound, yield 50%.MS (EI) calculated value: (M+H) ⁺=299.1; Actual value: 299.0.

Step C

2-(1-hydroxyl-4-oxo cyclohexyl)-N-methyl isophthalic acid, the 3-thiazole-4-carboxamide.Prepare titled reference compound according to embodiment 218 methods by the ketal of step B.MS (EI) calculated value: (M+H) ⁺=255.1; Actual value: 255.0.

Step D

2-(1-hydroxyl-4-{ (3R)-3-[({[3-(trifluoromethyl) benzoyl] amino } ethanoyl) amino] tetramethyleneimine-1-yl } cyclohexyl)-the N-methyl isophthalic acid, 3-thiazole-5-benzamide.Prepare titled reference compound according to embodiment 218 methods by the ketone of step C.MS (EI) calculated value: (M+H) ⁺=554.2; Actual value: 554.1.

Embodiment 221

Steps A

8-(1,3-thiazoles-5-yl)-1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-alcohol.(2.5g, (11.9ml, the hexane solution of 1.6M is in THF 19.07mmol) (20ml) solution 15.89mmol) to be added to n-Butyl Lithium with the 2-TMS-thiazole under-78 ℃ and nitrogen protection.Stirring is after 0.5 hour down at-78 ℃, and under-78 ℃, with 1, (2.48g, THF 15.89mmol) (20ml) solution are added in the lithiated compound and at-78 ℃ through syringe and stirred 1 hour down 4-cyclohexanedione list condensed ethandiol.Add entry (5ml) and ethyl acetate, allow reaction mixture be warmed to room temperature and with 3 times (3 *) of EtOAc extraction.Use MgSO ₄The dry organic layer that merges, filter and from ethyl acetate crystallization obtain 3.4g 8-(1,3-thiazoles-5-yl)-1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-alcohol, productive rate 90%.MS calculated value: (M+H) ⁺=242.1; Actual value: 242.1.

Step B

3-(trifluoromethyl)-N-[2-((3R)-and 1-[4-hydroxyl-4-(1,3-thiazoles-5-yl) cyclohexyl] tetramethyleneimine-3-yl } amino)-the 2-oxoethyl] benzamide.According to embodiment 218 methods by 8-(1,3-thiazoles-5-yl)-1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-alcohol preparation titled reference compound.MS (EI) calculated value: (M+H) ⁺497.1; Actual value: 497.1.

Embodiment 222

Steps A

[5-(8-hydroxyl-1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-yl)-1,3-thiazoles-2-yl] Urethylane.Under-78 ℃, nitrogen protection and stirring, (15.93mmol) solution is added to 1,3-thiazoles-2-aminocarbamic acid methyl esters (1.05g is in THF 6.64mmol) (10ml) solution for 10.0ml, the hexane solution of 1.6M with n-Butyl Lithium.Stirring is after 1 hour down at-78 ℃, and with 1, (1.84g, THF 11.75mmol) (10ml) solution is added in the lithiated compound through syringe 4-cyclohexanedione list condensed ethandiol under-78 ℃.Allow reaction mixture slowly be warmed to room temperature and stirring is spent the night.Add entry and ethyl acetate, with EtOAc aqueous layer extracted 3 times (3 *).With the organic layer that the saturated nacl aqueous solution washing merges, use MgSO ₄Dry, concentrate and obtain 0.744g titled reference compound, productive rate 51% with chromatogram purification (50% ethyl acetate/hexane to 75% ethyl acetate/hexane wash-out).MS calculated value: (M+H) ⁺=315.1; Actual value: 315.0.

Step B

[5-(1-hydroxyl-4-oxo cyclohexyl)-1,3-thiazoles-2-yl] Urethylane.Prepare titled reference compound according to the method for embodiment 218 step B by the ketal of steps A.MS (EI) calculated value: (M+H) ⁺=270.1; Actual value: 270.0.

Step C

[5-(1-hydroxyl-4-{ (3R)-3-[({[3-(trifluoromethyl) benzoyl] amino } ethanoyl) amino] tetramethyleneimine-1-yl } cyclohexyl)-1,3-thiazoles-2-yl] Urethylane.Prepare titled reference compound according to the method for embodiment 218 by the ketone of step B.MS (EI) calculated value: (M+H) ⁺569.2; Actual value: 569.1.

Embodiment 223

Steps A

2-sec.-propyl-1,3-thiazoles.(1.8g, methyl alcohol 14.38mmol) (25ml) solution then adds Pd (OH) to add 2-pseudoallyl-1,3-thiazoles in Parr hydrogenation bottle ₂(0.6g).Hydrogenated mixture is 48 hours under the hydrogen of 50psi.Use methanol wash after leaching catalyzer, concentrated filtrate obtains 1.65g 2-sec.-propyl-1,3-thiazoles under vacuum.MS (EI) calculated value: (M+H) ⁺=128.1; Actual value: 128.0.

Step B

8-(2-sec.-propyl-1,3-thiazoles-5-yl)-1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-alcohol.According to the method for embodiment 221 steps A intermediate preparation titled reference compound by steps A.MS (EI) calculated value: (M+H) ⁺=284.1; Actual value: 284.2.

Step C

4-hydroxyl-4-(2-sec.-propyl-1,3-thiazoles-5-yl) pimelinketone.At room temperature, will be at the 8-in the 15mlTHF/1N hydrochloric acid (1: 1) (2-sec.-propyl-1,3-thiazoles-5-yl)-1, (0.714g 2.52mmol) stirred and spent the night 4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-alcohol.To regulate PH be 8 and extract with EtOAc (3 *) with sodium carbonate solution.With the organic layer of saturated nacl aqueous solution washing merging, through MgSO ₄Dry and concentrated, obtain 0.65g (productive rate 98%) 4-hydroxyl-4-(2-sec.-propyl-1,3-thiazoles-5-yl) pimelinketone.MS (EI) calculated value: (M+H) ⁺=240.1; Actual value: 240.0.

Step D

N-[2-((3R)-and 1-[4-hydroxyl-4-(2-sec.-propyl-1,3-thiazoles-5-yl) cyclohexyl] tetramethyleneimine-3-yl } amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide.In Parr hydrogenation bottle, add 4-hydroxyl-4-(2-sec.-propyl-1,3-thiazole-5-yl) pimelinketone (0.363g, 1.52mmol) and N-[2-oxo-2-(the 2-oxo-2-[(3R)-tetramethyleneimine-3-base is amino] ethyl } amino) ethyl]-3-(trifluoromethyl) benzamide (0.435g, 1.38mmol) methylene dichloride (20ml) solution, then add 10%Pd (OH) ₂(0.8g).Hydrogenated mixture is 24 hours under the hydrogen of 50psi.Use methanol wash after leaching catalyzer, concentrated filtrate obtains the 0.345g titled reference compound under vacuum, productive rate 62%.MS (EI) calculated value: (M+1) ⁺=539.2; Actual value: 539.1.

Embodiment 224

Steps A

8-(5-pyridin-3-yl-1,3-thiazoles-2-yl)-1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-alcohol.Under-78 ℃, nitrogen protection and stirring, (12.45mmol) solution is added to 8-(1,3-thiazoles-5-yl)-1 for 7.8ml, the hexane solution of 1.6M, and 4-dioxo spiro ring [4.5] last of the ten Heavenly stems-(1.0g is in THF 4.15mmol) (20ml) solution for 8-alcohol with n-Butyl Lithium.After stirring 0.5 hour under-78 ℃, add the THF solution of the zinc chloride (6.23mmol) of 12.5ml 0.5M.At room temperature stir the mixture 0.5 hour of gained, and with the 3-bromopyridine (0.40ml, 4.15mmol) and PdCl ₂(PPh ₃) ₂(0.11g, 0.16mmol) mixture in THF (5ml) adds through syringe.After backflow is spent the night, with the described reactant of 10ml ammonium chloride solution quencher.With 3 times (3 *) of EtOAc extraction.Use MgSO ₄The dry organic layer that merges filters, and concentrates under vacuum and uses chromatogram purification, obtains the 0.68g titled reference compound, productive rate 52%.MS (EI) calculated value: (M+H) ⁺=319.1; Actual value: 319.1.

Step B

N-[2-((3R)-and 1-[4-hydroxyl-4-(5-pyridin-3-yl-1,3-thiazoles-2-yl) cyclohexyl] tetramethyleneimine-3-yl } amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide.Prepare titled reference compound according to the method for embodiment 218 step B by the ketal of steps A.MS (EI) calculated value: (M+H) ⁺574.2; Actual value: 574.1.

The method of describing with similar embodiment 218-224 prepares the following example.

Embodiment #	R	MS(M+H) ⁺
Embodiment #	R	MS(M+H) ⁺	225	5-(morpholine-4-base carbonyl)-1,3-thiazoles-2-base	610
226	5-aminocarboxyl-1,3-thiazoles-2-base	540	225	5-(morpholine-4-base carbonyl)-1,3-thiazoles-2-base	610
226	5-aminocarboxyl-1,3-thiazoles-2-base	540	227	5-dimethylamino carbonyl-1,3-thiazoles-2-base	568
228	5-(tetramethyleneimine-1-base carbonyl)-1,3-thiazoles-2-base	594	227	5-dimethylamino carbonyl-1,3-thiazoles-2-base	568
228		594	229	5-allyl group-1,3-thiazoles-2-base	536
230	5-propyl group-1,3-thiazoles-2-base	538	229	5-allyl group-1,3-thiazoles-2-base	536
230	5-propyl group-1,3-thiazoles-2-base	538	231	5-ethylamino carbonyl-1,3-thiazoles-2-base	568
232	5-phenyl-1,3-thiazoles-2-base	573	231	5-ethylamino carbonyl-1,3-thiazoles-2-base	568
232	5-phenyl-1,3-thiazoles-2-base	573	233	The 5-methyl isophthalic acid, the 3-thiazol-2-yl	511
234	5-hydroxymethyl-1,3-thiazoles-2-base	527	233	The 5-methyl isophthalic acid, the 3-thiazol-2-yl	511
234	5-hydroxymethyl-1,3-thiazoles-2-base	527	235	5-(1-hydroxyl-1-methylethyl)-1,3-thiazoles-2-base	555
236	5-methoxymethyl-1,3-thiazoles-2-base	541	235	5-(1-hydroxyl-1-methylethyl)-1,3-thiazoles-2-base	555
236	5-methoxymethyl-1,3-thiazoles-2-base	541	237	5-(pyridine-2-yl)-1,3-thiazoles-2-base	574
238	2-(pyridine-1-yl)-1,3-thiazoles-4-base	566	237	5-(pyridine-2-yl)-1,3-thiazoles-2-base	574
238	2-(pyridine-1-yl)-1,3-thiazoles-4-base	566	239	2-(morpholine-4-yl)-1,3-thiazoles-4-base	(M-H ₂O+H) ⁺＝564
240	The 2-methyl isophthalic acid, 3-thiazole-5-base	511	239	2-(morpholine-4-yl)-1,3-thiazoles-4-base	(M-H ₂O+H) ⁺＝564
240	The 2-methyl isophthalic acid, 3-thiazole-5-base	511	241	2-(1-hydroxyl-1-methylethyl)-1,3-thiazoles-5-base	555
242	2-(tetramethyleneimine-1-yl)-1,3-thiazoles-5-base	566	241	2-(1-hydroxyl-1-methylethyl)-1,3-thiazoles-5-base	555
242	2-(tetramethyleneimine-1-yl)-1,3-thiazoles-5-base	566	243	2-oxyethyl group-1,3-thiazoles-5-base	541
244	2-ethyl-1,3-thiazoles-5-base	525	243	2-oxyethyl group-1,3-thiazoles-5-base	541
244	2-ethyl-1,3-thiazoles-5-base	525	245	2-(tetramethyleneimine-1-ylmethyl)-1,3-thiazoles-5-base	580
246	2-(morpholine-4-yl)-1,3-thiazoles-5-base	582	245	2-(tetramethyleneimine-1-ylmethyl)-1,3-thiazoles-5-base	580
246	2-(morpholine-4-yl)-1,3-thiazoles-5-base	582	247	2-methoxymethyl-1,3-thiazoles-5-base	541
248	2-isobutyl--1,3-thiazoles-5-base	553	247	2-methoxymethyl-1,3-thiazoles-5-base	541
248	2-isobutyl--1,3-thiazoles-5-base	553	249	2-ethylamino carbonyl-1,3-thiazoles-5-base	568
250	2-(tetramethyleneimine-1-base carbonyl)-1,3-thiazoles-5-base	594	249	2-ethylamino carbonyl-1,3-thiazoles-5-base	568

251	2-(morpholine-4-base carbonyl)-1,3-thiazoles-5-base	610
251	2-(morpholine-4-base carbonyl)-1,3-thiazoles-5-base	610	252	2-(pyridin-3-yl)-1,3-thiazoles-5-base	574
253	2-(pyridine-2-yl)-1,3-thiazoles-5-base	574	252	2-(pyridin-3-yl)-1,3-thiazoles-5-base	574
253	2-(pyridine-2-yl)-1,3-thiazoles-5-base	574	254	The 4-methyl isophthalic acid, the 3-thiazol-2-yl	511
255	1,3-benzothiazole-2-base	547	254	The 4-methyl isophthalic acid, the 3-thiazol-2-yl	511

Embodiment 256

Steps A

2-(1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-7-alkene-8-yl)-1,3-thiazoles.Under 0 ℃ and nitrogen protection, to 8-(1,3-thiazoles-2-yl)-1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-alcohol (0.8g, add in pyridine 3.32mmol) (10ml) solution thionyl chloride (2.5ml, 34.3mmol).Under 0 ℃ and nitrogen, stir after 2 hours, add entry and ethyl acetate.With EtOAc aqueous layer extracted 3 times (3 *).The organic layer that the saturated nacl aqueous solution washing merges is used MgSO ₄Drying concentrates and is elutriant with 10% ethyl acetate/hexane, carries out chromatogram purification and obtains the 0.27g titled reference compound, productive rate 36%.MS calculated value: (M+1) ⁺=224.1; Actual value: 224.2.

Step B

2-(1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-yl)-1,3-thiazoles.(1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-7-alkene-8-yl)-(0.22g, methyl alcohol 0.99mmol) (15ml) solution then adds 10%Pd/C (0.08g) to 1,3-thiazoles to add 2-in Parr hydrogenation bottle.Hydrogenated mixture spends the night under the hydrogen of 50psi.Use methanol wash after leaching catalyzer, concentrated filtrate obtains 0.21g (yield 95%) 2-(1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-yl)-1,3-thiazoles under vacuum.MS (EI) calculated value: (M+1) ⁺=226.1; Actual value: 225.9.

Step C

4-(1,3-thiazoles-2-yl) pimelinketone.Under 50 ℃, will be in that the 2-in the 10ml THF/3N hydrochloric acid (1: 1) (1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-yl)-(0.21g 0.93mmol) stirs 2 hours 1,3-thiazoles.After being chilled to room temperature, extract with the sodium carbonate solution treating mixture and with EtOAc (3 *).With the organic layer of saturated nacl aqueous solution washing merging, through MgSO ₄Dry and concentrated, obtain 0.16g (productive rate 95%) 4-(1,3-thiazoles-2-yl) pimelinketone.MS (EI) calculated value: (M+H) ⁺=182.1; Actual value: 181.9.

Step D

N-[2-oxo-2-((3R)-and 1-[4-(1,3-thiazoles-3-yl) cyclohexyl] tetramethyleneimine-3-yl } amino) ethyl]-3-(trifluoromethyl) benzamide.To 4-(1, the 3-thiazol-2-yl) pimelinketone (0.069g, 0.38mmol) and N-[2-oxo-2-(the 2-oxo-2-[(3R)-tetramethyleneimine-3-base is amino] ethyl } amino) ethyl]-3-(trifluoromethyl) benzamide (0.10g, 0.32mmol) add in the mixture in 2% ethanol/dichloromethane (10ml) sodium triacetoxy borohydride (0.134g, 0.634mmol).After stirring under nitrogen and the room temperature is spent the night, wash with the ethyl acetate diluted reaction mixture and with saturated sodium carbonate.With EtOAc aqueous layer extracted 3 times (3 *).Use MgSO ₄The dry organic layer that merges concentrates and obtains the 0.129g titled reference compound, productive rate 85% through purification by flash chromatography [to methanol/ethyl acetate (1: 9), using methanol/ethyl acetate/triethylamine (1: 9: 0.5) of 5% then with ethyl acetate] wash-out.MS calculated value: (M+H) ⁺=480.2; Actual value: 480.3.

Embodiment 257

Steps A

2-(8-chloro-1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-yl)-5-(tetramethyleneimine-1-base carbonyl)-1,3-thiazoles.Under 0 ℃ and nitrogen protection, to 8-[-5-(tetramethyleneimine-1-base carbonyl)-1,3-thiazoles-2-yl]-1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-alcohol (0.2g, add in pyridine 3.32mmol) (3ml) solution thionyl chloride (0.5ml, 6.86mmol).Mixture is warmed to room temperature and stirring is spent the night.After reaction mixture concentrated, add entry and ethyl acetate.With EtOAc aqueous layer extracted 2 times (2 *).The organic layer that the saturated nacl aqueous solution washing merges is used MgSO ₄Drying concentrates and is elutriant with 50% ethyl acetate/hexane to ethyl acetate, carries out chromatogram purification and obtains the 0.10g titled reference compound, productive rate 53%.MS calculated value: (M+1) ⁺=356.1; Actual value: 357.0.

Step B

2-(1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-yl)-5-(tetramethyleneimine-1-base carbonyl)-1,3-thiazoles.(tetramethyleneimine-1-base carbonyl)-(0.095g, methyl alcohol 0.266mmol) (10ml) solution then adds 10%Pd/C (0.02g) to 1,3-thiazoles to add 2-(8-chloro-1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-yl)-5-in Parr hydrogenation bottle.Hydrogenated mixture spends the night under the hydrogen of 50psi.Use methanol wash after leaching catalyzer, concentrated filtrate obtains 0.083g (yield 97%) 2-(1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-yl)-5-(tetramethyleneimine-1-base carbonyl)-1,3-thiazoles under vacuum.MS (EI) calculated value: (M+H) ⁺=322.1; Actual value: 322.0.

Step C

4-[5-(tetramethyleneimine-1-base carbonyl)-1,3-thiazoles-2-yl] pimelinketone.Prepare titled reference compound according to the method for embodiment 256 step C by the ketal of step B.MS (EI) calculated value: (M+H) ⁺=279.1; Actual value: 279.0.

Step D

The N-{2-oxo-2-[((3R)-1-{4-[5-(tetramethyleneimine-1-base carbonyl)-1,3-thiazoles-2-yl] cyclohexyl } tetramethyleneimine-3-yl) amino] ethyl }-3-(trifluoromethyl) benzamide.Prepare titled reference compound according to embodiment 256 methods by the ketone of step C.MS (EI) calculated value: (M+H) ⁺=578.2; Actual value: 578.1.

With the synthetic the following examples of similar method.

Embodiment 258

N-[2-oxo-2-((3R)-and 1-[4-(2-thienyl) cyclohexyl] tetramethyleneimine-3-yl } amino) ethyl]-3-(trifluoromethyl) benzamide.MS (EI) calculated value: (M+H) ⁺=479.2; Actual value: 479.3.

Embodiment 259

3-(trifluoromethyl)-N-{2-[((3R)-1-{4-[5-(methoxymethyl)-1,3-thiazoles-2-yl] cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl } benzamide.MS (EI) calculated value: (M+H) ⁺525.2; Actual value: 525.2.

Embodiment 260

3-(trifluoromethyl)-N-{2-[((3R)-1-{4-[5-(morpholine-4-base carbonyl)-1,3-thiazoles-2-yl] cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl } benzamide.MS (EI) calculated value: (M+H) ⁺594.2; Actual value: 594.2.

Embodiment 261

Steps A

(3R)-and 1-[4-hydroxyl-4-(2-sec.-propyl-1,3-thiazoles-5-yl) cyclohexyl] tetramethyleneimine-3-yl } t-butyl carbamate.In Parr hydrogenation bottle, add 4-hydroxyl-4-(2-sec.-propyl-1,3-thiazole-5-yl) pimelinketone (0.50g, 2.09mmol) and (3R)-(0.373g, methylene dichloride 2.0mmol) (20ml) solution then adds 10%Pd/C (0.12g) to tetramethyleneimine-3-aminocarbamic acid tert-butyl ester.Hydrogenated mixture is 24 hours under the hydrogen of 35psi.Use methanol wash after leaching catalyzer, concentrated filtrate and with methanol/ethyl acetate/triethylamine (1: 9: 0.5) wash-out under vacuum carries out chromatogram purification, obtains the 0.62g titled reference compound.MS (EI) calculated value: (M+1) ⁺=409.2; Actual value: 410.2.

Step B

4-[(3R)-3-amino-pyrrolidine-1-yl]-1-(2-sec.-propyl-1,3-thiazoles-5-yl) hexalin.At room temperature, stir (3R)-1-[4-hydroxyl-4-(2-sec.-propyl-1,3-thiazoles-5-yl) cyclohexyl] tetramethyleneimine-3-yl } t-butyl carbamate (0.50g, 4N hydrochloric acid/dioxane (10ml) solution 1.22mmol) 1 hour.Concentrate the dihydrochloride that described solution obtains the 0.397g titled reference compound.MS (EI) calculated value: (M+1) ⁺=309.2; Actual value: 310.2.

Step C

N-{ (3R)-1-[4-hydroxyl-4-(2-sec.-propyl-1,3-thiazoles-5-yl) cyclohexyl] tetramethyleneimine-3-yl }-4-oxo-4-[3-(trifluoromethyl) phenyl] butyramide.To 4-[(3R)-3-amino-pyrrolidine-1-yl]-1-(2-sec.-propyl-1,3-thiazole-5-yl) hexalin 3 hydrochloride (0.233g, 0.557mmol) and 4-oxo-4-[3-(trifluoromethyl) phenyl] butyric acid (0.15g, 0.61mmol) add triethylamine (0.34ml in the mixture in DMF (5mL), 2.44mmol), then add BOP (0.296g, 0.67mmol).At room temperature stir the mixture and spend the night.Then with the ethyl acetate diluted reaction mixture and with saturated sodium carbonate and salt water washing.Use MgSO ₄Dry organic layer concentrates and is elutriant with methyl alcohol/EtOAc of EtOAc to 10%, carries out purification by flash chromatography, obtains the 0.075g titled reference compound.MS (EI) calculated value: (M+H) ⁺=538.2; Actual value: 538.1.

With the synthetic the following example of similar method.

Embodiment 262

4-[3-(trifluoromethyl) phenyl]-N-((3R)-1-{4-hydroxyl-4-[5-(methoxymethyl)-1,3-thiazoles-2-yl] cyclohexyl } tetramethyleneimine-3-yl)-4-oxo butyramide.MS (EI) calculated value: (M+H) ⁺540.2; Actual value: 540.2.

Embodiment 263

Embodiment 264

N-((3R)-1-{4-hydroxyl-4-[5-(methoxymethyl)-1,3-thiazoles-2-yl]-4-hydroxyl-cyclohexyl } tetramethyleneimine-3-yl)-4-[3-(trifluoromethyl) phenyl] butyramide.To N-((3R)-1-{4-hydroxyl-4-[5-(methoxymethyl)-1, the 3-thiazol-2-yl] cyclohexyl } tetramethyleneimine-3-yl)-4-oxo-4-[3-(trifluoromethyl) phenyl] butyramide (19.2mg, 0.036mol) methyl alcohol (1.0ml) solution in add Sodium Borohydride (2.7mg, 0.071mmol) and stirred the mixture 1 hour.Use the preparation HPLC purified mixture, water/CH ₃The CN/0.05%TFA wash-out obtains required compound, is two kinds of non-enantiomer mixtures (10mg, purity 99.7%).LCMS：542.2(M+H ⁺，100％)； ¹HNMR(CD ₃OD)δ7.70(s，1H)，7.63-7.53(m，4H)，4.80-4.77(m，1H)，4.65(s，2H)，4.4(m，1H)，3.96-3.93(m，1H)，3.84-3.72(m，1H)，3.57-3.49(m，1H)，3.38(s，3H)，3.24-3.12(m，0.5H)，3.10-3.06(m，0.5H)，2.53-2.51(m，0.5H)，2.36-2.31(m，4.5H)，2.19(s，2H)，2.09-1.99(m，6H)，1.92-1.86(m，2H)。

Embodiment 265

Steps A

[(3-trifluorophenyl) alkylsulfonyl] hydrogen guanidine-acetic acid.In 0 ℃, 5 minutes, the glycine among Xiang Zaishui (30ml) and the THF (30ml) (0.75g, 10mmol) divide in the solution several parts add 3-(trifluoromethyl) benzene sulfonyl chlorides (2.44g, 10mmol).After adding, at room temperature the restir reaction mixture is 0.5 hour, then further cools off with ice bath.With concentrated hydrochloric acid reaction mixture being acidified to pH is 1 o'clock, extracts crude product with EtOAc.Merge organic extract,, use dried over sodium sulfate, under vacuum, concentrate, form white viscous solid precipitation with salt solution (50ml) washing.Product aqueous ethanolic solution recrystallization obtains required [(3-trifluorophenyl) alkylsulfonyl] Padil compound (58%), for having the white crystalline solid of following feature.LCMC：282.2(M-H) ^-。

Step B

N-((3R)-1-{4-[5-(methoxymethyl)-1,3-thiazoles-2-yl]-the 4-hydroxy-cyclohexyl } tetramethyleneimine-3-yl)-2-({ [3-(trifluoromethyl) phenyl] sulphonyl } amino) ethanamide.Under 0 ℃, to ({ [3-(trifluoromethyl) phenyl] sulphonyl } amino) acetate (64mg in DMF (5mL), 0.22mmol) and 4-[(3R)-3-amino-pyrrolidine-1-yl]-1-[5-(methoxymethyl)-1, the 3-thiazol-2-yl] cyclohexanol dihydrochloride salt (72mg, 0.19mmol) add TEA (38mg in the solution, 0.38mmol) and BOP (benzotriazole-1-base oxygen base) three (dimethylamino) phosphonium hexafluorophosphate (99mg, 0.22mmol).Stirred reaction mixture 2 hours, water (5ml) quencher and with ethyl acetate extraction (2 * 25ml).Merge organic extract,, use dried over sodium sulfate, under vacuum, concentrate with salt solution (10mL) washing.Residuum is an elutriant with the ethyl acetate solution/methyl alcohol (100/0 to 90/10) of 1% ammonium hydroxide, carries out chromatogram purification.Merge suitable elution fraction, obtain two kinds of isomer (1: 1) of required compound, have following feature MS:577.4 (M+H ⁺, 100%).

Embodiment 266

Steps A

3-(trifluoromethyl) benzaldoxime.To be equipped with 3-trifluro benzaldehyde in methyl alcohol (25mL) (1.74g, 10mmol) and oxammonium hydrochloride (0.76g, 11mmol) add in the flask of solution TEA (0.65g, 11mmol).Heating reflux reaction mixture 3 hours is neutralized to pH and is 6.0 and with ethyl acetate extraction (3 * 20ml).Merge organic extract,, use dried over sodium sulfate, under vacuum, concentrate 3-(trifluoromethyl) benzaldoxime (1.9g) that obtains colorless oil with salt solution (20ml) washing.LCMS：190.2(M+H ⁺，100％)。

Step B

N-hydroxyl-3-(trifluoromethyl) benzene imido acyl chloride.Under 0 ℃, slowly to be equipped with 3-(trifluoromethyl) benzaldoxime in methylene dichloride (100mL) (1.89g, add in dry flask 10mmol) N-chloro-succinimide (1.40g, 10.5mmol).With reaction mixture be warmed to 45 ℃ following 2 hours, be poured on ice water (20ml) dilution and with ethyl acetate extraction (100ml).Water (2 * 25ml) and the organic phase that merges of salt brine solution (25ml) washing, use dried over sodium sulfate, concentratedly under vacuum can obtain N-hydroxyl-3-(trifluoromethyl) benzene imido acyl chloride (2g, 90%).LCMS：224.4(M+H) ⁺。

Step C

3-[3-(trifluoromethyl) phenyl]-4,5-dihydro-isoxazole-5-methyl-formiate.Under 0 ℃ and inert atmosphere, to be equipped with N-hydroxyl-3-(trifluoromethyl) benzene imido acyl chloride in methylene dichloride (100mL) (2g, 8.9mmol) and methyl acrylate (0.7g, 8mmol) add in the flask of solution TEA (0.90g, 8.8mmol).Reaction mixture slowly is warmed to room temperature, stirred 20 hours, water (30ml) quencher and with dichloromethane extraction (2 * 50ml).Merge organic extract, wash with salt solution (50ml), use dried over sodium sulfate, under vacuum, concentrate and with methylene chloride (100/1 to 95/5) wash-out on silica gel, merge suitable elution fraction and vacuum concentration, obtain 3-[3-(trifluoromethyl) phenyl]-4,5-dihydro-isoxazole-5-methyl-formiate (2.3g, 100%): LCMS:274.2 (M+H ⁺, 100%); ¹HNMR (CDCl ₃) δ 8.03 (s, 1H), 7.92 (d, 1H), 7.71 (d, 1H), 7.59 (dd, 1H), 5.28 (dd, 1H), 3.86 (s, 3H), 3.71 (dd, 2H).

Step D

3-[3-(trifluoromethyl) phenyl]-4,5-dihydro-isoxazole-5-formic acid.Under 0 ℃, to 3-[3-(trifluoromethyl) phenyl in THF (10mL)]-4,5-dihydro-isoxazole-5-methyl-formiate (2.3g, 8.4mmol) the middle 2M aqueous sodium hydroxide solution (10ml) that adds.Reaction mixture slowly is warmed to room temperature, stirred 2 hours, being neutralized to pH with 2N hydrochloric acid is 7, and with ethyl acetate extraction (2 * 50ml).Merge organic extract,, use dried over sodium sulfate, under vacuum, concentrate with salt brine solution (50ml) washing.Residuum is an elutriant with methylene chloride (95/5 to 80/20), carries out the silica gel chromatography purifying.Merge suitable elution fraction and under vacuum, concentrate, obtain 3-[3-(trifluoromethyl) phenyl]-4, the white crystal solid of 5-dihydro-isoxazole-5-formic acid (2.18g, 100%): LCMS:258.2 (M-H ^-, 100%).

Step e

N-((3R)-1-{4-hydroxyl-4-[2-(methoxymethyl)-1,3-thiazoles-5-yl] cyclohexyl } tetramethyleneimine-3-yl)-3-[3-(trifluoromethyl) phenyl]-4,5-dihydro-isoxazole-5-methane amide.To the 4-[(3R in DMF (5mL))-3-amino-pyrrolidine-1-yl]-1-[2-(methoxymethyl)-1,3-thiazole-4-yl] cyclohexanol dihydrochloride salt (90.0mg, 0.234mmol) middle 3-[3-(trifluoromethyl) phenyl that adds]-4,5-dihydro-isoxazole-5-formic acid (60.7mg, 0.234mmol), N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride (49.4mg, 0.258mmol) and TEA (28.4mg, 0.281mmol).Reaction mixture was stirred 2 hours, water (5ml) quencher, and with ethyl acetate extraction (2 * 25ml).Merge organic extract,, use dried over sodium sulfate, under vacuum, concentrate with salt brine solution (10ml) washing.Residuum is an elutriant with methylene chloride (100/0 to the 90/10) solution of 1% ammonium hydroxide, carries out the silica gel chromatography purifying.Merge cis and trans-isomer(ide) that suitable elution fraction obtains 1: 1.Every kind of isomer is further used HPLC purifying, water/CH ₃CN/TFA (10/90/0.05 to 100/0/0.05) wash-out, obtain N-((3R)-1-{4-hydroxyl-4-[2-(methoxymethyl)-1,3-thiazole-5-yl] cyclohexyl } tetramethyleneimine-3-yl)-3-[3-(trifluoromethyl) phenyl]-4, the white solid of the tfa salt of 5-dihydro-isoxazole-5-methane amide (gross weight is 40mg, 31%).LCMS：553(M+H ⁺，100％)。Each elution fraction shows that on analysis mode HPLC two peaks (1: 1) and purity are greater than 95%.

Embodiment 267

(4Z) and (4E)-4-(oxyimino)-N-((3R)-1-{4-hydroxyl-4-[5-(methoxymethyl)-1,3-thiazoles-2-yl] cyclohexyl } tetramethyleneimine-3-yl)-4-[3-(trifluoromethyl) phenyl] butyramide.To ((the 3R)-1-{4-hydroxyl-4-[5-(methoxymethyl)-1 of the N-in methyl alcohol (1.0mL), the 3-thiazol-2-yl] cyclohexyl } tetramethyleneimine-3-yl)-4-oxo-4-[3-(trifluoromethyl) phenyl] butyramide (19.2mg, 0.036mmol) the middle oxammonium hydrochloride (9.9mg that adds, 0.14mmol) and TEA (14mg, 0.14mmol).Allow reaction mixture refluxed after 4 hours, enriched mixture and with residuum purifying on preparation HPLC, water/CH ₃The CN/0.05%TFA wash-out obtains the tfa salt (15mg, purity is 97%) of required compound.LCMS：555.2(M+H) ⁺。 ¹HNMR：(CD ₃OD)δ7.98(s，1H)，7.92(m，1H)，7.67-7.55(m，3H)，4.64(s，2H)，4.31(m，1H)，3.86-3.66(m，2H)，3.50-3.45(m，1H)，3.44(s，3H)，3.20(m，0.5H)，3.11(m，2H)，2.98(m，0.5H)，2.51(m，3H)，2.33(m，2H)，2.16(s，2H)，1.97(m，4H)，1.84(m，2H)。

Embodiment 268

(4Z) and (4E)-4-(ethoxy imino)-N-((3R)-1-{4-hydroxyl-4-[5-(methoxymethyl)-1,3-thiazoles-2-yl] cyclohexyl } tetramethyleneimine-3-yl)-4-[3-(trifluoromethyl) phenyl] butyramide.Method with similar embodiment 267 prepares titled reference compound.MS(M+H) ⁺583.2。

Embodiment 269

N-[2-((3R)-and 1-{4-fluoro-4-(1,3-thiazoles-2-yl) cyclohexyl } tetramethyleneimine-3-yl } amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide.Under-78 ℃, nitrogen protection and stirring; to N-[2-((3R)-1-{4-hydroxyl-4-(1; the 3-thiazol-2-yl) cyclohexyl } tetramethyleneimine-3-yl } amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide (0.06g; 0.12mmol) methylene dichloride (5ml) solution in add DAST (0.2ml, 1.5mmol).Allow solution slowly be warmed to 0 ℃ and stirred 1 hour.Add entry and ethyl acetate.With ethyl acetate extraction water 3 times (3 *).With the organic layer that the saturated nacl aqueous solution washing merges, use MgSO ₄Drying concentrates and with flash chromatography and reversed-phase HPLC purifying, obtains the 0.020g titled reference compound, productive rate 31%.MS (EI) (M+H) ⁺499.2; Actual value: 499.1.

With the synthetic following embodiment of similar method.

Embodiment 270

N-(2-{[(3R)-1-(4-fluoro-4-pyridin-3-yl cyclohexyl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide.MS(M+H) ⁺493.2。

Embodiment 271

N-[2-((3R)-and 1-[4-fluoro-4-(6-methoxypyridine-3-yl) cyclohexyl] tetramethyleneimine-3-yl } amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide.MS(M+H) ⁺523.2。

Embodiment 272

N-[2-((3R)-[(1-{4-fluoro-4-[6-(1,3-oxazole-2-yl) pyridin-3-yl] cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide.MS(M+H) ⁺560。

Embodiment 273

N-(2-{[(3R)-1-(4-fluoro-4-{4-[(methylamino) carbonyl] phenyl } cyclohexyl)-tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide.MS calculated value (M+H) ⁺549, actual value 549.

Embodiment 274

Steps A

8-pyrimidine-5-base-1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-alcohol.Under-78 ℃, nitrogen protection and stirring, (4.32ml, the hexane solution of 1.6M add 5-bromo pyrimi piperidine (1.0g, THF 6.29mmol) (10ml) solution in 6.92mmol) to n-butyllithium solution.Stirring is after 1 hour down at-78 ℃, and with 1, (0.982g, THF 6.29mmol) (10ml) solution are added in the lithiated compound and at-78 ℃ through syringe and stirred 4 hours down 4-cyclohexanedione list condensed ethandiol.Add water (5ml), and allow mixture be warmed to room temperature ethyl acetate extraction water 3 times (3 *).Use MgSO ₄The dry organic layer that merges filters, and concentrates under the vacuum and through chromatogram purification, obtains 0.18g 8-pyrimidine-5-base-1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-alcohol, productive rate 12%.MS (EI) calculated value (M+H) ⁺=237.1, actual value 237.2.

Step B

4-hydroxyl-4-pyrimidine-5-basic ring hexanone.At room temperature, will be at the 8-pyrimidine-5-base-1 among the HCl (1: 1) of 10mlTHF/1N, 4-dioxo spiro ring [4.5] last of the ten Heavenly stems-(0.14g, 0.59mmol) solution stirring is 24 hours for 8-alcohol.Use Na ₂CO ₃Treating mixture is to PH=8 and with ethyl acetate extraction three times.With the organic layer that the saturated nacl aqueous solution washing merges, use MgSO ₄Dry and concentrated 0.11g 4-hydroxyl-4-pyrimidine-5-basic ring hexanone, the productive rate 79% of obtaining.MS (EI) calculated value: (M+H) ⁺=192.1; Actual value: 192.1.

Step C

N-(2-{[(3R)-1-(4-hydroxyl-4-pyrimidine-5-basic ring hexyl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide.Prepare titled reference compound according to being similar to method that embodiment 218 describes ketone by step B.MS (EI) calculated value: (M+H) ⁺=492.2; Actual value: 492.2.

Embodiment 275

Steps A

8-pyrimidine-2-base-1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-alcohol.Under-78 ℃, with n-butyllithium solution (240mmol, 150ml) add 2-stannyl pyrimidine (200mmol, 80g) (as preparation that document is described, Tetrahedron, 1994,50,275-284) in THF (1L) solution.-78 ℃ of following reaction stirred 30 minutes and add 1, and 4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-alcohol (200mmol, 30g).Reactant is warmed to room temperature to be stirred simultaneously and spends the night.With the described reactant of ammonium chloride quencher and with ethyl acetate extraction (3 * 400ml).Merge organic layer, use MgSO ₄Concentrate under drying and the vacuum.Crude product is used for next step reaction.

Step B

4-hydroxyl-4-pyrimidine-2-base pimelinketone.With the product of steps A (190mmol, THF 44g) (200ml) add hydrochloric acid soln (300mmol, 100ml) in.Reaction stirred 2 days is used ether washing reaction thing thereafter.Use NaOH (50%) quencher water layer to make that pH is 11 then.With ethyl acetate extraction water layer (6 * 300ml).Merge organic layer, use MgSO ₄Dry and concentrated under vacuum.Residuum obtains required ketone (18g, 49%) through chromatogram purification.MS[M+H] ⁺193.1。

Step C

N-{[(R)-1-(4-hydroxyl-4-pyrimidine-2-base-cyclohexyl)-tetramethyleneimine-3-base formamyl]-methyl }-3-trifluoromethyl-benzamide.Product (62mmol to step C, add N-((3R)-tetramethyleneimine-3-base carbamoyl methyl)-3-trifluoromethyl-benzamide (60mmol in methylene dichloride 12g) (500ml), 20g), then add sodium triacetoxy borohydride (100mmol, 30g).Reaction stirred 2 hours uses NaOH (2M) quencher water layer to make that pH is 11 then.With dichloromethane extraction reaction mixture (3 * 300ml).Merge organic layer, use MgSO ₄Dry then concentrated under vacuum.Residuum through purification by flash chromatography to separate two kinds of diastereomers, then with the HPLC purifying to obtain required amine diastereomer.MS[M+H] ⁺492.1。

Embodiment 276

Steps A

8-pyridazine-3-base-1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-alcohol.Under-78 ℃, to pyridazine (17.7mmol adds 2,2,6 in THF 1.28ml) (60ml) solution, 6-tetramethyl piperidine lithium solution (71mmol, 10g).Stir described reactant then 6 minutes and added 1, and 4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-ketone (71mmol, 11g).-78 ℃ of following reaction stirred 5 hours, use the described reactant of ethanol, hydrochloric acid and THF (30ml 1: 1: 1) solution quencher then.Reactant is warmed to room temperature and uses the ethyl acetate extraction reaction mixture.Merge organic layer, use MgSO ₄Dry.Then residuum through purification by flash chromatography with obtain required alcohol (44%, 1.84g).MS[M+H] ⁺2371。

Step B

4-hydroxyl-4-pyridazine-3-basic ring hexanone.With the product of steps A (7.79mmol, THF 1.84g) (15ml) add HCl (45mmol, 15ml) in.Reaction stirred is spent the night, then with yellow soda ash quencher reactant.With ethyl acetate extraction reactant (3 * 100ml).Merge organic layer, dry and concentrated to obtain required ketone (780mg, 52%) under vacuum.MS[M+H] ⁺193.1。

Step C

N-[2-((3R)-and 1-(4-hydroxyl-4-pyridazine-3-base-cyclohexyl) tetramethyleneimine-3-yl } amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide.Product (1.19mmol to step B, add N-((3R)-tetramethyleneimine-3-base carbamoyl methyl)-3-trifluoromethyl-benzamide (1.19mmol in methylene dichloride 215mg) (10ml) solution, 375mg), then add sodium triacetoxy borohydride (2.38mmol, 504mg) and reaction stirred 4 hours, use NaOH (1M) quencher then.Use the dichloromethane extraction water layer.Merge organic layer, then with the salt water washing and use MgSO ₄Dry.Under vacuum, concentrate organic layer, behind flash chromatography and HPLC purifying, obtain required amine diastereomer (17%, 10mg).MS[M+H] ⁺492.1。

Embodiment 277

N-(2-{[(3R)-1-(4-hydroxyl-4-pyrazine-2-basic ring hexyl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide.Prepare titled reference compound according to the method that is similar to embodiment 276 descriptions.MS(M+H) ⁺492.1。

Embodiment 278

Steps A

5-bromo-2-ethoxy pyridine.0 ℃ in ethanol (15ml), add lentamente sodium hydride (14mmol, 330mg).Stirred described reactant 30 minutes and add 5-bromo-2-chloropyrimide (3.2mmol, 620mg).Allow reaction mixture be warmed to ambient temperature overnight, then water quencher and use ethyl acetate extraction.Merge organic layer, vacuum concentration obtains required bromide (470mg, 72%).MS(M+2) ⁺203.4。

Step B

8-(2-oxyethyl group pyrimidine-5-yl)-1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-alcohol.(2.3mmol, THF 471mg) (20ml) solution are cooled to-78 ℃ and drip n-Butyl Lithium (2.8mmol is 1.7ml) in described solution with the product of steps A.Stir down described reactants 10 minutes and add 1 at-78 ℃ then, and 4-two oxa-s-volution [4.5] last of the ten Heavenly stems-8-ketone (3.5mmol, 540mg).Allow reactant in 12 hours, be warmed to room temperature, with the described reactant of ammonium chloride quencher and with ethyl acetate extraction (3 * 30ml).Use MgSO ₄Dry organic layer, concentrated under vacuum then (22%, 184mg), product is used for next step reaction to obtain required thick ketal.

Step C

4-(2-oxyethyl group pyrimidine-5-yl)-4-hydroxy-cyclohexanone.With the product of step B (0.3mmol, 184mg) add aqueous hydrochloric acid (30mmol, 10ml) in.Reaction stirred is spent the night, then with sodium hydroxide (1N) quencher reactant.With ethyl acetate extraction reactant (2 * 30ml).Dry organic layer and concentrated under vacuum.Residuum through the HPLC purifying obtain required ketone (70%, 100mg).MS[M+H] ⁺237.1。

Step D

N-(2-{[(3R)-1-(4-hydroxyl-4-pyrazine-2-base-cyclohexyl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide.Ketone (0.4mmol to step C, add N-((3R)-tetramethyleneimine-3-base carbamoyl methyl)-3-trifluoromethyl benzamide (0.4mmol in methylene dichloride 100mg) (10ml) solution, 100mg), then add sodium triacetoxy borohydride (0.8mmol, 200mg).Reaction stirred is spent the night, and uses NaOH (1N) quencher then.With ethyl acetate (3 * 10ml) extractive reaction things.Merge organic layer, use MgSO ₄Drying concentrates under vacuum then.Residuum behind the HPLC purifying, obtain required amine diastereomer (18%, 40mg).MS[M+H] ⁺536.1。

Embodiment 279

N-{2-[((3R)-1-{4-[2-(2-fluorine oxyethyl group) pyrimidine-5-yl]-the 4-hydroxy-cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide.Prepare titled reference compound according to the method that is similar to embodiment 278 descriptions.MS(M+H) ⁺554.2。

Embodiment 280

N-[2-((3R)-and 1-[4-hydroxyl-4-(2-methoxy pyrimidine-5-yl) cyclohexyl] tetramethyleneimine-3-yl } amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide.Prepare titled reference compound according to the method that is similar to embodiment 278 descriptions.MS(M+H) ⁺522。

Embodiment 281

N-(2-{[(3R)-1-(4-hydroxyl-4-pyrimidine-4-basic ring hexyl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide.Prepare titled reference compound according to the method that is similar to embodiment 276 descriptions.MS(M+H) ⁺492.2。

Embodiment 282

Steps A

8-(4-iodo-phenyl)-1,4-two oxa-s-volution [4.5] last of the ten Heavenly stems-8-alcohol.Under-78 ℃, in 1 hour to 1, the 4-diiodo-benzene (16.5g, add in THF 50mmol) (350ml) solution n-butyllithium solution (2.5M, 24ml).Behind the restir 30 minutes, add 1,4-two oxa-s-volution [4.5] last of the ten Heavenly stems-8-ketone (7.8g, (30ml) solution of THF 50mmol) and allow the mixture of gained continue to stir 3 hours.In mixture, add TMSCl (5.4g, 50mmol) and allow mixture be warmed to room temperature and at room temperature stirred 18 hours.It is 6.0 that reaction mixture is neutralized to pH, and with ethyl acetate extraction (3 * 50ml).Merge organic layer, (MgSO is used in 2 * 50ml) washings with salt solution ₄Dry and concentrated under vacuum.Residuum hexane/EtOAc (95/5 to 100/0) wash-out on silica gel chromatography.Merge suitable elution fraction, obtain 8-(4-iodo-phenyl)-1,4-two oxa-s-volution [4.5] last of the ten Heavenly stems-8-alcohol (12g, 66.6%), its LCMS:361.2 (M+H ⁺, 100%) and { [8-(4-iodophenyl)-1,4-two oxa-s-volution [4.5] last of the ten Heavenly stems-8-yl] oxygen base } (trimethylammonium) silane (6g, 27%), its LCMS:433.1 (M+H ⁺, 100%)

Step B

4-hydroxyl-4-(iodophenyl)-2-basic ring hexanone.To 8-(4-iodo-phenyl)-1, add 5% hydrochloric acid (20ml) in acetone (10ml) solution of 4-two oxa-s-volution [4.5] last of the ten Heavenly stems-8-alcohol (2g) and at room temperature stirred 14 hours.With the 1NNaOH neutralise mixt to pH be 7, concentrate through rotary evaporation, use ethyl acetate extraction (2 * 50ml) then.Merge organic layer, (2 * 50ml) washings concentrate with dried over sodium sulfate and under vacuum, obtain 4-hydroxyl-4-(iodophenyl) pimelinketone (1.7g, 98%) with salt solution.LCMS：317.3(M+H ⁺，100％)

Step C

N-[2-((3R)-and 1-[4-hydroxyl-4-(4-iodophenyl) cyclohexyl] tetramethyleneimine-3-yl } amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide.(624mg, ((3R)-1-tetramethyleneimine-3-base carbamoyl methyl)-(730mg 2mmol), adds NaBH (OAc) to the 3-trifluoromethyl benzamide then to add N-in methylene dichloride 2mmol) (10ml) solution to 4-hydroxyl-4-(4-iodophenyl) pimelinketone ₃(666mg, 3mmol).Stir after 1 hour,, use ethyl acetate extraction with 10% sodium bicarbonate quencher reaction.Merge organic layer, use the salt water washing, concentrate with dried over sodium sulfate and under vacuum.Residuum carries out the silica gel chromatography purifying and obtains main isomer (544mg, 44.2%) and accessory isomer (446mg, productive rate 36.3%) with EtOAc solution/methyl alcohol (100/0 to 10/90) wash-out of 1% ammonium hydroxide.For main isomer, LCMS:615.2 (M+H ⁺, 100%); ¹HNMR:(CDCl ₃) δ 8.09 (s, 1H); 7.98 (s, 1H); 7.77 (d, 1H); 7.67 (d, 2H); 7.57 (t, 1H); 7.28 (d, 2H); 7.22 (t, 1H, NH); 6.44 (d, 2H, NH); 4.49 (m, 1H); 4.12 (m, 2H); 2.87 (m, 1H); 2.64 (m, 2H); 2.38 (m, 1H); 2.25 (m, 4H); 1.93 (m, 2H); 1.54-1.70 (m, 6H).

Step D

N-[2-((3R)-and 1-[4-hydroxyl-4-(4-pyrimidine-5-base phenyl) cyclohexyl] tetramethyleneimine-3-yl } amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide.To N-[2-({ (3R)-1-[4-hydroxyl-4-(4-iodophenyl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide (61mg, 0.1mmol) and pyrimidine-5-ylboronic acid (26mg adds 2M sodium bicarbonate (5ml) and with nitrogen purging mixture 3 times in THF 0.2mmol) (5ml) solution.Then to wherein adding Pd (0) (PPh ₃) ₄(5.7mg, 5%) is then with the mixture of gained reflux 4 hours under nitrogen.(2 * 10ml) washing organic layers concentrate with dried over sodium sulfate and under vacuum with ethyl acetate (50ml) diluted mixture thing and with salt solution.Residuum is with EtOAc solution/methyl alcohol (100/0 to 10/90) wash-out of 1% ammonium hydroxide, carry out the silica gel chromatography purifying and then use AcCN solution/water wash-out purifying on HPLC of 0.05%TFA, obtain N-[2-({ (3R)-1-[4-hydroxyl-4-(4-pyrimidine-5-base phenyl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-tfa salt (28.5mg, 41%) of 3-(trifluoromethyl) benzamide.LCMS：568.4(M+H ⁺，100％)。For neutral molecule, ¹HNMR:(CD ₃OD) δ 9.15 (s, 1H), 9.08 (s, 1H), 8.22 (s, 1H), 8.14 (s, 1H), 7.86 (s, 1H); 7.76-7.67 (m, 5H), 4.45-4.40 (m, 1H), 4.05 (s, 2H), 2.86 (t, 2H), and 2.60-2.53 (m, 2H), 2.42-2.38 (m, 2H), 2.32-2.68 (m, 2H), 2.05-2.01 (m, 2H), 1.75-1.72 (m, 2H), 1.67-1.63 (m, 3H); ¹⁹FNMR:(CDCl ₆) δ-64.58.

Embodiment 283

Steps A

4-hydroxyl-4-[4-(1,3-oxazole-2-yl) benzyl ring hexanone.-78 ℃ of Xia Xiang oxazole (240mg, add in THF 3.5mmol) (5ml) solution n-Butyl Lithium (1.6M, 2.6ml).After stirring the mixture 1 hour, add zinc chloride THF solution (0.5M, 8.2ml) and in 1 hour, allow the mixture of gained be warmed to 0 ℃.Add 8-(4-iodo-phenyl)-1 in mixture, 4-two oxa-s-volution [4.5] last of the ten Heavenly stems-8-alcohol, (1.35g was 3.5mmol) and with the mixture of nitrogen purging gained 3 times.Then to PdCl ₂(PPh ₃) ₂(1.6M, 0.26mL) mixture with gained is added in the said mixture to add n-Butyl Lithium in (122mg, 5%) suspended substance in THF (2ml).The mixture of gained reflux 4 hours under nitrogen.With ethyl acetate (50ml) diluted mixture thing.(2 * 10ml) wash filtrates concentrate with dried over sodium sulfate and under vacuum organic layer with the Celite diatomite filtration and with salt solution.Residuum was at room temperature handled 24 hours with THF (2.5ml) dissolving and with 5% hydrochloric acid (22.5ml).It is 7 that mixture is neutralized to pH with 1N sodium hydroxide, concentrates through rotary evaporation, uses ethyl acetate extraction (2 * 50ml) then.Merge organic extract, (2 * 50ml) washings concentrate with dried over sodium sulfate and under vacuum with salt solution.Residuum carries out the silica gel chromatography purifying with hexane/EtOAc (100/0 to 100/0) wash-out, obtains the compound (0.56g, the productive rate in two steps is 62%) that needs.LCMS：258.2(M+H ⁺，100％)。 ¹HNMR：(CDCl ₃)δ8.06(d，2H)，7.73(s，1H)，7.63(d，2H)，2.99-2.91(m，2H)，2.42-2.30(m，4H)，2.22-2.05(m，2H)。

Step B

N-[2-((3R)-and 1-[4-hydroxyl-4-(4-oxazole-2-base phenyl) cyclohexyl] tetramethyleneimine-3-yl } amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide.Prepare titled reference compound according to being similar to method that embodiment 282 describes ketone by steps A.MS(M+H) ⁺557.3。

Embodiment 284

Steps A

4-hydroxyl-4-[4-(1H-imidazoles-1-yl) phenyl] pimelinketone.To imidazoles (102mg, 1.5mmol) and 8-(4-iodo-phenyl)-1,4-two oxa-s-volution [4.5] last of the ten Heavenly stems-8-alcohol (316mg, add in DMF 1mmol) (1ml) solution cuprous iodide (19mg, 0.1mmol) and Cs ₂CO ₃(488mg 1.5mmol) and in microwave oven stirred the mixture under 190 ℃ 10 minutes.With ethyl acetate (50ml) and water (10ml) diluted mixture thing.(2 * 10ml) wash filtrates concentrate with dried over sodium sulfate and under vacuum organic layer with the Celite diatomite filtration and with salt solution.Residuum was at room temperature handled 14 hours with THF (1ml) dissolving and with 5% hydrochloric acid (9ml).It is 7 that mixture is neutralized to pH with 1N sodium hydroxide, concentrates through rotary evaporation, uses ethyl acetate extraction (2 * 50ml) then.Merge organic extract, (2 * 50ml) washings concentrate with dried over sodium sulfate and under vacuum with salt solution.Residuum carries out the silica gel chromatography purifying with hexane/EtOAc (100/0 to 0/100) wash-out, obtains the compound (180mg, the productive rate in two steps is 70%) that needs.LCMS：257.2(M+H ⁺，100％)。 ¹HNMR：(CDCl ₃)δ7.82(s，1H)，7.64(d，1H)，7.40(s，1H)，7.28(s，1H)，7.21(s，1H)，2.99-2.91(m，2H)，2.43-2.28(m，4H)，2.23-2.18(m，2H)。

Step B

N-[2-((3R)-and 1-[4-hydroxyl-4-(4-1H-imidazoles-1-base phenyl) cyclohexyl] tetramethyleneimine-3-yl } amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide.Prepare titled reference compound according to being similar to method that embodiment 282 describes ketone by steps A.MS(M+H) ⁺556.3。

Embodiment 285

Steps A

4-hydroxyl-4-(4-morpholine-4-base phenyl) pimelinketone.Pd packs in the flask of drying in baking oven ₂(dba) ₃(4.6mg, 0.005mmol), (tertiary butyl) ₂(neighbour-xenyl) P (6.0mg, 0.02mmol, 2mol%) and NaOt-Bu (135mg, 1.4mmol).Emptying flask and being full of with nitrogen again covers rubber plug then.Add toluene (0.5ml), aryl iodide (360mg, 1.0mmol), morpholine (102mg, 1.2mmol) and other toluene (0.5ml).At room temperature stir until aryl iodide completely consumed finish (by the TLC assay determination).With ether (20ml) diluted mixture thing, through Celite diatomite filtration and vacuum concentration.Thick residuum is dissolved among the THF (1ml), and the hydrochloric acid with 5% (9ml) was at room temperature handled 14 hours.It is 7 that mixture is neutralized to pH with 1N sodium hydroxide, concentrates through rotary evaporation, uses ethyl acetate extraction (2 * 50ml) then.Merge organic extract, (2 * 50ml) washings concentrate with dried over sodium sulfate and under vacuum with salt solution.Residuum carries out the silica gel chromatography purifying with hexane/EtOAc (100/0 to 0/100) wash-out, obtains the compound (100mg, the productive rate in two steps is 36%) that needs.LCMS：276.2(M+H ⁺，100％)。 ¹HNMR：(CDCl ₃)δ7.42(d，2H)，6.88(d，2H)，3.99-3.94(m，4H)，3.86-3.84(m，4H)，3.16-3.13(m，4H)。

Step B

N-[2-((3R)-and 1-[4-hydroxyl-4-(4-morpholine-4-base phenyl) cyclohexyl] tetramethyleneimine-3-yl } amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide.Prepare titled reference compound according to being similar to method that embodiment 282 describes ketone by steps A.MS(M+H) ⁺575.3。

Embodiment 286

Steps A

8-(5-bromopyridine-2-yl)-1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-alcohol.Under-78 ℃, to 2, the 5-dibromo pyridine (4.10g, drip in dry toluene 17mmol) (250ml) solution n-butyllithium solution (1.6M, 12ml).Stirred 2.5 hours down at-78 ℃.In reaction mixture, add 1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-ketone (2.73g, methylene dichloride 17mmol) (25ml) solution.Stir the mixture 1 hour of gained in addition, allow it slowly be warmed to room temperature.Reaction mixture is poured in the sodium bicarbonate aqueous solution (200ml), used ethyl acetate extraction (2 * 50ml) then.Merge organic extract, (2 * 50ml) washings concentrate with dried over sodium sulfate and under vacuum with salt solution.The solid of gained grinds and collects filtrate with ether.Remove ether and with solid with hexane/EtOAc (2: 1) wash-out, carry out the silica gel chromatography purifying, obtain light yellow solid, 8-(5-bromopyridine-2-yl)-1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-alcohol (4.27g).LCMS：316.10/314.10(M+H ⁺，100％)。 ¹HNMR：δ8.6(s，1H)，7.82(d，1H)，7.38(d，1H)，4.6(s，1H)，4.0(m，4H)，2.2(m，4H)，1.7(m，4H)。

Step B

8-(5-pyrazine-2-yl pyridines-2-yl)-1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-alcohol.At room temperature, to 8-(5-bromopyridine-2-yl)-1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-alcohol (0.50g, drip in THF 1.59mmol) (7.5ml) solution isopropylmagnesium chloride solution (the THF solution of 2M, 1.8ml).Stir after 1 hour, use N2 purged solution three times.Under room temperature and nitrogen purging, to another part added in deflated THF (2.5ml) solution acetylacetonate nickel (20mg, 0.080mmol) and 1, two (the diphenylphosphine)-ethane of 2-(32mg, 0.080mmol).Stir after 10 minutes, (0.155ml 1.59mmol) and with the mixture of gained stirred 30 minutes to add the 2-chloropyrazine.Mixture is transferred in the grignard reagent solution of prepared fresh then.At room temperature stirred the mixture 18 hours, and with saturated ammonium chloride solution quencher.Use the ethyl acetate extraction aqueous solution, (organic phase that 2 * 50ml) washings merge concentrates with dried over mgso and under vacuum to use salt solution then.Residuum carries out the silica gel chromatography purifying with hexane/EtOAc (1: 1) wash-out, collects suitable elution fraction, obtains oily 8-(5-pyrazine-2-yl pyridines-2-yl)-1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-alcohol (95mg, 19%).LCMS：314.2(M+H ⁺，100％)。

Step C

4-hydroxyl-4-(5-pyrimidine-5-yl pyridines-2-yl) pimelinketone.To 8-(5-pyrazine-2-yl pyridines-2-yl)-1,4-dioxo spiro ring [4.5] last of the ten Heavenly stems-8-alcohol, (95mg added 10% hydrochloric acid (2ml) in THF 0.30mmol) (2.0ml) solution.40 ℃ of following stirred reaction mixtures 60 minutes, and be cooled to room temperature.Mixture neutralizes with solid sodium bicarbonate, uses ethyl acetate extraction.Merge organic extract, use the salt water washing, concentrate with dried over mgso and under vacuum.Residuum usefulness hexane/EtOAc (1: 1) wash-out carries out the silica gel chromatography purifying, obtains the white solid (32mg, 40%) of the product of needs.LCMS：270.2(M+H ⁺，100％)。 ¹HNMR：δ9.22(s，1H)，9.10(s，1H)，8.72(d，1H)，8.60(d，1H)，8.40(d，1H)，7.56(d，1H)，5.36(s，1H)，3.04(m，2H)，2.44(dd，2H)，2.36(m，2H)，2.10(m，2H)。

Step D

N-[2-((3R)-and 1-[4-hydroxyl-4-(5-(pyrazine-2-yl) pyridine-2-yl) cyclohexyl] tetramethyleneimine-3-yl } amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide.Prepare titled reference compound according to being similar to method that embodiment 282 describes ketone by step C.MS(M+H) ⁺569.3。

Embodiment 287

Steps A

N-{2-[((3R)-and 1-{4-hydroxyl-[4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron mix penta ring-2-yl) phenyl] cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide.Under nitrogen, hypoboric acid two pinacol esters of in flask, packing into (538mg, 2.1mmol), KOAc (589mg, 6mmol) and PdCl ₂(dppf) (49mg, 0.06mmol).N-[2-({ (3R)-1-[4-hydroxyl-4-(4-iodine substituted phenyl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl is housed in another funnel]-3-(trifluoromethyl) benzamide (1.23g, DMSO 2mmol) (12ml) solution is to wherein leading to nitrogen bubble; Add flask then and with mixture heating up to 70 ℃.After 1 hour, water quencher reactant with the ethylene dichloride extraction, concentrates the compound (190mg, 15%) that needs to obtain.LCMS：616.2(M+H ⁺，100％)。

Step B

N-{2-[((3R)-and 1-{4-hydroxyl-4-[4-(1-methyl isophthalic acid H-imidazoles-5-yl) phenyl] cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide.To deflated N-{2-[((3R)-1-{ is trans-4-hydroxyl-4-[4-(4,4,5,5-tetramethyl--1,3, the 2-two oxa-boron penta ring-2-yl of mixing) phenyl] cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide (60mg, 0.1mmol), (63mg 0.39mmol) and in the mixture of aqueous sodium carbonate (0.5ml) in DMF (0.5ml) adds PdCl to 5-bromo-1-Methylimidazole ₂(dppf) (4mg, 0.005mmol).After stirring 18 hours under 80 ℃, finished 66% by LCMS judgement reaction.Crude product merges by preparation type LCMS purifying and with suitable component, obtain N-{2-[((3R after the lyophilize)-1-{4-hydroxyl-4-[4-(1-methyl isophthalic acid H-imidazoles-5-yl) phenyl] cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-white powder of the two-tfa salt (8mg, 14%) of 3-(trifluoromethyl) benzamide.LCMS：570.2(M+H ⁺，100％)。 ¹⁹FNMR (CD ₃OD): δ-64.6 (aryl-CF ₃);-77.50 (TFA); ¹HNMR (CD ₃OD): δ 9.02 (s, 1H); 8.18 (s, 1H); 8.12 (d, 1H); 7.81 (d, 2H); 7.78 (d, 1H); 7.63 (t, 1H); 7.55 (s, 1H); 7.32 (d, 2H); 4.40 (m, 1H); 4.11 (s, 2H); 3.90 (m, 1H); 3.83 (s, 3H); 3.48 (m, 2H); 3.20 (m, 1H); 2.70 (m, 1H); 2.37 (m, 3H); 2.24 (m, 2H); 2.01 (m, 2H); 1.82 (m, 3H).

Compound below the method preparation of similar embodiment 282-287.

Embodiment #	R	MS(M+H) ⁺
Embodiment #	R	MS(M+H) ⁺	288	4-(4,6-dimethyl pyrimidine-5-yl) phenyl	596.4
289	6-bromopyridine-3-base	569.3	288	4-(4,6-dimethyl pyrimidine-5-yl) phenyl	596.4
289	6-bromopyridine-3-base	569.3	230	5-bromopyridine-2-base	569.3
291	4 '-(methyl sulphonyl) biphenyl-4-base	644.4	230	5-bromopyridine-2-base	569.3
291	4 '-(methyl sulphonyl) biphenyl-4-base	644.4	292	3 '-(methyl sulphonyl) biphenyl-4-base	644.4
293	3 '-(methoxycarbonyl) biphenyl-4-base	624.3	292	3 '-(methyl sulphonyl) biphenyl-4-base	644.4
293	3 '-(methoxycarbonyl) biphenyl-4-base	624.3	294	4-(2,3-dihydro-1,4-benzo dioxine-6-yl) phenyl	624.3
295	4 '-(dimethylamino) biphenyl-4-base	609.4	294	4-(2,3-dihydro-1,4-benzo dioxine-6-yl) phenyl	624.3
295	4 '-(dimethylamino) biphenyl-4-base	609.4	296	4-(pyridin-3-yl) phenyl	567.3
297	4-(1H-pyrazoles-4-yl) phenyl	556.3	296	4-(pyridin-3-yl) phenyl	567.3
297	4-(1H-pyrazoles-4-yl) phenyl	556.3	298	3,3 '-dipyridyl-6-base	568.2
299	3,4 '-dipyridyl-6-base	568.2	298	3,3 '-dipyridyl-6-base	568.2
299	3,4 '-dipyridyl-6-base	568.2	300	5-(3-acetyl phenyl) pyridine-2-base	609.3
301	5-[3-(dimethylamino) phenyl] pyridine-2-base	610.4	300	5-(3-acetyl phenyl) pyridine-2-base	609.3
301	5-[3-(dimethylamino) phenyl] pyridine-2-base	610.4	302	5-[3-(trifluoromethyl) phenyl] pyridine-2-base	634.3
303	5-[4-(methyl sulphonyl) phenyl] pyridine-2-base	645.2	302	5-[3-(trifluoromethyl) phenyl] pyridine-2-base	634.3
303	5-[4-(methyl sulphonyl) phenyl] pyridine-2-base	645.2	304	5-(4-p-methoxy-phenyl) pyridine-2-base	597.3
305	5-(3-p-methoxy-phenyl) pyridine-2-base	597.3	304	5-(4-p-methoxy-phenyl) pyridine-2-base	597.3
305	5-(3-p-methoxy-phenyl) pyridine-2-base	597.3	306	5-[3-(aminocarboxyl) phenyl] pyridine-2-base	610.3
307	5-(4-fluorophenyl) pyridine-2-base	585.4	306	5-[3-(aminocarboxyl) phenyl] pyridine-2-base	610.3
307	5-(4-fluorophenyl) pyridine-2-base	585.4	308	5-(3, the 4-difluorophenyl) pyridine-2-base	603.3
309	5-(3,5-dimethyl isoxazole-4-yl) pyridine-2-base	585.4	308	5-(3, the 4-difluorophenyl) pyridine-2-base	603.3
309	5-(3,5-dimethyl isoxazole-4-yl) pyridine-2-base	585.4	310	5-(1-methyl isophthalic acid H-pyrazoles-4-yl) pyridine-2-base	571.4
311	5-(1H-pyrazoles-4-yl) pyridine-2-base	557.3	310		571.4
311	5-(1H-pyrazoles-4-yl) pyridine-2-base	557.3	312	5-(1-cumarone-4-yl) pyridine-2-base	607.2
313	5-(1,3-benzodioxole-5-yl) pyridine-2-base	611.3	312	5-(1-cumarone-4-yl) pyridine-2-base	607.2
313	5-(1,3-benzodioxole-5-yl) pyridine-2-base	611.3	314	5-(2-formyl radical phenyl) pyridine-2-base	595.3
315	4-(2 '-formyl biphenyl-4-base	594.3	314	5-(2-formyl radical phenyl) pyridine-2-base	595.3
315	4-(2 '-formyl biphenyl-4-base	594.3	316	5-(1,3-oxazole-2-yl) pyridine-2-base	558.4
317	6-(1,3-oxazole-2-yl) pyridin-3-yl	558.4	316	5-(1,3-oxazole-2-yl) pyridine-2-base	558.4
317	6-(1,3-oxazole-2-yl) pyridin-3-yl	558.4	318	4-(1,3-thiazoles-2-yl) phenyl	573.2

319	5-(1,3-thiazoles-2-yl) pyridine-2-base	574.2
319	5-(1,3-thiazoles-2-yl) pyridine-2-base	574.2	320	6-(1,3-thiazoles-2-yl) pyridin-3-yl	574.2
321	6-(1H-imidazoles-1-yl) pyridin-3-yl	557.4	320	6-(1,3-thiazoles-2-yl) pyridin-3-yl	574.2
321	6-(1H-imidazoles-1-yl) pyridin-3-yl	557.4	322	5-(1H-imidazoles-1-yl) pyridine-2-base	5574
323	6-phenylpyridine-3-base	567.3	322	5-(1H-imidazoles-1-yl) pyridine-2-base	5574
323	6-phenylpyridine-3-base	567.3	324	5-(pyrimidine-5-yl) pyridine-2-base	569.3
325	5-(pyrimidine-2-base) pyridine-2-base	569.3	324	5-(pyrimidine-5-yl) pyridine-2-base	569.3
325	5-(pyrimidine-2-base) pyridine-2-base	569.3	326	5-(3-aminocarbonyl-phenyl) pyridine-2-base	620.3
327	4-(1-methyl isophthalic acid H-imidazol-4 yl) phenyl	570.3	326	5-(3-aminocarbonyl-phenyl) pyridine-2-base	620.3
327	4-(1-methyl isophthalic acid H-imidazol-4 yl) phenyl	570.3	328	4-(1H-imidazol-4 yl) phenyl	556.4
329	5-[2-(hydroxymethyl) phenyl] pyridine-2-base	597.4	328	4-(1H-imidazol-4 yl) phenyl	556.4
329	5-[2-(hydroxymethyl) phenyl] pyridine-2-base	597.4	330	2 '-(hydroxymethyl) biphenyl-4-base	596.2
331	The 5-{2-[(dimethylamino) methyl] phenyl } pyridine-2-base	624.3	330	2 '-(hydroxymethyl) biphenyl-4-base	596.2
331	The 5-{2-[(dimethylamino) methyl] phenyl } pyridine-2-base	624.3	332	2 '-[(dimethylamino) methyl] biphenyl-4-base	623.3

Embodiment 333

Steps A

(4-oxo cyclohexyl) t-butyl carbamate.In ice bath, to trans-4-Trans-4-Amino Cyclohexanol hydrochloride (5g, 33mmol) and the 1-methylmorpholine (9ml, add in acetonitrile 82mmol) (35ml) and water (30ml) solution tert-Butyl dicarbonate (7.2g, 33mmol).At room temperature stir the mixture and spend the night, add ethyl acetate.Isolate organic phase.With ethyl acetate extraction water layer 2 times.With the organic phase that the salt water washing merges, use MgSO ₄Dry and concentrated.

To the oxalyl chloride (2.33ml of cooling under-60 ℃, 26.7mmol) methylene dichloride (50ml) solution in add DMSO (4ml, methylene dichloride 56mmol) (5ml) solution, then add trans-4-tert-butoxycarbonyl Trans-4-Amino Cyclohexanol (5g, methylene dichloride 23mmol) (20ml) solution that above obtains.After stirring 20 minutes under-60 ℃, and the adding triethylamine (16.1ml, 116mmol).Allowing mixture be warmed to room temperature and to continue stirred 30 minutes.Add entry.Isolate organic phase and with dichloromethane extraction water layer 2 times.With the organic phase that the salt water washing merges, use MgSO ₄Dry and concentrated.Ethanol/methylene with 3% to 5% to 10% is a gradient eluent, carries out purification by flash chromatography, obtains 4.5g (90%) titled reference compound.MS (M+H) ⁺214, actual value 236 (M+Na) ⁺

Step B

(4-{ (3R)-3-[({[3-(trifluoromethyl) benzoyl] amino } acetyl) amino] tetramethyleneimine-1-yl } cyclohexyl) t-butyl carbamate.To the ketone of steps A (0.4g, 1.9mmol) and the tetramethyleneimine intermediate that obtains of embodiment 114 step C (0.4g, add in THF 1.3mmol) (15ml) solution sodium triacetoxy borohydride (0.4g, 19mmol).At room temperature reaction stirred is spent the night and is passed through to add sodium bicarbonate aqueous solution quencher reactant.Ethyl acetate extraction 3 times of the solution of gained.With the organic phase that sodium bicarbonate and salt water washing merge, use MgSO ₄Dry and concentrated.Ethanol/methylene with 0-20% is a gradient eluent, carries out purification by flash chromatography, obtains the 300mg titled reference compound.MS calculated value (M+H) ⁺513, actual value 513.

Step C

N-(2-{[1-((3R)-4-aminocyclohexyl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide.(256mg 0.5mmol) is dissolved in 4N hydrochloric acid/dioxane (10ml) with the intermediate of step B.Mixture was at room temperature stirred 1 hour, and concentrated solution obtains solid.MS calculated value (M+H) ⁺413; Actual value 413.1.

Step D

N-[2-((3R)-and 1-[4-(benzamido) cyclohexyl] tetramethyleneimine-3-yl } amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide.To the amine of step C (80mg, 0.18mmol) add in the mixture in methylene dichloride (2mL) Benzoyl chloride (25 μ l, 0.21mmol), then add triethylamine (62 μ L, 0.45mmol).After at room temperature stirring 2 hours, concentrated solution.Ethanol/methylene with 0-20% is a gradient eluent, carries out purification by flash chromatography, obtains titled reference compound.MS calculated value (M+H) ⁺517, actual value 517.

With the synthetic following embodiment of the method that is similar to embodiment 333.

Embodiment #	R	MS(M+H) ⁺
Embodiment #	R	MS(M+H) ⁺	334	Pyridine-2-base	518
335	Pyridin-3-yl	518	334	Pyridine-2-base	518
335	Pyridin-3-yl	518	336	Pyridin-4-yl	518
337	6-picoline-2-base	532	336	Pyridin-4-yl	518
337	6-picoline-2-base	532	338	5-picoline-2-base	532
339	4-picoline-2-base	532	338	5-picoline-2-base	532
339	4-picoline-2-base	532	340	6-methoxypyridine-2-base	548
341	Quinolyl-4	568	340	6-methoxypyridine-2-base	548

Embodiment 342

Steps A

3H-volution [dicyclo [3.2.1] octane-8,2 '-[1,3] two oxa-, penta ring]-3-ketone.Prepare titled reference compound (M.Povarny etc., Tetrahedron Lett., 1984,25,1311-1312 and the document of quoting) according to the described method of document.MS calculated value (M+H) ⁺183, actual value 183.0.

Step B

3-pyridine-2-base volution [dicyclo [3.2.1] octane-8,2 '-[1,3] two oxa-, penta ring]-3-alcohol.To the cooling-78 ℃ under the 2-bromopyridine (0.04ml, in ether 0.422mmol) (2ml) solution adding 2.5M n-Butyl Lithium hexane solution (0.17ml, 0.425mmol).After stirring 1 hour under-78 ℃, add ketone (70mg, ether 0.384mmol) (2ml) solution that steps A obtains.Continued stirring 2 hours down and before adding aqueous ammonium chloride solution quencher reactant, be warmed to 0 ℃ at-78 ℃.With the solution of extracted with diethyl ether gained 3 times.Use MgSO ₄The dry ether layer that merges and concentrated.Ethyl acetate/hexane with 50% is an elutriant, carries out the silica gel chromatography purifying, obtains 58mg (60%) titled reference compound.MS calculated value (M+H) ⁺262, actual value 262.1.

Step C

3-hydroxyl-3-pyridine-2-base dicyclo [3.2.1] octane-8-ketone.(58mg 0.22mmol) is dissolved in methyl alcohol (2ml) and 10% hydrochloric acid (1ml) ketal that step B is obtained.At room temperature stir spend the night after, reflux solution 10 minutes and after being cooled to room temperature adds sodium hydroxide solution and neutralizes.Under reduced pressure rotary evaporation concentrates, and the solution of condensation is crude product, can be used for next step reaction and need not purifying.MS calculated value (M+H) ⁺218, actual value 218.0.

Step D

N-(2-{[(3R)-1-(3-hydroxyl-3-pyridine-2-base dicyclo [3.2.1] suffering-8-yl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide.With the ketone of above-mentioned acquisition and the pyrrolidin derivatives reductive amination of embodiment 1 step B acquisition, obtaining titled reference compound with the method that is similar to embodiment 1 step D description, is two kinds of mixture of isomers (2: 3).MS calculated value (M+H) ⁺517, actual value 517.1.

Embodiment 343

N-[2-((3R)-and 1-(3-hydroxyl-3-(5-picoline-2-yl) dicyclo [3.2.1] suffering-8-yl) tetramethyleneimine-3-yl } amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide.With being similar to the synthetic titled reference compound of method that embodiment 342 describes.MS calculated value (M+H) ⁺531, actual value 531.2.

Embodiment 344

N-(2-{[(3R)-1-(3-hydroxyl-3-pyridin-3-yl dicyclo [3.2.1] suffering-8-yl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide.With being similar to the synthetic titled reference compound of method that embodiment 342 describes.MS calculated value (M+H) ⁺517, actual value 517.1.

Embodiment 345

N-[2-((3R)-and 1-(3-hydroxyl-3-(6-methoxypyridine-3-yl) dicyclo [3.2.1] suffering-8-yl) tetramethyleneimine-3-yl } amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide.With being similar to the synthetic titled reference compound of method that embodiment 342 describes.MS calculated value (M+H) ⁺547, actual value 547.2.

Embodiment 346

Steps A

[(3R)-and 1-volution [dicyclo [3.2.1] octane-8,2 '-[1,3] two oxa-, penta ring]-3-base tetramethyleneimine-3-yl] t-butyl carbamate.Ketone (0.1g to the acquisition of embodiment 342 steps A, 0.55mmol) and (3R)-(+)-3-(tert-butoxycarbonyl amino) tetramethyleneimine (0.1g, 0.55mmol) add in the solution in methylene dichloride (4mL) sodium triacetoxy borohydride (0.13g, 0.60mmol).At room temperature stir the mixture and spend the night and use the sodium bicarbonate aqueous solution quencher.With the solution of EtOAc extraction gained 3 times.Use MgSO ₄The dry ethyl acetate layer that merges and concentrated.Use the 30%EtOAc/ hexane, EtOAc is an elutriant with 10% ethanol/methylene then, carries out purification by flash chromatography, obtains two kinds of isomer of titled reference compound.MS calculated value: (M+H) ⁺353, actual value 353.1.

Step B

[(3R)-and 1-(8-oxo dicyclo [3.2.1] oct-3-yl) tetramethyleneimine-3-yl] t-butyl carbamate.(30mg 0.085mmol) is dissolved in hydrochloric acid (0.5ml) solution of methyl alcohol (1ml) and 2N with the isomer 1 that above obtains.After at room temperature stirred solution spends the night, 110 ℃ of following reflux solution 2 hours.After being cooled to room temperature, use in the sodium hydroxide solution and described solution.To the THF that wherein adds tert-Butyl dicarbonate (50mg) (2ml) solution, then add triethylamine (0.05ml).After at room temperature stirring is spent the night down, dilute described solution with vinyl acetic monomer.Isolate organic phase, and with twice of ethyl acetate extraction water layer.The organic phase that merges with dried over mgso also concentrates.Use methylene dichloride, 5%, 10% and 20% ethanol/methylene is an elutriant, carries out the flash chromatography on silica gel purifying, obtains the 10mg titled reference compound.MS calculated value 9M+H) ⁺309, actual value 309.0.

Step C

[(3R)-and 1-(8-hydroxyl-8-phenyl dicyclo [3.2.1] oct-3-yl) tetramethyleneimine-3-yl] t-butyl carbamate.To the ketone that obtains with ice bath refrigerative step B (65mg, THF (0.25) solution of the phenyl-magnesium-bromide of adding 1M in THF 0.21mmol) (2ml) solution.Stir described mixture 3 hours down and use NH at-78 ℃ ₄The quencher of the Cl aqueous solution.The solution of gained extracts three times with EtOAc.Use MgSO ₄The dry EtOAc layer that merges and concentrated.Ethanol/methylene with 5%, 10% and 50% is an elutriant, carries out the flash chromatography on silica gel purifying, obtains the titled reference compound of 27mg, is two kinds of mixture of isomers (7: 3).MS calculated value (M+H) ⁺387, actual value 387.1.

Step D

N-(2-{[(3R)-1-(8-hydroxyl-8-phenyl dicyclo [3.2.1] oct-3-yl) tetramethyleneimine-3-yl] amino-2-oxoethyl)-3-(trifluoromethyl) benzamide.(27mg 0.07mmol) is dissolved in the dioxane of 2ml 4N hydrochloric acid the alcohol that will be obtained by step C.After at room temperature stirring 1 hour, concentrate described solution.Absorb residuum with DMF (1ml).To wherein add the carboxylic acid that embodiment 1 step C obtains (25mg, 0.1mmol), then add BOP (45mg, 0.1mmol) and NEt ₃(0.05mL, 0.36mmol).Mixture was at room temperature stirred 5 hours and dilute with ethyl acetate.The solution of gained can be used sodium bicarbonate and salt water washing, uses MgSO ₄Dry and concentrated.Obtaining the 22mg titled reference compound through the reversed-phase HPLC purifying, is two kinds of mixture of isomers (7: 3).MS calculated value (M+H) ⁺516, actual value 516.1.

According to the method described above, the topic of the isomer 2 transitional layer individual isomer forms of steps A is stated mixture.MS calculated value (M+H) ⁺516, actual value 516.0.

Embodiment 347

Steps A

Dicyclo [2.2.1] hept-2-ene"-5-ketone.According to the method for document prepare titled reference compound (G.T.Wang etc., J.Org.Chem.2001,66,2052-2056).

Step B

2-phenyl dicyclo [2.2.1] heptan-5-alkene-2-alcohol.According to the method for document prepare titled reference compound (C.J.Collins, B.M.Benjamin, J.Am.Chem.Soc.1967,89,1652-1661).

Step C

2-phenyl dicyclo [2.2.1] heptane-2, the 5-glycol.According to the method for document prepare titled reference compound (C.J.Collins, B.M.Benjamin, J.Org.Chem.1972,37,4358-4366).

Step D

5-hydroxyl-5-phenyl dicyclo [2.2.1] heptane-2-ketone.Prepare titled reference compound by the ketone that above obtains by the Swern oxidation.MS calculated value (M+H) ⁺203, actual value 203 ﹠amp; 225 (M+Na) ⁺

Step e

N-(2-{[(3R)-1-(5-hydroxyl-5-phenyl dicyclo [3.2.1] heptan-2-yl) tetramethyleneimine-3-yl] amino-2-oxoethyl)-3-(trifluoromethyl) benzamide.To the ketone that obtains by embodiment 45 step D (0.28g, 1.38mmol) and the tetramethyleneimine intermediate that obtains of embodiment 1 step B (0.43g adds acetate (0.1ml) in THF 1.38mmol) (15ml) solution.After stirring 30 minutes under 50 ℃, concentrate described solution.Absorb residuum with THF (5ml).To wherein adding Na (OAc) ₃BH (300mg, 1.42mmol).After at room temperature stirring described mixture overnight, use NaHCO ₃The described reactant of quencher.The solution of gained extracts three times with EtOAc.With the organic phase that the salt water washing merges, use MgSO ₄Dry and concentrated.Use the reversed-phase HPLC purifying, obtain the tfa salt of titled reference compound.MS calculated value (M+H) ⁺502, actual value 502.

Embodiment 348

N-(2-{[(3R)-1-(5-hydroxyl-5-pyridine-2-base dicyclo [2.2.1] heptan-2-yl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide.With being similar to the synthetic titled reference compound of method that embodiment 347 describes.MS calculated value (M+H) ⁺503, actual value 503.

Embodiment 349

N-(2-{[(3R)-1-(5-hydroxyl-5-pyridin-3-yl dicyclo [2.2.1] heptan-2-yl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide.With being similar to the synthetic titled reference compound of method that embodiment 347 describes.MS calculated value (M+H) ⁺503, actual value 503.

Embodiment 350

N-[2-((3R)-and 1-[5-hydroxyl-5-(6-methoxypyridine-3-yl) dicyclo [2.2.1] heptan-2-yl] tetramethyleneimine-3-yl } amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide.With being similar to the synthetic titled reference compound of method that embodiment 347 describes.MS calculated value (M+H) ⁺533, actual value 533.

Embodiment 351

N-(2-{[(3R)-1-(5-hydroxyl-5-pyridin-4-yl) dicyclo [2.2.1] heptan-2-yl] tetramethyleneimine-3-yl } amino)-the 2-oxoethyl)-3-(trifluoromethyl) benzamide.With being similar to the synthetic titled reference compound of method that embodiment 347 describes.MS calculated value (M+H) ⁺503, actual value 503.

Embodiment 352

Steps A

(2S, 4R)-4-hydroxy-2-methyl tetramethyleneimine-1-t-butyl formate.According to the method for document prepare titled reference compound (T.Rosen etc., J.Med.Chem.1988,31,1598-1611).

Step B

(2S, 4S)-4-(benzoyloxy)-2-methylpyrrolidin-1-t-butyl formate.To the alcohol of steps A (0.81g, 4.0mmol), phenylformic acid (0.74g, 6.0mmol) and triphenylphosphine (2.11g, add in toluene 8.0mmol) (20ml) solution DIAD (1.67ml, 8.0mmol).After at room temperature stirring 4 hours, concentrate described solution.Residuum is an elutriant with 0%, 5% and 20% ethyl acetate/hexane, carries out purification by flash chromatography, obtains the titled reference compound of 1.0g.MS calculated value (M+H) ⁺308, actual value 308.1.

Step C

(2S, 4S)-4-hydroxy-2-methyl tetramethyleneimine-1-t-butyl formate.To the ester of step B (1.0g, add in methyl alcohol 3.48mmol) (30ml) solution salt of wormwood (1.2g, 8.7mmol).After at room temperature stirring 4 hours, concentrate described solution.Absorb residuum with ether.The salt water washing of the solution of gained is with dried over mgso and concentrated.Ethyl acetate/hexane with 0% to 20% to 40% is an elutriant, carries out purification by flash chromatography, obtains the titled reference compound of 0.56g.MS calculated value (M+H) ⁺202, actual value 202.1.

Step D

(2S, 4R)-4-azido--2-methylpyrrolidin-1-t-butyl formate.To the cooling in ice bath step C alcohol (0.55g, add in methylene dichloride 2.73mmol) (30ml) solution triethylamine (0.51ml, 3.69mmol), then add methylsulfonyl chloride (0.29ml, 3.69mmol).In ice bath, stir after 30 minutes, continue at room temperature to stir described reactant 40 minutes.Wash described solution with water, with dried over mgso and concentrated.

The residuum that above obtains is dissolved in DMF (15ml) and adds NaN ₃(1.06g, 16.3mmol).Mixture stirring under 50 ℃ is spent the night and is diluted with methyl tert-butyl ether.The solution of gained through dried over mgso and concentrated, obtains the titled reference compound of 0.58g with salt solution, 5% citric acid and saturated sodium bicarbonate solution washing.MS calculated value (M+H) ⁺227, actual value 227.2.

Step e

(2S, 4R)-4-amino-2-methyl tetramethyleneimine-1-t-butyl formate.To the triazo-compound that above obtains (0.58g, the Pd/C (100mg) of adding 5% in methyl alcohol 2.56mmol) (30ml) solution.In nitrogen atmosphere (air bag air feed), stirred the mixture 3 hours.Leach the titled reference compound that catalyzer and concentrated filtrate obtain 0.5g.MS calculated value (M+H) ⁺201, actual value 201.1.

Step F

(2S, 4R)-2-methyl-4-[({[3-(trifluoromethyl) benzoyl] amino } ethanoyl) amino] tetramethyleneimine-1-t-butyl formate.To the amine of the step D of cooling in ice bath (0.5g, 2.5mmol), the carboxylic acid that obtains of embodiment 114 steps A and triethylamine (0.7ml, add in methylene dichloride 5.0mmol) (25ml) solution EDC (0.53g, 2.75mmol).After at room temperature stirring is spent the night, concentrate described solution.Residuum is a gradient eluent with the 0-4% ethanol/methylene, carries out the silica gel chromatography purifying, obtains the titled reference compound of 0.6g.MS calculated value (M+H) ⁺430, actual value 430.1.

Step G

N-(2-{[(3R, 5S)-5-methylpyrrolidin-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide.(0.6g 1.4mmol) is dissolved in the dioxane solution (3ml) of hydrochloric acid of methyl alcohol (3ml) and 4N with the intermediate of step F.After at room temperature stirring 4 hours, concentrated solution obtains the 0.56g titled reference compound.MS calculated value (M+H) ⁺330, actual value 330.2.

Step H

N-(2-{[(3R, 5S)-1-(4-hydroxy-4-phenyl cyclohexyl)-5-methylpyrrolidin-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide.With being similar to the method amine reductive amination of 4-hydroxy-4-phenyl ketone that embodiment 114 describes, synthetic titled reference compound with step G.MS calculated value (M+H) ⁺504, actual value 504.1.

According to being similar to the synthetic following embodiment of method that embodiment 352 describes.

Embodiment #	R	MS(M+H) ⁺
Embodiment #	R	MS(M+H) ⁺	353	The 4-aminomethyl phenyl	518
354	Pyridine-2-base	505	353	The 4-aminomethyl phenyl	518
354	Pyridine-2-base	505	355	5-picoline-2-base	519
356	Pyridin-3-yl	505	355	5-picoline-2-base	519
356	Pyridin-3-yl	505	357	6-methoxypyridine-3-base	535
358	Pyridin-4-yl	505	357	6-methoxypyridine-3-base	535

Embodiment 359

2-(1,3-benzothiazole-2-base is amino)-N-[(3R)-1-(4-hydroxyl-4-pyridine-2-basic ring hexyl) tetramethyleneimine-3-yl] ethanamide.With 2-amino-N-[(3R)-1-(4-hydroxyl-4-pyridine-2-basic ring hexyl) tetramethyleneimine-3-yl] ethanamide (0.080g, 0.25mmol), triethylamine (0.35ml, 2.5mmol) and 2-chloro-benzothiazole (0.424g, 2.5mmol) mixture in Virahol stirs down at 90 ℃ and spends the night.Concentrated reaction mixture and obtain the 55mg titled reference compound through chromatogram purification, productive rate is 49%.MS (EI) calculated value (M+H) ⁺=452.2, actual value 452.2.

Embodiment 360

N-[(3R)-1-(4-hydroxyl-4-pyridine-2-basic ring hexyl) tetramethyleneimine-3-yl]-2-{[5-(trifluoromethyl) pyrimidine-2-base] amino } ethanamide.Method with similar embodiment 359 prepares titled reference compound.MS (EI) calculated value (M+H) ⁺=465.2, actual value 465.1.

Embodiment 361

N-[1-([(3R)-and 1-(4-phenyl hexamethylene, base) tetramethyleneimine-3-yl] amino } carbonyl) cyclopropyl]-3-(trifluoromethyl) benzamide.Method with similar embodiment 114 prepares titled reference compound.MS (EI) calculated value (M+H) ⁺500.2 actual value 500.4. ¹HNMR(CDCl ₃)δ＝8.61(1H，d)，8.21(1H，s)，8.15(1H，d)，7.78(1H，s)，7.75(1H，d)，7.58(1H，dd)，7.22(5H，m)，4.81(1H，m)，3.8(1H，m)，3.62(1H，dd)，3.17(1H，m)，2.92(2H，m)，2.8(1H，m)，2.48(1H，m)，2.18(2H，m)，2.1(2H，m)，1.75(3H，m)，1.55(4H，m)，1.18(2H，m)。

Embodiment 362

Steps A

2-(methyl fluoride) ethyl propenoate.To be cooled to 2-(methylol) ethyl propenoate under-78 ℃ (5g, add in methylene dichloride 38mmol) (50ml) solution DAST (6.0ml, 46.1mmol).Down stirred described reaction mixtures 1 hour at-78 ℃, allow solution be warmed to room temperature then and continue to stir and spend the night.Add 20ml saturated sodium bicarbonate aqueous solution and 20ml ethyl acetate quencher reactant.Isolate organic layer and with ethyl acetate extraction water layer 2 times (20ml * 2).Use MgSO ₄Dry organic extract and the evaporation that merges obtains oily residuum (2.8g, productive rate: 56%).MS(m/z)131(M+1) ⁺。

Step B

1-benzyl-3-(methyl fluoride) tetramethyleneimine-3-ethyl formate.To the N-benzyl-1-methoxyl group-N-[(trimethyl silyl that is cooled under 0 ℃) methyl] methylamine (2.5g, 21mmol) and 2-(methyl fluoride) ethyl propenoate (5.0g, add in methylene dichloride 21mmol) (30ml) solution TFA (0.15ml, 2.1mmol).Stir described mixture overnight down at 0 ℃.Add 20ml saturated sodium bicarbonate aqueous solution and 20ml ethyl acetate quencher reactant.Isolate organic layer and with ethyl acetate extraction water layer 2 times (20ml * 2).Use MgSO ₄Dry organic extract and the evaporation that merges obtains the oily residuum.EtOAc-hexane solution with 10% is an elutriant, carries out chromatogram purification, obtain 1.27g (4.8mmol, productive rate: 1-benzyl-3-(methyl fluoride) tetramethyleneimine-3-ethyl formate 23%): ¹HNMR (400Hz, CDCl ₃) δ 7.39-7.20 (5H, m), 4.62-4.44 (2H, m), 4.18-4.21 (2H, m), 3.62 (2H, s), 2.81-2.72 (2H, m), 2.60-2.50 (2H, m), 2.22 (2H, s), 1.25 (3H, t, J=6.7Hz); MS (m/e): 266 (M+1) ⁺

Step C

3-(methyl fluoride) tetramethyleneimine-3-ethyl formate.(1.27g adds 500mgPd/C (10%, load on the carbon) and 1.5g (24mmol) HCCONH in methyl alcohol 4.8mmol) (20ml) solution to 1-benzyl-3-(methyl fluoride) tetramethyleneimine-3-ethyl formate ₄Reflux described reaction mixture 1 hour filters and evaporation obtains residuum through Celite diatomite filter plate.Use the acetic acid ethyl dissolution residuum then, with the solution of saturated sodium bicarbonate aqueous solution, salt water washing gained, use dried over sodium sulfate, evaporation obtains final crude product (426mg, 2.4mmol, productive rate: 50%): MS (m/e): 176 (M+H) ⁺

Step D

3-(methyl fluoride) tetramethyleneimine-1,3-dioctyl phthalate 1-tert-butyl ester 3-ethyl ester.In methylene dichloride (20ml) solution of 3-(methyl fluoride) tetramethyleneimine-3-ethyl formate (2.4mmol), add 786mg (Boc) ₂O (3.6mmol) and 0.67ml (4.8mmol) triethylamine.Stirred reaction mixture spends the night.Direct purifying on silica gel chromatography, obtain 562mg (2.0mmol, productive rate: required product 85%), 3-(methyl fluoride) tetramethyleneimine-1,3-dioctyl phthalate 1-tert-butyl ester 3-ethyl ester:

¹H NMR(400MHz，CDCl ₃)δ4.65-4.42(2H，m)，4.28-4.19(2H，m)，3.80-3.72(1H，m)，3.56-3.40(3H，m)，2.40-2.20(1H，m)，2.08-1.93(1H，m)，1.45(9G，s)，1.1.32-1.25(3H，m)；MS(m/e)：276(M+1) ⁺。

Step e

1-(tert-butoxycarbonyl)-3-(methyl fluoride) tetramethyleneimine-3-formic acid.Under the room temperature,, add 420mg LiOH.H in the solution of 3-dioctyl phthalate 1-tert-butyl ester 3-ethyl ester (2.0mmol) in 10mlTHF and 5ml water to 562mg3-(methyl fluoride) tetramethyleneimine-1 ₂O (10mmol).Stirred reaction mixture 5 hours.With aqueous hydrochloric acid quencher reaction-ure mixture and the adjusting pH to 3-4 of 1N, with twice of ethyl acetate extraction (20ml * 2).With the extract that the salt water washing merges, use dried over sodium sulfate, evaporate obtain final product (530mg, 2.0mmol), 1-(tert-butoxycarbonyl)-3-(methyl fluoride) tetramethyleneimine-3-formic acid:

¹H NMR(400MHz，CDCl ₃)δ4.70-4.22(2H，m)，3.81-3.75(1H，m)，3.60-3.41(3H，m)，2.41-2.30(1H，m)，2.10-1.99(1H，m)，1.47(9H，s)；MS(m/e)：248(M+1) ⁺.

Step F

The 3-{[(benzyloxy) carbonyl] amino }-3-(methyl fluoride) tetramethyleneimine-1-t-butyl formate.In toluene (30ml) solution of 530mg (2.0mmol) 1-(tert-butoxycarbonyl)-3-(methyl fluoride) tetramethyleneimine-3-formic acid, add 0.69ml (3.2mmol) DPPA and 0.36ml (2.6mmol) triethylamine.110 ℃ of following stirred reaction mixtures 4 hours.Add 0.33ml (3.2mmol) benzylalcohol then and spend the night 110 ℃ of following reaction stirred.Cool off described mixture and evaporation to obtain residuum.Residuum is dissolved in the methylene dichloride, and Na is used in the aqueous citric acid solution with 5%, unsaturated carbonate aqueous solutions of potassium, salt water washing ₂SO ₄Drying, evaporation.Directly obtain 540mg (1.53mmol, productive rate: required product 73%), 3-{[(benzyloxy) carbonyl with the silica gel chromatography purifying] amino }-3-(methyl fluoride) tetramethyleneimine-1-t-butyl formate:

¹H NMR(400MHz，CDCl ₃)δ7.40-7.35(5H，m)，5.10(2H，s)，4.94(1H，s)，4.70-4.50(2H，m)，3.60-3.40(4H，m)，2.40-2.00(2H，m)，1.45(9H，s)；MS(m/e)：353(M+1) ⁺.

Step G

3-amino-3-(methyl fluoride) tetramethyleneimine-1-t-butyl formate.To the 540mg in 10ml methyl alcohol (1.53mmol) 3-{[(benzyloxy) carbonyl] amino }--add the Pd/C of 330mg (10%, load on the charcoal) in 3-(methyl fluoride) tetramethyleneimine-1-t-butyl formate.Stirred described suspended substance 2 hours down in room temperature and nitrogen atmosphere (air bag).Reactant filters through Celite diatomite filter plate, and evaporation obtains 337mg (1.52mmol, productive rate: crude product 99%), 3-amino-3-(methyl fluoride) tetramethyleneimine-1-t-butyl formate: MS (m/e): 219 (M+1) ⁺

Step H

3-(methyl fluoride)-[({ [3-(trifluoromethyl) benzoyl] amino } ethanoyl) amino] tetramethyleneimine-1-t-butyl formate.At room temperature, with 337mg (1.52mmol) 3-amino-3-(methyl fluoride) tetramethyleneimine-1-t-butyl formate and 457mg (1.85mmol) { [3-(trifluoromethyl) benzoyl] amino } acetate, bop reagent (817mg, 1.85mmol) and 0.64ml triethylamine (4.6mmol) be dissolved in the 15mlDMF solution.Allowing reaction mixture at room temperature stir spends the night.With 50% ethyl acetate-hexane is elutriant; directly carry out silica gel (flash chromatography level) chromatogram purification; obtain 578mg (1.29mmol, 84%) 3-(methyl fluoride)-[({ [3-(trifluoromethyl) benzoyl] amino } ethanoyl) amino] tetramethyleneimine-1-t-butyl formate:

¹H NMR(400MHz，CDCl ₃)δ8.15-8.12(1H，m)，8.05-7.98(1H，m)，7.81-7.77(1H，m)，7.63-7.58(1H，m)，6.64-6.62(1H，m)，4.20.4.16(2H，m)，3.61-3.57(2H，m)，3.55-3.42(1H，m)，2.98-2.94(2H，m)，2.90-2.86(2H，m)，1.62-1.60(2H，m)，1.45(9H，s)；MS(m/e)：448(M+1) ⁺.

Step I

N-(2-{[3-(methyl fluoride) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide.The dioxane solution that in THF (5ml) solution of 578mg (1.29mmol) 3-(methyl fluoride)-[({ [3-(trifluoromethyl) benzoyl] amino } ethanoyl) amino] tetramethyleneimine-1-t-butyl formate, adds 2ml 4N hydrochloric acid.Allow reaction mixture at room temperature stir 1 hour and evaporate obtain yellow solid N-(2-{[3-(methyl fluoride) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide hydrochloride salt: MS (m/e): 347 (M+1) ⁺

Step J

N-(2-{[3-(methyl fluoride)-1-(4-hydroxy-4-phenyl cyclohexyl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide.With 100mg (0.53mmol) 4-hydroxy-4-phenyl-pimelinketone and 184mg (0.53mmol) N-(2-{[3-(methyl fluoride) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide is dissolved in the 10ml methylene dichloride.In solution, add 221mg (1.06mmol) sodium triacetoxy borohydride.At room temperature reaction stirred is 2 hours.Directly carry out the silica gel chromatography purifying, obtain required final product 41mg (first peak of the spot at TLC top and HPLC, productive rate: 16.7%, MS:522 (M+1) ⁺) and another kind of isomer 51mg (second peak of HPLC, productive rate: 20%, MS:522 (M+1) ⁺).

Embodiment 363

Steps A

(3a ' R, 6a ' S)-tetrahydrochysene-1 ' H-spiral shell [1,3-dioxolane-2,2 '-pentalene]-5 ' (3 ' H)-ketone.With cis-tetrahydrochysene pentalene-2,5 (1H, 3H)-diketone (5g, 36mmol) and ethylene glycol (2.3g 36mmol) is dissolved in the toluene.In the solution of gained, add PTSA (684mg, 3.6mmol).Allow reaction mixture refluxed 12 hours, remove simultaneously and anhydrate.Directly carry out the silica gel chromatography purifying, obtain 2.0g (11mmol, productive rate: required product (3a ' R, 6a ' S)-tetrahydrochysene-1 ' H-spiral shell [1,3-dioxolane-2,2 '-pentalene]-5 ' (3 ' H)-ketone: MS (m/e): 183 (M+1) 31%) ⁺

Step B

(3a ' R, 6a ' S)-5 '-(6-methoxypyridine-3-yl) six hydrogen-1 ' H-spiral shells [1,3-dioxolane-2,2 '-pentalene]-5 '-alcohol.Will (1g 5.3mmol) be cooled to-78 ℃ under nitrogen at the 5-bromo-2-methoxypyridine among the anhydrous THF of 50ml.Drip n-butyllithium solution (3.5ml, 5.6mmol, the hexane solution of 1.6M).Stir orange solution 1 hour down at-78 ℃ in addition, in 10 minutes, drip 1 then, 4-cyclohexanedione list condensed ethandiol (960mg, 5.3mmol) solution in anhydrous THF (20ml).Stirred reaction mixture 1 hour allows it be warmed to 20 ℃ and pour in the frozen water (400ml).Isolate orange layer, with ethyl acetate extraction water layer 2 times (20ml * 2).Use MgSO ₄Dry orange organic extract that merges and evaporation.Obtain 1.08g (3.7mmol, productive rate: white crystal 70%), (3a ' R, 6a ' S)-5 '-(6-methoxypyridine-3-yl) six hydrogen-1 ' H-spiral shells [1,3-dioxolane-2,2 '-pentalene]-5 '-alcohol: MS:292 (M+1) with the silica gel chromatography purifying ⁺

Step C

(3aR, 6aS)-5-hydroxyl-5-(6-methoxypyridine-3-yl) six hydrogen pentalene-2 (1H)-ketone.With typically going protection method, by (3a ' R, 6a ' S) the synthetic titled reference compound of-5 '-(6-methoxypyridine-3-yl) six hydrogen-1 ' H-spiral shells [1,3-dioxolane-2,2 '-pentalene]-5 '-alcohol.

Step D

N-[2-((3R)-and 1-[(3aR, 6aS)-5-hydroxyl-5-(6-methoxypyridine-3-yl) octahydro pentalene-2-yl] tetramethyleneimine-3-yl } amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide.Synthesize titled reference compound with the reductive amination method that embodiment 114 describes.MS：(M+H) ⁺547。

Embodiment 364

N-[2-((3R)-and 1-[(3aR, 6aS)-5-hydroxyl-5-phenyl octahydro pentalene-2-yl] tetramethyleneimine-3-yl } amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide.With being similar to the synthetic titled reference compound of method that embodiment 363 describes.MS：(M+H) ⁺516。

Embodiment 365

N-[2-((3R)-and 1-[(3aR, 6aS)-5-hydroxyl-5-pyridin-3-yl octahydro pentalene-2-yl] tetramethyleneimine-3-yl } amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide.With being similar to the synthetic titled reference compound of method that embodiment 363 describes.MS：(M+H) ⁺517。

Embodiment 366

Steps A

5-pyridin-3-yl spiral shell [dicyclo [2.2.2] octane-2,2 '-[1,3] dioxolane]-5-alcohol.Under nitrogen, (1.13g 7.13mmol) is dissolved in the anhydrous diethyl ether, is cooled to-78 ℃, drips n-butyllithium solution (4.50ml, 7.13mmol, the hexane solution of 1.6M) then with the 3-bromopyridine.After 30 minutes, Dropwise 5 H-spiral shell [dicyclo [2.2.2] octane-2,2 '-[1,3] dioxolane]-5-ketone (0.65g, 3.56mmol, J.Org.Chem.1991,56, the 1052-1058) solution in ether and mixture stirred 2 hours at-78 ℃.Allow mixture be warmed to 0 ℃ and dilute then with ethyl acetate.With sodium bicarbonate/water and the orange extract of salt water washing, use MgSO then ₄Drying is filtered and is concentrated.Residuum is elutriant with the ethyl acetate, carries out the silica gel chromatography purifying, obtains the white solid of two kinds of isomer products: higher R _fThe product of value, 0.294g (32%); Low R _fThe product of value, 0.220g (24%).Higher R _fThe product of value:

¹H NMR(CDCl ₃)□δ8.87(s，1H)，8.49(d，1H)，7.91(dt，1H)，7.27(m，1H)，3.92(m，4H)，2.69(dt，1H)，2.20(m，1H)，1.85-2.15(m，3H)，1.60-1.83(m，4H)，1.50(m，1H).

Low R _fThe product of value:

¹H NMR(CDCl ₃)□δ□□8.80(s，1H)，8.50(d，1H)，7.86(dt，1H)，7.29(m，1H)，3.90-4.10(m，4H)，2.44(dt，1H)，2.33(dd，1H)，2.15-2.27(m，2H)，2.00(m，1H)，1.75-1.88(m，2H)，1.70(m，1H)，1.51(m，2H)，1.34(m，1H).

Step B

5-hydroxyl-5-pyridin-3-yl dicyclo [2.2.2] octane-2-ketone.Under nitrogen, with alcohol (the higher R of steps A _fThe isomer of value, 0.290g 1.11mmol) is dissolved among the THF (10ml).(2.0ml, the 4.0M aqueous solution 8.0mmol), at room temperature stirred mixture 4 hours to add hydrochloric acid.Also use twice of ethyl acetate extraction with sodium bicarbonate/water diluted mixture thing.With salt water washing extract, use MgSO ₄Drying is filtered and is concentrated, and obtains light yellow solid, 0.204g (85%).Crude product 2 need not to be further purified and directly can be used for next step.

¹H NMR(CDCl ₃)□δ□□8.74(s，1H)，8.52(d，1H)，7.72(dt，1H)，7.30(dd，1H)，2.66(dt，1H)，2.53(m，2H)，2.41(t，1H)，2.18(t，1H)，2.13(d，1H)，2.09(m，1H)，1.99(m，1H)，1.89(m，1H)，1.62(m，2H).

Step C

N-(2-{[(3R)-1-(5-hydroxyl-5-pyridin-3-yl dicyclo [2.2.2] suffering-2-yl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide.N-{2-oxo-2-[(3R)-tetramethyleneimine-3-base is amino] ethyl }-3-(trifluoromethyl) benzamide hydrochloride salt (100mg, 0.284mmol) and 5-hydroxyl-5-pyridin-3-yl dicyclo [22.2] octane-2-ketone (62.0mg 0.284mmol) is dissolved among the anhydrous THF (10ml).Add triethylamine (80 μ l, 0.57mmol) and sodium triacetoxy borohydride (120mg, 0.57mmol) and at room temperature reaction stirred is spent the night.It is about 1: 1 required product that the TCL demonstration can change into isomer proportion.Reaction mixture is adsorbed on the silica gel, is elutriant with methylene dichloride to 10% ethanol/methylene/0.5 ammonium hydroxide, carries out chromatogram purification.Merge elution fraction, obtain higher R _fThe pure isomer of value and low R _fThe pure isomer of value.Higher R _fThe product of value: LC/MS (positively charged ion) m/z=517.1 (M+H) ⁺Low R _fThe product of value: LC/MS (positively charged ion) m/z=517.2 (M+H) ⁺

Embodiment 367

Steps A

3-methyl isothiazole.Method according to document prepares titled reference compound (Lucchesini, F.; Picci, N.; Pocci, M., Heterocycles, 1989,29,97).Under 0 ℃, with 3-crotonylene-ketone (2.5ml, 0.032mol) and azanol-o-sulfonic acid (3.67g, 0.0324mol) (15ml 0.83mol) mixes with water.Stir after 30 minutes, (3.0g 0.036mol) slowly adds several times with sodium bicarbonate solid in 30 minutes.(3.3g, (25ml, 1.4mol) drips of solution is added in the above-mentioned reaction mixture water 0.036mol) with the Sodium sulfhydrate dihydrate.Remove ice bath then.At room temperature continue in addition to stir 4 hours.Use the extracted with diethyl ether mixture.Dry extract also concentrates.With ether/hexane (1/3) is elutriant, carries out the silica gel chromatography purifying, obtains 1.37g (48.2%) titled reference compound.

Step B

8-(3-methyl-isothiazole-5-yl)-1,4-two oxa-s-spiral shell [4.5] decane-8-alcohol.At-78 ℃, hexane (6.7ml) solution of the n-Butyl Lithium of 1.5M was added to 3-methyl isothiazole lentamente in 20 minutes (1.0g is in tetrahydrofuran (THF) 0.010mol) (15ml) solution.After stirring 30 minutes in addition, in 10 minutes, add 1,4-two oxa-s-spiral shell [4.5] decane-8-ketone (1.56g, tetrahydrofuran (THF) 0.0099mol) (5ml) solution.Reaction mixture stirs 3 hours and warm spending the night to room temperature down in addition at-78 ℃.Behind salt solution quencher reactant, use the ethyl acetate extraction mixture.Dry organic layer also concentrates.With hexane/ethyl acetate (1: 5～1: 1) is elutriant, carries out the silica gel chromatography purifying, obtains 1.8g (70.6%) titled reference compound.MS(M+H) ⁺256。

Step C

4-hydroxyl-4-(3-methyl-isothiazole-5-yl)-pimelinketone.With 8-(3-methyl-isothiazole-5-yl)-1, (0.76g 0.0030mol) is dissolved in the tetrahydrofuran (THF) (10ml) 4-two oxa-s-spiral shell [4.5] decane-8-alcohol, and adds water (5.0ml) solution of the hydrogenchloride of 3.0M.Stir described mixture overnight.Add the potash solid neutralizing acid and add the ethyl acetate extraction product.Extract is dry and concentrated, obtain crude product, can be directly used in next step.

Step D

N-[2-((3R)-and 1-[4-hydroxyl-4-(3-methyl isothiazole-5-yl) cyclohexyl] tetramethyleneimine-3-yl } amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide.With preparing titled reference compound by the ketone that step D makes with the similar method of the description of embodiment 114.MS(M+H) ⁺511。

Embodiment 368

N-{2-[((3R)-1-{4-[3-(methyl fluoride) isothiazole-5-yl]-the 4-hydroxy-cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide.Prepare titled reference compound with the method that is similar to embodiment 367.MS(M+H) ⁺529。

Embodiment 369

N-(2-{[(3R)-1-(4-hydroxyl-4-isothiazole-5-basic ring hexyl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide.Prepare titled reference compound with the method that is similar to embodiment 367.MS(M+H) ⁺497。

Embodiment 370

N-[2-((3R)-and 1-[4-hydroxyl-4-(4-pyrimidine-2-base phenyl) cyclohexyl] tetramethyleneimine-3-yl } amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide.Prepare titled reference compound with the method that is similar to embodiment 282.MS 568(M+H) ⁺。

Embodiment 371

N-[2-((3R)-and 1-[4-(2-cyclopropyl pyrimidine-5-yl)-4-hydroxy-cyclohexyl] tetramethyleneimine-3-yl } amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide.Prepare titled reference compound with the method that is similar to embodiment 276.MS 532(M+H) ⁺。

Embodiment 372

N-(2-{[(3R)-1-(4-hydroxyl-4-pyridazine-4-basic ring hexyl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide.Prepare titled reference compound with the method that is similar to embodiment 276.MS 492(M+H) ⁺。

The pharmaceutical application of The compounds of this invention

The ability of new compound antagonism CCR2 of the present invention effect can be determined by suitable filler test (as the high throughput test).For example, can to certain reagent carry out extracellular acidification test, the test of calcium flux, part in conjunction with test or chemotaxis test (referring to as Hesselgesser etc., J Biol.Chem.273 (25): 15687-15692 (1998); WO00/05265 and WO 98/02151).

In reality test, use can separated or reorganization deutero-CCR2 albumen, and this albumen has at least a Mammals CCR2 property of protein, activity or functional character.Concrete character can be associativity (as with the associativity of part or inhibitor), the signal activity is (as the proteic activation of Mammals G, kytoplasm free ca [Ca ⁺⁺] concentration fast and instantaneously induce increases), cellular response function (as the chemotaxis of white corpuscle release or the hormesis of inflammatory mediator) etc.

In one embodiment, the composition that will contain CCR2 albumen or its various variants remains on and is fit in the bonded environment.Make the CCR2 acceptor contact and detect or test combination between it with tested compounds.

A kind of as the embodiment of selecting in, this test is the test based on cell, wherein employed cell is stablized or transient transfection with solvent or expression test kit with nucleotide sequence (coding CCR2 acceptor).Cell is kept in the environment that is suitable for expression of receptor and takes place to contact in the bonded environment being fit to reagent.Can use standard technique test combination.For example, the bonded degree can be determined with respect to suitable contrast.Simultaneously, the cell part (as the cytolemma part) that contains acceptor can replace whole cell to use.

In conjunction with or the mensuration that is compounded to form can directly or indirectly carry out.For example, available suitable mark (as fluorescent mark, mark, isotopic labeling, enzyme labelling etc.) comes labelled reagent, determines combination by measuring mark then.Specific and/or complicated combination can be assessed as the rival with unmarked reagent or part by competition or substitution investigation.

The CCR2 antagonistic activity of agent (as 3 of formula I of the present invention, II or III, 4-disubstituted pyrroles hydride compounds) of being had a try can suppress (IC for 50% of particular combination in receptors bind test ₅₀Value) desired inhibitor concentration is reported, and wherein uses ¹²⁵MCP-1 of I mark (as part) and peripheral blood lymphocytes (PBMCs is by preparing normal people's whole blood density gradient centrifugation).Preferably particular combination is defined as total binding (as the total cpm on the strainer) and deducts nonspecific combination.Nonspecific combination is defined as the amount of the cpm that still can survey in the presence of excessive unmarked rival (as MCP-1).

Above-mentioned human PBMC s can be used in the suitable combination test.For example, can be with 200,000 to 500,000 cells and 0.1 to 0.2nM ¹²⁵The MCP-1 of I mark in the presence of the tested compounds that is with or without unmarked rival (10nM MCP-1) or various concentration, cultivates together. ¹²⁵The MCP-1 of I mark can make by suitable method or can be available from each goods providers (Perkin Elmer, Boston MA).Association reaction can at room temperature carry out 30 minutes in 50 to 250 μ l binding buffer liquid (by 1M HEPES (pH7.2) and 0.1%BSA (foetal calf serum)).Can be by stopping association reaction by glass fibre filter (Perkin Elmer, preimpregnation is in 0.3% polymine or phosphate buffered saline (PBS) (PBS)) results film fast.Can be with of the binding buffer liquid rinsing that contain 0.5M NaCl or PBS of described strainer with about 600 μ l, dry then, and count the amount of measuring in conjunction with radioactivity by Gamma counter (Perkin Elmer).

The ability of compound antagonism CCR2 effect also can be carried out the leucocyte chemotaxis measurements determination by using suitable cell.Suitable cell comprises that as groups of cells, reconstitution cell or isolated cells these cell expressings CCR2 also experiences the chemotaxis that the CCR2 part is induced (as MCP-1).The human peripheral blood mononuclear cell among the Boyden Chamber (NeuroProbe) that is kept at modification has been used in employed test.Be in or be not in inhibitor and exist down, 500,000 cells in the serum that does not contain the DMEM medium (Vitrogen) are cultivated, and be warming up to 37 ℃.Simultaneously also with chemotaxis test cabinet (Neuro Probe) preheating.With the 10nMMCP-1 of 400 μ l heat add the bottom compartment except that negative contrast porose in, wherein in contrast, add DMEM.8 micron membranes strainers (Neuro Probe) are placed the top and with the sealing of described chamber cap.Subsequently, cell is added to the hole of chamber cap, the hole under itself and the filter membrane is corresponding.With whole chamber insulation under 37 ℃, 5% carbonic acid gas 30 minutes.Subsequently cell is aspirated out, open chamber cap, remove filter membrane lightly.With the top of PBS washing filter membrane 3 times, but do not touch its bottom.Air-dry filter membrane is also used Wright Geimsa staining agent (Sigma) dyeing.With microscope filter membrane is counted.With negative contrast as a setting, all values all deducts this test value.The cell count of the cell count by relatively moving to the hole, bottom compartment that contains antagonist and the bottom compartment that contains MCP-1 contrast hole of migration is determined antagonistic ability.

When using in conjunction with testing scheme, the IC50 of The compounds of this invention is about 0.01 to about 500nM.In chemotaxis test, the IC50 of The compounds of this invention is about 1 to about 3000nM.

Give Mammals such as people with The compounds of this invention, but also can give other Mammalss as needing the animal of veterinary treatment, as performing animal (as dog, cat etc.), farm-animals (as ox, sheep, pig, horse etc.) and laboratory animal (as mouse, rat, cavy etc.).Adopting the Mammals of the inventive method treatment is male or female mammal, and these animals need the adjusting of chemokine receptor activity.Term is regulated will comprise antagonistic action, agonism, part antagonism or part agonism.

In this manual, term treatment significant quantity is meant tissue, system or animal or human's that titled reference compound causes investigator, animal doctor, doctor or other clinicians and studies the biology or the amount of pharmacy response.

Compound of the present invention is given with the treatment significant quantity, for example to treat disease such as class rheumatoid arthritis.The treatment significant quantity of compound be meant can suppress to suffer from assemble with abnormal white cell and/or the patient of activation diseases associated in the amount of one or more processes that mediated by chemokine and receptors bind.The representative instance of this process comprises free ca [Ca in leucocyte migration, integral protein activation, the born of the same parents ²⁺] the instantaneous raising of i concentration and the particle release of proinflammatory medium.Perhaps, the treatment significant quantity of compound is that requirement obtains the required amount that treats and/or prevents effect, if can suppress or reduction and abnormal white cell gathering and/or the relevant disease of activation.

The people that available CFI of the present invention or conditioning agent are handled or the other diseases or the illness of other species include but not limited to: inflammation or anaphylactic disease and illness, comprise the respiratory tract anaphylaxis disease, as asthma, allergic rhinitis, the supersensitivity lung disease, hypersensitivity pneumonitis, eosinophilic cellulitis's (as Well syndrome), the acidophilia pneumonia is (as Loeffler syndrome, the chronic eosinophilic pneumonia), eosinophilic fasciitis's (as Shulman syndrome), delayed type hypersensitivity, interstitial lung disease (ILD) (as the spontaneous lung fibrosis, or the relevant class rheumatoid arthritis of ILD, systemic lupus erythematous, spondylarthritis,ankylosing, the whole body sclerosis, Sjogern syndrome, polymyositis or dermatomyositis); General anaphylaxis or anaphylaxis, drug allergy (as to penicillin, cynnematin allergy), because acidophilia muscle pain syndrome, the insect bite allergy that the picked-up tryptophane causes; Immunological disease is as rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, systemic lupus erythematous, myasthenia gravis, juvenile onset diabetes; Glomerulonephritis, autoimmune thyroiditis, Behcet disease; Transplant rejection (, comprising homograft rejection and/or graft versus host disease (GVH disease)) as in transplantation; Enteritis is as Crohn disease and ulcerative conjunctivitis; Arthritis vertebralis; Scleroderma; Psoriasis (comprising the psoriasis that T is cell-mediated) and inflammatory tetter such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria; Nodular vasculitis (as necrotizing angiitis, cutaneous vasculitis and allergic angiitis); Acidophilia myositis, eosinophilic fasciitis; Have skin or organize the cancer of leukocyte infiltration feature.Also can treat disease or illness that other wherein should suppress not meet the inflammatory response of needs, include but not limited to toxicity (as septic shock, endotoxin shock), polymyositis, the dermatomyositis of reperfusion injury, atherosclerosis, restenosis, some blood malignant tumour, cytokine induction.

Formula I of the present invention, II or III compound can be as oral polarity administrations such as tablet, capsule (various extended release dosage form or the timing release dosage form of comprising), tablet, powder, granule, elixir, tincture, suspensoid, syrup and emulsions.They also can be through intravenously (perfusion or infusion fast), intraperitoneal, subcutaneous or intramuscular administration, the formulation administration that all use the pharmaceutical field those of ordinary skill to know.They can be individually dosed, but usually with the pharmaceutical carrier administration, wherein pharmaceutical carrier is selected according to route of administration and standard pharmaceutical practice.

The dosage regimen of The compounds of this invention certainly should be according to various known factors and different, for example pharmacokinetics feature and the administering mode and the approach of concrete medicament; The length of the applied in any combination of recipient's metabolic stability, discharge rate, medicine, compound effects time, kind, age, sex, healthy state, treatment situation and body weight; The nature and extent of symptom; The kind of Zhi Liao other diseases simultaneously; The frequency of treatment; Concrete route of administration, patient's kidney and liver function situation and the required effect that reaches.Doctor in charge or animal doctor can measure and specify prevention, containment or eliminate the needed effective amount of drug of progress that specifically needs the disease of treatment.

Usually, when being used for above-mentioned effect, the day oral dosage of various activeconstituentss is every day about 0.0001 to 1000mg/kg body weight, preferred about 0.001 to 100mg/kg body weight, and 0.1 to a 20mg/kg body weight most preferably from about.For intravenous administration, with the constant rate of speed infusion time, most preferred dosage is about 0.1 to about 10mg/kg/min.For oral administration, preferred described composition is with the tablet form administration, wherein contain 1.0 to 1000 milligrams of activeconstituentss, particularly 1.0,5.0,10.0,15.0,20.0,25.0,50.0,75.0,100.0,150.0,200.0,250.0,300.0,400.0,500.0,600.0,750.0,800.0,900.0 and 1000.0 milligrams of activeconstituentss, the symptom that is used for patient to be treated is regulated preparation.Can every day give compound of the present invention 1 to 4 time, preferred 1 or 2 time.

The compounds of this invention also can use suitable intranasal administration device with form administration in the nose by local, or uses transdermal patch through the skin administration.When with the transdermal delivery system form administration, certainly, should be in a continuous manner but not intermittent mode gives preparation.

Pharmaceutical diluents, vehicle or carrier (being commonly referred to as pharmaceutical carrier in this manual) that The compounds of this invention is general and suitable mix administration, these carriers are suitably selected according to purpose form of medication (promptly being oral tablet, capsule, elixir, syrup etc.), and meet conventional pharmacy practice.

For example, for with tablet or Capsule form oral administration, active medicine component can be combined described carrier such as lactose, starch, sucrose, glucose, methylcellulose gum, Magnesium Stearate, Lin Suanergai, calcium sulfate, mannitol, Sorbitol Powder etc. with oral, non-toxicity, pharmaceutically acceptable inert support.For combining described carrier such as ethanol, glycerine, water etc. with any oral, non-toxicity, pharmaceutically acceptable inert support with the described oral pharmaceutical component of liquid form oral administration.In addition, when needs or must the time, also suitable binder, lubricant, disintegrating agent and tinting material can be mixed in the mixture.Suitable binder comprise starch, gelatin, natural sugar such as glucose or-lactose, corn sweetener, natural and synthetic gum such as Sudan Gum-arabic, tragakanta or sodiun alginate, carboxymethyl cellulose, polyoxyethylene glycol, wax etc.The lubricant that is used for these formulations comprises sodium oleate, sodium stearate, Magnesium Stearate, Sodium Benzoate, sodium acetate, sodium-chlor etc.Disintegrating agent includes but not limited to starch, methylcellulose gum, agar, wilkinite, xanthan gum etc.

The compounds of this invention can also give the patient by the liposome form of medication, as little unilamelar liposome, big unilamelar liposome and multilamelar liposome.Liposome can derive from various phosphatide, as Yelkin TTS, octadecannamide or phosphatidylcholine.

The compounds of this invention also can combine with various soluble polymers as the target pharmaceutical carrier.This polymkeric substance can comprise Polyvinylpyrolidone (PVP), pyran co-polymer, poly-hydroxypropyl Methacrylamide-phenol, poly-hydroxyethyl l-asparagine phenol or the poly-oxyethylene polylysine that is replaced by palmitoyl.In addition, the present invention also can combine with the biodegradable polymkeric substance of a class, to obtain the controllable release of medicine, described polymkeric substance is the crosslinked or unbodied segmented copolymer of multipolymer, poly-epsilon-caprolactone, polyhydroxybutyrate, poly-former ester, polyacetal, poly-dihydropyrane and the hydrogel of poly(lactic acid), polyglycolic acid, poly(lactic acid) and polyglycolic acid for example.

The formulation per unit dosage that is fit to the The compounds of this invention of administration can comprise about 0.1 milligram to about 100 milligrams of activeconstituentss.In these pharmaceutical compositions, the common content of activeconstituents is about 0.5-95% weight, based on the total weight of composition.

Also can use the gelatine capsule formulation, and can comprise activeconstituents and efflorescence carrier, as lactose, starch, derivatived cellulose, Magnesium Stearate, stearic acid etc.Can use similar thinner to prepare compressed tablets.Tablet and capsule all can be made into the extended release product, so that the lasting release of medicine in for some time to be provided.Compressed tablets can be with sweet tablet or film coating, and covering any offending smell and tablet and air is isolated, or enteric coating is with selectivity disintegration in intestines and stomach.

When using liquid dosage form in the oral administration, they can comprise tinting material and correctives, to improve patient's tolerance.

Usually, water, suitable oil, salt solution, moisture dextrose (glucose) and relevant sugar soln and dibasic alcohol such as propylene glycol or polyoxyethylene glycol are the suitable carrier of parenteral solution.The solution of parenteral admin preferably contains the aqueous solution, the suitable stabilizers of activeconstituents salt, and if desired, buffer substance.Antioxidant alone or in combination such as sodium bisulfite, S-WAT or xitix are suitable stabilizers.Also can use citric acid and salt thereof and EDTA sodium.In addition, parenteral solution can contain sanitas, as alkyl benzyl dimethyl ammonium chloride, methyl p-hydroxybenzoate or propyl ester and butylene-chlorohydrin.Suitable pharmaceutical carrier sees and is set forth in Remington ' sPharmaceutical Sciences that Mack Publishing Company, this book are the canonical reference book of pharmaceutical field.

Pharmaceutical composition of the present invention also can be the oil-in-water form.Oil phase can be vegetables oil, for example sweet oil or peanut oil; Or mineral oil, as whiteruss or its mixture.Suitable emulsifying agent can be naturally occurring natural gum, for example Sudan Gum-arabic or tragakanta; Naturally occurring phosphatide, for example soybean oil, Yelkin TTS and derived from lipid acid and hexose alcohol ester and part ester, the for example condenses of dehydrated sorbitol mono-fatty acid ester and described part ester and ethylene oxide, for example polyoxyethylene dehydrated sorbitol mono-fatty acid ester.Described emulsion also can contain sweeting agent and correctives.

The compounds of this invention can also be used for the suppository form administration of rectal administration.These compositions can be by mixing described medicine and suitable non-irritating excipient preparation, and wherein said vehicle is solid under conventional temperature, but is liquid under rectal temperature, thus will be in rectum fusion to discharge medicine.This class material is Oleum Cocois and polyoxyethylene glycol.

For topical application, can use creme, paste, gelifying agent, solution or the suspensoid etc. that contain The compounds of this invention.When using herein, topical application also comprises collutory and mouth-washes.

Pharmaceutical composition of the present invention and method can comprise that also other are generally used for treating the therapeutical active compound of above-mentioned pathology symptom.

The representational following example of pharmaceutical dosage form that can be used for giving The compounds of this invention:

Capsule

A large amount of unit capsules can be divided into by respectively fill 50 milligrams of powder activities in two part hard gelatin capsules of standard, 100 milligrams of lactose, 25 milligrams of Mierocrystalline celluloses and 3 milligrams of Magnesium Stearates make.

Soft gelatin capsule

Can prepare the mixture of activeconstituents in digestible oil such as soybean oil, oleum gossypii seminis or sweet oil, and it be pumped into the soft gelatin capsule that contains 75 milligrams of activeconstituentss in the gelatin with formation by volumetric pump.Firmly with described capsule washing and dry.

Tablet

Can prepare tablet by the method for routine, unitary dose is 75 milligrams of activeconstituentss, 0.15 milligram of silica gel, 4 milligrams of Magnesium Stearates, 250 milligrams of single crystal fibre elements, 9 milligrams of starch and 75 milligrams of lactose like this.Can apply suitable dressing well known to those skilled in the art, absorb to improve palatability or to postpone.

Injection

The parenteral composition that is fit to by drug administration by injection can be by stirring the formulations prepared from solutions of 1.0% weight activeconstituents in 8% volume propylene glycol and water.This solution application sodium-chlor etc. oozes and sterilizes.

Suspensoid

Can followingly make the aqueous suspensions that is used for oral administration, make to contain 75mg active ingredient dispersed in small, broken bits, 150mg Xylo-Mucine, 3.75mg Sodium Benzoate, 0.75g sorbitol solution, U.S.P. and 0.015ml vanillin food grade,1000.000000ine mesh in the preparation of 5ml.

Embodiment 373

This embodiment describes the drug effect of the CCR2 antagonist of estimating the treatment rheumatoid arthritis.

Animal Model of Rheumatoid Arthritis can be brought out rheumatoid arthritis by the solution in the adjuvant of selecting to rodent injection II Collagen Type VI and be obtained.When beginning and the 21st day, with three groups of rodents (every group of mouse or rat by 15 gene susceptible to (geneticallysusceptible) formed) through the subcutaneous or emulsion of intradermal injection II Collagen Type VI in Complete Freund adjuvant.When initial sensitization and after different administrations, first group of rodent also through peritoneal injection phosphate buffered saline (PBS) (PBS) and Tween 0.5%.When initial sensitization and after different administrations, second group of rodent accepted the CCR2 antagonist of various dose through intraperitoneal, intravenously, subcutaneous, intramuscular, oral cavity or other administering modes.The 3rd group of rodent be as positive control, when initial sensitization and after different administrations, through intraperitoneal with mouse IL-10 or anti-TNF antibiotic treatment.

Monitor the development of animal, and carry out classification according to standard disease depth dimensions (standard disease severity scale) from the 3rd the thoughtful the 8th all swellings joint or sole.The degree of depth of disease is confirmed by the fabric analysis to the joint.

For various purposes, all open source literatures, patent and patent application comprise all its precursors and being attached to herein by reference of the prior art of all references and bibliography.

Though many forms of the present invention disclosed herein are made of exemplary preferred embodiment, many other embodiments also are feasible, and the details of embodiment preferred and other feasible embodiments is not to be restrictive.It only is illustrative, and not restrictive should understanding term used herein.In not departing from the present invention's aim required for protection or scope, can make various equivalent variations.

Claims

1. the compound of a formula I:

R ₁Be independently selected from: carbocyclic ring, heterocycle, aryl, heteroaryl, arylalkyl, heteroarylalkyl, aryl alkenyl, heteroaryl thiazolinyl, aromatic yl polysulfide yl, heteroaryl alkynyl, aromatic yl aminocarbonyl, heteroaryl amino carbonyl, aryl-amino-carbonyl, heteroaryl amino formyl radical, aryl-ureido, heteroaryl urea groups, aryloxy, heteroaryloxy, alkoxy aryl, heteroaryl alkoxyl group, arylamino or heteroaryl amino, and wherein said carbocyclic ring, heterocycle, aryl, arylalkyl, heteroaryl or heteroarylalkyl can be by 0-3 R _1aSubstituting group replaces, wherein R _1aBe independently selected from: halogen; alkyl; thiazolinyl; alkynyl; alkoxyl group; alkoxyalkyl; alkyl-thio-alkyl; hydroxyalkyl; single-; two-or tri haloalkyl; single-; two-or three halogenated alkoxies; nitro; amino; single-or two-substituted-amino; single-or two-substituted-amino alkyl; aminocarboxyl; single-or two-substituted aminocarbonyl; cyclic aminocarbonyl; amino-sulfonyl; single-or two-substituted-amino alkylsulfonyl; alkyl-carbonyl; the cyclic alkyl carbonyl; aryl carbonyl; the heteroaryl carbonyl; alkyl sulphonyl; the cyclic alkyl alkylsulfonyl; aryl sulfonyl; heteroarylsulfonyl; carboxylic acid; the esterification carboxylic acid; alkyl-carbonyl-amino; the cyclic alkyl carbonylamino; aryl-carbonylamino; the heteroaryl carbonylamino; cyano group; arylalkyl; heteroarylalkyl; aryloxy alkyl; the heteroaryloxy alkyl; the aryl alkylthio; the heteroaryl alkylthio; the carboxylamine base; single-or two-substituted-amino formyloxy; R _1b-aryl or R _1b-heteroaryl, wherein R _1bFor H, halogen, OH, amino, list-or two-substituted-amino, list-, two-or tri haloalkyl, alkoxyl group, list-, two-or three halogenated alkoxies, hydroxyalkyl, alkoxyalkyl, aminoalkyl group, list-or two-substituted-amino alkyl, formamyl, sulfamyl, carboxylamine base, urea or cyano group;

Optional R ₁And R ₂Bonding forms volution each other;

r＝0-3。

2. the compound of a formula II:

Y is a key, or be selected from oxygen, sulphur, nitrogen, amido linkage, sulphonamide, ketone ,-CHOH-,-the CHO-alkyl-, oxime or urea;

Z is selected from has 0-3 R ₁₁Substituent carbocyclic ring, aromatic ring, heterocycle or hetero-aromatic ring group, wherein R ₁₁Be independently selected from: halogen; alkyl; thiazolinyl; alkynyl; alkoxyl group; alkoxyalkyl; alkyl-thio-alkyl; alkylthio; single-; two-or tri haloalkyl; single-; two-or three halogenated alkoxies; nitro; amino; single-or two-substituted-amino; single-or two-substituted-amino alkyl; carboxyl; esterifying carboxyl group; formamyl; single-or two-substituted-amino formyl radical; the carboxylamine base; single-or two-substituted-amino formyloxy; sulfamyl; single-or two-replacement sulfamyl; alkyl-carbonyl; the cyclic alkyl alkylsulfonyl; aryl sulfonyl; heteroarylsulfonyl; alkyl-carbonyl; the cyclic alkyl carbonyl; aryl carbonyl; the heteroaryl carbonyl; thiocarbamoyl; cyano group and R _11a-aryl or R _11a-heteroaryl, wherein R _11aFor H, halogen, OH, amino, list-or two-substituted-amino, list-, two-or tri haloalkyl, alkoxyl group, list-, two-or three halogenated alkoxies, formamyl, sulfamyl, carboxylamine base, urea or cyano group;

R ₁Be independently selected from: H; alkyl; thiazolinyl; alkynyl; cycloalkyl; cycloalkenyl group; alkoxyl group; alkylthio; tri haloalkyl; halogen; carbocyclic ring; heterocycle; aryl; heteroaryl; arylalkyl; heteroarylalkyl; aryl alkenyl; the heteroaryl thiazolinyl; aromatic yl polysulfide yl; the heteroaryl alkynyl; aromatic yl aminocarbonyl; the heteroaryl amino carbonyl; aryl-amino-carbonyl; the heteroaryl amino formyl radical; aryl-ureido; the heteroaryl urea groups; aryloxy; heteroaryloxy; alkoxy aryl; the heteroaryl alkoxyl group; arylamino or heteroaryl amino, and wherein said carbocyclic ring; heterocycle; aryl; arylalkyl; heteroaryl or heteroarylalkyl can be by 0-3 R _1aSubstituting group replaces, wherein R _1aBe independently selected from: halogen; alkyl; thiazolinyl; alkynyl; alkoxyl group; alkoxyalkyl; alkyl-thio-alkyl; hydroxyalkyl; single-; two-or tri haloalkyl; single-; two-or three halogenated alkoxies; nitro; amino; single-or two-substituted-amino; single-or two-substituted-amino alkyl; aminocarboxyl; single-or two-substituted aminocarbonyl; cyclic aminocarbonyl; amino-sulfonyl; single-or two-substituted-amino alkylsulfonyl; alkyl-carbonyl; the cyclic alkyl carbonyl; aryl carbonyl; the heteroaryl carbonyl; alkyl sulphonyl; the cyclic alkyl alkylsulfonyl; aryl sulfonyl; heteroarylsulfonyl; carboxylic acid; the esterification carboxylic acid; alkyl-carbonyl-amino; the cyclic alkyl carbonylamino; aryl-carbonylamino; the heteroaryl carbonylamino; cyano group; arylalkyl; heteroarylalkyl; aryloxy alkyl; the heteroaryloxy alkyl; the aryl alkylthio; the heteroaryl alkylthio; the carboxylamine base; single-or two-substituted-amino formyloxy; R _1b-aryl or R _1b-heteroaryl, wherein R _1bFor H, halogen, OH, amino, list-or two-substituted-amino, list-, two-or tri haloalkyl, alkoxyl group, list-, two-or three halogenated alkoxies, hydroxyalkyl, alkoxyalkyl, aminoalkyl group, list-or two-substituted-amino alkyl, formamyl, sulfamyl, carboxylamine base, urea or cyano group;

Optional R ₁And R ₂Bonding forms volution each other;

R ₉And R ₁₀Be independently selected from H, OH, amino, alkoxyl group, list-or disubstituted amido, alkyl, thiazolinyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, carbocyclic ring or heterocycle; And

Optional R ₉And R ₁₀But cyclisation forms carbocyclic ring or heterocycle.

3. the compound of claim 2, wherein R ₂Be OH, R ₃, R ₄, R ₅, R ₆, R ₇And R ₈Be hydrogen, R ₁Be selected from phenyl; the 4-aminomethyl phenyl; 3-methyl-phenyl; the 2-aminomethyl phenyl; the 4-bromophenyl; the 3-bromophenyl; the 4-chloro-phenyl-; 3-chloro-phenyl; the 4-trifluoromethyl; the 3-trifluoromethyl; the 2-trifluoromethyl; the 2-p-methoxy-phenyl; 2-methoxyl group-5-pyridyl; 2-oxyethyl group-5-pyridyl; 3; the 4-methylenedioxyphenyl; the 4-fluorophenyl; 3-Trifluoromethyl-1 H-pyrazol-1-yl; the 3-fluorophenyl; the 4-p-methoxy-phenyl; the 3-p-methoxy-phenyl; quinolyl-4; 3-methyl isophthalic acid H-pyrazol-1-yl; 3; 5-dimethyl-1H-pyrazol-1-yl; the 4-trifluoromethyl; the 3-trifluoromethyl; 3; the 4-methylenedioxyphenyl; the 4-cyano-phenyl; 4-(amino-carbonyl) phenyl; pyridine-2-base; pyridin-3-yl; pyridin-4-yl; 4-picoline-2-base; 5-picoline-2-base; 6-picoline-2-base; 6-methoxypyridine-2-base; 6-methoxypyridine-3-base; 6-picoline-3-base; 6-ethylpyridine-3-base; 6-isopropyl pyridine-3-base; 6-cyclopropyl pyridin-3-yl; 1-oxidation-pyridin-3-yl; 1-pyridine oxide-2-base; quinolyl-4; the 3-cyano-phenyl; 3-(amino-carbonyl) phenyl; 1-pyridine oxide-4-base; 4-(morpholine-4-base carbonyl)-phenyl; 5-(morpholine-4-base carbonyl) pyridine-2-base; 6-(morpholine-4-base carbonyl) pyridin-3-yl; 4-(4-methylpiperazine-1-base-carbonyl) phenyl; 6-(azetidine-1-yl) pyridin-3-yl; 5-cyanopyridine-2-base; 6-cyanopyridine-3-base; 5-(methoxyl group-methyl) pyridine-2-base; 5-(1-hydroxyl-1-methylethyl) pyridine-2-base; 4-(B aminocarbonyl) phenyl; 4-(isopropyl amino-carbonyl) phenyl; 4-(uncle's fourth aminocarboxyl) phenyl; 4-(dimethylamino carbonyl) phenyl; 4-[(azetidine-1-yl) carbonyl] phenyl; 4-[(pyridine-1-yl) carbonyl] phenyl; 4-[(morpholine-4-yl) carbonyl] phenyl; 4-(dimethyl-aminocarboxyl)-2-aminomethyl phenyl; 2-methyl-4-(methylamino--carbonyl) phenyl; 3-methyl-4-(methylamino carbonyl) phenyl; 4-(dimethylamino carbonyl)-3-aminomethyl phenyl; 3-methyl-4-(tetramethyleneimine-1-base carbonyl) phenyl; 4-(dimethylamino carbonyl)-3-fluorophenyl; 4-[(2; 2; the 2-trifluoroethyl) aminocarboxyl] phenyl; 3-fluoro-4-amino-carbonyl-phenyl; 4-ethyl-aminocarboxyl-3-fluorophenyl; 3-amino-carbonyl phenyl; 3-dimethyl-aminocarbonyl-phenyl; 5-dimethylamino carbonyl-2-p-methoxy-phenyl; 2-methoxyl group-5-methyl-aminocarbonyl-phenyl; 3-(methylamino carbonylamino) phenyl; 6-(morpholine-4-yl)-pyridin-3-yl; 6-Dimethylamino pyridine-3-base; 6-sec.-propyl aminopyridine-3-base; 6-(tetramethyleneimine-1-yl)-pyridin-3-yl; 6-cyclopropyl aminopyridine-3-base; 6-ethoxy pyridine-3-base; 6-(2-fluorine oxyethyl group) pyridin-3-yl; 6-(2; the 2-difluoroethoxy) pyridin-3-yl; 6-(2; 2; the 2-trifluoro ethoxy) pyridin-3-yl; the 4-iodophenyl; 5-(tetramethyleneimine-1-base carbonyl)-2-pyridyl; 5-(morpholine-4-base-carbonyl)-2-pyridyl; 5-dimethylamino carbonyl-2-pyridyl; 4-amino-carbonyl-aminophenyl; 6-(1-hydroxyl-1-methylethyl) pyridin-3-yl; 4-(1-hydroxyl-1-methylethyl)-phenyl; 4-(methoxymethyl) phenyl; 3-fluoro-4-(methoxymethyl) phenyl; 4-(dimethylamino) phenyl; 4-(dimethylamino)-3-fluorophenyl; 1H-indazole-5-base; 1-methyl isophthalic acid H-indazole-5-base; 2-methyl isophthalic acid H-indazole-5-base; 1; the 3-thiazol-2-yl; 5-ethyl-1; the 3-thiazol-2-yl; 5-(methyl-aminocarboxyl)-1; the 3-thiazol-2-yl; 1; 3-thiazole-5-base; 2-(methoxycarbonyl amino)-1; 3-thiazole-5-base; 2-sec.-propyl-1; 3-thiazole-5-base; 5-(pyridin-3-yl)-1; the 3-thiazol-2-yl; 5-(morpholine-4-base carbonyl)-1; the 3-thiazol-2-yl; 5-aminocarboxyl-1; the 3-thiazol-2-yl; 5-dimethylamino carbonyl-1; the 3-thiazol-2-yl; 5-(tetramethyleneimine-1-base carbonyl)-1; the 3-thiazol-2-yl; 5-allyl group-1; the 3-thiazol-2-yl; 5-propyl group-1; the 3-thiazol-2-yl; 5-B aminocarbonyl-1; the 3-thiazol-2-yl; 5-phenyl-1; the 3-thiazol-2-yl; the 5-methyl isophthalic acid; the 3-thiazol-2-yl; 5-methylol-1; the 3-thiazol-2-yl; 5-(1-hydroxyl-1-methylethyl)-1; the 3-thiazol-2-yl; 5-methoxyl group-methyl isophthalic acid; the 3-thiazol-2-yl; 5-(2-pyridyl)-1; the 3-thiazol-2-yl; 2-(tetramethyleneimine-1-yl)-1; 3-thiazole-4-base; 2-(morpholine-4-yl)-1; 3-thiazole-4-base; the 2-methyl isophthalic acid; 3-thiazole-5-base; 2-(1-hydroxyl-1-methylethyl)-1; 3-thiazole-5-base; 2-(tetramethyleneimine-1-yl)-1; 3-thiazole-5-base; 2-oxyethyl group-1; 3-thiazole-5-base; 2-ethyl-1; 3-thiazole-5-base; 2-(tetramethyleneimine-1-ylmethyl)-1; 3-thiazole-5-base; 2-(morpholine-4-yl)-1; 3-thiazole-5-base; 2-methoxyl group-methyl isophthalic acid; 3-thiazole-5-base; 2-isobutyl--1; 3-thiazole-5-base; 2-B aminocarbonyl-1; 3-thiazole-5-base; 2-(tetramethyleneimine-1-base carbonyl)-1,3-thiazoles-5-base; 2-(morpholine-4-base carbonyl)-1,3-thiazoles-5-base; 2-(3-pyridyl)-1; 3-thiazole-5-base; 2-(2-pyridyl)-1; 3-thiazole-5-base; the 4-methyl isophthalic acid, the 3-thiazol-2-yl; 1,3-benzo-thiazol-2-yl; pyrimidine-5-base; pyrimidine-4-base; pyrimidine-2-base; pyridazine-3-base; pyrazine-2-base; 2-methoxyl group-pyrimidine-5-base; 2-oxyethyl group-pyrimidine-5-base; 2-(2-fluorine oxyethyl group) pyrimidine-5-base; 2-methylpyrimidine-5-base; 2-ethyl-pyrimidine-5-base; 2-sec.-propyl pyrimidine-5-base; 2-cyclopropyl pyrimidine-5-base; pyrimidine-4-base; 4-(pyrimidine-5-yl) phenyl; 4-(1; 3-oxazole-2-yl) phenyl; 4-(1H-imidazoles-1-yl) phenyl; 4-(morpholine-4-yl) phenyl; 5-(pyrazine-2-yl) pyridine-2-base; 4-(1-methyl isophthalic acid H-imidazoles-1-yl) phenyl; 4-(4; 6-dimethyl pyrimidine-5-yl) phenyl; 6-bromopyridine-3-base; 5-bromopyridine-2-base; 4 '-(methylsulfonyl) biphenyl-4-base; 3 '-(methylsulfonyl) biphenyl-4-base; 3 '-(methoxyl group-carbonyl)-biphenyl-4-base; 4-(2,3-dihydro-1,4-benzo dioxine-6-yl) phenyl; 4 '-(dimethyl-amino)-biphenyl-4-base; 4-(pyridin-3-yl) phenyl; 4-(1H-pyrazoles-4-yl) phenyl; 4-(3; 3 '-dipyridyl-6-base; 4-(3; 4 '-dipyridyl-6-base; 5-(3-acetylphenyl) pyridine-2-base; 5-[3-(dimethyl-amino) phenyl] pyridine-2-base; 5-[3-(trifluoromethyl) phenyl] pyridine-2-base; 5-[4-(methylsulfonyl) phenyl)] pyridine-2-base; 5-(14-methoxyl group-phenyl) pyridine-2-base; 5-(3-methoxyl group-phenyl) pyridine-2-base; 5-[3-(aminocarboxyl) phenyl] pyridine-2-base; 5-(4-fluoro-phenyl) pyridine-2-base; 5-(34-difluorophenyl) pyridine-2-base; 5-(3,5-dimethyl isoxazole-4-yl) pyridine-2-base; 5-(1-methyl isophthalic acid H-pyrazoles-4-yl) pyridine-2-base; 5-(1H-pyrazoles-4-yl) pyridine-2-base; 5-(1-cumarone-2-yl) pyridine-2-base; 5-(1,3-benzodioxole-5-yl) pyridine-2-base; 5-(2-formyl-phenyl) pyridine-2-base; 4-(2 '-formyl) biphenyl-4-base; 5-(1; 3-oxazole-2-yl) pyridine-2-base; 6-(1; 3-oxazole-2-yl) pyridin-3-yl; 4-(1,3-thiazoles-2-yl) phenyl; 5-(1,3-thiazoles-2-yl) pyridine-2-base; 6-(1; the 3-thiazol-2-yl) pyridin-3-yl; 6-(1H-imidazoles-1-yl) pyridin-3-yl; 5-(1H-imidazoles-1-yl) pyridine-2-base; 6-phenylpyridine-3-base; 5-(pyrimidine-5-yl) pyridine-2-base; 5-(pyrimidine-2-base) pyridine-2-base; 5-(3-aminocarbonyl-phenyl) pyridine-2-base; 4-(1-methyl isophthalic acid H-imidazol-4 yl) phenyl; 4-(1H-imidazol-4 yl) phenyl; 5-[2-(methylol) phenyl] pyridine-2-base; 2 '-(methylol) biphenyl-4-base; the 5-{2-[(dimethylamino) methyl] phenyl } pyridine-2-base; 2 '-[(dimethylamino) methyl] biphenyl-4-base; 5-methyl fluoride pyrazine-2-base; 5-two fluoro-methyl-pyrazines-2-base; 5-methyl-pyrazine-2-base; 2-methylpyrimidine-5-base; 2-methyl fluoride-pyrimidine-5-base; 2-difluoromethyl pyrimidine-5-base; 2-trifluoromethyl pyrimidine-5-base; 2-cyclopropyl pyrimidine-5-base; isothiazole-5-base; 3-methyl isothiazole-5-base; 3-methyl fluoride-isothiazole-5-base; 4-(dimethylamino-carbonyl) phenyl; 4-(methylamino-carbonyl) phenyl; 4-(morpholine-4-base carbonyl) phenyl; 4-(piperidines-1-base carbonyl) phenyl; 3-fluoro-4-(tetramethyleneimine-1-base carbonyl) phenyl; 5-(tetramethyleneimine-1-base carbonyl) pyridine-2-base; 5-(dimethylamino carbonyl) pyridine-2-base; 5-(morpholine-4-base carbonyl) pyridine-2-base; quinoline purine-4-base; 6-methoxypyridine-3-base; 6-(morpholine-4-yl) pyridin-3-yl; 4-(dimethyl-amino methyl) phenyl; 5-(dimethylamino methyl) pyridine-2-base; 5-(dimethylamino carbonyl)-pyridine-2-base; 4-[hydroxyl (pyridin-3-yl) methyl] phenyl; 6-[(hydroxyl-(pyridin-3-yl) methyl) pyridin-3-yl; 6-(dimethylamino carbonyl)-pyridin-3-yl; 4-(4-hydroxy piperidine-1-base carbonyl) phenyl; 4-(4-methoxyl group piperidines-1-base carbonyl) phenyl; 5-(4-methoxyl group piperidines-1-base carbonyl)-pyridine-2-base; 6-(4-methoxyl group piperidines-1-base carbonyl) pyridin-3-yl; phenoxy group; benzyloxy; the 2-thienyl; 2-sec.-propyl-1,3-thiazoles-5-base; 4-(pyrimidine-2-base) phenyl; 4-(pyrimidine-4-yl) phenyl and 5-(methoxymethyl) pyridine-2-base and X-Y-Z are

M=1 wherein.

4. the compound of claim 2, wherein R ₂Be H, R ₃, R ₄, R ₅, R ₆, R ₇And R ₈Be hydrogen, R ₁Be selected from phenyl; pyridine-2-base; the 4-aminomethyl phenyl; 3-methyl-phenyl; the 2-aminomethyl phenyl; the 4-bromophenyl; the 3-bromophenyl; the 4-chloro-phenyl-; 3-chloro-phenyl; the 4-trifluoromethyl; the 3-trifluoromethyl; the 2-trifluoromethyl; the 2-p-methoxy-phenyl; 3; the 4-methylenedioxyphenyl; the 4-fluorophenyl; 3-Trifluoromethyl-1 H-pyrazol-1-yl; the 3-fluorophenyl; the 3-chloro-phenyl-; the 4-p-methoxy-phenyl; the 3-p-methoxy-phenyl; pyridin-4-yl; pyridin-3-yl; 6-picoline-2-base; 6-picoline-3-base; 6-ethylpyridine-3-base; 6-isopropyl pyridine-3-base; quinolyl-4; 3-methyl isophthalic acid H-pyrazol-1-yl; 3; 5-dimethyl-1H-pyrazol-1-yl; the 4-cyano-phenyl; 4-(amino-carbonyl) phenyl; 1-epoxy pyridin-4-yl; pyridine-2-base; 4-picoline-2-base; 5-picoline-2-base; 6-picoline-2-base; 6-methoxypyridine-3-base; 6-picoline-3-base; 6-ethylpyridine-3-base; 6-isopropyl pyridine-3-base; 6-cyclopropyl pyridin-3-yl; 1-pyridine oxide-3-base; 1-pyridine oxide-2-base; the 3-cyano-phenyl; 3-(amino-carbonyl) phenyl; 1-pyridine oxide-4-base; 4-(morpholine-4-base carbonyl)-phenyl; 5-(morpholine-4-base carbonyl) pyridine-2-base; 6-(morpholine-4-base carbonyl) pyridin-3-yl; 4-(4-methylpiperazine-1-base-carbonyl) phenyl; 6-(azetidine-1-yl) pyridin-3-yl; 5-cyanopyridine-2-base; 6-cyanopyridine-3-base; 5-(methoxyl group-methyl) pyridine-2-base; 5-(1-hydroxyl-1-methylethyl) pyridine-2-base; the 5-dimethylamino methyl; 4-B aminocarbonyl-phenyl; 4-sec.-propyl aminocarbonyl-phenyl; 4-tertiary butyl aminocarbonyl-phenyl; 4-dimethylamino carbonyl phenyl; 4-(azetidine-1-yl) carbonyl phenyl; 4-(tetramethyleneimine-1-yl) carbonyl phenyl; 4-(morpholine-4-yl) carbonyl phenyl; 4-(dimethyl-aminocarboxyl)-2-aminomethyl phenyl; 2-methyl-4-(methylamino--carbonyl) phenyl; 3-methyl-4-(amino-carbonyl) phenyl; 4-(dimethylamino carbonyl)-3-aminomethyl phenyl; 3-methyl-4-(tetramethyleneimine-1-base carbonyl) phenyl; 4-(dimethylamino carbonyl)-3-fluorophenyl; 4-[(2; 2; the 2-trifluoroethyl) aminocarboxyl] phenyl; 3-fluoro-4-amino-carbonyl-phenyl; 4-ethyl-aminocarboxyl-3-fluorophenyl; 3-amino-carbonyl phenyl; 3-dimethyl-aminocarbonyl-phenyl; 5-dimethylamino carbonyl-2-p-methoxy-phenyl; 2-methoxyl group-5-methyl-aminocarbonyl-phenyl; 3-(methylamino carbonylamino) phenyl; 6-(morpholine-4-yl)-pyridin-3-yl; 6-Dimethylamino pyridine-3-base; 6-sec.-propyl aminopyridine-3-base; 6-(tetramethyleneimine-1-yl)-pyridin-3-yl; 6-cyclopropyl aminopyridine-3-base; 6-ethoxy pyridine-3-base; 6-(2-fluorine oxyethyl group) pyridin-3-yl; 6-(2; the 2-difluoroethoxy) pyridin-3-yl; 6-(2; 2; the 2-trifluoro ethoxy) pyridin-3-yl; the 4-iodophenyl; 5-(tetramethyleneimine-1-base carbonyl)-2-pyridyl; 5-(morpholine-4-base-carbonyl)-2-pyridyl; 5-dimethylamino carbonyl-2-pyridyl; 4-dimethylamino carbonyl-aminophenyl; 6-(1-hydroxyl-1-methylethyl) pyridin-3-yl; 4-(1-hydroxyl-1-methylethyl)-phenyl; 4-(methoxymethyl) phenyl; 3-fluoro-4-(methoxymethyl) phenyl; 4-(dimethylamino) phenyl; 4-(dimethylamino)-3-fluorophenyl; 1H-indazole-5-base; 1-methyl isophthalic acid H-indazole-5-base; 2-methyl isophthalic acid H-indazole-5-base; 1; the 3-thiazol-2-yl; 5-ethyl-1; the 3-thiazol-2-yl; 5-(methyl-aminocarboxyl)-1; the 3-thiazol-2-yl; 1; 3-thiazole-5-base; 2-(methoxycarbonyl amino)-1; 3-thiazole-5-base; 2-sec.-propyl-1; 3-thiazole-5-base; 5-(pyridin-3-yl)-1; the 3-thiazol-2-yl; 5-(morpholine-4-base carbonyl)-1; the 3-thiazol-2-yl; 5-aminocarboxyl-1; the 3-thiazol-2-yl; 5-dimethylamino carbonyl-1; the 3-thiazol-2-yl; 5-(tetramethyleneimine-1-base carbonyl)-1; the 3-thiazol-2-yl; 5-allyl group-1; the 3-thiazol-2-yl; 5-propyl group-1; the 3-thiazol-2-yl; 5-B aminocarbonyl-1; the 3-thiazol-2-yl; 5-phenyl-1; the 3-thiazol-2-yl; the 5-methyl isophthalic acid; the 3-thiazol-2-yl; 5-methylol-1; the 3-thiazol-2-yl; 5-(1-hydroxyl-1-methylethyl)-1; the 3-thiazol-2-yl; 5-methoxyl group-methyl isophthalic acid; the 3-thiazol-2-yl; 5-(2-pyridyl)-1; the 3-thiazol-2-yl; 2-(tetramethyleneimine-1-yl)-1; 3-thiazole-4-base; 2-(morpholine-4-yl)-1; 3-thiazole-4-base; the 2-methyl isophthalic acid; 3-thiazole-5-base; 2-(1-hydroxyl-1-methylethyl)-1; 3-thiazole-5-base; 2-(tetramethyleneimine-1-yl)-1; 3-thiazole-5-base; 2-oxyethyl group-1; 3-thiazole-5-base; 2-ethyl-1; 3-thiazole-5-base; 2-(tetramethyleneimine-1-ylmethyl)-1; 3-thiazole-5-base; 2-(morpholine-4-yl)-1; 3-thiazole-5-base; 2-methoxyl group-methyl isophthalic acid; 3-thiazole-5-base; 2-isobutyl--1; 3-thiazole-5-base; 2-B aminocarbonyl-1; 3-thiazole-5-base; 2-(tetramethyleneimine-1-base carbonyl)-1,3-thiazoles-5-base; 2-(morpholine-4-base carbonyl)-1,3-thiazoles-5-base; 2-(3-pyridyl)-1; 3-thiazole-5-base; 2-(2-pyridyl)-1; 3-thiazole-5-base; the 4-methyl isophthalic acid, the 3-thiazol-2-yl; 1,3-benzo-thiazol-2-yl; pyrimidine-5-base; pyrimidine-2-base; pyridazine-4-base; pyridazine-3-base; pyrazine-2-base; 2-methylpyrimidine-5-base; 2-ethylpyridine-5-base; 2-sec.-propyl pyrimidine-5-base; 2-cyclopropyl pyrimidine-5-base; 2-methoxyl group-pyrimidine-5-base; 2-oxyethyl group-pyrimidine-5-base; 2-(2-fluorine oxyethyl group) pyrimidine-5-base; pyrimidine-4-base; 4-(pyrimidine-5-yl) phenyl; 4-(1; 3-oxazole-2-yl) phenyl; 4-(1H-imidazoles-1-yl) phenyl; 4-(morpholine-4-yl) phenyl; 5-(pyrazine-2-yl) pyridine-2-base; 4-(1-methyl isophthalic acid H-imidazoles-5-yl) phenyl; 4-(4; 6-dimethyl pyrimidine-5-yl) phenyl; 6-bromopyridine-3-base; 5-bromopyridine-2-base; 4 '-(methylsulfonyl) biphenyl-4-base; 3 '-(methylsulfonyl) biphenyl-4-base; 3 '-(methoxyl group-carbonyl)-biphenyl-4-base; 4-(2,3-dihydro-1,4-benzo dioxine-6-yl) phenyl; 4 '-(dimethyl-amino)-biphenyl-4-base; 4-(pyridin-3-yl) phenyl; 4-(1H-pyrazoles-4-yl) phenyl; 4-(3; 3 '-dipyridyl-6-base; 4-(3; 4 '-dipyridyl-6-base; 5-(3-acetylphenyl) pyridine-2-base; 5-[3-(dimethyl-amino) phenyl] pyridine-2-base; 5-[3-(trifluoromethyl) phenyl] pyridine-2-base; 5-[4-(methylsulfonyl) phenyl] pyridine-2-base; 5-(4-methoxyl group-phenyl) pyridine-2-base; 5-(3-methoxyl group-phenyl) pyridine-2-base; 5-[3-(aminocarboxyl) phenyl] pyridine-2-base; 5-(4-fluoro-phenyl) pyridine-2-base; 5-(3, the 4-difluorophenyl) pyridine-2-base; 5-(3,5-dimethyl isoxazole-4-yl) pyridine-2-base; 5-(1-methyl isophthalic acid H-pyrazoles-4-yl) pyridine-2-base; 5-(1H-pyrazoles-4-yl) pyridine-2-base; 5-(1-cumarone-2-yl) pyridine-2-base; 5-(1; 3-benzodioxole-5-yl) pyridine-2-base; 5-(2-formyl-phenyl) pyridine-2-base; 4-(2 '-formyl) biphenyl-4-base; 5-(1; 3-oxazole-2-yl) pyridine-2-base; 6-(1,3-oxazole-2-yl) pyridin-3-yl; 4-(1,3-thiazoles-2-yl) phenyl; 5-(1; the 3-thiazol-2-yl) pyridine-2-base; 6-(1; the 3-thiazol-2-yl) pyridin-3-yl; 6-(1H-imidazoles-1-yl) pyridin-3-yl; 5-(1H-imidazoles-1-yl) pyridine-2-base; 6-phenylpyridine-3-base; 5-(pyrimidine-5-yl) pyridine-2-base; 5-(pyrimidine-2-base) pyridine-2-base; 5-(3-aminocarbonyl-phenyl) pyridine-2-base; 4-(1-methyl isophthalic acid H-imidazol-4 yl) phenyl; 4-(1H-imidazol-4 yl) phenyl; 5-[2-(methylol) phenyl] pyridine-2-base; 2 '-(methylol) biphenyl-4-base; the 5-{2-[(dimethylamino) methyl] phenyl } pyridine-2-base; 2 '-[(dimethylamino) methyl] biphenyl-4-base; 5-methyl fluoride pyrazine-2-base; 5-two fluoro-methyl-pyrazines-2-base; 5-methyl-pyrazine-2-base; 2-methylpyrimidine-5-base; 2-methyl fluoride-pyrimidine-5-base; 2-difluoromethyl pyrimidine-5-base; 2-trifluoromethyl pyrimidine-5-base; 2-cyclopropyl pyrimidine-5-base; isothiazole-5-base; 3-methyl isothiazole-5-base; 3-methyl fluoride-isothiazole-5-base; 4-(dimethylamino-carbonyl) phenyl; 4-(methylamino-carbonyl) phenyl; 4-(morpholine-4-base carbonyl) phenyl; 4-(piperidines-1-base carbonyl) phenyl; 3-fluoro-4-(tetramethyleneimine-1-base carbonyl) phenyl; 5-(tetramethyleneimine-1-base carbonyl) pyridine-2-base; 5-(dimethylamino carbonyl) pyridine-2-base; 5-(morpholine-4-base carbonyl) pyridine-2-base; quinolyl-4; 6-methoxypyridine-3-base; 6-(morpholine-4-yl) pyridin-3-yl; 4-(dimethyl-amino methyl) phenyl; 5-(dimethylamino methyl) pyridine-2-base; 5-(dimethylamino carbonyl)-pyridine-2-base; 4-[hydroxyl (pyridin-3-yl) methyl] phenyl; 6-[(hydroxyl-(pyridin-3-yl) methyl) pyridin-3-yl; 6-(dimethylamino carbonyl)-pyridin-3-yl; 4-(4-hydroxy piperidine-1-base carbonyl) phenyl; 4-(4-methoxyl group piperidines-1-base carbonyl) phenyl; 5-(4-methoxyl group piperidines-1-base carbonyl)-pyridine-2-base; 6-(4-methoxyl group piperidines-1-base carbonyl) pyridin-3-yl; phenoxy group; benzyloxy; the 2-thienyl; 2-sec.-propyl-1,3-thiazoles-5-base; 4-(pyrimidine-2-base) phenyl; 4-(pyrimidine-4-yl) phenyl and 5-(methoxymethyl) pyridine-2-base, and X-Y-Z is

M=1 wherein.

5. the compound of claim 2, wherein R ₂Be H, R ₃, R ₄, R ₅, R ₆Be hydrogen, R ₇Be hydroxyl and R ₈Be hydrogen, R ₁Be selected from phenyl; pyridine-2-base; the 4-aminomethyl phenyl; 3-methyl-phenyl; the 2-aminomethyl phenyl; the 4-bromophenyl; the 3-bromophenyl; the 4-chloro-phenyl-; 3-chloro-phenyl; the 4-trifluoromethyl; the 3-trifluoromethyl; the 2-trifluoromethyl; the 2-p-methoxy-phenyl; 3; the 4-methylenedioxyphenyl; the 4-fluorophenyl; 3-Trifluoromethyl-1 H-pyrazol-1-yl; the 3-fluorophenyl; the 3-chloro-phenyl-; the 4-p-methoxy-phenyl; the 3-p-methoxy-phenyl; pyridin-4-yl; pyridin-3-yl; quinolyl-4; 3-methyl isophthalic acid H-pyrazol-1-yl; 3; 5-dimethyl-1H-pyrazol-1-yl; the 4-cyano-phenyl; 4-(amino-carbonyl) phenyl; 1-pyridine oxide-4-base; the 4-aminomethyl phenyl; the 4-p-methoxy-phenyl; the 3-p-methoxy-phenyl; the 4-fluorophenyl; the 3-fluorophenyl; pyridine-2-base; pyridin-3-yl; pyridin-4-yl; 4-picoline-2-base; 5-picoline-2-base; 6-picoline-2-base; 6-methoxypyridine-2-base; 6-methoxypyridine-3-base; 6-picoline-3-base; 6-ethylpyridine-3-base; 6-isopropyl pyridine-3-base; 6-cyclopropyl pyridin-3-yl; 1-pyridine oxide-3-base; 1-pyridine oxide-2-base; the 3-cyano-phenyl; 3-(amino-carbonyl) phenyl; 1-pyridine oxide-4-base; 4-(morpholine-4-base carbonyl-)-phenyl; 5-(morpholine-4-base carbonyl) pyridine-2-base; 6-(morpholine-4-base carbonyl) pyridin-3-yl; 4-(4-methylpiperazine-1-base-carbonyl) phenyl; 6-(azetidine-1-yl) pyridin-3-yl; 5-cyanopyridine-2-base; 6-cyanopyridine-3-base; 5-(methoxyl group-methyl) pyridine-2-base; 5-(1-hydroxyl-1-methylethyl) pyridine-2-base; the 5-dimethylamino methyl; 4-B aminocarbonyl phenyl; 4-isopropyl amino-carbonyl phenyl; uncle's 4-fourth aminocarbonyl-phenyl; 4-dimethylamino carbonyl-phenyl; 4-(azetidine-1-yl) carbonyl phenyl; 4-(tetramethyleneimine-1-yl) carbonyl phenyl; 4-(morpholine-4-yl) carbonyl phenyl; 4-(dimethyl-aminocarboxyl)-2-aminomethyl phenyl; 2-methyl-4-(methylamino--carbonyl) phenyl; 3-methyl-4-(amino-carbonyl) phenyl; 4-(dimethylamino carbonyl)-3-aminomethyl phenyl; 3-methyl-4-(tetramethyleneimine-1-base carbonyl) phenyl; 4-(dimethylamino carbonyl)-3-fluorophenyl; 4-[(2; 2; the 2-trifluoroethyl) aminocarboxyl] phenyl; 3-fluoro-4-amino-carbonyl-phenyl; 4-ethyl-aminocarboxyl-3-fluorophenyl; 3-amino-carbonyl phenyl; 3-dimethyl-aminocarbonyl-phenyl; 5-dimethylamino carbonyl-2-p-methoxy-phenyl; 2-methoxyl group-5-methyl-aminocarbonyl-phenyl; 3-(methylamino carbonylamino) phenyl; 6-(morpholine-4-yl)-pyridin-3-yl; 6-Dimethylamino pyridine-3-base; 6-sec.-propyl aminopyridine-3-base; 6-(tetramethyleneimine-1-yl)-pyridin-3-yl; 6-cyclopropyl aminopyridine-3-base; 6-ethoxy pyridine-3-base; 6-(2-fluorine oxyethyl group) pyridin-3-yl; 6-(2; the 2-difluoroethoxy) pyridin-3-yl; 6-(2; 2; the 2-trifluoro ethoxy) pyridin-3-yl; the 4-iodophenyl; 5-(tetramethyleneimine-1-base carbonyl)-2-pyridyl; 5-(morpholine-4-base-carbonyl)-2-pyridyl; 5-dimethylamino carbonyl-2-pyridyl; 4-amino-carbonyl-aminophenyl; 6-(1-hydroxyl-1-methylethyl) pyridin-3-yl; 4-(1-hydroxyl-1-methylethyl)-phenyl; 4-(methoxymethyl) phenyl; 3-fluoro-4-(methoxymethyl) phenyl; 4-(dimethylamino) phenyl; 4-(dimethylamino)-3-fluorophenyl; 1H-indazole-5-base; 1-methyl isophthalic acid H-indazole-5-base; 2-methyl isophthalic acid H-indazole-5-base; 1; the 3-thiazol-2-yl; 5-ethyl-1; the 3-thiazol-2-yl; 5-(methyl-aminocarboxyl)-1; the 3-thiazol-2-yl; 1; 3-thiazole-5-base; 2-(methoxycarbonyl amino)-1; 3-thiazole-5-base; 2-sec.-propyl-1; 3-thiazole-5-base; 5-(pyridin-3-yl)-1; the 3-thiazol-2-yl; 5-(morpholine-4-base carbonyl)-1; the 3-thiazol-2-yl; 5-aminocarboxyl-1; the 3-thiazol-2-yl; 5-dimethylamino carbonyl-1; the 3-thiazol-2-yl; 5-(tetramethyleneimine-1-base carbonyl)-1; the 3-thiazol-2-yl; 5-allyl group-1; the 3-thiazol-2-yl; 5-propyl group-1; the 3-thiazol-2-yl; 5-B aminocarbonyl-1; the 3-thiazol-2-yl; 5-phenyl-1; the 3-thiazol-2-yl; the 5-methyl isophthalic acid; the 3-thiazol-2-yl; 5-methylol-1; the 3-thiazol-2-yl; 5-(1-hydroxyl-1-methylethyl)-1; the 3-thiazol-2-yl; 5-methoxyl group-methyl isophthalic acid; the 3-thiazol-2-yl; 5-(2-pyridyl)-1; the 3-thiazol-2-yl; 2-(tetramethyleneimine-1-yl)-1; 3-thiazole-4-base; 2-(morpholine-4-yl)-1; 3-thiazole-4-base; the 2-methyl isophthalic acid; 3-thiazole-5-base; 2-(1-hydroxyl-1-methylethyl)-1; 3-thiazole-5-base; 2-(tetramethyleneimine-1-yl)-1; 3-thiazole-5-base; 2-oxyethyl group-1; 3-thiazole-5-base; 2-ethyl-1; 3-thiazole-5-base; 2-(tetramethyleneimine-1-ylmethyl)-1; 3-thiazole-5-base; 2-(morpholine-4-yl)-1; 3-thiazole-5-base; 2-methoxyl group-methyl isophthalic acid; 3-thiazole-5-base; 2-isobutyl--1; 3-thiazole-5-base; 2-B aminocarbonyl-1; 3-thiazole-5-base; 2-(tetramethyleneimine-1-base carbonyl)-1,3-thiazoles-5-base; 2-(morpholine-4-base carbonyl)-1,3-thiazoles-5-base; 2-(3-pyridyl)-1; 3-thiazole-5-base; 2-(2-pyridyl)-1; 3-thiazole-5-base; the 4-methyl isophthalic acid, the 3-thiazol-2-yl; 1,3-benzo-thiazol-2-yl; pyrimidine-5-base; pyrimidine-2-base; pyridazine-4-base; pyridazine-3-base; pyrazine-2-base; 2-methoxyl group-pyrimidine-5-base; 2-oxyethyl group-pyrimidine-5-base; 2-(2-fluorine oxyethyl group) pyrimidine-5-base; 2-methylpyrimidine-5-base; 2-ethylpyridine-5-base; 2-sec.-propyl pyrimidine-5-base; 2-cyclopropyl pyrimidine-5-base; pyrimidine-4-base; 4-(pyrimidine-5-yl) phenyl; 4-(1; 3-oxazole-2-yl) phenyl; 4-(1H-imidazoles-1-yl) phenyl; 4-(morpholine-4-yl) phenyl; 5-(pyrazine-2-yl) pyridine-2-base; 4-(1-methyl isophthalic acid H-imidazoles-1-yl) phenyl; 4-(4; 6-dimethyl pyrimidine-5-yl) phenyl; 6-bromopyridine-3-base; 5-bromopyridine-2-base; 4 '-(methylsulfonyl) biphenyl-4-base; 3 '-(methylsulfonyl) biphenyl-4-base; 3 '-(methoxyl group-carbonyl)-biphenyl-4-base; 4-(2,3-dihydro-1,4-benzo dioxine-6-yl) phenyl; 4 '-(dimethyl-amino)-biphenyl-4-base; 4-(pyridin-3-yl) phenyl; 4-(1H-pyrazoles-4-yl) phenyl; 3; 3 '-dipyridyl-6-base; 3; 4 '-dipyridyl-6-base; 5-(3-acetylphenyl) pyridine-2-base; 5-[3-(dimethyl-amino) phenyl] pyridine-2-base; 5-[3-(trifluoromethyl) phenyl] pyridine-2-base; 5-[4-(methylsulfonyl) phenyl] pyridine-2-base; 5-(4-methoxyl group-phenyl) pyridine-2-base; 5-(3-methoxyl group-phenyl) pyridine-2-base; 5-[3-(aminocarboxyl) phenyl] pyridine-2-base; 5-(4-fluoro-phenyl) pyridine-2-base; 5-(3, the 4-difluorophenyl) pyridine-2-base; 5-(3,5-dimethyl isoxazole-4-yl) pyridine-2-base; 5-(1-methyl isophthalic acid H-pyrazoles-4-yl) pyridine-2-base; 5-(1H-pyrazoles-4-yl) pyridine-2-base; 5-(1-cumarone-2-yl) pyridine-2-base; 5-(1; 3-benzodioxole-5-yl) pyridine-2-base; 5-(2-formyl-phenyl) pyridine-2-base; 4-(2 '-formyl) biphenyl-4-base; 5-(1; 3-oxazole-2-yl) pyridine-2-base; 6-(1,3-oxazole-2-yl) pyridin-3-yl; 4-(1,3-thiazoles-2-yl) phenyl; 5-(1; the 3-thiazol-2-yl) pyridine-2-base; 6-(1; the 3-thiazol-2-yl) pyridin-3-yl; 6-(1H-imidazoles-1-yl) pyridin-3-yl; 5-(1H-imidazoles-1-yl) pyridine-2-base; 6-phenylpyridine-3-base; 5-(pyrimidine-5-yl) pyridine-2-base; 5-(pyrimidine-2-base) pyridine-2-base; 5-(3-aminocarbonyl-phenyl) pyridine-2-base; 4-(1-methyl isophthalic acid H-imidazol-4 yl) phenyl; 4-(1H-imidazol-4 yl) phenyl; 5-[2-(methylol) phenyl] pyridine-2-base; 2 '-(methylol) biphenyl-4-base; the 5-{2-[(dimethylamino) methyl] phenyl } pyridine-2-base; 2 '-[(dimethylamino) methyl] biphenyl-4-base; 5-methyl fluoride pyrazine-2-base; 5-two fluoro-methyl-pyrazines-2-base; 5-methyl-pyrazine-2-base; 2-methylpyrimidine-5-base; 2-methyl fluoride-pyrimidine-5-base; 2-difluoromethyl pyrimidine-5-base; 2-trifluoromethyl pyrimidine-5-base; 2-cyclopropyl pyrimidine-5-base; isothiazole-5-base; 3-methyl isothiazole-5-base; 3-methyl fluoride-isothiazole-5-base; 4-(dimethylamino-carbonyl) phenyl; 4-(methylamino-carbonyl) phenyl; 4-(morpholine-4-base carbonyl) phenyl; 4-(piperidines-1-base carbonyl) phenyl; 3-fluoro-4-(tetramethyleneimine-1-base carbonyl) phenyl; 5-(tetramethyleneimine-1-base carbonyl) pyridine-2-base; 5-(dimethylamino carbonyl) pyridine-2-base; 5-(morpholine-4-base carbonyl) pyridine-2-base; quinolyl-4; 6-methoxypyridine-3-base; 6-(morpholine-4-yl) pyridin-3-yl; 4-(dimethyl-amino methyl) phenyl; 5-(dimethylamino methyl) pyridine-2-base; 5-(dimethylamino carbonyl)-pyridine-2-base; 4-[hydroxyl (pyridin-3-yl) methyl] phenyl; 6-[(hydroxyl-(pyridin-3-yl) methyl) pyridin-3-yl; 6-(dimethylamino carbonyl)-pyridin-3-yl; 4-(4-hydroxy piperidine-1-base carbonyl) phenyl; 4-(4-methoxyl group piperidines-1-base carbonyl) phenyl; 5-(4-methoxyl group piperidines-1-base carbonyl)-pyridine-2-base; 6-(4-methoxyl group piperidines-1-base carbonyl) pyridin-3-yl; phenoxy group; benzyloxy; the 2-thienyl; 2-sec.-propyl-1,3-thiazoles-5-base; 4-(pyrimidine-2-base) phenyl; 4-(pyrimidine-4-yl) phenyl and 5-(methoxymethyl) pyridine-2-base, and X-Y-Z is

M=1 wherein.

6. the compound of a formula III:

Optional R ₁And R ₂Bonding forms volution each other;

And m=0-5.

7. one kind is selected from following compound:

(1) N-(2-{[(3S, 4S)-1-cyclohexyl-4-hydroxyl pyrrolidine-3-yl] amino-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(2) N-(2-{[(3S, 4S)-4-(fourth-2-alkynes-1-base oxygen base)-1-cyclohexyl tetramethyleneimine-3-yl] amino-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(3) N-(2-{[(3S, 4S)-4-(benzyloxy)-1-cyclohexyl tetramethyleneimine-3-yl] amino-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(4) N-(2-{[(3S, 4S)-1-cyclohexyl-4-(pyridine-2-ylmethoxy)-tetramethyleneimine-3-yl] amino-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(5) N-(2-{[(3S, 4S)-1-cyclohexyl-4-(pyridin-3-yl methoxyl group) tetramethyleneimine-3-yl] amino-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(6) N-(2-{[(3S, 4S)-4-hydroxyl-1-(4-hydroxy-4-phenyl cyclohexyl) tetramethyleneimine-3-yl] amino-2-oxoethyl-3-(trifluoromethyl) benzamide,

(7) N-(2-{[(3S, 4S)-4-hydroxyl-1-(4-hydroxyl-4-pyridine-2-basic ring hexyl) tetramethyleneimine-3-yl] amino-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(8) N-(2-{[(3S, 4S)-4-hydroxyl-1-(4-hydroxyl-4-(4-aminomethyl phenyl) cyclohexyl) tetramethyleneimine-3-yl] amino-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(9) N-(2-{[(3S, 4S)-4-hydroxyl-1-(4-hydroxyl-4-(3-aminomethyl phenyl) cyclohexyl) tetramethyleneimine-3-yl] amino-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(10) N-(2-{[(3S, 4S)-4-hydroxyl-1-(4-hydroxyl-4-(2-aminomethyl phenyl) cyclohexyl) tetramethyleneimine-3-yl] amino-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(11) N-[2-((3S, 4S)-1-[4-(4-bromophenyl)-4-hydroxy-cyclohexyl]-4-hydroxyl pyrrolidine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(12) N-[2-((3S, 4S)-1-[4-(3-bromophenyl)-4-hydroxy-cyclohexyl]-4-hydroxyl pyrrolidine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(13) N-[2-((3S, 4S)-1-[4-(4-chloro-phenyl-)-4-hydroxy-cyclohexyl]-4-hydroxyl pyrrolidine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(14) N-[2-((3S, 4S)-1-[4-(3-chloro-phenyl-)-4-hydroxy-cyclohexyl]-4-hydroxyl pyrrolidine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(15) N-[2-((3S, 4S)-4-hydroxyl-1-[4-hydroxyl-4-(4-trifluoromethyl) cyclohexyl]-tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(16) N-[2-((3S, 4S)-4-hydroxyl-1-[4-hydroxyl-4-(3-trifluoromethyl) cyclohexyl]-tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(17) N-[2-((3S, 4S)-4-hydroxyl-1-[4-hydroxyl-4-(2-trifluoromethyl) cyclohexyl]-tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(18) N-[2-((3S, 4S)-4-hydroxyl-1-[4-hydroxyl-4-(4-p-methoxy-phenyl) cyclohexyl]-tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(19) N-[2-((3S, 4S)-4-hydroxyl-1-[4-hydroxyl-4-(3-p-methoxy-phenyl) cyclohexyl]-tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(20) N-[2-((3S, 4S)-4-hydroxyl-1-[4-hydroxyl-4-(2-p-methoxy-phenyl) cyclohexyl]-tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(21) N-[2-((3S, 4S)-4-hydroxyl-1-[4-hydroxyl-4-(3, the 4-methylenedioxyphenyl) cyclohexyl]-tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(22) N-(2-{[(3S, 4S)-4-hydroxyl-1-(4-hydroxyl-4-pyridin-3-yl cyclohexyl)-tetramethyleneimine-3-yl] amino-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(23) N-(2-{[(3S, 4S)-4-hydroxyl-1-(4-hydroxyl-4-pyridin-4-yl cyclohexyl)-tetramethyleneimine-3-yl] amino-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(24) N-(2-{[(3S, 4S)-4-hydroxyl-1-(4-hydroxyl-4-pyridine-2-basic ring hexyl)-tetramethyleneimine-3-yl] amino-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(25) N-[2-((3S, 4S)-4-hydroxyl-1-[4-hydroxyl-4-(6-methoxypyridine-3-yl) cyclohexyl]-tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(26) N-[2-((3S, 4S)-1-[4-(6-ethoxy pyridine-3-yl)-4-hydroxy-cyclohexyl]-4-hydroxyl pyrrolidine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(27) N-(2-{[(3S, 4S)-1-(4-cyano group-4-benzyl ring hexyl)-4-hydroxyl pyrrolidine-3-yl] amino-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(28) N-[2-((3S, 4S)-1-[4-(4-fluorophenyl) cyclohexyl]-4-hydroxyl pyrrolidine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(29) N-(2-{[(3S, 4S)-4-hydroxyl-1-(4-pyridine-2-basic ring hexyl) tetramethyleneimine-3-yl] amino-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(30) N-{2-[((3S, 4S)-4-hydroxyl-1-{4-[3-(trifluoromethyl)-1H-pyrazol-1-yl] cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(31) N-[2-((3S, 4S)-1-[4-(3-fluorophenyl) cyclohexyl]-4-hydroxyl pyrrolidine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(32) N-[2-((3S, 4S)-1-[4-(4-chloro-phenyl-) cyclohexyl]-4-hydroxyl pyrrolidine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(33) N-[2-((3S, 4S)-1-[4-(3-chloro-phenyl-) cyclohexyl]-4-hydroxyl pyrrolidine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(34) N-[2-((3S, 4S)-1-[4-(4-bromophenyl) cyclohexyl]-4-hydroxyl pyrrolidine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(35) N-[2-((3S, 4S)-1-[4-(3-bromophenyl) cyclohexyl]-4-hydroxyl pyrrolidine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(36) N-[2-((3S, 4S)-4-hydroxyl-1-[4-(4-aminomethyl phenyl) cyclohexyl] tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(37) N-[2-((3S, 4S)-4-hydroxyl-1-[4-(3-aminomethyl phenyl) cyclohexyl] tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(38) N-[2-((3S, 4S)-4-hydroxyl-1-[4-(2-aminomethyl phenyl) cyclohexyl] tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(39) N-[2-((3S, 4S)-4-hydroxyl-1-[4-(4-p-methoxy-phenyl) cyclohexyl] tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(40) N-[2-((3S, 4S)-4-hydroxyl-1-[4-(3-p-methoxy-phenyl) cyclohexyl] tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(41) N-[2-((3S, 4S)-4-hydroxyl-1-[4-(pyridin-4-yl) cyclohexyl] tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(42) N-[2-((3S, 4S)-4-hydroxyl-1-[4-(pyridine-2-yl) cyclohexyl] tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(43) N-[2-((3S, 4S)-4-hydroxyl-1-[4-(5-picoline-2-yl) cyclohexyl] tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(44) N-[2-((3S, 4S)-4-hydroxyl-1-[4-(6-picoline-2-yl) cyclohexyl] tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(45) N-[2-((3S, 4S)-4-hydroxyl-1-[4-(quinolyl-4) cyclohexyl] tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(46) N-[2-((3S, 4S)-4-hydroxyl-1-[4-(4-trifluoromethyl) cyclohexyl] tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(47) N-[2-((3S, 4S)-4-hydroxyl-1-[4-(3-trifluoromethyl) cyclohexyl] tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(48) N-[2-((3S, 4S)-4-hydroxyl-1-[4-(2-trifluoromethyl) cyclohexyl] tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(49) N-[2-((3S, 4S)-4-hydroxyl-1-[4-(3, the 4-methylenedioxyphenyl) cyclohexyl] tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(50) N-{2-[((3S, 4S)-4-hydroxyl-1-{4-[3-(methyl)-1H-pyrazol-1-yl] cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(51) N-[2-((3S, 4S)-1-[4-(3,5-dimethyl-1H-pyrazol-1-yl) cyclohexyl]-4-hydroxyl pyrrolidine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(52) N-(2-{[(3S, 4S) 4-hydroxyl-1-(3H-spiral shell [2-cumarone-1,1 '-hexanaphthene]-4 '-yl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(53) N-(2-{[(3S, 4S)-4-hydroxyl-1-spiral shell [hexanaphthene-1,1 '-indenes]-4-base tetramethyleneimine-3-yl] amino-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(54) N-(2-{[(3S, 4S)-1-(2,3 '-dihydro spiral shell [hexanaphthene-1,1 '-indenes]-4-yl)-4-hydroxyl pyrrolidine-3-yl] amino-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(55) N-(2-{[(9S)-7-(4-hydroxy-4-phenyl cyclohexyl)-1-oxa--7-azaspiro [4.4] ninth of the ten Heavenly Stems-9-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(56) N-(2-{[(3S, 4S)-4-oxyethyl group-1-(4-hydroxy-4-phenyl cyclohexyl) tetramethyleneimine-3-yl] amino-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(57) N-[2-((3S, 4S)-1-[4-(4-cyano-phenyl)-4-hydroxy-cyclohexyl]-4-oxyethyl group tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(58) N-[2-((3S, 4S)-1-[4-(4-cyano-phenyl)-4-hydroxy-cyclohexyl]-4-oxyethyl group tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(59) N-[2-((3S, 4S)-4-oxyethyl group-1-[4-hydroxyl-4-(1-pyridine oxide-4-yl) cyclohexyl] tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(60) N-[2-((3S, 4S)-4-oxyethyl group-1-[4-hydroxyl-4-(4-aminomethyl phenyl) cyclohexyl] tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(61) N-[2-((3S, 4S)-4-oxyethyl group-1-[4-hydroxyl-4-(4-p-methoxy-phenyl) cyclohexyl] tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(62) N-[2-((3S, 4S)-4-oxyethyl group-1-[4-hydroxyl-4-(3-p-methoxy-phenyl) cyclohexyl] tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(63) N-[2-((3S, 4S)-4-oxyethyl group-1-[4-(4-fluorophenyl)-4-hydroxy-cyclohexyl] tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(64) N-[2-((3S, 4S)-4-oxyethyl group-1-[4-(3-fluorophenyl)-4-hydroxy-cyclohexyl] tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(65) N-[2-((3S, 4S)-4-oxyethyl group-1-[4-(4-chloro-phenyl-)-4-hydroxy-cyclohexyl] tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(66) N-[2-((3S, 4S)-4-oxyethyl group-1-[4-hydroxyl-4-(3, the 4-methylenedioxyphenyl) cyclohexyl] tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(67) N-[2-((3S, 4S)-4-oxyethyl group-1-[4-hydroxyl-4-(pyridine-2-yl) cyclohexyl] tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(68) N-[2-((3S, 4S)-4-oxyethyl group-1-[4-hydroxyl-4-(pyridin-3-yl) cyclohexyl] tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(69) N-[2-((3S, 4S)-4-oxyethyl group-1-[4-hydroxyl-4-(pyridin-4-yl) cyclohexyl] tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(70) N-[2-((3S, 4S)-4-oxyethyl group-1-[4-hydroxyl-4-(4-picoline-2-yl) cyclohexyl] tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(71) N-[2-((3S, 4S)-4-oxyethyl group-1-[4-hydroxyl-4-(5-picoline-2-yl) cyclohexyl] tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(72) N-[2-((3S, 4S)-4-oxyethyl group-1-[4-hydroxyl-4-(6-picoline-2-yl) cyclohexyl] tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(73) N-[2-((3S, 4S)-4-oxyethyl group-1-[4-hydroxyl-4-(6-methoxypyridine-3-yl) cyclohexyl] tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(74) N-[2-((3S, 4S)-4-oxyethyl group-1-[4-hydroxyl-4-(1-pyridine oxide-2-yl) cyclohexyl] tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(75) N-[2-((3S, 4S)-4-oxyethyl group-1-[4-hydroxyl-4-(1-pyridine oxide-3-yl) cyclohexyl] tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(76) N-[2-((3S, 4S)-4-oxyethyl group-1-[4-hydroxyl-4-(quinolyl-4) cyclohexyl] tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(77) N-[2-((3S, 4S)-4-oxyethyl group-1-[4-(3-cyano-phenyl)-4-hydroxy-cyclohexyl] tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(78) N-[2-({ (3S, 4S)-4-oxyethyl group-1-[4-hydroxyl-443-methylamino carbonyl phenyl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(79) N-(2-{[(3S, 4S)-4-oxyethyl group-1-(4-pyridin-4-yl cyclohexyl) tetramethyleneimine-3-yl] amino-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(80) N-(2-{[(3S, 4S)-4-oxyethyl group-1-(4-pyridin-3-yl cyclohexyl) tetramethyleneimine-3-yl] amino-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(81) N-(2-{[(3S, 4S)-4-oxyethyl group-1-(4-pyridine-2-basic ring hexyl) tetramethyleneimine-3-yl] amino-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(82) N-[2-((3S, 4S)-4-oxyethyl group-1-[4-(1-pyridine oxide-4-yl) cyclohexyl] tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(83) N-[2-((3S, 4S)-4-oxyethyl group-1-[4-(1-pyridine oxide-3-yl) cyclohexyl] tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(84) N-[2-((3S, 4S)-4-oxyethyl group-1-[4-(1-pyridine oxide-2-yl) cyclohexyl] tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(85) N-[2-((3S, 4S)-4-oxyethyl group-1-[4-(6-methoxypyridine-3-yl) cyclohexyl] tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(86) N-{2-[((3S, 4S)-4-oxyethyl group-1-{4-[4-(morpholine-4-base carbonyl) phenyl] cyclohexyl }-tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(87) N-{2-[((3S, 4S)-4-oxyethyl group-1-{4-[5-(morpholine-4-base carbonyl) pyridine-2-yl] cyclohexyl }-tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(88) N-{2-[((3S, 4S)-4-oxyethyl group-1-{4-[6-(morpholine-4-base carbonyl) pyridin-3-yl] cyclohexyl }-tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(89) N-{2-[((3S, 4S)-4-oxyethyl group-1-{4-[4-(4-methylpiperazine-1-base carbonyl) phenyl] cyclohexyl }-tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(90) N-[2-((3S, 4S)-4-oxyethyl group-1-[4-(3-methyl isophthalic acid H-pyrazol-1-yl) cyclohexyl] tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(91) N-[2-((3S, 4S)-4-oxyethyl group-1-[4-(3-Trifluoromethyl-1 H-pyrazol-1-yl) cyclohexyl] tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(92) N-(2-{[(3S, 4S)-4-oxyethyl group-1-(3H-spiral shell [2-cumarone-1,1 '-hexanaphthene]-4 '-yl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(93) N-(2-{[(3S, 4S)-4-oxyethyl group-1-spiral shell [hexanaphthene-1,1 '-indenes]-4-base tetramethyleneimine-3-yl] amino-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(94) N-(2-{[(3S, 4S)-1-(2 ', 3 '-dihydro spiral shell [hexanaphthene-1,1 '-indenes]-4-yl)-4-oxyethyl group tetramethyleneimine-3-yl] amino-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(95) N-[2-((3S, 4S)-1-[4-hydroxyl-4-(1-pyridine oxide-4-yl) cyclohexyl]-4-propoxy-tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(96) N-[2-((3S, 4S)-1-[4-hydroxyl-4-(pyridin-4-yl) cyclohexyl]-4-propoxy-tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(97) N-[2-((3S, 4S)-1-[4-hydroxyl-4-(pyridin-3-yl) cyclohexyl]-4-propoxy-tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(98) N-[2-((3S, 4S)-1-[4-hydroxyl-4-(pyridine-2-yl) cyclohexyl]-4-propoxy-tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(99) N-[2-((3S, 4S)-1-[4-hydroxyl-4-(quinolyl-4) cyclohexyl]-4-propoxy-tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(100) N-[2-((3S, 4S)-1-[4-hydroxyl-4-(6-methoxypyridine-3-yl) cyclohexyl]-4-propoxy-tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(101) N-[2-((3S, 4S)-1-[4-hydroxyl-4-(4-picoline-2-yl) cyclohexyl]-4-propoxy-tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(102) N-[2-((3S, 4S)-1-[4-hydroxyl-4-(5-picoline-2-yl) cyclohexyl]-4-propoxy-tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(103) N-[2-((3S, 4S)-1-[4-hydroxyl-4-(6-picoline-2-yl) cyclohexyl]-4-propoxy-tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(104) N-[2-((3S, 4S)-1-[4-hydroxyl-4-(6-methoxypyridine-2-yl) cyclohexyl]-4-propoxy-tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(105) N-[2-((3S, 4S)-1-[4-hydroxyl-4-(1-pyridine oxide-3-yl) cyclohexyl]-4-propoxy-tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(106) N-[2-((3S, 4S)-1-[4-hydroxy-4-phenyl cyclohexyl]-4-propoxy-tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(107) N-[2-((3S, 4S)-1-[4-hydroxyl-4-(4-p-methoxy-phenyl) cyclohexyl]-4-propoxy-tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(108) N-[2-((3S, 4S)-1-[4-hydroxyl-4-(3, the 4-methylenedioxyphenyl) cyclohexyl]-4-propoxy-tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(109) N-(2-oxo-2-{[(3S, 4S)-4-propoxy--1-(4-pyridin-3-yl cyclohexyl) tetramethyleneimine-3-yl] amino-ethyl)-3-(trifluoromethyl) benzamide,

(110) N-(2-oxo-2-{[(3S, 4S)-4-propoxy--1-(4-pyridin-4-yl cyclohexyl) tetramethyleneimine-3-yl] amino-ethyl)-3-(trifluoromethyl) benzamide,

(111) N-[2-((3S, 4S)-1-[4-(3-methyl isophthalic acid H-pyrazol-1-yl) cyclohexyl]-4-propoxy-tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(112) N-[2-((3S, 4S)-1-[4-(3,5-dimethyl-1H-pyrazol-1-yl) cyclohexyl]-4-propoxy-tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(113) N-(2-oxo-2-{[(3S, 4S) 4-propoxy--1-(3H-spiral shell [2-cumarone-1,1 '-hexanaphthene]-4 '-yl) tetramethyleneimine-3-yl] amino } ethyl)-3-(trifluoromethyl) benzamide,

(114) N-(2-oxo-2-{[(3S, 4S)-4-propoxy--1-spiral shell [hexanaphthene-1,1 '-indenes]-4-base tetramethyleneimine-3-yl] amino ethyl)-3-(trifluoromethyl) benzamide,

(115) N-({ (3R)-1-[4-hydroxyl-4-(6-methoxyl group-pyridin-3-yl)-cyclohexyl] tetramethyleneimine-3-base formamyl }-methyl)-3-trifluoromethyl-benzamide,

(116) N-(2-{[(3R)-1-(4-hydroxyl-4-pyridine-2-basic ring hexyl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(117) N-[2-({ (3R)-1-[4-(6-azetidine-1-yl pyridines-3-yl)-4-hydroxy-cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(118) N-[2-({ (3R)-1-[4-(5-cyanopyridine-2-yl)-4-hydroxy-cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(119) N-[2-({ (3R)-1-[4-(6-cyanopyridine-3-yl)-4-hydroxy-cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(120) N-{2-[((3R)-and 1-{ is trans-4-hydroxyl-4-[5-(methoxymethyl) pyridine-2-yl] and cyclohexyl }-tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(121) N-{2-[((3R)-and 1-{4-hydroxyl-4-[5-(1-hydroxyl-1-methylethyl) pyridine-2-yl] cyclohexyl }-tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(122) N-(2-{[(3R)-1-(4-{5-[(dimethylamino) methyl] pyridine-2-yl }-the 4-hydroxy-cyclohexyl)-tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(123) N-(2-{[(3R)-1-(4-hydroxyl-4-pyridin-3-yl cyclohexyl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(124) N-(2-{[(3R)-1-(4-hydroxyl-4-pyridin-3-yl cyclohexyl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(125) N-[2-({ (3R)-1-[4-hydroxyl-4-(6-picoline-2-yl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(126) N-[2-({ (3R)-1-[4-hydroxyl-4-(5-picoline-2-yl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(127) N-[2-({ (3R)-1-[4-hydroxyl-4-(4-picoline-2-yl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(128) N-[2-({ (3R)-1-[4-hydroxyl-4-(1-pyridine oxide-2-yl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(129) N-[2-({ (3R)-1-[4-hydroxyl-4-(1-pyridine oxide-3-yl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(130) N-[2-({ (3R)-1-[4-hydroxyl-4-(1-pyridine oxide-4-yl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(131) N-[2-({ (3R)-1-[4-hydroxyl-4-(6-methoxypyridine-2-yl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(132) N-[2-({ (3R)-1-[4-hydroxyl-4-(quinolyl-4) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(133) N-[2-({ (3R)-1-[4-(4-cyano-phenyl)-4-hydroxy-cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(134) N-[2-({ (3R)-1-[4-(3-cyano-phenyl)-4-hydroxy-cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(135) N-(2-{[(3R)-1-(4-hydroxyl-4-{4-[(methylamino) carbonyl] phenyl } cyclohexyl)-tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(136) N-(2-{[(3R)-1-(4-{4-[(ethylamino) carbonyl] phenyl }-the 4-hydroxy-cyclohexyl)-tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(137) N-(2-{[(3R)-1-(4-hydroxyl-4-{4-[(sec.-propyl amino) carbonyl] phenyl } cyclohexyl)-tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(138) N-(2-{[(3R)-1-(4-{4-[(tertiary butyl amino) carbonyl] phenyl }-the 4-hydroxy-cyclohexyl)-tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(139) N-(2-{[(3R)-1-(4-{4-[(dimethylamino) carbonyl] phenyl }-the 4-hydroxy-cyclohexyl)-tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(140) N-(2-{[(3R)-1-(4-{4-[(azetidine-1-yl) carbonyl] phenyl }-the 4-hydroxy-cyclohexyl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(141) N-(2-{[(3R)-1-(4-hydroxyl-4-{4-[(tetramethyleneimine-1-yl) carbonyl] phenyl } cyclohexyl)-tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(142) N-(2-{[(3R)-1-(4-hydroxyl-4-{4-[(morpholine-4-yl) carbonyl] phenyl } cyclohexyl)-tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(143) 4-(1-hydroxyl-4-{ (3R)-3-[({[3-(trifluoromethyl) benzoyl] amino } acetyl) amino] tetramethyleneimine-1-yl } cyclohexyl)-N, N, 2-Three methyl Benzene methane amide,

(144) N-{2-[((3R)-and 1-{4-hydroxyl-4-[3-methyl-4-(tetramethyleneimine-1-base carbonyl) phenyl] cyclohexyl }-tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(145) 2-fluoro-4-(1-hydroxyl-4-{ (3R)-3-[({[3-(trifluoromethyl) benzoyl] amino } acetyl) amino] tetramethyleneimine-1-yl } cyclohexyl)-N, the N-dimethyl benzamide,

(146) N-[2-({ (3R)-1-[4-hydroxyl-4-(4-{[(2,2,2-trifluoroethyl) amino] carbonyl } phenyl)-cyclohexyl] tetramethyleneimine-3-yl } amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(147) 2-fluoro-4-(1-hydroxyl-4-{ (3R)-3-[({[3-(trifluoromethyl) benzoyl] amino } acetyl) amino] tetramethyleneimine-1-yl } cyclohexyl)-N-methyl-benzamide,

(148) N-ethyl-2-fluoro-4-(1-hydroxyl-4-{ (3R)-3-[({[3-(trifluoromethyl) benzoyl] amino } acetyl)-amino] tetramethyleneimine-1-yl } cyclohexyl) benzamide,

(149) 3-(1-hydroxyl-4-{ (3R)-3-[({[3-(trifluoromethyl) benzoyl] amino } acetyl) amino] tetramethyleneimine-1-yl } cyclohexyl)-N-methyl-benzamide,

(150) 3-(1-hydroxyl-4-{ (3R)-3-[({[3-(trifluoromethyl) benzoyl] amino } acetyl) amino] tetramethyleneimine-1-yl } cyclohexyl)-N, the N-dimethyl benzamide,

(151) 3-(1-hydroxyl-4-{ (3R)-3-[({[3-(trifluoromethyl) benzoyl] amino } acetyl) amino] tetramethyleneimine-1-yl } cyclohexyl)-4-methoxyl group-N, the N-dimethyl benzamide,

(152) 3-(1-hydroxyl-4-{ (3R)-3-[({[3-(trifluoromethyl) benzoyl] amino } acetyl) amino] tetramethyleneimine-1-yl } cyclohexyl)-4-methoxyl group-N-methyl-benzamide,

(153) N-[2-({ (3R)-1-[4-hydroxyl-4-(3-{[(methylamino) carbonyl] amino } phenyl) cyclohexyl]-tetramethyleneimine-3-yl } amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(154) N-[2-({ (3R)-1-[4-hydroxyl-4-(6-morpholine-4-yl pyridines-3-yl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(155) N-{2-[((3R)-1-{4-[6-(dimethylamino) pyridin-3-yl]-the 4-hydroxy-cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(156) N-{2-[((3R)-and 1-{4-hydroxyl-4-[6-(sec.-propyl amino) pyridin-3-yl] cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(157) N-{2-[((3R)-and 1-{4-hydroxyl-4-[6-(tetramethyleneimine-1-yl) pyridin-3-yl] cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(158) N-{2-[((3R)-1-{4-[6-(cyclopropyl amino) pyridin-3-yl]-the 4-hydroxy-cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(159) N-[2-({ (3R)-1-[4-(6-ethoxy pyridine-3-yl)-4-hydroxy-cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(160) N-{2-[((3R)-1-{4-[6-(2-fluorine oxyethyl group) pyridin-3-yl]-the 4-hydroxy-cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(161) N-{2-[((3R)-1-{4-[6-(2, the 2-difluoroethoxy) pyridin-3-yl]-the 4-hydroxy-cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(162) N-{2-[((3R)-and 1-{4-hydroxyl-[6-(2,2, the 2-trifluoro ethoxy) pyridin-3-yl] cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(163) N-(2-{[(3R)-1-(4-hydroxy-4-phenyl cyclohexyl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(164) N-[2-({ (3R)-1-[4-hydroxyl-4-(4-aminomethyl phenyl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(165) N-[2-({ (3R)-1-[4-(4-fluorophenyl)-4-hydroxy-cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(166) N-[2-({ (3R)-1-[4-(3-fluorophenyl)-4-hydroxy-cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(167) N-[2-({ (3R)-1-[4-(2-fluorophenyl)-4-hydroxy-cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(168) N-[2-({ (3R)-1-[4-(4-bromophenyl)-4-hydroxy-cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(169) N-[2-({ (3R)-1-[4-(3-bromophenyl)-4-hydroxy-cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(170) N-[2-({ (3R)-1-[4-(4-chloro-phenyl-)-4-hydroxy-cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(171) N-[2-({ (3R)-1-[4-(3-chloro-phenyl-)-4-hydroxy-cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(172) N-[2-({ (3R)-1-[4-hydroxyl-4-(4-iodophenyl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(173) N-{2-[((3R)-and 1-{4-hydroxyl-4-[5-(tetramethyleneimine-1-base carbonyl) pyridine-2-yl] cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(174) N-{2-[((3R)-and 1-{4-hydroxyl-4-[5-(morpholine-4-base carbonyl) pyridine-2-yl] cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(175) 6-(1-hydroxyl-4-{ (3R)-3-[({[3-(trifluoromethyl) benzoyl] amino } acetyl) amino] tetramethyleneimine-1-yl } cyclohexyl)-N, the N-dimethyl nicotinamide,

(176) N-[2-({ (3R)-1-[4-hydroxyl-4-(4-{[(methylamino) carbonyl] amino } phenyl) cyclohexyl] tetramethyleneimine-3-yl } amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(177) N-{2-[((3R)-and 1-{4-hydroxyl-4-[6-(1-hydroxyl-1-methylethyl) pyridin-3-yl] cyclohexyl }-tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(178) N-{2-[((3R)-and 1-{4-hydroxyl-4-[4-(1-hydroxyl-1-methylethyl) phenyl] cyclohexyl }-tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(179) N-{2-[((3R)-and 1-{4-hydroxyl-4-[4-(methoxymethyl) phenyl] cyclohexyl } pyridin-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(180) N-{2-[((3R)-1-{4-[3-fluoro-4-(methoxymethyl) phenyl]-the 4-hydroxy-cyclohexyl } pyridin-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(181) N-(2-{[(3R)-1-(4-{4-[(dimethylamino) methyl] phenyl }-the 4-hydroxy-cyclohexyl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(182) N-(2-{[(3R)-1-(4-{4-[(dimethylamino) methyl]-the 3-fluorophenyl }-the 4-hydroxy-cyclohexyl)-tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(183) N-[2-({ (3R)-1-[4-hydroxyl-4-(1H-indazole-5-yl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(184) N-[2-({ (3R)-1-[4-hydroxyl-4-(1-methyl isophthalic acid H-indazole-5-yl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(185) N-[2-({ (3R)-1-[4-hydroxyl-4-(2-methyl isophthalic acid H-indazole-5-yl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(186) N, N-dimethyl-4-(4-{ (3R)-3-[({[3-(trifluoromethyl) benzoyl] amino } acetyl) amino]-tetramethyleneimine-1-yl } cyclohexyl) benzamide,

(187) N-(2-{[(3R)-1-(4-{4-[(methylamino) carbonyl] phenyl } cyclohexyl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(188) N-(2-{[(3R)-1-(4-{4-[(morpholine-4-yl) carbonyl] phenyl } cyclohexyl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(189) N-(2-{[(3R)-1-(4-{4-[(piperidines-1-yl) carbonyl] phenyl } cyclohexyl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(190) N-{2-[((3R)-and 1-{4-[3-fluoro-4-(tetramethyleneimine-1-base carbonyl) phenyl] cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(191) N-{2-oxo-2-[((3R)-1-{4-[5-(tetramethyleneimine-1-base carbonyl) pyridine-2-yl] cyclohexyl } tetramethyleneimine-3-yl) amino] ethyl }-3-(trifluoromethyl) benzamide,

(192) N, N-dimethyl-6-(4-{ (3R)-3-[({[3-(trifluoromethyl) benzoyl] amino } acetyl) amino]-tetramethyleneimine-1-yl } cyclohexyl) benzamide,

(193) N-{2-[((3R)-and 1-{4-[5-(morpholine-4-base carbonyl) pyridine-2-yl] cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(194) N-(2-oxo-2-{[(3R)-1-(4-pyridine-2-basic ring hexyl) tetramethyleneimine-3-yl] amino } ethyl)-3-(trifluoromethyl) benzamide,

(195) N-(2-oxo-2-{[(3R)-1-(4-pyridin-3-yl cyclohexyl) tetramethyleneimine-3-yl] amino } ethyl)-3-(trifluoromethyl) benzamide,

(196) N-(2-oxo-2-{[(3R)-1-(4-pyridin-4-yl cyclohexyl) tetramethyleneimine-3-yl] amino } ethyl)-3-(trifluoromethyl) benzamide,

(197) N-[2-({ (3R)-1-[4-(1-pyridine oxide-2-yl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(198) N-[2-({ (3R)-1-[4-(1-pyridine oxide-3-yl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(199) N-[2-({ (3R)-1-[4-(1-pyridine oxide-4-yl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(200) N-[2-({ (3R)-1-[4-(quinolyl-4) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(201) N-[2-({ (3R)-1-[4-(6-methoxypyridine-3-yl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(202) N-[2-({ (3R)-1-[4-(6-morpholine-4-yl pyridines-3-yl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(203) N-(2-{[(3R)-1-(4-{4-[(dimethylamino) methyl] phenyl } cyclohexyl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(204) N-(2-{[(3R)-1-(4-{5-[(dimethylamino) pyridine-2-yl] phenyl } cyclohexyl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(205) N-(2-{[(3R)-1-(4-{5-[(dimethylamino) carbonyl] pyridine-2-yl } cyclohexyl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(206) N-(2-{[(3R)-1-(4-{4-[hydroxyl (pyridin-3-yl) methyl] phenyl } cyclohexyl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(207) N-(2-{[(3R)-1-(4-{6-[hydroxyl (pyridin-3-yl) methyl] pyridin-3-yl } cyclohexyl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(208) N, N-dimethyl-5-(4-{ (3R)-3-[({[3-(trifluoromethyl) benzoyl] amino } acetyl) amino]-tetramethyleneimine-1-yl } cyclohexyl) pyridine-2-carboxamide,

(209) N-(2-{[(3R)-1-(4-{4-[(4-hydroxy piperidine-1-yl) carbonyl] phenyl } cyclohexyl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(210) N-(2-{[(3R)-1-(4-{4-[(3-hydroxy piperidine-1-yl) carbonyl] phenyl } cyclohexyl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(211) N-(2-{[(3R)-1-(4-{4-[(4-methoxyl group piperidines-1-yl) carbonyl] phenyl } cyclohexyl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(212) N-(2-{[(3R)-1-(4-{4-[(3-methoxyl group piperidines-1-yl) carbonyl] phenyl } cyclohexyl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(213) N-(2-{[(3R)-1-(4-{5-[(4-methoxyl group piperidines-1-yl) carbonyl] pyridine-2-yl } cyclohexyl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(214) N-(2-{[(3R)-1-(4-{6-[(4-methoxyl group piperidines-1-yl) carbonyl] pyridin-3-yl } cyclohexyl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(215) N-(2-oxo-2-{[(3R)-1-(4-phenoxy group cyclohexyl) tetramethyleneimine-3-yl] amino } ethyl)-3-(trifluoromethyl) benzamide,

(216) N-[2-({ (3R)-1-[4-(benzyloxy) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(217) N-(2-{[(3R)-1-(4,4-phenylbenzene cyclohexyl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(218) N-[2-((3R)-1-[is trans-2-(benzyloxy) cyclohexyl] tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(219) N-[2-({ (3R)-1-[cis-2-(benzamido) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(220) amino N-{2-oxo-2-[((3R)-1-{ cis-2-[(phenyl acetyl)]-cyclohexyl } tetramethyleneimine-3-yl) amino] ethyl }-3-(trifluoromethyl) benzamide,

(221) N-[2-({ (3R)-1-[cis-2-(benzylamino) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(222) N-[2-({ (3R)-1-[4-hydroxyl-4-(1,3-thiazoles-2-yl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(223) N-[2-({ (3R)-1-[4-(5-ethyl-1,3-thiazoles-2-yl)-4-hydroxy-cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(224) 2-(1-hydroxyl-4-{ (3R)-3-[({[3-(trifluoromethyl) benzoyl] amino } acetyl) amino] tetramethyleneimine-3-yl } cyclohexyl)-the N-methyl isophthalic acid, 3-thiazole-5-methane amide,

(225) 3-(trifluoromethyl)-N-[2-({ (3R)-1-[4-hydroxyl-4-(1,3-thiazoles-5-yl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl] benzamide,

(226) [5-(1-hydroxyl-4-{ (3R)-3-[({[3-(trifluoromethyl) benzoyl] amino } acetyl) amino]-tetramethyleneimine-1-yl } cyclohexyl)-1,3-thiazoles-2-yl] Urethylane,

(227) N-[2-({ (3R)-1-[4-hydroxyl-4-(2-sec.-propyl-1,3-thiazoles-5-yl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(228) N-[2-({ (3R)-1-[4-hydroxyl-4-(5-pyridin-3-yl-1,3-thiazoles-2-yl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(229) N-{2-[((3R)-and 1-{4-hydroxyl-4-[5-(morpholine-4-base carbonyl)-1,3-thiazoles-2-yl] cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(230) 2-(1-hydroxyl-4-{ (3R)-3-[({[3-(trifluoromethyl) benzoyl] amino } acetyl) amino] tetramethyleneimine-1-yl } cyclohexyl)-1,3-thiazoles-5-methane amide,

(231) 2-(1-hydroxyl-4-{ (3R)-3-[({[3-(trifluoromethyl) benzoyl] amino } acetyl) amino] tetramethyleneimine-1-yl } cyclohexyl)-N, N-dimethyl-1,3-thiazoles-5-methane amide,

(232) N-{2-[((3R)-and 1-{4-hydroxyl-4-[5-(tetramethyleneimine-1-base carbonyl)-1,3-thiazoles-2-yl] cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(233) N-[2-({ (3R)-1-[4-(5-allyl group-1,3-thiazoles-2-yl)-4-hydroxy-cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(234) N-[2-({ (3R)-1-[4-hydroxyl-4-(5-propyl group-1,3-thiazoles-2-yl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(235) N-ethyl-2-(1-hydroxyl-4-{ (3R)-3-[({[3-(trifluoromethyl) benzoyl] amino } acetyl) amino]-tetramethyleneimine-1-yl } cyclohexyl) amino)-1,3-thiazoles-5-methane amide,

(236) N-[2-({ (3R)-1-[4-hydroxyl-4-(5-phenyl-1,3-thiazoles-2-yl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(237) N-[2-({ (3R)-1-[4-hydroxyl-4-(5-methyl isophthalic acid, 3-thiazol-2-yl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(238) N-[2-({ (3R)-1-[4-hydroxyl-4-(5-methylol-1,3-thiazoles-2-yl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(239) N-{2-[((3R)-and 1-{4-hydroxyl-4-[5-(1-hydroxyl-1-methylethyl)-1,3-thiazoles-2-yl] cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(240) N-[2-({ (3R)-1-[4-hydroxyl-4-(5-methoxymethyl-1,3-thiazoles-2-yl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(241) N-[2-({ (3R)-1-[4-hydroxyl-4-(5-pyridine-2-base-1,3-thiazoles-2-yl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(242) N-[2-({ (3R)-1-[4-hydroxyl-4-(2-tetramethyleneimine-1-base-1,3-thiazoles-4-yl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(243) N-[2-({ (3R)-1-[4-hydroxyl-4-(2-morpholine-4-base-1,3-thiazoles-4-yl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(244) N-[2-({ (3R)-1-[4-hydroxyl-4-(2-methyl isophthalic acid, 3-thiazole-5-yl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(245) N-{2-[((3R)-and 1-{4-hydroxyl-4-[2-(1-hydroxyl-1-methylethyl)-1,3-thiazoles-5-yl] cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(246) N-[2-({ (3R)-1-[4-hydroxyl-4-(2-tetramethyleneimine-1-base-1,3-thiazoles-5-yl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(247) N-[2-({ (3R)-1-[4-(2-oxyethyl group-1,3-thiazoles-5-yl)-4-hydroxy-cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(248) N-[2-({ (3R)-1-[4-(2-ethyl-1,3-thiazoles-5-yl)-4-hydroxy-cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(249) N-{2-[((3R)-and 1-{4-hydroxyl-4-[2-(tetramethyleneimine-1-ylmethyl)-1,3-thiazoles-5-yl] cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(250) N-{2-[((3R)-and 1-{4-hydroxyl-4-[2-(morpholine-4-yl)-1,3-thiazoles-5-yl] cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(251) N-{2-[((3R)-and 1-{4-hydroxyl-4-[2-(methoxymethyl)-1,3-thiazoles-5-yl] cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(252) N-[2-({ (3R)-1-[4-hydroxyl-4-(2-isobutyl--1,3-thiazoles-5-yl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(253) N-ethyl-5-(1-hydroxyl-4-{ (3R)-3-[({[3-(trifluoromethyl) benzoyl] amino } acetyl) amino]-tetramethyleneimine-1-yl } cyclohexyl)-1,3-thiazoles-2-methane amide,

(254) N-{2-[((3R)-and 1-{4-hydroxyl-4-[2-(tetramethyleneimine-1-base carbonyl)-1,3-thiazoles-5-yl] cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(255) N-{2-[((3R)-and 1-{4-hydroxyl-4-[2-(morpholine-4-base carbonyl)-1,3-thiazoles-5-yl] cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(256) N-[2-({ (3R)-1-[4-hydroxyl-4-(2-pyridin-3-yl-1,3-thiazoles-5-yl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(257) N-[2-({ (3R)-1-[4-hydroxyl-4-(2-pyridine-2-base-1,3-thiazoles-5-yl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(258) N-[2-({ (3R)-1-[4-hydroxyl-4-(4-methyl isophthalic acid, 3-thiazole-5-yl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(259) N-[2-({ (3R)-1-[4-(1,3-benzothiazole-2-yl)-4-hydroxy-cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(260) N-[2-oxo-2-({ (3R)-1-[4-(1,3-thiazoles-2-yl) cyclohexyl] tetramethyleneimine-3-yl } amino) ethyl]-3-(trifluoromethyl) benzamide,

(261) N-{2-oxo-2-[((3R)-1-{4-[5-(tetramethyleneimine-1-base carbonyl)-1,3-thiazoles-2-yl] cyclohexyl } tetramethyleneimine-3-yl) amino] ethyl }-3-(trifluoromethyl) benzamide,

(262) N-[2-oxo-2-({ (3R)-1-[4-(2-thienyl) cyclohexyl] tetramethyleneimine-3-yl } amino) ethyl]-3-(trifluoromethyl) benzamide,

(263) 3-(trifluoromethyl)-N-{2-[((3R)-1-{4-[5-(methoxymethyl)-1,3-thiazoles-2-yl] cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl } benzamide,

(264) 3-(trifluoromethyl)-N-{2-[((3R)-1-{4-[5-(morpholine-4-base carbonyl)-1,3-thiazoles-2-yl] cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl } benzamide,

(265) N-{ (3R)-1-[4-hydroxyl-4-(2-sec.-propyl-1,3-thiazoles-5-yl) cyclohexyl] tetramethyleneimine-3-yl }-4-oxo-4-[3-(trifluoromethyl) phenyl] butyramide,

(266) 4-[3-(trifluoromethyl) phenyl]-N-((3R)-1-{4-hydroxyl-4-[5-(methoxymethyl)-1,3-thiazoles-2-yl] cyclohexyl } tetramethyleneimine-3-yl)-4-oxo butyramide,

(267) 4-[3-(trifluoromethyl) phenyl]-N-((3R)-1-{4-hydroxyl-4-[5-(methoxymethyl)-1,3-thiazoles-2-yl] cyclohexyl } tetramethyleneimine-3-yl)-4-oxo butyramide,

(268) N-((3R)-1-{4-hydroxyl-4-[5-(methoxymethyl)-1,3-thiazoles-2-yl]-4-hydroxyl-cyclohexyl tetramethyleneimine-3-yl)-4-[3-(trifluoromethyl) phenyl] butyramide,

(269) N-((3R)-1-{4-[5-(methoxymethyl)-1,3-thiazoles-2-yl]-the 4-hydroxy-cyclohexyl tetramethyleneimine-3-yl)-2-({ [3-(trifluoromethyl) phenyl] sulphonyl } amino) ethanamide,

(270) N-((3R)-1-{4-hydroxyl-4-[2-(methoxymethyl)-1,3-thiazoles-5-yl] cyclohexyl } tetramethyleneimine-3-yl)-3-[3-(trifluoromethyl) phenyl]-4,5-dihydro-isoxazole-5-methane amide,

(271) (4Z) and (4E)-4-(oxyimino)-N-((3R)-1-{4-hydroxyl-4-[5-(methoxymethyl)-1,3-thiazoles-2-yl] cyclohexyl } tetramethyleneimine-3-yl)-4-[3-(trifluoromethyl) phenyl] butyramide,

(272) (4Z) and (4E)-4-(ethoxy imino)-N-((3R)-1-{4-hydroxyl-4-[5-(methoxymethyl)-1,3-thiazoles-2-yl] cyclohexyl } tetramethyleneimine-3-yl)-4-[3-(trifluoromethyl) phenyl] butyramide,

(273) N-[2-({ (3R)-1-[4-fluoro-4-(1,3-thiazoles-2-yl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(274) N-(2-{[(3R)-1-(4-fluoro-4-pyridin-3-yl cyclohexyl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(275) N-[2-({ (3R)-1-[4-fluoro-4-(6-methoxypyridine-3-yl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(276) N-[2-({ (3R)-[(1-{4-fluoro-4-[6-(1,3-oxazole-2-yl) pyridin-3-yl] cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(277) N-(2-{[(3R)-1-(4-fluoro-4-{4-[(methylamino) carbonyl] phenyl } cyclohexyl)-tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(278) N-[2-({ (3R)-1-[4-hydroxyl-4-pyrimidine-5-yl] cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(279) N-{[(R)-1-(4-hydroxyl-4-pyrimidine-2-base-cyclohexyl)-tetramethyleneimine-3-base carbamyl]-methyl }-3-trifluoromethyl-benzamide,

(280) N-[2-({ (3R)-1-(4-hydroxyl-4-pyridazine-3-base-cyclohexyl) tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-trifluoromethyl-benzamide,

(281) N-(2-{[(3R)-1-(4-hydroxyl-4-pyrazine-2-base-cyclohexyl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(282) N-(2-{[(3R)-1-(4-hydroxyl-4-pyrazine-2-base-cyclohexyl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(283) N-{2-[((3R)-1-{4-[2-(2-fluorine oxyethyl group) pyrimidine-5-yl]-the 4-hydroxy-cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(284) N-[2-({ (3R)-1-[4-hydroxyl-4-(2-methoxy pyrimidine-5-yl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(285) N-(2-{[(3R)-1-(4-hydroxyl-4-pyrimidine-4-basic ring hexyl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(286) N-[2-({ (3R)-1-[4-hydroxyl-4-(4-pyrimidine-5-base phenyl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(287) N-[2-({ (3R)-1-[4-hydroxyl-4-(4-oxazole-2-base phenyl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(288) N-[2-({ (3R)-1-[4-hydroxyl-4-(4-1H-imidazoles-1-base phenyl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(289) N-[2-({ (3R)-1-[4-hydroxyl-4-(4-morpholine-4-base phenyl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(290) N-[2-({ (3R)-1-[4-hydroxyl-4-(5-(pyrazine-2-yl) pyridine-2-yl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(291) N-{2-[((3R)-and 1-{4-hydroxyl-4-[4-(1-methyl isophthalic acid H-imidazoles-5-yl) phenyl] cyclohexyl }-tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(292) N-{2-[((3R)-1-{4-[4-(4,6-dimethyl pyrimidine-5-yl) phenyl]-the 4-hydroxy-cyclohexyl }-tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(293) N-[2-({ (3R)-1-[4-(6-bromopyridine-3-yl)-4-hydroxy-cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(294) N-[2-({ (3R)-1-[4-(5-bromopyridine-2-yl)-4-hydroxy-cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(295) N-{2-[((3R)-and 1-{4-hydroxyl-4-[4 '-(methylsulfonyl) xenyl-4-yl] cyclohexyl }-tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(296) N-{2-[((3R)-and 1-{4-hydroxyl-4-[3 '-(methylsulfonyl) xenyl-4-yl] cyclohexyl }-tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(297) N-{2-[((3R)-1-{4-[4-(2,3-dihydro-1,4-benzo dioxine-6-yl) phenyl]-4-basic ring hexyl }-tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(298) N-{2-[((3R)-and 1-{4-[4 '-(dimethylamino) biphenyl-4-yl] the 4-hydroxy-cyclohexyl }-tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(299) N-[2-({ (3R)-1-[4-hydroxyl-4-(4-pyridin-3-yl phenyl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(300) N-{2-[((3R)-and 1-{4-hydroxyl-4-[4-(1H-pyrazoles-4-yl) phenyl] cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(301) N-[2-({ (3R)-1-[4-(3,3 '-dipyridyl-6-yl)-4-hydroxy-cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(302) N-{2-({ (3R)-1-[4-(3,4 '-dipyridyl-6-yl)-4-hydroxy-cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(303) N-{2-[((3R)-1-{4-[5-(3-acetyl phenyl) pyridine-2-yl]-the 4-hydroxy-cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(304) N-{2-[((3R)-1-{4-[5-(3-dimethylaminophenyl) pyridine-2-yl]-the 4-hydroxy-cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(305) N-(2-{[(3R)-1-(4-hydroxyl-4-{5-[4-(trifluoromethyl) phenyl] pyridine-2-yl } cyclohexyl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(306) N-(2-{[(3R)-1-(4-hydroxyl-4-{5-[4-(methylsulfonyl) phenyl] pyridine-2-yl } cyclohexyl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(307) N-{2-[((3R)-and 1-{4-hydroxyl-4-[5-(4-p-methoxy-phenyl) pyridine-2-yl] cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(308) N-{2-[((3R)-and 1-{4-hydroxyl-4-[5-(3-p-methoxy-phenyl) pyridine-2-yl] cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(309) N-(2-{[(3R)-1-(4-{5-[3-(aminocarboxyl) phenyl] pyridine-2-yl }-the 4-hydroxy-cyclohexyl)-tetramethyleneimine-3-yl] amino-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(310) N-{2-[((3R)-1-{4-[5-(4-fluorophenyl) pyridine-2-yl]-the 4-hydroxy-cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(311) N-{2-[((3R)-1-{4-[5-(3, the 4-difluorophenyl) pyridine-2-yl]-the 4-hydroxy-cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(312) N-{2-[((3R)-1-{4-[5-(3,5-dimethyl isoxazole-4-yl) pyridine-2-yl]-the 4-hydroxy-cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(313) N-{2-[((3R)-and 1-{4-hydroxyl-4-[5-(1-methyl isophthalic acid H-pyrazoles-4-yl) pyridine-2-yl] cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(314) N-{2-[((3R)-and 1-{4-hydroxyl-4-[5-(1H-pyrazoles-4-yl) pyridine-2-yl] cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(315) N-{2-[((3R)-1-{4-[5-(1-cumarone-2-yl) pyridine-2-yl]-the 4-hydroxy-cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(316) N-{2-[((3R)-1-{4-[5-(1-benzodioxole-5-yl) pyridine-2-yl]-the 4-hydroxy-cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(317) N-{2-[((3R)-1-{4-[5-(2-formylphenyl) pyridine-2-yl]-the 4-hydroxy-cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(318) N-{2-[((3R)-and 1-{4-hydroxyl-4-[5-(1,3-oxazole-2-yl) pyridine-2-yl] cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(319) N-{2-[((3R)-and 1-{4-hydroxyl-4-[6-(1,3-oxazole-2-yl) pyridin-3-yl] cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(320) N-{2-[((3R)-and 1-{4-hydroxyl-4-[4-(1,3-thiazoles-2-yl) phenyl] cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(321) N-{2-[((3R)-and 1-{4-hydroxyl-4-[5-(1,3-thiazoles-2-yl) pyridine-2-yl] cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(322) N-{2-[((3R)-and 1-{4-hydroxyl-4-[6-(1,3-thiazoles-2-yl) pyridin-3-yl] cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(323) N-{2-[((3R)-and 1-{4-hydroxyl-4-[5-(1H-imidazoles-1-yl) pyridine-2-yl] cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(324) N-{2-[((3R)-and 1-{4-hydroxyl-4-[6-(1H-imidazoles-1-yl) pyridin-3-yl] cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(325) N-[2-({ (3R)-1-[4-hydroxyl-4-(6-phenylpyridine-3-yl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(326) N-[2-({ (3R)-1-[4-hydroxyl-4-(5-pyrimidine-5-yl pyridines-2-yl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(327) N-[2-({ (3R)-1-[4-hydroxyl-4-(5-pyrimidine-2-base pyridine-2-yl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(328) N-(2-{[(3R)-1-(4-{5-[3-(aminocarboxyl) phenyl] pyridine-2-yl }-the 4-hydroxy-cyclohexyl)-tetramethyleneimine-3-yl] amino-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(329) N-{2-[((3R)-and 1-{4-hydroxyl-4-[4-(1-methyl isophthalic acid H-imidazol-4 yl) phenyl] cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl benzamide,

(330) N-{2-[((3R)-and 1-{4-hydroxyl-4-[4-(1H-imidazol-4 yl) phenyl] cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(331) N-(2-{[(3R)-1-(4-hydroxyl-4-{5-[2-(methylol) phenyl] pyridine-2-yl } cyclohexyl)-tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(332) N-{2-[((3R)-and 1-{4-hydroxyl-4-[2 '-(methylol) biphenyl-4-yl] cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(333) N-[2-({ (3R)-1-[4-(5-{2-[(dimethylamino) methyl] phenyl } pyridine-2-yl)-4-hydroxy-cyclohexyl] tetramethyleneimine-3-yl } amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(334) N-(2-{[(3R)-1-(4-{2 '-[(dimethylamino) methyl] biphenyl-4-yl-the 4-hydroxy-cyclohexyl)-tetramethyleneimine-3-yl] amino-2-oxoethyl)-3-(trifluoromethyl) benzamide,

(335) N-[2-({ (3R)-1-[4-(benzamido) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(336) N-(4-{ (3R)-3-[(2-{[3-(trifluoromethyl) benzoyl] amino } acetyl) amino] tetramethyleneimine-1-yl } cyclohexyl) pyridine-2-carboxamide,

(337) N-(4-{ (3R)-3-[(2-{[3-(trifluoromethyl) benzoyl] amino } acetyl) amino] tetramethyleneimine-1-yl } cyclohexyl) pyridine-3-carboxamide,

(338) N-(4-{ (3R)-3-[(2-{[3-(trifluoromethyl) benzoyl] amino } acetyl) amino] tetramethyleneimine-1-yl } cyclohexyl) pyridine-4-methane amide,

(339) 6-methyl-N-(4-{ (3R)-3-[({[3-(trifluoromethyl) benzoyl] amino } acetyl) amino] tetramethyleneimine-1-yl } cyclohexyl) pyridine-2-carboxamide,

(340) 5-methyl-N-(4-{ (3R)-3-[({[3-(trifluoromethyl) benzoyl] amino } acetyl) amino] tetramethyleneimine-1-yl } cyclohexyl) pyridine-2-carboxamide,

(341) 4-methyl-N-(4-{ (3R)-3-[({[3-(trifluoromethyl) benzoyl] amino } acetyl) amino] tetramethyleneimine-1-yl } cyclohexyl) pyridine-2-carboxamide,

(342) 6-methoxyl group-N-(4-{ (3R)-3-[({[3-(trifluoromethyl) benzoyl] amino } acetyl) amino] tetramethyleneimine-1-yl } cyclohexyl) pyridine-2-carboxamide,

(343) N-(4-{ (3R)-3-[(2-{[3-(trifluoromethyl) benzoyl] amino } acetyl) amino] tetramethyleneimine-1-yl } cyclohexyl) quinoline-4-methane amide,

(344) N-(2-{[(3R)-1-(3-hydroxyl-3-pyridine-2-base dicyclo [3.2.1] suffering-8-yl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(345) N-[2-({ (3R)-1-[3-hydroxyl-3-(5-picoline-2-yl) dicyclo [3.2.1] suffering-8-yl) tetramethyleneimine-3-yl } amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(346) N-(2-{[(3R)-1-(3-hydroxyl-3-pyridin-3-yl dicyclo [3.2.1] suffering-8-yl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(347) N-[2-({ (3R)-1-(3-hydroxyl-3-(6-methoxypyridine-3-yl) dicyclo [3.2.1] suffering-8-yl) tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(348) N-(2-{[(3R)-1-(8-hydroxyl-8-phenyl dicyclo [3.2.1] oct-3-yl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(349) N-(2-{[(3R)-1-(5-hydroxyl-5-phenyl dicyclo [2.2.1] heptan-2-yl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(350) N-(2-{[(3R)-1-(5-hydroxyl-5-pyridine-2-base dicyclo [2.2.1] heptan-2-yl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(351) N-(2-{[(3R)-1-(5-hydroxyl-5-pyridin-3-yl dicyclo [2.2.1] heptan-2-yl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(352) N-[2-({ (3R)-1-[5-hydroxyl-5-(6-methoxypyridine-3-yl) dicyclo [2.2.1] heptan-2-yl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(353) N-(2-{[(3R)-1-(5-hydroxyl-5-pyridin-4-yl dicyclo [2.2.1] heptan-2-yl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(354) N-(2-{[(3R, 5S)-1-(4-hydroxy-4-phenyl cyclohexyl)-5-methylpyrrolidin-3-yl] amino-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(355) N-[2-((3R, 5S)-1-[4-hydroxyl-4-(4-aminomethyl phenyl) cyclohexyl]-5-methylpyrrolidin-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide

(356) N-(2-{[(3R, 5S)-1-(4-hydroxyl-4-pyridine-2-basic ring hexyl)-5-methylpyrrolidin-3-yl] amino-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(357) N-(2-{[(3R, 5S)-1-(4-hydroxyl-4-pyridin-3-yl cyclohexyl)-5-methylpyrrolidin-3-yl] amino-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(358) N-(2-{[(3R, 5S)-1-(4-hydroxyl-4-pyridin-4-yl cyclohexyl)-5-methylpyrrolidin-3-yl] amino-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(359) N-[2-((3R, 5S)-1-[4-hydroxyl-4-(5-picoline-2-yl) cyclohexyl]-5-methylpyrrolidin-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide

(360) N-[2-((3R, 5S)-1-[4-hydroxyl-4-(6-picoline-3-yl) cyclohexyl]-5-methylpyrrolidin-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide

(361) 2-(1,3-benzothiazole-2-base is amino)-N-[(3R)-1-(4-hydroxyl-4-pyridine-2-basic ring hexyl) tetramethyleneimine-3-yl] ethanamide,

(362) N-[(3R)-1-(4-hydroxyl-4-pyridine-2-basic ring hexyl) tetramethyleneimine-3-yl]-2-{[5-(trifluoromethyl) pyrimidine-2-base] amino } ethanamide,

(363) N-[1-({ [(3R)-1-(4-benzyl ring hexyl) tetramethyleneimine-3-yl] amino } carbonyl) cyclopropyl]-3-(trifluoromethyl) benzamide,

(364) N-(2-{[3-(methyl fluoride)-1-(4-hydroxy-4-phenyl cyclohexyl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl-3-(trifluoromethyl) benzamide,

(365) N-[2-((3R)-1-[(3aR, 6aS)-5-hydroxyl-5-(6-methoxypyridine-3-yl) octahydro pentalene-2-yl] tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(366) N-[2-((3R)-1-[(3aR, 6aS)-5-hydroxyl-5-phenyl octahydro pentalene-2-yl] tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(367) N-[2-((3R)-1-[(3aR, 6aS)-5-hydroxyl-5-pyridin-3-yl octahydro pentalene-2-yl] tetramethyleneimine-3-yl amino)-the 2-oxoethyl]-3-(trifluoromethyl) benzamide,

(368) N-(2-{[(3R)-1-(5-hydroxyl-5-pyridin-3-yl dicyclo [2.2.2] suffering-2-yl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(369) N-[2-({ (3R)-1-[4-hydroxyl-4-(3-methyl isothiazole-5-yl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(370) N-{2-[((3R)-1-{4-[3-(methyl fluoride) isothiazole-5-yl]-the 4-hydroxy-cyclohexyl } tetramethyleneimine-3-yl) amino]-the 2-oxoethyl }-3-(trifluoromethyl) benzamide,

(371) N-(2-{[(3R)-1-(4-hydroxyl-4-isothiazole-5-basic ring hexyl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide,

(372) N-[2-({ (3R)-1-[4-hydroxyl-4-(4-pyrimidine-2-base phenyl) cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide,

(373) N-[2-({ (3R)-1-[4-(2-cyclopropyl pyrimidine-5-yl)-4-hydroxy-cyclohexyl] tetramethyleneimine-3-yl } amino)-2-oxoethyl]-3-(trifluoromethyl) benzamide and

(374) N-(2-{[(3R)-1-(4-hydroxyl-4-pyridazine-4-basic ring hexyl) tetramethyleneimine-3-yl] amino }-the 2-oxoethyl)-3-(trifluoromethyl) benzamide.

8. a treatment has the pharmaceutical composition of the mammiferous inflammation, rheumatoid arthritis, arteriosclerosis, neuropathic pain, lupus, systemic lupus erythematous, restenosis, immunity imbalance and the transplant rejection that need, wherein gives claim 1,2,3,4,5,6 or 7 compound and the pharmaceutically acceptable vehicle of these Mammalss treatment significant quantities, the mixture of diluent or carrier.

9. method that is adjusted in the chemokine receptor activity in the Mammals, described method comprises the claim 1,2,3,4,5 that gives significant quantity, 6 or 7 compound.

10. the illness of a CCR2 mediation for the treatment of the patient or the method for disease, described method comprises the claim 1,2,3,4,5 that needs the patient of this treatment significant quantity, 6 or 7 compound.

11. the illness of a CCR5 mediation for the treatment of the patient or the method for disease, described method comprises the claim 1,2,3,4,5 that needs the patient of this treatment significant quantity, 6 or 7 compound.