TWI354664B - Cyclic derivatives as modulators of chemokine rece - Google Patents

Description

1354664 IX. Description of the Invention: [Technical Field of the Invention] In general, the present invention relates to a modulator of chemical cytokine receptor activity, a pharmaceutical composition containing the same, and the use thereof as a medicament for treatment and prevention Inflammatory diseases, allergic and autoimmune diseases, and in particular, methods of asthma, rheumatoid arthritis, atherosclerosis, and multiple sclerosis. [Prior Art] The chemical cytokine is a chemotactic cytokine with a molecular weight of 6-15 kDa, which is released by a wide variety of cells to attract and activate, in particular, macrophages, T and other cell types. B lymphocytes, eosinophils, basophils, and neutrophils (reviewed: Luster, TVew V. g. /· Μβί/· 1998, 335, 436-445 and Rollins, 5/00ίΠ997, eg, 909- 928). There are two major chemical cytokines, CXC and CC, depending on whether the first two cysteine acids in the amino acid sequence are separated by a single amino acid (CXC) or adjacent (CC). CXC chemical cytokines, such as interleukin-8 (IL-8), neutrophil-activated protein-2 (ΝΑΡ-2), and melanoma growth-stimulated active protein (MGSA), mainly for neutrophils Chemotactic with sputum lymphocytes, however CC chemical cytokines such as RANTES, ΜΙΡ-1 α, ΜΙΡ-1 /3, unicellular chemotactic proteins (MCP-1, MCP-2, MCP-3, MCP) -4 and MCP-5) and eotaxin (-1 and -2), among other cell types, especially macrophages, T lymphocytes, eosinophils, dendritic cells and Alkaline cells are chemotactic. There are also some chemical cytokines, lymphoblastin-1, lymphotropin-2 (both are C chemical cytokines) and fractalkine (CX3 C chemical cytokines). It does not fall into any of the major chemical cytokines subpopulations. 95318 1354664 The chemical cytokine binds to a specific cell surface receptor belonging to the G-protein-coupled seven-transmembrane-functional site protein group (reviewed in: Horuk, I994, /乂159]65) It is called "chemical cytokines receptor". When conjugated to its cognate ligand, the chemical cytokine receptor transduces intracellular messages via the associated trimeric G protein, and in other responses, it specifically causes a rapid increase in intracellular calcium concentration and changes in cell shape. Increased expression of cell adhesion molecules, degranulation and promotion of cell migration. There are at least ten human chemical cytokine receptors that bind to or respond to CC chemical cytokines, which have the following characteristic patterns (reviewed in Zlotnik and Oshie Tmmw«, 2000, 72, 121): CCR-1 (or &quot ;CKR-Γ or "0>0^-1")[]^1?-1 a, MCP-3, MCP-4, RANTES] (Ben-Barmch et al., Ce//1993, 72, 415-425, With Luster, iVew V. [g. / MM. 1998, 335, 436-445); CCR-2A and CCR-2B (or "CKR-2A"/nCKR-2B" or "CC_CKR-2A"/"CC-CKR -2B")[MCP-1, MCP-2, MCP-3, MCP-4, MCP-5] (Charo et al., iVoc. Mzi/.dccw/.t/M 1994, 9/, 2752-2756, With Luster, iVew£«gJMei/. 1998, 338, 436-445); CCR-3 (or "CKR-3" or "CC-CKR-3") [曙otaxin (eotaxin)-l, 曙塔Eotaxin-2 'RANTES ' MCP-3 ' MCP-4] (Combadiere ^ A , /. Biol Chem. 1995, 270, 16491-16494, with Luster, iVew 5^./^4 1998, 3刈, 436-445); CCR-4 (or "CKR-4" or "CC-CKR-4") [TARC, MDC] (Power et al, / C/iew. 1995, 270,19495-19500 With Luster, «/. MM. 1998, 33 <5, 436-445) ; CCR-5 (or "CKR-5" or "CC-CKR-5") [MIP-1 a, RANTES, MIP-1 /3 ] (Sanson et al., 1996) , 35, 3362-3367); CCR-6 (or "CKR-6" or "CC-CKR-6")[LARC] (Baba et al., // 1997, 272, 14893-14898); CCR-7 (or "CKR-7" or "CC-CKR-7") [ELC] (Yoshie et al., 95318 1354664 / · Zewtoc., W. 1997, (52, 634-644); CCR-8 (or "CKR-8" or "CC-CKR-8") [l-309] (Napolitano et al.,··· //η/«Μ«σ/·, 1996, /57, 2759-2763 ); CCR-10 (or "CKR-10" or "CC-CKR-10") [MCP-1, MCP-3] (Bonini et al., ZWJam/Ce//) /. 1997, /( 5, 1249-1256); and CCR-11 [MCP-1, MCP_2 and MCP-4] (Schweickert et al., σ/. CAew. 2000, 275, 90550). In addition to mammalian chemical cytokine receptors, mammalian cytomegalovirus, herpes virus, and poxvirus have been shown to exhibit proteins with chemical cytokine receptor binding properties in infected cells (reviewed by: Wells and Schwartz) , Cwrr· 1997, 5, 741-748). Human CC chemical cytokines, such as RANTES and MCP-3, can cause rapid movement of calcium via these virally encoded receptors. Receptor performance can be mediated by allowing damage to normal immune system surveillance and response to infection. In addition, human chemical cytokine receptors, such as CXCR4 'CCR2, CCR3, CCR5 and CCR8, can be used as co-receptors for mammalian cells to be infected by microorganisms, such as human immunodeficiency virus (HIV). Chemical cytokines and their cognate receptors have been implicated in inflammatory, infectious and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathological diseases such as rheumatoid arthritis and atherosclerosis. Important mediators (reviewed in: PH Carter, 荸立立#荸J: 旎 龙 龙 2002 2002, (5, 510; Trivedi et al., _4««. and Indiana kiss Med. CAewi· 2000, 35, 191; Saunders And Tarby, Drug Disc. Today 1999, ¥, 80; Premack M Schall, Nature Medicine 1996, 2, 1174). For example, chemical cytokine single-cell chemoattractant-l (MCP-1) and its receptor CC chemistry Cytokinin receptor 2 (CCR-2) plays a zigzag role in attracting leukocytes to the site of inflammation and subsequent activation of these cells. When chemistry 95318 1354664 cytokine MCP-1 binds to CCR-2, it Lead to rapid increase in intracellular calcium concentration, increased expression of cell adhesion molecules, cell degranulation and promotion of leukocyte migration. Confirmation of the importance of MCP-1/CCR-2 interaction has been modified by genetic modification Mouse experiment provided. MCP-1 -/- mice have positive The number of white blood cells and macrophages, but after several different types of immune challenge, failed to add single cells to the inflammatory site (Bao Lu et al., ··· do;?· Mec?· 1998, /57,601). In place, CCR-2 -/- mice failed to supplement single cells or produce interferon-r when challenged with various exogenous agents; in addition, white blood cells without CCR-2 mice did not respond to MCP-1 and migrated ( Landing Boring et al, ·/· C/hua · 1997, 7 (10), 2552), to confirm the specificity of MCP-1/CCR-2 interaction. Two other groups have used different CCR-2 -/- mouse strains , independently report the same result (William A. Kuziel et al., /Voc. iVai/·also iw/. iSa·. C/&4 1997, 舛, 12053 ' with Takao Kurihara et al, / Ejcp. 1997, 7 you , 1757). The viability and general normal health of MCP-1 V- and CCR-2 -/- animals are noteworthy, as the disruption of MCP-1/CCR-2 interaction does not cause physiological crisis. The use of these data together led us to conclude that molecules that block the action of MCP-1 can be used to treat a variety of inflammatory and autoimmune disorders. This hypothesis is currently Confirmed in a wide variety of animal diseases in the modes described below. The MCP-1 line is known to be up-regulated in patients with rheumatoid arthritis (Alisa Koch et al., /C"«. /«vesi. 1992, milk, 772-779). Furthermore, several studies have demonstrated the potential therapeutic value of antagonism of MCP-1/CCR2 interaction in the treatment of rheumatoid arthritis. Recently, it has been confirmed that a DNA vaccine encoding MCP-1 can improve chronic polyadjuvant-induced arthritis in rats (Sawsan 95318 1354664)

Youssef et al., "/· /nvesi. 2000, 7 tear, 361). Similarly, inflammatory disease signs can be caused by arthritis directly induced by collagen (Hiroomi Ogata et al., Azi/w/. 1997, /<52, 106) or streptococcal cell wall (Ralph) C. Schimmer et al., / (10)/. 1998, M0, 1466) were administered with control of MCP-1 antibody. Most notably, peptide antagonists of MCP-1, MCP-1 (9-76) have been shown to prevent disease progression and reduce disease signs in the MRL-lpr mouse model of arthritis (depending on the time of administration) (Jiang-Hong Gong et al., Φ. Med 1997, 75(5, 131). MCP-1 is known to be up-regulated in atherosclerotic lesions and has been shown to have circulating levels of MCP-1. It is reduced by treatment with a therapeutic agent and plays a role in disease progression (Abdolreza Rezaie-Majd et al., Jrieriosc/er. 77^)^<:. calendar 0/.2〇〇2,22, 1194-1199). Four key studies have documented the potential therapeutic value of antagonism of MCP-1/CCR2 interactions in the treatment of atherosclerosis. For example, when MCP-1 -/- mice were mated with mice lacking LDL receptors, an 83% reduction in aortic lipid deposition was found (Long Gu et al., Mo/. Ce//1998, 2, 275). Similarly, when MCP-1 was genetically detached from mice that had overexpressed human apolipoprotein B, the resulting mice were protected from atherosclerosis in comparison to MCP-1 +/ten apoB control mice. Sexual damage formation (Jennifa Gosling et al., j_C7z>z./nveii. 1999, Sichuan 3, 773). Similarly, when CCR-2 -/- mice were crossed with apolipoprotein e mice, a significant reduction in the incidence of atherosclerotic lesions was found (Landin Boring et al., iVaiwre 1998, 394, 894^ final 'when lipid loading When a protein e-/- mouse is administered with a gene encoding a peptide antagonist of CCR2, the size of the lesion is reduced and the spot stability is increased (W. Ni et al. 2〇〇1, Chuan 3, 2) 〇96_21〇1). 95318 -10· 1354664 It is known that MCP-1 is up-regulated in human multiple sclerosis, and that effective therapy with interferon b-lb is recommended to reduce MCP in peripheral blood mononuclear cells. 1 Performance, which indicates that MCP-1 plays a role in disease progression (Carialarlori et al., / 2002, 723, 170-179). Other studies have documented the MCP-1/CCR-2 interaction in the treatment of resistance Potential therapeutic value in multiple sclerosis; all of these studies have been documented in experimental autoimmune encephalomyelitis (EAE), a common animal model of multiple sclerosis. MCP is administered to animals with EAE -1 antibody's significantly reduce disease recurrence (KJ Kennedy et al., JVewrmVwmwwi?/. 1998, 92, 98). Furthermore, two recent reports have now noted that CCR-2 -/- mouse strains are resistant to EAE (Brian T. Fife et al., /. Med. 2000, /P2, 899 ; Leonid Izikson et al., 乂 five; φ. her meaning 2000, i Xi 2, 1075). It is known that the MCP-1 line is up-regulated in patients with occluded tibial bronchitis after lung transplantation. Martine Reynaud-Gaubert et al., Xin Ying and Mo Hufa #广fy 2002, 2i, 721-730; John Belperio et al, / C"w. Tnvesi. 2001, Chuan 5, 547-556). In the rat model of bronchitis syndrome, administration of antibodies to MCP-1 causes a decrease in airway occlusion; likewise, CCR2 -/- mice are resistant to airway occlusion in this same pattern (John Belperio et al. J_C/i«_ /«vasi. 2001, 705, 547-556). These data indicate that the antagonism of MCP-1/CCR2 may be beneficial in the treatment of organ rejection after transplantation. Other studies have confirmed MCP-1/ The potential therapeutic value of antagonism of CCR2 interaction in the treatment of asthma. In ovalbumin-stimulated mice, sequestration of MCP-1 with neutralizing antibodies will A significant reduction in responsiveness and inflammation of the tracheal tube is caused (Jose-Angel Gonzalo et al., /_5; φ. Med. 1998, /55, 157). ΐ正95318 -11- 1354664 can be used to reduce the allergic airway inflammation in mice stimulated by Schistosoma mansoni eggs by administering antibodies to MCP-1 (Nicholas W. Lukacs et al., /· //w/wmwo/. 1997, /55, 4398). Consistent with the above, MCP-1 -/- mice showed a reduced response to the stimulation of the eggs of Schistosoma mansoni (Bao Lu et al., /. £"; φ· Med. 1998, /57, 601) . Other studies have demonstrated the potential therapeutic value of antagonism of MCP-1/CCR2 interaction in the treatment of kidney disease. In the mouse model of spheroid nephritis, administration of MCP-1 antibody causes a significant decrease in glomerular crescent formation and type I collagen deposition (Clare M. Lloyd et al., / and φ· Merf. 1997, / 55,1371) » In addition, MCP-1 -/- mice with induced toxic renal nephritis showed significantly less tubular damage than their MCP-1 +/+ counterparts (Gregory H. Tesch et al., J Clin. Invest, Ί999,103, ΊΤ). One study has demonstrated the potential therapeutic value of MCP-1/CCR2 interaction antagonism in the treatment of systemic lupus erythematosus. Hybridization of MCP-1 -/· mice with MRL-FASb1 mice - the latter with a deadly autoimmune disease that resembles the human system of lupus erythematosus - causes fewer diseases than wild-type MRL-FAS1! Long-lived mice (Gregory H. Tesch et al., 汾/λ Mec?. 1999, / eve 0, 1813). One study has demonstrated the potential therapeutic value of antagonism of MCP-1/CCR2 interaction in the treatment of colitis. The CCR-2 -/- mouse is protected from the effects of colitis caused by dextran sodium sulphate (Pietro G. Andres et al., */· /mmwwo/. 2000, /, 6303). One study has demonstrated the potential therapeutic value of antagonism of MCP-1/CCR2 interaction in the treatment of pneumocytitis. When the rats with IgA immune complex lung injury were treated with the antibody cultured against MCP-l (JE) in an intravenous manner, the signs of pulmonary inflammation were partially alleviated (Michael). L. Jones et al., J. Immunol. 1992, 149, 2147). One study has demonstrated the potential therapeutic value of MCP-1/CCR2 interaction antagonism in the treatment of cancer. When immunosuppressed mice with human breast cancer cells were treated with anti-MCP-1 antibody, inhibition and survival of lung micrometastasis were found to increase (Rosalba Salcedo et al., 2000, 34-40). One study has demonstrated the potential therapeutic value of antagonism of MCP-1/CCR2 interaction in treating re-narrowing. Mice lacking CCR2 showed a decrease in the ratio of intimal area to endocardial/medium ratio after femoral artery injury (relative to wild-type small animal partners) (Merce Roque et al. ▲ierfasr/er·polar sc· calendar/. 2002) , 22, 554-559). Other studies have provided evidence that the MCP-1 line is overexpressed in various disease states not mentioned above. These reports provide the following relevant evidence that MCP_1 antagonists may be useful therapeutic agents for this disease. Two reports describe that MCP-1 is overexpressed in intestinal epithelial cells and intestinal mucosa in patients with inflammatory bowel disease (HC Reinecker et al., GaWroewiera/ogy 1995, /05, 40, and Michael C. Grimm Etc., /.. 〇/. 1996, 59, 804). Two reports describe the overexpression of MCP-1 rats with brain trauma (JS King et al., */. iVewroz'mmMwo/. 1994, 5 (5, 127, and Joan W. Berman et al. /mwtmo/· 1996, /5(5, 3017). Another study has documented the overexpression of MCP-1 in cardiac allografts in hairy animals, indicating that MCP-1 is involved in the pathogenesis of graft arteriosclerosis. Role (Mary E. Russell et al. / / C/& 4 1993, 卯, 6086). Overexpression of MCP-1 has been found in patients with spontaneous lung fiber 95318 -13 - 1354664 degeneration of the lung Found in cells (Harry N. Antoniades et al., /Voc. A^/· &?··· ί/like 1992, 5P, 5371). Similarly, overexpression of MCP-1 is already in patients with psoriasis Found in the skin (M. Deleuran et al., J. Dermatol. Sci. 1996, 13, 228 » and R. Gillitzer et al., / «vest Z>e/7Wizto/. 1993, /0/, 127). Finally, Recent reports have mutated that the MCP-1 line is overexpressed in the brain and cerebrospinal fluid of patients with HIV-1 associated dementia (Alfredo Garzino-Demo, WO 99/46991). , CCR-2 has been implicated It is a co-receptor for some HIV species (BJ Doranz et al., Ο//1996, 55, 1149). CCR-2 has also been identified as a co-receptor for HIV and can be associated with disease progression (Ruth I. Connor) Et al., /. Office; MM. 1997, M5, 621). This finding is consistent with recent findings that the presence of CCR-2 mutant CCR2-64I is in human populations with HIV. Delayed unfolding of positive associations (Michael W. Smith et al., Sciewce 1997, 277, 959). Although MCP-1 has not been involved in these processes, it may be MCP-1 antagonism that acts via binding to CCR-2 in the following cases. In the case of HIV-infected patients, it may have a beneficial therapeutic effect in delaying the progression of the disease into AIDS. It should be noted that CCR-2 is also a chemical cytokine MCP-2, MCP-3, MCP-4 and MCP. Receptor of -5 (Luster «/· Med. 1998, 335, 436-445). Since the novel compound of formula (I) described herein antagonizes MCP-1 by binding to the CCR-2 receptor, it may be In the following case, the compound of the formula (I) may also be an effective antagonist of the action of MCP-2, MCP-3, MCP-4 and MCP-5 mediated by CCR-2. Therefore, when the term "antagonism of MCP-1" is referred to herein, it is assumed to be equivalent to the "antagonism of chemical cell stimulating stimulation of CCR-2". [Summary content] 95318 -14 - 1354664 Accordingly, the present invention provides a mcim receptor activity agonist/antagonist, or a pharmaceutically acceptable "soiler" or "salt" or "salt or prodrug." The present invention provides a pharmaceutical composition comprising at least one of the pharmaceutically acceptable and therapeutically effective amounts of the present invention, or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt thereof. Body drug form. The present invention provides a method for treating rheumatoid arthritis, multiple sclerosis, and atherosclerosis, which includes administering to a host in need of such treatment.

A therapeutically effective amount of at least one compound of the invention, or a pharmaceutically acceptable salt or prodrug form thereof. The invention provides a method of treating an inflammatory disease, comprising administering to a host in need of such treatment a therapeutically effective amount of at least one compound of the invention, or a pharmaceutically acceptable salt or prodrug thereof. The present invention provides novel cyclic derivatives for use in therapy. The present invention provides the use of novel cyclic derivatives for the manufacture of a medicament for the treatment of inflammatory diseases. These and other features of the present invention, as will be apparent from the following detailed description, have been achieved.

Or an exo isomer or a pharmaceutically acceptable salt thereof, wherein B, X, Z, m, η, S, carbon b, bond (4), R1, R2, R10, R11, R12 and R13 are defined as 95318 - 15- 1354664 Hereinafter, it is an effective modulator of MCP-1 and chemical cytokine activity. DETAILED DESCRIPTION OF THE INVENTION DETAILED DESCRIPTION OF THE INVENTION In one embodiment, the invention is directed to a compound of formula (I)

Or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: the cyclic oxime is a cycloalkyl group of 3 to 8 carbon atoms, wherein the cycloalkyl group is saturated or partially unsaturated; and is substituted by 1-2 R5 Or a heterocyclic ring of 3 to 7 atoms in which the heterocyclic ring is saturated or partially unsaturated, and the heterocyclic ring contains a hetero atom selected from _〇·, _S-, -S(=0)-, -S(= 0) 2· and -N(R4)-, the heterocyclic ring optionally contains -C(0)-, and is substituted by 0-2 R5; x is selected from Ο or S; Z is selected from a bond, nrS^o)·, -nrSco,, -NR8C(S)NH- '-NR8S〇2- '-NR8S02NH- '-C(0)NR8- '-OC(0)NR8- ' -NR8C(0)〇 - > -CR14=CR14- ' -CR15R15- ' -CR15 R15 C(O)- ' -C(0)CR15R15-,CR15R15C(=N-OR16)-,-0-CR14R14-, -cr14r14-o- , -o- ' -NR9- ^ -NR9-CR14R14- ' -CR14R14-NR9- ' -S(0)p- ' s(0)p -CR14 Ri 4 -, -CR14 Ri 4 -S(〇)p - and _s(0)p _nr9 -; wherein neither Z nor Ri3 is attached to the carbon atom identified (b); bond (8) is a single or double bond; or, when η is equal to 2, two The atom identified by (b) may be bonded by a double bond; 95318 -16- 1354664 R1 is selected from Η, R6, Ci 6 substituted by 0_3 R6 An alkyl group, a 匸2 -6 alkenyl group substituted by 0-3 R6, a C2-6 alkynyl group substituted by 〇-3 R6, a C6-1 aryl group substituted by 0-5 R6, and a 5-10 member hetero An aryl system containing one hetero atom selected from N, Ο and S, substituted by 〇3 尺6; with the proviso that if Ri is Η, then a) R5 is (CRR)rNR5aR5a, or b) Ring B is a heterocyclic ring system containing at least one N(R4); and another condition is that if R5 is hydrazine, either a) R1 is not hydrazine, or b) cycline is a heterocyclic ring system, Containing at least one N(R4); with the proviso that when Ria is equal to a c6_1() aryl or a 5-10 membered heteroaryl system containing from 1 to 4 heteroatoms selected from N, 0 and S, R1 is not - CH2 S(0)p -R a, -CH2S(0)2-Rla, -NHC(0)-Rla, -NHC(0)NH-Rla, -NHCH2-Rla, -NHS02-Rla '-NHS02NH- Rla; R2 is selected from C6_!〇 aryl substituted by 0-5 R7, and contains 1-4 heteroatoms selected from N, Ο and S with 5-10 membered heteroaryl systems, 〇-3 R7 is substituted; R4 is selected from fluorene, Cu alkyl, C3-8 alkenyl, C3-8 alkynyl, (CRR)t〇H, (CRR)tSH, (CRR)tOR4d, (CHR)tSR4d, (CRR)tNR4aR4a , (CRR)qC(0)0H, (CRR)r C(0)R4b, (CRR)rC(0)NR4aR4a, (CRR)t 0C(0)NR4aR4 a, (CRR)t NR4 a C(0)0R4 d, (CRR)t NR" C(0)R4 b, (CRR)rC(0)OR4d, (CRR)t0C(0)R4b, (CRR)r S(0)p R4 b, (CRR)rS(0)2NR4aR4a, (CRR)tNR4aS(0)2R4b, Cl.6 haloalkyl, (CRR)r-C3 -! 〇 carbocyclic residue substituted by 0-3 R4 e, and (CHR\-4-10 member heterocyclic ring system, containing 1-4 options) Heteroatoms from N, Ο and S are substituted by 〇_295318 17 1354664 R4e; R4a is independently selected from Η, methyl substituted by 0-1 R4c, 0-3 C4_6 alkyl substituted by R4e, C3_8 alkenyl substituted by 〇-3 R4e, C3-8 alkynyl substituted by 0-3 R4e, (CH2)r-C3-1 substituted by 〇-4 R4e ( a carbocyclic residue, and a (CHR)r-4-10 member heterocyclic ring system containing 1-4 heteroatoms selected from N, fluorene and S, substituted by 〇-2 R4e; R4b is present in each Wherein, it is selected from the group consisting of hydrazine, an alkyl group substituted by 0-3 R4e, a C3_8 alkenyl group substituted by 0-3 R4e, a C3_8 alkynyl group substituted by 3 R4e, and substituted by 0-2 R4e. (CH2)r-C3-6 carbocyclic residue, and (CHR)r-4-10 member heterocyclic ring system containing 1-4 selected from N, 0 and S Atom, substituted by 0-2 R4e; R4c is independently selected from -C(0)R4b, -C(0)0R4d ' -C(0)NR4fR4f, C(0)0H, (CH2)rC(0)NHS02 -R4h, NHS02R4h, (CH2)rw azolyl and (CH2; U group; R4d is selected from the group consisting of methyl, CF3, C2_6 alkyl substituted by 0-3 R4e, 0-3 R4e substituted C3_8 alkenyl, C-3-8 alkynyl substituted by 0-3 R4e and C3-1Q carbocyclic residue substituted by 0-3 R4e; R4e is selected from Cm alkane in each presence Base, C2_8, C2-8, (CH2)rC3_6 cycloalkyl, Cl, F, Br, I, CN, N〇2, (CF2)rCF3, (CHAOCh alkyl, 〇H, SH, ( CHJSCu alkyl, (CH2)rNR4fR4f, -C(0)R4i, _c(0)0R4j, -C(0)NR4hR4h, -〇C(0)NR4hR4h, -NR4hC(0)NR4hR4h -NR4hC(0)0R4j ' C(0)0H '(CH2)r C(0)-NHS02 -R4k' NHS02R4k, (αΐ2χtetrazolyl and (CH2)r phenyl; R4f is selected from Η, (^-6 in each presence) Alkyl, C3-6 cycloalkyl and phenyl; 95318 • 18 1354664 R4h is independently selected from the group consisting of Η, <: 6 alkyl, c3 8 alkenyl, C3-8 block and (CH2) r -C3 _1 Q rear ring family; R41 is selected from each of the '' Cu alkyl, C3-8 alkenyl, (:3-8 alkynyl and (CH2)r-C3_6 carbocyclic residue; R4] in each presence, selected from Cf3, Ci 6 alkyl, C3 8 Alkenyl, c3 8 block and C3-1Q carbon residue; R4k is selected from C15 alkyl, Cl-5 alkyl and C36 cycloalkyl, and phenyl at each position; R5 in each Where present is independently selected from Η, =〇, (^_6 alkyl 'C2-8 alkenyl, C2-8 alkynyl, F, Q, Br, I, (CRR) rOH, (CRR) rSH, ( CRR)rOR5d, (CRR)rSR5d, (CRR)rNR5aR5a, (CRR)rN(0)R5aR5a, (CRR)rC(0)0H, (CRR)rC(0)R5b, (CRR)rC(0)NR5aR5a, (CRR)rNR5aC(0)R5b ' (CRR)r〇C(〇)NR5aR5a ' (CRR)rNR5aC(0)0R5d, (CRR)rNR5aC(0)NR5aR5a, (CRR)rNR5aC(0)H, (CRR) rC(0)0R5d, (CRR)r0C(0)R5b, (CRR)rS(0)pR5b ' (CRR)rS(0)2NR5aR5a > (CRR)rNR5aS(0)2R5b ' (CRR)rNR5aS(0) 2NR5aR5a, Cu haloalkyl, (CRR)r-C3_10 carbon ring residue substituted by 0-3 R5c, and (CRR)r-5-10 member heterocyclic ring system, containing 1-4 selected from N, The hetero atom of Ο and S is substituted by 〇3 R5c; R5 a is independently selected from Η and replaced by 0-1 R5 g at each position Methyl group, C2_6 alkyl group substituted by 0-3 R5e, C3.8 alkenyl group substituted by 〇-2 R5e, C3-8 alkynyl group substituted by 0-2 R5e, 〇-5 R5e Substituted (CH2)r-C3-1() carbocyclic residue, and (CH2)r-5-10 member heterocyclic ring system containing 1-4 heteroatoms selected from N, fluorene and S, - 3 R5 e substitutions; 95318 -19- 1354664 wherein, when R5 is (CRR)rN(0)R5aR5a, neither of Rh is η; R5b is substituted at each position from 0-3 R5e a Cu alkyl group, a C3-8 alkenyl group substituted by 0-2 R5e, a C3-8 group substituted by 0-2 R5e, and a (CH2)r-C3_6 carbon ring group substituted by 0-2 R5e The residue, and the (CH2)r-5-6 member heterocyclic ring system 'containing 1-4 heteroatoms selected from N, 0 and S, are substituted by 0-3 R5e; R5e is selected at each presence From (^-6 alkyl, C2_8 fluorenyl, C2_8 block, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, (CF2)rCF3, N〇2, CN, (CH2)rNR5fR5f, (CH2)rOH, (CHAOCh alkyl, (CHASCh alkyl, (CH2)rC(0)0H, (CH2)rC(0)R5b, (CH2)rC(0)NR5fR5f, (CH2)r0C(0)NR5fR5f , (CH2)rNR5fC(0)R5b, (0^)/(0)0(^-4 alkyl, (CH2)rNR5fC(0)OCb4 alkyl , (CH2)rOC(0)R5b, (CH2)rC(=NR5f)NR5fR5f ' (CH2 )r S(0)p R5 b > (CH2)rNHC(=NR5f)NR5fR5f,(CH2)rS(0) 2NR5fR5f, (CH2)rNR5fS(0)2R5b, C(0)0H, (CH2)rC(0)NHS02-R5h, NHS02R5h, (CH2)rWzolyl and (CH2)rphenyl, 0-3 R5e Substituted; R5d is selected from the group consisting of methyl, CF3, C2-6 alkyl substituted by 0-2 R5e, C3_8 alkenyl substituted by 0-2 R5e, substituted by 0-2 R5e a C3.8 alkynyl group, and a C3-1Q carbocyclic residue substituted by 0-3 R5e; 1^56 in each of the presences is selected from the group consisting of Ci_6, C2-8, and C2-8 Block group, (: 3-6 cycloalkyl, a, F, Br, I, CN, N〇2, (CF2)rCF3, (CHAOCu alkyl, OH, SH, (CHASCu alkyl, (CH2)rNR5fR5f, (CH2)rC(0)NHR5h, (CH2)r0C(0)NHR5h, (CH2)rOH, (CH2)rC(0)0H, (CH2)rC(0)NHS02-R5h, NHS02R5h, (CH2)r- a 5-6 member heterocyclic ring system containing 1-4 heteroatoms selected from N, O and S, and (CH2)r 95318 -20- 1354664 phenyl; R5f is selected from the group consisting of hydrazine, ^·6 alkyl and (: 3-6 cycloalkyl;

Independently selected from -CN, -C(0)R5b, -C(0)0R5d, -C(0)NR5fR5f, -C(0)0H and (CH2)rphenyl; R5h is selected at each presence From q-5 alkyl, Ci-5-alkyl and C3_6 cycloalkyl, and phenyl; R in each presence, selected from hydrazine, alkyl substituted by 0-3 R5e, C2-8 thiol, C2_8 alkynyl, (012) -6 Cycloalkyl and (CH2)r phenyl, substituted by 0-3 R5e; R6 in the presence of the parent' is selected from the group consisting of Cl-8, C2 · 8 , C2 - 8 cyclyl, (CH2)rC3-6 cycloalkyl, a, Br, I, F, N02, CN, (CRiROrNRhRh, (CR'RlOH, (CR'R')rO(CR'R,) rR6d, (CR, R') rSH, (CR, R,) rC(0)H, (CR'R'XSCCR'R'XR60' . (CR'R'XSCCOXCR'R'XR615 > (CR'R ')rC(0)0H ' (CR'R,)rC(0)(CR'R,)rR6b, (CR,R,)rNR6aR6a, (CR,R,)rC(0)NR6aR6a, (CR,R ,)rNR6fC(0)(CR.R,)rR6b, (CR'R,)rC(0)0(CR,R')rR6d, (CR'R'XOQOXCR'R'XR65, (CR'R,) r0C(0) service 6a(CR'R')rR6d, (CR,R')rNR6aC(0)NR6a(CR'R|)rR6d, (CR'R')rNR6aC(S)NR6a(CR,R') rR6d ' (CR'R%NR6fC(0)0(CR,R')rR6b,(CR,R')rC(=NR6f)NR6aR6a, (CR'R')rNHC(=NR6f)NR6fR 6f ' (CR'R')r S(0)p (CR'R')r R6 b ' (CR'R')rS(0)2NR6aR6a ' (CR'R')rNR6fS(0)2NR6aR6a ' (CR 'R,)rNR6fS(0)2(CR,R')rR6b, (CR'R^CCCONHSC^R615, Cu haloalkyl, 0-3 R; substituted C2-8 alkenyl, 0-3 R' substituted (: 2-8 alkynyl, substituted by 0-3 R6e (CR'R% phenyl, and (CH2)r-5-10 member heterocyclic system 95318 • 21 · 1354664 system, containing 1-4 heteroatoms selected from n, 〇 and s, substituted by 0-2 R6e; or 'R2' on two adjacent atoms on R1 may be joined to form a cyclic acetal; R6a is present at each , is selected from the group consisting of hydrazine, a methyl group substituted by 〇-1 R6g, a C2-6 alkyl group substituted by 0-2 R6e, a C3-8 alkenyl group substituted by 〇-2 R6e, and replaced by 0-2 R6e a c3_8 alkynyl group, a 0-5 substituted (CH2)r-C3-1Q carbocyclic residue ' and a (CH2)r-5-l 杂环 heterocyclic ring system, containing 1-4 selected from N,杂 and S heteroatoms' are substituted by 〇_2; R6b is selected from Η, Ci.6 alkyl substituted by 0-2 R6e, C3_8 substituted by 0-2 R6e a C3_8 cycline substituted by 〇-2 R6e, a (CH2)rC3_6 carbon cyclone residue substituted by 0-3 R6e, and (CH 2) a r-5-6 member heterocyclic ring system containing 1-4 heteroatoms selected from n, fluorene and S, substituted by 0-2 R6e; R6d is selected from the group 〇_2 at each presence a C3-8 alkenyl group substituted by R6e, a C3_8 alkynyl group substituted by 〇2 R6e, a methyl group, a CF3 group, a C2-6 alkyl group substituted by 0-3 R6e, a C2-4 alkyl group, a beacyl group 3 R6e substituted (CH2)r-C3-10 carbon ring residues, and (CH2)r-5-6 member heterocyclic ring system containing 1-4 heteroatoms selected from N, fluorene and S, 0- 3 R6 e substituted; R6e is selected from the group consisting of Ck alkyl 'C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2)rCF3, (CHJOCh alkyl, OH, SH, (CHASCu alkyl, (CH2)rNR6fR6f, C(0)NHR611, (CH2)rOH, C(0)0H, (CH2)rC ( 0) NHS02-R611, NHS02R6h, (CH2)rW azolyl and (CH2)r phenyl, and (CH2)r-5-6 heterocyclic ring system, containing 1-4 selected from N, 0 and S Atom; in each presence, 'selected from hydrazine, Ci-5 alkyl and C3-6 cycloalkyl, and phenyl 95318 • 22-1354664; R6gS is independently selected from -C(0)R6b, -C (0)0R6d, -C(0)NR6fR6f, (CH2)rOH, C(0)0H, (CH2)rC(0)N HS02-R6h, NHS02R6h, (CH2) rsazolyl and (CH2X phenyl; R6h, in each presence, selected from C^-5 alkyl, Ci-5 alkyl and 03-6 cycloalkyl, and Phenyl; R7 in the presence of a parent-- is selected from the group consisting of Ci-8, '2', 匚2- 8, C2-8, (CH2)rC34, cn, Br, I, F'N 〇2, CN ' (CR'ROrNRhRh, (CR'R') rOH, (CR'R')rO(CR'R')rR7d, (CR,R')rSH, (CR,R')rC(0 H, (CR'R^SCCR'R'XI^d, (CR'R'XCCCOOH, (CR'ROrCCOXCR'R'XR715, (CR'R')rC(0)NR7aR7a ' (CR'R') rNR7fC(0)(CR'R')rR7b ' (CR'R')rC(0)0(CR|R')rR7d, (CR'R')r0C(0)(CR'R')rR7b, ( CR'R')r0C(0)NR7a(CR'R')rR7a ' (CR'R'^NR^C^NR^CCR'R'^R73 ' (CR;R,)rNR7fC(0)0(CR 'R')rR7d, (CR'R')rC(=NR7f)NR7aR7a, (CR'R')rNHC(=NR7f)NR7fR7f ' (CR'R')r S(0)p (CR'R') r R7 b ' (CR'R')rS(0)2NR7aR7a, (CR'R')rNR7aS(0)2NR7aR7a, (CR'R,)rNR7fS(0)2(CR'R')rR7b, (CR, R')rC(0)NHS02R7b, Cu haloalkyl, C2-8 alkenyl substituted by 0-3 R', C2-8 alkynyl substituted by 0-3 R', substituted by 0-3 R7e (CIHOrChio carbon ring, replaced by 0-3 R7e a (CR'R')r phenyl group, and a (CH2)r-5-6 member heterocyclic ring system containing 1-4 heteroatoms selected from N, fluorene and S, substituted by 0-3 R7e; , two R7 on adjacent atoms on R2 may be joined to form a cyclic acetal; R7a is independently selected from the group consisting of hydrazine, methyl substituted by 0-1 R7g, and 95318-23- 1354664 0-2 R7e substituted C2_6 alkyl, C-2-8 alkenyl substituted by 0-2 R7e, C3-8 alkynyl substituted by 0-2 R7e, substituted by 0-5 R7e (CH2) r-C3_ i 〇Carbocyclic residue, and (CH2)r-5-10 member heterocyclic ring system containing 1-4 heteroatoms selected from N, Ο and S, substituted by 0-2 R7e; R7b In each presence, it is selected from Ci-6 alkyl substituted by 0-2 R7e, C!-6 halogen alkyl, C3-8 alkenyl substituted by 0-2 R7e, substituted by 〇-2 R7e a C3-8 alkynyl group, a (CH2)rC3_6 carbon ring residue substituted with 0-3 R7e, and a (CH2)r-5-6 member heterocyclic ring system containing 1-4 selected from N, fluorene and S a hetero atom, substituted by 0-2 R7e; R7d, at each occurrence, selected from a C3-8 alkenyl group substituted by 0-2 R7e, a C3-8 alkynyl group substituted by 0-2 R7e, a methyl group , CF3, C2-4 haloalkyl, 0-3 R7 E-substituted C2-6 alkyl group, (CH2)r-C3-1() carbocyclic group residue substituted by hydrazine-3 R7e, and (CH2)r-5-6 member heterocyclic ring system containing 1- 4 heteroatoms selected from N, oxime and S; substituted by 0-3 R7e; each of R7% is selected from the group consisting of Cl-6 alkyl, C2_8 fluorenyl, C2-8 block, (CH2)rC3- 6 cycloalkyl, ci, F, Br, I, CN, N02, (CF2) rCF3, (CHAOCu alkyl, (CH2)rOH, OH, SH, C(0)0H, C(0)NHR7h, (: (0)0 (^-5 alkyl, (CHASq-5 alkyl, (CH2)rNR7fR7f, (CH2)rC(0)NHS02-R7h, NHS02R7h and (CH2)r phenyl, (CH2)r tetrazolyl 117 £ at each occurrence 'selected from hydrazine, Cl_5 alkyl and C3_6 cycloalkyl, and phenyl; heart is independently selected from -C(0)R7b, -C(0)0R7d, -C(0 NR7fR7j (CH2)r phenyl; R7h in each of the positions 'selected from Ci.5 alkyl, Q-5-alkyl and C3 6 cycloalkane 95318 •24·1354664, with phenyl; RI in each Where present, is selected from the group consisting of Η, Q-6 alkyl substituted by 0-3 R6e, C2.8 alkenyl, C2-8 alkynyl, (CH2)rC3_6 cycloalkyl and (CH2)^ 0-3 R6e substituted; R8 is selected from Η, (V4 alkyl and C3_4 cycloalkyl; R9 is selected from Η, (: 4 alkyl, C3_4 cycloalkyl, -C(0)H and alkyl; R10 is independently selected from the group consisting of Q-4 alkyl substituted with 0-1 R1Qb; R10b is independent in each presence It is selected from the group consisting of -OH, -SH, -NR1QcR1()c, -qC^NR1. c R1. c and -NHCCC^R10 c ; R10c is selected from fluorene, (V4 alkyl and (: 3-6 cycloalkyl; R11 is selected from hydrazine, Q.4 alkyl, (CHR)qOH, (CHR)qSH, (CHR)qORlld, (CHR)qS(0)pRlld, (CHR)rC(0)Rllb, (CHR)rNRllaRlla, .(CHR)r C(0)NR11 a R11 a > (CHR)r C(0 )NR11 a OR11 d ' (CHIOqNR11 redundancy 11 b, (CHRjqNR11 a (:(0)01111 d, (CHR)q0C(0)NRllaRlla, (CHR)rC(0)0Rlld, replaced by 0-5 Rlle a (CHR)r-C3_6 carbocyclic residue, and a (CHR)r-5-10 member heterocyclic ring system containing from 1 to 4 heteroatoms selected from N, 0 and S, substituted with 〇-3 Rlle;

Rlla is independently selected from the group consisting of hydrazine, (^_4 alkyl, C3_4 alkenyl, C3-4 cyclyl, (〇12乂(:3_6 cycloalkyl, substituted by 0-5 R11 e) CH2)r-C3-6 carbocyclic residue, and (CH2)r-5-6 heterocyclic ring system containing 1-4 heteroatoms selected from N, oxime and S, 〇3 R11 e Replace

Rllb is in each of the positions '(C2)r-C3-6 carbocyclic residue independently selected from Cl_4 alkyl, C2 4 alkenyl, C2 4 alkynyl, 0-2 Rne, and (CH2) a rh-5-6 heterocyclic ring system containing μ heterogeneously selected from n, oxime and S, 95318 -25 - 1354664 sub-substituted by 0-3 Ri1 e;

Rlld, at each occurrence, is independently selected from the group consisting of hydrazine, methyl, -CF3, C2_4 alkyl, A.6 alkenyl 'C3-6 alkynyl, C3_6 carbon ring residue substituted by 0-3 Rlle, And (CH2)r-5-6 member heterocyclic ring system 'containing 1-4 heteroatoms selected from N, oxime and S, substituted by 0-3 R11 e;

Rlle is selected from Cm alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, cn, F, Br, I, CN, N〇2, (CF2)rCF3, in each presence. (CHAOCh alkyl, OH, -O-Cu alkyl, SH, (CHASCh alkyl, (CHANRUfRnKCHdr phenyl;

Rllf is selected from H, Cl-6 alkyl and C3_6 cycloalkyl at each occurrence; R12 is selected from hydrazine; R13 is independently selected from hydrazine and substituted by 0-1 R13b in each presence. Q.4 thiol, -OH, -NH2, F, Cl, Br, I, -OR13a, -N(R13a)2 and (^_4 alkyl substituted by 0-3 R13b; R13 a is selected from Η , Ch alkyl and C 3 -6 cycloalkyl; R 13b is independently selected from the group consisting of -〇H, -SH, -NR13cR13c, -(10) serving 13 c R13 c and -NHqc^R13 c; R13c is selected From H, cw alkyl and (: 3.6 cycloalkyl; R14 in each presence is independently selected from H and alkyl; or two R14 are bonded to the carbon atom to which they are attached to form C3 6 carbon Ring; R15 is independently selected from H, Ci-4 alkyl, OH, NH2, 4 alkyl, NR15aR15a, c(0)NR15aR15a, NR15aC(0)R15b, NR15aC(0)0R15d, 〇 C(〇)NRl5aR15a and (CHR)rC(〇)〇R15d; 95318 -26· 1354664 Alternatively, two RUs are bonded to form one or more carbon atoms to form a C3-6 carbon ring;

Rl5a, at each occurrence, is independently selected from the group consisting of 11 and (:1_4 alkyl;

Rl5b, at each occurrence, is independently selected from the group consisting of Ci-4 alkyl, C36, and C36; R15d, at each occurrence, is independently selected from the group consisting of c 4 alkyl, c 3 6 alkenyl, and c3 6 alkyne R16 is selected from the group consisting of 〇^4 alkyl; 1 is selected from 1, 2 and 3; η is selected from 〇, 1, 2 and 3; m is selected from 0 and 1; P is present at each Independently selected from the group consisting of ruthenium, osmium and 2; q in each presence, independently selected from 1, 2, 3 and 4; r in each presence, independently selected from 〇, 丨, 2, 3 and 4; In each presence, the lines are independently selected from 2, 3, and 4; the s is selected from the group consisting of 〇 and 1. In another specific embodiment, the invention provides a novel compound of formula 1:

Or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein: the ring is a ring of 3 to 8 carbon atoms, β L ^ ... clothing & base ' wherein the cycloalkyl group is saturated or traced Unsaturated; or 3 to 7 atoms in the evening, K heterozygous, wherein the heterocycle is saturated or the fraction 95318-27. 1354664 is unsaturated, the heterocycle contains a hetero atom selected from -ο-, -s- , -s(=o)-, -s(=o)2-, and -N(R4)- 'the heterocyclic ring optionally contains ·(:(0)-; ring B is substituted by 1-2 R5; or Ring B is substituted by 0-2 R5; X is selected from Ο or S; Z is selected from a bond, -NR8 c(〇)_, _ clothes 8 c(s)_, _ clothes 8 c (〇 )nh-, -NR8C(S)NH- '-NR8S〇2- ^ -NR8S02NH- ' -C(0)NR8- ' -0C(0)NR8- ' -NR8C(0)〇- ^ -(CR15R15) r ' -CR14=CR14- ' -CR15R15C(0)-, -C(0)CR15Ri5_, CRbRUceN-OR16)-, φ -0-CR14R14- ^ -CR14R14-〇. . . .〇. λ _nr9- ^ -NR9 -CR14R14- ' -CR14R14-NR9- ' -S(0)p- ^ -S(0)p-CR14R14- ' -CR14R14-S(0)p- and -S(0)p-NR,; Non-Z and non-Ri3 are attached to the carbon atom identified (9); bond (8) is a single or double bond; or 'when η is equal to 2', the two identified (9) atoms can pass Through double bond bonding; R1 is selected from Η, R6, ·3 尺6 尺6 substituted q·6 alkyl, 〇3 03 replaced by C2 -6 basal, bedding _3 feet 6 Substituted alkynyl group, Q·丨〇万基' and 5_1〇 heteroaryl system substituted by 〇5 R6, containing ι_4 heterogenes selected from n, 〇 and S, 0-3 R6 Substituted; with the proviso that when Rla is equal to aryl or heteroaryl, r1 is not -CH2S(0)p-Ria x _ch2S(0)2-R^ . -NHCCO)-^^ -NHC^NH- R1 a 'NHOi2^u, s〇2Nh r1 a, a y y y y y y y y y y y y y y y y y y y y y y y y y y y y y y y y y y y y y y y y y y y y y y U.S. Provisional Patent Application No. 60/446,850 (PH7442) and 5/1/03 filed by U.S. Patent Application Serial No. 95/28, pp. U.S. Provisional Patent Application Serial No. 60/467,003 (PH7470); R2 is selected from the group consisting of 0-5 R7 substituted C6_10 aryl and 5-10 member heteroaryl systems, containing 1-4 selected From X, 0 and S heteroatoms, substituted by 0-3 R7; R4 is selected from fluorene, Cu alkyl, C3-8 alkenyl, C3_8 alkynyl, (CRR)t〇H, (CRR)tSH, (CRR)tOR4d, (CHR)tSR4d, (CRR)tNR4aR4a, (CRR)qC(0)0H, (CRR)rC(0)R4b, ( CRR)rC(0)NR4aR4a, (CRR)t0C(0)NR4aR4a, (CRR)tNR4aC(0)0R4d, (CRR)tNR4aC(0)R4b, (CRR)rC(0)0R4d, (CRR)t0C(0 R4b, (CRR)rS(0)pR4b, (CRR)rS(0)2NR4aR4a, (CRR)tNR4aS(0)2R4b, Q-6 functional alkyl, substituted by 0-3 R4e (CRR)r- a C3-1() carbocyclic residue, and a (CHR)r-4-10 member heterocyclic ring system containing 1-4 heteroatoms selected from N, fluorene and S, substituted by 0-2 R4e; R4a In each place, it is independently selected from hydrazine, a methyl group substituted by 0-1 R4c, a C2-6 alkyl group substituted by 0-3 R4e, a C3_8 fluorenyl group substituted by hydrazine-3 R4e, 0-3 R4e substituted C3-8 alkynyl, substituted by 4 R4e (CH2)r-C3.1() carbocyclic residue, and (CHR)r-4-10 member heterocyclic system Containing 1-4 heteroatoms selected from N, oxime and S, substituted by 〇-2 R4e; R4b, at each occurrence, is selected from Η, Cu alkyl substituted by 0-3 R4e, 0-3 R4e substituted C3_8 alkenyl, C3-8 alkynyl substituted by 〇3 R4e, (CH2)r-C3-6 substituted by 0-2 R4e a cyclocyclic residue, and a (CHR)r-4-10 member heterocyclic ring system containing 1-4 heteroatoms selected from n, fluorene and S, substituted by 0-2 R4e; 95318 • 29· 1354664 R4c Independently selected from -C(0)R4b, -C(0)0R4d, -C(0)NR4fR4f, and (CH2)r phenyl; R4d is selected from methyl, CF3, and 0-3 in each presence. a C4-6 alkyl group substituted by R4e, a C3_8 fluorenyl group substituted by 0-3 R4e, a C3-8 alkynyl group substituted by 0-3 R4e, and a C3_1() carbon ring group substituted by 0-3 R4e Residues; 1^ at each position, selected from (ν6 alkyl, C2-8 fluorenyl, C2-8 block, (CH2)rC3_6 cycloalkyl, Cl, F, Br, I, CN, N 〇2, (CF2)rCF3, alkyl group, OH, SH, alkyl group, (GH2)rNR4fR4f, -C(0)R4i ' -C(0)0R4J ' -C(0)NR4hR4h ' -0C(0)NR4 h R4 h ' · -NR4hC(0)NR4hR4h, -NR4hC(0)0R4j and (CH2)r phenyl; R4f, at each occurrence, is selected from H, alkyl, C3-6 cycloalkyl and phenyl R4h is independently selected from the group consisting of hydrazine, 0-hexa-alkyl, C3-8-alkenyl, C3-8, and (CH2)r-C3 - 1 anthracene; R4i is present in each Wherein, selected from the group consisting of hydrazine, Cu alkyl, C3-8 alkenyl, (: 3-8 thiol and (CH2)r-C3-6 Carbocyclic residue; R4] in each presence, selected from the group consisting of CF3, Cu alkyl, C3.8 alkenyl, C3-8 alkynyl and C3.1() carbocyclic residues; _R5 in each presence Wherein, independently selected from Η, =0, q.6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CRR)rOH, (CRR)rSH, (CRR)rOR5d, (CRR)rSR5d, (CRR) rNR5aR5a, (CRR)rN(0)R5aR5a, (CRR)rC(0)0H, (CRR)rC(0)R5b, (CRR)rC(0)NR5aR5a, (CRR)rNR5aC(0)R5b, (CRR) r0C(0)NR5aR5a, (CRR)rNR5aC(0)0R5d, (CRR)rNR5aC(0)NR5aR5a, (CRR)rNR5aC(0)H, (CRR)rC(0)0R5d, (CRR)r0C(0)R5b '(CRR)rS(0)pR5b ' (CRR)r S(0)2 NR5 a R5 a ' (CRR)rNR5aS(0)2R5b, (CRR)rNR5aS(0)2NR5aR5a, Cu Haloalkyl, 95318 -30 · 1354664 (CRR)r-C3-1() carbocyclic residue substituted by 0-3 R5c, and (CRR)r-5-l 杂环 heterocyclic ring system ' containing 1-4 selected from n, The hetero atom of Ο and S is substituted by 〇_2 R5 e; R5a is independently selected from Η, methyl substituted by 0-1 R5g, C2_6 substituted by 0-2 R5e a C3_8 alkene substituted by 〇2 R5e, a C3_8 alkynyl group substituted by 0-2 R5e, and substituted by 〇-5 R5e (CH2)r-C3.10 Carbocyclic residue ' and (CH2)r-5-10 heterocyclic ring system containing 1-4 heteroatoms selected from N, fluorene and S, 0-3 R5 e substitution; wherein, when R5 is (CRR)rN(0)R5aR5a, R5a is not H; R5b is selected from the group consisting of 0-3 R5e substituted Cu alkyl, 0-2 a C3-8 alkenyl group substituted by R5e, a C3_8 alkynyl group substituted by 〇-2 R5e, a (CH2)r-C3_6 carbocyclic group residue substituted by 0-2 R5e, and (CH2)r-5- a 6-membered heterocyclic ring system containing 1-4 heteroatoms selected from N, hydrazine and S, substituted by 0-3 R5e; R5e, at each occurrence, selected from (^-6 alkyl, C2-8 olefin , C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, (CF2)rCF3, N〇2, CN, (CH2)rNR5fR5f, (CH2)rOH, (CHAOC^ m alkyl, (CHJSCm alkyl, (CH2)rC(0)0H, (CH2)rC(0)R5b, (CH2)rC(0)NR5fR5f, (CH2)r0C(0)NR5fR5f, (CH2)rNR5fC( 0) R5b, (0^)/(0)0 (^-4 alkyl, (CHANT^CCOpCu alkyl, (CH2)r0C(0)R5b, (CH2)rC(=NR5f)NR5fR5f, (CH2)rS (0) pR5b, (CH2)rNHC(=NR5f)NR5fR5f, (CH2)rS(0)2NR5fR5f, (CH2)rNR5fS(0)2R5b&(CH2)rphenyl, 0-3 R5e is substituted; R5d is selected from the group consisting of methyl, CF3, C2-6 alkyl substituted by 0-2 R5e, C3-8 fluorenyl substituted by 0-2 R5e, and 0- 2 R5e substituted C3-8 95318 -31 - 1354664 alkynyl and C3_1G carbocyclic residue substituted by 0-3 R5e; R5e is selected from Cm alkyl, C2-8 alkenyl at each occurrence , C2_8 alkynyl, C3-6 cycloalkyl, C, F, Br, I, CN, N〇2, (CF2)rCF3, (CHAOCu alkyl, OH, SH, (CHASCu alkyl, (CH2)rNR5fR5f& (CH2)r phenyl, R5f is selected from H, Ci-6 alkyl and C3-6 cycloalkyl at each position; R5 g is independently selected from -C(0)R5 b, -C(0 ) 0R5 d, -C(0)NR5 f R5 f and (CH2)r phenyl; R in each of the places, selected from H, substituted by R5e, q-6 alkyl, C2-8 alkenyl, a C2.8 block, a (CH2)rC3_6 cycloalkyl group and a (CH2)r phenyl group substituted by R5e; R6 is selected from the group consisting of Ci-8 alkyl, C2-8, C2-8 in each presence. Alkyl, (CH2)rC3.6 cycloalkyl, a, Br, I, F, N〇2, CN, (CR, R,) rNR6aR6a, (CR'R')rOH ' (CR'R') T0 (CR'R'\R6d ' (CR'R')rSH ' ' (CR'R')rS(CR'R')rR6d, (CR'R')rSC(0)(CR 'R')rR6b, (CR.R,)rC(0)0H, (CR'R'^QOXCR'R'XR615 ' (CR'R')rNR6aR6a ' (CR'R')rC(0)NR6aR6a ' (CR'R'XNRMqOXCR'ROrR615, (CR'R'XCXOWCR'R'XI^d, (CR'R')rOC(0)(CR'R,)rR6b ' (CR'R'^OC^NR^ CCR'R'^R^ ' (CR,R')rNR6aC(0)NR6a(CR,R')rR6d, (CR,R')rNR6aC(S)NR6a(CR'R,)rR6d ' (CR'R 'XNRMqOXXCR'R'XR615, (CR'R,)rC(=NR6f)NR6aR6a, (CR,R,)rNHC(=NR6f)NR6fR6f,(CR'ROrS^pCCR'R'XR615, (CR,R,) rS(0)2NR6aR6a, (CR,R,)rNR6fS(0)2NR6aR6a, (CR|R|)rNR6fS(0)2(CR|R')rR6b, (:Bu 6 haloalkyl, 0-3 R. Substituted C2-8 alkenyl, C2-8 alkynyl substituted by 0-3 R', substituted by 0-3 R6e (CR'R〇r phenyl, and (CH2)r-5- a 6-membered heterocyclic ring system containing 1-2 heteroatoms selected from N, 95318 -32- 1354664 0 and S, substituted by 0-2 R6 e; or two R6 on adjacent atoms on R1 may be bonded And forming a cyclic acetal; R6a is selected from the group consisting of hydrazine, a methyl group substituted by 0-1 R6g, a C2_6 alkyl group substituted by 0-2 R6e, and a ruthenium of 2 R6e. C3_8 thiol, C3-8 alkynyl substituted by 〇_2 R6e, bedding _5 R&a Mp; substituted (CH2)r-C3-1Q carbocyclic residue ' and (CH2)r-5-l 杂环 heterocyclic ring system containing 1-4 heteroatoms selected from N, 0 and S, 0- 2 R6e substitutions; R6b, in each presence, selected from the group consisting of hydrazine, an alkyl group substituted by 0-2 R6e, a C3_8 phenyl group substituted by 0-2 R6e, and a C3_8 alkyne substituted by 〇-2 R6e a (CH2)rC3_6 carbocyclic residue substituted with 0-3 R6e, and a (CH2)r-5-6 member heterocyclic ring system containing 1-4 heteroatoms selected from N, fluorene and S, Substituted by 0-2 R6e; R6d is selected from C3_8 alkenyl substituted by 0-2 R6e, C3-8 alkynyl substituted by 0-2 R6e, methyl, CF3, in each presence 0-3 R6e substituted C2-6 alkyl, C2-4 haloalkyl, (CH2)r-C3-10 carbocyclic residue substituted by 0-3 R6e, and (CH2)r-5- a 6-membered heterocyclic ring system containing 1-4 heteroatoms selected from N, oxime and S, substituted by 0-3 R6e; R6e, at each occurrence, selected from Q-6 alkyl, C2-8 Alkyl, C2-8 block, (CH2)rC3.6 cycloalkyl, Cl, F, Br, I, CN, N〇2, (CF2)rCF3, (CHAOCu alkyl, OH, SH, (CHASCu alkane) Base, (CH2)rNR6fR6f and (CH2)r phenyl; R6f in each Wherein, selected from H, Ci-5 alkyl and C3_6 cycloalkyl, and phenyl; R6gS independently selected from -C(0)R6b, -C(0)0R6d, -C(0)NR6fR6f and (CH2 r phenyl; 95318 · 33 · 1354664 R7 is selected from the group consisting of: (8-alkyl, C2-8-decyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, a , Br, I, F, N02, CN, (CR'R,) rNR7aR7a, (CR'R')rOH ' (CR'R'XO^R'R'XR^ > (CR'R')rSH &gt ; (CR'R')r C(0)H ' (CR'R'XSCCR'R'^R^ ' (CR'R')rC(0)0H ' (CR'R'XCCOXCR'R'^R71 » ^ (CR'R')rC(0)NR7aR7a ' (CR'R'XNR^C^CCR'R'XR715 ' (CR'R'^C^OCCR'R^R^ > (CR'R' )r 0C(0)(CR'R')r R7 b ' (CRiR'XOCXCONRhCCR'R'XR73, (CR'R'XNR^C^NR^iCR'R'^R73 ' (CR'R'^NR ^qopCCR'R^R^ ' (CR'R')rC(=NR7f)NR7aR7a ' (CR'R')rNHC(=NR7f)NR7fR7f ' (CR'R')r S(0)p (CR'R ')r R7 b ' (CR'R')rS(0)2NR7aR7a ' (CR'R')rNR7aS(0)2NR7aR7a ' (CR'R')rNR7fS(0)2(CR'R')rR7b, CV6 Haloalkyl, C2_8 fluorenyl substituted by 0-3 R|, C2-8 alkynyl substituted by 0-3 R', and (CR'R')r phenyl substituted by 0-3 R7e Or, two R7 on adjacent atoms on R2 can be joined to form a cyclic acetal R7a is independently selected from the group consisting of hydrazine, a methyl group substituted by 0-1 R7g, a C2_6 alkyl group substituted by 0-2 R7e, and a C3-8 fluorenyl group substituted by 0-2 R7e. a C3_8 alkynyl group substituted by 0-2 R7e, substituted by 0-5 R7e (CH2X-C3.1() carbocyclic residue, and (CH2)r-5-10 member heterocyclic ring system, containing 1-4 heteroatoms selected from N, oxime and S, substituted by 0-2 R7e; R7b, at each occurrence, selected from q-6 alkyl substituted by 0-2 R7e, 0- 2 R7e substituted C3-8 alkenyl, C3-8 block substituted by 0-2 R7e, (CH2)rC3-6 carbocyclic residue substituted by 0-3 R7e, and (CH2)r a -5-6 membered heterocyclic ring system containing 1-4 heteroatoms selected from N, oxime and S, substituted by 0-2 R7e; 95318 • 34-1354664 R7d, at each occurrence, selected from 0 - 2 R7e substituted c3_8 alkenyl, C3-8 alkynyl substituted by 〇_2 R7e, methyl, CF3, C2-4 haloalkyl, C2-6 alkyl substituted by 〇3 R7e, a (CH2)r-C3-1Q carbocyclic residue substituted with 0-3 R7e, and a (CH2)r-5-6 member heterocyclic ring system containing 1-4 selected from the group consisting of N, hydrazine and S Atom, replaced by 0-3 R7e; R7e is selected at each place of existence Cm alkyl, C2_8 fluorenyl, C2_8 alkynyl, (CH2)rC3.6 cycloalkyl, Cl, F, Br, I, CN, N02 '(CF2)rCF3, (CHAOCu alkyl, OH, SH, (: (0)0 (ν5 alkyl, (CH2)rS (V5 alkyl, (CH2)rNR7fR7f and (CH2)r phenyl; R7f, in each presence, is selected from Η, Q-5 alkyl and C3- 6 cycloalkyl, and phenyl; R7g is independently selected from -C(0)R7b, -C(0)0R7d, -C(0)NR7fR7f&(CH2)rphenyl; R' is present at each occurrence, It is selected from the group consisting of ruthenium, Q-6 alkyl group substituted by R6e, <:2_8 fluorenyl group, C2_8 block group, (CH2)rC3-6 cycloalkyl group and (CH2)r phenyl group substituted by R6e; From hydrazine, Cm alkyl and C3-4 cycloalkyl; R9 is selected from the group consisting of hydrazine, Cm alkyl, C3-4 cycloalkyl, -C(0)H and -C(0)-Ci-4 alkyl; R1G is independently selected from the group consisting of hydrazine and an alkyl group substituted by 0-1 R1Gb; R1Gb is independently selected from the group consisting of -OH, -SH, -NR1GeR1Qc, - in each presence. (.G10 c R10 c and -NHC^COR10 c ; R1Ge is selected from H, Ch alkyl and C3.6 cycloalkyl; R11 is selected from fluorene, (: 4 alkyl, (CHR) qOH, ( CHR)qSH, (CHR)qORlld, (CHR)qS(0)pRlld, (CHR)rC(0)Rllb, (CHR)rNRllaRlla, (CHR)rC(0)NRnaRlla, (CHR)rC(0)NRlla0Rlld, (CHR)q NR11 a CCCOR11 b, (CHR)q NR11 a CCOPR11 d, 95318 -35· 1354664 (CHR)q (DC(O)NR11 a R11 a, (CHR)r CCCOOR11 d, 0-5 R11 e substituted (CHR)r-C3-6 carbocyclic residue, and (CHR)r-5-l 杂环 heterocyclic ring system containing 1-4 heteroatoms selected from N, 0 and S, - 3 Rlle replacements;

Rlla is independently selected from H, Cy alkyl, C3-4 alkenyl, C3-4 alkyl, (CH2)rC3-6 cycloalkyl, and substituted by 〇-5 R1 le (CH2). a r-C3_6 carbocyclic residue ' and a (CH2)r-5-6 heterocyclic ring system containing from 1 to 4 heteroatoms selected from N, 0 and S, substituted by 〇3 R11 e ;

Rllb, at each occurrence, is independently selected from the group consisting of Cl_4 alkyl, C2 4 fluorenyl, C2_4 alkynyl, (CH2)r-C3_6 carbocyclic residue substituted by 0-2 R1 le, and (CH2)r a -5-6 membered heterocyclic ring system containing from 1 to 4 heteroatoms selected from N, oxime and S, substituted by 0-3 Rlle;

Rlld, at each occurrence, is independently selected from the group consisting of H, methyl, -CF3, C2-4 alkyl, C3-6 alkenyl, C3-6 alkynyl, C3_6 carbon ring residues substituted by 0-3 Rlle And a (CH2)r-5-6 member heterocyclic ring system containing from 1 to 4 heteroatoms selected from N, oxime and S, substituted by 0-3 Rlle; RIle is selected from each occurrence (^_6 alkyl, C2_8 alkenyl, C2_8 alkynyl, C3-6 cycloalkyl, a, F, Br, I, CN, N02, (CF2) rCF3, (CHAOCh alkyl, OH, -0-(ν6 Alkyl, SH, (CHASCu alkyl, (CH2)r NR11 f R11 f and (CH2)r phenyl;

Rllf, at each occurrence, is selected from the group consisting of H, (V6 alkyl and C3-6 cycloalkyl; R12 is selected from the group consisting of hydrazine, Cm alkyl, (CHR)qOH, (CHR)qSH, (CHR)qOR12d, ( CHR)qS(0)pR12d, (CHR)rC(0)R12b, (CHR)rNR12aR12a, (CHR)rC(0)NR12aR12a, (CHR)rC(0)NR12a0R12d, (CHR)qNR12aC(0)R12b > (CHR)qNR12aC(0)0R12d ' 95318 -36- 1354664 (CHR)q 0(:(0) Service 2 a R12 a, (CHR)r C(0)0Ri2 d, 0-5 R1 2 e Substituted (CHR)r-C3·6 carbocyclic residue, and (CHR)r-5-10 member heterocyclic ring system containing 1-4 heteroatoms selected from N, fluorene and S, 〇·3 R12e is substituted; R12a is independently selected from H, Ch alkyl, C3_4 alkenyl, C3-4 alkynyl, (CH2)rC3-6 cycloalkyl, substituted by 〇5 Rl2e in each presence. (CH2)^C3 6 Carbocyclic residue, and (CH2)r-5-6 heterocyclic ring system containing 1-4 heteroatoms selected from N, oxime and S, substituted by 0-3 R1; R12b Each of the present positions is independently selected from the group consisting of Cl-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, (CH2)r_c3 6 carbocyclic residue substituted by 0-2 R12e, and (CH2) R-5-6 member heterocyclic system containing i_4 heterogenes selected from n, 0 and S Substituted by 0-3 R12 e; R12d is independently selected from the group consisting of hydrazine, methyl, -CF3, C2 4 alkyl, C3·6 alkenyl, C3_6 alkynyl, benz-3 in each presence. R12e substituted c3_6 carbocyclic residue ' and (CH2)Γ-5_6 member heterocyclic ring system containing 1-4 heteroatoms selected from N, Ο and S, substituted by 0-3 R12 e; R12e exists in each Where 'selected from Cl6 alkyl, C28 alkenyl, C28 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, N〇2, (CF2) rCF3, (CHJOCu alkyl, OH, -O-Cualkyl, SH, (CHASCu alkyl, (CH2)rNRi2fRi2f and (CH2)r phenyl; R12f, at each occurrence, is selected from H'q.6 alkyl and C3.6 cycloalkyl R13 is independently selected from the group consisting of Η and Ci_4 alkyl substituted by oi Riw, -OH, -NH2 'F, Cl, Br, I, -ORUa, _N(Ri3a)2 and by 0- 3 R13b substituted Ci 4 alkyl; R13a is selected from the group consisting of hydrazine, Ch alkyl and 〇 3.6 cycloalkyl; 95318 • 37· 1354664 R is in each of its existence, independently selected from 〇H, _SH, service... Ruler (1), -. (. Hui 13 c R13 c and _nhC(〇) ri 3 c ; R: 3c is selected from the group consisting of Η, 44 alkyl and .36 cycloalkyl; R14 is independently selected from 11 at each 〇1_4 alkyl; or two R14 are bonded to each other with their attached carbon atoms to form a carbon ring;

R15 is independently selected from the group consisting of H, Ci 4 fluorenyl, 4 alkyl, NR15aR15a, (^(9)赃^(1), NR15aC(0)0R15d ^ 〇C(〇)NR15aRi5a^(CHR) C. 〇) 〇Ri5d; or 'two R15s with their attached _ or multiple faces joined to form a C3_6 carbocyclic ring; RUa is independently selected from each of 11 and (: 1-4 alkyl; R15b, at each-existence, is independently selected from the group consisting of Ci-4 alkyl, c3 6 fluorenyl, and 3-6 alkynyl;

RI5d is independently selected from the group consisting of Ci 4 alkyl, C3_6 fluorenyl and at each presence. 3-6 alkynyl; R16 is selected from the group consisting of Ch alkyl; 1 is selected from 1, 2 and 3; η is selected from 〇, 1, 2 and 3; m is selected from 〇 and 1; P is present at each , independently selected from 〇, t and 2; q in each presence, independently selected from 1 ' 2, 3 and 4; Γ in each presence, independently selected from 〇, 1, 2, 3 and 4 ; t is independently selected from 2, 3, and 4 in each presence; 95318 • 38 - 1354664 s is selected from 0 and 1. Thus, in another embodiment, the invention provides a novel compound of formula 1: m is zero. In another specific embodiment, the present invention provides a novel Formula 1 compound wherein: Ring B is selected from the group consisting of

4 Ac ^ ^lA

Z1» K

A R4 .S- -s o2s

A A

• Q ·〇· •so, Ring B is replaced by 0-1 R5 as appropriate; and R11 and R12 are Η. In another embodiment, the invention provides a novel compound of formula 1, wherein: the guanidine is selected from the group consisting of a Ρλ a q f ' ′ \, each substituted by 1-2 R5, and 95318 -39- 1354664

Each is substituted by 0-1 R5; and R11 and R12 are Η. In another embodiment, the invention provides a novel compound of formula (I), wherein: R5, in each occurrence, is independently selected from the group consisting of hydrazine, Ci-6 alkyl, C2-8 fluorenyl, C2.8 Alkynyl, (CRR)rOH, (CRR)rSH, (CRR)rOR5d, (CRR)rSR5d, (CRR)rNR5aR5a ' (CRR)rC(0)0H, (CRR)rC(0)R5b, (CRR)rC (0) NR5aR5a, (CRR) rNR5aC(0)R5b, (CRR)rNR5aC(0)0R5d, (CRR)r0C(0)NR5aR5a, (CHR)rNR5aC(0)NR5aR5a 'CRR(CRR)rNR5aC(0)H '(CRR)rC(0)0R5b, (CRR)r0C(0)R5b ' (CRR)rS(0)pR5b, (CRR)rS(0)2NR5aR5a, (CRR)rNR5aS(0)2R5b&C1_6 Haloalkyl R5a, at each occurrence, is independently selected from the group consisting of hydrazine, methyl, Q-6 alkyl substituted by 0-2 R5e, wherein the alkyl group is selected from the group consisting of ethyl, propyl, iso-propyl, butyl. , iso-butyl, pentyl, hexyl, C3 alkenyl substituted by 0-1 R5e, wherein alkenyl is selected from allyl, C3 alkynyl substituted by 〇_1 R5e, wherein alkynyl is selected a (CH2)r-C3_4 carbocyclic residue substituted with 0-5 R5e, wherein the carbocyclic residue is selected from the group consisting of cyclopropyl and cyclobutyl; 95318 • 40· 1354664 R5b Every place, Is selected from the group consisting of 0-2 R5e substituted (^-6 alkyl, wherein the alkyl group is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, pentyl and hexyl, a (CH2)r-C3-4 carbocyclic residue substituted with 0-2 R5e, wherein the carbocyclic residue is selected from the group consisting of a cyclopropyl group and a cyclobutyl group; and R5d is selected in each presence from Methyl, CF3, C2_6 alkyl substituted by 0-2 R5e, wherein the alkyl group is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, pentyl and hexyl, C3_8 alkenyl, C3.8 alkynyl and C3_1() carbocyclic residue substituted by 0-3 R5e. In another specific embodiment, the invention provides a novel compound of formula (I), wherein: R4 Is selected from the group consisting of Η, ¢^6 alkyl, C3_8 alkenyl, C3_8 block, (CRR)tOH, (CRR)tSH, (CRR)tOR4d, (CRR)tSR4d, (CRR)tNR4aR4a, (CRR)qC(0 )0H, (CRR)rC(0)R4b, (CRR)rC(0)NR4aR4a, (CRR)tNR4aC(0)R4b ' (CRR)t0C(0)NR4aR4a ' (CRR)tNR4aC(0)0R4d, (CRR tNR4aC(0)R4b, (CRR)rC(0)0R4b, (CRR)t0C(0)R4b, (CRR)rS(0)pR4b, (CRR)rS(0)2NR4aR4a, (CRR)rNR4aS(0) 2R4b ; R at each place of existence, Independently selected from H, decyl, ethyl, propyl, allyl, propynyl, (CH2)rC3_6 cycloalkyl and (CH2)r phenyl substituted by R5e; R5 is independent in each presence Selected from hydrazine, fluorenyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, allyl, propynyl, F, Cl, Br, I, (CH2)rOH, (CH2) rOR5d, (CH2)rNR5aR5a, (CH2)rC(0)〇H, (CH2)rC(0)R5b, (CH2)rC(0)NR5aR5a, (CH2)rNR5aC(0)R5b, (CH2)r0C(0 )NR5aR5a, (CH2)rNR5aC(0)0R5d, 95318 -41 - 1354664 (CH2)rNR5aC(0)R5b, (CH2)rC(0)0R5b, (CH2)r0C(0)R5b, (CH2)rNR5aS(0 2R5b and Cu halogen group, (CH2)r phenyl' and (CRR)r-5-10 member heterocyclic ring system substituted by 0-2 R5e, containing i_4 hetero atoms selected from n, 〇 and S 'Substituted by 〇_2, wherein the heterocyclic ring system is selected from the group consisting of tetrahydropyrrolyl, hexahydropyridyl and morpholinyl; R5a is independently selected from the group consisting of hydrazine, methyl, ethyl, and propyl. Base, iso-propyl, butyl, iso-butyl, pentyl, hexyl, cyclopropyl and cyclobutyl; and r is selected from the group consisting of hydrazine, 1 and 2. In another embodiment, the invention provides a novel compound of formula 1, wherein: R1 is selected from the group consisting of ruthenium, R6, Cl-6 alkyl substituted by 〇-3 R6, C substituted by 〇3 r6: 2·6 alkenyl, C6-1() aryl group substituted by K3 R6-substituted c2_6 alkynyl group, substituted by 〇-5 R6, wherein the aryl group is selected from phenyl and fluorenyl groups, and 5_1〇 The aryl system 'containing 1-4 heteroatoms selected from N, fluorene and S, substituted by 0-3 R6' wherein the heteroaryl is selected from the group consisting of fluorenyl, benzimidazolyl, benzofuranyl, benzene And thiofuranyl, benzoxazolyl, benzoxazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolone, hydrazine Phytyl, furyl, imidazolyl, zosazolyl, azoxy, isotactic, iso-P-Quinyl, iso-p-sept, iso-dihydroindenyl, isoxazolyl, carbazolyl, Hydrazine, mercaptopyridyl, pyridinyl, P-indenyl, ha-11, P-salt, P-bite, sulphate, Bihah, oxazoline, quinolyl , pyrazolyl, porphinyl, tri-farming and tetrazolyl; R2 is selected from 0-2 R7 substituted phenyl, and 5_1 杂 heteroaryl system containing 1-4 heteroatoms selected from N, 0 and S, substituted by 〇-3 R7, of which 95318 • 42-1354664 heteroaryl From fluorenyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzoxazolyl, benzoxazolyl, benzotriazolyl, benzotetrazolyl, benzisoindole Azyl, benzisothiazolyl, benzimidazolone, porphyrin, furyl, imidazolyl, 5-oxazolyl, fluorenyl, isoquinolyl, isoxazolyl, isoxazolyl, Carbazolyl hydrazine, pyridinyl, pyrazolyl, hydrazine, pyridyl, pyridyl, pyrimidinyl, pyrrolyl, pyrrolotrienyl, oxazoline, porphyrin, carbazolyl, Pyrimenyl and tetrazolyl; R4 is selected from the group consisting of hydrazine, methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, allyl, propynyl, (CRR) tOH, CRR)tSH, (CRR)tOR4d, (CRR)tSR4d, (CRR)tNR4aR4a, (CRR)qC(0)0H, (CRR)rC(0)R4b, (CRR)rC(0)NR4aR4a, (CRR)tNR4aC (0) R4b, (CRR)t0C(0)NR4aR4a > (CRR)tNR4aC(0)0R4d ^ (CRR)tNR4aC(0)R4b ' (CRR) rC(0)0R4b ' (CRR)t 0C(0)R4 b ' (CRR)rS(0)pR4b ' (CRR)rS(0)2NR4aR4a ' (CRR)rNR4aS(0)2R4b ; R4a at each place of existence , independently selected from H, a methyl group substituted by 0-1 R4c, a C2.6 alkyl group substituted by 0-3 R4e, wherein the C2_6 alkyl group is selected from the group consisting of ethyl, propyl, iso-propyl, Butyl, iso-butyl, tert-butyl, pentyl and hexyl, and (CH2)r-C3_6 carbocyclic residues substituted by 0-4 R4e, wherein the carbocyclic residue is selected from the ring a propyl group, a cyclohexyl group and a phenyl group; R4b is selected from the group consisting of hydrazine, methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl and cyclopropyl; R4d is selected from the group consisting of decyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl and cyclopropyl; and 95318-43-1354664 R8 is selected from the group consisting of hydrazine , methyl, ethyl, propyl, iso-propyl and cyclopropyl. In another embodiment, the invention provides a novel compound of formula (I) wherein: R6, at each occurrence, is selected from the group consisting of (^-8 alkyl, C2-8 alkenyl, C2-8 alkynyl) , (CH2)rC3.6 cycloalkyl, CbBr, I, F, N〇2, CN, (CH2)rNR6aR6a, (CH2)rOH, (CH2)rO(CH2)rR6d, (CH2)rSH, ( CH2)rC(0)H, (CH2)rS(CH2)rR6d, (CH2)rC(0)0H, (CH2)rC(0)(CH2)rR6b, (CH2)rC(0)NR6aR6a, (CH2) rNR6fC(0)(CH2)rR6b, ·(CH2)rC(0)0(CH2)rR6d, (CH2)rNR6aC(0)NR6aR6a, (CH2)rNR6aC(S)NR6aR6a,(CH2)r0C(0)(CH2 rR6b, (CH2)rS(0)p(CH2)rR6b, (CH2)rS(0)2NR6aR6a, (CH2)rNR6fS(0)2(CH2)rR6b, (CH2)rNR6fS(0)2NR6aR6a 'Cu halogen. Alkyl and (CH2)r phenyl, substituted by 0-3 R6e, and (CH2)r-5-6 heterocyclic ring system containing 1-2 heteroatoms selected from N, fluorene and S, - 2 尺^, wherein the heterocyclic ring system is selected from the group consisting of aziridine, nitrotetradecyl, pyrrolyl, hexahydrop, and chloroform; and R6a is present at each site. Independently selected from the group consisting of hydrazine, methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, and tert-butyl Pentyl, hexyl, cyclopropyl and phenyl; R6b, at each occurrence, is selected from the group consisting of hydrazine, methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl Base, pentyl, hexyl, cyclopropyl and phenyl; R6d is selected from the group consisting of fluorenyl, CF3, ethyl, propyl, iso-propyl, butyl, iso-butyl, and third - butyl, pentyl, hexyl, cyclopropyl 95318 -44· 1354664 and phenyl; R6e is selected from the group consisting of (V6 alkyl, C2-8 anthracene, C2.8 alkynyl, (CH2)rC3 -6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2)rCF3, (CHJOCu alkyl, OH, SH, (CHJSCu alkyl, (CH2)rNR6fR6f and (CH2)r phenyl; R6f In each presence, selected from H, methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl, cyclopropyl and phenyl R7 is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, second-butyl, tert-butyl 'pentyl, hexyl, (CH2)rC3-6 Cycloalkyl, Cl, Br, I, F, N〇2, CN, (CH2)rNR7aR7a, (CH2)rOH, (CH2)rO(CH2)rR7d, (CH2)rSH (CH2)rC(0)H, (CH2)rS(CH2)rR7d, (CH2)rC(0)0H, (CH2)rC(0)(CH2)rR7b, (CH2)rC(0)NR7aRh, (CH2 rNR7fC(0)(CH2)rR7b, (CH2)rC(0)0(CH2)rR7d, (CH2)r0C(0)(CH2)rR7b, (CH2)r0C(0)NR7aR7a, (CH2)rNR7aC(0 NR7aR7a, (CH2)rNR7aC(0)0(CH2)rR7d, (CH2)rS(0)p(CH2)rR7b, (CH2)rS(0)2NR7aR7a, (CH2)rNR7fS(0)2(CH2)rR7b , Cu haloalkyl, gold steel alkyl and (CH2)r phenyl substituted by 0-3 R7e, and (CH2)r-5-6 heterocyclic ring system, containing 1 - 4 selected from N, 〇 And the hetero atom of S is substituted by 0-3 R7e, wherein the heterocyclic ring system is selected from the group consisting of thienyl, pyridyl, benzopyrazolyl and tetrazolyl; 1173 is selected from the group in each presence. Base, ethyl 'propyl, iso-propyl, butyl, iso-butyl 'tri-butyl, pentyl, hexyl, prop-2-yl, 2-mercapto-2-propenyl, ring Propyl, cyclobutyl, cyclopentyl, cyclohexyl, 95318 • 45· 1354664 CH2 cyclopropyl and benzyl; R7b, in each presence, selected from decyl, ethyl, propyl, iso-propyl , butyl, iso-butyl, tert-butyl, pentyl, hexyl, cyclopropyl, ring a group, a CH2-cyclopentyl group, a cyclohexyl group, a CH2-cyclohexyl group, a cf3, a tetrahydropyrrolyl group, a morpholinyl group, a hexahydropyrylene group substituted with 0-1 R7e, and a nitrotetradecyl group; Each presence is selected from the group consisting of fluorenyl, CF3, CF2CF3, CHF2, CH2F, ethyl, propyl, isopropyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl and cyclopropane. R7e is selected from the group consisting of Cl-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (012), (: 3.6 cycloalkyl, ci, F, Br, I, CN, N〇2, CF2)rCF3, (CHAOCh alkyl, (CH2)rOH, OH, SH, C(0)0H, C(0)NHR7h, (:(0)〇〇1-5 alkyl, (〇12)3(: 1_5 alkyl, (012) 11^7£1^, (CH2)rC(0)NHS02-R7h, NHS02R7h and (CH2)r phenyl, (CH2)r tetrazolyl; R7f in each presence, Selected from H, methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl, cyclopropyl and phenyl; and r is 0 or 1 . In another embodiment, the invention provides a novel compound of formula (I), wherein: R6, in each occurrence, is selected from the group consisting of (^-8 alkyl, C2-8 thiol, c2-8 thiol, (CH2)rC3 -dl alkyl, Cl, Br, I, F ' N〇2, CN, (CH2)rNR6aR6a, (CH2)rOH ^ (CH2)rOR6d ^ (CH2)rSH ^ (CH2)rC(0)H ^ (CH2 rSR6d > 95318 -46- 1354664 (CH2)rC(0)0H, (CH2)rC(0)R6b, (CH2)rC(0)NR6aR6a, (CH2)rNR6fC(0)R6b,(CH2)rC( 0) 0R6d, (CH2)rNR6aC(0)NR6aR6a, (CH2)rNR6aC(S)NR6aR6a, (CH2)r0C(0)R6b, (CH2)rS(0)pR6b, (CH2)rS(0)2NR6aR6a, ( CH2)rNR6fS(0)2R6b, (CH2)rNR6fS(0)2NR6aR6a, Ci-6 haloalkyl and substituted by 0-3 R6e (CHR% phenyl; R7 is selected from methyl, ethyl, propyl , iso-propyl, butyl, iso-butyl, second-butyl, pentyl, hexyl, Q, Br, I, F, CN, N〇2, NR7aR7a, NHC(0)NHR7a, NR7aC(0 R7b, NR7aC(0)0R7d, CF3, CF2CF3, CHF2, CH2F, OCF3, C(0)R7b, C(0)0R7d, NR7fC(0)NR7aR7a, NHS(0)2R7b '

In another embodiment, the invention provides a novel compound of formula (I) wherein: ring B is selected from 4, each substituted by 1-2 R5, and 95318-47- 1354664 R4 R4

Each is substituted by 0-1 R5; Z is selected from a bond, -NR8C(0)-, -NR8-, -C(0)NR8-, and -NHC(0)NH-; R1 is selected from hydrazine, (^_6 alkyl substituted by 0-3 R6, wherein the alkyl group is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, pentyl and hexyl, substituted by 0-3 R6 C2-6 alkenyl, C2-6 alkynyl substituted by deuterium-3 R6; R2 is a phenyl group substituted by 0-2 R7; R4 is selected from hydrazine, methyl, ethyl, propyl, iso- Propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl and (CH2Xq0)R4b; R6 is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, F, Cl, Br, I, N〇2, CN, (CH2)r〇(CH2)rR6d, C(0)R6d, SR6d, NR6aR6a, C(0)NR6aR6a, NC(〇)R6b, 〇c(〇)R6b , s(〇)pR6b, (CHR')rS(0)2NR6aR61CF3; Rule 63 is H, methyl, ethyl, propyl, iso-propyl, butyl and phenyl; or, two R6a and their The linked N is joined together to form a 3-8 member heterocyclic ring containing 0-1 other heteroatoms selected from N, 0 and S, wherein the heterocyclic ring is selected from the group consisting of aziridine, nitrotetradecyl, pyrrolyl, Hexahydropyridyl and morphine; R6b* Η , fluorenyl, ethyl, propyl, iso-propyl or butyl; R6d is fluorenyl, phenyl, cf3 and (ch2)-phenyl; and r is 0 or 1. 95318 -48· 1354664 In a specific embodiment, the invention provides a novel compound of formula (I) wherein: R7 in each occurrence is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl , second-butyl, tert-butyl, pentyl, hexyl, (CH2)rC3.6 cycloalkyl, a, Br, I, F, N02 'CN, (CH2)rNR7aR7a, (CH2)rOH ' (CH2)rOR7d ' (CH2)rSH ' (CH2)rC(0)H ^ (CH2)rSR7d ^ (CH2)rC(0)0H, (CH2)rC(0)R7b, (CH2)rC(0)NR7aR7a , (CH2)rNR7fC(0)R7b, (CH2)rC(0)0R7d, (CH2)r0C(0)R7b, (CH2)r0C(0)NR7aR7a, (CH2)rNR7aC(0)NR7aR7a, (CH2)rNR7fC (0)0R7d, (CH2)rS(0)pR7b, (CH2)rS(0)2NR7aR7a, (CH2)rNR7aS(0)2NR7aR7a, (CH2)rNR7fS(0)2R7b, Cu haloalkyl, (CH2)r a gold steel alkyl group, a (CH2)r phenyl group substituted by 0-3 R7e, and a (CH2)r-5-6 member heterocyclic ring system containing 1-4 hetero atoms selected from N, 0 and S, Substituted by 0-3 R7e, wherein the heterocyclic ring is selected from thiophenyl, pyridyl, benzo "Septy and four toki. In another embodiment, the invention provides a novel compound of formula (la) wherein:

In another specific embodiment, the invention provides a novel compound of formula (la) wherein: 95318 • 49· 1354664

Wherein Z is selected from the group consisting of -NHC(O)-, -NHC(0)NH-, -ΝΗ·' R1 is selected from Ci-6 alkyl substituted by 0-1 R6, -0(0)0-( ^-6 alkyl; R2 is selected from phenyl substituted by 0-2 R7 and 5-10 membered heteroaryl system 'containing 1-4 heteroatoms selected from N, fluorene and S, 0-3 Substituted by R7, wherein the heteroaryl system is selected from the group consisting of oxazoline groups, tri-cultivation groups, pyrimidinyl groups, methyl pyridyl groups, different from the test group, fluorenyl group, β-mercapto group, anthracenyl group, and thiophene group. , hydrazine, thiazolyl, thiophenyl and isoxazolyl; R5 is independently selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, Allyl, propynyl, F, C, Br, I, (CH2X〇H, (CH2)rOR5d, (CH2)rNR5aR5a, (CH2)rC(0)0H, (CH2)rC(0)R5b, ( CH2)rC(0)NR5aR5a, (CH2)rNR5aC(0)R5b, (CH2)r0C(0)NR5aR5a, (CH2)rNR5aC(0)〇R5d, (CH2)rNR5aC(0)R5b . (CH2)rC( 0) 0R5b . (CH2 )r 0C(0)R5 b > (CH2)rNR5aS(0)2R5b and Cl ·6 _ alkyl' and (CRR)r_51 杂环 heterocyclic ring system, containing M selected from N,杂 and S heteroatoms, replaced by 〇_2 RSc, of which heterocyclic system is selected Μ tetrahydro-yl, hexahydro-yl lake and cushions Four pour it over the other group - of specific embodiments "The present invention provides a novel compound of the formula ①, in which:. 95318 • 50- 1354664

R2

R1 is selected from the group consisting of hydrazine, a Cu alkyl group substituted by 0-1 R6, a -qop-Cu alkyl group; and R5 is independently selected from the group consisting of F, Cl, Br, I, (CH2)rOH, (CH2)rOR5d, (CH2)rNR5aR5a, and (CRR)r-5-10 heterocyclic ring system containing 1-4 heteroatoms selected from N, oxime and S, substituted by 0-2 R5e, wherein The ring system is selected from the group consisting of tetrahydropyrrolyl, hexahydropyridyl and morpholinol. In another specific embodiment, the invention provides a novel compound of formula (I) wherein: R4 is selected from the group consisting of hydrazine, Ch alkyl, C3-8 fluorenyl, C3-8 alkynyl, (CRR)qOH, ( CRR)tSH, (CRR)tOR4d, (CRR)tSR4d, (CRR)tNR4aR4a, (CRR)qC(0)0H ' (CRR)rC(0)R4b ' (CRR)rC(0)NR4aR4a ' (CRR)tNR4aC (0) R4b, (CRR)t0C(0)NR4aR4a, (CRR)tNR4aC(0)0R4d, (CRR)tNR4aC(0)R4b, (CRR)rC(0)0R4b, (CRR)t0C(0)R4b, (CRR)rS(0)pR4b, (CRR)rS(0)2NR4aR4a, (CRR)rNR4aS(0)2R4b; R is independently selected from H, decyl, ethyl, propyl, hydrazine in each presence. a propyl group, a propynyl group, a (CH2)rC3-6 cycloalkyl group, and a (CH2)r phenyl group substituted by R6e; each of R5 is independently selected from the group consisting of hydrazine, methyl, ethyl, propyl, Isopropyl, butyl, iso-butyl, decyl, propyl, (CH2\OH, (CH2)rOR5d ' (CH2)rNR5aR5a, (CH2)rC(0)0H, (CH2)rC ( 0) R5b, (CH2)rC(0)NR5aR5a, (CH2)rNR5aC(0)R5b, 95318 •51- 1354664 (CH2)r0C(0)NR5aR5« χ (CH2)rNR5aC(0)0R5d . (CH2)rNR5aC (0) R5b, (CH2)rC(0) 〇 R5b , (CH2 )r 〇C(〇)R5 b . (CH2)rNR5aS(0)2 R5b and Ci 6 alkyl; R5a is independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, pentyl, hexyl, cyclopropene And a cyclobutyl group; and r is selected from the group consisting of hydrazine, [and 2. In another embodiment, the invention provides a novel compound of formula 1, wherein: R1 is selected from the group consisting of hydrazine, R6, Cl-6 alkyl substituted by 0-3 R6, 〇3 substituted C2·6 alkenyl, c2-6 alkynyl substituted by 0-3 R6, bet _5 R6 Substituted Cm aryl, wherein the aryl group is selected from the group consisting of phenyl and fluorenyl, and the 5_1 杂 heteroaryl system contains 1-4 heteroatoms selected from N, fluorene and S, and is substituted by 〇·3 R6 Wherein the heteroaryl is selected from the group consisting of fluorenyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzoxazolyl, benzoxazolyl, benzotriazolyl, benzotetra Azolyl, benzisoxazolyl, benzisoxazolyl benzimidazolone, porphyrin, furyl, imidazolyl, oxazolyl, fluorenyl, isoindolyl, isotazolyl ,isodihydrocarbazolyl, isoxazolyl, oxazolyl, hydrazine, pyrene a pyridyl group, a pyridyl group, a pyridyl group, a pyridyl group, a pyridyl group, a pyrimidinyl group, a pyrrolyl group, a quinazolinyl group, a quinolyl group, a thiazolyl group, a porphinyl group, and a tetrazolyl group; 2 R7 substituted phenyl and 5-1 anthracene heteroaryl systems containing 1-4 heteroatoms selected from N, 0 and S, substituted by 〇3 r7, wherein the heteroaryl is selected from 吲Mercapto, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzoxazolyl, benzothiazolyl, benzotriazolyl 'benzene 95318 • 52- 1354664 and tetrazolyl, benzo Isoxazolyl, benzisothiazolyl, benzimidazolone, oxime I»linyl, guanidinyl, sulphate, sulphate, 4丨tr, sulphate, isopyrazole Base, isoxazolyl, carbazolyl, hydrazine, pyridinyl, biszolyl, hydrazine, P butyl, pyridyl, pyrimidinyl, oxime, carbazole, porphyrin , thiazolyl, thienyl and tetrazolyl; R4 is selected from the group consisting of hydrazine, methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, allyl, propynyl, (CRR) qOH, (CRR)tSH, (CRR)tOR4d, (CRR)tSR4d ' (CRR)tNR4aR4a ' (CRR)q C(0)OH ' (CRR)r C(0)R4 b ' (CRR)rC(0)NR4aR4a, (CRR)tNR4aC(0)R4b ' (CRR)t0C(0)NR4aR4a, (CRR)tNR4aC(0 ) 0R4d, (CRR)tNR4aC(0)R4b, (CRR)rC(0)0R4b, (CRR)t0C(0)R4b, (CRR)rS(0)pR4b > (CRR)rS(0)2NR4aR4a ' ( CRR)rNR4aS(0)2R4b; R4a, at each occurrence, is independently selected from H, methyl substituted by 0-1 R4e, C2_6 alkyl substituted by 0-3 R4e, wherein C2_6 is selected from B Base, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl and hexyl, and (CH2)r-C3.6 carbocyclic residues substituted by 0-4 R4e a group wherein the carbocyclic residue is selected from the group consisting of cyclopropyl, cyclohexyl and phenyl; R4b is selected from the group consisting of hydrazine, methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, Tri-butyl, pentyl and cyclopropyl; R4d is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl and cyclopropyl And R8 is selected from the group consisting of hydrazine, methyl, ethyl, propyl, iso-propyl and cyclopropyl. In another embodiment, the invention provides a novel compound of formula (I) wherein: 95318 - 53 · 1354664 R6, in each presence, is selected from the group consisting of q.8 alkyl, C2-8, c2 .8 alkynyl, (CR|R,)rC3-6 cycloalkyl, CbBr, I, F, N02, CN, (CR,R,)rNR6aR6a, (CRR)rOH, (CR'R'XCKCR' ROrR611, (CR, R,) rSH, (CR'R,) rC(0)H, (CR'R'^SCCR'R'^R^ ' (CR'R')rC(0)0H ' (CR 'R')r C(0)(CR'R')r R6 b ' (CR'R')rC(0)NR6aR6a, (CR'R|)rNR6fC(0)(CR'R')rR6b, ( CR'R'XC^O^R'R'^R6*1 ' (CR'R')rNR6aC(0)NR6aR6a > (CR'R')rNR6aC(S)NR6aR6a ' (CR'R')r 0C (0)(CR'R')r R6 b ' (CR'R')rS(0)p(CR'R,)rR6b, (CR'R,)rS(0)2NR6aR6a, (CR'R'XNR ^S^CCR'R^R615 ' (CR'R')rNR6fS(0)2NR6aR6a ' ^.6 Haloalkyl and (CR'R')r stupyl substituted by 0-3 R6e, and (CH2) a r-5-6 member heterocyclic ring system containing 1-2 heteroatoms selected from N, 0 and S, substituted by 0-2 R6e; R6a, at each occurrence, independently selected from hydrazine, methyl, Ethyl, propyl, iso-propyl, butyl 'iso-butyl, tert-butyl, pentyl 'hexyl, cyclopropyl and phenyl; Alternatively, the two 1163 are joined to the hydrazine to which they are attached to form a 3-8 membered heterocyclic ring containing 0-1 other heteroatoms selected from the group consisting of hydrazine, 0 and S, wherein the heterocyclic ring is selected from the group consisting of aryl acrylates. a radical, a nitrotetradecyl group, a ρ-pyrrolyl group, a hexahydro-pyridyl group, and a ruthenium ruthenium group, each of which is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, Butyl, iso-butyl, tert-butyl, pentyl, hexyl, cyclopropyl and phenyl; R6d, in each presence, is selected from the group consisting of methyl, CF3, ethyl, propyl, iso-propyl Base, butyl, iso-butyl, tert-butyl, pentyl, hexyl, cyclopropyl and phenyl; 95318 • 54· 1354664 R6e, in each presence, selected from Q.6 alkyl, C2 -8 alkenyl, C2_8 alkynyl, (012), (: 3-6 cycloalkyl, Cl, F, Br, I, CN, N〇2, (CF2)rCF3, (CHAOCu alkyl, OH, SH, (CH2)rSC, 5 alkyl, (CH2)rNR6fR6f and (CH2)r phenyl; R6f, in each presence, is selected from the group consisting of H, methyl, ethyl, propyl, iso-propyl, butyl, Isobutyl, tert-butyl, pentyl, hexyl, cyclopropyl and phenyl; R7 is selected from methyl, ethyl, propyl, iso- Base, butyl, iso-butyl, second-butyl, tert-butyl, pentyl, hexyl, (CRR)rC3_6 cycloalkyl, Cl, Br, I, F, N02, CN, (CRR) rNR7aR7a, (CRR)rOH, (CRR)rO(CH)rR7d, (CRR)rSH, (CRR)rC(0)H, (CRR)rS(CRR)rR7d ' (CRR)rC(0)0H > ( CRR)rC(0)(CRR)rR7b ' (CRR)rC(0)NR7aR7a ' (CRR)rNR7fC(0)(CRR)rR7b, (CRR)rC(0)0(CRR)rR7d, (CRR)rOC( 0) (CRR)rR7b, (CRR)rNR7aC(0)NR7aR7a, (CRR)rNR7aC(0)0(CRR)rR7d, (CRR)rS(0)p(CRR)rR7b, (CRR)rS(0)2NR7aR7a (CRR)rNR7fS(0)2(CRR)rR7b, q.6 haloalkyl and (CRR)r phenyl substituted by 0-3 R7e; R7a is selected from H, fluorenyl at each presence , ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl, prop-2-enyl, 2-methyl-2-propenyl, ring a propyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a CH2 cyclopropyl group and a nonyl group; and each of R7b is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, and iso- -butyl, tert-butyl, pentyl, hexyl, cyclopropyl, cyclopentyl, CH2-cyclopentyl, cyclohexyl, CH2-cyclohexyl CF3, tetrahydropyrrole 95318-55. 1354664 base, morpholinyl group, hexahydropyridinyl substituted by 0-1 R7e and mononitrotetradecyl; R7d is selected from methyl group in each presence Cf3, CF2CF3, chf2, ch2f, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl and cyclopropyl; R7e in each presence, Selected from Cm alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2\CF3, (CHAOCu alkyl, OH, SH, (: (0) 0 (^1 ^ base, (CHASCu alkyl, (CH2) rNR7fR7f & (CH2) r phenyl; R7f in each presence, selected from H, thiol, ethyl, C Base, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl, cyclopropyl and phenyl; and r is 0 or 1. In another embodiment, the invention provides a novel compound of formula (I), wherein: R6, in each occurrence, is selected from the group consisting of CV8 alkyl, C2-8 fluorenyl, C2-8 alkynyl, (CHR') rC3_6cycloalkyl, a, Br, I, F, N02, CN, (CHR,)rNR6aR6a, (CHR')rOH ' (CHR')rOR6d ' (CHR')rSH ' (CHR')rC(0)H '(CHR丨)rSR6d, (CHR,)rC(0)0H, (CHR|)rC(0)R6b, (CHR')rC(0)NR6aR6a ' (CHR')rNR6fC(0)R6b ' (CHR' )rC(0)0R6d ' (CHR')rNR6aC(0)NR6aR6a ' (CHR')r NR6 a C(S)NR6 a R6 a ' (CHR')r0C(0)R6b,(CHR,)rS(0 ) pR6b, (CHR,)rS(0)2NR6aR6a, (CHR,)rNR6fS(0)2R6b, (CHR')rNR6fS(0)2NR6aR6a, Cb6 haloalkyl and substituted by 0-3 R6e (CHR) % phenyl; 95318 -56· 1354664 R7 is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, second-butyl, pentyl, hexyl, a, Br, I, F, CN, N〇2, NR7aR7a, NHC(0)NHR7a, NR7aC(0)R7b, NR7ac(0)0R7ci, CF3, CF2CF3, CHF2, CH2F, OCF3, C(0)R7b, C(0) 0R7d, NR7fC(0)NR7aR7a, NHS(0)2R7b '

N\ \c(0)0-t-butyl < -NR7aC(0),

In another specific embodiment, the invention provides a novel compound of formula (I) wherein:

,versus

Ring B is optionally substituted with 0-1 R5; Z is selected from a linkage, -NR8C(0)-, -NR8-, -C(0)NR8-, and -NHC(0)NH-; R1 An alkyl group selected from hydrazine, substituted with 0-3 R6, wherein the alkyl group is selected from the group consisting of methyl 95318 • 57· 1354664, ethyl, propyl, iso-propyl, butyl, pentyl and hexyl, - 3 R6 substituted C2-6 fluorenyl groups, C2_6 alkynyl groups substituted by 0-3 R6; R2 is a phenyl group substituted by 0-2 R7; R4 is selected from the group consisting of hydrazine, methyl, ethyl, and propyl Base, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl and (CH2)rC(0)R4b; R is selected from methyl, ethyl, propyl 'iso- Propyl, butyl, F, Cl, Br, I, Ν02, CN, (CH2)r〇(CH2)rR6d, C(0)R6d, SR6d, NR6aR6a, C(0)NR6aR6a 'NC(0)R6b - 0C(0)R6b ' S(0)pR6b ^ (CHR% S(0)2 NR6 a R6 a and cf3 ; R6ag H, methyl, ethyl, propyl, iso-propyl, butyl and phenyl; Alternatively, two R6a are joined together with the N to which they are attached to form a 3-8 membered heterocyclic ring containing 0-1 other heteroatoms selected from N, 0 and S, wherein the heterocyclic ring is selected from the group consisting of aziridine groups, Nitrotetradecyl, pyrrolyl, hexahydropyridyl and Rhofolinyl; R is hydrazine, methyl, ethyl, propyl, isopropyl or butyl; R6d is methyl 'phenyl, Cf3 & (CH2) phenyl; and r is 0 or 1. In another specific embodiment, the invention provides a novel compound of formula (I) wherein: ring B is selected from the group consisting of;

Ring B is taken from 0-1 R5 and R4 is selected from the group consisting of hydrazine, methylethyl, propyl, iso-propyl, butyl, iso-butyl, 95318 1354664 tri-butyl, pentyl, hexyl, Allyl and (CH2)rC(0)R4b; R5 is selected from the group consisting of hydrazine, OH, OCH3 and NR5aR5a; R5a is selected from the group consisting of hydrazine, methyl, ethyl, propyl, iso-propyl, butyl, and second -butyl, iso-butyl, tert-butyl, pentyl, hexyl, decyl, block: propyl, cyclopropyl, cyclopropyl decyl, ethyl sulfonyl, methylsulfonyl, - C(0)CF3, C(=N)NH2, benzyl and -C(0)0-tert-butyl; R7 is selected from the group consisting of decyl, ethyl, propyl, iso-propyl, butyl, Iso-butyl, second-butyl, pentyl, hexyl, (:Br, I, F, CN, N〇2, NR7aR7a, NHC(0)NHR7a, NR7aC(0)R7b, NR7aC(0)0R7d , CF3, CF2CF3, CHF2, CH2F, OCF3, OCF2CF3, OCHF2 and OCH2F, C(0)0R7d, C(0)R7b, NR7fC(0)NR7aR7a, NHS(0)2R7b,

R7a is selected from the group consisting of H, methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, neopentyl, cyclopropyl, cyclobutyl, Cyclopentyl and cyclohexyl; Rule 715 is selected from cyclohexyl and CF3; and 95318-59-1354664 R7d is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl and Tri-butyl. In another specific embodiment, the present invention provides a novel class (1) compound wherein: the ring is selected from the group consisting of

A / ring B is substituted by 0-1 R5; R5 is selected from Η, OH, OCH3 and NR5aR5a; R is selected from Η, methyl, ethyl, propyl, iso-propyl, butyl, second Butyl, iso-butyl, tert-butyl, pentyl, hexyl, decyl, propargyl, cyclopropyl, cyclopropyl decyl, ethyl, methyl, -C (0) CF3, C(=N)NH2, fluorenyl and -C(0)0-tri-butyl; R7 is selected from a, Br, CN, NR7aR7a, cf3, CF2CF3, CHF2, CH2f, 〇CF3 , OCF2CF3, OCHF2 and OCH2F; and R7a is selected from the group consisting of H, methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, neopentyl , cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In another embodiment, the invention provides a novel compound of formula (I) wherein:

In another embodiment, the invention provides a novel compound of formula (I) wherein: R5 is selected from the group consisting of NR5aR5a; and R5a is selected from the group consisting of hydrazine, hydrazino, ethyl, propyl, iso-propyl, butyl , second - 95318 • 60- 1354664 butyl, iso-butyl, tert-butyl, pentyl, hexyl, propargyl, decyl, cyclopropyl decyl, cyclopropyl and phenyl. In another embodiment, the invention provides a novel compound of formula (I) wherein: Z is selected from the group consisting of a bond, -NHC(O)-, -NH-, -C(0)NH-, and NHC(0)NH-. In another embodiment, the invention provides a novel compound of formula (I), wherein: R7 is selected from the group consisting of a, Br' NR7aR7a' NR7aC(0)0R7d, 〇α?3, and CF3; R7a is selected From hydrazine, methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, second-butyl, pentyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl and Cyclohexyl; R7d is selected from the group consisting of methyl 'ethyl, propyl, iso-propyl 'butyl, iso-butyl and tert-butyl. In another specific embodiment, the invention provides a novel Formula 1 compound wherein the compound is selected from the group consisting of the indole compounds. In another embodiment, the invention is directed to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (1). In another embodiment, the invention is directed to a method of modulating the activity of a chemical cytokine or a chemical cytokine receptor, comprising administering a therapeutically effective amount of a compound of formula (7) to a patient in need thereof. . In another embodiment, the method of activity of the invention, wherein the kit (IV) is required to administer a needle/infested, to administer a therapeutically effective amount of 95318 -61 - OH- of the compound of formula (I). In another specific embodiment, the CCR2, WC, and Cp2, MCP, McP-3, and MCP-4 and MCP-5 activities are regulated by CCR2. In the case of a method, the patient is administered a therapeutically effective amount of a compound of the formula (I). In another specific embodiment, the present invention is directed to a A method of modulating MCP-1 activity comprising administering a therapeutically effective amount of a compound of formula (I) to a patient in need thereof. In another specific embodiment, the invention is directed to a method of treating a condition, This comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula 1 selected from the group consisting of bone and joint, aneurysm 1 disease, cardiovascular function, Crohn's disease, septic heart failure, an autoimmune disease, Infection, dementia associated with HIV, psoriasis, spontaneous pulmonary fibrosis, graft arteriosclerosis, physical or chemically induced brain trauma, inflammatory bowel disease, lung cells, colitis, systemic lupus erythematosus, Toxic kidney serum nephritis, spheroid nephritis, asthma, multiple sclerosis, atheroma In another embodiment, the present invention is directed to a method of treating a condition in Formula 1, wherein the condition is selected from the group consisting of psoriasis, spontaneous lung fiber Degeneration, graft arteriosclerosis, physical or chemical brain trauma, inflammatory bowel disease, pulmonary cytoatitis, colitis, systemic lupus treatment, venous nephritis, spheroid nephritis, asthma, multiple sclerosis , atherosclerosis and rheumatoid arthritis, restenosis 'organ transplantation and cancer. In another specific embodiment, the present invention is directed to a method of treating a condition of 95318 - 62 · 1354664 by Formula 1 wherein the condition is Selected from pneumocytitis, eight broken Shengyan 'systemic lupus erythematosus, poisonous kidney serum nephritis, spheroid nephritis, friends, x breast asthma, multiple sclerosis, atherosclerosis and rheumatoid arthritis, i Human restenosis, organ transplantation, and a method of treating a painful condition by formula (I), wherein the condition is selected from Weng Jun, ', ' evening sclerosis' atheroma hardening and rheumatic joint In another specific embodiment, the present invention is directed to a method for treating a condition, wherein the condition is selected from the group consisting of the formula (4) and the other embodiment, the present invention is narrow, Organ Transplantation and Cancer. A method of arthritis, including a compound of formula (I), which is desirable for the treatment of wind leakage. W Manding therapeutically effective amount of low tear bursting • In another embodiment a method of hardening comprising administering a therapeutically effective amount to a patient in need thereof.

In another embodiment, a method of tumor hardening comprising the compound of formula (I). The present invention is directed to the treatment of a patient with a therapeutic effect in a particular embodiment, T the invention 彳| A | method 'which includes the need, 'for a treatment of asthma The patient is administered, and the compound is administered. /Q therapeutically effective amount (I) in another embodiment, the method comprising the treatment of restenosis

Back and patient cast; A compound. </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; In another embodiment, the method of the present invention comprises the treatment of a compound for treating cancer. <Desc/Clms Page number> · The formula of the effective one is in the other specific 佑 丨丨 b b b b . . . _ : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : 'This includes the need for an item, in which the present invention is directed to an adjustment _ 2; includes administering a therapeutically effective amount to a patient in need thereof in another specific embodiment. A method of modulating the activity of M and _ES by means of a body, comprising: administering a therapeutically effective amount of a compound of formula 1 as needed. In the specific implementation, the present invention is directed to a compound of the formula (1). The medicament is used for the treatment of osteoarthritis, arterial t fever, cardiovascular action, Crohn's disease, hemorrhagic heart failure, Autoimmune disease, HIV infection, dementia associated with HIV, psoriasis pulmonary fibrosis, graft arteriosclerosis, physical or chemically induced brain trauma, inflammatory bowel disease, pulmonary cytoatitis, colon Inflammation, system red wolf 95318 -64- 1354664 sore, poisonous kidney serum nephritis, spheroid nephritis 'asthma, atherosclerosis and rheumatoid arthritis. In another specific embodiment, the invention is directed to a compound of formula (I). In another specific embodiment, the ring B is selected from the group consisting of multiple for the treatment of hardening and treatment.

Ring B is replaced by 〇-1 R5 as appropriate.

Ring B is selected from

In another specific embodiment

&lt;Ring B is replaced by 0-1 R5 95318 -65· 1354664 In another embodiment, Ring B is

Ring B is replaced by 0-1 R5. R5

In another specific embodiment, in another specific embodiment

, each being 1-2 R5 t

and

Each is replaced by 0-1 R5.

1-2 R5 each in another specific embodiment, ring B is selected from

Replace with R5. In another specific embodiment, the Z system is selected from the group consisting of a bond, -NR8C(0)-, 95318-66- 1354664-NR8C(0)NH-, -C(0)NR8., -(CR15R15)1 -, -CR15R15C(0)-, -C(0)CR15R15-, -0-CR14R14-, -CRl4R14-〇-, -〇-, -NR9-, -NR9-CR14R14-, -CR14R14-NR9-,- S(0)p-, -S(0)p-CR14R14- and -S(0)p-NR9- In another embodiment, the Z series is selected from a bond, -NR8C(0)- -NR8C(0)NH-, -NR9- and -C(0)NR8-. In another specific embodiment, the Z series is selected from the group consisting of a bond, -NR8C(0)-, -C(0)NH-, and -NR9- 另一 in another embodiment, Z is -C( 0) NR8-. In another specific embodiment, Z is -NR8C(0)-. In another specific embodiment, Z is -NR9-. In another specific embodiment, the Z series is selected from a bond and _nhc(0)-; in another embodiment, Z is a bond; and R2 is a 5_1 member heteroaryl system, Containing 1-4 heteroatoms selected from N, 0 and S, substituted by 〇3, r7, wherein the heteroaryl is selected from the group consisting of fluorenyl, benzimidazolyl, benzofuranyl, benzothiofuran Benzo, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolone, porphyrin, furanyl , imidazolyl, oxazolyl, fluorenyl, isoindolinyl, isoxazolyl, isoxazolyl, oxazolyl, hydrazine, pyridinyl, pyrazolyl, hydrazine, pyridyl, Pyridyl, pyrimidinyl"pyrrolyl, yl, yl, fluorenyl, thiophene, and quaternary. In another embodiment, Z is 掀9·; a base system containing from 1 to 4 heteroatoms selected from 1 and 3, substituted by _r7, 95318 1354664 wherein the heteroaryl is selected from the group consisting of fluorenyl, benzimidazolyl, benzofuranyl, benzosulfur Dehydrofuranyl, benzoxazolyl, benzopyrazolyl Benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzoisopyrazolyl, benzimidone, rotenyl, indolyl, imipenyl, oxime, oxime嗓基, 异〃奎11林基, 异&gt;»塞吐基, 异的号, 基基基,吠11井基, H比p基基, P比吐基, answer p井基, P is more than the base, I» than bite base, shouting base, Ye Haohaji, P Kuiling p Linji, I»奎尼林基, mobilization base, "Sepeno and four thiol, three ploughing In another embodiment, R4 is selected from the group consisting of H, CV6 alkyl, C3_8 fluorenyl, C3.8 alkynyl, (CRR)qOH, (CHR)sSH, (CRR)tOR4d, (CHR)tSR4(i, (CHR)tNR4aR4a ' (CHR)qC(0)0H ' (CHR)r C(0)R4 b ' (CHR)rC(0)NR4aR4a, (CHR)tNR4aC (0) R4b, (CHR)t0C(0)NR4aR4a, (CHR)tNR4aC(0)0R4d, (CHR)tNR4aC(0)R4b, (CHR)rC(0)0R4b, (CHR)t0C(0)R4b, (CHR)rS(0)pR4b &gt; (CHR)rS(0)2NR4aR4a '(CHR)rNR4aS(0)2R4b ; and R is independently selected from H, decyl, ethyl, propyl at each occurrence , allyl, propynyl, (CH2)rC3.6 cycloalkyl and taken by R6e (CH2)rphenyl. In another specific embodiment, R4 is selected from the group consisting of hydrazine, fluorenyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, allyl, and propyl. Alkynyl, (CRR)qOH, (CRR)tSH, (CRR)tOR4d, (CRR)tSR4d, (CRR)tNR4aR4a, (CRR)qC(0)0H, (CRR)rC(0)R4b, (CRR)rC (0) NR4aR4a, (CRR)tNR4aC(0)R4b, (CRR)t0C(0)NR4aR4a, (CRR)tNR4aC(0)0R4d, (CRR)tNR4aC(0)R4b, (CRR)rC(0)0R4b, 95318 -68- 1354664 (CRR)t0C(0)R4b, (CRR)rS(0)pR4b, (CRR)rS(0)2NR4aR4a, (CRR)rNR4aS(0)2R4b 〇R4b is selected from H, methyl, Ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl and cyclopropyl; and R4d is selected from the group consisting of decyl, ethyl, propyl, iso-propyl , butyl 'iso-butyl, tert-butyl, pentyl and cyclopropyl. In another specific embodiment, R4 is selected from the group consisting of hydrazine, methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, allyl, propynyl, (CH2)rC ( 0) R4b. In another specific embodiment, R4 is selected from the group consisting of hydrazine, Cu alkyl, C3.8 alkenyl, C3.8 alkynyl, (CRR) tOH, (CRR) tSH, (CRR) tOR4d, (CRR) tSR4d , (CRR)tNR4aR4a ' (CRR)qC(0)0H ' (CRR)r C(0)R4 b ' (CRR)rC(0)NR4aR4a ^ (CRR)tNR4aC(0)R4b ' (CRR)t0C(0 )NR4aR4a ' (CRR)tNR4aC(0)OR4d ' (CRR)tNR4aC(0)R4b, (CRR)rC(0)0R4b, (CRR)tOC(0)R4b, (CRR)rS(0)pR4b, (CRR rS(0)2NR4aR4a, (CRR)rNR4aS(0)2R4b. In another specific embodiment, R4 is selected from the group consisting of H, methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, decyl, propynyl, (CRR) tOH, (CRR)tSH, (CRR)tOR4d, (CRR)tSR4d, (CRR)tNR4aR4a, (CRR)qC(0)0H, (CRR)rC(0)R4b, (CRR)rC(0)NR4aR4a, (CRR) tNR4aC(0)R4b, (CRR)t0C(0)NR4aR4a, (CRR)tNR4aC(0)0R4d, (CRR)tNR4aC(0)R4b, (CRR)rC(0)0R4b, (CRR)t0C(0)R4b (CRR)rS(0)pR4b, (CRR)rS(0)2NR4aR4a, (CRR)rNR4aS(0)2R4b; R4a is independently selected from H and replaced by 0-1 R4e at each position Base, 95318 - 69· 1354664 C2-6 alkyl substituted by 0-3 R4e, wherein C2-6 alkyl is selected from the group consisting of ethyl, propyl, iso-diyl, butyl, iso-butyl, Tri-butyl, pentyl and hexyl, and (CH2)r-C3-6 carbocyclic residues substituted by 0-4 R4e, wherein the carbocyclic residue is selected from the group consisting of cyclopropyl, cyclohexyl and benzene R4b is selected from the group consisting of hydrazine, methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, tert-butyl, pentyl and cyclopropyl; R4d is selected from thiol, Ethyl, propyl, iso-propyl, butyl, iso - butyl, tert-butyl, pentyl and cyclopropyl. In another specific embodiment, R5 is independently selected from the group consisting of hydrazine, methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, allyl, propyne Base, (CH2)rOH, (CH2)rOR5d, (CH2)rNR5aR5a, (CH2)rC(0)0H, (CH2)rC(0)R5b, (CH2)rC(0)NR5aR5a, (CH2)rNR5aC(0 R5b, (CH2)r0C(0)NR5aR5a, (CH2)rNR5aC(0)0R5d, (CH2)rNR5aC(0)R5b, (CH2)rC(0)0R5b, (CH2)r 0C(0)R5 b, (CH2)r NR5 a S(0)2 haloalkyl; and R5a, at each occurrence, independently selected from H, methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl , pentyl, hexyl, cyclopropyl and cyclobutyl. In another specific embodiment, R5 is independently selected from the group consisting of hydrazine, OH, OR5d, (CH2)rNR5aR5a, (CH2)rNR5aC(0)R5b&amp;(CH2)rNR5aC(0)0R5d In another specific embodiment, R5 is NR5aR5a. In another specific embodiment, R5, at each occurrence, is independently selected from the group consisting of hydrazine, methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, allyl, 95318. 70- 1354664 Propynyl, F, C, Br, I, (CH2)rOH, (CH2)rOR5d, (CH2)rNR5aR5a, (CH2)rC(0)0H, (CH2)rC(0)R5b, (CH2 rC(0)NR5aR5a, (CH2)rNR5aC(0)R5b, (CH2)r0C(0)NR5aR5a, (CH2)rNR5aC(0)0R5d, (CH2)rNR5aC(0)R5b,(CH2)rC(0) 0R5b, (CH2)r0C(0)R5b, haloalkyl, (CH2)r phenyl substituted by 0-2 R5e, and (CRR)r-5-10 heterocyclic ring system, containing 1-4 options Heteroatoms from N, oxime and S are substituted by 0-2 R5c, wherein the heterocyclic ring system is selected from the group consisting of tetrahydrop-pyrrolidyl, hexahydro-P-precipitate and whal-based; and R5a is present in each It is independently selected from the group consisting of hydrazine, methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, pentyl, hexyl, cyclopropyl and cyclobutyl. In another specific embodiment, R5 is independently selected from the group consisting of decyl, ethyl, propyl, isopropyl, butyl, iso-butyl, propyl, propynyl, F, Q, Br, I, (CH2)rOH, (CH2)rOR5d, (CH2)rNR5aR5a, (CH2)rC(0)0H, (CH2)rC(0)R5b, (CH2)rC(0)NR5aR5a, (CH2)rNR5aC(0)R5b, (CH2)r0C(0)NR5aR5a, (CH2)rNR5aC(0)0R5d, (CH2)rNR5aC(0)R5b, (CH2)rC(0)0R5b, (CH2)r0C( 0) R5b, haloalkyl, and (CRR)r-5-10 member heterocyclic ring system containing 1-4 heteroatoms selected from N, O and S, substituted by 0-2 R5c, wherein the heterocyclic system It is selected from the group consisting of tetrahydropyrrolyl, hexahydrop to butyl and whalamide. In another specific embodiment, R5, at each occurrence, is independently selected from the group consisting of F'Cl, Br, I, (CH2)rOH, (CH2)rOR5d, (CH2)rNR5aR5a, and (CRR)r-5 a 10-membered heterocyclic ring system containing 1-4 heterologous 95318-71 · 1354664 selected from N, O and S, substituted by 0-2 R5c, wherein the heterocyclic ring system is selected from the group consisting of tetrahydropyrrolyl, Gas p is more than a bite group and a buckwheat group. In another embodiment, 'R1 is selected from the group consisting of ruthenium, R6, and ruthenium-3 R6. 6 alkyl, 0-3 R6 Substituted C2·6 alkenyl, substituted by 0-3 R6, C: 2-6 alkynyl, aryl substituted by 0-5 R6, wherein aryl is selected from phenyl and naphthyl, and 5- A 10-membered heteroaryl system containing μ heteroatoms selected from n ' 0 and S, substituted by 0-3 R 6 , wherein the heteroaryl is selected from the group consisting of fluorenyl, benzimidazolyl, benzofuranyl, Benzothiofuranyl, benzoxazolyl, benzopyrazole, benzotriazolyl, benzotetrazolyl, benzoisoazole, benzisopyrazole, benzimidazole Keto group, indolinyl, furyl, imidazolyl, oxazolyl, fluorenyl, isoquinolinyl, isothiazolyl, isohydrogen 4 , 》 号 嗅,, azozolyl, phenyl group, P ratio _ base, P ratio bite base, tower tillage base, P ratio base, bite base, P dense base, 峨 洛, P Ku嗤U Linkyl, P-quinolyl, P-sulphonyl, thiophene and tetradecyl. In another specific embodiment, R1 is selected from the group consisting of hydrazine, R6, and hydrazine alkyl substituted with 0-3 R6, wherein the alkyl group is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, A butyl group, a pentyl group and a hexyl group, a C2_6-substituted group substituted with 0-3 R6 groups, and a C2.6 alkynyl group substituted with 0-3 R6 groups. In another specific embodiment, R1 is selected from the group consisting of ruthenium, R6, Α6 alkyl substituted by 〇-3 R6, C2_6 alkenyl substituted by 〇-3 R6, substituted by 〇-3 R6 2_6 alkynyl, C6_1() aryl substituted by 0-5 R6, and 5-10 membered heteroaryl systems containing 1-4 heteroatoms selected from N, fluorene and S, 〇-3 R6 Substituting; with the proviso that when Rla is equal to aryl or heteroaryl, Ri is not 95318 -72· 1354664 -CH2S(0)2-Rla, -CH2S(0)2-Rla, -NHC(0)- Rla, -NHC(0)NH-Rla, -NHCH2 -R1 a, -SC^NH-R1 a, -NHSOzNH-R1 a ; (with the proviso that the compound of the present invention is not filed as 12/20/01 U.S. Patent Application Serial No. 10/027,644 (Case No. PH7268), U.S. Patent Application Serial No. 10/383,391, filed on Jan. (PH7442) and U.S. Provisional Patent Application Serial No. 60/467,003, filed on Jan. No. No. No. No. No. No. No. No. No. No. No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No Ci_6 alkyl group, -qop-Cu alkyl group substituted by ΜR6. In another specific embodiment , Ri is selected from Η, Cu alkyl substituted by 0-3 R6, wherein the alkyl group is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, pentyl and hexyl, by 0- 3 R6 substituted C2-6 alkenyl, C2_6 alkynyl substituted by 0-3 R6; in another specific embodiment, R2 is selected from phenyl substituted with 〇_2 R7, and 5- A 10-membered heteroaryl system containing i_4 heteroatoms selected from N, hydrazine and S, substituted by 0-3 R7, wherein the heteroaryl is selected from the group consisting of benzimidazolyl, benzofuranyl, benzothio Furanyl, benzoxazolyl, benzopyrazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisoxazolyl, benzimidazolone, porphyrin , furanyl, imidazolyl, oxazolyl, fluorenyl, isoindolyl, isoxazolyl, isoxazolyl, carbazolyl, pyridinyl, p-infrared, tasa, P-bit a group, a p-bite group, a η-dense group, a P-hahyl group, an oxazoline group, a porphyrin group, a thiazolyl group, a pyrenyl group, and a tetrazolyl group. In another specific embodiment, the R 2 is selected from the group consisting of Phenyl substituted by 〇_2 R7" 95318 -73- 1354664 in another embodiment R2 is selected from the group consisting of a phenyl substituted with a ulnar 7 and a 5-1 heteroaryl system containing i_4 heteroatoms selected from N, oxime and s, substituted by 0-3 R7, wherein the heteroaryl Is selected from the group consisting of fluorenyl, naphthyl, hydrazine, porphyrin, quinolyl, isoquinolyl, oxazolyl and oxazoline, benzimidazolyl, benzofuranyl, benzothio Furanyl, benzoxazolyl, benzoxazolyl, benziso, isozolyl and benzisopyrazolyl. In another specific embodiment, z is a bond, and R2 is selected from a 5_1 member heteroaryl system containing 1-4 heteroatoms selected from N, fluorene, and 8 and is 〇3 R7 Substituting 'wherein the heteroaryl is selected from the group consisting of anthracenyl, naphthyl, anthracenyl, porphyrinyl, porphyrinyl, isoindolyl, oxazolyl and quinazolinyl, benzimidazolyl, benzindene Meryl, benzothiofuranyl, benzoxazolyl, benzoxazolyl, benzisoxazolyl and benzisoxazole. In another embodiment, the R2 is selected from the group consisting of 苯基-2 R7 substituted phenyl and 5-10 membered heteroaryl systems containing 1-4 heteroatoms selected from n, fluorene and S, 0- 3 R7 substitutions in which the heteroaryl system is selected from the group consisting of quinazolinyl, tri-pirty, pyrimidinyl, methylpyridyl, iso-nicotinyl, furyl, fluorenyl, pyridyl, pyrazolyl, pyridyl Tillage, carbazolyl, thienyl, thiophenyl and isosaki. In another embodiment, 'R6, at each occurrence, is selected from the group consisting of Cu alkyl, -8 alkenyl, - 8 block, (CR'R')r C3-6 cyclodecyl, C1, Br , I, F, Ν〇2, CN, (CR, R,) rNR6aR6a, (CRR)rOH, (CR'R'XCXCR'R'XR6*1, (CR'R')rSH, (CR, R, )rC(0)H, (CR'R'XSCCR'R'XR6*1, (CR,R')rC(0)0H, (CR,R')rC(0)(CR,R')rR6b, (CR'R,)rC(0)NR6aR6a, (CR'R'XNRWqOXCR'ROrRU, (CR,R')rC(0)0(CR'R,)rR6d, 95318 -74- 1354664 (CR,R, rNR6aC(0)NR6aR6a, (CR,R,)rNR6aC(S)NR6aR6a, (CR'ROrOCCOXCR'ROrR61» '(α^,)Γ3(0)ρ(αΐΊΙ')ΓΙ1613, (CR'R|)rS (0) 2NR6aR6a, (CR'R')rNR6fS(0)2(CR,R')rR6b, (CR'R')rNR6fS(0)2, NR6aR6a, .6 6 halogenated group and 0-3 R6e substituted (CR'R|)r phenyl, and (CH2)r-5-6 heterocyclic ring system containing 1-2 heteroatoms selected from N, fluorene and S, substituted by 〇-2 R6e R6a is independently selected from the group consisting of hydrazine, methyl, ethyl, propyl, iso-propyl, butyl 'iso-butyl, tert-butyl, pentyl, hexyl, cyclopropyl, in each presence. And phenyl; The two 1163s are joined to the ruthenium to which they are attached to form a 3-8 membered heterocyclic ring containing 0-1 other heteroatoms selected from the group consisting of Ν'〇 and S, wherein the heterocyclic ring is selected from the group consisting of nitrogen and propylene. a base, a nitrotetradecyl group, a pyrrolyl group, a hexahydropyridyl group, and a morpholinyl group; each of R6b is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, iso- Butyl, tert-butyl, pentyl, hexyl, cyclopropyl and phenyl; R6d, in each presence, is selected from the group consisting of methyl, Cf3, ethyl, propyl, iso-propyl, butyl, Iso-butyl, tert-butyl, pentyl, hexyl, cyclopropyl and phenyl; R6e, in each presence, is selected from Ci 6 alkyl, C 2 decyl, C 2-8 alkynyl, (CH 2 ) rC3.6 cycloalkyl, Cl, F, Br, I, CN, N〇2, (CF2)rCF3, (CHAOCm alkyl, 〇H, SH, (CHJSCh), (CH2)rNR6fR6f and (CH2)r Phenyl; R6f, at each occurrence, selected from the group consisting of 11, fluorenyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl-cyclopropane Base and benzene 95318 • 75 · 1354664 base. In another specific embodiment, R6 is selected from the group consisting of Cu alkyl, C2-8 alkenyl, C2-8 alkynyl, (απα(:3-6 cycloalkyl, Cl, Br, I, F, N〇2, CN, (CHR')rNR6aR6a, (CHR,)rOH, (CHR')rOR6d, (CHR')rSH ' (CHR')rC(0)H ' (CHR')rSR6d ' (CHR')r C(0)0H ' (CHR')rC(0)R6b, (CHR')rC(0)NR6aR6a, (CHR')rNR6fC(0)R6b, (CHR')rC(0)0R6d , (CHR,)rNR6aC(0)NR6aR6a, (CHR')rNR6aC(S)NR6aR6a ' (CHR')r 0C(0)R6 b ' (CHR')r S(0)p R6 b ' (CHR') rS(0)2NR6aR6a '(CHR')rNR6fS(0)2R6b '(CHR')rNR6fS(0)2NR6aR6a, Cu haloalkyl, and (CHR')r phenyl substituted by 0-3 R6e. In a specific embodiment, R6 is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, F, CU, Br, I, .N02, CN, (CH2)rO(CH2)rR6d, C(0)R6d, SR6d, NR6aR6a, C(0)NR6aR6a, NC(0)R6b, 0C(0)R6b, S(0)pR6b, (CHR,)rS(0)2NR6aR6a&amp;CF3; R6aah, fluorenyl , ethyl, propyl, iso-propyl, butyl, and phenyl; or, two 116&amp; and their attached N-bonded to form a 3-8 membered heterocyclic ring containing 0-1 Other heteroatoms selected from the group consisting of N, hydrazine and S, wherein the heterocyclic ring is selected from the group consisting of aziridine, nitrotetradecyl, pyrrolyl, hexahydropyridyl and whufrid; 1161) is H, methyl, Ethyl, propyl, iso-propyl or butyl; R6d is methyl, phenyl, CF3 and (CH2)-phenyl. In another specific embodiment, R6 is selected, in each presence, from (^_8 alkyl, C2_8, C2-8 alkynyl, (CH2)rC3_6 cycloalkyl, Cl, Br, I, 95318 -76· 1354664 F, N02, CN, (CH2)rNR6aR6a, (CH2)rOH , (CH2)rOR6d, (CH2)rSH, (CH2)rC(0)H, (CH2)rSR6d, (CH2)rC(0)0H, (CH2)rC(0)R6b, (CH2)rC(0) NR6aR6a, (CH2)rNR6fC(0)R6b, (CH2)rC(0)0R6d, (CH2)rNR6aC(0)NR6aR6a, (CH2)rNR6aC(S)NR6aR6a, (CH2)r0C(0)R6b, (CH2) rS(0)pR6b, (CH2)rS(0)2NR6aR6a, (CH2)rNR6fS(0)2R6b, (CH2)rNR6fS(0)2NR6aR6a, Cu haloalkyl and substituted by 0-3 R6e (CHR,) r Phenyl. In another embodiment, R6, in each occurrence, is selected from the group consisting of alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3.6 cycloalkyl, Cl, Br, I, F, N〇2, CN, (CH2)rNR6aR6a, (CH2)rOH, (CH2)rO(CH2)rR6d, (CH2)rSH, (CH2)rC(0)H, (CH2)rS(CH2)rR6d, (CH2)rC(0)0H, (CH2)rC(0)(CH2)rR6b, (CH2)rC(0)NR6aR6a, (CH2)rNR6fC(0)(CH2)rR6b,(CH2)rC(0)0 (CH2)rR6d, (CH2)rNR6aC(0)NR6aR6a, (CH2)rNR6aC(S)NR6aR6a, (CH2)r0C(0)(CH2)rR6b, (CH2)rS(0)p(CH2)rR6b, (CCH2 rS(0)2NR6aR6a, (CH2)rNR6fS(0)2(CH2)rR6b, (CH2)rNR6fS(0)2NR6aR6a, Cu haloalkyl and (CH2)rphenyl substituted by 0-3 R6e, (CH2)r-5-6 member heterocyclic ring system containing 1-2 heteroatoms selected from N, oxime and S, substituted by 0-2 R6e, wherein the heterocyclic ring system is selected from the group consisting of a nitrogen propylene group Nitrotetradecyl, p to p, hexahydro 1», and pheno-p-lin; R6a, at each occurrence, is independently selected from the group consisting of hydrazine, methyl, ethyl, propyl, iso-propyl Base, butyl, iso-butyl, tert-butyl, pentyl, hexyl, 95318-77· 1354664 cyclopropyl and phenyl R6b is selected from the group consisting of hydrazine, methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl, cyclopropyl and Phenyl; R6d is selected from the group consisting of methyl, CF3, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl, cyclopropene And phenyl; R6e is selected from the group consisting of (^-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3.6 cycloalkyl 'Cl, F, Br, I, CN, N02, (CF2)rCF3, (CHAOCw alkyl, OH, SH, (CH2)rSC, 5 alkyl, (CH2)rNR6fR6f and (CH2)r phenyl; R6f, in each presence, is selected from H , methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl, cyclopropyl and phenyl. In another embodiment, R6 is selected from the group consisting of Cu alkyl, C2.8 alkenyl, C2.8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F 'N〇2 ' CN ' (CR'R')rNR6a,R6a, '(CR'R')rOH ' (CR'ROrOCCR'R'XR64, (CR'R,)rSH, (CR'R')rC(0)H, (CR 'R'^SCCR'R'XR^ ' (CR'K^SC^CCR'K^R613 &gt; (CR'R')r C(0)0H ' (CR'R')rC(0)(CR'RI)rR6b ' (CR'R')r C(0)NR6 a R6 a ' (CR,R ')rNR6fC(0)(CR,R')rR6b, '(CR'R'XC(0)0(CR'R')rR6d &gt; (CR'RlOqOXCR'R1),, (. Grab, owe 0 (: (0 Hui 63 Yang, 1^116 &lt; 1, (CR'R'XNR^C^NR^CCR'R'XR6^ &gt; (CR'R')rNR6aC(S)NR6a(CR 'R')rR6d ' 95318 -78· 1354664 (CR.RlNRWqOXXCR'ROrR615, (CR,R,)rC(=NR6f)NR6aR6a, (CR'R')rNHC(=NR6f)NR6fR6f &gt; (CR'R' )r S(0)p (CR'R'X R6 b' ' (CR'R')rS(0)2NR6aR6a ' (CR'R')rNR6fS(0)2NR6a,R6a, ' (αΐ,ΙΙ,) ΓΝΚ64(Ο)2(0ΚΧ)ΓΙ161}, (CR'R|)rC(0)NHS02R6b, Cu haloalkyl, C2-S alkenyl substituted by 0-3 R', 0-3 R· a substituted C2-8 alkynyl group, a (CR'R)r phenyl group substituted by 0-3 R6e, and a (CH2)r-5-10 member heterocyclic ring system containing 1-4 selected from N, fluorene and a hetero atom of S, substituted by 0-2 R6e; or two R6 on adjacent atoms on R1 may be joined to form a cyclic acetal; R6a is selected from Η, 0-1 at each presence a R6g substituted methyl group, a C2_6 alkyl group substituted by 0-2 R6e, a C3-8 fluorenyl group substituted by 0-2 R6e, a C3-8 alkynyl group substituted by 0-2 R6e, and 0- 2 R6e substituted (CH2)r-C3-1() carbocyclic residue, and (CH2)r-5-10 member heterocyclic ring system containing 1-4 heterogeneous selected from N, Ο and S To be replaced by 0-2 R6e; R6a 'At each occurrence, selected from hydrazine, Ci-6 alkyl and C3.6 cycloalkyl; R6b, at each occurrence, is selected from the group consisting of oxime, Cu alkyl substituted by 0-2 R6e, 0-2 R6e substituted C3_8 alkenyl, C-2_alkynyl substituted by 0-2 R6e, (CH2)rC3_6 carbocyclic residue substituted by 0-3 R6e, and (CH2)r-5-6 Heterocyclic system containing 1-4 heteroatoms selected from N, hydrazine and S, substituted by 0-2 R6e; R6b', at each occurrence, is selected from hydrazine, Ci-6 alkyl and C3- 6 cycloalkyl;

R6d, at each occurrence, is selected from C3-8 fluorenyl substituted by 0-2 R6e, C3_8 alkynyl substituted by 0-2 R6e, methyl, CF3, C2 substituted by 0-3 R6e .6 alkyl, C2-4 haloalkyl, (CH2)r-C3-10 carbocyclic residue 'substituted with 0-3 R6e' and (CH2)r-5-6 beta heterocyclic ring system containing 1 - 4 heteroatoms selected from N, 0 and S 95318 • 79 · 1354664, substituted by 0-3 R6e; R6e, in each presence, selected from Ci-6 alkyl, C2-8 alkenyl, C2-8 , (CH2)rC3-6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2)rCF3, (αί2)Γ0 (ν5 alkyl, OH, SH, (CHASCh alkyl, (CH2)rNR6fR6f , C(0)NHR6h, (CH2)rOH, C(0)0H, (CH2)rC(0)NHS02-R6h, NHS02R6h, (CH2)rtetrazolyl and (CH2)rphenyl, and (CH2) a r-5-6 heterocyclic ring system containing from 1 to 4 heteroatoms selected from the group consisting of N, O and S; R6d', in each presence, selected from the group consisting of H, CF3 and alkyl and C3.6 cycloalkyl R6f is selected from the group consisting of hydrazine, q.5 alkyl and C3_6 cycloalkyl, and phenyl; R6g is independently selected from _C(0)R6b, -C(0)OR6d, -C( 0) NR6fR6f, (CH2)rOH, C(0)0H, (CH2)rC(0)NHS02-R6h, NHS02R6h (012) tetrazolyl and (CH2)rphenyl; and R6h, in each presence, selected from the group consisting of Cu alkyl, Cu from alkyl and C3-6 cycloalkyl, and phenyl. In another embodiment Wherein R7 is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, second-butyl, tert-butyl, pentyl, hexyl, (CH2)rC3. 6 cycloalkyl, Cl, Br, I, F, N〇2, CN, (CH2)rNR7aR7a, (CH2)rOH, (CH2)rO(CH)rR7d, (CH2)rSH, (CH2)rC(0) H, (CH2)rS(CH2)rR7d, (CH2)rC(0)0H, (CH2)rC(0)(CH2)rR7b, (CH2)rC(0)NR7aR7a, (CH2)rNR7fC(0)(CH2 rR7b, (CH2)rC(0)0(CH2)rR7d, (CH2)r0C(0)(CH2)rR7b, (CH2)rNR7aC(0)NR7aR7a, (CH2)rNR7aC(0)0(CH2)rR7d, (CH2)rS(0)p(CH2)rR7b, 95318 •80· 1354664 (CH2)rS(0)2NR7aR7a, (CH2)rNR7fs(9)2(CH2)rR7b, q 6 haloalkyl and substituted by 0-3 R7e (CH2)rphenyl; R7a, at each occurrence, is selected from the group consisting of H, methyl 'ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, Hexyl and cyclopropyl; R7b is selected from methyl, ethyl, propyl, iso-propyl in each presence Base, butyl, iso-butyl, tert-butyl, pentyl, hexyl and cyclopropyl; R7d is selected from the group consisting of sulfhydryl, CF3, ethyl, propyl, isopropyl at each , butyl, iso-butyl, tert-butyl, pentyl, hexyl and cyclopropyl; R7e, in each presence, is selected from Ci 6 alkyl, C 2 8 alkenyl, C 2 8 alkynyl, CH2)rC3-6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2)rCF3, (CHJOCh alkyl, 〇H, SH, (CHJSCu alkyl, (CH2)rNR7fR7f and (CH2)r Phenyl; and R7f, at each occurrence, selected from the group consisting of H, methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl, cyclo Propyl and phenyl. In another specific embodiment, R7 is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, second-butyl, pentyl, hexyl, C1, Br &gt ; I ' F ' N〇2 ' NR7aR7a ^ NHC(0)NHR7a ' NR7aC(0)R7b ' NR7aC(0)0R7d, CF3, 〇CF3, C(0)R7b, NR7fC(0)NHR7a&amp; NHS(0) 2R7b In another embodiment, R7 is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, second-butyl, pentyl, hexyl, C1. Br, I, F, N〇2, NR7aR7a, NHC(0)NHR7a, NR7aC(0)R7b, NR7aC(0)0R7d 'CF3, OCF3, C(0)0R7d 'C(0)R7b ' 95318 -81 - 1354664 7b,

NR7fC(0)NR7aR7a ' NHS(0)2R -NR7aC(0), -NR7aC(0). •Ν' ,0

, NH

In another specific embodiment, R7a is selected from the group consisting of H, methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, neopentyl , cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; 715 is selected from cyclohexyl and cf3; and R7d is selected from methyl, ethyl, propyl, iso-propyl, butyl, iso- Butyl and tert-butyl. In another specific embodiment, R7 is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, second-butyl, tert-butyl, pentyl, Hexyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, N〇2 'CN, (CH2)rNR7aR7a, (CH2)r0H, (CH2)rO(CH2)rR7d, (CH2)rSH, (CH2)rC(0)H, (CH2)rS(CH2)rR7d, (CH2)rC(0)OH, (CH2)rC(0)(CH2)rR7b, (CH2)rC(0)NR7aR7a, (CH2 rNR7fC(0)(CH2)rR7b, (CH2)rC(0)0(CH2)rR7d, (CH2)r0C(0)(CH2)rR7b, (CH2)r0C(0)NR7aR7a, (CH2)rNR7aC(0 )NR7aR7a, (CH2)rNR7aC(0)0(CH2)rR7d, •82· 95318 1354664 (CH2)rS(0)p(CH2)rR7b, (CH2)rS(0)2NR7aR7a, (CH2)rNR7fS(0) 2(CH2)rR7b, (: 6 haloalkyl, gold steel alkyl and (CH2)r phenyl substituted by 0-3 R7e, and (CH2)r-5-6 heterocyclic ring system, containing 1 - 4 heteroatoms selected from N, oxime and S, substituted by 0-3 R7e, wherein the heterocyclic ring system is selected from the group consisting of pyrenyl, pyridyl, benzopyrazolyl and tetrazolyl; R7a in each Where present, selected from the group consisting of hydrazine, methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl , pentyl, hexyl, propyl-2. fluorenyl, 2-methyl-2-propenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, _CH, propyl and aryl; R7b Each presence is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl, cyclopropyl, cyclopentyl, CH2 a cyclopentyl group, a cyclohexyl group, a CH2-cyclohexyl group, a CF3 group, a tetrahydropyrrolyl group, a morpholinyl group, a hexahydropyrylene group substituted with 0-1 R7e, and a nitrogen tetradecyl group; R7d in each Where present, selected from the group consisting of methyl, CF3, CF2CF3, CHF2, CH2F, ethyl 'propyl, iso-propyl, butyl, iso-butyl, tert-butyl, oxime, hexyl and cyclopropyl Each R7e is selected from the group consisting of Ci 6 alkyl, C 2 8 alkenyl, C 2-8 alkynyl, (CH 2 ) r C 3.6 cycloalkyl, a, F, Br, I, CN, N〇 2. (CF2)rCF3, (CH2)r〇Ci-5 alkyl, (CH2)r〇H, OH, SH, C(0)0H, C(0)NHR7h, QOXX^alkyl, (CH2)rSCi -5 alkyl, (CH2)rNR7fR7f, (CH2)rC(0)NHS02-R7h, NHS02R7h and (CH2)r phenyl, (012\tetrazolyl; R7f in each presence, selected from H, A base, Group, propyl, iso - propyl, 95318 • 83 · 1354664 butyl, iso - butyl 'III - butyl, pentyl, hexyl, cyclopropyl and phenyl. In another embodiment, 'R7, at each occurrence, is selected from the group consisting of decyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, second-butyl, third- Butyl, pentyl, hexyl, ((:112), 03_6 cycloalkyl, Q, Br, I, F, N〇2, CN, (CH2)rNR7aR7a, (CH2)rOH, (CH2)rOR7d, (CH2 rSH, (CH2)rC(0)H, (CH2)rSR7d, (CH2)rC(0)OH, (CH2)rC(0)R7b, (CH2)rC(0)NR7aR7a, (CH2)rNR7fC(0 ) R7b, (CH2)rC(0)0R7d, (CH2)r0C(0)R7b, (CH2)r0C(0)NR7aR7a, (CH2)rNR7aC(0)NR7aR7a, (CH2)rNR7fC(0)0R7d, (CH2 rS(0)pR7b, (CH2)rS(0)2NR7aR7a, (CH2)rNR7aS(0)2NR7aR7a, (CH2)rNR7fS(0)2R7b, Cl_2 haloalkyl, (〇^2\金钢alkyl, 0-3 R7e substituted (CH2)r stupyl, and (CH2)r-5-6 member heterocyclic ring system containing 1-4 heteroatoms selected from N, 〇 and s, 0-3 R7e Substituted wherein the heterocyclic ring is selected from the group consisting of thiophenyl, pyridyl, benzoxepylene and tetradecyl. In another specific embodiment, R8 is hydrazine. In another specific embodiment, Rii and Ri2 In another embodiment, the ring system is at least An R5 substitution, which is -NR5aR5a, may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The invention also encompasses all combinations of the alternative aspects of the invention indicated herein. Any and all embodiments of the present invention may be employed in conjunction with any other specific embodiment to describe additional 95318, 84-(3)4064 inventions, and other elements of a particular embodiment, </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> </ RTI> </ RTI> The compounds of the invention may be optically active or in racemic form. It is known in the art how to prepare optically active forms, for example by external:, /弋, or by synthesis from optically active starting materials. Many geometric isomers, such as bonds, may also be present in the &quot;&quot; and all such stable isomers are intended to be encompassed by the present invention: The cis and trans geometric isomers of the invented compounds are described, and ° is isolated as a mixture of isomers or as isolated isomeric forms. All of the formulas are all palmo, diastereomeric, racemic and all isomeric forms, unless specifically indicated to be a particular stereoisomer or isomeric form. One palm of the compound of formula I, in comparison to the other, exhibits superior activity. Therefore, all stereochemistry is considered to be part of the present invention. When required, the separation of the racemic material can be achieved by HPLC, using a column of the palm of the hand, or by resolution, using a resolving agent, such as gasified camphor sulfonate, as in Steven D. Young et al. Shovel Chemical Side Method 1995, 26〇2 26〇5. As used herein, the term "substituted" means that any one or more hydrogen radicals at a specified atom or % are replaced by a group selected from the indicated, provided that the specified The normal valence bond of an atom or a ring atom, and this takes 95318 -85 - 1354664 to cause a stable compound. When the substituent is a keto group (ie, = 〇), then the two hydrogen systems on the atom are replaced. A variable (e.g., Ri 〇) is defined in each of the existences of the &lt;combination&lt;comprising&lt; constitutively or chemically, and is independent of the definition of each occurrence of 匕. 'For example, if the group is shown to be substituted by 2 R, the anthracene group may be replaced by up to two R10 groups, and R1. In each presence, it is independently selected from the definition of R1. , a combination of substituents and/or variables' is permissible only if such a combination results in a stability compound. The bond of the pair of substituents is shown as a bond across two atoms in a linker. Such a substituent may be bonded to any atom on the ring. When such a substituent is not shown to be bonded to the atom through which the remainder of the compound of the formula is passed, such substituent may be bonded via any atom of such substituent. Substituent and/or The combination of variables and enthalpy is only allowed if such a combination results in a stable compound. The term "C octaalkyl" is used herein to mean both branched and linear saturated aliphatic hydrocarbon groups. The number of carbon atoms specified, examples of which include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, di-butyl, tert-butyl, Amyl and hexyl. The Ch alkyl group is intended to include, c2, C3, C4, C5, c6, (:7 and c8 alkyl. &quot;alkenyl,' is intended to include hydrocarbon chains, whether linear or branched, and Appears at one or more unsaturated carbon-carbon bonds along any stable point along the chain, such as vinyl, propylene-based. ''Alkynyl' is intended to include either straight-chain or branched configurations. The hydrocarbon chain 'and one or more may appear at any stable point along the chain; saturated: 95318 • 86 - 1354664 carbon-carbon bond, such as ethynyl, propynyl, etc. e "C3_6 cycloalkyl" Is intended to include a saturated ring group having the specified number of carbon atoms in the ring, including mono-, bi- or polycyclic ring systems such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and In the case of a cycloalkyl group, it is a cycloheptyl group. The c3 6 cycloalkyl group is intended to include c3, c4, c5 and (:6 cycloalkyl) as used herein, a functional group &quot; or &quot; , refers to fluoro, chloro, bromo and iodo; and "dentate alkyl" is intended to include both branched and linear saturated aliphatic hydrocarbon groups, such as CF3, having the specified The number of atoms, replaced by deuterium or a plurality of halogens (for example, -CVFW, where v = 1 to 3, and w = 1 to (2v+1). The &quot;5-6-membered cyclic ketal used in this article&quot; The term "2,2.disubstituted U-dioxo" or 2,2-disubstituted l,3-dioxane and its derivatives. "Carbon ring" used in this article. ; or &quot;carbocyclic residue&quot;, means any ampule 3, 4, 5, 6 or 7-membered single or double ring, or 7, 8, 9, 1 〇 11, 12 or 13_ member bis or tricyclic, any of which may be saturated, partially unsaturated or aromatic. Examples of hydrazine carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, ^Hexyl, cycloheptyl, gold steel, cyclooctyl; [3 3 look around ring xin' [43 〇] again % decane, [4.4.0] bicyclononane (decahydroquinone), [2 2.2 Bicyclooctane, genomic, pen, gan, naphthyl, hydroquinone, gold alkyl or tetrahydronaphthyl (tetrahydronaphthalene). &quot;heterocycle&quot; or &quot; Heterocyclic system &quot;terminology, meaning stability 1 354 464 contains -c (〇 >, carbonyl. Heterocycle can be in any hetero atom that will cause a stable structure a carbon atom attached to its pendant group. The heterocyclic ring described herein may be substituted on a carbon or nitrogen atom, if the compound formed is stable. If specifically indicated, the nitrogen in the heterocycle may be Tertiary. When the total number of § and 〇 atoms in the heterocycle exceeds 1, then the oligos are preferably not adjacent to each other. The &quot;aromatic heterocyclic system&quot; or &quot; The term "base" means a stable ring to a 7-membered monocyclic or bicyclic or 7- to ι 〇 bicyclic heterocyclic aromatic ring comprising a carbon atom and 1 to 4 independently selected from N, 〇 and 8 heteroatoms, and in nature are aromatic. Examples of heterocycles include, but are not limited to, 1H•, azole, 2_tetrahydropyrrolidino, 2H, 6H-1, 5,2-jl stilbenyl, 2H-ppyrrolyl, 1Η·+, 4-hexahydropyridinone, 4aH-carbazole, 4Η-gorcoal, 6Η-1,2,5-ρ2, acridinyl, aziridine, benzimidazolyl, benzene And furyl, benzothiofuranyl, benzothiophenyl 'benzoxazolyl, benzopyrazolyl, benzotriazolyl, benzotetrazolyl, stupid isoxazolyl, benzo Isothiazolyl, benzoimidazolone, aryl, 4aH-fazolyl, /5-carbolinyl, fluorenyl, nonenyl, porphyrin, decahydrol-yl '211, 611-1, 5,2-dithia, well base, dihydropyrano[2,3-1)]tetrahydroc-butanyl, fluorenyl, furazinyl, tetrahydroimidazolyl, dihydromitomyl, imipenyl , carbazolyl, decenyl, indanyl, quinone, indenyl, isobenzofuranyl, isodecyl, isoxazolyl, isoindolyl, isodecyl, Isoquinolyl (benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, acridinyl, octafluoroisoquinolinyl, oxadiazolyl, 1,2,3-indole Diazolyl, 1,2,4-11 diazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, tetrahydrocarbazolyl, dithiol, tetrahydrogen P-based base, morphine, morphine, lining, morphine, 95318 • 88 · 1354664 lining, morphine, phenoxy sulphate, porphyrin, glutinous Plough, hexahydropyridinyl, hexahydropyridyl, acridinyl, hexahydropyridinyl, 4-6 hexa-p-bit, cytosolic, sulfhydryl, p-decyl, 峨p well Base, tetrahydrogen? Bispy, dihydroP, sulfhydryl, P, squaring, tower 11, well, p, bite, bite, bite, taste, blown H plug, P ratio, I» ratio bite, Shouting: base, tetrahydrop-bihaki, dihydropyrrolyl, pyrrolyl, quinazolinyl, porphyrinyl, 4H-quinoline, quinoline, P-King, Yelin, IV Hydrogen thiol, tetrahydroiso"» quinolyl, tetrahydroporphyrin, 6H-1, 2,5-peak diplough, 1,2,3-oxadiazolyl, 1,2,4- Farodiazole φ group, 1,2,5-thiadiazolyl, 1,3,4-oxadioxalyl, fluorenyl, pyrazolyl, pyrenyl, porphinyl, pyridinium Azyl, thiophenazolidinyl, thiophenyl, tri-cultivation, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl 1, 1,3 - Triazolyl, tetrasyl and fluorenyl. In another aspect of the invention, a heterocyclic ring includes, but is not limited to, a decyl group, a thiophenyl group, a fluorenyl group, a hydrazino group, a benzoheptene group, a benzopyrylene group, a benzophenyl group, Benzofuranyl, benzoxyl, benzoisoxazolyl, quinolyl, isoindolyl, imidazolyl, indolyl, isodecyl, hexahydropyridyl, hexahydropyridone Base, 4_hexahydropyridinone, sunflower base, lubibutyl, 1,2,4-dijunyl, iota, 2,3-trisyl, tetrasyl, η siraki, oxime And pyridinyl and pyrimidinyl also include fused rings and spiro compounds containing, for example, the above heterocyclic ring. Examples of heteroaryl groups are 1 Η carbazole, hydrazine, cation-1, 5,2 bis thiomorphyl, choline thiol, 4aH. carbazole, 4 Η 峻 耕 、, 阳-丨. ·pyrimidinyl, acridinyl, a = octadecyl, stupid and milanosyl, benzoheptyl, benzothiofuranyl, abbreviated thiophenyl, benzoxanthyl, benzene And far-opening, benzotrimyl, benzotetrathyl, benzoiso W, benzohetero, benzopyrene, succinyl (4), 95318 • 89- 1354664 oxazolyl, 4aH-carbazolyl, tablets Porphyrin, indenyl, nonenyl, decyl, decahydroquinolinyl, 2H, 6H-1,5,2-diindole, dihydrofuro[2,3-7]tetrahydrofuran, cumin Phenyl, p-hydrocarbyl, tetrahydroimidin, dihydromithiol, imizeryl, carbazolyl, decenyl, indanyl, hydrazine, sulfhydryl, isobenzopyrene Cyclol, isodentyl, isoindolyl, isoindole, isodecyl, isoquinolinyl (benzimidazolyl), isoxazolyl, isoxazolyl, morpholinyl, Acridinyl, argon-isoisoquinolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1 , 3,4-« oxadiazolyl, tetrahydrocarbazolyl, oxime, tetrahydropyryl pg aryl, morphine, clock, lining, bell whistle, cultivating Pyrimidinyl, phenoxythiol alkenyl, porphyrin, argon, hexahydropyrryl, hexahydropyridyl, acridinyl, hexahydropyridinyl, 4-hexahydro-11 Base, noise base, sulfhydryl group, I»chenyl group, P-hv group, tetrahydro-p-butyl group, dihydro-P-pyryl group, p-square base, tower tillage base, p-precipitate Sodium, pyridoxine, pyridazole, pyridyl, pyridyl, pyrimidinyl, tetrahydropyranyl, dihydropyrrolyl, pyrrolyl, quinazolinyl, porphyrinyl, 4H-morphinyl, Quinolinyl, acenaphthyl, leaf beta-linyl, tetrahydrofuranyl, tetrahydroisoquino-p-linyl, tetrahydroquinolyl, 6H-1,2,5-pyrimidine, 1, 2,3-soulodiazolyl, 1,2,4-distazazolyl, 1,2,5-«&gt;soxadiazolyl, 1,3,4-oxooxazolyl, thiol, pyrimidine Azolyl, porphinyl, pyrenopyrazolyl, cumenazozolyl, porphinyl imidazolyl, thiophenyl, tri-farming, 1,2,3-triazolyl, 1,2,4-triazole Base, 1,2,5-triazolyl, 1,3,4-triazolyl, tetrazolyl and fluorenyl. In another aspect of the invention, examples of heteroaryl are fluorenyl, benzimidazole Benzofuran , benzothiofuranyl, benzo-11, benzopyrazole, benzotriazolyl, benzotetrazolyl, benzoiso-B, benzoxazolyl, benzo Imidazolidinone, porphyrin, furyl, 95318 -90- 1354664 mito, μ decyl, fluorenyl, iso-p-quine, iso-p-thenyl, isoindolyl, carbazolyl, Pyridinyl, pyrazolyl, hydrazine, pyridyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, porphyrinyl, thiazolyl, porphinyl and tetradecyl. The wording "circular acetal" used in this article or when two variables &quot;joined to form a cyclic acetal, means the substituent ·OfH^O... used in this article "Pharmaceutically acceptable" means the compounds, substances, compositions and/or dosage forms which are suitable for safe and reliable medical judgment and which are suitable for use in contact with human and animal tissues without excessive Toxic, irritating, allergic reactions or other problems or complications are accompanied by a reasonable benefit/risk ratio. By reference is made to a derivative of a &quot;pharmaceutically acceptable salt as used herein, wherein the parent compound is modified by the manufacture of its acid or base salt. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; acidic residues such as bases or organic salts of carboxylic acids, and the like. The pharmaceutically acceptable salts 'include, for example, the conventional non-toxic salts or quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrogen acid, hydrogen/o-acid, sulfuric acid, aminosulfonic acid, phosphoric acid, nitric acid, and the like, and salts derived from organic acids, such as Acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, hydroxamic acid, cis-sebacic acid, hydroxy-cis-conoic acid, phenylacetic acid, bran ^ Acid, benzoic acid, salicylic acid, sulfamic acid '2-acetoxybenzoic acid, anti-butene dihydrogen acid, toluenesulfonic acid, methanesulfonic acid, ethane disulfonic acid, oxalic acid, 95318 91· 1354664 et al. The pharmaceutically acceptable pharmaceutically acceptable salt of the present invention can be derived from a parent compound containing a basic or acidic moiety, by chemical methods. In general, such salts can be obtained by subjecting such compounds + 6 , "physical &lt; free acid or base forms with chemically appropriate tests or acids, in water, in the presence of a scorpion or in an organic solvent, or in It is preferred that the mixture of the two is reacted; one, .., A^u, and a non-aqueous medium such as ether, ethyl acetate from 0, ethanol, isopropanol or acetonitrile.豸当盐的清单 can refer to ^«_成成药存学第第! 7th edition, Inspection Publishing Company ^ 2 PAU985, page 1418, the disclosure of which is hereby incorporated by reference. Since the prodrug is known to enhance many of the desired pharmaceutical qualities (eg, solubility, bioavailability, system, etc.), the compounds of the invention may be delivered as prodrugs, and the present invention is intended to encompass the present Compound I prodrugs are claimed, methods of delivery thereof, and compositions containing the same. &quot;Prodrugs&quot; are intended to include any covalently bonded carrier which, when administered to a mammalian patient, releases the active parent drug of the present invention in vivo. By making modifications to the functional groups present in the compound in such a way as to cause such modifications, whether in routine operation or in vivo, to split into the parent compound. Prodrugs include the compounds of the invention 'hydroxyl The amine or thiol group is bonded to any guanidine. When the prodrug of the present invention is administered to a mammalian patient, it will be cleaved to form a free radical, a free amine or a free hydrogen. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the invention. Stabilizing compounds &quot;and&quot;stable structure&quot; Represents a compound whose 95318-92-1354664 is sufficiently robust to survive from the reaction mixture, is isolated to useful purity, and formulated into an effective therapeutic agent. The present invention is intended to be embodied &quot;Therapeutically effective amount&quot; is intended to include the amount of the compound of the invention alone, or the combination of the claimed compounds, or the amount of the compound of the invention in combination with other active ingredients, which is effective to inhibit MCP-1 or Effective treatment or prevention of inflammatory conditions. The "treatment" or "treatment" used in this article covers the treatment of disease states in mammals, especially in humans, and includes: (8) Prevention The disease state occurs in a mammal, particularly when such a mammal is susceptible to the disease state, but has not been diagnosed as having the disease; (9) inhibiting the disease state, meaning to curb its development; and/or (6) alleviating the disease State, meaning to cause deterioration of the disease state. Synthesis of the compounds of the present invention can be prepared in a variety of ways well known to those skilled in the art of organic synthesis. The compounds of the present invention can be used as described below, as well as synthetic methods known in synthetic organic chemistry. Or synthesizing as it is described in the artisan. Preferred methods include, but are not limited to, those described below All references cited herein are hereby incorporated by reference in their entirety in their entireties in the entireties in the the the the the the the the the the the the the It is carried out in a solvent and is suitable for achieving the conversion. Moreover, in the description of the synthesis method described below, it should be understood that 'all proposed reaction conditions, including solvent, reaction atmosphere, reaction temperature' during the experiment period and the choice of processing procedure , have been selected as the conditions for the reaction standard of 95318 1354664 'It should be easy to be familiar with this artist's understanding 1 Please organic synthesis experts should be clear that there are functional groups on different parts of this molecule: must be The limitations of the proposed reagents and reactions compatible with the substituents compatible with the reaction strips are immediately apparent to those skilled in the art, and an alternative method must then be used. This sometimes requires judging whether to modify the order of the synthetic steps, or selecting a particular process plan that is better than the other to obtain the desired compound of the invention. It should also be understood that another major consideration in designing any synthetic route in the art is the judicious choice for protecting the protecting groups of reactive functional groups present in the compounds of the present invention. The authoritative report describing many alternatives to trained performers is Greene and Wuts (also reduced by 4, Wiley &amp; s〇ns, 1999). The chemical cytokine antagonist can be derived from the formula u compound as shown in Figure -6, and the synthesis of the compound of formula 1.1 is depicted in Figure 7 and the accompanying text. A compound of formula 1.5 which contains four members of the indoleamine, as shown in formula i, is derived from a compound of formula 1.1. Removal of protection, coupling with known peptides of serine derivative 1.2 and cyclization under Mits〇n〇bu conditions (see GM Salituro and CA Townsend J./wC/zem. Soc. 1990, &quot;2, 760-770), which provides the removal of the indoleamine Μ β 〇χ protecting group from the urethane U (see GM Sahturo and CA Townsend·/·. eg. aem. 1990, //2, 760-770), A primary amine is provided which can be conjugated in a variety of ways known to those skilled in the art (see also Figure 4 and the accompanying text). 95318 •94- 1354664 Figure 1

The compound of formula 2.4, which contains five members of the indoleamine, is synthesized as shown in Scheme 2. Acid-mediated Boc removal, coupled with known peptides of methionine derivative 2.1 'sulfanylation and intramolecular guanamine alkylation under basic conditions (also using NaH, see Freidinger Et al, / sigh. c / i hunger 1982, 47, 104), from the urethane 1.1 provides r · indoleamine 2.3. Removal of the protecting group provides a primary amine which can be conjugated in a variety of ways known to those skilled in the art (see also Figure 4 and the accompanying text). Figure 2 1) H2, Pd/c 2) 2.11 HATU NHCbz - APr2NEt CH2CH2SMe

2.2 r1v^

R R5 2.4 H〇Y^NHCbz 0 2.1 NHCbz

2.3 A hydrazine compound of the formula containing a six-membered indoleamine as shown in Figure 3 is synthesized as a synthesis of 95318-95·1354664 acid-mediated B〇c removal with known reductive amination of glutamic acid derivative 31 Effect (X. Zhang, W. Han, WO PCT 0164678 '2001), ester hydrolysis and intermolecular guanamine formation from the urethane U to provide 5 _ indoleamine 3·3. The removal of the protecting group provides a primary amine which can be conjugated in a variety of ways known to those skilled in the art (see also Figure 4 and the accompanying text). Figure 3

The indoleamine of formula 4.1 can be prepared from compounds such as l4, 23 and 丄3 (removal protection and selective reductive amination to install r8) ^41 variant with Rl 〇 substituent can be synthesized analogously as shown in Scheme 1-3 It is only made by substituting the starting material substituted by the appropriate R1 〇. Derivatization of the guanamines can be accomplished by a variety of conventional methods to form chemical cytokine receptor antagonists; some of these methods are shown in Scheme 4. Thus, the indole bond formation gives 4.2 compound, the reductive amination results in compound 4.3, and the reaction with isocyanate gives compound 4.0 or the amine 4.1 can be arylated (see d. Zim &amp; SL BUChWald' From π 2003, 5, 2413, with T. Wang, DR Magnia &amp; LG

Hamann, supra, 897 and references cited therein, to give compounds 4·5 ° or amine 4.1 can be arylated with imino chloride to give 4.6. 95318 1354664 Figure 4

The combination of chemistry shown in Figures 1-4 produces a large number of chemical cytokine receptor antagonists. Conceptually related antagonists can be made using the chemistry shown in Scheme 5. Thus, the deprotection of 1.1 and the reductive amination of aldehyde 5.1 (derived from deuteration by dissociation and ozonolysis, derived from dinonyl malonate) afforded compound 5.2 which can be cyclized to 5.3 with a base. The hydrolysis of this methyl ester provides an acid which can be coupled to an amine and which is of interest to us, having the formula 5.4. If R2 is suitably functionalized, the compound of formula 5.4 can be cyclized to obtain a heterocyclic ring of formula 5.5 (K. Takeuchi et al. oorg. Mei/. CAew. Zeii. 2000 2347, G. Nawwar et al. C&lt;;?//eci. CzecA. CAew. Cctwwmw. 1995, 2200 ; T. Hisano et al. Oiem. P/iarm· 1982, 2996) 〇 Other heterocycles (see Equation 5·6) can be learned by those skilled in the art Known methods are prepared from compounds of formula 5.4 (see 95318 • 97· 1354664 T. L. Gilchrist, Heterocyclic Chemistry, Longman Science &amp; Technology, 1985). Figure 5 R5

B V—NHCbz 1.1 1) H2f Pd/C 2) 5.1, MeOH NaCNBMs ^L)n Me02C into C02Me 5.1

Catalyst NaOMe MeOH, heated

Lewis or Browns acid: heating to functionalize R2 1. aq. UOH 2. HATU, DIEA r5 h2nr2

CO2M6

R7

Other chemistries can make conceptually related chemical cytokine antagonists. For example, as shown in Scheme 6, the compound of formula 1.1 is readily removable and conjugated to the compound of formula 6.1 in decyl alcohol via 1,4-addition. The ketone 6.2 formed can be homologated to 6.3 (isolated via chromatography), which is subsequently deprotected and cyclized to give the compound of formula 6.4 of interest to us. 95318 •98· Figure 6

Under the chemistry described above in Schemes 1-6, only the synthesis of the compound of Formula 1.1 is left as desired. The compound of formula 1.1 can often be derived in a customary manner from commercially available cyclic amines (Note: although the amine of formula 1.1 is shown to have Cbz protection' but it can be substituted for a protecting group or synthesized in an unprotected form; In this case, only minor corrections of chemical patterns 1 and 2 are required). In other cases, which are shown in Figure 7, are readily derived from commercially available ketones of the formula 7.1. These ketones can be alpha-functionalized (as fully described in the synthetic literature; this alternative to alkylation is available) to give compounds of formula 7.2. In some cases (Ε1 = halide, hydroxyl or azide), these compounds can be further elaborated (by nucleophilic or electrophilic substitution chemistry, where necessary, depending on the protecting group), A compound of formula 7.3 is obtained which can be converted by reductive amination and protection (see above) to give a compound of formula 7.4 (a variant of 1.1). If R1 is a carbon-linked linking group, a suitable method for the synthesis of the compound shows a selective conversion of 7.2 (El = C02 R) to 7.6 via the enamine 7.5 (C. Cimarelli et al., J. Org. Chem 1996, 61, 5557, and Y. Hayashi et al, J. Am. Chem. Soc_ 95318 -99-1354664 1996, / 5502). Delicate completion of 7.4 (derivatives of formula U) can be carried out directly from 7.6 or via the initial epimerization to 7.7. Figure 7

1) Test 2) Electrophile 7.1

Crafted _ as needed For EHr, OH 舆 N3

For 曰:cop

1. NH4CI; NaHB(〇Ac)3

2. CbzCI, R3N

H^NHCbZ 7.4

7.6 Crafted as needed

7.7 Other methods for the synthesis of 1,2-diaminocarbo- and heterocyclic rings (see R. Chemey WO-PCT 02/060859), and the synthesis of 2-aminocycloalkanecarboxylic acids, do exist (reviewed by Ference Fulop, CAem. 2001, Chuanren 2181; see also J. Duan et al. WO-01/70673 and Soo S. Ko et al. WO-02/02525). In particular, 2-aminocycloalkanecarboxylic acids (and their heterocyclic variants) are susceptible precursors of the compound of formula 1.1 because the carboxylic acid can undergo addition reactions, guanamine formation, Wittig extension, reduction Derivatization with an alcohol, reduction followed by reductive amination, Curtius rearrangement, etc., is evolved into a plurality of R1 groups. In the case where the cycloalkyl group contains a pendant olefin, the carboxylic acid can also be used to exchange stereochemical information and allow for further functionalization of the ring to provide stereoselective mounting of R5. This is 95318 -100- 1354664 T-like! The description is in the literature (F_F, c-一, text: 朿略 <special examples are described in the example paragraphs (see below, and the other law is accompanied by the important events of the pattern 7 towel - from the beginning, it is easy to see Yes, a large number of compounds of the formula 1.1 can be synthesized. Other features of the present invention will be described in the following description of the specific embodiments, and the description of the present invention is given, and is not intended to be a limitation thereof. It is also indicated that 'otherwise the reaction can be assumed to be in an inert atmosphere or domain. The abbreviations used in the examples are defined as follows: &quot;1X&quot; is a y'2x&quot; for two times &quot;3χ&quot; ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, ML, "lH&quot; is proton, &quot;h" is one hour or several hours, "M" is the molar concentration, w is - minutes or minutes, &quot;MHz&quot; is megahertz, &quot;MS&quot; for quality Spectrum, &quot;nmr&quot; for NMR light Spectroscopy, &quot;rt&quot; is room temperature, &quot;dc&quot; is thin layer chromatography, &quot;v/v&quot; is volume to volume ratio. &quot;〆, &quot;点&quot;,&quot;R&quot; and S" is a familiar term for the stereochemistry familiar to the artist. &quot;RP-HPLC&quot; refers to reverse phase high performance liquid chromatography. The chromatographic method is typically not specified, as many different methods are equally well performed. Typically, it is eluted with a gradient of acid-doped MeOH/water or acid-doped acetonitrile/water. The product is often obtained as an acid salt after RP-HPLC; if desired, the parent free base can be It is derivatized by dissolving in an aqueous base and extracted with an organic solvent, as is apparent to those skilled in the art. The chemical name was derived using ChemDmw Ultra version 8.0.8 (May 2004). When this program fails to discuss 95318 -101 · When a name is provided for a precise structure, the appropriate name is prepared by the same method as that used in the program. Preparation of a non-standard 丨盥 丨盥 synthesis intermediate prepared by the procedure A1: Benzyloxycarbonylamino J7-ketone Base_6_nitrogen-bicyclic oxime 3.21]octane·6_acid Synthesis of tri-butyl ester ΜΑ Α 1 Step 1: Prior to the addition of triethylamine (43.4 g), (1S,2R)-cis-2-methoxycarbonyl-cyclohex-4-en-1-carboxylic acid (66.0 Gram, see Bolm et al. / C/zew. 2000, 仏 6984-6991) dissolved in anhydrous acetone (815 ml). The solution was cooled to 0 ° C and ethyl chloroformate (46.7 g) was added. The resulting solution was stirred for 1 hour before the addition of NaN3 (35.0 g). The cooling bath was removed and the reaction allowed to warm to rt overnight. All solid matter was removed by filtration and the solution was partially concentrated. Water was slowly added and the organic layer was separated. The aqueous layer was extracted with acid. The combined organic layers were washed with water and brine then dried, filtered and concentrated. The oil formed (66.1 g) was dissolved in benzene (800 mL) and warmed to warm reflux. After 4 hours, the solution was allowed to cool to room temperature. Decanol (37.5 g) and p-TsOH (1.5 g) were added and the solution was warmed to warmness to reflux overnight. After cooling to room temperature, the reaction was washed with NaHCO.sub.3 and brine, dried, filtered, and concentrated to give &lt;RTIgt; MS found: (M+H)+ = 290.2. Preparation A1 Step 2: (lR,6S)-6-oxocarbonylamine before adding NaOH (25.3 g) in water (95 ml) dropwise. A benzyl-cyclohexan-3-indole tasting sample (91.4 g) was dissolved in MeOH (500 mL). After 3 hours, the solution was partially concentrated, and the Et20/water mixture was added. The aqueous layer was separated and acidified with concentrated HCl (pH ~ 2). The resulting mixture was extracted with KOAc. The combined organic layers were washed with water and brine, 95318 - 102 - 1354664, then dehydrated, filtered, and concentrated to afford (1R, 6S &gt;6-; oxycarbonylamino-cyclohex-3-enecarboxylic acid (72.7 g). MS found: (M+H) + = 276.2. Preparation A1 Step 3: Before adding CDI (50.9 g), (lR^SM-benzyloxycarboxyamino-cyclohex-3- The carboxylic acid sample (72 g) was dissolved in CH2C12 (750 ml). After 2 hours, water was added and the solution was extracted with CH2C12. The combined organic layers were dried, filtered, and concentrated. Dissolved in CH2C12, and foamed ammonia through the solution for 1.5 hours. After stirring overnight, 'remove most of the solvent and add Et2 Ο. The product precipitated as a white solid and was collected to obtain (lR, 6S)-6-Aminomercapto-cyclohexan-3-indolyl)-amine methyl benzyl ester (61.5 g). MS found: (M+H)+= 275.3. Preparation A1 Step 4: (1) 63)-6-Aminomethylamido-cyclohex-3-enyl)-amine methyl benzylate (30.7 g) was dissolved in THF (1100 mL) and NMP (220 mL). 2.3Mn-BuLi (96.3 ml) was added dropwise at -78 °C. After 2 hours, a solution of Boc20 (24.4 g) in THF (4 mL) was applied dropwise. This solution was stirred for 1.2 hours before quenching the reaction with a saturated NH4C1 solution. Add water and Et2 Ο. The organic layer was filtered, washed with water and brine, dried over water, filtered and concentrated. The residue thus formed was subjected to flash chromatography to give (1R,6S)-(6-tris-butoxycarbonylaminocarbonyl-cyclohexane-3-indolyl)-amine methyl decanoate (29.2 g) . MS found: (M+Na)+= 397.4. Preparation A1 Step 5: (lR^S)%-tris-butoxycarbonyl-aminocarbonyl-cyclohex-3-enyl)-amine methyl acid A decyl ester sample (29.0 g) was dissolved in THF (1290 mL). It was allowed to cool in an ice/brine bath before adding n-BuLi (1.5 mL, 2.4 M). After 30 minutes, iodine (59.0 g) was added in one portion. The bath was removed and the reaction allowed to warm to rt overnight. The resulting solution 95318 • 103 - 1354664 was quenched with a saturated thiosulfate solution. Water and EtOAc were added. The organic layer was washed with water, brine, dried and dried filtered & evaporated. The resulting slurry was diluted with Ε^Ο and collected by vacuum filtration (111,28,43,5-2-benzyloxycarbonylamino)iodo-7- keto-6-nitro-bicyclo[3.2. 1] Octane- 6-carboxylic acid tert-butyl ester (22.8 g). MS found: (M-C5H8 〇2+H)+ = 401.1. 簠AAUlMAL was added with Bu3SnH (27_8 g) and AIBN (0.7 g) Before (), (111,28,48,511)-2-Ethyloxyl-4-mothyl-7-keto-6-nitro-bicycloindole.2·1]octane-6-carboxylic acid A third-butyl ester sample (43.3 g) was dissolved in benzene (580 ml). The resulting mixture was allowed to warm to a gentle reflux over 3 h. After cooling, solvent was removed and hexane was added. The title compound (lR, 2S, 5R)-2-benzyloxycarbonylamino-7-keto-6-nitro-bicyclo[3.2.1]octane-6-carboxyl Acidic third-butyl ester (29.5 g). MS found: (M+Na) += 397.4. Preparation A2: 7· keto-6-oxo-bicyclo[3.2.1]oct-2-yl)- Synthesis of the amine methyl decanoate The title compound is the method using Suga (H. Suga et al., / J/n. C/iem. *Soc. 1994, /M, 11197-98), from known 1S, 2R -cis 2-methoxycarbonylcyclohex-4-ene-1-carboxylic acid (see: Bolm et al., Og. CAem. 2000, (55, 6984-6991). Preparation A3: (lR, 2S, 5R) )-2-((S)-3-(indolylcarbonylamino)-2-ketotetrahydropyrrole small)-7-keto-6-nitro-bicyclo[3.2.1]octane-6 -Synthesis of a carboxylic acid tert-butyl ester A3 Step 1 : (lR,2S,5R)-2-benzyloxycarbonylamino-7-keto-6-nitro-bicyclic in MeOH (30 mL) And [3.2.1] Octane-6-carboxylic acid tri-butyl ester (4.0 g), 10% Pd/C Degussa (600 mg) was added. The reaction flask was evacuated and then counter-filled with hydrogen; The reaction was repeated three more times. The reaction was stirred at 1 atm H2 under a gas chromatogram of 95318 -104 - 1354664 for 3 hours, followed by filtration and concentration to provide (1R,2S,5R)-2-amino-7-keto-6-nitrogen - Bicyclo[3.2.1] octane 6 butyl acid (25 g). MS (ES+) = 241.1 (M+H)+. 盘_备A3 Step 2: Add N-Cbz Methionine (5.3 g), 4-mercaptoprene (3.7 g) and BOP (8.3 g) before 'make (1Ri2S 5R)_2_amino-7-keto-6_nitrogen_bicyclo And [3.2.1] Octane-6-carboxylic acid tri-butyl ester solution (25 g) dissolved in DMF (34 ml ) and cooled to 〇 °C. The reaction was stirred at room temperature for 12 h then partitioned between EtOAc and 1NCI. The combined organic phases were washed with saturated NaHC(R) and brine, dried, filtered, and concentrated in EtOAc. The residue was purified by flash chromatography to give (1Rj2s, 5R)·············· Base 7-keto-6-nitro-bicyclo[3.2.1]octanecarboxylate (5.1 g). MS found: (M+H)+= 506.2. Preparation A3 Step 3: (lR,2S,5R)-2-((S)-2-(word oxyalkylamino)-4-(sulfonium sulphide) Butylamino)-7--yl-6-nitro-bicyclo[3.2.1]octane-6-carboxylic acid tert-butyl ester (5.1 g) was dissolved in methyl iodide (40 mL). The resulting solution was stirred at room temperature for 12 hours and then concentrated in vacuo. The residue was dissolved in dichloromethane and the resulting solution was concentrated; this was repeated to give a salt. This material was dissolved in DMF (30 mL) and Cs2C03 (6-6 g) was added to the solution. After 12 hours, the reaction was partitioned between EtOAc and brine. The organic phase was dried (MgS 4), filtered, and concentrated. The resulting residue was purified by flash chromatography to give (l,,,,,,,,,,,,,,,, 1-yl)-7-from the same group 6-nitro-bicyclo[3.2.1]octyl-6-acid acid third-butyl vinegar (2. gram). MS measured value: (M+H) + = 458.6. 95318 • 105· 1354664 Preparation of B1: Synthesis of 2-(3-ethylureido)-5-(trifluoromethyl)benzoic acid B1 Step 1: "吏N-Boc 2_Amino-5 -(Trifluoromethyl)benzoic acid (S. Takagishi et al., „/故1992, 36〇; 5 克, 17 mmol) dissolved in DMp (42 liters) and added in solution 3-bromopropanone (3.8 ml, 44 mmol) with potassium carbonate (3.4 g, 25 mmol). The slurry was stirred at room temperature for 14 hrs, diluted with EtOAc and continuously with brine, water and brine. Washing. Dehydration of the organic phase (Naz SO*), filtration, and concentration in vacuo to afford EtOAc as a white solid. &lt; Stir in TFA (15 ml) and at room temperature for 2 hours. The residue was dissolved in dichloromethane. The solution was concentrated in vacuo; this procedure was repeated twice to provide the hypothetical tfa salt of 2-amino-5-(trimmethyl)benzoic acid allylic acid. MS found: (free state m+H)+= 246.29. Preparation step B1 Step 2: The 2-amino-5-(trifluoromethyl)benzoic acid allyl ester from step 1 (about 15.7 mmol) was dissolved in THF (60 mL) and Under 〇〇c, phosgene (24.9 ml, 47 mmol) was added dropwise. The reaction was stirred at 〇 °c for 15 min. triethylamine (13.1 mL, 94 mmol) was slowly added and continued. Stirred for 2 hours. The reaction was concentrated in vacuo to give a white solid. </RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Amine (20 ml of a 2.0 Μ solution in THF). The reaction was stirred at room temperature for 14 h then diluted with EtOAc. The organic phase was washed successively with INHC1 (2x) and brine (1x) 〇4), EtOAc, EtOAc (EtOAc m. M+Na)+=339.29. Pan preparation B1 Step 3: Make 2-(3-ethyl-yl)-5-(trifluoromethyl)benzoic acid propyl propyl ester 95318 -106· 1354664 (1·8 g' Approximately 5.7 millimoles) is dissolved in B. (5 liters). In solution, add tetrahydrogen 14 (1. mM, 12 mM mph (pph3) 4 (i4 〇 mg (four) millimolar)' It was then stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was diluted with EtOAc and washed successively with EtOAc &lt;RTI ID=0.0&gt;&gt; The residue was triturated with m to give pure 2. (3·ethylethyl)·5-(trifluoromethyl)benzene f^(0.89^) 〇1H-NMR (3 〇〇MHz, d4-MeOH): d 8.59 (d, 1 H, J-9.6 Hz), 8.26 (d, 1 H, J=1.5 Hz), 7.72 (dd, 1H, J=9.2, 1.8 Hz), 3.23 (q, 2H, J=7.3 Hz) ), 1.17 (t, 3H, J = 7.2 Hz). Preparation B2: Synthesis of 2-(isopropylureido)-5-(trifluoromethyl)benzoic acid according to the complete three-step procedure described in Preparation B1, The ethylamine in step 2 was replaced with isopropylamine to afford the title compound. Ms measured value: as prepared by the preparation of ruthenium: 2-(mononitrogen tetra--1 cytosineamino)-5-(trifluoromethyl)benzoic acid according to the complete three-step procedure described in Preparation B1 Substituting the ethylamine in step 2 with a nitrous tetrafluorene to provide the title compound: MS found: (MH)· = 287. Preparation B4: 2_(cyclopropylureido)_5•(trifluoromethyl)benzoquinone Synthesis of the acid Following the complete three-step procedure described in Preparation B1, the ethylamine in Step 2 was replaced with cyclopropylamine to afford the title compound. iHNMR (3〇〇MHzCD3〇D) δ 8.56 (d, J=9.8 Hz, 1H), 8.32 (s, 1H), 7.59 (d, J=9.8 Hz, 1H), 2.62-2.61 (m, 1H), </ RTI> <RTIgt; Synthesis of benzoic acid Β5 # @ 1 丄 in 4-(trifluoromethyl)aniline (1 gram, 〇〇617 mole) in a solution of methanol (200 ml) at room temperature Single gasified iodine (1 〇 49 g, 〇 148 mol) in anhydrous MDC (40 mL) was slowly added. The reaction mixture 95318 - 107 - 1354664 was stirred at room temperature overnight. The reaction mixture was concentrated, water was added, and ethyl acetate (2. The organic layer was washed with water, brine (2············ The crude product was purified by column chromatography eluting with EtOAc EtOAc EtOAc (EtOAc) iHNMR (4 〇〇 MHz, CDC13) δ 4.42 (bs, 2H), 6.75 (d, 1H), 7.38 (d, 1H), 7.87 (s, 1H). Compound B5 Step 2: 2-iodo- 4-(Trifluoromethyl)aniline (ii.o gram, 〇·〇382 莫)' 〃 pyridine (40 ml), chlorinated methane sulfonate (5 3 g, 〇〇46 mol) and DMAp ( 0.46 g '0.0038 mol) of the mixture in a 100 ml rb flask was slowly heated to 105 C' and kept at the same temperature overnight. The reaction mixture was concentrated to remove acridine. The obtained crude product was purified by column chromatography using 10% ethyl acetate in petroleum ether as a solvent to obtain N_(2_bromo-4-(trifluoromethyl)phenyl)methanesulfonamide (4.5 g '32%), a white solid? iHNMR (400MHz, CDCI3) δ 3.08 (s, 3H), 6.88 (bs, 1H), 7.65 (d, 1H), 7.75 (d, 1H), 8.07 (s, 1H). Preparation B5 Step 3: On N- a mixture of (2-iodo-4-(trifluoromethyl)phenyl)decanesulfonamide (3_5 g, 9.589 mmol), anhydrous methanol (3 mL), DMF (30 mL) At room temperature, add acetic acid (Π) (〇.〇7 g, 0.35 mmol), 1,1-bis(diphenylphosphine) dicyclopentadienyl iron (〇·32 g, 0.577 mmol) And TEA (1.96 grams, 19_4 millimoles). The reaction mixture was degassed with carbon monoxide for 30 minutes at room temperature. The reaction mixture was slowly heated to 6 ° C and kept at the same temperature overnight under a carbon monoxide atmosphere. Water was added and the reaction mixture was extracted with ethyl acetate (3×50 mL). The organic layer was washed with brine, dried (Na2SO4) and concentrated. The crude product was purified by column chromatography eluting with 15% ethyl acetate in petroleum ether to afford 2-(methylsulfonamide 95318-108-1354664)-5-(trifluoromethyl)benzene. Methyl formate (2_0 g, 70%) was obtained as a white solid. 1H NMR (400 MHz, CDC13) 5 3.14 (s, 3H), 3.99 (s, 3H), 7.78 (d, 1H), 7.87 (d, 1H), 8.34 (s, 1H), 10.75 (bs, 1H) Preparation B5 Step 4: Methyl 2-(decylsulfonylamino)-5-(trifluoromethyl)benzoate (1.0 g, 3.367 mmol) in THF (20 mL) with water (20 mL Lithium hydroxide (0.4242 g, 10.10 mmol) was added to the mixture, and stirred at room temperature for 6 hours. The reaction mixture was acidified with EtOAc (EtOAc) (EtOAc) The organic layer was washed with water, brine, dried (Na2SO4) and concentrated. The solid was filtered and dried <RTI ID=0.0></RTI> in vacuo to give 2-(methanesulfonylamino)-5-(trifluoromethyl)benzoic acid (7 g, 73%) as a white solid. 1 H NMR (400 MHz, CDC13 ) (5 3.31 (s, 3 Η), 7.78 (d, 1 Η), 7.97 (d, 1 Η), 8.24 (s, 1H), 11.13 (bs, 1H); 13 C NMR ( 100 MHz, CDC13) δ 40.74, 116.5, 118.3, 122.8 (m), 128.8, 131.6, 144.3, 169.1. LC-MS [C9 H8 F3 N04 SH] 282. Preparation of B6: 5-(trifluoromethyl)-2 Synthesis of -(trifluoromethylsulfonylamino)benzoic acid B6 Step 1: In a solution of 4-trifluoromethylaniline (5 g, 0,031 mol) in 50 ml of anhydrous benzene in hydrazine. Next, triethylamine (6.26 g, 8.63 Ί: liter '0.06 mol) was added. Trimethyl acetyl chloride (4.5 g, 〇. 〇 4 mol) was slowly added, and stirred at room temperature overnight. The reaction mixture was quenched with EtOAc (EtOAc)EtOAc. _ Trimercaptoacetamide (6.7 g) as a white solid. Compound B6 Step 2: N-(4-(trifluoromethyl)phenyl)trimethylacetamide, 4,08 mmol [ears] in a solution of 2 ml of anhydrous THF, add n-butyl under nitrogen and 〇ec (Square · 65 g '4_1 mL). The reaction mixture was maintained at 95318 • 109 - 1354664 at 0 ° C for 3 hours and added to dry ice and stirred at room temperature overnight. The reaction mixture was concentrated, and the obtained solid product was dissolved in 25 ml of anhydrous methanol, and HCl gas was purged for 30 minutes at 〇 ° C. The mixture was stirred at room temperature for 2 hours and heated at 55 ° C. overnight. The reaction mixture was concentrated, basified with sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with water and brine and concentrated. The crude product was purified by flash chromatography eluting elut elut elut Preparation B6 Step 3: Methyl 2-amino-5-(trifluoromethyl)benzoate (0·25 g, 1.141 mmol) and triethylamine (0.115 g, 0-16 mL, 1.14 mmol) Trifluoromethanesulfonic anhydride (0.64 g, 2.28 mmol) was added at -78 °C in a solution of 3 mL of dry dichloromethane. The mixture was kept at -40X: for 3 hours and stirred at room temperature overnight. Water was added and extracted with methylene chloride. The organic layer was dehydrated and concentrated. The product was purified by flash chromatography eluting to afford crystals (yield: (30%) of (55%) of 5-(trifluoromethyl)-2-(trifluoromethylphenylamino)benzoic acid as a white solid. MS found: (M+H)+ = 352. Preparation B6 Step 4: decyl 5-(trifluoromethyl)-2-(trifluoromethylsulfonylamino)benzoate (2.7 g, 7.7 m In a solution of 55 ml of THF, lithium hydroxide (0.97 g, 23.1 mmol) in 55 ml of water was added and stirred at room temperature overnight. The reaction mixture was acidified with 1.5N EtOAc and extracted with ethyl acetate. The organic layer was washed with water, brine, and evaporated,]]]]] iHNMR (DMSO-d6, 400 MHz) &lt;5,7 (4) 2H), 8.18 (s, 1H). MS found: (Μ-Η)· = 336. Preparation B7: 5-isopropyl-2- Synthesis of (trifluoromethylsulfonylamino)benzoic acid 95318 -110· 1354664 Substituting 4-diisopropylnonylaniline in step 1 with 4 • isopropylaniline according to the complete four-step procedure described in Preparation B6 t , providing the title compound. ΐΗ (DMSO-d6,400 MHz) ^1.19 (d, 6H), 2.92 (m, 1H), 7.37 (d, 1H), 7.47 (d, 1H), 7.77 (s,1H)· MS measured value: ah _ take = 31 〇 Preparation of Cl : 2- Third - butyl pyrimidine · 4 - carboxylic acid synthesis Preparation of Cl step · Step 1 3 - 22% solution of sodium ethoxide in ethanol (53 ml, 165 mmol) Add dropwise to a magnetically stirred suspension of tris-butylurea hydrochloride (2 g, M6 mmol) in ethanol (1 mL). When adding the finish, warm the chromatic suspension to 5 〇»c, remove the heating hood, and add the bromic acid (15·7 g, 61) at a rate that does not allow the fox to exceed 55 C. Millol) A solution in ethanol (50 ml). When this addition was completed, a 22% solution of ethanol in ethanol (32 mL, 98 mmol) was added dropwise, and then the mixture was cooled to room temperature. The suspension was filtered, and the solid was washed with ethyl acetate (2 EtOAc) and concentrated. The residue thus obtained was stirred in 2? HCl 1 solution (30 ml). The solid formed was collected by filtration, washed with ice cold water (2.times.20 mL) and air dried to give &lt;RTI ID=0.0&gt;&gt; MS (ES+) = 259, 261 (Μ+Η)+· &amp; Preparation of the C1 step with 5-bromo-2-tri-butyl-pyrimidine-4-carboxylic acid (1.65 g, 6.37 moles) Aqueous sodium hydroxide (丨〇N, 19 mL, 19 1 mmol) mixture in methanol (100 mL) was treated with a catalytic amount of 1% palladium on carbon. The mixture was degassed under vacuum / nitrogen and then hydrogenated at 50 psi for 2 hours. The methanol was removed under vacuum by removing the catalyst, and the aqueous solution was acidified by adding 1 N aqueous hydrochloric acid (4 mL). The resulting suspension was extracted with ethyl acetate (4×50 s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s The third _ butyl pyrimidine-4-carboxylic acid is a white powder. MS (ES+)=181 (M+H+) Preparation C2: Synthesis of 3-tert-butyl-benzoic acid M C2 Step 1: J吏 commercially available 3-bromo group _5_third butyl Methyl benzoate (700 mg, 2.58 mmol), aqueous Na0H (1 N, 7 75 mL, 7 75 mmol) and Peariman's catalyst (1 〇 0 mg) in methanol (2 mL) The mixture was hydrogenated at 50 psi for 22 hours. Remove the catalyst by filtration and rinse with a small amount of methanol. The filtrate was concentrated in vacuo to remove methanol and the aqueous mixture was acidified with &lt;RTI ID=0.0&gt;&gt; The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Analysis of the formed material by LC/MS showed that the ester had been hydrolyzed to the carboxylic acid, but bromide was still present. This material was dissolved in MeOH (2 mL) and hydrogenated at <RTI ID=0.0># </ RTI> </ RTI> <RTIgt; </RTI> <RTIgt; Analysis of the crude reaction mixture by LC/MS showed that bromine was still present &quot; peaflman's catalyst (2 mM) was then added and hydrogenation was continued at 50 psi for 23 hours. MS showed that the reaction was now redundant. The reaction was then taken in this example as previously described to yield 376 mg (81% yield) of white powder as product. Ms (AP-) = 177 (MH) Preparation of C3: Synthesis of 6-Third-Butylpyridinecarboxylic acid HC丨 salt: Prepare C3 Step G1: Make 2-Terve-butyl p bite (2.00 g) , 14.8 mmol, 1 eq.) was dissolved in HOAc (10 mL) and 30% hydrogen peroxide (1·6 mL '14.8 mmoles 1 eq) at room temperature, then the reaction was refluxed for 2 hrs. . The reaction was stripped to give an amber oil which was dissolved in dichloromethane (1 mL), EtOAc EtOAc EtOAc EtOAc EtOAc N-oxide (丨.60 g) is an amber oil. Yield = 71.5%. LCMS detection (M+H)+= 152.09.

[Preparation - C3 step ^ ^ 2-2-butylpyridine-N• oxide (1.6 g, 1〇6 耄 mol, 1 eq.), dissolved in dichloromethane at room temperature under nitrogen ( 25 ml), then add trimethyl decane cyanide (179 ml, 134 mmol, 127 vol.), followed by dropwise addition of dimethylamine formazan (1.24 ml, 13.4 mmol, 1.27 equivalents) ), after 3 minutes. Stir for 2 hours. Treatment was carried out by adding 1% potassium carbonate (water/cold solution) (25 ml). Foaming occurred. The mixture was stirred and then extracted three times with dichloromethane (25 mL). The organic layers were combined, dried over sodium sulfate and then evaporated to give amber oil. Purified on 3:1 hexane/hydrous acid ethyl ester on silica gel. Obtain 6_Third-Butyl-Methylpyridine Guess (1.08 g), which is a color oil. Yield = 59% LCMS detection (M+H) + = 161 14 Preparation C3 Step 3: 6-T-butylpyridylpyridonitrile (1·05 g) at room temperature at 6 N HC1 (aqueous solution), then refluxed for 2 hours. The treatment was carried out by stripping three times from acetonitrile. Obtain a solid. The solid was refluxed in 10 mL of acetonitrile. Undissolved solids were filtered off. The filtrate was stripped to obtain 6·t-butylpyridinecarboxylic acid HC1 salt (680 mg) as a colorless oil. Yield = 48% · LCMS detection (Μ + Η) + = 180.16. Preparation of C4: Synthesis of 6-(trifluoromethyl)pyridinecarboxylic acid. Preparation _C4 Step 1 • 2-bromo-6- (Trifluoromethyl)-pyridine (1 mg, 0.44 mmol) (1 eq.) was dissolved in diethyl ether at room temperature under nitrogen and then cooled to -70 C. The n-butyl group in the pit (0.28 ml, 0.44 mmol) was added dropwise via an addition funnel. Stir at -40 Torr for 15 minutes, then cool 95318 -113 · 1354664 but to -70 ° C ' and foam in C 〇 2 gas for ί ο. Allow to warm to room temperature. Water was added and then rinsed 3 times with diethyl ether. The pH of the aqueous solution was adjusted to 3» with concentrated HC1 to extract the acidic aqueous layer three times with ethyl acrylate. The ethyl acetate layers were combined, dried over sodium sulfate and stripped to give 6-(trifluoromethyl)pyridinecarboxylic acid (3 mg) as a white solid. Yield = 35% LCMS detection (m+H)+= 192.06. Preparation of C5: 3-(Goldol-11-ylpyrrole_5_Resin synthesis Preparation C5 Step 1 Pyrrole-2-carboxylic acid B Ester (2.09 g, 15 mmol, 1 equivalent) was added to a mixture of gallium chloride (111) (2 90 g, 16 5 mmol, i丨 equivalent) in carbon disulfide (40 mL) and The contents were heated at 4 Torr for 30 minutes. Then, 丨-chloroadamantane (2 82 g, 16 5 mmoles of 1.1 equivalent) was added thereto, and the contents were heated for another 40 minutes. The reaction was poured. On a mixture of ice and 1.0 N HCl, and extracted with EtOAc. EtOAc (EtOAc) Produce 2 batches of 3_(gold steel alkane small base)_峨 _5_ 酸酸乙 brew. The first batch weight = 0.67 g. The second batch weight = 1.1 gram. MS measured value: individual (M + H) += 274.44 with 274.45. M·备C5 Step 2: 3-(Golden-Silver-1-yl)-!»Bilo-5-acid acid ethyl ester (0.29 g, 11 mmol, 1 equivalent), l. 〇〇〇NNaOH (2.20 ml, 2.2 mmol, 2 equivalents) and MeOH (1 Mix 5 ml) and stir overnight. After only partial reaction, add more 1.000 N NaOH (21 mL) together with more MeOH to dissolve it' and allow the contents to reflux for 4 hours. Make contents with 1. 〇NHC1 The acidified to pH = 1. The MeOH was stripped to give a solid and aqueous solution. The mixture was extracted with Et EtOAc (the EtOAc layer was combined, washed with brine, dehydrated to dry Mgsa), and stripped to yield 250 mg of 3-(gold) Tallin-1-yl)-pyrrole-5-carboxylic acid, white powder 95318.114-1354664. MS measured value: (μ+η^·=246 44 Preparation of C6: 3-(golden alkane small base) small methylpyrrole·5•succinic acid synthesis New Zealand rainbow 1_ make 3 pass the domain · 1. base) It is easy to dissolve in acid (0 20 grams, 0.7 millimoles '丨 equivalent) in coffee (9) ml). Add bis(trimethyl)-amine (0.5 Μ in toluene, 162 ml, 〇81 mmol, u equivalent) followed by iodomethylation (0.102 ml, 16 mmol, 22 equivalents) ). The same amount of bis(trimethylsulfonyl)amine and armor-burning were added again every other day, and the driving reaction was completed. The reaction was completed within 4 hours. Add acetic acid ethyl acetate ((10) pen liter), and wash the organic layer with water (2 χ), brine, dehydrated and dried _ (five), and stripped to produce 600 mg of 3_(金钢烧基)methylpyrrolidate B The ester was used as it is in the next step. MS measured value: (M+H)+ = 288.16. 1· Prepare C6 step 2: _ By preparing the procedure in step 2 of C5, carry out 3_(金钢烷基基)-1-methylpyrrole_5_ The saponification of the ethyl carboxylate (from the entire contents of step i) yielded 16 mg of 3 _(gold sulphate _ 丨 _ yl) _ 丨 _ methyl pyrrole 5 carboxylic acid. MS measured value: (M_h)+=258 1〇. Preparation of C7: 6·Third-butyl chloropyrrolo[^claw" (4) Synthesis of three tillages 1. Preparation of C7 Step 1: _ Pyrrole-2- Ethyl carboxylate (7.24 g, 52 mmol, 1 equivalent), 2-chloro-2-methylpropane (6 18 mL, 57 mmol, 丨丨 equivalent), gallium dichloride (10.0 g, 57 mmol, U equivalent) and carbon disulfide (200 ml) thirsty and closed for 45 minutes. The reaction was poured onto a mixture of ice and 1 Nhc1. The aqueous mixture was extracted with chloroform and the chloroform layer was saturated with hydrogen. Sodium washing 'dehydrated with magnesium sulfate, and stripped to produce 9 78 g of golden oil, which is finally crystallized. On a tannin extract, in a 9:1 hexane/ethyl acetate flash 95318.115-1354664 layer Analysis: yielded 3.62 g of ethyl 4-tri-butyl-1H-pyrrole-2-carboxylate. MS found: (MH)+ = 196.28. Base: Prepared C7 step by John Hynes, Jr. et al. /· 2004, sigh ^ 68 method 'to prepare monochloramine: (3 grams, 56 millimoles) in the key (110 ml) mixed, and cooled to _5. 〇. Then add concentrated Nj ^ OH (4 7 ml) 'then drop by drop Bleaching agent (chi〇rox, 72 ml) was allowed to stand for 15 minutes. The mixture was stirred for 15 minutes, the liquid layer was separated, and the organic layer was washed with brine. The organic layer was powdered in a freezer. Hour, and 1 is used in the subsequent step. Ethyl 4-_t-butyl-1H_pyrrole-2-carboxylic acid (丨67 g '8_6 mmoles' 1 equivalent) is dissolved in DMF. Then, Hydrogenated steel (6 〇 % suspension in oil) (〇 41 g, 1 〇 mmol, 12 eq.) was carefully added thereto and stirred at room temperature under nitrogen for 45 minutes. Amine (〇·15Μ 'in mystery' 68.4 ml, 10 mmol, 1.2 eq.). The next morning, the reaction was quenched with saturated aqueous Na.sub.2.sub.2.sub.3, diluted with water and extracted in ether. Dehydration and drying 'filtration, and stripping, to produce 3 19 g of 3_Tct. Butyl-1. Amine-based Hook-to-acid ethyl ester, which is a yellow oil, and the final crystal is a long needle. MS measured value :(M+H)+= 211.34. C7 Step 3 1_Addition of 3-t-butylbutylaminopyrrolidine-5-carboxylate (丨.00 g '4·76 mmoler 1 equivalent) A Acetate acetate (1.46 g, 14.3 mmol, 3 parts) and 2-ethoxyethanol (1 mL) were mixed and refluxed for 3 hours. The stripping agent was then stripped from chloroform (3 Torr). A solid was produced. The solid was stirred in 5 mL of MeOH, filtered, and the collected solid was rinsed and dried to yield 233 mg of 6-tris-butyl-pyrene and [2,1 - Magic [1, 2, 4] three tillage - 4 - alcohol 'as a white solid. LCMS measured value: (Μ+Η)+= 191. 95318 •116- 1354664 i prepared C7 step 4 ·6·2nd-butyl-pyrrolo(4) Nashen III, well-operated alcohol (〇_43 mg, 2.26 millimolar, ! equivalent) was mixed with p〇cl3 (42i ml, grazing 2 millimoles '20 equivalents) and refluxed for 4 hours. Strip the mixture, then strip the mixture 3X from the methylene chloride, then dissolve it in the second gas, and rinse it with 3% of the saturated leg %. Rinse the organic layer with 1 Χ of brine, dry, and lift in vacuum. Produced 490 ® g 6 · Ternary-butyl-4-chloro-pyrrolo[2,i_f][i,2,4]Sanhu' as the color oil. LCMS detection (M+H)+ = 210. Preparation C8: 3-(T-butyl)-pyro-_5_Resin synthesis L·i% C8 4·Second-butyl_1H-pyrrole Ethyl 2-carboxylate (from C7 Step 1) (38 mg, ι_95 mmol, 1 eq.), 丨〇〇〇NNa〇H (39 mL, 39 mM, 20 eq.) and MeOH (50) Mix in ml) and reflux for i hours. The mixture was acidified with l.ONHCl (1.ON), and then evaporated to ethyl acetate (2x). The organic layers were combined, dried (MgSO.sub.4), and extracted to yield 290 mg. + 2 drops of DMS〇-D6) 5 6.50 (s,1H) ; 6.46 (s,1H) ; 0.95 (s,9H). Preparation of C9 · 3-(T-butyl)-ΐ·methylpyrrole_5 The synthesis of tracism is prepared by c9-free first. 'Methyl 4-(4-butyl-1H.pyrrole-2-carboxylate) is methylated by the method of C6, and then saponified by the method of C8. (Reflux for 4 hours) to give 3-(tert-butyl) hydrazinopyrrole-5-carboxylic acid. MS found: (M+H)+= 1821 〇. Preparation of C10: 2-T-butyl-I- ketone-pyrimidine_4_Resin of lithium sulphate The title compound was synthesized using 2-phenylisoindole The procedure used to test the acid clock N-oxide (preparation of H1) was prepared from 2-3-tributylpyrimidine carboxylic acid. This synthesis produces the desired product 2-tri-butyl-1·-bromo-4-carboxylic acid via debutyrylation 95318 •117· I354664 Bio 2-tri-butylpyrimidine_4_carboxylic acid A 3:1 mixture of lithium esters. This mixture was used as it is. MS found: (M+H)+ = 197.24. Preparation of Dl. 6-Chloro-Synthe-Butyl-4-ol. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Cool to room temperature and then add half of water. Precipitate the solid. Stir the solid! hour. The solid was filtered and stirred with hexane (2 mL). The solid was filtered and dried under EtOAc (EtOAc) EtOAc (EtOAc)jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 7.85 (d, 1H); 7.74 (t, 1H); 7.62 (m, 1H). System _ Preparation D2 Step 2: 6-Fluorooxazoline alcohol (L gram, 6.09 mmol) , 1 equivalent), phosphonium chloride (3. 41 ml '36.6 mmol, 6 equivalents) and triethylamine (5.09 ml, 36.6 mmol, 6 equivalents) were mixed at room temperature and then refluxed for 2 hours. Treatment from dichlorofane by stripping 3 times. Dissolve the residue in dioxane (25 ml) and rinse 3 times with saturated sodium bicarbonate (25 ml) and brine (25 liters) Rinse IX. The organic layer is dehydrated and dried (sodium sulfate), and stripped to give a crude oil. Purified on a silica gel in 9:1 to 3:1 hexanes / ethyl acetate. 6·Fluorooxazoline (〇% 克), as a tan solid. Yield = 86%. LCMS detection (Μ+Η)+= 183.16. Preparation of D3 ·· 4-Alkyl-6-(trifluoro Synthesis of methyl) thiazoline weight Jj_.D3 Step 1: 2-(Third-butoxycarbonylamino)_5_ (Trifluoromethyl)benzoic acid (56.34 g, 185 mmol' see: S. Takagishi et al., Synlett 1992) in a suspension of dioxane (100 ml) with dropwise addition of dioxane The solution was treated with 4N hydrochloric acid (25 mL, EtOAc), and the mixture was stirred for 4 hr. The analysis by LC/MS showed that the reaction was not completed, so 4N hydrochloric acid in the other dioxane was added. Solution (250 ml, 1.0 mol) and the mixture was stirred overnight. The analysis by LC/MS showed that the reaction still contained about 5% starting material, therefore, a solution of 4N hydrochloric acid in additional dioxane (100) was added. ML '0.4 mol), and the mixture was stirred for 4 hours. Analysis by lC/MS 95318 - 119 - 1354664 showed that the reaction was completed "The mixture was concentrated in vacuo and the residue was stripped from dioxane 2 X To remove any residual Ηα. The 2-amino-5-(difluoromethyl)benzoic acid hydrochloride thus obtained was used immediately in the next step. MS (ES+) = 206 (M+H+) . Preparation of D3 Step 2-Amino-5-(trifluoromethyl)benzoic acid hydrochloride (44.7 g '185 mmol) with A A suspension of hydrazine acetate (38.52 g, 370 mmol) in 2-ethoxyethanol (200 mL) was heated at reflux overnight, during which time a clear solution was found. The mixture was allowed to cool to room temperature. The solid formed was collected by filtration, washed with a small amount of &lt;RTI ID=0.0&gt;&gt; The combined filtrate was concentrated in vacuo and EtOAc was crystallised from EtOAc EtOAc EtOAc (EtOAc) 5 ppm 12.60 (s, 1H), 8.35 (s, 1H), 8.24 (d, J=4.83 Hz, 1H), 8.13-8.09 (m, 1H), 7.85 (dd, J= 8.35, 4.39 Hz, 1H) MS (ES+) = 215 (M+H+).

Kf D3 Step 3: _ A suspension of 6-(trifluoromethylsulfonyl) quinazolin-4-propanol (0 41 g, 48 4 mmol) in phosphonium chloride (100 mL) was refluxed Heat under 3 hours 'during this time' to find a clear amber solution. The solution was allowed to cool to room temperature &apos;concentrated in vacuo&apos; and stripped from &lt;RTIgt;&lt;/RTI&gt; The residue was partitioned between Et EtOAc and saturated sodium bicarbonate (1. The layers were separated, EtOAc (EtOAc)EtOAc. The residue was purified on EtOAc EtOAc EtOAc (EtOAc) elute elute = 233, 235 Preparation of 4-methyl-6-trifluoromethoxyquinazoline

Gold^11_ A solution of 4-(trifluoromethoxy)phenyl isocyanate (975 g, 48 〇 mmol) in THF (10 mL) was cooled to π and a third was added dropwise. Butanol I 1.0 MTHF solution (53 ml, 53 mmol) warm the mixture to the chamber and stir for 7 hours. Pour the solution into saturated ammonium sulfate solution (2 ml) with ether (200 liters) In the mixture, add enough water to redissolve the ammonium chloride that has been suddenly broken. The mixture is shaken in a separatory funnel and the liquid layer is separated. The organic phase is saturated with ammonium chloride (1 ml), water. (1 〇〇 ml), brine (100 liters), washed with sodium sulfate, and concentrated in vacuo. The residue was purified on EtOAc EtOAc EtOAc Yield 11.7 g of a white solid as the product. N^RpOOMHADNISC);) (5 (s, 1H)' 7.54 (d, 2H' J = 7 Hz), 7.23 (d, 2H, J = 8 Hz), L45 (s , 9H) Yield = rib % Step 2 (2·_Tri-butoxycarbonylamine-based _5_trifluoromethyl hydrazine, its synthesis):-(4_Trifluoromethoxyphenyl) -Amino acid methyl third butyl ester (2.31 g, 8.33 a solution of molybdenum in anhydrous THF (5 liters of liters) at _78 under 1.4M solution of second butyl lithium in cyclohexane at a rate that does not allow the internal temperature to exceed _6 (TC rate) (13 ml, 18.33 mmol). The solution was stirred at _78 °C for 15 minutes, then allowed to warm to _4 〇〇c and stirred for 25 hours. The reaction was treated with gaseous C 〇 2 Stir for 30 minutes while warming to _2 Torr, then quenched with saturated ammonium chloride. The mixture was warmed to room temperature and extracted with ethyl acetate (3×50 mL). Washed with water (5 〇 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 NMR (500 MHz, DMSO) 5 12.89 (s, 1H), 8.24 (d, 1 H, J = 9 Hz), 7.84 (s 1H), 7.21. (d, 1 H, J = 7 Hz), 1.51 (s, 9 Hz). Yield = 72% . Phoenix AP4 Step 3 (2-Amino-5-trifluoromethane - 茇ψ酩HC1 pound 厶吏 2- 3 -butoxycarbonylamine 5--5-trifluoromethoxybenzoic acid (19 g, 5.91 mmol) The ear was dissolved in 4NHC1 solution (15 ml) in dioxane, and the resulting suspension was stirred at room temperature for 6 hours. The analysis by LC/MS showed that the reaction was not redundant. (1 ml) followed by methylene chloride (2 mL) to dissolve solids and the mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo and then stripped from methanol (3 X 50 mL) to remove any excess HCl. The solid formed is used as such in the next step. MS(ES+) = 222(M+H)+· basket invites ^^ϋί^^A_£_fi!_AJfl_^_!#lz4ISLi^lAli_2-amino-5-trifluoromethoxy-benzoic acid The mixture of HC1 salt (1.52 g, 5.91 mmol) and formazan acetate (U4 g ' 17.73 mmol) in 2-ethoxyethanol (20 mL) was heated under reflux for 2 h. Analysis by LC/MS showed that the reaction was completed, therefore, the mixture was concentrated in vacuo and the residue was purified on silica gel eluting with 50% ethyl acetate / heptane - 100% ethyl acetate to give L1 g. White solid as product. MS (ES+) = 231 (Μ + Η) + · Yield = 82% · Preparation D4 Step 5: I 6-(trifluoromethoxy)quinazolin-4-ol (515 mg, 2.23 mmol) The suspension in gasified phosphonium (1.9 ml) was treated with triethylamine (3 mL &lt;RTI ID=0.0&gt; The resulting solution was cooled to room temperature and stripped of 3X from dichloromethane to remove 95318 • 122·1354664 residual phosphonium chloride. The residue was dissolved in 1 mL of dichloromethane, and 100 liters of saturated sodium hydrogen carbonate was carefully added to cause a vigorous gas evolution, and the mixture was stirred for 10 minutes until the gas evolution ceased. The layers were separated and EtOAc (EtOAc m. The residue was purified on silica gel eluting with 4% EtOAc / hexanes to afford 377 mg of 4-chloro-6-(trifluoromethoxy) oxazoline as a colorless oil. 1H NMR (400 MHz, CDC13) 5 ppm 9.10 (s, 1H), 8.16 (d, J = 9.23 Hz, 1H), 8.10 (s, 1H), 7.83 (dd, J = 9.23, 2.20 Hz, 1H). MS (ES+) = 249 (M+H)+. Preparation of DS: 2-Terti-butyl-8-chloro-pyrimidoindole-5,4-d]pyrimidine Synthesis of D5 Step Π5_Bromo-2 Synthesis of _T-Butyl dimethyl 4-carboxylic acid methyl ester _L_3 dimethyl hydrazine diazomethane 2. 〇 hexane solution (11·8 ml, 23.62 mmol) Adding dropwise to the solution of 5-bromo-2-t-butyl-pyrimidine_4_carboxylic acid (6.12 g ' 23.62 mmol) in 9: 1 benzene/nonanol (1 mL) The reaction was stirred for 2 days. TLC analysis indicated that the reaction had been completed 'so' to concentrate the mixture in vacuo. The residue was dissolved in EtOAc (EtOAc)EtOAc. Purification on silica gel, eluting with 10% ethyl acetate / hexanes afforded 5.2 g of colourless oil as product. MS (ES+) = 273,275 (Μ+Η)+·yield = 81%. Prepare D5 Step 2 (5-Third-butane carbonyl amine -2-tri-butyl-pyrimidine-4- Synthesis of methyl ester. Methyl ester of dimethyl carbamate (140 mg, 1.2 mM) cesium carbonate (456 mg, 1.4 mmol), 4,5-bis (diphenyl) Phosphinyl)-9,9-dimercaptoxanthine (18 mg, 0.03 mmol) and ginseng (diphenylmethylene 95318-123·1354664 acetone)-palladium (0) (19 mg, 0.02 mM The flame-dried reaction tube of Mohr) is drawn under true S and then counter-filled with argon. Dioxanthine (2 ml) and 5-bromo-2-tri-butyl pyridine are added. Methyl carboxylate (273 mg, 丨〇 mmol), and the mixture was degassed under vacuum. Then, the tube was back-filled with argon, sealed, and heated at 100 c for 2 hours. The analysis showed complete consumption of the starting bromide. The mixture was diluted with dichloromethane (2 mL), filtered to remove solids, and concentrated in True 2. The residue was purified on hard gel to 10% vinegar. Ethyl ester / heptane; dissolved, resulting in 152 mg of white solid MS (ES+) = 310 (M+H)+. Yield = 50% · Preparation of JP5 Step 3 (5. Amino-2-tert-butyl-Yu-Yang-Jia vinegar HC1 salt main.. Jin. ): a solution of 5_th-butoxycarbonylamino-2-tri-butyl-pyrimidine- 4-polyacid methyl ester (2.4 g ' 7.75 mmol) dissolved in HC丨 in a dioxane garden (30 ml). After stirring for 10 minutes, a thick white solid precipitated. The reaction was stirred overnight, during which time the mixture became a homogeneous amber solution, concentrated in vacuo and the residue was taken from toluene (2×50 ml Then, it was stripped from dichloromethane (3 X 50 ml) to remove excess HCl. The 185 g of the yellow solid formed was used in the next step without further purification. MS (ES+) = 210 (M+ H)+. Prepare D5 Step 4. (^ι三-丁丁·pyrimidine _4·酵之合HL will 5-amino-2-tri-butyl pyridine _4_carboxylic acid A A mixture of the ester HCl salt (ii gram, 4.48 mmol) and hydrazine acetate (1.86 g, 17.90 mmol) in 2-ethoxyethanol (20 mL). MS analysis showed the reaction was essentially complete 'so the mixture was allowed to cool The mixture was concentrated in vacuo, and the residue was purified on EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc 6 gm color solid, as product. MS (ES+) = 2〇5(10)+H)+yield=94% pyrimidine Γ5.44 嘧 之 使 6 Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ [5,4-d]pyrimidin-4-ol (210 mg, 丨·03 mmol) was dissolved in phosphorus chloride (10 mL) and the mixture was heated to 4H under reflux. The solution was concentrated in vacuo and then filtered from chloroform (3 χ 5 mL). The residue was stirred in saturated sodium bicarbonate (5 liters EtOAc) for 10 min then ethyl acetate (3 EtOAc). The combined organic phases were washed with water (30 mL)EtOAc. The residue was purified on silica gel eluted with 50% ethyl acetate / heptane to give 15 g of white solid as product. NMR (500MHz, CDC13h9.61 (s, 1h), 915 (s, 1h) 152 (s, 9H). Preparation of D6: 4-Alkyl_6·(2·methoxyphenyl)quinazoline Synthesis Ά3 D6 2-Amino-5-bromobenzoic acid (2.00 g, 9.26 mmol) and suspension of formamidine acetate (3.86 g, 37·mmol mmol) in I ethoxyethanol (2 mL) The liquid was heated under reflux for 2 hours, during which time a clear solution was found. The reaction was allowed to cool to room temperature, during which time solids precipitated. The precipitate was collected by filtration and washed with diethyl ether to give material. It contains the desired product, but is not pure by NMR analysis. The solid is partitioned between ethyl acetate and water, the undissolved small amount is removed by filtration, and the liquid layer is separated. The organic phase is washed with water. Twice twice, dehydrated with sodium sulfate, and concentrated in vacuo to give 690 mg of 6-bromo 4 s- _ 4- ol as a tan solid. The crude organic filtrate was concentrated to give a solid. Medium 95318 • 125- 1354664 Stirred, collected by filtration, and air dried to give 430 mg of 6-bromoquinazolin-4-ol as a tan solid. MS (E S+) = 225/227 (M+H+).

Preparation of D6 from step 2: _ 6-bromo group.奎嗤琳-4-ol (227 mg, 1.01 mmol), 2-methoxyphenyldihydroxyborane (3〇7 mg, 2〇2 mmol), 2〇M potassium phosphate (aqueous solution) A mixture of 1.5 ml '3.0 mmol) and DMF (3 ml) in a 5 ml microwave tube was degassed under vacuum. A catalytic amount of ruthenium (triphenylphosphine) (0) was added to the tube, the mixture was again degassed, the tube was sealed, and the reaction was heated in a microwave for 3 minutes at 15 °C. The resulting black mixture was filtered and concentrated in vacuo. The residue was dissolved in EtOAc / EtOAc (EtOAc) (EtOAc) The residue was purified on a crushed gel, and then acetonitrile was used to purify, and the ethyl acetate was then succinated, followed by 9:1 ethyl acetate/methanol to give 25.0 mg of 6·(2_methoxyphenyl)&gt; For example, the collar is white powder. Ms (es+) = 253 _+) ♦ methoxyphenyl) ( 唆 唆 · · 4 醇 醇 醇 醇 醇 醇 醇 醇 醇

Milliliter) The suspension in 3 (10 ml) is heated under reflux! Hours, during which time a clear solution was found. The mixture was cooled to room temperature, concentrated in vacuo, and then concentrated from hexanes (3 &lt;RTI ID=0.0&gt;&gt; Residue, vinegar ethyl ester (25 ml) and saturated

A liquid separation was carried out between NaHC(R) 3 (30 ml) and the mixture was stirred until the gas was released (10 minutes;). The liquid layer was separated, and the organic phase was dried with saturated NaHCO.sub.3, water and water, dried over sodium sulfate, and dried in vacuo. The residue was purified on crushed rubber and dissolved in 1:3 vinegar 彡 'know/heptane to give 217 gram of 4-mercapto- winter (2. methoxyphenyl)

Yulin' is a white solid. iHNMR 95318 • 126 - 1354664 (500 MHz, CDC13) δ ppm 9.03 (s5 1H), 8.36 (s, 1H), 8.19 (d, J=7.15 Hz, 1H), 8.10 (d, J=8.80 Hz, 1H) , 7.42 (m, 2H), 7.10 (t, J = 7.42 Hz, 1H), 7.04 (d, J = 8.25 Hz, 1H), 3.86 (m, 3H). Preparation D7 : 3-(4- gas based hydrazine Synthesis of oxazoline-6-yl)benzonitrile The 2-methoxyphenyldihydroxyborane in step 2 of D6 was prepared by substituting 3-cyanobenzenedihydroxyborane according to the procedure described for the preparation of D6. MS (ES+) = 266/268 (M+H+). Preparation of El: 4-T-butylcarbazole-2-resinic acid ethyl thioglycolate (0.75 g, 5.6 mol) A solution of 1-bromo 3,3-dimethylbutanone (1.0 g '5.6 mol) in ethanol was heated to reflux for 2 hours. The solvent was removed in vacuo and the residue was taken in EtOAc (EtOAc m. _8 g of ethyl 4-tert-butylcarbazole-2-carboxylate as an oil. The ester was dissolved in MeOH (5 mL) EtOAc (EtOAc) The solution was acidified with IN HCl and extracted in CHjCl2 and washed with water. The solvent was removed in vacuo to afford EtOAc (EtOAc):EtOAc: MS measured value: eg +11) += 186.24 Preparation E2: 4-(perfluoroethyl) plug bite _2-rebel acid is synthesized using the procedure described in the preparation of E1" MS measured value: (M+H) + = 248 Preparation E3: 4-(3-(Trifluoromethyl)phenyl)pyrazole-2-carboxylic acid was synthesized using the procedure described for the preparation of E1. MS found: (M+H)+= 274.3 95318 • 127·1354664 Preparation E4: 4-Phenylpyrazine Rebels The system was synthesized using the procedure described for the preparation of E1. MS found: (M+H)+=206.17 Preparation E5: 4-(4-Phenylphenyl)-bite-j-acids. MS found: (M+H)+ = 240.14 Preparation E6: 4-(benzo-thiazol-2-yl) lacquer 1 acid was synthesized using the procedure described for the preparation of E1. MS found: (M+H)+ = 263.13 Preparation E7: 4-(1-Gold-steel alkyl) ρ 嗖 酸 其 其 其 其 其 其 其 其 其 其 其 其 其 其 其 。 。 MS found: (M-H)* = 262.25 Preparation E8: 4-(pyridin-2-yl)pyrimidine-2-dicarboxylic acid This was synthesized using the procedure described for the preparation of E1. MS found: (M+H)+ = 207.22 Preparation E9: 4-(thiophen-2-yl), ethazol-2-carboxylic acid. MS found: (M+H)+ = 212.05 Preparation E10: 4-(p-s-phen- -3- yl) </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Ms measured value: (M+H)+ = 212.05 Preparation F1: 4-phenylfuran-2-rebel plug AIL Step 1: 4-Bromo screaming 20%: estimated commercially available 4,5-two &gt; Stinyl-2-pyrolic acid (6.1 g '22.6 mol) suspended in 1 ml of gas oxidized 95318 • 128- 1354664 by medium, and treated with zinc powder (1_48 g, 22.6 mol) And stir at room temperature for a few minutes. The reactant was filtered, and the filtrate was acidified with 5NHC1 and extracted several times with dichloromethane. The extract was washed with brine and concentrated to give 2.93 g of white solid. MS (ES-) found: (Μ-Η)·=190·95 and 188.95. NMR (500 MHz, DMSO-D6) &lt;5 13.3 (bs, lH), 8.14 (s, 1H), 7.36 (s, 1 Η). The product was contaminated with 25% furan-2-acid by-products. NMR (500 MHz, DMSO-D6) &lt;5 13.3 (bs, 1 Η), 7.90 (m, 1 Η), 7.19 (4) 1 Η), 6.64 (m, 1H). Preparation of FI Step 2: Synthesis of 4-styl-pyrene-2-# acid: 4-bromopyran-2-carboxylic acid (380 mg, 2 mmol), phenyl A solution of dihydroxyborane (488 mg, 4 mmol) in DMF (3 mL) was placed in a microwave reaction tube and treated with 2 Μ K3 P04 (aq) (2 mL, 4 mM). Before adding pd (pph3 \ (1.5 mg) catalyst, the solution was purged with nitrogen for 10 minutes. The mixture was again purged with nitrogen for 5 minutes, then the reaction tube was sealed and the mixture was placed at 15 ° C in the microwave oven. Heat for 30 minutes. The reaction mixture was filtered, and the filtrate was poured into &lt;RTI ID=0.0&gt;&gt; Found: = 187.07. Preparation of F2: 4-(4-methoxyphenyl)furan-2-carboxylic acid was synthesized using the procedure described for the preparation of F1 (MS-): (Μ-Η )·= 217.12 Preparation of F3 ··· 4-(4-(Trifluoromethyl)phenyl)furan-2-reactive acid was synthesized using the procedure described for the preparation of F1. MS (ES-) found. (Μ -Η)·== 255.14 95318 -129- 1354664 Preparation of G1: 5-Phenylfuran_2_Resin synthesis 5. 5-Bromopyran-2-pyrraceic acid (381 mg, 2 mmol), phenyl A solution of dicakixane (488 mg '4 mmol) in DMF (3 mL) was placed in a microwave reaction tube and treated with 2MK3P s 4 (aq) (2 mL, 4 mM). Add Pd (PPh3 \ (1. Before 5 mg of the catalyst, the solution was purged with nitrogen for 1 minute. The mixture was again purged with nitrogen for 5 minutes, and then the reaction tube was sealed. The mixture was heated at 150 ° C for 3 minutes in a microwave oven. The reaction mixture was poured into 1 NHC1 (100 mL) and stirred. 遽 遽 遽 ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' :(Μ-Η)·= 187.13. Preparation of G2: 5-(4-(Trifluoromethyl)-phenyl)pyran-2-dezine synthesis The synthesis was carried out using the procedure described for the preparation of G1. (ES-) found: (Μ-Η)· = 255.11 Preparation of G3: 5-(4-fluorophenyl)furan-2-carboxylic acid was synthesized using the procedure described for the preparation of G1. MS (ES_ Found: (MH)' = 205.10 Preparation of G4: 5-(3-fluorophenyl)pyran-2-carboxylic acid was synthesized using the procedure described for the preparation of G1. ms (ES-). : (MH)' = 205.10 Preparation of G5: 5-(3,4-difluorophenyl)pyran-2-acid synthesis The synthesis was carried out using the procedure described for the preparation of G1. MS (ES_) found: (MH)'= 223.09 Preparation of G6: 5-(4-isopropylphenyl) The synthesis of the oxime-2_acid was synthesized using the procedure described for the preparation of G1. MS (ES_) found: 95318 • 130 - 1354664 (Μ-Η)·= 229.15 Preparation G7: 5-(3-A The synthesis of oxyphenyl)furan-2-retinic acid was synthesized using the procedure described for the preparation of G1. MS (ES-) found: (M-H)-= 217.13 Preparation of G8: 5-(3-cyanophenyl)furan-2-carboxylic acid. The synthesis was carried out using the procedure described for the preparation of G1. MS (ES-) found: (MH)-= 212.12 Preparation of G9: 5-(4-cyanophenyl)furan-2-carboxylic acid as a synthesis using the procedure described for the preparation of G1: MS (ES) -) Found: (MH)' = 212.12 Preparation of HI: Synthesis of lithium 2-phenylisonicotinate N-oxide_Preparation H1 Step 1: Make 2-bromo-4-pyridinecarboxylic acid (U克, 5_45 mmol, phenyl dihydroxyborane (1.3 g, 1 〇 _9 mmol), 2.0 Μ potassium phosphate (aqueous solution) (8.2 ml, 16.34 mmol) and DMF (10 ml) The mixture in a 20 ml microwave tube was degassed under vacuum / Ar. A catalytic amount of ruthenium (triphenylphosphine) palladium (9) was added to the tube. The mixture was again degassed, the tube was sealed, and the reaction was heated in a microwave at 150 ° C for 30 minutes. The reaction mixture was filtered, and the filtrate was evaporated mjjjjjj The mixture was acidified to pH = 6 by addition of 1.0 NHC1 and the precipitate formed was collected by filtration, washed with two portions of ice-cold water, and air-dried to yield 575 g of 2-phenyl-nicotinic acid' as an off-white solid. MS (ES+) = 2〇〇(M+H+). Prepare HI Step 2: Make 2-phenylisonicotinic acid (459 mg, 2·30 mmol) in 9:1 benzene/methanol (20 ml) The solution was cooled to ye and treated with dropwise addition of (trimethyldecyl)diazomethane in 2 hexanes (1. <RTI ID=0.0></RTI> </RTI> <RTIgt; The mixture was allowed to return to room temperature and stirred for 6 hours. "The reaction was incomplete by the analysis of jlc." The mixture was then taken up in a mixture of (trimethyl-trimethane) diazomethane (230 μL, 0.23 mmol). Treat and the reaction was stirred for a further 2 hours. The tlc of the mixture remains unchanged. The solvent was stripped and the residue was partitioned between ethyl acetate and saturated sodium hydrogensulfate. The organic layer was washed with saturated aqueous sodium bicarbonate, and the combined aqueous phases were extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and evaporated. The residue was purified on silica gel eluting with 20% ethyl acetate /Heptane to afford 372 mg of &lt;RTIgt; iHNMR (400MHz, CDCl3) occupies (10), 汍j= 5.27 Hz, 1H), 8.29 (s, 1H), 8.04 (d, J=7.03 Hz, 2H), 7.77 (d, J=3.52 Hz, 1H), 7.51-7.42 (m, 3H), 3.98 (s, 3H). The phenyl group is different from the acid methyl ester N-oxide by the method of Sharpless et al. (j 〇rg Chem 199MJ, (d)). A solution of 2-phenylisonicotinic acid methyl vinegar (370 mg, 1 J3 mmol) with methyltrioxy chain (¥11) (3 mg, 0.01 mmol) in dichloromethane (2 mL) Treatment with 3 % aqueous hydrogen peroxide (347 μl ' 3.47 mmol) resulted in a colorless solution that turned yellow and the mixture was stirred overnight. Analysis by LCMSi showed an 8:2 mixture of the desired product to the starting material, and therefore, additional methyltrihydrate (VII) (30 mg, 〇.1 €) was added and the mixture was allowed to stand for 6 hours. A catalytic amount of manganese oxide was added and the mixture was stirred until gas evolution ceased (3 Torr). The mixture was diluted with di-methane (2 mL), the layers were separated, and then aqueous layer was extracted with EtOAc (5 mL). The combined organic phase was dried over sodium sulfate and then concentrated in vacuo. Broken glass. Analysis by 95318 -132· 1354664 showed that the ratio of 95:5 to 2 phenyl was different from that of acid acetate ν·oxide/2-phenylisoacid. This material was used as such in the next step. MS(ES+) = 230(M+H+), i Prepare HI Step 4: A solution of 2_phenyl isonicotinate methyl N-oxide (397 mg, (7) mmol) in 6 mL) Treated with 〇5N a gas oxidized aqueous solution (3.65 mL, 1.81 mmol) and the mixture was stirred overnight. The THF was stripped and the aqueous solution was lyophilized to give a 2-phenylphenylnicotinic acid lithium N-oxide as a colorless glass material which was used in the next step. Preparation of H2: Synthesis of 5-phenylnicotinic acid 1_Preparation of H2 Step 1: 5-bromonicotinic acid (500 mg, 2 48 mmol, 1 equivalent), phenyldihydroxyborane (454 mg) , 3.71 millimolar, 1.5 equivalents), cerium (triphenylphosphine) red (0) (143 mg, 〇·124 mmol, 〇〇 5 equivalents) and sodium carbonate (787 gram, 7.43 millimolar, 3 Equivalent), mixed in ethanol (5 mL), toluene (25 mL) and water (5 mL) at room temperature under nitrogen. Then, the reaction was refluxed for 20 hours. The treatment is carried out by adding water followed by stripping ethanol. The aqueous layer was washed twice with diethyl ether. Adjust the water layer ρΗ = 3 with concentrated HC1. The acidic aqueous layer was extracted three times with ethyl acetate and a small amount of THF. Ethyl acetate / THF was layered and dried <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI> <RTIgt; Yield = 67%. LCMS detection (M+H)+= 198.1. Preparation of H3: 3,-trifluoromethylsulfonylamino-, ·biphenyl]_3•Resin synthesis Preparation of H3 Step 1: _ 3-Iodobenzoic acid ethyl ester (0.92 g, 3.34 mmol, 1 equivalent), phenyl dihydroxyborane (0.87 g, 5.02 mmol, 1.5 equivalent), palladium acetate (11) (37 mg , 167.167 mmol, 〇.〇5 equivalent) and sodium carbonate (706 mg, 6.66 mmol, 2 equivalents), dissolved in DMF (20 95318 -133·1354664 ml) at room temperature under nitrogen . Then, the reaction was heated at 80 ° C for 5 hours. The treatment was carried out by adding ethyl acetate and rinsing 4 times with water. The organic layer was dehydrated with sodium sulfate and stripped to give a dark oil. Purified on a crushed rubber in 9:1 to 1:1 hexane/ethyl acetate to give 3·-amino-[ι,Γ-biphenylepic acid ethyl ester (420 mg)' as an oil. . Yield = 55% . LCMS detection (Μ + Η) + = 242.41. Preparation of Η3, Step 2: Ethyl 3-(3-aminophenyl)benzoate (1 mg, 〇44 mmol) , 1 equivalent), dissolved in di-methane (1 mL) at room temperature, and added potassium carbonate (91 mg, 0.66 mmol, i_5 equivalent). Cool to _7 (rc, then add three elephants via the addition funnel 'drops (74 μl, ο# millimoles, 1 equivalent). After 1 hour, add 0.2 equivalents of each of the above reagents. After 1 hour, the reaction was stripped to give 3'·trifluoromethylsulfonylamino #, ,, _biphenyl]-3-acid ethyl ester (150 mg) as an oil. Rate = 91% Mass Spectrometry (orphan) Detection (M+H) += 372.1. Preparation of H3 Step 3: Making 3'-trifluoromethylsulfonamido·biphenyl]_3_acid ethyl ester (150 Mg, 0.40 mmol, 1 eq.) and i 〇〇〇N Na〇H (〇8 〇 ml, 0.80 mM, 2 eq.) dissolved in thf (5 mL) at room temperature and stirred 2 〇 Hour. Almost no reaction. Add 1 mg of Na0H and heat at 5 (rc for 2 hr.) by adding water and then rinsing twice with a riddle. Adjust the pH of the aqueous layer with in HC1 to 3. The acidic aqueous layer was extracted three times with ethyl acetate. The ethyl acetate layers were combined, dehydrated and dried over sodium sulfate, and stripped to obtain 3,-difluoromethylsulfonylamino group _[1,1'- Biphenylcarboxylate 3-carboxylic acid (9 mg) amber solid. Yield = 65%. Spectrum (ESI) detection (M+H)+= 344.0. Preparation of H4: 3-phenyl-4-benzoic acid synthesis U_g4 step _li 3-bromo-4-hydroxybenzoic acid (5 〇〇 mg , 2 3 〇 millimoles, 95318 • 134- 1354664 1 when), phenyl dihydroxyborane (281 mg, 2 3 〇 millimolar, i equivalent of palladium (11) (16 g, 0.069 Millol, 〇〇 3 equivalents) and 15M carbonic acid (water-cooled liquid) (4.61 liters), dissolved in DMp (ι 〇 ml) at room temperature under nitrogen, and then heated at 45 ° C for 20 hours. The treatment was carried out by adding water (1 ml), followed by 1 NHC1 to pH = 3'. The acid aqueous solution was extracted 3 times with the purpose of the acid. The ethyl acetate layer was combined and water (1 ml) Rinse 3 times. Then, the ethyl acetate layer was dried over sodium sulfate and stripped to an oil. The oil was purified on a silica gel and purified in 1:1 hexane/ethyl acetate. (330 mg) 'is an oily substance, which is finally cured by hydrazine yield = %. LCMS detection (M+H) + = 257.23. Preparation of H5: 2 phenyl pyridinic acid synthetic cover _H5 step Insult 1: .2-Phenylindole-6·carboxylic acid E. Fdder, D., S. Boven and EB Grabitz, Chem. Ber. 100 (1967) 555-559 Method Synthesis. LCMS Detection (M+H)+= 201.29. Preparation H6: 3-Third Synthesis of butyl _5_(2H-tetrazole-S-yl)benzoic acid H H6 Step 1. _ 5-Phenyl-butyl isophthalate (25 g, 1 Torr) A solution of lithium hydroxide monohydrate (168 mg, 7 mmol) in 5 mL of water was added dropwise to a solution of TC in 20 mL of THF. The reaction mixture was stirred at room temperature for 3 hours. The THF ' was removed under reduced pressure to give a yellow oil, which was diluted with 10 ml of 1NHC1. The aqueous phase was extracted with EtOAc (2×25 mL) and evaporated. MS found: (M+H)+ = 237. mi -^ 3-tri-butyl-5-(indoleoxycarbonyl)benzoic acid (700 mg) 95318 -135 - 1354664 in DMF (15 ml) In the solution, HATU (1.2 equivalents), 3-aminopropionitrile (L2 equivalent) and 2 equivalents were added at room temperature. The mixture was stirred at room temperature for 16 hours before adding water and EtOAc. The organic layer was separated and washed twice more, then collected, dehydrated and dried with Na s 〇 4, and concentrated to provide 3-tris-butyl-5-((2. cyanoethyl)amine carbhydryl. Methyl benzoate, a glassy solid (520 mg). MS measured value: (Μ+Η)+= 289. Η Η 6 Steps 3:. 3-benzo-butyl-5-((2-cyanoethyl)amine-based benzoic acid) 520 mg, 1.8 mM) in a solution of MeCN (15 ml) at 〇C, NaN3 (117 mg '1.8 mmol) and Tf2 〇 (〇.3 mL, 18 moles) were added. The mixture was stirred at room temperature for 16 hours before the addition of aqueous NaHCO3 and EtOAc. The organic layer was separated and washed twice, then collected, dehydrated and dried over NazSO4, and concentrated to form 3-tris-butyl-5-(2-(2-cyanoethyl)-2H-tetrazol-5-yl Methyl benzoate as an oil (45 mg, 8 % yield). MS found: (m+H)+=314. Prepare H6 Step 4:: 3-3-tert-butyl-5-(2-(2-cyanoethyl)_2Η-tetrasal-5 base) A solution of methyl benzoate (500 mg) in a volume of 〇〇c in 20 ml of THF was added dropwise a solution of lithium hydroxide monohydrate (76 mg) in 5 mL of water. The reaction mixture was stirred at room temperature for 16 hours. Removal of THF&apos; under reduced weight afforded a yellow oil which was diluted with 10 <RTIgt; The aqueous phase was extracted with Et 〇Ae (2×25 mL), and the extracts were combined, dried over Na 2 S 〇 4 and concentrated to give 3-t-butyl-5-(2H-tetrazol-5-yl)benzene. Formic acid.实., Value: (Μ+Η), 247· "Preparation of Η7:3_(1Η-tetrazol-5-yl)benzoic acid in a synthetic disk prepared in 3-(methoxycarbonyl)benzoic acid (800 mg, 4.4 亳) Moer) 95318 • 136- 1354664 In DMF (153⁄4 liters) "In solution, add gentyl, u millimolar at room temperature", 3-amino-propion (0.33 ml, 44 mmol) And the beer ML 533⁄4 mol). Stir the mixture at room temperature before adding water and Et〇Ac! The knife is separated from the organic layer and washed twice, then collected, dehydrated and dried with Na2S04, and concentrated. (1) Acetylethyl)amine carbaryl) benzoic acid formazan' is a glassy solid (9 〇〇 mg). MS found: (M+H)+ = 233.

[Preparation of H7 #骤^^ in a solution of methyl 3-((2-cyanoethyl)amine-carbamoyl)benzoate (4 mil, 1.7 mM WMeCN 〇 5 ml) Under the armpit, add NaNdlll gram, 1 / 7 millimoles) with 邛〇 (〇 3 ml, mouth milli-Merbu added to the NaHC 〇 3 aqueous solution with Duan 〇 eight (; before mixing the mixture at room temperature 16 The organic layer was separated and washed twice more, then collected, dehydrated with Naz SO*, and concentrated to 3_(1_(2-cyanoethyl)_1H_tetrazole-5-phenyl)benzoic acid The methyl ester was an oily substance (180 mg, 41% yield). MS found: (M+H)+=258. Tomb _HH Step 31 in 3-(1-(2-cyanoethyl) -1 Η-tetrazol-5-yl)benzoic acid methyl vinegar (180 mg, 0.7 mmol) was cooled in a solution of 20 ml of THF - dropwise addition of lithium hydroxide monohydrate (5 mg, 2.1 To a solution of EtOAc (2 x 25 mL). Extracting the aqueous phase and combining the extracts to dehydrate by &gt;^8〇4 Drying, and concentrating to give 100 mg (yield: 58%) of 3-(1?-tetrazol-5-yl)benzoic acid. MS found: (M+H)+= 191. Preparation H8: 3-(4 Synthesis of -methylpyrazol-2-yl)benzoic acid 95318-137· 1354664 The title compound was synthesized by the literature procedure described in OM. C/iew. 1999, 5, 7, 1559-1566. MS found: (M+H)+ = 220. Preparation of H9: Synthesis of 6-phenylpyridinecarboxylic acid ϋ 2 steps _^1^ Add yttrium triphenylphosphine palladium (572 mg), 2M Na2C03 (5 ml) and Prior to phenyldihydroxyborane (9 〇 5 mg), 6 bromopyridinecarboxylic acid (1.0 g) was dissolved in 1,2-dimethoxyethane (15 mL). After heating for 48 hours, after cooling, 1NHC1 was added to adjust the pH &lt;4» to form a white precipitate, which was removed by filtration. A small portion of the filtrate was purified by reverse phase HPLC (gradient elution, water/acetonitrile/TFA). 6-phenylpyridinecarboxylic acid (25 mg). MS found: (M+H)+=200.1. Preparation H10: 5-phenylnicotinic acid N-oxide synthesis 1_H10 Step 1: 5-phenylnicotinic acid (50) before adding 77% mCPBA (250 mg)克) Dissolved in dichloroethane (2 ml). The reaction was stirred for 15 h, then concentrated and filtered, and purified by reverse phase HpLC (gradient elution 'water / acetonitrile / TFA') to give 5-benzene Nicotinic acid N-oxide (20 mg). MS found: (M+H)+= 216.1. Preparation of H11:3 Tetrazole-2-yl)benzoic acid. Preparation of H11 Step 1: 1 g (0.068 mol) of 3-cyanobenzoic acid Dissolved in 150 ml of anhydrous dichloromethane and cooled to - 〇 ° C. 50 ml of chlorinated hydrazine was added dropwise followed by 5 drops of anhydrous DMF. The reaction mixture was stirred at room temperature overnight. The dichlorofane was removed and anhydrous methanol (50 mL) was added and stirred at room temperature for 2 hours. Excess methanol was removed and the residue was dissolved in ethyl acetate. The ethyl acetate layer was washed with 10% aqueous hydrogen carbonate, brine and concentrated to give methyl 3-cyanobenzoate (7 g) as a white solid. 95318 -138- 1354664 篕-Prepare 1 step hui 2: Add 2 3 g to a solution of 2 g (〇, 〇 1 mol) of methyl 3-cyanobenzoate in 32 ml of THF and 8 ml of water. (〇〇12 mol) monoethyl dithiophosphate and heated at 8 ° C for 24 hours. The THF was removed and the residue was dissolved in ethyl acetate. The extract was washed with water and concentrated to give ethyl <RTI ID=0.0> Prepare H11 Step 3: _6 gram (0.003 mol) of 3-aminomethylthiomethanebenzoic acid methyl ester in 6 ml of acetic acid, add U5 g (〇〇〇9 mol) Chloroacetaldehyde dimethyl acetal with a catalytic amount of PTSA. The reaction mixture was heated to 1 〇〇 c overnight. Acetic acid was removed under vacuum, and the crude product was purified by a 60-120 矽 rubber column using 5% ethyl acetate in petroleum acid as the eluent to provide methyl 3-septazol-2-yl)benzoate (〇.5 g), as a white solid. Preparation of H11 Step 4: In a solution of 6 g (〇_0〇27 mol) 3-7-sodium-2-yl)benzoic acid methyl ester in 6 ml of THF and 1.2 ml of water, add 〇u gram (〇 〇〇46 Moer) Hydrogen peroxide. The reaction mixture was stirred at room temperature overnight. The THF' was removed and the aqueous layer was washed with a key and acidified with EtOAc. The solid product was extracted with ethyl acrylate. The organic layer was washed with brine and concentrated to give EtOAc EtOAc (EtOAc) iHnmr(4〇〇MHz, CDC13): 7.45 (d, 1H), 7.63 (m, 1H), 8.0 (d, 1H), 8,22 (d, 1H), 8.30 (d, 1H), 8.79 (s , 1H)· MS found: (MH)_ = 204. Example la - li Example la: cis- and trans-(3S)-l-(4-(t-butylamino)cyclohexyl) Synthesis of _3_(6_(trifluoromethyl)-anthracene-4-ylamino)tetrahydro-p-bi-2-imine: real_example la step 1: 1,4-cyclohexanedione ethylene condensation Ketone (5.00 g, 32.0 mmol, 1 eq.), sodium triethoxy borohydride (8.14 g, 38.4 mmol, 95318-139-1354664 1.2 eq.) and decylamine (3.50 mL, 32.0 mmol) , 1 equivalent), mixed in di-methane (100 mL) at room temperature. Stir for 20 hours" Add 50 ml of 1.0 NaOH. Stir for 1 minute. Extracted 3 times with dichloromethane (5 mL). The organic layers were combined, dehydrated and dried with sodium thiosulfate, and stripped to obtain N_(phenylmethyl)+4-dioxospiro[4.5]癸-8- Amine (7.91 g), light amber oil, was obtained. Yield = 100% . LCMS detection (M+H) + = 248.26. Example la Step 2: Carefully dip 20% palladium hydroxide (i.oo) in methanol (50 mL) under nitrogen N,N_(phenylmethyl)-1,4-dioxospiro[4.5]dec-8-amine in wet 'addition of methanol (5 mL) (7.91 g of ρ to hydrogenate the mixture on a Parr shaker 20 H. Under nitrogen, the glass fiber filter paper was passed through a catalyst to remove the filtrate. The filtrate was stripped to give 1,4-dioxospiro[4.5]dec-8-amine (6.40 g) as an oily solid. Yield = 1%. LCMS detection (M+H) + = 158.1. Example 1a Step 3: 丨,4-dioxospiro[4.5]癸-8-amine (5.03 g, 32.0 mmol) , 1 equivalent), CBZ-L-oxime thioglycolic acid (10.90 g, 38.4 mmol, 1_2 equivalent), 1-hydroxybenzotriazole hydrate (HOBTX 5.19 g, 38.4 mmol, 1.2 equivalent), 1-[3-(Dimethylamino)propyl]_3_ethylcarbodiimide Ηα select DCI) (7 % g, 38.4 mmol, i.2 eq.), triethylamine (8 92 ml, 64 Torr, 2 eq.) and dichloromethane (150 mL) were stirred at room temperature under nitrogen for 72 hr. The treatment was carried out by rinsing three times with saturated sodium bicarbonate (50 ml). The organic layer was dehydrated and dried over sodium sulfate and stripped to give an amber oil which was solidified. The solid was triturated with diethyl ether (100 mL) and stirred overnight to afford a solid filtered to afford 8-((2S)-2-(indoleoxycarbonylamino). 4-(methylthio)butanamine. [4.5] simmering (8.75 g) as a white solid. Yield = 64% · mass spectrometry detection (Μ + Η) + = 423.22. 95318 - 140 - 1354664 i · Example 1a Step 4a_j_ will 8-( (2S)-2-(indolylcarbonylamino) sulfonium (sulfonylthio)butylidene)-1,4-dioxospiro[4.5]decane (8-75 g, 20.7 mmol, 1 equivalent) Sandwood was mixed in iodomethane (38.76 ml, 621.0 mmol, 30 equivalents) for 20 hours at room temperature under nitrogen. The reaction was stripped 4 times from dichloromethane (5 mL) and then obtained from chloroform (50 mL) twice to obtain the corresponding sulfonium salt (12.0 g) as a tan solid amorphous solid LCMS ( M+)+ = 437.06. This sulfonium salt (11.7 g, 20.7 mmol, 1 eq.) and cesium carbonate (33,7 g, 103.5 mmol, 5 eq.) were taken at room temperature under nitrogen and in DMF ( Stir in 75 ml) for 20 hours. Ethyl acetate (100 mL) was added and the organic layer was washed 4 times with brine (5 mL). The organic layer was dried over sodium sulfate and stripped to give an oil. Purified on cerium gel in 3:1 to 1:1 hexane/ethyl acetate to 1% ethyl acetate. 8-((3S)-3-(indolylcarbonylamino)-2-yl-4-tetrahydroindol-1-yl)-1,4-dioxospiro[4.5]decane (2.70 g) was obtained as Yellow-brown glass material. Yield = 35% · LCMS detection (M+) + = 375.14. Example la step 4b: salt (4 g, 1.77 mmol, 1 as I) from step 4a, at room temperature under nitrogen Dissolved in THF and then added 60% sodium hydride (370 mg, 9.30 mmol, 5 eq.) in 5 portions. Stir for 20 hours. Treatment was carried out by adding saturated ammonium chloride (20 ml) followed by extraction with ethyl acetate three times. The organic extracts were combined and dried under sodium sulfate, and stripped to give an oil. Purified on a silica gel in 3:1 to 1:1 hexane/ethyl acetate to 100% ethyl acetate. 8-((3S)_3_((Oxocarbonylamino))-ketotetrahydropyrrole-1-yl)-1,4-dioxospiro[4.5]decane (460 mg) was obtained as an almost colorless oil. As a product. Yield = 69%. LCMS detection (M+) + = 375.14. Straight example la step zen 5. Make 8-((3S)-3-( 氧 谈 胺 胺 胺 yl)-2- keto tetrahydro! Ratio p-1 - 95318 -141 - 1354664 base) - 1,4-dioxospiro[4.5] 癸 entertainment &lt; (2.70 g, 7.21 mmol, 1 equivalent) with p-toluenesulfonic acid (0.14 g, 0.721 mmol [0.1 eq.), dissolved in acetone (20 mL) at room temperature. "Reflow for 4 hours." The reaction was not completed by TLC. Add IN HC1 (10 ml). Reflux for 10 minutes. Steam raised acetone. Add saturated sodium hydrogencarbonate (25 ml) and extract three times with di-methane (25 mL). The organic layer was combined and dried under sodium sulfate and stripped to give (3S)-2-keto-1-(4-ketocyclohexyl)-tetrahydrop-ha-haz-ylaminocarbamate. Ester (2.40 g) is a color-coded glass material. Yield = 95%. LCMS detection (M+) + = 375.14. 3 cases la step 骡 6 : (3S)-2-keto-1-(4-ketocyclohexyl)_tetrahydrop Ethyl carbazate (2.40 g ' 7.26 mmol, 1 eq.), tert-butylamine (0.84 mL, 7.99 mmol, 1 1 eq.) and titanium isopropoxide (4.68 mL, 16.0 mmol) , 2.2 equivalents) were mixed and stirred at room temperature under nitrogen for 2 hours. Treated by adding methanol (50 ml) and stirring for 1 hour 'then adding sodium borohydride (granules) (0.27 g ' 7.26 mmol, 1 equivalent p after 1 hour, add 50 ml of l. 〇NNaOH, and Stir. After 2 minutes, extract 3 times with dichloromethane (5 mL). Combine the organic layers, dehydrate with sodium sulfate, and strip the 'amber oil' on the crushed gel' in 100% acetic acid. Purification of ethyl ester to 4: ^ dichloromethane / methanol. Obtained cis and trans _ isomer (38) small (4 - (t-butylamino) cyclohexyl)-2- ketotetrahydro A mixture of pyrrolic acid carboxylic acid (700 mg) in amber oil. Yield = 25%. LCMS detected as +in + two 388.2.

[Example la step _2 2 under nitrogen, 20% fine hydroxide (150 mg) was carefully wetted down with methanol (10 ml), then cis and trans isomers (3S) were added. -l-(4-(Third-butylamino)cyclohexyl)_2-ketotetrahydropyrrole_3_ylaminomethyl 95318-142· 1354664 Sour vinegar (700 mg) is dissolved in methanol mixture. The mixture was hydrogenated on a Parr shaker for 20 hours. The glass fiber filter paper was passed through a glass filter under nitrogen to be treated by a catalyst. Stripping the mash, and obtaining cis- and trans-(Μ)·]amino-1-(4-(tri-butylamino)-cyclohexyl)tetrahydro-p-Bolo_2_嗣 ( 45〇 mg), as an oil. Yield = 98%. LCMS detection (M+H) + = 254.26. t Example la and lb Step 8: Small cis and trans-isomer (3S)-3-amine groups (4-( a mixture of tris-butylamino)cyclohexyl)tetrahydropyrrole-2-one (6 mg, 〇.237 mmol, 1 equivalent), 4-chloro-6-(trifluoromethyl)carbazole Porphyrin (72 mg, 〇3〇8 when Mohr '1.3 equivalent) and triethylamine (0.13 ml, 0.947 mmol, 4 equivalents), soluble in ethanol at room temperature, then at l ° ° C Microwave for 1 hour. Purified by HpLC. Separation of two dispersing fractions: the first dissolving fraction produces cis: trans (3S)-l-(4-(tri-butylamino)cyclohexyl)·3·(6·(trifluoromethyl) a 1:1 mixture of p-quinazoline-4-ylamino)tetrahydropyrrole-2-one, TFA salt (25 mg) as a white solid. LCMS detection (Μ+Η)+=450·17. The second dissolving fraction produced 100% trans (3S) 1·(4_(second-butylamino)J-hexyl)-3-(6- (Tri-gas methyl) 〇 唾 唾 _ _ 4-amino-amino) tetrahydro-p-ha-2-one TFA salt (27 mg) 'as a white solid. LCMS detection (M+H)+= 450.17. Examples le and If: cis- and trans-(3S)_3_tri-butyl(tris-butylamino)cyclohexyl)-2-one Synthesis of tetrahydropyrrole _3_yl)-benzylbenzimidamide _ Example le and If Step 1: cis and trans-isomer (3S)-3-amino-1-( a mixture of 4-(t-butylamino)-cyclohexyl)tetrahydropyrrole-2-one (60 mg, 0.237 耄mol' 1 equivalent), tert-butyl-4-cyclobenzoic acid ( 55 mg, 0.284 mmol [1.2 equivalents), 1-hydroxybenzotriazole hydrate (Η〇ΒΤχ38 mg, 〇284 mmol) 1.2 equivalents, 1-[3-(dimethylamino)propyl ]_3_Ethylcarbodiimide 95318-143- 1354664 HCl (EDCI) (54 mg, 0.284 mmol, 1.2 eq.), triethylamine (66 μL, 0.474 mmol, 2 equivalents) and dichloro Methane (5 mL) was stirred at room temperature under nitrogen overnight. Purified by HPLC. Separating the two dissolving fractions, the first dissolving fraction produces cis- and trans-(3S)-3-tri-butyl-N-(l-(4-(tri-butylamino)-)- A 3:1 mixture of cyclohexyl)-2-g-isotetrahydropyrrol-3-yl)-4-carbylbenzamide, TFA salt (10 mg), as a white solid. LCMS detection (M+H)+ = 430.23. The second fraction produced 100% trans-(3S)-3-tri-butyl-N-(l-(4-(t-butylamine) The base)-cyclohexyl)-2-ketotetrahydropyrrol-3-yl)-4-hydroxybenzoguanamine TFA salt (20 mg) was obtained as a white solid. LCMS detection (M+H)+= 430.23.

Table 1-A The compounds in the table below were prepared using the methods exemplified above. The substituents listed in the tables are intended to be paired with the structure embedded in the header. In the synthesis of certain example compounds, the substitution of key reagents is performed to provide different compounds, and the point of variation is shown in the "Steps of Change" column. Some of these changes require reagents that are not commercially available, and this The synthesis of a particular reagent is described in the paragraph entitled "Preparation of Non-Standard Reagents and Synthetic Intermediates Used in the Examples" above. The nature of any changes made in the context of a large number of statements made before and after this table is obvious to those skilled in the art. In the step-by-step column of the change, it is said that the (10)&quot; indicates that the &quot;unintentional&amp;&quot; order has been performed as written by the author, without change. The data in the &quot;ms" column indicates the value of (m+h)+ ions found in the electrospray mass spectrometry experiment. 95318 -144- 1354664 Example la R5 t-Bu-NH 1:1 mixture of cis and trans R2 Changed MS Data Step lb t-Bu-NH 100% Trans lc

Id t-Bu-NH cis and trans 2:3 mixture t-Bu-NH 100% trans

Nv^N n/a n/a la Step 7 la Step 7 450.2 450.2 427.2 427.2 le

If t-Bu-NH cis and trans 3:1 mixture t-Bu-NH 100% trans n/a 430.2 Ο I ο n/a 430.2 95318 -145 - 1354664 t-Bu-NH V le Step 1 403.3 cis and Jr trans •s^ ^ Ο 1:1 V mixture 0 Η t-Bu-NH \J le Step 1 417.2 cis and Jr&quot; trans li 1:1 V mixture 〇 \ t-Bu -NH le Step 骡 1 481.3 cis and trans / Γ 1:1 N mixture 〇 \ H t-Bu-NH r\i le step 49 1 495.2 cis and trans 1:1 N mixture ο \ ig Lh li

Ij

Table 1-B The list of chemical names for the specific examples shown in Table 1-A is shown below. Example name la cis-(3S)-l-(4-(Third-butylamino)cyclohexyl)-3-(6-(trifluoromethyloxazol-4-ylamino)tetrahydropyrrole · 2-keto lb trans-(3S)-l-(4_(Third-butylamino)cyclohexyl)-3-(6-(trifluoromethyl)-endo-p-lin-4-ylamino Tetrahydrop-bi-H-2-indene with lc cis-(3S)-l-(4-(tris-butylamino)cyclohexyl)-3-(6-tri-butylpyrrolo[ l,2-f][l,2,4]Triton-4amino)dihydropyrrole-2-one Id trans-(3S)-l-(4-(tri-butylamino) Cyclohexyl)-3-(6-tris-butylpyrrolo[1,2-hunger 1,2,4]trin-4-ylamino)tetrahydropyrrol-2-one le cis-( 3S)-3-Terti-butyl-N-(l-(4-(t-butylamino)cyclohexyl)-2-one tetrathiapyrrole-3-yl)-4-carbylbenzene Formamide 53518 -146- 1354664

If trans-(3S)-3-tert-butyl-indole-(1-(4.(T-butylamino)cyclohexyl)-2-mercaptotetrahydropyrrol-3-yl)- 4-Phenylbenzamide ig cis-and trans-(3S)-4-tri-butyl-N-(l-(4-(tri-butylamino)cyclohexyl)-2 -ketotetrahydropyrrol-3-yl&gt;1H-pyrrole-2-indene lh cis- and trans-(3S)-4-third-butyl-n_(1_(4_(third Butyl-amino)cyclohexyl)-2-ketotetrahydropyrrol-3-yl)small methyl-1H-pyrrole·2·sodium amidoxime cis-and trans-(3S)·4-gold Talane-1·yl·v_(1-(4-(t-butylamino)cyclohexyl)-2-onetetrahydropyrrole_3_yl)·1Η_pyridin_2_ And-trans-(3S)-4-gold alkyl-1-yl-Ν-(ΐ·(4-(tri-butylamino)cyclohexyl)-2-one-tetrahydropyrrole_3 _ base)-1_methyl_1Η_ 峨洛-2- aryl amine Example 2a · 2av Example 2a: N_{(3S) small oxime (ls, 2R, 4R)-4·(isopropylmethylamine Synthesis of 2) propyl·cyclohexyl yl-2-hydrazyl _tetrahydropyrrole _3_ kib 2-(3-isopropylcarbyl)_5-trifluoromethylbenzamide 骤 1. (lR, 2S, 5R)-2-aryloxycarbonylamino-7-keto-6-nitro-bicyclo[3_2.1] Alkyl-6-carboxylic acid tert-butyl ester (46 g, 12 3 mmol) in a cooled (〇 〇) solution in (100 ml), add seven (37 ml, 1 in THF). The solution was stirred at 〇〇c for 1 〇 5 minutes. The reaction was quenched with 1 N HCl and extracted with Et EtOAc (2 EtOAc). The organic extracts were combined and washed with brine and dried (NaaSO4) ), filtered and concentrated in vacuo to give (lR,2S,5R,7R/S)-2-(benzyloxycarbonylamino)_7_ylamino-6-nitro-bicyclo[3 21]octane -6-dibasic acid third · butyl ester' is a mixture of diastereomers ^ ms measured value: (M-H2 〇 + H) + = 359.2. This substance is dissolved in thf (2 〇 ml) And added to the mothium ethyltriphenyl scale (6 4 g, 95318 -147·1354664 14.8 mmol) and khmDS (31 ml, 0.5 Μ solution in toluene) by cannula (6 ml THF rinse) Pre-mixed (15 minutes) pre-cooled (〇. (:) in solution. The reaction was stirred at (TC for 25 min. with EtOAc (2 χ). The extracts are combined and washed with brine , dehydration and drying (Na2SO4), filtration, and concentrating in vacuo. Purify the residue by flash chromatography to provide the desired [(111,3Min 43)-(4-benzyloxycarbonyl-amino-3-propyl归-cyclohexyl)-aminomethyl acid tert-butyl ester, colorless oil (3·44 g, 72% yield). MS found: (Μ+Η:)+= 389.3. Example 2a·» Step 2: [-(111,3Min 43)-(4-Benzyloxycarbonyl-amino-3-propenyl-cyclohexyl)-amine methyl acid tert-butyl ester (3.44 g) in MeOH (50 ml 5% Pd/CDegussa (1 g) was added to the solution. The reaction flask was evacuated and then counter-filled with hydrogen; it was repeated three more times. The reaction was stirred at 1 atmosphere H2 for 4 h then filtered and concentrated in vacuo to give (1r,3r,4S)-(4-amino-3-propyl-cyclohexyl)-aminemethyl Acidic third-butyl ester (quantitative). MS found: (M+H)+= 257.3. Yichuang 2a Step 3: Let (lR,3R,4S)-(4-amino-3-propyl-cyclohexyl)-amine methyl acid third- A butyl ester sample (1.9 mmol) was dissolved in 1:1 CH2Cl2/DMF (4 mL) and N-Cbz methionine (591 mg, 2.1 mmol) was added to the resulting solution. , N,N-diethylisopropylamine (1 ml, 5.7 mmol) and bop (1, gram, 2.3 mmol). The reaction was stirred at room temperature for 12 hours and then partitioned between Et EtOAc and sat. NaHC EtOAc. The organic phases were combined, washed with brine, dried and dried, filtered and concentrated in vacuo. The residue is purified by flash chromatography to give (1r,3r,4s)_[4-((2S)-2-yloxycarbonylaminomethylmethylthio-butanylamino)_3_propyl-cyclo ???95318-148- 1354664 base]-amino-mercaptoic acid tert-butyl ester (375 mg). MS measured value: such as + India += 522 3 Change sword 2a Step 4: _ Compound (UUR, 4S)-[4-((2S)-2-芊 oxycarbonylamine carbamoyl-butanylamino) -3-propyl·cyclohexyl]-amine methyl acid tert-butyl ester (375 mg) was wetted with EtOAc, then most of the Et? In 6 ml), the resulting solution was stirred at room temperature for 48 hours and then concentrated in vacuo. The residue is dissolved in methylene chloride and the resulting solution is concentrated; this is repeated to give a salt. MS found: (M+H)+=536.3. This material was dissolved in DMF (12 mL), and Cs2C〇3 (470 mg &lt; It was stirred for 12 hours and then partitioned between EtOAc and brine. The organic phase was dried (NazSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography to give {(3S)-l-[(lS,2R,4R)-4-tris-butoxycarbonylamino-2-hydroxy-cyclohexyl]-2- Reticyl-tetrahydropyrrol-3-yl}-amine methyl benzylate (185 mg). MS found: (M+H)+ = 474.3. Optimum _ Example 2a Step 5: at {(3S)-l-[(lS,2R,4R)-4-Terti-butoxycarbonylamino-2-phenyl Add 5% pd to a solution of benzyl-cyclohexyl]-2-keto-tetrahydropyrrol-3-yl}-amine methyl benzylate (185 mg '0.54 mmol) in MeOH (8 mL) /c Degussa (180 mg). The reaction flask was evacuated and then counter-filled with hydrogen; it was repeated three more times. The reaction was stirred at 1 atm for 12 hours, then filtered and concentrated in vacuo to give (l,,,,,,,,,,,,,,,,,, Hydrogen pyrrol-1-yl]-3-propyl-cyclohexyl}-amine methyl acid tert-butyl ester. MS found: (M+H:)+=340.3. Example 2a Step 6: (1 Min 3 Min 43)-{4-[(33)-3-Amino-2-keto-tetrahydropyrrole _1·yl]-3-propyl-cyclohexyl}-amine mercapto acid tert-butyl ester (assumed to be 0.27 mmol) 95318 • 149- 1354664 In a solution of DMF (4 ml), add 2 -(3-isopropyl-ureido)-5-trifluoromethyl-benzoic acid (82 mg, 〇. 3 mmol), N N-diethylisopropylamine (〇 19 mL, 1.1 mmol) And B〇P (142 mg, 〇32 mmol). The reaction was stirred at room temperature for 48 h then partitioned between EtOAc and sat. NaHC.sub.3; The organic phases are combined, washed with brine, dried (NazSO4), filtered, and concentrated in vacuo to give (lR,3R,4S)-(4-{(3S)-3-[2-(3-isopropyl) 5-ureido)-5-trifluoromethyl_benzylammonium]_2-keto-tetrahydropyrrole-l-yl}-3-propyl-cyclohexyl)-amine methyl acid Vinegar. MS found: (m+h)+=612.3. i Example 2a, H will (lR,3R,4S)-(4-{(3S)-3-[2-(3-isopropyl-urea) _5_trifluoromethyl-benzylaminoamido]-2-keto-tetrahydropyrrole-i-yl}-3-propyl-ring A solution of hexyl-tert-methyl-acid-tert-butyl ester in CH2C12 (6 ml), trifluoroacetic acid (4 ml), and mixed. After 1 hour, the mixture was concentrated in vacuo. The residue was dissolved in EtOAc (aq) (EtOAc) (EtOAc) The organic phase was washed with brine, dried and dried (Na2SO4), filtered, and concentrated in vacuo to give an amine. MS found: (Μ+Η)+=512·3· In MeOH (6 mL), add acetone (-0.75 mL); stir the mixture for 5 min' then add NaCNBH3 (~100 mg). The reaction was stirred at room temperature for 4 hrs. 33 ml, 30% aqueous solution) The mixture was stirred for 1.5 hours, the reaction was quenched with saturated NaHC 〇3, and extracted with Et EtOAc (2×). The organic extracts were combined and washed with brine. &amp;2§〇4), Filtration' and concentration in vacuum "purification of the residue by reverse phase HPLC on freeze 95318 -150· 1354664 After drying, 'obtained the title compound> 1-{(33)-1-[(18,2Min 41〇-4-(isopropyl-methylamino)-2-propyl-cyclohexyl ]-2-keto-tetrahydropyrrole·3_kib 2-(3-isopropyl-ureido)-5-trifluoromethyl-benzamide (also known as isopropyl (fluorenyl) a TFA salt of amino)-2-propylcyclohexyl)-2-copperyltetrahydropyrrol-3-yl)amine-methylmethyl]-4-(trifluoromethyl)phenyl b. As a white powder (9 mg). MS found: (free state M+H)+= 568 3. Example 2c: l-{2-[(((S), 2R,4R)-4-(isopropyl(methyl)amino) ······························································ 3S)-l-[(lS,2R,4R)-4-Terve-butoxycarbonylamino-2-hydroxy-cyclohexyl]-2-keto-tetrahydropbilo-3·ylbumin To a solution of decyl decyl ester (3 88 g, 8.2 mmol) in CH.sub.2. The residue was partitioned between EtOAc EtOAc (EtOAc (EtOAc) And concentrated in vacuo to give (S)-l-[(lS,2R,4R)-4-amino-2-propylcyclohexyl]-2-onetetrahydropyrrole-3-ylaminocarboxylic acid芊 ester. MS measured value: (m + H) + = 374.3. Preferably _M_2c Step 2: Make all (S)-l-[(lS, 2R, 4R)-4-amino group produced in step 1 - 2-propylcyclohexyl]-2-ketotetrahydropyrrole Ethyl carbazate (presumed to be 8.2 mmol) was dissolved in methanol (40 mL). Acetone (6 liters, 82 mmol) was added to the resulting solution and stirred at room temperature 1 After a few minutes, a sodium cyanoborohydride (2.6 g, 41 mmol) was added in one portion. The reaction was stirred at room temperature for 10 hrs, then EtOAc (3 mL, 37 wt%

• 15 U 1354664 liquid '41 mmoles) with sodium cyanoborohydride (〇 52 g, 8.2 mmol). The reaction was stirred at room temperature for additional 9 hr then sat. NaHC.sub.3 (150 mL) Quenched. The aqueous mixture was extracted with EtOAc (200 mL then 2 X 75 mL). The organic extracts were combined, washed with brine (3 mL EtOAc), dried and evaporated. After the formed oil was allowed to stand, a portion of the polyoxymethylene-related product solidified; it was removed by dissolving the mixture in a minimum volume of EtOAc and filtering. Concentration followed by benzyl 4-(isopropyl(methyl)amino)-2-propylcyclohexyl]-2-ketotetrahydropyrrol-3-ylcarbamate. MS found: (m+H)+=430.5. Example 2c Step 3: To make all (S)-l-[(lS,2R,4R)-4-(isopropyl (methyl) Benzylamino)-2-propylcyclohexyl]_2-ketotetrahydropyrrol-3-ylaminocarbamate (assumed to be 8-2 mmol) wet with 3 ml of EtOAc, then 30% HBr/AcOH (30 ml). The reaction vessel was allowed to warm and a vigorous gas evolution occurred. The mixture was stirred at room temperature for 25 minutes, and then the flask was placed in a cooling water bath, followed by the addition of 150 ml of 1:1 Et20/H20. This mixture was mixed, separated, and the aqueous phase was extracted once with Et 2 hydrazine. The aqueous phase was basified to pH 14 by addition of solid NaOH (the temperature of this exothermic process was controlled by intermittent use of an external ice bath) and the mixture was extracted with EtOAc (75 mL, then 2 X 35 mL). . The organic extracts were combined, washed with brine (3 mL, EtOAc) EtOAc (EtOAc) elute The mixture was dissolved in a minimum volume of EtOAc, filtered and concentrated to afford (8) </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; Hydrogen p is more than ha-2-indole (2.31 g, 1H-NMR shows 7F to 30% EtOAc, which indicates an estimated 7. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; MS found: (M+H)+= 296.6. 4: ^(8)-3-Amino group small [(13,2艮4 ft)-4-(isopropyl(methyl)amino)-2-propanthene Add N,N-diisopropylethylamine (〇32 ml), 2_(in solution of cyclohexyl)tetrahydropyrrole-2-one (77 mg, 0.26 mmol) in DMF (2 mL) 3_ethylureido)-5-(trifluoromethyl)benzoic acid (80 mg) and HATU (129 mg). The reaction was stirred at room temperature for 14 hours, diluted with water, filtered, and purified by RP-HPLC to give 1-{2-[((3)) -(isopropyl(indenyl)amino)-2-propylcyclohexyl)-2-copperyltetrahydrop-pyrrol-3-yl)aminemethyl-yl-4-(trifluoromethyl)benzene Base}-3-ethylurea. MS found: (M+H)+ = 554.4. [Note: For larger scale preparations, the reaction is often carried out using CH2C12 as a cosolvent and before the RP-HPLC purification, using the aqueous solution described below. The volatiles were removed and the residue was dissolved in EtOAc. The organic phase was washed with saturated NaHC03' water, 1NHQ, sat. NaCI, then dried (MgSO4), filtered and concentrated in vacuo. Example 2i: 6-Tertibutyl-indole-((38)-1-((18,2ΙΜΙ〇-4-(isopropyl(methyl)amino)-2-propylcyclohexyl)-2- Synthesis of thio-tetrachloro-p-pyridin-3-yl)methyl-p-rh- s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s Propyl (fluorenyl)amino)-2-propylcyclohexyl)tetrahydropyrrole-2-one (41.7 mg, 0.14 mmol, 1 equivalent), 6-tert-butylpyridinecarboxylic acid HC1 salt ( 37 mg, 0.168 mmol, 1.2 eq.), 1-hydroxybenzotriazole hydrate (H0BT) (19 mg, 0.168 mmol, 1.2 eq.), 1-[3-(dimethylamino)propyl ]-3-ethylcarbodiimide HC1 (EDCI) (28 mg, 0.168 mmol, 1.2 eq.), triethylamine (24 μL, 0.282 mmol, 2 eq.) and THF (5 mL) Stir at room temperature under nitrogen overnight. Purify by RP-HPLC. After lyophilization, obtain 41 mg of 6-t-butyl-butyl 95318 • 153- 1354664 good ((38)-1-((18,2 411 )-4-(isopropyl(methyl)amino)·2·propylcyclohexyl)·2·copperyltetrahydro'^pyr-3-yl)methyl ρ is a tfa salt of bitten amine Double JFA salt, white solid. MS measured (Μ+Η)+= 457.4. Example 2k: (8)-1-[(18,2 Min 4 ft)-4-(isopropyl(methyl)amino)_2-propylcyclohexyl]_3_ ( Synthesis of 6-(trifluoromethyl)(indolyl-4-ylamino)tetrahydropyrazole-2-germination tl1〗 2k Step 1: On (S)-3-amino-l-[(lS, 2R,4R)-4-(isopropyl(methyl)amino)-2-propylcyclohexyl]tetrahydropyrrole-2-one (7.0 mmol) in EtOH (23 mL) Add triethylamine (2.5 ml, 17.5 mmol) with 4-chloro-6-(trifluoromethyl) quinazoline (2.03 g, 8.75 mmol). Heat the mixture at 75 °C. Hour' then concentrated in vacuo [Note: This residue can be diluted in water/acetonitrile at a smaller reaction scale] and directly purified by RP-HPLC. The residue is dissolved in 6 mL 2 : 1 H20/Ac0H and extracted twice with .Etz®. The aqueous phase was basified to pH 14 with solid NaOH (the temperature of this exothermic process was controlled by intermittent use of an external ice bath), followed by extraction with EtOAc Three times. The organic extracts were combined, washed with brine, dried (Na2SO*), filtered and concentrated in vacuo. The title compound (8) small [(1S,2R,4R)_4_(isopropyl(indenyl)amino)-2-propylcyclohexyl]-3-(6- (Trifluoromethyl)quinazolin-4-ylamino)tetrahydropyrrol-2-one as a white microcrystalline solid (1.83 g, 52% yield). MS found: (M+H)+ = 492.4. [Note: Purification of the mother liquor using rp-HPLC afforded the title compound as its bis-TFA salt]. Example 2P: (3S)-l-((lS,2R,4R)_4-(isopropyl(methyl)amino)2propylcyclohexyl)-3-(6-(2-methoxyphenyl) Synthesis of oxazoline-4-ylamino)tetrahydropyrrole-2·one Example 2p Step H: In a sealed 5 ml microwave tube, (3S)-3-amino group 95518 • 154· 1354664 -1- ( (18,21^411)-4-(isopropyl(methyl)amino)·2-propylcyclohexyl)tetrahydropyrrole-2-one (38 mg '0.13 mmol), 4-chloro group a solution of 6-(2-methoxyphenyl) thiazoline (42 mg, 0.15 mmol) and triethylamine (0.054 mL, 0.39 mmol) in ethanol (2 mL) At 1〇〇. Heat under the arm for 60 minutes. The reaction was cooled to room temperature, EtOAc (EtOAc m. MS found: (M+H)+= 530. Example 2r and 2s: (S)-3-(6-yl-quinazolinylamino)-l-((lS,2R,4R)-4-( Isopropylamino)-2-propylcyclohexyl)tetrahydroindolyl 2-ketone with (S)-3-(6-chloropyridinium-4-ylamino)-l-((lS Synthesis of 2R,4R)-4-(ethyl(isopropyl)amino)-2-propylcyclohexyl)tetrahydropyrrole-2-immunization Example 2r and 2s Step 1: On (lR, 3R, 4S)-{4-[(3S)-3-Amino-2-keto-tetrahydropyrrol-1-yl]-3-propyl-cyclohexyl}-amine methyl acid tert-butyl ester (〇· 66 mM) in EtOH (8 mL), add triethylamine (0.5 mL, 3.3 mmol) and 4,6-dichlorooxazoline (200 mg, 1.0 mmol), then Heating at 8 (rC for 12 hours). The reaction mixture was cooled and purified by flash chromatography to give (lR,3R,4S)-4-((S)-3-(6-chloro-kiquix) 4-Aminoamino)-2-ketotetrahydrop-haha·ι_yl)-3-propylcyclohexylaminocarboxylic acid tert-butyl ester. MS found: (Μ+Η)+ = 502.2. Example 2r and 2s Step 2: Part of (lR,3R,4S)-4-((S)-3-(6-chloroquinazolin-4-ylamino)-2-oneyl-4 Hydrogen p-hah-1-yl)-3-propyl ring The hexylaminocarboxylic acid tri-butyric acid was subjected to the procedure outlined in Step 7 of Example 2a, replacing the furfural with acetonitrile. Purification by RP-HPLC provided two products: (s)-3-(6-chloro) , Kudolin-4-ylamino)-l-((lS,2R,4R)-4-(isopropylamino)_2-propylcyclohexyl)tetrahydrop ratio 95318-155· 1354664 Ha- 2-嗣TFA salt [MS found: (M+H) + = 444], and (5)-3-(6-chloro; quinamicolin-4-ylamino)-1-((13,2ϊΜΙΙ) TFA salt of 4-(ethyl(isopropyl)amino)-2-propylcyclohexyl)tetrahydropyrrole-2-one [MS found: (M+H)+ = 472]. And such as: (8)-1-((18,2 收)-4-(Third-butylamino)_2 propylcyclohexyl)-3-(6-(trifluoromethylzoline-4 -ylamino)tetrahydropyrrole-2-ketone with (s)-i-((lS,2R4S)-4-(t-butylamino)-2-propylcyclohexyl)-3-(6 -(Trifluoromethylphosphazinylamino)tetrahydropyrrole-2-one Synthesis Example 2t and 2u Step 1: _ 7-keto-6-oxo-bicyclo[3.2.1] octane- A solution of the 2-yl)-amino decyl decyl ester (2.2 g, 8.2 mmol) in toluene (80 mL) was cooled to -78 ° C and taken to DIBAL-H (15 mL, 1.5Μ the benzene solution) treatment. The reaction was stirred at -78 °C for 4 hours and quenched with a 1N HCl solution. The mixture was allowed to warm to room temperature and extracted with EtOAc. The organic extracts were combined and washed with brine, dried, filtered, and concentrated in vacuo. The residue was dissolved in THF (20 mL) and taken to EtOAc (EtOAc &lt;RTI ID=0.0&gt;&gt; 30 minutes) pre-cooled (0 ° C) in the solution. The reaction was stirred at 0 °C for 20 minutes before quenching the reaction with saturated ammonium sulfate. The organic layer was separated and the aqueous mixture was extracted with ethyl acetate. The combined organic phases were washed with brine, dried, filtered, and concentrated in vacuo to purify the residue by flash chromatography (lS, 2S, 4R)-4-Benzyl-2-((Z)-propan-1-yothyl)cyclohexylaminocarbamate was contaminated with a small amount of its (E)-isomer (1.2 g). Found: (M+H)+=290. Example 2t舆2u Step 2: (lS,2S,4R)-4-Pylan·2-((Ζ)-propan-1-yl)cyclohexylamine A solution of benzyl carbamate (6.0 g, 20-7 mmol) in dichloromethane (6 mL), 95318 - 156 - 1354664 was treated with imidazole (2.1 g) and cooled to EtOAc. To the resulting solution was added 't-butylchlorodimethyl decane (3.4 g, 22.8 mmol), and then stirred at 30 C for 18 hours, then quenched with water. The organic phase was separated&apos; and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with brine, dried <RTI ID=0.0>~~~~~~~~~~~ The residue was purified by flash chromatography to give (lS,2S,4R)-4-(tris-butyldimethylmethylalkyloxy)_2·((ζ)-propan-1-yl) Ethyl cyclohexylaminocarbamate (6 g). MS measured value: ^+印+= 404. Suitable-example 2t and 2u step _11_((lS,2S,4R)-4-(T-butyldimethyl decyloxy)-2- ((Z)-propan-1-phenyl) decyl carbaryl carbazate (3 g, 〇74 mmol) in 10 ml of 7:3 EtOH: EtOAc, palladium hydroxide, and Stir under a helium atmosphere for 22 hours. The saturatedness was removed by filtration and fresh palladium hydroxide was added to the solution and then placed again under a hydrogen atmosphere (5 kg pressure). After 3 hours, it was washed with EtOAc (EtOAc) and filtered and evaporated. The residue was dissolved in DMF (3 mL) and the resulting solution was cooled to 0 ° C then successively added (S)-Cbz methionine (0.31 g '1 亳 亳 耳), N· 曱 曱Joffin (0.24 ml, 2.2 mmol) and B0P reagent (0.48 g '1.1 mmol). The reaction was allowed to warm slowly to 3 liters then stirred for 12 hours then quenched with water. The mixture was extracted with EtOAc and EtOAc (EtOAc)EtOAc. The residue was purified by flash chromatography to give 4-(t-butyl-dimethyl- succinyloxy)-2-propylcyclohexylamino)-'(methylthio)-1-one Ethyl keto-2-ylaminocarboxylate (〇_25 g). MS found: (μ+Η)+ = 537. 95318 -157- 1354664 Let (3)-KdsjMRM-c tris-butyldimethylmethylalkyloxy)-2-propylcyclohexylamine)_4_(A A sample of thio))- butylbutan-2-carboxylate (4.0 g, 7.45 mmol) was dissolved in methyl iodide (8 mL) and stirred at 3 ° C for 3 days. The solution was concentrated in vacuo. The residue was dissolved in methylene chloride and the resulting solution was concentrated again in vacuo; this procedure was repeated twice and then the residue was placed under high vacuum for 4 hours. The resulting pale yellow foam solid was dissolved in THF (40 mL) and the formed residue was cooled to &lt;RTI ID=0.0&gt;&gt; The mixture was slowly warmed to 30 C ' and stirred for 12 hours before quenching the reaction with saturated ammonium chloride. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic phases were washed with brine, dried over Celite, filtered and concentrated in vacuo. The residue is purified by flash chromatography to give (s) small ((ls, 2Rj4R)-4- 4-(t-butyldimethyl decyloxy) 2 - propylcyclohexyl) 2 - copper Benzyl tetrahydroindol-3-ylaminocarbamate (〇9 g). MS found: (M+H)+= 489.2. Preferably jH2t and 2 ιι Step 5: (S)-l-((lS,2R,4R)-4-(T-butyl-dimethyl dimethyl ketone A sample of oxy)-2-propylcyclohexyl)-2-ketotetrahydrop-pyrrol-3-ylaminocarbazate (0.4 g '0.82 mmol) dissolved in 36 ml 4:1:1 HOAc / THF / water and stirred at room temperature for 5 days. The volatiles were removed in vacuo and the residue dissolved in EtOAc. The organic phase was washed with saturated NaHC03, dried (MgSO.sub.4), filtered and concentrated in vacuo. The residue was dissolved in dichloromethane (4 mL) and the resulting solution was cooled to &lt;RTI ID=0.0&gt;&gt; After stirring at room temperature for 2 hours, the solution was again cooled to 〇 ° C, and Dess-Martin (0.27 g) was added. The reaction was stirred at room temperature for 14 hours and treated with EtOAc. The suspension formed by 95318 -158· 1354664 was washed with IN NaOH, saturated Na] S2 〇3 and saturated NaHC03. The organic phase is dried (MgS 4), filtered, and concentrated in vacuo to give (S)-2-keto-l-((lS,2R)-4- keto-2-propylcyclohexyl Tetrahydro-u-bilo- 3-ylaminocarbazate (114 mg). MS found: (M+Na)+= 395.4, Example 2t and 2u Step 6: 佬(S)-2-keto-l-((lS,2R)-4-keto-2-propylcyclohexyl A sample of benzyl tetrahydropyrrol-3-ylamino decanoate (114 mg) dissolved in Ti(0iPr)4 (1_5 ml, 5.0 mmol) and a third-butylamine (0.14 ml, L8 mmol) In the ear). The resulting solution was stirred at room temperature for 3 hours then cooled to EtOAc and MeOH (2 mL) and NaBH4 (2. The mixture was stirred for 90 minutes while allowing the solution to slowly warm to room temperature. The solution was diluted with methylene chloride (10 liters) and 0.5 N NaOH was added. After pulverization, the mixture was washed with EtOAc, and the resulting suspension was filtered, and the filtrate was dried, filtered, and concentrated in vacuo to give (3)-1-((18,2,41)-4 - (Third-butylamino)-2-propylcyclohexyl)_2-ketotetrahydropyrrole-3-ylaminocarboxylic acid vinegar as an inseparable mixture of diastereomers. MS found: (m+H)+ = 430.5. Example 2t舆2u+唧7: Your carbamic acid (5) is small ((lSJMR/SVM tert-butylamine)-2-propylcyclohexyl)-2- A sample of ketotetrahydropyrrol-3-yl ester (11 mg) was dissolved in MeOH 'and in the solution formed, 1% pd/CDegussa type (22 mg) was added' and then pumped off, and hydrogen was added. . The mixture was stirred under 1 atm of hydrogen for 14 hours before being washed with EtOAc (EtOAc). The filtrate was concentrated in vacuo to give EtOAc (EtOAc). To the 4 solution formed, triethylamine (0.15 ml) and 4·chloro-6-trifluoromethylquinazoline were added, followed by 8 Torr. (: heating under 14 hours. The reaction was allowed to cool to room temperature and concentrated in vacuo. The residue was dissolved in Et EtOAc and sat. sat.

Wash with NaHC03, water and saturated NaCl. The organic phase was dried (MgS04), filtered and concentrated in vacuo. The residue was purified by RP-HPLC. After lyophilization, (3)-1-((13,2) -4-(tris-butylamino)-2-propylcyclohexyl)- The TFA salt of 3-(6-(trifluoromethyl)quinazolin-4-ylamino)tetrahydropyrrole-2-one is a white powder. MS found: (M+H)+= 492.4. This product (S)-l-((lS,2R4S)-4-(Third-butylamino)-2-propylcyclohexyl)-3-(6-(trifluoromethyl)oxazoline- The diastereomer of 4-aminoamino)tetrahydropyrrole-2-one was also isolated from RP-HPLC. MS found: (M+H)+ = 492.4. Example 2ai: 1-((8)_1-((18,21^41〇-4-(isopropyl)methyl)) Synthesis of Cyclohexyl)-2-ketotetrahydropbilo-3-yl)-3-(3-(trifluoromethyl)phenyl) pulsin 2ai Step 1 : (S)-3-amine Base-l-[(lS,2R,4R)-4-(isopropyl(indenyl)amino)-2-propylcyclohexyl]tetrachloro-p-pyrene-2-repay (33 house, 0.11 mil a solution of acetonitrile (1 ml) in N,N-diisopropylethylamine (0.12 mL, 0.66 mmol) with 1-isocyanato-3-(trifluoromethyl)benzene (0.05 ml, 0.33 mmol). The reaction was stirred at room temperature for 14 h, diluted with water, and filtered. The obtained solution was purified by RP-HPLC. TFA salt, white powder (12.3 mg). MS found: (m+H)+= 483.4. Example 2aj: l-((S)-l-((lS,2R,4R)-4-(isopropyl Synthesis example of (meth)amino) 2 - propylcyclohexyl)-2-indenyltetramethylene pyl-3-yl)-3-(3-(trifluoromethyl)phenyl) Step 1: :(S)-3-Amino-l-[(lS,2R,4R)-4-(isopropyl(methyl)) a solution of 4-hydroxycyclohexyl]tetrahydro-p-ha-2-one (90 mg, 0.3 mmol) in MeOH (4 mL), 3-trifluoromethylbenzaldehyde (0.061 mL) , ο% millimolar), and stirred at room temperature for 10 minutes, then add cyanoborohydride 95318 -160-1354664 nal (60 mg, 0.992 mmol). The reaction was stirred at room temperature. After 4 hours, the reaction was quenched with EtOAc EtOAc (EtOAc)EtOAc. Purified by RP-HPLC, EtOAc (EtOAc) (EtOAc)叩 'take 丨 决 彳 彳 methyl 腾 ^ ^ - propyl cyclohexyl)-3- (6-(trifluoromethyl) + Lin _4_ ylamino) tetrahydropylo-2-one and (R)-l-((1S,2R»4R)_4_(isopropyl(f-)amino)-2-propylcyclohexyl)-3-(6-(trifluoromethyl)-4 -4 -Amino group) tetrahydro- late-half-has · germination synthesis complex _ example 2al and 2am step 1: on (S)-3-amino group -l-((lS,2R,4R)-4-(isopropyl(methyl)amino)-2-propylcyclohexyl)tetrahydropyrrole-2.one (1 mg) in toluene (2 In the solution in ML), sodium tributoxide (42 mg) and acetate (2'-di-tert-butylphosphino-1,1'-diphenyl-2-yl) were added. 11) (7.8 mg) and 4-chloro-6-(trifluoromethyl)porphyrin (102.3 mg). The mixture was taken at 8 Torr. (: heating under 14 hours, then filtering it' and concentrating in vacuo. The residue was purified by palm chromatography (OD column '80/20/0.1 hexane/iPr〇H/ Et2NH for mobile phase) ), which gives (8)-l-((lS,2R,4R)-4-(isopropyl(methyl)amino)_2-propylcyclohexyl)_3_(6-(trifluoromethyl)-4: 4-aminoamino)tetrahydrofurfuryl-2-ketone [8 mg; MS found: (M+H)+ = 491.3] and (S)-l-((lS,2R,4R)-4-( Isopropyl(indenyl)amino)_2-propylcyclohexyl)-3-(6-(trifluoromethyl)pyridin-4-ylamino)tetrahydropyrrole-2-one [18 mg; MS found: (Μ+Η)+ = 491·3]. Example 2bb: 3-(((S)-l-((lS,2R,4R)-4-(isopropyl(methyl)amino) Synthesis of _2·propylcyclohexyl)_2-ketotetrahydropyrrol-3-yl)aminecarboxylidene)_5·t-butylbenzoic acid 95318 -161 - 1354664 as described in step 4 of Example 2c The method is such that (3)_3 amine group is small [(1S 2 4R)_ 4-(isopropyl(methyl)amino)-2-propylcyclohexyl]tetrahydropyrrole_2-one (223 mg) with 3- Third-butyl-5-(methoxycarbonyl)benzoic acid (165 mg, see Preparation Xing Step 1), at Coupling in 8 ml of DMF. After 14 hours, 2 ml of this reaction mixture was removed and purified to provide Example 2ba. LiOH aqueous solution (48 g, in 2 ml of water) was continuously added to the remainder of the reaction mixture. Me 〇 H (1 mL) was then stirred at room temperature for 14 hours. The mixture was diluted with EtOAc EtOAc EtOAc EtOAc. H)+= 500.4. Table 2-A^ 1-A off, and form. Refer to the table for a complete description of the header. Example 2a

Η / Ν' R2

Change step n/a his data 568.3

95318 -162- 1354664 2b i-Pr(Me)N ?F3 2a Step 6 566.3

0 ηΎ° 6

2d i-Pr (Me)N

2c Step 4 566, 2c i-Pr (Me)N CF3 n/a 554.4 2e i-Pr (Me) N CF3 2c Step 4 468.3

2f i-Pr (Me) N 2c Step 4 456.

2g i-Pr(Me)N

2h i-Pr (Me)N 0 N々N ov^°H o 2c Step 4 458. 2c Step 4 472. 95318 •163- 1354664 2i

i-Pr(Me)N

n/a 457.4 2j

i-Pr(Me)N 2k

i-Pr(Me)N 21

i-Pr(Me)N 2m

i-Pr(Me)N 2n

i-Pr(Me)N

2i Step 1 457.4 n/a 492.4 2k Step 1 2Jc Step 1 2k Step 1 508.3 458.3 442.4 2o

i-Pr(Me)N

2k step 1 482 95318 -164- 1354664 2p

i-Pr(Me)N 2q

i-Pr(Me)N 2r

i-Pr (H)N 2s

i-Pr (Et)N 2t 2u t-Bu (H)N [(S)- configuration]

2p step 1 n/a n/a n/a n/a n/a 530 525 444 472 492.4 492.4 2v

Me2N

2c steps 2 and 4 (see 2k) 464.3 95318 -165- 1354664 2w

Me2N

OCF

N^N 3 2c steps 2 and 4 (see 2k) 480.3 2x

Me2N 2y

Me2N 2z

Me2N 2aa

Me2N 2ab

Me2N 2ac

Me2N

2c steps 2 and 4 2c steps 2 and 4 2c steps 2 and 4 2c steps 2 and 4 (see 2p) 2c steps 2 and 4 2c steps 2 and 4 444.3 440.2 430.3 502.3 429.3 472.2 95318 -166- 1354664 2ad Μβ2Ν 2ae

Et2N 2af

Et2N 2ag

Et2N 2ah

Et2N 2ai 2aj 2ak

i-Pr(Me)N i-Pr(Me)N i-Pr(Me)N

2c steps 2 and 4 (see 2k) 2c steps 2 and 4 (see 2k) 2c steps 2 and 4 (see 2k) 2c steps 2 and 4 2c steps 2 and 4 454.3 492.5 508.5 468.3 458.4

n/a n/a 2aj 483.4 454.3 522.3

95318 -167- 1354664 2al 2 am (isomer of lal) 2 an

i-Pr(Me)N i-Pr(Me)N i-Pr(Me)N

2i step 1 n/a n/a 491.3 491.3 623.3 2ao

i-Pr(Me)N

492.4 2ap 2aq

i-Pr(Me)N i-Pr(Me)N

475.7 493.4 2ar

i-Pr(Me)N

453 95318 • 168 - 1354664 2as 2 at

i-Pr(Me)N i-Pr(Me)N

2c step 4 2c step 4 453 561 2au 2av i-Pr(Me)N 2c step 4

524 497

95318 169- 1354664

袅2-B

The list of chemical names for the specific examples shown in Table 2-A is set forth below. Example name 2a N-{(3S)-H(lS,2R,4R)-4-(isopropyl-methylamino)_2•propyl·cyclohexyl]-2-keto·tetrahydropyrrole-3 -yl}-2-(3-isopropyl-ureido)-5-trifluorodecyl-benzoguanamine 2b-azatetraindole-1-teric acid (2-{(3S)-l-[( lS,2R,4R)-4-(isopropyl-methyl-amino)-2-propyl-cyclohexyl]-2-keto-tetrahydropyrrole-3-ylaminecarbamyl}-4- Trifluoromethyl-phenyl)-decylamine 95318-170- 1354664 2c l-{2-[((S)-l-((lS,2IMR)-4-(isopropyl(methyl)amino) -2-propylcyclohexyl)-2-propenyltetrazine pbilo-3-yl)amineyl]-4-(trimethylmethyl)phenyl-3-ethylurea 2d 1-(2- (((8)-1-((18,2min 4 ft)-4-(isopropyl(methyl)amino)·2-propylcyclohexyl)-2-one-tetrahydro-ρ-ha- 3-yl)amine-mercapto)-4-(trifluoromethyl)phenyl)-3-cyclopropylurea 2e Ν-((8)·1-((13,2ΐν^)-4·(different Propyl (methyl)amino)-2-propylcyclohexyl)-2-indenyltetrahydropyrrol-3-yl)-3-(trifluoromethyl)benzamide 2f 3_third -butyl-N-((S)-l-((lS,2R,4R)-4-(isopropyl(methyl)amino)-2-propylcyclohexyl)-2-@同基四Hydrogen leaf 1: 嘻-3 -yl)benzamide 2g 2-tris-butyl-N-((S)-l-((lS,2R,4R)-4-(isopropyl(methyl)amino)-2- Propylcyclohexyl)-2-mercaptotetrahydrop-haha-3-yl)π-bite-4- Rebel amine 2h 3-third-butyl-4-hydroxy-:^(6)-1- ((13,21^411)-4-(isopropyl(methyl)amino)-2-propylcyclohexyl)-2-oneyltetrahydropbilo-3-yl)benzamide 2i 6-Terti-butyl-N-((S)-l-((lS,2R,4R)-4-(isopropyl(indenyl)amino)-2-propylcyclohexyl)-2- Dihydrotetrahydropyrrol-3-yl)methylpyridinium 2j 2-tert-butyl-N-((S)-l-((lS,2R,4R)-4_(isopropyl (A) Amino)-2-propylcyclohexyl)-2-ketotetrahydropyrrol-3-yl) different from the amine 2k (S)-l-[(lS,2R,4R)-4-( Isopropyl (indenyl)amino)-2-propylcyclohexyl]-3-(6-(trifluoromethyl)p-indole-4-ylamino)tetrahydrop-pyr-2-one 21 (3)-1-((15,2,4 ft)-4-(isopropyl(indenyl)amino)_2-propylcyclohexyl)-3-(6-(trifluorodecyloxy quinine) Tetolin-4-ylamino) tetrahydrop-pyridin-2-one 2m (3)-3-(6-chlorooxazolin-4-ylamino)-l-((lS,2R,4R)- 4-(isopropyl (methyl)amine ))-2-propylcyclohexyl)tetrahydrotrbibron-2-one 2n (3)-3-(6-fluoroquinazolin-4-ylamino)-l-((lS,2R,4R) -4-(isopropyl(indenyl)amino)-2-propylcyclohexyl)tetrahydropyrrole-2·one 2o (S)-3-(6-tri-butylpyrimidine[5,4 -d]pyrimidin-4-ylamino)-1-((13,2's 41〇-4-(isopropyl(methyl)amino)-2-propylcyclohexyl)tetrahydro-p-lo- 2-_ 95318 • 171 - 1354664 2p (^-1-((18,2min 4 ft)-4-(isopropyl(methyl)amino)&gt;2_propylcyclohexyl)-3-(6- (2-methoxyphenyl)β奎奎莎_4_ylamino)tetrahydropyrrol-2-one 2q 3-(4-((3)-1-((13, 2 411)-4-) (isopropyl(methyl)amino)_2-propylcyclohexyl)-2-onetetrahydropyrrole-3-ylamino>&gt; quinazoline-6-yl)benzonitrile 2r (S)-3 -(6-Chloro-4-isolin-4-ylamino)-1-((13,2Min 411;)-4-(isopropylamino)-2-propylcyclohexyl)tetrahydro-p ratio Ha_2-copper 2s (S)-3-(6-chloroquinazolin-4-ylamino)-1-((18,21^48)-4-(ethyl(isopropyl)amine Base)-2-propylcyclohexyl)tetrahydrop-haha_2·嗣2t (8)-1-((18,2min 411)-4-(tri-butylamino)_2·propyl Cyclohexyl)-3-(6-(three Methyl &gt; quizrazin-4-ylamino)tetrahydropyrrole·2-keto 2u (3)-1-((13,2min 43)-4-(tri-butylamino)_2-propyl Cyclohexyl)-3-(6-(trifluoromethyl) quinazolin-4-ylamino)tetrahydropyrrole_2-one 2v (S)-l-((lS,2R,4R)-4 ·(Dimethylamino)·2·propylcyclohexyl)_3_(6·(dimethylmethyl ketone 11 lin-4-ylamino) tetrachloro ρ than 嘻-2-嗣2w (S)-l -((lS,2R,4R)-4-(dimethylamino)-2-propylcyclohexyl)-3-(6-(trifluoromethoxy)p-quinazolin-4-ylamino) Tetrahydropyrrole-2-one 2x 3-tert-butyl-1^-((8)-1-((18,2 ft, 411)-4-(dioxin)-2-propylidene Hexyl)-2-self-isodentyltetrahydropbiloryl-3-yl)-4-hydroxybenzamide 2y N-((S)-1-((1 S,2R,4R)-4-(two Methylamino)-2-propylcyclohexyl)-2-ketotetrahydropyrrol-3-yl)-3-(trifluoromethyl)benzamide 2z N-((S)-l-(( lS,2R,4R)-4·^methylamino)-2-propylcyclohexyl)-2-ketotetrahydropyrrol-3-yl)·2-(trifluoromethyl)-hydan-4-carboxy Indoleamine 2aa (S)-1-((1 S,2R,4R)-4-(dimethylamino)-2-propylcyclohexyl)-3-(6-(2-methoxy.phenyl) , quinazoline _4_ylamino) four Pyrrol-2-one 2ab 6-tris-butyl-N-((S)-l-((lS,2R,4R)-4-(dimethylamino)-2-propylcyclohexyl)-2 -Sephatic tetrahydropyrrol-3-yl)methylpyridinium 2ac 5-(4-chlorophenyl)-N-((S)_l-((lS,2R,4R)-4-(dimethyl Amino)-2-propylcyclohexyl)-2-g-isotetrahydropyrrol-3-yl)pyran-2-dexamine 2ad (S)-3-(6-tri-butyl&quot; Bite and [5,4-d] lyl-4-ylamino)-1-((211,4 ft)-4-(dimethylamino)-2-propylcyclohexyl)tetrahydro Pyrha-2-ketone 95318-172-2ae Ol-KlSJMRH-(diethylamino)-2-propylcyclohexyl)-3-(6-(trifluoromethyl) quinazolin-4-ylamine Tetrahydropyrrol-2-one 2af (S)-l-((lS,2^,4R)-4-(diethylamino)-2-propylcyclohexyl)-3-(6-(three Fluoromethoxy&gt; quinazolin-4-ylamino)tetrahydropyrrole-2-one 2ag is called (8)-1-((13,2min 411)-4-(diethylamino)-2 -propylcyclohexyl)-2-ketotetrahydropyrrole-3-yl)_3_(trifluoromethyl)benzoguanamine 2ah 2-th^^butyl^^-((8)-1-( (18,21^411)-4-(diethylamino)-2-propylcyclohexyl)-2-mercaptotetrahydro 17-pyloryl·3 lymidate-4-rebel amine 2ai l-( (S)-l-((lS,2R 4R)-4-(isopropyl(methyl)amino)-2-propylcyclohexyl)-2-onetetrahydropyrrol-3-yl)-3-(3-(trifluoromethyl)benzene Urea 2aj (S)-3-(3-(trifluoromethyl)benzylamino)_i_((is,2R,4R)-4-(isopropyl(methyl)amino)-2-propanyl Cyclohexyl)tetrahydropyrrole-2-one 2ak (S)-3-(3,5-bis(trifluoromethyl) stilbene)-1_((13, 2's 4 ft)-4-(iso Propyl (hydrazino)amino>&gt; 2-propylcyclohexyl)tetrahydropyrrole-2-one 2al @)-1-((13,2's 41〇-4-(isopropyl(methyl)amine) ))-2-propylcyclohexyl)-3-(6-(trifluoromethyl)anthrace-4-ylamino)tetrahydro I»biro-2-one 2am (foot)-1-(( 13,2's 4 ft) bucket (isopropyl (methyl) amino)-2-propylcyclohexyl)-3-(6-(trifluoromethyl) quinate-4-ylamino) Hydrogen P piroxan-2-an N-((S)-l-((lS,2R,4R)-4-(isopropyl(methyl)amino)-2-propylcyclohexyl)-2 -ketotetrahydropyrrol-3-yl)-3-(3-trifluoromethylsulfonylaminophenyl)-benzamide 2ao 4-hydroxy-N-((S)-l-((lS , 2R,4R)-4-(isopropyl(methyl)amino)-2-propylcyclohexyl)-2-ketotetrahydropyrrol-3-yl)-3-phenyl-phenylhydrazine 2ap N-((S)-l-((lS,2R,4R)-4-(isopropyl(methyl)amino)-2-propylcyclohexyl)-2-onetetrahydropyrrole-3 -yl)-3-phenyl-benzamide 2aq (((3)-1-((13,2&4 ft)-4-(isopropyl(indolyl)amino)-2-propyl Cyclohexyl)-2-ketotetrahydropyrrol-3-yl)-2-phenyl-isonicotinamide decylamine N-oxide 2 N-((S)-l-((lS,2R,4R)- 4-(isopropyl(methyl)amino)-2-propylcyclohexyl)-2-copperyltetrazine pbi-3-yl)-1-methyl-1Η-ρ5丨嗓-3- Chitosan 2as 乂((8)-1-((18,2min 41〇-4-(isopropyl(methyl)amino)-2-propylcyclohexyl)-2. P-(3-yl)-1-methyl-1Η-ρ5丨嗓-2- apoein 2at N-((S)-l-((lS,2R,4R)-4-(isopropyl ( Methyl)amino)-2-propylcyclohexyl)-2-mercaptotetraki-p-pyrrol-3.yl)_2-(indolyl hydrazino)-5·(trifluoromethyl)benzene Indole 95318 • 173- 1354664 2au 3-Third-butyl batch ((8)-1-((18,2 4 ft.)-4-(isopropyl(methyl)amino)-2-propanol Cyclohexyl)-2-aryldihydropyrrole_3·yl)_5-(lH-tetrazol-5-yl)benzamide 2av )like)-1-((13,2民411)-4 - (isopropyl (Methyl)amino)·2·propylcyclohexyl)-2-ketotetrahydropyrrol-3-yl)-3-(4-methyloxazol-2-yl)benzamide 2aw N- ((3)-1-((18,21^411)-4-(isopropyl(methyl)amino)_2-propylcyclohexyl)-2-copperyltetrahydropyrrol-3-yl)-5- (trifluoromethyl)-2-(trifluoromethylsulfonylamino)benzamide 2ax 5-isopropyl-:^((3)-1-((18,2's 41〇-4- (isopropyl(methyl)amino)-2-propylcyclohexyl)-2-onetetrahydropyrrol-3-yl)-2-(trifluoromethylsulfonylamino)benzamide 2ay 2-Chloro-N-KSH-aiSJR^RH-C isopropyl(methyl)amino)-2-propylcyclohexyl)-2-ketotetrahydropyrrol-3-yl)-5-(trifluoro Methyl) benzoguanamine 2az N-((S)-l-((lS,2R,4R)-4-(isopropyl(methyl)amino)·2-propylcyclohexyl)-2- Ketotetrahydropyrrol-3-yl)-3-indole, thazol-2-yl)benzamide 2ba methyl 3-(((8)-1-((13,211,411)-4-) Propyl (methyl)amino)-2-propylcyclohexyl)-2'. ketotetrahydropyrrol-3-yl)amine carbazyl)-5-tris-butyl benzoate 2bb 3 -(((S)-l-((lS,2R,4R)-4-(isopropyl(indolyl)amino)-2-propyl) Cyclohexyl)-2-ketotetrahydropyrrol-3-yl)aminecarboxylidene-5-tris-butylbenzoic acid 2bc 2-tris-butyl-1-keto-N-((S )-l-((lS,2R,4R)-4-(isopropyl(methyl)amino)-2-propylcyclohexyl)-2-one-tetrahydropyrrol-3-yl)pyrimidine-4 - Carboxylamidine Example 3a-3e Example 3a: (S)-l-((lS,2S,4R)-2-isopropyl-4-(isopropyl(methyl)amino)cyclohexyl)-3 -(6-(trifluoromethyl) quinazolinylaminotetrahydropyrrol-2-one and its diastereomer (S)-l-((lS,2S,4S)-2 -isopropyl-4-(isopropyl(methyl)amino)cyclohexyl)-3-(6-(trifluoromethyl)propazolin-4-ylamino)tetrahydropyrrole-2-one Synthesis Example 3a Step 1: The N,0-dimethylhydroxylamine hydrochloride (5.7 g) was suspended in 95318 -174 - 1354664 CH2C12 (80 ml) and added to hexanes in MeOH. Before liters, cool to 0 ° C » warm the mixture to room temperature over 1 hour, then add (1 &amp; 28,511)-7-keto-6-oxo-bicyclic in CHzCl2 (80 mL) [3.2.1] Iso-2-ylaminocarbazate (8 g) was cooled to 〇〇c. After 5 hours at 〇〇c, the reaction was quenched with 10% losel salt solution and extracted with Et EtOAc (2×). The organic extracts were combined, washed with brine, dried (MgSO4), filtered and concentrated. The resulting residue was dissolved in DMF (100 mL) before EtOAc (1. The reaction was stirred at room temperature for 12 h. then was partitioned between EtOAc and saturated brine. The organic phases were combined, dried (MgSO.sub.4), filtered and concentrated in vacuo. The residue was purified by flash chromatography to give (l,,,,,,,,,,,,,,,,,,, )) Cyclohexylaminocarbazate (11·2 g)” MS measured: (M+H)+ = 451.3. f Example 3a Step 2: Let (lS, 2R, 4R) -4- (third Butyl dimethyl decyloxy)-2-(methoxy(methyl)amine carbhydryl)cyclohexylamino decanoate (4.0 g) was dissolved in THF (40 mL) and taken in Et20 Before adding 1.6MMeLi (14.5 ml), cool to -22 °C. The reaction was quenched with EtOAc (EtOAc) (EtOAc) The organic extracts were combined, washed with brine, dried (MgSO4), filtered and concentrated. The resulting residue is purified by flash chromatography to give (lS,2R,4R)-2-ethenyl-4-(tris-butyldimethylsilyloxy)cyclohexylamino hydrazide. Oxalate ester (5.7 g). MS found: (Μ + Η) + = 406.3 · Example 3a Step 3: Suspension of guanidinium triphenyl hydrazine (1.2 g) in toluene (16 ml), then add 0.5 Μ potassium in toluene (Trimethyldecyl)amine (5.8 mils 95318 - 175 - 1354664 liters). After 1 hour, (lSJR^R) in the addition of toluene (5.4 ml): decyl-4-(t-butyldimethylsilyloxy)cyclohexylaminocarbazate (660 mg) ) 'Before cooling this solution to 〇. (: ^ 〇 〇. (: After the next 20 minutes, the reaction was quenched with EtOAc EtOAc (EtOAc) (EtOAc) Purification of the formed residue by flash chromatography to give (lS,2S,4R)-4-(t-butyldimethylmethylalkyloxy)-2-(propan-2-pyrene-2- Benzyl cyclohexylaminocarbamate (380 mg). MS found: (M+H) + = 404.2. Example 3a Step 4: ( s, 2S, 4R) (Third-butyl dimethyl dimethyl sulphate base) 2-(prop-1-en-2-yl)cyclohexylamino carboxylic acid (4.8 g), 10% Pd/C Degussa (600 mg). The reaction flask was evacuated and then refilled with hydrogen; this was repeated three more times and the reaction was stirred at 1 atm H2 for 4 hours then filtered and concentrated to provide (is, 2S, 4R) 4-(Third-butyldimethylammoniooxy)-2-isopropylcyclohexylamine (2.9 g). MS (ES+) = 272.3 (M+H)+. Example 3a Step 5: (lS, 2S, 4R)-4-(Third-butyldimethylmethylalkyloxy)-2-isopropylcyclohexylamine ( 2.9 g) dissolved in DMF (36 ml) and cooled to 0 ° before adding N-Cbz methionine (5.5 g), 4-methylmorpholine (3.8 g) and BOP (8.7 g) C. The reaction was stirred at room temperature for 12 hours, then partitioned between EtOAc and EtOAc (EtOAc). And concentrating in vacuo, and purifying the residue by flash chromatography to give (S)-i-((is,2S,4R)-4-(tris-butyldimethyl syloxy) Benzyl 2-benzylcyclohexylamino)-4-(methylthio)-1-ketobutan-2-ylcarbamate (5.3 g). MS found: (M+H)+= 95318 • 176· 1354664 537.3. Step 3a to give (^-(08,28,411)-4-(tris-butyldidecyldecyloxy)-2-isopropylcyclohexylamino)·4_( Methylthio)-indole-ketobutyl 2-aminocarbamic acid vinegar (5.3 g) was dissolved in methyl iodide (9 ml), and the resulting solution was stirred at room temperature for 72 hours, then Concentrate in vacuo, dissolve the residue in methylene chloride and concentrate the resulting solution; repeat it, The salt was obtained. MS found: (M+H) + = 586.5. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Dispensing treatment with brine. The organic phase was dried (MgSO.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub. Propylcyclohexyl)·2__yltetrahydropyrrole·3-ylaminocarbazate [580 mg; MS found: (Μ+Η)+=375.3], and (S)-l-((lS, 2S,4R)-4-(Third-butyldimethylsilyloxy)_2-isopropylcyclohexyl)-2-mercaptotetrahydropyrrole_3_ylamino decanoate [1〇克;MS found: (M+H)+= 489.4] Example 3a Step 7: (S)-l-((lS,2S,4R)-4-(T-butyl-tert-decylalkyl) Ethyl oxy)-2-isopropylcyclohexyl)-2-oxotetrahydropyrrol-3-ylaminocarbazate (1.0 g) dissolved in AcOH/THF/H2 0 4/1A mixture (60 mL) After 72 hours, add another mixture of AcOH/THF/H.sub.2/1/1 (30 mL). The mixture was stirred for a further 24 hours before concentration. The residue was dissolved in EtOAc and sat. Washing, dehydration drying (MgS04), filtration, and concentration in vacuo to give (S)-l-((lS,2S,4R)-4-hydroxy-2-isopropylcyclohexyl)-2-yl Tetrahydropyrrol-3-ylamine Ethyl formate (750 mg). MS found: (M+H) + = 375.3. Example 3a Step 8: Estimate (S)-l-((lS,2S,4R)-4-hydroxy-2-isopropyl Cyclohexyl)-2- 95318 -177· 1354664 Benzyl tetrahydropyrrol-3-ylamino decanoate (333 mg) was dissolved in CH 2a 2 (5 mL) and was added with Dess-Martin reagent (678.9 mg) Before cooling to 〇C. Allow the solution to warm to room temperature for 1 hour, then, before adding more Dess-Martin reagent (260 mg), cool to room temperature for 丄 hours, after EGO and INNaOH The reaction is quenched. The organic extracts are combined, washed with saturated Na^O3 and NaHC〇3 solution, dehydrated and dried, and dried, and concentrated to give (S)-l-((lS, 2S) 2-Isopropyl-4-ketocyclohexyl)-2-ketone benzyl tetrahydrofuran-3-ylcarbamate (350 mg). MS found: (m+H)+= 373.4. Child Example 3a Step 9: Before adding iPr(Me)NH (642 mg), make (s&gt;1_((lS,2S)-2-isopropyl- Benzyl 4-ketocyclohexyl)_2--tetrahydropyrrole-3-ylcarbamate (350 mg) was dissolved in Ti(Oi-Pr) 4 (2 mL). After 3 hours, MeOH was added (3 ml) and NaBH4 (66.8 mg) were allowed to cool to 〇. (:&quot; After 1 hour at 罜 temperature, the reaction was quenched with 〇·5 NNa0H solution and extracted with (33⁄43⁄4) Combine the organic extracts, dehydrate dry (MgS〇4), filter, and concentrate to diastereomers (3) small ((1S,2S,4R/S)_2_isopropyl-4 (isopropyl) a mixture of methyl)amino)cyclohexyl)-2-yl-4-tetrahydrop-benzylidene benzylate (I62.4 mg). MS found: (M+H)+ = 430.5. .3a Step 10: .__(S)-l-((lS,2S,4R/S)-2-Isopropyl (isopropyl(methyl)amino)cyclohexyl)-2-one Benzyl tetrahydropyrrole-3-ylaminocarbamate (16 mg) was dissolved in MeOH (6 mL) and then added to 2% pd (〇H) 2 (5 mg) in a Parr bottle. Pumping, followed by hydrogen Reverse loading; it was repeated three more times. The reaction was stirred at 60 psi H2 for 5 hours, then filtered and concentrated. Residue formed before adding 20% Pd(OH)2 (75 mg) in a Parr bottle Dissolved in MeOH (6 mL). The flask was suctioned and then refilled with hydrogen; then re-weighed three times at 95318 1354664. The reaction was stirred at 50 psi H2 for 24 hours, then filtered and concentrated. (3)-3-Amino-1-((1S,2S,4R/S)-2-isopropyl-4-(isopropyl(methyl)amino)cyclohexyl)tetrahydropyrrole-2-one ( 101 mg) MS (ES+) = 296.3 (M+H) +. Example 3a Step 11: (S)-3-Amino-l-((lS,2S,4R/S)-2-isopropyl -4-(isopropyl(methyl)amino)cyclohexyl)tetrahydropyrrole-2-one (85 mg) in a solution of EtOH (2.5 mL) - triethylamine (0.2 mL) and 4- Chloro-6-(trifluoromethyl) sulphone (100.1 mg). The mixture was heated at 80 ° C for 14 h then filtered and concentrated in vacuo. AD S column ' EtOH as mobile phase) '(S)-l-((lS,2S,4R)-2-isopropyl_4-(isopropyl (Methyl)amino)cyclohexyl)-3-(6-(trifluoromethyl) sulphonyl-4,ylamino)tetrahydropyrrolidone [52 mg; MS found: (Μ+Η) +=492·4], with (SH_((1S,2S,4S)_2-isopropyl-4-(isopropyl(methyl)amino)cyclohexyl)_3_(6•(tri-methyl) Quinazolin-4-ylamino)tetrahydropyrrole-2-one [8 mg; Ms found. (M+H), 492.4].

Table 3-A The compounds in the table below were prepared using the method exemplified above. 1-Α A complete description of the header. Agricultural i Cheng. See the difference 95318

-179- 实例 Example R5 R2 Changed MS data 3a Step i-Pr(Me)N _yN=\ //N n/a 492 3b

(5) Configured i-Pr(Me)N

F3C

^k, see 3a 492 3c

i-Pr (Me)N f3c

3a step 11 508 3d F3CO i-Pr (Me) N N=\

Cl 3a step 11 458 3e

i-Pr(Me)N 3a Step 11 457 The chemical name series for the specific examples shown in Table 3·Α is given below. Example ----- Name 3a (S)-l-((lS,2S,4K)-2-isopropyl_4_(isopropyl(methyl)amino)cyclohexyl)-3-(6- (trifluoromethyl)p-quinazoline_4_ylamino)tetrahydropyrrole-2-one 3b (S)-l-((lS,2S,4S)-2-isopropyl-4·(different Propyl (methyl)amino)cyclohexyl)-3-(6-(trifluoromethyl)&gt;» quinazoline-4-amine i) tetrahydropyrrole_2-one 3c (S)-l- ((lS,2S,4R)-2-isopropyl_4_(isopropyl(indenyl)amino)cyclohexyl)-3-(6-(trifluoromethoxy)&lt;»奎嗤琳_ 4·ylamino)tetrahydroppirin-2-one 95318-180- 1354664 3d (8)-3-(6-chloroquinazolinopylamino)-l-((lS,2S,4R)- 2-isopropyl-4-(isopropyl(methyl)amino)cyclohexyl)tetrahydropyrrole 2·ketone 3e 6-tris-butyl-N-((S)-l-((lS , 2S,4R)-2-Isopropyl 4-(isopropyl(methyl)amino)cyclohexyl)-2-one-tetrahydropyrrol-3-yl)methylpyridinamide Examples 4a-4d Example 4a: N-((S)-l-((lS,2R,4R)~4-(isopropyl(methyl)amino)-2-methylcyclohexyl)-2-indenyltetrahydropyrrole Synthesis of -3-yl)-3-(trifluoromethyl)benzoguanamine _ Example 4a Step 1: Adding Na Prior to BH4 (827 mg), (1 Min 2\511)-2-((S)-3-(benzyloxycarbonylamino)-2-one-tetrahydropyrrole small))-7-keto-6- Nitro-bicyclo[3.2.1]octane-6-carboxylic acid tert-butyl ester (2.0 g) was dissolved in THF (50 ml) and water (15 ml). After 5 hours, the reaction was carried out with a saturated NaHC03 solution. Quenched and extracted with EtOAc (2x). EtOAc (EtOAc) 3-Hydroxycarbonylamino-2, ketotetrahydropyrrol-1-yl)-3-(hydroxymethyl)cyclohexylaminocarboxylic acid, tert-butyl ester (2.1 g). MS (ES+) = 462.5 ( M+H)+. Example 4a Step 2: Prior to the addition of diphenyl disulfide (190 mg) and n-Bu3P (〇.16 mL), (lR,3R,4S)-4-((S)-3 - ethoxycarbonylamino-2-ketotetrahydro-l-yl)-3-(hydroxymethyl)cyclohexylaminocarbamic acid tert-butyl ester (2 g) dissolved in THF (50 ml) The reaction was heated under reflux for 12 hours. After cooling to room temperature, the residue was concentrated and purified by flash chromatography to give (lR,3R,4S)-4-(( S)-34 oxycarbonyl Aminobutan-2-ketotetrahydropyridyl)-3-(phenylthiomethyl)cyclohexylaminocarboxylic acid tert-butyl ester (2 mg). Found: (M+H)+ = 554.4. Width _ Example 4a Step 3: Before adding 2% nickel (1 〇〇 mg) in water, 95318 -181 - 1354664 (1 s 3 48)-4 -((8)-3-oxiranylamino-2-ketotetrahydroindole 嘻·ι_yl)_3_(phenylthiomethyl)cyclohexylaminocarboxylic acid tert-butyl ester (150 mg ) Dissolved in Et〇H (2 ml). The reaction was heated under reflux for 12 hours. The reaction was concentrated after cooling to room temperature. The resulting residue is purified by flash chromatography, and 4 (1, 3, 45, -4-((8)-3-yloxycarbonylamino-2-one-4-hydropyranyl) _Base)_3_ Methylcyclohexylaminocarbamic acid tert-butyl ester (64 mg). MS found: (M+H)+ = 446.4. Example 4a Step 4. Before adding trilactacetic acid (2 ml), make (ir, 3r 4S)_ 4-((S)-3-Ye oxygen The amino-amino-2-ketotetrahydrop-pyrrol-1-yl)-3-methylcyclohexylaminocarbamic acid tert-butyl ester (91 mg) was dissolved in CH2C12 (3 mL). After 1 hour, the reaction was concentrated in vacuo. The residue formed was dissolved in Me 〇H (3 mL) and acetone (0.15 mL) was added. The mixture was stirred for 5 minutes before the addition of NaCNBH3 (68 mg). The reaction was stirred for 4 hours then formaldehyde (0.5 mL, 37% aq.). The mixture was stirred for 1 hr. The organic extracts were combined, dehydrated (MgS04) filtered and concentrated. The residue was purified by reverse phase HpLC (gradient elution, water / acetonitrile / TFA) to give (S)-3- methoxycarbonylamino-l-((lS,2R,4R)-4-(isopropyl TFA salt (81 mg) of (methyl)amino)-2-methylcyclohexyl)tetrahydro I»biha 2_ ketone. MS found: (M+H) + = 388.3. Example 4a Step 5: (S)-3-benzyloxycarbonylamino-l-((lS,2R,4R)-4 in MeOH (5 mL) To (isopropyl(methyl)amino)-2-indolylcyclohexyl)tetrahydropyrrole-2-one (47 mg) was added 20% Pd(OH) 2 (70 mg). The reaction flask was evacuated and then refilled with hydrogen; this was repeated three more times. The reaction was stirred at 1 atm H2 for 4 h then filtered and concentrated to afford (s) &lt;RTI ID=0.0&gt; 18, 2 411) - 95318 - 182 · 1354664 4 · (isopropyl (indenyl) amino) - 2 - methylcyclohexyl) tetrahydropyrrole 2 - ketone (3 〇 mg). MS (ES+) = 268.3 (Μ+Η)+. Example 4a Dreams Step 6: Addition of 3-(trifluoromethyl)benzoic acid (37 mg), 4-methyl-moffone (0.07 ml) and BOP (86) before (s) _3_amino group ((18,2 411 411)-4-(isopropyl(methyl)amino)_2·methylcyclohexyl)tetrahydropyrrole-2·one (28 grams) was dissolved in DMF (1 ml). The reaction was mixed with sandalwood for 1 hour and then directly purified by reverse phase HPLC (gradient elution, water/acetonitrile / rppA) to give N-((S)-l-((lS,2R,4R)-4-(iso) TFA salt (6 mg) of propyl (methyl)amino) 2 - decylcyclohexyl)-2-ketotetrahydropyrrol-3-yl)-3-(trifluoromethyl)benzamide. MS found: (M+H)+ = 440.4. Example 4d: (S)-1-((1S,2R,4R)_2-ethyl_4-(isopropyl(methyl)aminocyclohexyl) _ 3-(6-(Difluoromethyl) thiazole _4·ylamino) tetrahydropyrazole 2 germination synthesis 4d step zen 1: according to the procedure described in step 2a of Example 2, and replaced Broken methyltriphenyl scale in step 1 to give (1R,2S,5R)_2_芊oxycarbonylamino-7-keto-6-nitro-bicyclo[3.2.1]octane-6- Conversion of the third-butyl carboxylic acid to {(3S)-l-[(lS,2R,4R)-4-tris-butoxycarbonylamino-2-alkyl-cyclohexyl]-2-indenyl Four 虱'»Bilo-3-yl}-amine methyl ketone vinegar. One part of this material (995 mg '2.2 mmol) was dissolved in 2 liters of 4:1 CH2C12/TFA. The formed solution was stirred at room temperature for 3 hours and concentrated in vacuo. The residue was dissolved in methylene chloride and concentrated in vacuo. This procedure was repeated twice again to give (S)-l -((lS,2R,4R)-4-Amino-2·ethylcyclohexyl)-2-g-iso-tetrahydropyrrole-3-ylcarbamic acid oxime ester MS found: (M+H) += 360.2. Exemption from exemption 2: Estimate (S)-l-((lS,2R,4R)-4-amino-2-ethyl Hexyl) 2 - ketotetrahydropyrrole · dimethyl carbazate (presumed to be 2.2 mmol) dissolved in ι, 2_ 95318 -183 - 1354664 dichloroethane (27 ml), and formed In the solution, acetic acid (0.27 ml), propylene _ and NaHB (〇Ac) 3 (5 g) were continuously added, and then heated to 5 Torr for 18 hours. The reaction was concentrated in vacuo and the residue was dissolved. Formaldehyde and sodium cyanoborohydride were continuously added to the resulting solution in acetonitrile. The reaction was concentrated in EtOAc and purified by flash chromatography to give (3)-1-((13,21) ^410-2-ethyl·4·(isopropyl(methyl)amino)cyclohexyl)_2-ketobenzyltetrahydroindolo-3-ylcarbamate (6〇7 mg). Value: (μ+η)+= 416.3. Aminocarboxylic acid (S)-l-((lS,2R,4R)-2-ethyl-4-(isopropyl(methyl)amino)cyclohexyl) A sample of 2-ketotetrahydropyrrole-3-yl ester (1 mg) was dissolved in 2.5 ml of 33% HBr/AcOH and stirred for 25 minutes, then treated with shame. A solid substance appeared. 'And dry the remaining solid under vacuum to provide (S)-3-amino-1-((iS,2R,4R) 2-ethyl-4-(isopropyl(methyl)amino)cyclohexyl)tetrahydropyrrole-2-one bis-HBr salt as a white solid (43 mg). MS found: (M+H )+=283.2. Actual Jj4d free stem 4: (S)-3-aminol-l-((lS,2R,4R)-2-ethylidene (isopropyl(indenyl)amino)cyclohexyl A sample of tetrahydropyrrole-2-one bis-HBr salt (147 mg) was dissolved in EtOH (5 ml) and added to the resulting solution, triethylamine (〇55 ml) and 4-chloro-6. -Trifluoromethylquinazoline (183 mg)' was then heated at 8 ° C for 14 hours. The reaction was cooled and concentrated under reduced pressure and the residue was partitioned between diethyl ether and water. The organic phase was extracted twice with water. The combined aqueous extracts were lyophilized, and the formed powder was purified by RP-HPLC to give (S)-l-((lS'2R,4R)-2-ethyl-4-(isopropyl (A) Amino))-cyclohexyl)_3_(6-(trifluoromethyl) quinazoline-4-ylamino)tetrahydropyrrole-2-one. Ms found: 95318 •184· 478.4. 44^ The compounds listed in the table below were prepared using the method exemplified above to give a complete description of the header.

X 9Λ!

4c

Me F3C N: =\

F3CO 4a Steps 6 480

4d

Et N l=\

F3C n/a 478 ‘R2 instance Rl R2 changed MS data 4a Me cf3 Step 440 n/a 4b Me , n==\ 4a Step 464 6

Table 4-B 4a N-((S)-l-((ls,2R,4R)-4-(isopropyl(methyl)amino)-2-methylcyclohexyltetrahydropyrrole-3-yl )-3-(trifluoromethyl)phenyl decylamine 95318 -185· 1354664 4b (3)-1·((13,2ΜΙΙ)-4·(isopropyl(methyl)amino)_2 fluorenyl ring Hexyl)-3-(6-(trifluoromethyl)oxaquinazoline-4-ylamino)tetrahydropyridinium-2_嗣4c (8)-1-((13,2min411)-4 -(isopropyl(methyl)amino)_2_decylcyclohexyl)-3-(6-(trifluoromethoxy) 嗤 嗤 p _4_ylamino) tetrahydropyrrole-2-one 4d (S)-1-((1S,2R,4R)·2-ethyl·4-(isopropyl(indenyl)amino)-cyclohexyl)-3-(6-(trifluoromethyl)jun Oxazoline-4 aminoguanyl)tetrahydropyrrole-2-ketone Example 5a-51 Example 58:]\-((8)-1-((18,211,411)-4-(isopropyl(methyl)) Synthesis of Amino)_2_(Methoxymethyl)cyclohexyl)-2·ketotetrahydropyrrol-3-yl)-3-(trifluoromethyl)benzamide 皇_Example 5a·· 1 : (1艮23,5 noisy 2-benzyloxycarbonyl-amino-7-keto-6-azabicyclo[3.2.1]octane-6-decanoic acid tert-butyl ester (2. g) in tetrahydrofuran (4 ml) solution in water (8 ml), then Treated with sodium borohydride (1 g). The mixture was stirred at room temperature for 5 hr then EtOAc (aq. The combined extracts were washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated and evaporated.芊 - 谈 谈 谈 谈 谈 谈 谈 谈 _ 3 3 , , , , , , , , , , , , , , , , , 379 379 379 379 379 379 379 379 379 379 379 379 379 379 Step 5a Step 7 Dissolve (lR,3R,4S)-(4-benzyloxycarbonylamino-3-3-hydroxymethyl-cyclohexyl)amine methyl acid tert-butyl ester (1.8 g) in N, N-dimethylformamide (15 ml), iodomethane (5 mL) was added, followed by silver oxide (5 52 g), and the mixture was stirred overnight at room temperature. The solid was washed with ethyl acetate. The filtrate was washed successively with water and brine, dried over sodium sulfate and evaporated and evaporated. 8 -186· 1354664 (iiuimsh^芊oxycarbonylamino-3-methoxymethylcyclohexyl)amine methyl acid tert-butyl ester, colorless gum (1.78 g). MS found: (M+H ) += 393. Example 5a Step 3: (1 Min 3 Min 43)-(4-Benzyloxycarbonylamino-3-oxooxymethylcyclohexyl)amine methyl acid tert-butyl ester (1.24 g) The solution was dissolved in MeOH (20 mL), and 20% by weight of Pd(OH) 2 / C (300 mg) was added to the resulting solution, followed by evacuation and degassing with hydrogen. The reaction was stirred at 1 atmosphere H2 for 3 hours, then passed through a pad of EtOAc (EtOAc). The filtrate was concentrated in vacuo to give (1,,,,,,,,,,,,,,,,,,,,,,,,, MS found: (M+H)+=259.2. f Example 5a Step 4: (lR,3R,4S)-(4-Amino_3_methoxymethyl-cyclohexylamine methyl acid third - butyl ester (1.6 g, 6.2 mmol) in a solution of MeCN (30 ml), sequentially added N,N-diisopropylethylamine (2.2 ml, Π. 4 mmol), N -Cbz methionine (1.75 g, 6.2 mmol) and HATU (2.59 g, 6.82 mmol). The mixture was stirred overnight and concentrated in vacuo. Washed with saturated NaHC 3, water and brine. The organic phase was dried (Na 2 S 〇 4), filtered, and concentrated in vacuo. The residue was chromatographed to afford (lR, 3R, 4S)-[4-( 2S)-(2-Benzyloxynidylcarbamethylthiomethylbutanylamino)-3-methoxymethylcyclohexyl]amine methyl acid third-butyl (174 g)' as a white foam MS found: (m+H)+=524.6. f Example&gt; Step 5丄(1R,3R,4SH4-(2SH2-hydroxycarbonylamino-4-methylthiobutanylamino)-3- a sample of decyloxymethylcyclohexyl]amine methyl acid tert-butyl ester (0.95 g, 1.82 mmol) dissolved in methyl iodide (5 mL) Vigorous mechanical action was carried out, and the resulting solution was stirred at room temperature for about 2 hours, then concentrated in vacuo. The residue was dissolved in dichloromethane and concentrated to give a crystals of 95318 - 187. This procedure was repeated twice more, then the material was placed under high vacuum for 12 hours. The product solid was dissolved in ML), and the formed solution was cooled to 〇t, and sodium hydride (218 mg) was added in one portion. The reaction was allowed to proceed for 2.5 hours, then quenched with EtOAc EtOAc (EtOAc (EtOAc). The residue is purified by chromatography to give bis-butoxy-t-butylamino-2-methoxymethylcyclohexyl)-2- ketotetrapyrrole-3-yl]amine succinate Ester (570 mg). MS found: (m+h)+ = 476 3. 丰-I'] 5a step 6: PSHHISJMR) #-T-butoxy-carbonylamino-2-methoxy A sample of methyl methenyl)-2-ketotetrahydropyrrole-3-ylaminomethyl methacrylate (0.57 g) was subjected to the procedure described in Example 2c, steps 1 and 2, to provide the crude product. . It was purified by RP-HPLC to give (8)-1-((18,2 411)-4-(isopropyl(methyl)amino)-2-(methoxymethyl)cyclohexyl. _2_ketotetrahydropyrrole_3_ylaminocarbamic acid vinegar TFA salt 'as white powder (415 mg ^ MS measured value: (M + H) + = 432.4. _ Example 5a step 7: use The procedure outlined in Step 3 of Example 5a (replacement of MeOH as solvent with Et?H) to make (S) small ((1S,2Rj4R)_4_(isopropyl(methyl)amino)-2-(methyl group)曱Base)cyclohexyl)_2_ from the same base tetrahydrop-heptylamino formate vinegar TFA salt sample (75 mg) converted to (S)-3-amino-l-((lS,2R,4R - 4-(isopropyl(methyl)amino)-2-(f-oxymethyl)cyclohexyl)tetrahydro-hydropurine 2-ketone (57 mg). MS found: (M+H) += 298.3. Real_Example 5a Step 8: Following the procedure outlined in Step 4 of 2c, to give (3)-3-amino-1-((13,211^)-4-(isopropyl(methyl)amino) a sample of 2-(methoxyindenyl)cyclohexyl)tetrahydro-rheptan-2-one is converted to the title compound. Purified by Rp_HpLC to provide 95318 • 188·1354664 isopropyl (methyl)amine) 2·(methoxymethyl)cyclohexyl The μ salt of 2-ketotetrahydropyrrol-3-yl)-3-(trifluoromethyl)benzamide is a white powder. MS found: (M+H)+=470.3. Example Sj: ^((^-( 仰 ^ 异丙 ” ” ” 基 基 ^ ^ ^ methoxy ethoxy) ethyl cyclohexyl)-2- keto Synthesis of Hydropyrrol-3-yl)-3-(trifluoromethyl)benzamide No. 5j Step 1: According to the procedure described in Step 1 of Example 2a above, 13 g (1, 28, 5) 7700 million ^)-2-(+lactosylamino)-7-ylamino-6-nitro-bicyclo[3 2 1]octane-6-carboxylic acid tert-butyl ester' and made from L7 The solution of the sulfonium iodide triphenyl scale sulfhydryl compound and 8.5 ml of 0.5 MKHMDS was combined, and after the ruthenium chromatography, [(lS, 2R, 4R)-[4-tri-butoxycarbonylamino group] was obtained. 2-(vinyl)-cyclohexyl]-amine methyl decanoate (0.50 g). MS found: (M+H)+= 375.2. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> , 4R)-[4-Terti-butoxycarbonylamino-2-(ethylheptyl)-cyclohexyl]• Amino acid (0.82 g, 2.2 mmol) dissolved in THF (15 ml) The resulting solution was cooled to 〇〇c, and 9·ββν (0.5 ml of '0.5 Μ solution in THF) was added. The mixture was stirred at room temperature for 2 hrs, then continuously with sodium acetate aqueous solution (0.6 Gram The reaction was quenched with EtOAc (3 mL) EtOAc (EtOAc)EtOAc. And the combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography to give [(lS,2R,4R)-[4 -T-butyloxycarbonylamino-2-(ethyl)-cyclohexyl]-amine methyl decanoate (0.42 g) as a white foam. MS found: (M+H)+= 393 Example 5i Step 3: [(lS,2R,4R)-[4-T-Butoxycarbonylamino-2-(hydroxyethyl)-cyclohexyl]-amine methyl decanoate (0.42 g, 1.07) Methanol) in a solution of DMF (4 ml) 95318 -189- 1354664, add methyl iodide (2 ml) and Ag2 (1 24 g, 5·35 mmol) and stir at room temperature. After 14 hours, the mixture was filtered, and the filtrate was diluted with EtOAc EtOAc EtOAc EtOAc. 4), filtration, and concentration in vacuo, and the residue was purified by silica gel chromatography to give [dSJR^R)-^3·butoxycarbonylamino-2-((oxyethyl)-cyclohexyl ]-Amidoxime acid ester (0.255 g). MS found: (m+H)+= 429.2. Step 4: [(1S,2R,4R)-[4·3·Butoxycarbonylamino-2-(methoxyethyl)cyclohexyl The -benzyl benzyl methoxide sample was subjected to the procedure detailed in Example 5, Step 3, and after RP-HPLC purification and lyophilization, the titled product n-((s)_i-((iS, 2S) was obtained. , 4rm-(isopropyl(methyl)amino)_2_(2-methoxy'ethylhexyl)-2-onetetrahydropyrrole_3_yl)_3_(trifluoromethyl)benzamide White powder. MS found: (M+H)+ = 484.4. Table 5.4 Refer to the table in the table below for a complete description of the header made using the method exemplified above. 95318 -190- 1354664 Examples 5a

Rl MeOCH2

'R2 change step n/a MS data 470.3

5b

MeOCH2

556.4 5c

MeOCH2 5d

MeOCH2

5a, step 8 (see 2k) 494.3

5a, step 8 (see 2k) 460.3 5e

MeOCH2

5a, step 8 (see 2k) 510.3 5f

MeOCH2

MeO

N^N 5a, step 8 (see 2k) 532.5 95318 -191 - 1354664 5g EtOCH2 CF3 0 5a. Step 2 &amp; 484.4 8 5h EtOCH2 CF,

Nv^N 5i EtOCH2 CF, 5j MeOCH2CH2 5k MeOCH2CH2

5a Step 2 &amp; 508.4 8 (see 2k) 5a Step 2 &amp; 570.5 8 n/a 484.4 5j Final 570.5 Step 51 MeOCH2CH2 CF:

Ν^Ν 5j final step (see 2k) 508

Table 5-B The list of chemical names for the specific examples shown in Table 5-A is given below. Example name 5a N-((S)-l-((lS,2R,4R)-4-(isopropyl(methyl)amino)-2-(methoxymethyl)cyclohexyl)-2- Ketotetrahydropyrrol-3-yl)-3-(trifluoromethyl)benzamide 95332 -192- 1354664 5b 1-(2-((())-1-((18,21^41〇) -4-(isopropyl(methyl)amino)·2·(methoxymethyl)cyclohexyl)-2-onetetrahydropyrrole-3-yl)aminemethanyl-4-(III) Fluoromethyl)phenyl)-3-ethylurea 5c (8)-1-((18,2Min 411)-4-(isopropyl(methyl)amino)·2_(decyloxy) Cyclohexyl)-3-(6-(trifluoromethyl)4; junolin_4_ylamino)tetrahydropyran-2-one 5d (S)-3-(6-chlorooxazoline- 4-ylamino)-1_((13,2' 411)-4-(isopropyl(methyl)amino)-2-(methoxymethyl)cyclohexyl)tetrahydro-biha_2 _5e (8)-1-((18,2 Min 411)-4_(isopropyl(indenyl)amino)_2_(decyloxymethyl)cyclohexyl)-3-(6-(trifluoro)曱oxy)"»奎奎淋-4-amino-amino) tetrahydro-p-ha-2-steel 5f (S)-l-((lS,2R,4R)-4-(isopropyl (methyl) Amino)·2_(methoxymethyl)cyclohexyl)-3-(6-(2-methoxyphenyl)&gt; Kuantan, Lin_4_ylamino) Hydrogen pr-r-butanone 5g N-((S)-l-((lS,2R,4R)-2-(ethoxymethyl)_4-(isopropyl(methyl)amino) ring Hexyl)-2-ketotetrahydropyrrol-3-yl)-3-(trifluoromethyl)benzamide 5h (S)-l-((lS,2R,4R)-2-(ethoxy Methyl)-4-(isopropyl(methyl)amino)cyclohexyl)-3-(6-(trifluoromethyl)p-quinepinin-4-ylamino)tetrahydro-p-ha- 2-酉同5i 1_(2-(((S)-1-((1 S,2R,4R)-2-(ethoxycarbonyl)·4-(isopropyl(indenyl)amino)) Cyclohexyl)-2·ketotetrahydropyrrol-3-yl)aminecarbenyl)-4-(trifluoromethyl)phenyl)-3•ethylurea~ 5j N-((S)-1-(( 1 S,2S,4R)-4-(isopropyl(methyl)amino)-2-(2-methoxyethyl)cyclohexyl)-2-onetetrahydropyrrol-3-yl)· 3·(trifluoromethyl)benzoguanamine 5k (S)-l-((lS,2S,4R)-4-(isopropyl(methyl)amino)-2-(2-methoxy Ethyl)1⁄4-hexyl)-3-(6-(dimethylmethyl)p-quinolyl-4-ylamino)tetrahydro-p-pyrid-2-one 51 l-(2-(((S))- L-((lS,2S,4R)-4-(isopropyl(indenyl)amino)_2-(2-methoxyethyl)cyclohexyl)-2-one-tetrahydrop-pyrazole-3 Amine Brewing base)-4-(trifluoromethyl)phenyl)-3-ethyl month urine 95318-193- J354664 Example 6a-6k Example 68: 1-((18,211,411)-2-(1-礼丙Synthesis of 4-(isopropyl(methyl)amino)cyclohexyl)-3-(6-(trifluoromethyl phthalazin-4-ylamino)tetrahydroindole_2_嗣. Example. Package·Step 1: On (1^2S,5R)-2-((S)-3-(芊-oxycarbonylamino)_2_indolyltetrahydrop-pyrid-1-yl)-7-net Base-6-nitro-bicyclo[3.2.1]octane-6-acid acid tert-butyl vinegar (520 mg '1_14 mmol) in THF (16 ml) in a stirred solution at 0 ° C under the addition of 2.0 Μ ethyl magnesium chloride (1.7 ml, 3.4 mmol) in THF. The mixture was stirred at 0 °C for 20 minutes and at room temperature for 30 minutes. After cooling to 0 C, the reaction was quenched with EtOAc (EtOAc) (EtOAc) (EtOAc) The semi-amine aldehyde is obtained as an oil. MS found: (M+H)+ = 488.1. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; (At TC, add NaBH4 (85 mg, 2.25 mmol), and the mixture was stirred at 〇〇c for 2 hrs and at room temperature for 40 min. The reaction was quenched with saturated EtOAc and Et. The mixture was extracted with 〇Ac (2 χ). The organic extracts were combined, washed with brine, dried and dried (WhSW), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with 6·· 4, 7: 3, then 8: 2 EtOAc and hexanes to afford the desired ((1 ' '3 ft, 43) -4- (8) -3-(芊oxycarbonyl)amino-2-keto-tetrahydropyrrole_1-yl) 3-(1-propyl)cyclohexyl)amine methyl acid, two-butyl esters Enantiomers (~1.5 fast and slow isomers) are oils. MS found: (M+H)+ = 490.3. J:. Example 6a Step 3: _ Step 2 The slow isomer of the hydroxypropyl compound (419 s s s s s s s s s s s s s s s s s Trifluoroacetic acid (0.66 mL, 8.6 mmol) was added to a solution of CH.sub.2 (4 mL), and the mixture was stirred for 75 minutes. The acid and solvent were evaporated and the residue was dissolved in CH2CI. Saturated Na2C〇3 wash strip 'dehydrated dry (Na? SO4) 'over 遽' and concentrated in vacuo to give the desired (5)-1-((13,2艮411)-4-amino-2- (1-Hydroxypropyl)cyclohexyl)_2-ketotetrahydropyridin-3-ylaminocarbamate, as an oil. ms found: ...j+fj)+= 390.2. Step 4: _(SHAISJMRM-Amino Winter (1-Hydroxypropyl)cyclohexyl)-2-yl-tetrahydropyrrole-3-ylaminocarbamate (〇·86 mmol) in Me〇 Into a solution of H (5 mil liter), acetone (〇. 6 ml) was added, and the mixture was stirred for 1 hr. Then, sodium diethoxide borohydride (544 mg, 2% mmol) was added, and the mixture was stirred at room temperature for 4 hours. After the end of the stirring, a 37% aqueous solution of HCHO (〇4 ml) was added, and the mixture was stirred at room temperature for 3 hr. Finally, an additional sodium triethoxysulfonate (181 mg, 〇·86 mmol) was added, and the mixture was stirred at room temperature for 18 hours. The reaction was quenched by the addition of a saturated solution of EtOAc (EtOAc). _ The residue was purified by flash chromatography on EtOAc (EtOAc: EtOAc: EtOAc (EtOAc) Benzyl (meth)amino)cyclohexyl)-2-ketotetrahydropyrrole-3-ylcarbamate (267 mg) was obtained as an oil. 6a # ^ _^(S)-l-((lS,2R,4R)-2-(l-propyl)_4-(isopropyl(methyl)amino)cyclohexyl)·2-steel Benzyl tetrahydropyrrole-3-ylaminocarbamate (267 mg) was added 10% Pd/C Degussa (~100 mg) in a solution of Me〇H (15 mL). The reaction flask was evacuated and then counter-filled with hydrogen; it was repeated twice more. 95318 -195- 1354664 The reaction was stirred at 60 psi for 2 hours, then filtered and concentrated in vacuo to give the desired (S)-3-amino-1-((18,2, 4 ft)-2 -(1-Hydroxypropyl)-4-(isopropyl(methyl)amino)cyclohexyl)tetrahydropyrrole-2-one (190 mg) as an oil. Pour 6a Step 6: (S)-3-Amino-l-((lS,2R,4R)-2-(l-hydroxypropyl)-4-(isopropyl(methyl)amino) ring Benzyl)tetrahydropyrrolidone (47.6 mg, 0.153 mmol) in a solution of EtOH (3 mL) - 4-chloro- 6-(trifluoromethyl)-trazoline (46.3 mg, 0.2) Millol) with triethylamine (0·064 ml, 〇46 mmol). The mixture was heated in a microwave oven at 100 ° C for 30 minutes. The solvent was evaporated, and the residue was purified mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj L-propyl)-4-(isopropyl(methyl)amino)cyclohexyl)_3_(6-(trifluorotauyl)quinazolin-4-ylamino)tetrahydropyrrolidone (47.3 mg ), as a solid ^ MS found: (M+H) + = 508.3 Example 6b: 1-((18,2 411)-2-(1·light propyl)-4-(isopropyl (methyl) Synthesis of amino)cyclohexyl)-3-(6-(trifluoromethyl) quinazoline-4-ylamino)tetrahydropyrrole-2-ketone as described in Steps 6-6 of Example 6a Method 'The step 2 of Example 6a was converted to the title compound 1-(lS,2R,4R)-2-(l-hydroxypropyl M-(isopropyl(methyl)amine) by the slow isomer of the propyl compound. (cyclohexyl)-3-(6-(trifluoromethyl)p- quinazolin-4-ylamino)tetrahydropyrrole-2-one' is isomerized to the 6a of the propyl chain at the hydroxyl group of the propyl chain. Found: (m+H)+= 508.3 Example 6c: N-(1-((1S,2R,4R)_2-(1-propyl) winter (isopropyl(methyl)amino)cyclohexyl )-2-ketotetrahydropyrrole_3_yl)_3_(trifluoromethyl Synthesis of benzamide to (S)-3-amino-i-((1S,2R,4R)-2-(1.hydroxypropyl) pipe (isopropyl(indenyl)amino)cyclohexyl) Tetrahydroindole 嘻-2-_ (47.6 mg, 0.153 mmol) in a solution of CH3CN (2 s s s s s s s s s s s s s s s s s s Mohr), 3_trimethylmethyl benzoic acid (38 mg, 〇. 2 mmol) and TBTU (73.7 mg, 0.23 mmol) and the mixture was stirred at room temperature for 8 hours. Diluted with EtOAc and washed with EtOAc EtOAc EtOAc EtOAc (EtOAc m. - MeOH-CH 2 Cl 2 was dissolved to give the title compound N-(l-((lS,2MR)-2-((R)-l-hydroxypropyl)-4-(isopropyl(methyl)amino) ring Hexyl)-2-ketotetrahydropyrrol-3-yl)-3-(trifluoromethyl)benzamide (38.5 mg) as a solid. Ms found: (m+h)+ = 484.3. 6f. l-((lS,2R54R)-2-(1--ethyl)&gt; 4-(isopropyl(methyl)amino)cyclohexyl)-3-(6-(trifluoromethyl) Synthesis of thiazolylamino)tetrahydropyrrole-2·one The title compound 1-((lS,2R,4R)-2-(l-hydroxyethyl)-4-(isopropyl(methyl)) Amino) % hexyl)-3-(6-(dimethylmethyl)u kujunlin _4_ylamino)tetrahydro-P-ha_2_self, by the use of Example 6a, steps 1-6 Said method, from (ir, 2S, 5R)-2_((s)-3-(indolylcarbonylamino)-2-ketotetrahydropyrrole small)·7·keto-6-nitro-bicyclic And [3.2.1] octane_6_carboxylic acid tri-butyl ester was started by using methyl magnesium bromide instead of ethyl magnesium chloride in step i. MS found: (Μ+Η)+ = 494.3. Example 6g: N-(l-((lS,2R,4R)-2-(l-ethyl)_4·(isopropyl(methyl)amine Synthesis of cyclohexyl)-2-ketotetrahydropyrrol-3-yl)-3-(trifluoromethyl)benzamide The title compound N-(l-((lS,2R,4R)-2 -(l-hydroxyethyl)_4.(isopropyl(methyl)amino)cyclohexyl)-2-onetetrahydropyrrol-3-yl)-3-(trifluoromethyl)benzamide (s)_3_Amino-l-((lS,2R,4R)-2-(l-hydroxyethyl)-4 prepared by the method of Example 6f, using the method described in Example 6c -(isopropyl(methyl)amino)cyclohexyl)tetrahydropyrrole-2-one. MS found: (M+H)+=470.3. 95318 -197· 1354664 Example 6h: 1-(( 18, 2 People's Daily) -2-(hydroxymethyl)_4_(isopropyl(methyl)amino)cyclohexyl)-3-(6-(trifluoromethyl) 攻 琳 _4·ylamino Synthesis of tetrapyrrole-2-one in isobutyric acid ((lR, 2S, 5R)-5-(isopropyl(methyl)amino)·2_(2·keto-3-(6-(trifluoro) Methyl group &gt; quinazolin-4-ylamino) tetrahydropyrrole small) cyclohexyl) methyl ester (Example 7a '4 mg) in MeOH (1 mL) 1N_Na〇H (〇j ml) was added, and the mixture was stirred at room temperature for 9 hr. After neutralizing with saturated NJLC!, it was extracted with EtOAc (2×). Na^SO4) 'Filtering' and concentrating in vacuo. The residue was purified by flash chromatography on EtOAc EtOAc EtOAc: EtOAc: EtOAc: EtOAc: , 2R,4R)-2_(monomethyl)-4-(isopropyl(methyl)amino)cyclohexyl)-3-(6-(difluoromethyl) quinazoline-4-ylamine Base) tetrahydropyrrole_2-one. MS found: (M+H)+ = 480.2. Example 6i. l-((lS,2R,4R)_2-(2-hydroxypropan-2-yl) ice ( Synthesis of isopropyl (methyl)amino)cyclohexyl)-3-(6-(difluoromethyl)oxazole 4 _4_ylamino)tetrahydropyrrole-2-one oxime Example 6 ι Step 1: Ether 3M-methylmagnesium bromide (U ml, 3.3 millimoles... 'here' added dropwise (10) sees the cleavage of oxycarbonyl-based hydrazino-tetrahydro-p--1-ylisopropyl a solution of methyl (meth)amino)cyclohexanecarboxylate (295 mg, 0.66 mmol) in THF, and the mixture was taken at 〇1 ° ° C Stirred for 2.5 hours, and. By the addition of saturated ni ^ ci reaction was quenched at 4〇 1〇_25〇c minutes, and to Et0Ac (3χ) extract the product. The combined extracts were washed with brine, dried EtOAc (EtOAc)EtOAc. The residue was purified by flash chromatography on glutamic acid and eluted with μ: 7.2 · 92 cN^OHUO^Cl2 to give the desired product (8) (2-propan-2-yl)-4-(isopropyl) (Methyl)amino)cyclohexyl)_2-ketotetrahydropyrrolium 95318-198- 1354664 benzyl carbamate (164 mg), with recovered starting material (119 mg). _Example 6i Step 2: (S)-l-((lS,2R,4R)-2-(2-hydroxypropan-2-yl)-4-(isopropyl(methyl)amino) ring To a solution of hexyl)-2-ketotetrahydropyrrol-3-ylaminocarbazide (224 mg) in MeOH (15 mL), 10% Pd/c Degussa (~100 mg). The reaction flask was evacuated&apos; and then counter-filled with hydrogen; it was repeated two more times. The reaction was stirred at 60 psi H.sub.2 for 7 h then filtered and concentrated in vacuo to give the desired (8) &lt;RTI ID=0.0&gt; -2-yl)-4-(isopropyl(methyl)amino)cyclohexyl)tetrahydropyran-2-one as an oil. MS found: (M+H)+=312.2. Example 6i Step 3: By the method described in Step 6 of Example 6a, (S)-3-aminol-l-((lS,2R,4R)-2-(2-hydroxypropan-2-yl)- Conversion of 4-(isopropyl(methyl)amino)cyclohexyl)tetrahydropyrrole-2-one to the desired 1-((iS,2R,4R)-2-(2-hydroxypropan-2-yl) 4-(Isopropyl (methyl)amino)cyclohexyl)-3-(6-(trifluoromethyl)oxazoline-4 aminoalkyl)tetrahydropyrrole-2-one. MS found: (M+H)+=508.3. Example 6j: N-((S)-1-((1S,2R,4R)-2-(2_(C)-based)·4_(different Synthesis of propyl(indenyl)amino)cyclohexyl)-2-ketotetrahydropyrrol-3-yl)-3-(trifluoromethyl)benzamide as claimed in Example 6c (8)-3-Amino-propan-2-yl)-4-(isopropyl(methyl)amino)cyclohexyl)tetrahydropyrrole-2-one is converted to the desired hydroxypropyl-2-yl)- 4. (Isopropyl (methyl) amino) cyclohexyl)-2-ketotetrahydropyrrol-3-yl)-3-(trifluoromethyl)benzamide. MS measured value: (M+H)+ = 484.4.

The compounds of the bombardment 6-A in the table below were prepared using the methods exemplified above. See Table 1-A for a complete description of the header. 95318 -199- 1354664

Ο

Example R6' r6&quot; R2 Change Step MS Data 6a H Et i JWU n/a 508.3

6b

H

Et

n/a 508.3 6c

H

Et 6d

H

Et

484.3 474.4 6e

H 6f

H 6g

H

Et Me Me

516,3 494.3 470.3 95318 -200- 1354664 6h

Η H 6i

Me Me 6j

Me Me 6k

Me Me

n/a 480.2 n/a 508.3 n/a 484.4 6j Step 474.4 3

Table 6-B The list of chemical names for the specific examples shown in Table 6-A is set forth below. Example name 6a l-((lS,2R,4R)-2-(l-hydroxypropyl)_4_(isopropyl(methyl)amino)cyclohexyl)-3-(6-(trifluoromethyl) P-quinazoline-4-ylamino) Tetrahydropyrrole-2-one 6b (diastereomer of 6a) l-((lS,2R,4R)-2-(l-hydroxypropyl)_4 -(isopropyl(methyl)amino)cyclohexyl)-3-(6-(trifluoromethyl) 吱 吱 _4_ylamino) Four winds?比鸣· -2-酉同6c ~~ 1^-(1-((18,2民411)-2-(1-hydroxypropyl)-4-(isopropyl(methyl)amino) ring Hexyl)-2-ketotetrahydropyridin-3-yl)-3-(trifluoromethyl)benzamide 6d 1^-(1-((13, 2's 41〇-2-(1-) Hydroxypropyl)-4-(isopropyl(methyl)amino)cyclohexyl)-2-onetetrahydropyrrol-3-yl)-2-(tris-butyl)pyrimidine-4-carboxyindole Amine 6e 5-(4-chlorophenyl)-N-(l-((lS,2R,4R)-2-(l-propyl)-4·(isopropyl(methyl)amino) ring Hexyl)-2-ketotetrahydroindol-3-yl)-n-carboxylamine 95318-201 - 1354664 6f 1-((13,2min 4 ft)-2-(1-hydroxyethyl -4-(isopropyl(indenyl)amino)cyclohexyl)-3-(6-(trifluoromethyl) junsin_4_ylamino)tetrahydropyrrol-2-one 6g ]^ -(1-((13,2,4 ft)-2-(1-monoethyl)-4-(isopropyl(methyl)amino)cyclohexyl)-2-one-tetrahydropyrrole-3 -yl)-3.(trifluoromethyl)benzamide 6h l-((lS,2R,4R)-2-(indolyl)-4-(isopropyl(methyl)amino) ring Hexyl)-3-(6-(trifluoromethyl)u-quinone-4-ylamino) Tetrahydrobiha-2-_-6i l-((lS,2R,4R)-2_(2- Hydroxypropyl-2- 4-(isopropyl(methyl)amino)cyclohexyl)-3-(6-(trifluoromethyl)kutlin-4-ylamino)tetrahydropyrrol-2-one 6j 怵((3)-1-((13,2,41〇-2-(2-hydroxypropan-2-yl)-4-(isopropyl(methyl)amino)cyclohexyl)-2-one) Tetrahydropyrrol-3-yl)-3-(trifluoromethyl)benzamide- 6k 6-tris-butyl-N-((S)-l-((lS,2R,4R)-2 -(2-Hydroxypropan-2-yl)-4-(isopropyl(methyl)amino)cyclohexyl)-2-one-tetrahydropyrrol-3-yl)methylpyridinamide Example 7a-7f Example 7a: isobutyric acid ((lR,2S,5R)-5-(isopropyl(methyl)amino)-2-(2-indolyl-3-(6-(trifluoromethylazoline)- Synthesis of 4-aminoamino)tetrahydropyrrol-1-yl)cyclohexyl)methyl ester f Example 7a Step 1: On (lR,2S,5R)-2-((S)-3-(benzyloxycarbonylamine) Benzyl-2-ketotetrahydropyrrole-1-ylindole-S-yl-6-nitro-bicyclo[3.2.1]octane-6-carboxylic acid tert-butyl ester (4.55 g, 9.94 mmol) In a solution of THF (50 ml) and water (50 ml), NaBH?? The reaction was quenched with saturated NaHC EtOAc (EtOAc) (EtOAc). The combined extracts were washed with brine, dried (MgSO4), filtered, and evaporated 3 feet, 48) -4-((8)-3-(benzyloxy)amino-2-ketotetrahydro 17 pirin-1- 95318 •202- 1354664 base)-3-(3⁄4甲甲Base) cyclohexyl)amine mercapto acid tert-butyl ester (2 6 ιg). 1_Example% Step 2: _ Step 1 Hydroxymethyl Compound (2.61 g, 5 66 mmol) In a solution of CH2C12 (22 liters), add trifluoroacetic acid (4 % cc, brother 6 mM) Ear)' and the mixture was stirred at room temperature for 2 hours. The acid and solvent were evaporated and the residue dissolved in EtOAc. The solution was neutralized with saturated NaHC〇3 and EtOAc and water were evaporated in vacuo. The solid residue was treated in Me 〇 H and filtered. The filtrate is obtained, and the desired (3)-丨-(10) is obtained as an amine: (monodecyl)cyclohexyl)-2-g-iso-tetrahydropyrrole-3-ylaminocarbazate as a wax Solid. Example 7a Step 3: To a solution of the crude product in EtOAc (EtOAc m. Then, sodium triethoxysulfonate hydride (3.9 g, 18 4 mmol) was added, and the mixture was stirred at room temperature for 16 hours. A large amount of solid remained to precipitate. After the end of the stirring, a 37% aqueous HCl solution (2.9 ml) was added, and MeOH (20 ml) was also added to make the solution homogeneous. After stirring for 1 hour, another diethoxylated shed was added (2 g of '9.4 mmol) and the mixture was stirred at room temperature for 2 hours. Next, another 2 g of triethoxyphosphoric boron hydride (9.4 mmol) was added and stirred for 20 hours. The reaction was quenched by the addition of saturated EtOAc (EtOAc) The combined extracts were dehydrated (Na2SO4) eluted with brine, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with 1:9:90 cNH4OH-MeOH-CH2Cl2 to give 0.8 g of (S)-l-((lS,2R,4R)-2-(hydroxyl Benzyl-4-(isopropyl(methyl)amino)cyclohexyl)-2-one tetrahydro-P ratio benzyl p--3-ylaminocarbamate, MS found: (M+H)+ =418.2 ' with U g(S)-l-((lS,2R,4R)-4- 95318 -203 - 1354664 (dimethylamino)-2-(methyl)cyclohexyl)·2-keto Tetrahydropyrrole _3_ylaminocarbazate 'MS measured value: (μ + Η) + = 390.2, which is a crystal. _Example 7a Step 4: (S)-1-((1 S,2R,4R)-2-(hydroxymethyl)-4-(isopropyl(indenyl)amino)cyclohexyl &gt;2-Tetrahydrotetrahydropyrrole_3_yl ester (300 mg, 0.77 mmol) in a stirred solution of acridine (3 ml), added gasified isobutyl brew (0.16 ml '1.54 mmol) Ears with 4·(dimethylamino)P pyridine (2 〇 mg), and the mixture was stirred at room temperature for 4 hours. The reaction was quenched by the addition of Me〇H (several drops) and stirred for 30 minutes. Then, the volatiles were evaporated, and the residue was partitioned between EtOAc and water. The aqueous layer was extracted with Et.sub.Ac. Concentration in vacuo to give isobutyric acid ((lR,2S,5R)-2-((S)-3-(indolylcarbonyl)-2-ketotetrahydropyrrole-1-yl)-5-(( Isopropyl (methyl)amino)cyclohexyl)methyl ester as an oil. Example 7a Step 5: Step 4 crude product isobutyric acid ((lR, 2S, 5R)-2-((S)- 3-(Indolylcarbonyl)-2-ketotetrahydropyrrole-1-yl)-5-(isopropyl(methyl)amino)cyclohexyl)methanone (0.77 mmol) In a solution of MeOH (15 mL), 1% Pd/CDegussa (~100 mg) was added. The reaction flask was evacuated and then refilled with argon; it was repeated twice more. The reaction was taken at 60 psi. Stir under H2 for 4 hours, then filter 'and concentrate in True 2' to give the desired isobutyric acid ((1R,2S,5R)_2_((s)·3-amino-2-ketotetrahydropyrrole- L-yl)-5-(isopropyl(methyl)amino)cyclohexyl)methyl ester as an oil. 倒.7.a Step 6: By the method described in Step 6 of Example 6a, Isobutyric acid ((lR,2S,5R)-2-((S)-3-amino-2-ketotetrahydrop to 嘻_1_yl)_5_(isopropyl(methyl)amino) Conversion of cyclohexyl)methyl ester to the desired isobutyric acid ((1R,2S,5R)-5-(isopropyl(methyl)amino)-2-(2-keto-3-(6-() Trifluoromethyl &gt; quinazoline _4·ylamino) tetrahydropyrimidine 95318 204- 1354664 hex-1-yl)cyclohexyl) broth. MS found: (M+H)+= 550.4. Example 7b :Isobutyric acid isopropyl (methyl)amino)_2·(2·ketotrifluoromethyl)benzylideneamino)tetrahydropyrrole-1—yl)cyclohexyl)methyl ester Synthesis by example 6c The method described in ((1Rj2S,5R)_2_((8)·3_Amino·2·decyltetrahydropyrrole-1-yl)-5-(isopropyl(methyl)amino)cyclohexyl)methyl ester is converted into the desired Isobutyric acid ((1&amp;28,511)-5-(isopropyl(indenyl)amino)-2-(2-keto-3-(3-(trifluoromethyl)benzylidene) Hydropyrrole small) cyclohexyl) methyl ester. MS found: (M+H)+= 526.3. Example 7d: Isobutylhydrazine ((lR,2S,5R)-5-(dimethylamino)-2-(2-mercapto-3-(6-) Synthesis of (trifluoromethyl)indolines-4-mercaptoamino)tetrahydropyrrole_ι_yl)cyclohexyl)methyl ester By the method described in Example 7a, Steps 4-6, Example 7a, Step 3 Product hydroxyformic acid (S)-l-((lS,2R,4R)-4-(dimethylamino)-2-(methyl)cyclohexyl)-2-copperyltetrahydropyrrol-3-yl Conversion of the ester to the desired isobutyric acid ((1R,2S,5R)-5-(dimethylamino)-2-(2-keto-3-(6-(trifluoromethyl))- 4-Carboxynonylamino)tetrahydropyrrol-1-yl)cyclohexyl)decyl ester. MS found: (M+H)+= 522.3. Example 7e: Isobutylhydrazine ((ir,2s,5r)_5-(dimethylamino)-2-(2•keto-3-(3-) Synthesis of trifluoromethyl)benzhydrylamino)tetrahydropyrrol-1-yl)cyclohexyl)methyl ester By the method described in Example 6c, the product of Example 7a, step 3, the amine carboxylic acid (S)-l- ((lS, 2R, 4R)-4-(dimethylamino)-2-(hydroxymethyl)cyclohexyl)-2-onetetrahydropyrrol-3-yl ester, converted to the desired isobutyric acid ( (ir, 2S, 5R)-5-(dimethylamino)-2-(2-keto-3-(3-(trifluoromethyl)benzamideamino)tetrahydropyrrole-1-yl) Cyclohexyl)methyl ester. MS found: (M+H)+= 498.3. 95318 • 205· 1354664

Table 7-A The compounds in the table below were prepared using the methods exemplified above. See Table 1-A for a complete description of the header. R5

R2 instance R5 RS 7a iPr iPr 7b iPr iPr 7c iPr iPr 7d Me iPr 7e Me iPr 7f Me iPr

MS data step for change n/a 550.4 n/a 526.3

7b 518.4 Step 6 n/a 522.3 n/a 498.3 7e 490.4 Step 6 The chemical name series of the specific examples shown in Table 7-B, Table 7-A, is given below. 95318 -206- 1354664 The name '7Γ isobutyric acid ((1min 23,5卟5-(isopropyl(methyl)amino)_2_(2-copperyl-3-(6-(trifluoromethyl)) p奎峻淋_4_ylamino)tetrahydroindolyl-1-yl)cyclohexyl)methyl ester^^7b&quot; isobutyric acid ((1,28,5 ft)-5-(isopropyl (A) Amino) 2,2-(2· keto-3-(3-(trifluoromethyl)benzylideneamino)tetrahydropyrrole-丨-yl)cyclohexyl)methyl ester isobutyric acid ((111^411 )-2-(3-(3-Terve-butyl small methyl. ιη-pyrazole-5-rebellant amino)-2-self-isotetrahydro ρ-pyridin-1-yl)-5- (isopropyl(methyl)amino)cyclohexyl)methyl ester isobutyric acid ((lR,2S,5R)-5-(dimethylamino)-2-(2-copperyl-3-(6-) (trifluoromethyl) ferrocene-4-mercaptoamino) tetrahydropyrrole·ι_yl) cyclohexyl)methyl ester ^^7e isobutyric acid ((lR, 2S, 5R)-5-(two Amidino)-2-(2-keto-3-(3-(trifluoromethyl)benzylideneamino)tetrahydro-p-l-yl-yl)cyclohexyl)methyl ester _^--- - isobutyric acid ((111^,510-2-(3-(3-tert-butyl-1-methyl-1H-pyrazole-5-sodium)-keto-tetrahydrop Pyrrol-1-yl)-5-(dimethylamino)cyclohexyl)methyl ester Example 8a: N-( (S)-l-((lS,2R,4R)-4-(isopropyl(methyl)amino) winter (methanesulfonyl)cyclohexyl)-2-ketotetrahydropyrrole_3 · Synthesis of ·3_(trifluoromethyl)benzamide. Example 8a Step 1: Before adding NaBH4 (252.4 mg), make (11^28,511)-2-indoleoxycarbonylamino-7- Keto-6-aza-bicyclo[3.2.1)octane-6-carboxylic acid tert-butylate (500 mg, 1.3 mmol) was dissolved in THF (10 mL) and water (2.2 mL). After 5 hours, the solution was quenched with saturated NaHC03 and extracted with EtOAc (2×). The organic extracts were combined, dehydrated (MgS 〇 4), filtered, and re-reduced in vacuo to give (lR, 3R , 4S)-4-benzyloxycarbonylamino-3-3-(methyl)cyclohexylamine sulfonium tri-butyl ester (505 mg). MS (ES+) = 375.4 (M+H)+ · 95318 • 207· 1354664 Example 8a Step 2: Prior to the addition of Et3N (186.9 mg), (ir^R^SM-benzyloxynimino-3-(methyl)cyclohexylamine decanoic acid tert-butyl ester (5 〇〇 mg) was dissolved in CH 2 C 12 (4.5 ml). After cooling to 〇 ° C, a chlorinated succinimide (196.7 gram) was added dropwise. The solution was allowed to warm to room temperature over 1 hr then the solution was quenched with sat. NaHC.sub.3, and extracted with CH.sub.2Cl.sub.2 (2x). The organic extracts were combined, dehydrated (MgS04), filtered, and concentrated in vacuo to give methanesulfonic acid ((lR,2S,5R)-2-indoleoxycarbonylamino-5-(tris-butoxy) Carbonyl) Cyclohexyl) decyl ester (MS (ES+) = 457.4 (M+H)+) as a foam. It was immediately dissolved in DMF and added dropwise to a flask containing sodium thiodecanate (370 mg) in DMF (7 mL) and water (0.5 mL). After 20 minutes, the reaction was quenched with sat. NaH.sub.3 solution and extracted (EtOAc). The organic extracts were combined and dehydrated (MgS〇4), filtered, and concentrated. The resulting residue was dissolved in MeOH (15 mL) and water (4 mL). After cooling to 〇〇c, 'Oxygen (2.1 g) was added and stirred for 5 hours, then filtered, and concentrate. The residue was purified by flash chromatography to give (1,,,,,,,,,,,,,,,,,,,,,,,,, . MS (ES+) = 441.2 (M+H)+. Example 8a Step 3: (1艮311,48)-4-benzyloxycarbonylamino-3-(methylsulfonylmethyl)cyclohexylaminocarboxylic acid Add a 10% Pd/C Degussa (800 mg) to a solution of the third butyl ester (5.5 g) in MeOH (40 mL). The reaction flask was evacuated and then counter-filled with hydrogen; it was repeated three more times. The reaction was scrambled at 1 atm for 3 hours' followed by filtration and concentration. The resulting residue was dissolved in DMF (41 mL) and cooled to EtOAc, then EtOAc EtOAc EtOAc EtOAc 〇p (9.92 g). The reaction was stirred at room temperature 95318 • 208·1354664 for 12 hours then partitioned between EtOAc and &lt The combined organic phases were washed with saturated aHC.sub.3 and brine, dried and evaporated and evaporated. The residue is purified by flash chromatography to give (1,3,3,43)-4-((8)-2-indoleoxycarbonylamino-4-(indolylthio)butanyl)-3-( A butyl butyl hexyl amide (69 g). MS found: (M+H)+=572.4. Example 8a_stem^(lR,3R,4S)-4-((S)-2-indoleoxycarbonylamino-4-(methylsulfide) Base butylamino)-3-(methylsulfonylmethyl)cyclohexylaminocarbamic acid tert-butyl ester (69 g) dissolved in qi methane (100 ml) and the resulting solution was placed in the chamber Stir at room temperature for 72 hours' then concentrate in vacuo. The residue was dissolved in dichloromethane and the resulting solution was reduced; the mixture was repeated to give a salt. MS found: (M+H)+= 586.5. This material was dissolved in Dmf (20 mL) and &lt;EMI ID&gt;&gt; After 12 hours, the reaction was partitioned between Et 〇Ac and brine. The organic phase was dried (MgS 4), filtered, and concentrated in vacuo. The residue is purified by flash chromatography to give (1R,3R,4S)_4_((S)-3-benzyloxycarbonylamino-2-ketotetrahydropyrrole-1-yl)_3_(methylsulfonium) Methyl) Cyclohexylaminocarboxylic acid tert-butyl vinegar (2.4 g). MS found: (M+H)+= 524.3. J: Example 8a Step 5: (lR,3R,4S)-4-((S)-3-benzyloxycarbonyl-2-yl) Hydrogen pyrrol-1-yl)-3-(methylsulfonylhydrazino)cyclohexylamino decanoic acid tert-butyl ester (835 mg) in MeOH (5 mL), 1% pd/ CDegussa (8 mg). The reaction flask was evacuated&apos; and then counter-filled with hydrogen; it was repeated three more times. The reaction was stirred at 1 atm H2 for 2 h then filtered and concentrated to afford (l,,,,,,,,,,,,,,,,,,, Io_yl)_3_(曱 醯 甲基 methyl) Cyclohexylaminocarbamic acid tert-butyl ester (566 mg). MS found 95318-209· 1354664: (M+H)+= 390.3. 3-(trifluoromethyl)benzoic acid (252.4 mg) dissolved in DMF (5 mL) Previously, 4-methylmorpholine (〇·42 ml) was added. After 1 minute, add (1Rj3min 4S) 4 ((8)_3•amino-2-ketotetrahydrop-ha-1-yl)-3-(methylsulfonylmethyl)cyclohexylaminocarboxylic acid third_ Butyl ester (3 〇〇 house grams). The reaction was stirred for 1 hour and then partitioned between Et EtOAc and 1N EtOAc. The organic phases were combined, washed with saturated NaHC3 and brine, dried (MgSO. The residue was purified by flash chromatography to give (1艮3民43)-3-(oxasulfonylmethyl)-4-((3)-2-keto-3-(3-(3) Fluoromethyl)benzamide amino)tetrahydropyrrole_丨-yl)cyclohexylaminocarbamic acid tert-butyl vinegar (56 mg). MS found: (m+H)+= 562.2. f Example 8a Step 7: Before adding trifluoroacetic acid (5 mL), (take 3 ft, 48) -3-(sulfonylmethyl) -4-((S)-2-keto-3-(3-(trifluoromethyl)benzylideneamino)tetrahydropyrrole-1-yl)cyclohexylaminocarboxylic acid tert-butyl ester (56 〇mg) is dissolved in CH2C12 (5 liters). After 1 hour, the reaction was concentrated in vacuo. The resulting residue was dissolved in MeOH (5⁄4L) and EtOAc (EtOAc) The mixture was mixed for 5 knives before adding NaCNBH3 (261 mg). The reaction was spoiled for 4 hours, then mL of formic acid was added, 37% water was added). The mixture was stirred for 1.5 h. EtOAc (EtOAc) The organic extracts were combined, dried (MgSO.sub.4), filtered and concentrated. The residue was purified by reverse phase HPLC (gradient elution, water / acetonitrile / hexanes hexanes) to obtain the group ((3)-1-((13,211,411)_4-(isopropyl(methyl)amino)) - (A ~ Linyl methyl) cyclohexyl)-2-yltetrahydroindole 嘻 _3_ yl) _3_ (tri-gas methyl) TFA salt of lanthanum amide (347 gram). MS found: (μ+η)+ = 504.2. 95318 -210- 1354664 Example 8p: (8)-1-((18,2 where 4 is 4-(isopropyl(methyl)amino)_2_( Methanesulfonylmethyl)cyclohexyl)-3-(6~(trifluoromethyl) phosphatide &quot;4·ylamino)tetrahydropbilo_2_ Meng synthesis Example 8p Step 1 : Before adding trifluoroacetic acid (7 ml), (1^31^48)-4-((S)-3- oxalylamino-2-ketotetrahydro I» is compared with ρ--1-yl _3_(methyl succinylmethyl) Cyclohexylaminocarbamic acid tert-butyl ester (714 mg) was dissolved in ch2C12 (15 mL). After 1 hour at room temperature, the reaction was concentrated in vacuo. The residue was dissolved in MeOH (15 mL) and EtOAc (EtOAc &lt;RTI ID=0.0&gt;&gt; Then, the mixture was stirred for 1 hour, and the mixture was stirred with EtOAc (EtOAc) (EtOAc) (EtOAc) (MgS〇4) 'Filtering' and concentrating' (s)_l_((is,2R,4R)-4-(isopropyl Benzyl (methyl)amino)-2-(methylsulfonylmethyl)cyclohexyl)-2-onetetrahydropyrrol-3-ylcarbamate (1.5 g). MS found: (M+ H) + = 466.4. Example 8p Step 2: #from the above material (S)-l-((lS,2R,4R)-4-(isopropyl(indenyl)amino)-2-( Benzylmethyl)cyclohexyl)-2-ketotetrahydrop-pyrrol-3-yl carbamic acid benzyl ester (600 mg), soluble in 33% HBr/AcOH (10 ml at room temperature) In the process of adding Et2 Ο, the solution is stirred for 30 minutes. This will cause the precipitate to 'single away, and the (5)-3-amino group is small ((is, 2R, 4R)-4-(isopropyl ( Methyl)amino)-2-(methylsulfonylhydrazino)cyclohexyl)tetrahydropyrrole-2-one bis-hydrobromide salt (525 mg). MS found: (Μ+Η)+= 346·5. Preferably J_8p Step 3: (S)-3-Amino-l-((lS,2R,4R)-4-(isopropyl(methyl)amino)-2-(methylsulfonate) Add methyl triethylamine (0.14 ml) and 4-chloro-6-(trifluoromethyl 95318) to a solution of methylcyclo)cyclohexyl)tetrahydropyrrole-2-one (100 mg) in EtOH (5 mL) -211 - 1354664 base &gt; quinazoline (68,7 mg). It was heated 14 hours at 80 ° C, then filtered, and concentrated in vacuo. The residue was purified by reverse phase HPLC (gradient elution, water / acetonitrile / TFA) to give (3)-1-((^21^411)-4-(isopropyl(methyl)amino)-2 TFA salt of ((methylsulfonylmethyl)cyclohexyl)-3-(6-(trifluoromethyl)quinazolin-4-ylamino)tetrahydropyrrole-2-one (30 mg). MS found: (M+H)+= 542.6. 95318 -212- 1354664

Table 8-A The compounds in the table below were prepared using the methods exemplified above. See 1-A for a complete description of the header. Example 8a 8b 8c 8d

Η

R5 R2 Change step i-Pr (Me)N n/a i-Pr (Me) N 〇cf3 8a Step 〇nh2 6 A N 8a Step 6 Ο ' i-Pr (Me)N 8a Step MS data 518 549 510 507

O 95318 -213- 1354664 8e

i-Pr(Me)N 8f

i-Pr(Me)N 8g

i-Pr(Et)N 8h

Third - BuCH2(H)N

Phγί cf3V5 8a Step 6 8a Step 6 8a Step 7 8a Step 7 519 527 532 532 8i 8j 8k

.i-Pr (Me) N i-Pr (Me) N i-Pr (Me)N

532 552 506 81

i-Pr (Me)N

526 95318 -214- 1354664 8m

i-Pr(Me)N 8n 80

Ph i-Pr(Me)N i-Pr(Me)N

8a step 骡 6 8a step 6 8a step 6 528 536 534 8p

i-Pr(Me)N

F3c n/a 542 8q

i-Pr(Me)N

8p step 3 508 8r i-Pr(Me)N PF3 Y^CFs 0 8a step 6 586 8s i-Pr(Me)N Λ 0 8a step 6 518

Table 8-B The list of chemical names for the specific examples shown in Table 8-A is set forth below. 95318 • 215 · 1354664 Example name 8a N-((S)-l-((lS,2R,4R)-4-(isopropyl(methyl)amino)-2-(methylsulfonylmethyl) Perhexyl)-2-mercaptotetrachlorop-bi-3-yl)-3-(trimethylmethyl)benzamide 8b 2-amino-N-((S)-l-((lS, 2R,4R)-4-(isopropyl(methyl)amino)-2-(indolylmethyl)cyclohexyl&gt;2-ketotetrahydropyrrol-3-yl)-5· (three Fluoromethoxy)benzamide 8c 3-T-Butyl ((3)-1-((13,2 ft.)-4-(isopropyl(indenyl)amino)-2-(A) Sulfomethyl)cyclohexyl)-2-ketotetrahydropyrrole-3-yl)-1-methyl-1H-pyrazole-5-carboxamide 88d 6-tris-butyl-N-( (S)-l-((lS,2R,4R)-4-(isopropyl(methyl)amino)-2-(methylmercaptomethyl)cyclohexyl)-2-yltetrahydrop Biha-3-yl) decyl pyridylamine 8e N-((S)-l-((lS,2R,4R)-4-(isopropyl(methyl)amino)-2-(methane) Mercaptomethyl)cyclohexyl)-2-ketotetrahydropyrrol-3-yl)-6-(trifluoromethyl)methylpyridiniumamine 8f N-((S)-l-((lS,2R , 4R)-4-(isopropyl(methyl)amino)_2_(nonylsulfonylmethyl)cyclohexyl)-2-ketotetrahydrop ratio -3-yl)-6-phenylmethylpyridiniumamine 8g N-((S)-1-((1S,2R,4R)-4-(ethyl(isopropyl)amino)·2· (Methanesulfonylmethyl)cyclohexyl)-2-ketotetrahydropyrrol-3-yl)_3_(trimethylene)benzamine 8h N-((S)-1-((1S,: 2R,4R)-2-(methyl-decylmethyl)_4_(neopentylamino)cyclohexyl)-2-ketotetrahydropbilol-3-(yl)-3-(trifluoromethyl)benzene Methionamine 8i N-((S)-l-((lf,2R,4R)-4-(isopropyl(methyl)amino)_2_(methylsulfonylmethyl)cyclohexyl)-2- Keto-tetrahydropyrrole-3_yl)_4·methyl_3. (Trifluoromethyl)benzamide 8j 4-disorder ((8)-1-((18, 2's 4 ft)-4 -(isopropyl(indenyl)amino)_2_(methyl-bromomethyl)%hexyl)-2-g-isotetrahydro-p ratio, each _3_yl)_3_(trifluoromethyl)benzene Indole 8k 3-second-butyl-N-((S)-l-((lS,2R,4R)-4-(isopropyl(methyl)amino)-2·(methylsulfonyl) Methyl)cyclohexyl ketotetrahydropyrrole _3•yl) awkward amine 95318 -216- 1354664 81 3-phenyl-1^-((8)-1-((18,2min 4 ft)- 4-(isopropyl(methyl)amino)_2_(methyl Simethyl)cyclohexyl)-2-one 4 p is 嘻·3_yl) benzoylamine 8m scam ((5)-1-((18,2,4 ft)-4-(isopropyl(indenyl)amino)-2-(methyl sulfonate) Mercaptomethyl)cyclohexyl)-2-ketotetrahydropyrrol-3-yl)-6-phenylpyridin-2-carboxamide 8n 3-fluoro ((8)-1-((2 411)-4-(isopropyl(methyl)amino)_2_(methylsulfonylmethyl)cyclohexyl)-2-onetetrahydropurpur-3-yl)-5-(trifluoromethyl) Benzomethaneamine 8〇N-KSH-ais^MRM-cisopropyl(methyl)amino)-2-(methylsulfonylhydrazino)cyclohexyl)-2-ketotetrahydropyrrole- 3·yl)-3-(trim methoxy)benzamide 8P (S)-l-((lS,2R,4R)-4-(isopropyl(methyl)amino)-2_( Sulfosylmethyl)cyclohexyl)-3-(6-(trifluoromethyl)(t-tonyl-4-ylamino)tetrahydro»piro-2-one 8q "(S)-3- (6-Alkyl-4-oxazolin-4-ylamino)-l-((lS,2R,4R)-4-(isopropyl(methyl)amino)-2-(methyl-bromomethyl) Cyclohexyl)tetrahydrop-pyloryl-2-y8r N-((S)-1-((1 S,2R,4R)-4_(isopropyl(methyl)amino)_2-(a cross Styrene methyl)cyclohexyl)-2-ketotetrahydropyrrol-3-yl)-3,5-bis(trilacmethyl)benzene Methionine 8s 3,5-Dichloro-N-((S)-l-((lS,2R,4R)-4-(isopropyl(methyl)amino)_2_ (methylsulfonylmethyl) Cyclohexyl)-2-ketotetrahydropyrrol-3-yl) benzylideneamine Example 9a-9k Example 9a: N-((S)-l-((lS,2R,4R)-2-( Tris-butylsulfonyl fluorenyl) 4-(isopropyl(methyl)amino)cyclohexyl)-2-onetetrahydropyrrol-3-yl)-4·fluoro-3-(trifluoromethyl) Synthesis of benzinamide f Example 9a Step 1: methanesulfonic acid ((lR,2S,5R)-2-indoleoxycarbonylamino-5-(tris-butoxycarbonyl)cyclohexyl)methyl ester (12.1 grams), in the 〇. (:, dissolved in DMF (50 ml) and HMPA (25 ml), then added 2-methyl-2-propanesulfide in DMF (50 ml) over sodium sulfate (6.3 g). After that, the reaction was quenched with cold water <RTI ID=0.0># </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> Purification of 'Providing (1R)3Ri4S)_4·芊Oxycarbonylaminosyl_3_(Thrs.thylthiomethyl)cyclohexylaminocarbamic acid tert-butyl ester (13.0 g) MS(ES+) = 451.4 (M+H)+. Step 2: (LiUR^SM-benzyloxycarbonylamino-3-(t-butylthiomethyl)cyclohexylaminocarbamic acid tert-butyl ester (12.1 g) Dissolved in MeOH (120 mL) and water (60 mL). After cooling to EtOAc (EtOAc: EtOAc (EtOAc) Purification by flash chromatography, provided (1 Min 3 Min 43) -4- methoxycarbonylamino-3-(tert-butylsulfonylmethyl)cyclohexylaminocarboxylic acid tert-butyl ester (7.35 g)) MS (ES+) = 483.3 (M+H)+. Example 9a 3: (lR,3R,4S)-4-indoleoxycarbonylamino-3-(t-butylsulfonylmethyl)cyclohexylaminocarboxylic acid tert-butyl ester (7.3 g) in MeOH ( 10% Pd/C Degussa (5.0 g) was added to the solution in 80 ml). The reaction flask was evacuated and then refilled with hydrogen; this was repeated three more times. The reaction was stirred at 1 atmosphere H2 for 3 hours. Filtration followed by concentration afforded (ir,3R,4S)-4-amino-3-(t-butylthiomethyl)cyclohexylaminocarbamic acid tert-butyl ester (5. gram). MS (ES+) = 349.3 (M+H)+. </RTI> Example 9a Step 4: (1R,3R,4S)-4-amino-3-(tris-butylthiomethyl)cyclohexylaminocarboxylic acid A solution of the third-butyl ester (4.8 g) was dissolved in OMF (40 ml) with N-Cbz methionine (4_3 g), 4-methylmorpholine (7.6 g) and BOP (7.9). Before gram), cooled to 〇 ° C. The reaction was stirred at room temperature for 12 h then partitioned between EtOAc and EtOAc (EtOAc). MgS04), filtration 95318 218- 1354664 'and concentrated in vacuum. The residue was purified by flash chromatography to give (1R53R,4S)_4_((S)_2-benzyloxyamino-4-(methylthio)butaninyl)_3_(T. Tertylmethyl) butyl hexylaminocarbamate (8.4 g). Jyjs found: (M+H)+ = 614.4. Example 9a Step 5: (lIUR, 4S)-4-((S)-2-Benzyloxycarbonylamino-4-(methylthio)butyl Amidino)-3-(t-butylsulfonylmethyl)cyclohexylaminocarbamic acid tert-butyl ester (6.2 g) was dissolved in methyl iodide (60 ml) and CH2C12 (15 ml). The resulting solution was stirred at room temperature for 72 hours before concentration in the air. The residue is dissolved in di-methane and the resulting solution is concentrated; it is repeated to give a salt. This material was dissolved in DMF (60 mL) and Cs 2 C 3 (13.2 g) was added to the solution. After 12 hours, the reaction was partitioned between EtOAc and brine. The organic phase is dried (MgS〇4), filtered, and concentrated to give (lR,3R,4S)-4-((S)-3-indoleoxycarbonylamino-2-ketotetrahydropyrrole-1 • Base) _3_(T-butylsulfonylhydrazino)cyclohexylaminocarbamic acid tert-butyl ester (55 g). MS found: (M+H)+= 566.5. Example 9a Step 6: Before adding trifluoroacetic acid (1 mL), make (lR^RAS)-4-((S)-3-; oxygen胺 · 2 ) ) ) ) ) ) ) ) ) ) ) ) ) 880 880 880 880 880 880 880 880 880 880 880 880 880 880 880 880 880 880 880 880 880 880 Dissolved in CH2C12 (5 mL). After 1 hour at room temperature, the mixture was concentrated in vacuo. The resulting residue was dissolved in Et.sub.Ac and washed with saturated Na.sub.2CO.sub.3 solution. The organic phase was dried (MgS 4), filtered, and concentrated. This residue was dissolved in dichloroethane (6 ml) and acetone (6 ml). After 2 hours, a brew (6.0 mL, 37% aqueous solution) was added along with NaBH(〇Ac)3 (31 mg). The mixture was stirred with EtOAc (EtOAc) (EtOAc) (EtOAc) The organic extracts are combined, dehydrated (MgS04), filtered, and concentrated to give (SM-GISJR^R)-2-(t-butylsulfonylmethyl)_4_(isopropyl (methyl) Benzylamino)cyclohexyl)-2-ketotetrahydropyrrol-3-ylcarbamate (1.0 g). MS found: (M+H)+ = 522.5. f Example 9a Step 7: #Substance from above (3)-1-((13,2艮411)-2-(T-butylsulfonyl) Benzyl)-4-(isopropyl(methyl)amino)cyclohexyl)-2-onetetrahydropyrrol-3-ylcarbamate benzyl ester (1.0 g), dissolved in 33 at room temperature % HBr/AcOH (5 ml). The solution was stirred for 30 minutes before the addition of Et20. This causes the sediment to 'single away. The solid was dissolved in EtOAc and washed with saturated aq. The organic phase is dried (MgS04), filtered, and concentrated to give (S)-3-amino-l-((lS,2R,4R)-2-(t-butylsulfonylmethyl) 4-(isopropyl(methyl)amino)cyclohexyl)tetrahydropyrrole-2-one (250 mg). MS found: (M+H)+= 388.4. Suitable A~9a Step 8: (8)-3-Amino-l-((lS,2R,4R)-2_(T-butylsulfonylhydrazine) 4-(isopropyl(indenyl)amino)cyclohexyl)tetrahydropyrrole: ketone (23 mg) dissolved in DMF (1.5 φ liters) and cooled to 〇, then 4 fluoro _3-(Trifluoromethyl)benzoic acid (23 mg), 4-methylfifelin (〇.〇 2 ml) and BOP (49 mg). The reaction was stirred at room temperature for 12 hours, followed by liquid separation between EttAc and saturated (:3 solution). The organic phases were combined, dehydrated (MgS〇4), filtered and vacuum Concentration in the residue. Purification of the residue by reverse phase HpLC (gradient elution of 'water / acetonitrile / TFA') afforded N-((S)-l-((lS,2R,4R)-2-(second-butyl) Sulfomethyl)-4-(isopropyl(methyl)amino)cyclohexyl)_2-ketotetrahydropyrrol-3-yl)-4-fluoro-3-(trifluoromethyl)benzene Methotrexate TFA salt (8 mg) 95318 -220- 1354664. MS found: (M+H)+= 578.3. Example 9j: (S)-l-((lS,2R,4R)_4-(different Propyl (methyl)amino)_2_(Third-butyl-butyl-methyl)cyclohexyl)-3-(6-(trifluoromethyl-trazolinyl-ylamino)tetrahydropyrrole-2- Synthesis Example of Bismuth 丨 丨 Step 1: On (S)-3-Amino-1-((18,2 Å)-4-(isopropyl(methyl)amino)-2-(Third- Addition of triethylamine (〇〇76 ml) with 4 butyl sulfonyl fluorenyl)cyclohexyl)tetrahydropyrrole 2 ketone bis-bromide (100 mg) in EtOH (2 mL) -Chloro-6-(trifluoromethyl)oxazoline (63克). The mixture was heated at 8 ° C for 6 hours, then it was simmered and concentrated in vacuo. The residue was purified by reverse phase HPLC (gradient elution, water / acetonitrile / wa) to give (5) ( 1S,2R,4R)_4_(isopropyl(indenyl)amino)_2_(tris-butylsulfonylmethyl)cyclohexyl)-3-(6-(trifluoromethyl)p- quinazoline · 4_ylamino)tetrahydropyrrole_2-one octadecyl salt (63 mg). MS found: (Μ+Η)+= 584.6. 95318 221 - 1354664

Table 9-A The compounds in the table below were prepared using the methods exemplified above. See Table 1-A for a complete description of the header.

Example R5 R2 Changed MS Data Lu Step 9a i-Pr (Me)N CF3 n/a 578

•A o

95318 -222 - 1354664 9c

i-Pr(Me)N

Step 9a 8 560 9d

i-Pr(Me)N

0 9a steps 8 549 9e 9f 9g

i-Pr(Me)N i-Pr(Me)N i-Pr(Me)N

9a step 8 9a step 8 9a step 8 576 578 591 9h

i-Pr(Me)N 9i

CF, i-Pr (Me)N

9a step 8 9a step 8 575 585 9j

i-Pr(Me)N

F3C n/a 584 95318 - 223 - 1354664 9k

i-Pr(Me)N

550 91 i-Pr(Me)N γ2 ^〇Η 3a.Step 8 564 9m i-Pr(Me)N V 5 9aStep 8 569.5

Table 9-B The list of chemical names for the specific examples shown in Table 9-A is given below. Example name 9a N-aSWAlSJR^R)-2·(T-butylsulfonylmethyl)_4·(isopropyl(methyl)amino)cyclohexyl)-2-ketotetrahydropyrrole- 3-yl)-4-fluoro-3-(trifluoromethyl)benzamide 9b N-((S)-l-((lS,2R,4R)-2-(tris-butylsulfonate) Methyl)-4-(isopropyl(methyl)amino)cyclohexyl)-2-onetetrahydropyrrol-3-yl)«trifluoromethyl)methylpyridinium 9c N-(( S)_l-((lS,2R,4R)-2_(T-butylsulfonylmethyl)-4-(isopropyl(methyl)amino)cyclohexyl)-2-oneyltetrahydro Pyrrol-3-yl)-3-(trifluoromethyl)benzamide 9d 6-tris-butyl-N-((S)-l-((lS,2R,4R)-2-( Tris-butylsulfonylmethyl)-4-(isopropyl(methyl)amino)cyclohexyl)-2-onetetrahydropyrrol-3-yl)methylpyridinium 9e 1 N-( (S)-l-((lS,2R,4R)-2-(T-butylsulfonylmethyl)-4·(isopropyl(methyl)amino)cyclohexyl)-2-one Tetrahydropyrrol-3-yl)-3-(trifluoromethoxy)benzamide 95318 -224- 1354664 9f 汴((3)-1-((13,2艮411)-2-(第Tris-butylsulfonylmethyl)-4-(isopropyl (methyl) (cyclohexyl)-2-ketotetrahydropyrrol-3-yl)-3-fluoro-5-(trifluoromethyl)benzamide 9g 2-amine base ((8)-1-( (13, 2 min 4 ft)-2-(t-butylsulfonylmethyl)-4-(isopropyl(methyl)amino)cyclohexyl)-2-ketotetrahydropyrrole_3_ 5-(3-trifluoromethoxy)benzamide 9h 3-Amino-N-((S)-l-((lS,2Rj4R)-2-(T-butyl-decyl) 4-(isopropyl(methyl)amino)cyclohexyl)-2.ketotetrahydropyrrole·3_yl)-5-(trifluoromethyl)benzoguanamine 9i N-((S )-l-((lS,2Rj4R)-2-(Third-butyl-butyl-methyl)_4-(isopropyl(methyl)amino)cyclohexyl)-2-g-iso-tetrahydro-p-Bilo -3-yl)-5-phenylnicotinate decylamine N-oxide 9j (S)-l-((lS,2Rj4R)-2-(tri-butylbutyl arylmethyl)_4-(iso Propyl (methyl)amino)cyclohexyl)-3-(6-(trifluoromethyl)p-kutungu _4_ylamino)tetrahydropyrrol-2-one 9k (S)-1- ((1 S,2R,4R)-2-(T-Butyl-butyl-methyl)4-(isopropyl(methyl)amino)cyclohexyl)-3-(6-chloro-based quinone Lin-4-ylamino) tetrahydropyrrol-2-one 91 3-tri-butyl-1^like)-1-((18) , 2 ft. 2)-2-(t-butylsulfonylmethyl)-4-(isopropyl(methyl)amino)cyclohexyl)-2-ketotetrahydrop-pyrazole-3 -yl)-4-ylphenylbenzamine 9m N-((S)-l-((lS,2R,4R)-2-(T-butylidenemethyl)_4_(isopropyl (Methyl)amino)cyclohexyl)-2-yltetrahydropyrrol-3-yl)-5-phenyl IfAcamine f Example 10a-10m Example l〇a : N-((S)-l -((lS,2R,4R)-4-(isopropyl(methyl)amino)·2_(isopropylsulfonylmethyl)cyclohexyl)-2-onetetrahydropyran-3- Synthesis of benzyl-3-(trifluoromethyl)benzamide Example 10a Step 1: On N-(lS,2R,4R)-4-(oximeoxycarbonylamino-3-hydroxymethyl-cyclohexyl --Aminomethyl-tert-butyl ester (440 mg, 1.16 mmol, see step 5 of Example 5) in 20 ml (33⁄43⁄4, cooled to 〇 ° C solution, add 95318 -225 - 1354664

Et3N (o.3 ml '2 mmol) and shirt (: 1 (0.1 mL, 139 mmol). The reaction mixture was stirred at room temperature for 2 hours, then water was added. 2 X 25 ml) extraction 'and concentrated to oil for further use. In another flask, propane-2-thiol (0.22 mL, 2.3 mmol) was dissolved in 1 mL of DMF 'cooled to 〇 °C, and followed by NaH (93 mg, 2 32 mmol). The reaction mixture was stirred at room temperature for 2 hr then slowly added to a solution of the crude oil in 10 ml of DMF. After stirring for 16 hours, water and EtOAc were added, and the organic layer was separated, dried over Na2SO4, and concentrated to give the oil, which was applied to the silica gel by column chromatography, using Et〇Ac: hexane (30: 70) Purification to give N-(lS,2R,4R)-4-hydrazinocarbonylamino-3-3-isopropylthiomethyl-cyclohexyl)-amine mercapto acid tert-butyl ester (160 mg , 33%). MS [M+H]+437. 实J; Column 10a Step 2: over N-(lS,2R,4R)-4-indoleoxycarbonylamino-3-isopropylthiomethyl-cyclohexyl)- Oxygen methic acid tris-butyl ester (1 g, 2.3 mmol) in a solution of iPr 〇 H (20 mL) - Add oxygen (1 gram in water) at room temperature (2.8 g) , 4.6 millimoles). The mixture was stirred at room temperature for 16 hours then water and EtOAc was added. The organic layer was separated, dried over Na2SO4, and concentrated to give crude N-(lS,2R,4R)-4-benzyloxycarbonylamino-3-(propane-2-sulfonylmethyl)-cyclohexyl] - Aminomethyl 3-butyrate (900 mg, 90%). MS [M+H]+ 469. Example 10a Step 3: N-(lS,2R,4R)-4-benzyloxycarbonylamino-3-(propan-2-sulfonylmethyl)-cyclohexyl] - A solution of the amine-amino acid tert-butyl ester (2 g) in MeOH (50 mL) was added 10% Pd/CDegussa (1.5 g). The reaction flask was evacuated and then counter-filled with hydrogen; it was repeated three more times. The reaction was stirred at 1 atm. H.sub.2 for 4 h then filtered and concentrated in vacuo to give </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> Methyl) Cyclobutylaminocarbamic acid tert-butyl ester (1 g). MS found: (M+H)+= 335. Example 10a Step 4: (1 mp3) 4-amino-3-(isopropylcarbylmethyl)cyclohexylaminocarboxylic acid A sample of tri-butyl ester (1 g '2.9 mmol) was dissolved in DMF (20 mL) and N-Cbz methionine (85 mg, 2.9 mmol) was added to the resulting solution. N,N-diethylisopropylamine (0.5 ml, 2.9 mmol) and HATU (1.1 g, 2.9 mmol). The reaction was stirred at room temperature for 2 hrs. then was partitioned between EtOAc and sat. NaHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH ), filter 'and concentrate in vacuum. The residue was purified by flash chromatography to obtain (lR,3R,4S)-4-((S')-2-amino-4-(methylthio)butylamino)_3_(isopropyl The continuation of the methyl group) cyclohexylaminocarbamic acid methoxycarbonyl third _ vinegar (1 4 g, 82%). MS found: (M+H)+= 599. Example 10a Step 5: Compound (lR,3R,4S)-4-((S)-2-amine-based (sulfonylthio)-butylamino) Benzyloxycarbonyl tri-butyl -3-(isopropylsulfonylmethyl)cyclohexylaminocarbamate (1.4 g) was EtOAc &quot;wet &quot; and then most of the EtOAc was removed under a stream of nitrogen. The residue was dissolved in methyl iodide (2 mL) and the resulting mixture was stirred at room temperature for 48 hr then concentrated in vacuo. The residue was dissolved in dichloromethane, and the resulting solution was concentrated; this was repeated to give a salt. MS spectroscopy. (M+H)+= 616. This material was dissolved in DMF (20 mL), and Csz CO3 (2.2 g) was added to the mixture and stirred at room temperature for 12 hours, then The mixture was partitioned between EtOAc and brine. The organic phase was dehydrated and dried. 03⁄42 SO#) was filtered and concentrated in vacuo. The residue was purified by flash chromatography to obtain (111,3 mil)-4-((8)_3_amino-2- ketotetrahydropyhaminyl (iso-95318 • 227·1354664 C Benzylsulfonylmethyl) benzyloxycarbonyl cis-butyl ester (185 mg). MS found: (m+H)+= 552. (1艮3艮43)-4-( (8)-3-Amino-2-keto-tetrahydropyrrole small)-3-(isopropylsulfonylmethyl)cyclohexylaminocarbazate oxiranyloxycarbonyl tert-butyl ester (1 g) in MeOH 1% pd/Cdegussa (250 mg) was added to the solution in (20 ml). The reaction flask was evacuated and then counter-filled with hydrogen; this was repeated three more times. The reaction was stirred at atmospheric pressure for 12 hours. It is then filtered and concentrated in vacuo to give (1r,3R,4S)-4-((S)-3-amino-2-ketotetrahydropyrrol-1-yl)-3-(isopropyl Sulfhydrylmethyl)cyclohexylaminocarbamic acid tert-butyl ester. Ms found: (M+H)+=418.

[Example 10a, Step 12, (1R, 3MS) in DMF (10 mL), ((8)_3_Aminossyltetrahydropyrrole-1-yl)-3-(isopropylsulfonylmethyl) ring Add a solution of tris-butyl hexylaminocarbamate (200 mg, 〇_47 mmol) to 3·(trifluoromethyl)benzoic acid (109 mg, 〇·57 mmol), N, N _Diethyl isopropylamine (〇 1 ml '0.57 mmol) and HATU (216 mg, 〇. 57 mmol). The reaction was stirred at room temperature for 48 hr then EtOAc (EtOAc)EtOAc. The organic phases were combined, washed with brine, dried with EtOAc EtOAc EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj S)-2·Ketyl-3-(3-(trifluoromethyl)benzylideneamino) Tetrakirol-1-yl)cyclohexylaminopyruic acid tert-butyl ester. MS found: (M+H)+=590. 实110aStep 8丄_(lR,3R,4S)-3-(isopropylsulfonylhydrazino)_4_((s)_2_keto-3 -(3-(Difluoromethyl)benzylideneamino)tetrahydro-P-hahyl) a solution of a tri-butyl cyclohexylaminocarbamate in CH2C12 (10 mL) with trifluoroacetic acid (4) Processing from 95318 -228 - 1354664 liters. The reaction was concentrated in vacuo <RTI ID=0.0> The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. MS found: (m+H)+ = 490. mp. (30 mg, 〇 〇 6 mM) dissolved in EtOAc NaCNBH3 (50 mg, 0.12 mmol) was stirred at room temperature for 4 h then EtOAc (2 mL 30% aqueous). The mixture was stirred for 1.5 hours, the reaction was quenched with sat. NaHC.sub.3, and extracted (2x). The organic extracts were combined, washed with brine, dried (NzSO4) &apos; filtered and concentrated in vacuo. The residue was purified by reverse phase HpLC to give the title compound (isopropyl(decyl)amino)-2-(isopropylsulfonylmethyl)cyclohexyl)-2-ketotetrahydrol. TFA salt of pyrrol-3-yl)-3-(trifluoromethyl)benzamide as a white powder (15 mg). MS found: (M+H)+= 546. Example 10b: (S)-l-((lS,2R,4R)-4-(isopropyl(methyl)amino)_2_(isopropylsulfonate) Synthesis of mercaptomethyl)cyclohexyl)-3_(6-(trifluoroindolyl)oxazoline-4-ylamino)tetrahydropyrrole_2-one is preferred. Example 10b step 1: 1 (1R, 3R,4S)-4-((S)-3-Amino-2-ketotetrahydropyridinium)-3-(isopropylsulfonylmethyl)cyclohexylaminocarbazate benzyloxycarbonyl TCA (6 mL) was added at room temperature in a solution of tri-butyl ester (1 g) in CH2C12 (30 mL). The reaction was stirred for 5 hours and concentrated in vacuo. The residue was partitioned between 1N EtOAc (EtOAc) The aqueous layer was extracted with EtOAc (EtOAc (EtOAc) (EtOAcjjjjjjjjj -((13,2 Min 411)-4-amino-2-(isopropylsulfonylmethyl)cyclohexyl)-2 ketotetrahydropyrrol-3-ylaminocarbazate. MS found: (μ+η)+=452. Example 1〇b step 2: Make all the small ones made in step 1 ((岱,2艮4幻-4-amino-2-(isopropyl) Benzylsulfonylmethyl)cyclohexyl)_2_copperyltetrahydropyrrole·3·ylaminocarbamate (1 equivalent) is dissolved in 〇^〇2 (20 ml) in the solution formed, added Acetone (10 eq.), and stirred at room temperature for 1 Torr, then added sodium cyanoborohydride (2 eq.) in one portion. The reaction was stirred at room temperature for 1 hr. The reaction was quenched with sodium cyanoborohydride (2 eq.) in EtOAc EtOAc (EtOAc) 2 〇〇 ml, then 2 X 75 ml) extraction. The organic extracts were combined, washed with brine (3 mL), dried (MgSO4), filtered, and concentrated in vacuo. After set, some of the polyoxymethylene-related products are solidified; they are removed by dissolving the mixture in a minimum volume of Et0Ac and filtering. Then concentrated to provide (S)_l-((l S,2R,4R)-4-(isopropyl(methyl)amino)_2_(isopropylsulfonylmethyl)cyclohexyl)-2-onetetrahydropyrrole_3_ylaminocarbazide Estimated value of MS: (M+H)+=508. u 10b Step 3: All (5)·(isopropyl(methyl)amino)-2-(isopropylsulfonate) prepared in step 2. Benzylmethyl)cyclohexyl)-2-keto-tetrahydropyrrol-3-ylcarbamate benzyl ester (250 mg, 〇. 5 mmol) was added with 3% HBr/AcOH (5 mL). The reaction vessel was warmed and a vigorous gas evolution occurred. The mixture was stirred at room temperature for 25 minutes and then placed in a cooling water bath with the addition of 2 mL of Et20. The formed solid was collected, washed twice with % ' and concentrated in vacuo to give (5) _3_amines 95518 • 230-1548664 (isopropyl(methyl)amino)-2-(isopropyl) Methyl)cyclohexyl)tetrahydrop-pyrrol-2-one (240 mg '91% yield). MS found: (M+H)+= 374. Example 10b Step 4: __(8)-3-Amino-1-((18,2艮411)-4-(isopropyl(methyl)amine Add 3-ethylamine to a solution of 2-(isopropylsulfonylmethyl)cyclohexyl)tetrahydropyrrole-2-one (75 mg, 0,14 mmol) in EtOH (2 mL) (0 丨 2 ml, 0.84 mmol) with 4-chloro-6-(trifluoromethyl oxazoline (39 mg, 0.16 mmol). The mixture was heated at 80 ° C for 14 hours and then Concentrate in vacuo. Purify the residue by HPLC to provide the title compound (s) _i_((is,2R,4R)_4-(isopropyl(indenyl)amino)-2-(isopropyl decylmethyl) Cyclohexyl)_3_(6-(trifluoromethyl)quinazolin-4-ylamino)tetrahydropyrrole-2-one (35 mg, 44% yield). MS found: (M+H)+ = 570. Example 10c: 3-Terti-butyl-N-((S)-l-((lS,2R,4R)-4-(isopropyl(methyl)amino)-2. Synthesis of propylsulfonylhydrazino)cyclohexyl)_2-ketotetrahydropyrrole_3_yl)_丨_methyl-1Η-pyrazole-5-carboxyguanamine _Xun 10c Step 1: On ( S)-3-Amino-l-((lS,2R,4R)-4-(isopropyl(indenyl)amino)-2-(iso) Addition of diisopropylethylamine (〇j ml) to a solution of sulfonylmethyl)cyclohexyl)tetrahydropyrrole-2-one (4 mg, hydrazine (10) mmol) in DMF (2 mL) 〇.6 觉莫耳), 3-tert-butyl-1-methyl-1H-P than olfactory _5_acid (18 mg, 0.1 mmol) and _ (38 mg, 〇1 mmol) The reaction was stirred at room temperature for 14 h, EtOAc EtOAc m.

袅 10-A The compounds in the table below were prepared using the methods exemplified above. See Table 1-A for a complete description of the header. 95318 -231 · 1354664 R5/.

R2 Example R5 R2 Changed MS data Step 10a i-Pr (Me)N cf3 n/a 546 10b i-Pr (Me)N n/a 570 vv N^N 10c i-Pr (Me) N vi o ' n /a 538 lOd Tetrahydropyplo cf3 10a Step 544 γό 8 lOe i-Pr (Me) N 10a Step 534 6

95318 -232. 1354664 10f

i-Pr(Et)N

10b step 584 lOg

i-Pr(Et)N

10a steps 6 and 8 548 lOh

i-Pr(Pr)N lOi

i-Pr(Me)N lOj

i-Pr(Et)N

10b steps 2 and 4 10a steps 6 and 8 10b steps 4 562 586 600 10k

i-Pr(Et)N

10b step 2 584 101 10m

i-Pr(Me)N i-Pr(Et)N

10a step 6 10b step 2 &amp; 4 (see 10c) ο 531 560 95318 233 - 1354664

袅 10-B The list of chemical names for the specific examples shown in Table 10-A is given below. Example name 10a 1^((8)-1-((18,2min 4 ft)-4-(isopropyl(methyl)amino)-2_(isopropylsulfonylmethyl)cyclohexyl) -2-ketotetrahydropyrrole_3_yl)-3-(trifluoromethyl)benzamide 10b (S)-l-((lS,2R,4R)-4-(isopropyl (A Amino)-2-(isopropylsulfonylfluorenyl)cyclohexyl)-3-(6-(trifluoromethyl)u-set oxalin-xylylamino)tetrahydropyrrol-2-one 10c 3-Terti-butyl-N-((S)-l-((lS,2R,4R)-4-(isopropyl(methyl)amino)-2-(isopropyl aryl) ))cyclohexyl)-2-methylidyltetrahydroupyrrol-3-yl)-1-methyl-1Η-Ι»比峻-5-small amine 10d N-((S)-l-( (lS,2Rj4R)-2-(isopropyl aryl fluorenyl)_4-(tetrahydroppyrrol-1-yl)cyclohexyl)-2-g-isotetrahydropyrrol-3-yl)-3 -(trifluoromethyl)benzamide 5O-3-tert-butyl-N-((S)-l-((lS,2R,4R)-4-(isopropyl(methyl)amino) )-2-(isopropyl succinylmethyl)cyclohexyl)-2-network tetrahydrop ratio p each-3-yl)benzamide 1Of (S)-l-((lS,2R, 4R)-4-(ethyl(isopropyl)amino)-2-(isopropylsulfonylfluorenyl)cyclohexyl)-3-(6-(trifluoromethyl) ; quinazolin-4-ylamino) tetrahydro 5^ ratio p--2-one l〇g 3-tris-butyl-N-((S)-l-((lS,2R,4R) 4-(Ethyl(isopropyl)amino)-2-(isopropylsulfonylmethyl)cyclohexyl)-2-ketotetrahydropyrrole-3-yl)benzamide-5O 3- Third-butyl-N-((S)-l-((lS,2R,4R)-4-(isopropyl(propyl)amino)-2-(isopropylsulfonylmethyl) Cyclohexyl)-2-ketotetrahydropyrrol-3-yl)benzamide oxime lOi (3)-1-((13,2 Min 411)-4-(isopropyl(methyl)amino)- 2-(Isopropylsulfonylmethyl)cyclohexyl)-3-(6-(trifluoromethoxy)thiazolin-4-ylamino)tetrahydroindolebi-2-yl lOj (3 -1·((18,2ΙΙ,4ΙΙ)-4-(ethyl(isopropyl)amino)-2-(isopropyl hydrazinyl)cyclohexyl)-3-(6-(three Fluoromethoxy)oxazolin-4-ylamino)tetrahydroxanthene-2-indene 95318-234- 1354664 10k (3)-1-((13,2 Min 411)-4-(ethyl (isopropyl)amino)·2·(isopropyl thioglycolyl)cyclohexyl)-3-(6-(trifluoromethyl)p-kudolin-4-ylamino)tetrahydroanthracene Pilo-2-indene 101 N_((S)-1-((18,21^410-4-(isopropyl(fluorenyl))amino)_2·(isopropyl) Mercaptomethyl)cyclohexyl)-2-ketotetrahydropyrrole-3-yl)smallmethyl-1H-indole-2-carboxamide 10m N-((S)-l-((lS,2R , 4R) -4-(ethyl(isopropyl)amino)·2_(isopropyl succinylmethyl)cyclohexyl)-2-ketotetrahydro ρ-haha·3·yl)_3_(2Η -tetrazol-5-yl)benzamide t lla_11ri Example 11a: N-((S)-l-((lS,2R,4R)_2-(ethylsulfonylmethyl)-4_(different Synthesis of propyl (methyl)amino)cyclohexyl)-2-ketotetrahydropyrrol-3-yl)-3-(trifluoromethyl)benzamide 9a Step 1: On (lR, 3R, 4S)-4-Amino-3-(hydroxymethyl)cyclohexylaminoformate oxime oxycarbonyl-tert-butyl ester (5.60 g, 14.7 mmol) in CH2C12 (32 mL) At ° C, NEt3 (4.73 g, 44.2 mmol) was added with methanesulfonate (1.71 mL, 22.1 mmol). The reaction mixture was stirred at room temperature under nitrogen for 2 h then cooled to EtOAc EtOAc (EtOAc) The organic layer was washed with EtOAc EtOAc (EtOAc m. 1H NMR (300 MHz, CDC13) δ 7.40-7.31 (m, 5Η), 5.25 (s, 2H), 4.85-4.83 (m, 2H), 4.39 (s, 1H)} 4.17-3.96 (m, 3H), 3.70-3.35 (m, 1H), 3.30-3.20 (m, 1H), 2.96 (s, 3H), 2.10-0.94 (m, 7H), 1.44 (s, 9H); ESI MS m/z 457 [C2 i H3 4 N2 07 S + H]+. The solution of ethanethiol (908 μl, 12.3 mmol) and anhydrous DMF (31 ml) dissolved in 95318 -235 - 1354664 was cooled to 〇 ° C under nitrogen atmosphere, then Sodium hydride (60% dispersion in mineral oil; 491 mg, 12.3 mmol) was added to this mixture in hydrazine. A solution of the above-prepared intermediate (2.80 g '6.1 mmol) in anhydrous DMF (30 mL) was added. The reaction mixture was allowed to warm to rt EtOAc (EtOAc)EtOAc. The mixture was extracted with EtOAc (EtOAc) (EtOAc) (EtOAcjjjjjjjjj Base) Benzyloxycarbonyl benzyloxycarbonyl third-butyl ester (3.00 g). iHNMROOOME^CDCld occupies 7.61-7.20 (1^511), 5.10(8,211), 4.45-4.30 (m, 1H), 4.12-4.02 (m, 2H), 3.52-3.35 (m, 1H) 2.78-2.41 (m, 4H), 2.40-2.25 (m, 1H), 2.20-0.72 (m, 9H), 1.44 (s, 9H); ESI MS m/z 423 [C22H34N204S+H]+. Example 11a Step 2: at (lR, 3R,4S)-4-amino-3-(ethylthiomethyl)cyclohexylaminocarbazide oxime carbyl tertiary-butyl ester (3.00 g, 6.13 mmol) in 2-PrOH (16 mL) A suspension of Oxone® (23.0 g, 36.8 mmol) in water (30 mL) was added at 0 °C. The reaction mixture was stirred at rt EtOAc (EtOAc)EtOAc. The organic layer was washed with brine (50 mL) dried over Nat. The residue was purified by column chromatography (EtOAc EtOAc EtOAc) The third-butyl ester (1.89 g, 68%) was obtained as a white solid: m.p. 54-58 °C; 1H NMR (300 MHz, CDC13) δ 7.60-7.32 (m, 5H), 5.10 (s, 2H), 4.90 -4.87 (m, 1H), 4.41-4.30 (m, 1H), 4.07-3.98 (m, 1H), 3.58-3.35 (m, 1H), 3.28-3.10 (m, 1H), 3.08-2.88 (τη, 2H), 2.72-2.65 (m, 1H), 2.50-2.18 (m, 2H), 2.08- 95318 -236- 1354664 0.80 (m, 8H), 1.43 (s, 9H) ; ESI MS m/z 455 [C2 2 H3 4N2 06 S + H]+ ; HPLC 95.7% (% by area), tR = 3.76 min. Example 11a Step 3: Part of the amine 3-(ethylsulfonium) in MeOH (30 mL) Methyl)cyclohexylamino decanoate decyloxycarbonyl tri-butyl ester (1.7 g) was added with 10% Pd/C Degussa (300 mg). The reaction flask was evacuated and then counter-filled with hydrogen; it was repeated three more times. The reaction was stirred at 1 atm H2 for 4 h then filtered and concentrated in vacuo to afford (ir, &lt;RTI ID=0.0&gt; Third butyl carboxylic acid (ii). MS found: (M+H) + = 321. Example 11a Step 4: </ RTI> llUiMSH-Amino-3-(ethylsulfonylmethyl)cyclohexylamine decanoic acid tert-butyl ester sample (1.1 g, 3.4 mmol) dissolved in DMF (20 ml) and added to the resulting solution, N-Cbz thiol acid (U5 g, 4_08 mmol), N, N- Diethyl isopropylamine (〇7 ml, 4.08 mmol) and HATU (1.55 g '4.08 mM). The reaction was taken at room temperature for 12 h then EtOAc and sat. NaHC. The mixture was partitioned (1x), EtOAc (EtOAc)EtOAc. And (lR,3R,4S)-4-((S)-2-amino-4-(methylthio)butaninyl)·3_(ethylsulfonylmethyl)cyclohexylaminocarboxylic acid Benzyloxycarbonyl-tert-butyl ester (22 g). MS found: (Μ+Η)+= 586. Example 11a: Compound (lR,3R,4S)-4-((S)-2-amine Base (methylthio)butylamino)-3-(ethylsulfonylmethyl)cyclohexylaminocarbamic acid benzyloxycarbonyl third-butyl ester (3.4 Milliol) with EtOAc &quot;wet &quot;, then remove most of the EtOAc under a stream of nitrogen. The residue was dissolved in methyl iodide (2 mL) and the resulting solution of 95318-237·1354664 was Stir at room temperature for 48 hours' then concentrate the β in a vacuum to dissolve the residue in the dichloromethane lake' and concentrate the resulting solution; repeat it to obtain a salt. MS found: (Μ+Η)+= 602. Dissolve this material in DMF (20 mL), EtOAc (EtOAc: EtOAc. Liquid treatment. The organic phase is dehydrated and dried (Na2 S〇4)' filtered, and concentrated in vacuo. The residue is purified by flash chromatography to obtain (1 Min 3 Min 43)-4-((3)- 3-amino-2-ketotetrahydropyha-1-yl)-3-(ethyl decylmethyl)cyclohexylaminocarbamic acid benzyloxy-3-butyrate (1 g). MS Found: (M+h)+=538. t Example 11a Step β: (llUMSM-KS)"-Amino-2-ketotetrahydropyrrol-1-yl)-3-(ethyl fluorenyl) Mercapto) Cyclohexylaminocarbazide methoxycarbonyl third-butyl ester (1 g) in MeOH (2 In a solution of 0 ml), 1% pd/CDegussa (25 mg) was added. The reaction flask was evacuated and then counter-filled with hydrogen; it was repeated three more times. The reaction was stirred at 1 atmosphere under reduced pressure for 12 hours, then filtered and concentrated in vacuo to afford (111,311,43)-4-((8)-3-amino-2-one-tetrahydropyrrole. Small base)-3-(isopropylsulfonic acid methyl)cyclohexylamino decanoic acid tert-butyl ester. Ms found: (M+H)+ = 404. Rabbit.. Example 11a Step 7: (1R,3R,4s)-4-((S)-3-Amino-2 in DMF (10 mL) - a sample of di-butyl ketone tetrahydropyrrol-1-yl)-3-(ethylsulfonylmethyl)cyclohexylaminocarbamate (100 mg, 0.25 mmol), added 3_( Trifluoromethyl)benzoic acid (57 mg '0.29 mmol), N,N-diethylisopropylamine (0 05 mL, 0.29 moles) and HATU (U4 mg, 0.29 mmol) The mixture was stirred at room temperature for 48 hours then partitioned between EtOAc and sat. NaHC. The organic phase was combined, washed with brine, dried (EtOAc EtOAc EtOAc EtOAc EtOAc EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj -((S)-2-keto-3-(3-(trifluoromethyl)benzylideneamino)tetradecene p-semi-1-yl)cyclohexylaminocarboxylic acid third-butan. MS found: 0j+H)+ = 578. f _ffUIaStep 8: (1艮3民43)-3-(ethyl cross-branched methyl) bucket ((8)·2·keto-3-(3) a solution of -(trifluoromethyl)benzamideamino)tetrahydropyrrole-yl)cyclohexylaminocarbamic acid second-butyl vinegar (0.25 mmol) in CH/l2 (10 mL) After treatment with trifluoroacetic acid (4 mL), EtOAc (EtOAc)EtOAc. The organic phase was washed with brine, dried (Na.sub.2), filtered and concentrated in vacuo to afford amine. MS found: (M+H)+ = 476. This amine (0.25 mmol) was dissolved in CH2 C12 (10 mL) and acetone (~2 mL) was added; the mixture was stirred for 5 min then NaCNBH3 was added (1 mmol). The reaction was stirred at room temperature for 4 h then EtOAc (2 mL (30 mL)). 2x). The organic extracts were combined, washed with brine, dried (1) EtOAc EtOAc. The residue was purified by reverse phase HPLC to give the title compound N-((S)-l-((lS,2R,4R)-4-(isopropyl(methyl)amino)-2-( TFA salt of decylmethyl)cyclohexyl)-2-ketotetrahydropyrrol-3-yl)-3-(trifluoromethyl)benzamide as a white powder (42 mg) after lyophilization. MS found: (M+H)+= 532. Example lib: (S)-l-((lS,2R,4R)-4-(isopropyl(methyl)amino)-2-(ethyl Synthesis of sulfonylmethyl)cyclohexyl)-3-(6•(trifluoromethyl)4oxalinoylamino)tetrahydropyrrole-2·one 95318 •239· 1354664 Example lib step]_^_ _(llUR^SM-KSH-Amino-2-ketotetrahydropyrrol-1-yl)-3-(ethylsulfonylfluorenyl)cyclohexylaminocarbazate 芊oxycarbonyl third-butyl ester ( 1 g) TFA (6 mL) was added at room temperature in CH2C12 (30 mL). The reaction was stirred for 5 h and EtOAc (EtOAc)EtOAc. The aqueous layer was extracted with EtOAc (EtOAc (EtOAc) (EtOAcjjjjjjjj 1 S,2R,4R)-4-Amino-2-(ethyl succinyl)cyclohexyl)_2--yltetrahydroylidene-3-ylamino decanoate. MS found: (m+H)+ = 438. Example J]b Step 2: All (8)-1-((18,2 Min 411)-4-amino-2) made in Step 1. -(ethylic acid methyl)cyclohexyl)-2-diyltetrahydrop-pyrrolyl-3-ylaminocarbazate (1 equivalent) dissolved in CH2C12 (20 ml) Acetone (10 equivalents) was added and stirred at room temperature for 1 Torr, then sodium cyanoborohydride (2 eq.) was added in one portion. The reaction was stirred at room temperature for 1 hour, then formaldehyde (10 eq. in a 37% by weight aqueous solution) and sodium cyanoborohydride (2 eq.). The reaction was stirred at room temperature for a further 9 hours then quenched with saturated NaHC. The aqueous mixture was extracted with EtOAc (200 mL then 2 X 75 mL). The organic extracts were combined, washed with brine (3 mL EtOAc) EtOAc (EtOAc) After the formed oil was allowed to stand, some of the polyoxymethylene-related products were solidified; they were removed by dissolving the mixture in a minimum volume of EtOAc and filtering. Concentration followed by (S)-l-((lS,2R,4R)-4-(isopropyl(indenyl)amino)_2_(ethylsulfonylmethyl)cyclohexyl)-2-indenyl Tetrahydrop is more than indole-3-ylamino decanoic acid; j^S measured value: (M+H)+ = 494. 95318 -240- 1354664 Example 1 lb Step 3 · All (8)_1_((182 411)-4-(isopropyl) (made in step 2) Addition of 30% HBr/AcOH (5 mg) of methyl)amino)-2-(ethylsulfonylmethyl)cyclohexyl)_2-ketotetrahydropyrrol-3-ylaminocarbazate (250 mg) ML). The reaction vessel was warm and a vigorous gas evolution occurred. The mixture was stirred at room temperature for 25 minutes, and then the flask was placed in a cooling water bath before adding 20 ml of Et 2 hydrazine. The solid formed was collected, washed twice with Et2, and concentrated in vacuo to give (S)-3-amino-1-((18,2min 4 ft)-4-(isopropyl (A) Amino)-2-(ethylsulfonylhydrazino)cyclohexyl)tetrahydropyrrole-2-ketone (15 mg). MS found: (M+H)+ = 360. Example lib Step 4: (S)-3. Amino-l-((lS,2R,4R)-4-(isopropyl(methyl)amine a solution of 2-(ethylidene fluorenyl)cyclohexyl)tetrahydropyrrole·2·one (5 〇 mg, 〇.1 mmol) in EtOH (2 mL), adding triethyl Amine (ο ι ml, 〇 6 mM) with 4-chloro-6-(trifluoromethyl)p-quino-p-lin (27 mg, 0.11 mmol). The mixture was heated at 80 ° C for 14 hours and then concentrated in vacuo. The residue was purified by HPLC to give the title compound (S)-l-((lS,2R,4R)-4-(isopropyl(methyl)amino)-2-(ethylsulfonylmethyl) Cyclohexyl)-3-(6-(trifluoromethyl)quinazolin-4-ylamino)tetrahydropyrrole-2-one (35 mg). MS found: (M+H)+=556. 95318 -241 - 1354664

The compounds in Table ll-A are prepared using the methods exemplified above. See Table 1-A for a complete description of the header. Example lla lib 11c lid

R5 R2

i-Pr(Me)N

i-Pr(Me)N

i-Pr(Me)N

i-Pr(Me)N

Steps to change n/a MS data 532

o n/a 556 lla step 6 lla step 6 540 561

95318 -242- 1354664

Table ll-B The chemical name series of the specific examples shown in Table 11-A is shown below in the example name 11a N-((S)-1-((18,21^4 ft)-2-(ethyl continuation) Methyl)_4·(isopropyl(methyl)amino)cyclohexyl)-2-self-isodentyltetrahydrop-haha_3_yl)_3_(trifluoromethyl)benzamine lib (S) -i-((iS,2K,4K&gt;2-(ethylthenylmethyl)_4-(isopropyl(methyl)amino)cyclohexyl)-3-(6-(tris-decyl) p-Quinylline _4_ylamino) Tetrahydropyrrole-2-one 11c N_((S)-l-((lS,2R,4R)-2·(ethylsulfonylmethyl)_4_(different Propyl (methyl)amino)cyclohexyl)-2-ketotetrahydrou-bi _3·yl)_3_(phenyl) benzamide lidlid N-((S)-1-((1 S , 2R, 4R)-2-(ethyltra-acid methyl) 4-(isopropyl(methyl)amino)cyclohexyl&gt;2-ketotetrahydropyrrole_3_^)_3_ (4-A Pyrazol-2-yl)benzamide lie 3-(((S)-l-((lS,2R,4R)-2-(ethyl)methyl-4-(isopropyl) (fluorenyl)amino)cyclohexyl)-2-ketotetrahydroppyrrol-3-yl)amine oxime)-5-tris-butylbenzoic acid f Example I2a-12hh Example 12a: (lR , 2S, 5R)-5-(isopropyl (methyl) Synthesis procedure of methylamino)-2-((S)-2-mercapto-3-(3(trifluoromethyl)benzylideneamino)tetrahydropyrrol-1-yl)cyclohexanecarboxylic acid methyl ester 1丄(lR^SJR)-"芊-oxycarbonyl-amino"-7-keto-6-nitro-bicyclo[3.2.1]octane-6-carboxylic acid tert-butyl ester (9.6 g, 0.025 mmol of a solution in methanol, treated with 2.5 g of 10% Pd/C and hydrogenated in a Parr shaker at 55 psi Η2. The mixture was filtered and the filtrate was concentrated in vacuo. An oil comprising (lR,2S,5R)-2-amino-5-(tris-butoxy-carbonylamino)cyclohexanecarboxylic acid methyl ester with (lR, 2S, 5R)-2 a mixture of amino-7-keto-6-nitro-bicyclo[3.2.1]octane-6-remediation third-butan. Used without further purification of 95318-243·1354664. LCMS found two Absorption peak: (M + H) + = 273 and (M + H-BOC) + = 141. Example 12a Step 2: A solution of the crude amine from step 1 above in CH 2 Cl 2 'CBZ-L -Met (8.49 g '0.03 mol), EDCI (5.7 g, 0.03 mol), HOBT (4.1 g, 0.03 mol), Et3N (3.0 g 〇. 〇3 mur), and will form The reaction solution was stirred at room temperature overnight. This solution was washed with water and brine, dried (MgSO4), filtered, and concentrated in vacuo, and the residue was purified on silica gel (50-70% ethyl acetate /hexane) to give 5 5 g (40% yield) (lR, 2S, 5R)-2-((R)-2-(benzyloxycarbonylamino)_3-(methylthio)propanylamino)-5-(third-butyl Oxymethylamino)cyclohexane succinic acid methyl ester is a solid. Ms found: (M+H)+=538. Example 12a Step 3: (1艮23,5 ft)-2-((11)-2-(benzyloxycarbonylamino)·3·(methyl sulphide a solution of methyl propylamino)-5-(tris-butoxycarbonylamino)-cyclohexanecarboxylate in MeI (with minimal CHzCl2) at room temperature for 24 hours, then in the true 2 concentrated. The residue was triturated with hexanes and concentrated to form a suspension; this was repeated several times to give 7 g of salt as a white solid e MS found: (Μ+Η)+=552_2· dissolve this material In DMF (75 ml), CsfO3 (6.6 g, 20 mmol) was added to the solution and stirred at room temperature for 2 hrs. The reaction mixture was poured into a mixture of ice/IN HC1 while being mixed, and then further diluted with water (total volume 1 liter). The solid precipitate was filtered and air-dried to give 1.6 g (30% yield) (l,,,,,,,,,,,,,,,,,,,,, Hydrogen ρ ratio 17-1-yl)-5-(dioxa-butoxyamino)-cyclohexanoic acid methyl ester, used without further purification. MS measured value: (M+H)+ = 490.3 Step 4: (m,2S,5R)-2-((S)-3-(Hethoxycarbonylamino)-2-oneyltetrahydro 95318 •244· 1354664 峨嘻-1-yl)-5 -(T-butoxycarbonylamino)-methyl cyclohexanecarboxylate in CH2Cl2 (10*L), EtOAc (EtOAc) Concentrate in vacuo and the residue was dissolved in CH.sub.2 C.sub.2 and washed with brine. The solution was filtered and concentrated in vacuo to give EtOAc (EtOAc: EtOAc (EtOAc). Small base) cyclohexanecarboxylic acid methyl vinegar' is a white solid. MS found: (M+H)+= 390.3. Preferably, step 12a, step 5: will be obtained from step 4 (lR, 2S, 5R)-5-amino-2-((S)-3-( a solution of methyl benzyloxycarbonylamino)-2-g-isotetrahydropyrrole 4 yl)cyclohexanecarboxylate (75 g, 1-9 mol) in CH2Cl2 (1 mL), with acetone (丨ml) and NaBH(OAc)3 (0.85 g, 4 mmol) were treated and stirred at room temperature for 6 hours. A 37% aqueous solution of formazan (2 mL) was added and stirred at room temperature overnight. This solution was diluted with CH.sub.2Cl.sub.2 (5 mL.) and washed with 1N EtOAc, water, brine, and concentrated in vacuo and the residue was chromatographed (丨:9:9〇Nj^OH: Me〇H:CH2C12) ' And 0.4 g (50%) (1R, 2S 5R)-2_((5)_3_(爷 methoxycarbonylamino)_2_ copper-based tetrahydropyran-1-yl)-5-(isopropyl(indenyl)amine Methyl)cyclohexanecarboxylate is a white foam. MS found: (Μ + Η) + = 446.3 · Example 12a step 6: _ (lR, 2S, 5R)-2-((S)-3-(benzyloxycarbonylamino)-2-one a solution of tetrahydro-ha-1-yl)-5-(isopropyl (indenyl)amino y-cyclohexanecarboxylic acid methyl ester (0 6 g, 1.3 mmol) in methanol to 15 〇 Treatment with 1% pd/c and hydrogenation at 55 psi % overnight in a Parr shaker. Filter the catalyst and concentrate the filtrate in vacuo to give 4 g (ir, 2S, 5R) - Methyl 2-((S)-3-amino-2-ketotetrahydroyliden-1-yl)-5-(isopropyl(indenyl)amino)cyclohexanecarboxylate as white Solid. Used without further purification. MS found: eg +11) += 312 3. 95318 -245 - 1354664 Example 12a Step 7: (1^28,511)-2-((8)-3-amine Methyl-2-ketotetrahydropyrrole small)-5-(isopropyl(methyl)amino)-cyclohexylamine methyl ester (50 mg, 0.16 mmol), 3-(trifluoromethyl) Benzoic acid (38 mg, 0.20 mol), mX:I (38 mg, 0-20 mmol), HOBT (27 mg '0.20 mmol) and Et3N (20 mg, 0.20 mmol) in CK^ The solution in Cl2 is stirred at room temperature Night β was washed with water and brine, concentrated in vacuo, and the residue was crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj It is a white solid. MS found: (M+H)+ = 484.25 Example Ub: (1R, 2S, 5R)-S-(T-butylamino)-; 2_((s)-2-keto-3·( Synthesis of methyl 3-(trifluoromethyl)benzylideneamino)tetrahydropyrrole-1-yl)cyclohexanecarboxylate Example l2b Step 1: _(lR,2S,5R)-7-keto- a solution of 6-oxo-bicyclo[3.2.1]benzyl-2-octylaminocarbamate (20 g of '72.6 mmol) in ethyl acetate (125 ml), with 1.3 g of 10% Pd/C Treatment was carried out and hydrogenated overnight at 55 psi H2 in a Parr shaker. The catalyst was filtered and the filtrate was concentrated in vacuo to give 10.2 g (100%) of (lR,2S,5R)-2-amino-6-oxo-bicyclo[3.2.1]oct-7-one, It is an oily substance. Used without further purification. MS measured value: (M+H)+= 142.06. Example 12b step? _!_ will be obtained from step 1 above (lR, 2S, 5R)-2-amino-6-oxo-bicyclo-[3.2.1]oct-7-one (10.2 g, 72.6 mmol) Solution in CH2C12, with CBZ-L-Met (22.7 g, 80 mmol), EDci (15.3 g, 80 mmol), HOBT (10.8 g, 80 mmol), Et3lSf (8.1 g, 80 m The mixture was treated, and the resulting reaction solution was stirred at room temperature overnight. This solution was washed with water, brine, dried (MgSO4), filtered, and concentrated in vacuo to give 29.5 g (100% yield) of (R)-3-(methylthiol_i_((ir, 2S,5R)-7-keto-6-oxo-bicyclo[3·2·1]oct-2-ylamino)propan-2-yl carbamic acid benzyl ester, as a solid 95318 • 246· 1354664 For further use, the measured value of e MS should be further purified: (m+jj^+=407.3. Example 12b Step 3: (R)-3-(methylthio)-1-keto-_i_( (1Rj2S 5R)_7_fluorenyl_6_ oxo-bicyclo[3.2.1]oct-2-ylamino)propan-2-ylcarbamate benzyl ester (29.5 g, 72.6 mmol) in Mel (80) The solution in ML, and the minimum amount of CH2Cl2) was stirred at room temperature for 24 hours, then diluted (3⁄42%, then concentrated in vacuo) and the residue was triturated with hexane and concentrated. This was repeated several times to give 40 g of salt as a white solid. MS found: (M+H) + = 421.22. This material was dissolved in DMF (150 ml) and added Cs2C〇3 (47.19) Gram, 145 mmol; and stirred at room temperature for 25 hours. Pour the reaction mixture into ice / mixture of IN HC1 While stirring, and then further diluted with water (total volume of 1 liter), the solid of the sinking chamber was extracted into Ch2 q2 and washed with water and brine. The solvent was removed in vacuo and the solid formed was self-contained. Ethyl succinate recrystallized to give U.3 g (43%) (s) _2 • sun-heart-((1R, 2S, 5R&gt; 7-keto-6-oxo-bicyclo[3.2.1]辛-2·yl)tetrahydropyrrole·3_ylamino decanoate decanoate is a pale yellow solid. The mother liquor is concentrated in vacuo and the residue formed is chromatographed to give an additional 4.5 g (61%) Total yield) MS found: CM+H:)+ = 359.24 Example 12b with step 4: s(2-)-2-keto-l-((lR,2S,5R)-7-keto-6 - Oxy-bicyclo[3.2.1]oct-2-yl)tetrahydropyrrole-3-ylaminocarbamate (11.3 g, 315 mol) in decyl alcohol as a solid NaHC03 (4.0 g, 47.6 moles and treated at room temperature for 2 hours. Add water (1 mL) and extract the mixture in CH2Clz. Wash the extract with water, brine and concentrate to give lactone 12.3 g of an apparent equilibrium mixture with the desired alcohol ester (in a 40:60 ratio). Use this blend No further purification. MS found: (M+H)+= 391.29. 95318 -247- 1354664 A solution of a mixture of lactone and an alcohol ester (_5 mol) in acetone from step 4 above, Treat with j〇ne's reagent (35 ml) while stirring at the temperature to isopropanol to reduce the excess reagent, and # @α | # NaHCQ3 to make the mixture formed in water and cool acid B@ A liquid separation treatment was carried out between the crucibles, and the organic layer was washed with water and brine. The solvent was removed under the true conditions, and the residue of the line was recrystallized from ethyl acetate to obtain 6.6 S (54%) (1Rj2s)_2_((3)_3_((3)_3_(竿?洛1基)5 _ 基环己烧一酸甲@的. MS measured value: (M+H)+= 389.17 mother liquid king to contain lactone, (S)-2-keto group small ((lR^SJRH- Benzyl-6-oxo-bicyclo[3.2.1]oct-2-yl)tetrahydropyrrole-3-ylaminocarbamate, which is recovered and used in step 4. (lR, 2S)-2 -((S)-3-(Benzyloxycarboxyamino)_2-ketotetrahydropyrrole-1.yl)-5-ketocyclo-hexanecarboxylic acid methyl ester (31 g, 8 mmol) Treated in DMSO (7 ml), tributylammonium oxime 75 g, 24 mol), and mixed for 10 minutes, then added Ti(i 〇Pr)4 (6 8 g, 24 mol) And the resulting mixture was stirred at room temperature for 2.5 hours. Next, NaBH4 (0.3 g, 8 mol) was added and stirred for 15 hours, then slowly diluted with methanol (gas evolution) and The resulting solution was stirred for an additional hour. When the mixture was stirred vigorously, 'saturated solution of NaHC〇3 was added' and the resulting suspension was passed through diatomaceous earth. The filter cake was washed several times with CH2C12, and the combined washings were transferred to a separating funnel. The organic layer was separated, washed with water and brine, concentrated, and the residue was chromatographed MeOH/CH2Cl2- 8% NH4〇H/ MeOH/CH2Cl2) ' yielded 3.0 g (80%) of (lR,2S,5R)-2-((S)-3-(indolyloxycarbonylamino)-2-ketotetrahydro Pyrrole-丨-yl)_5_(Third-butylamino)cyclohexane acid A 95318-248- 1354664 ester. MS found: (M+H)+ = 446.30. Also obtained 400 mg of isomer (1R}2S,5S)-2-((s)-H-ethoxycarbonylamino)-2-ketotetrahydropyrrole Methyl-1-(5)-(t-butylamino)cyclohexanecarboxylate. MS found: (M+H)+ = 446.3. A.12b, step 7: (1) 23,51〇-2-((3)-3-(indolylcarbonylamino)-2-one Tetrahydrofuran-1-yl)-5-(t-butylamino)-cyclohexanecarboxylic acid methyl ester (2.42 g, 5.43 mmol) in methanol, 6 mg mg 10 % pd/C treatment, and hydrogenation at 55 psi Hz overnight in a Parr shaker, filter the catalyst, and concentrate the filtrate in vacuo to give 64.64 g (1 Min 2\511)-2- ((3)-3-Amino-2-ketotetrahydrofluoren-1-yl)-5-(t-butylamino)-cyclohexanecarboxylic acid methyl ester as a white solid. Without further purification. MS found: +11)+= 312 32. Example 12b, step 8: (1R,2S,5R)_2_((8)-3_Aminobutanyltetrahydropyrrole small group)- Methyl 5-(t-butylamine-yl)cyclohexanecarboxylate (56 mg, 〇18 mmol), 3-(trifluoromethyl)benzoic acid (42 mg '0.22 mol), EDCI A solution of (42 mg, 0.22 mmol), HOBT (30 mg '0.22 mmol) and Et3N (22 mg, 0.20 mmol) in CH2% was stirred overnight at room temperature. The solution was washed with water and brine, EtOAc (EtOAc mjjjjjjjjjjjjjjj , 2S, 5R)-5-(t-butylamino group;)_2_((s)-2-keto-3-(3-(trifluoromethyl)-benzylideneamino)tetrahydropyrrole small Methyl cyclohexanecarboxylate as a white solid. MS found: (M+H) + = 484.24. Example 12C: (1R,2S,5R)_5_(T-butyl(methyl)amine Synthesis of 2-((8)·2 keto_3_(3 (difluoromethyl)-benzylidinium) tetrahydropyrrole small) methyl cyclohexanecarboxylate (lR, 2S, 5R)- Methyl 2-((S)-3-(benzyloxycarbonylamino).2-ketotetrahydropyrrole-1-yl)-5-(tri-butylamino)cyclohexanecarboxylate (46 〇mg, i 〇95318 •249· 1354664 Mo) (from step 6b of Example 12 above) in CH2C12, with 37% aqueous formic acid (1 ml) and NaBH (OAc) 3 (436 mg, 2.0 mol) The mixture was stirred at room temperature overnight. The solution was diluted with CH2C12 (50 mL) and washed with &lt (1: 9 : 90NH4OH : MeOH : CH2C12), to give 330 mg (70%) (lIUS,5R)-2-((S)-3-(indolyloxycarbonylamino)-2-ketotetrahydropyrrole Small base) _5·(T-butyl(methyl)amino)-cyclohexanecarboxylic acid methyl ester. MS found: (Μ+Η)+ = 460.49 Step 2: Will (lR, 2S, 5R) -2-((S)-3-(benzyloxycarbonylamino)-2-one-tetrahydropyrrol-1-yl)-5-(tri-butyl(indenyl)amino)cyclohexanecarboxylate A solution of decanoate (33 mg, 0.65 mmol) in methanol was treated with 1 〇〇 10% Pd/C and hydrogenated at 55 psi % over a Parr shaker overnight. The filtrate was concentrated in vacuo to give 200 mg (1,,,,,,,,,,,,,,,,,,,,,,,, Methyl butyl (methyl)amino)-cyclohexanecarboxylate as a white solid. Used without further purification. MS found: (M+H)+= 326.50 i_fel_12C Step 3: (lR, 2S,5R)-2-((S)-3-Amino-2-ketotetrahydropyrroleyl)-5-(tris-butyl(methyl)amino)-cyclohexanecarboxylic acid Methyl ester, 018 mmol, 3-(trifluoromethyl)benzoic acid (4 2 mg, 0.22 mol), EDCI (30 mg, 0.21 mmol), HOBT (30 mg, 0.21 mmol) and Et3N (21 mg '0.21 mmol) in CH2C12 at room temperature overnight. This solution was washed with water and brine. The residue was concentrated in vacuo. (lR, 2S, 5R)-5-(tris-butyl(methyl)amino)-2-((S)-2-yl-3-(3-(tri-95318-250- 1354664) Methyl)-benzimidamide) tetrahydropyrrole-1.yl) Cyclohexanecarboxylate as a white solid. MS found: (Μ+Η)+ = 498.40. Example 1Μ: (lR,2S,5R)-5-(isopropyl(methyl)amino)-2-((S)·2-keto- Synthesis of 3-(6-(trifluoromethyl)thiazolinolinylamino)tetrahydropyrrol-1-yl)cyclohexanecarboxylic acid methyl ester Example 12d step! 1 : M-(lIUS,5R)-2-((S)-3-amino-2-ketotetrahydropyrrole-1-yl)-5-(isopropyl(f-)amino)-cyclo Methyl hexanecarboxylate (5 mg, 0.16 mol), 4-chloro-6-(trifluoromethyl)quinazoline (48 mg, 0.20 mol) and Et3N (100 mg '1.0 mol) The solution in EtOH (2 mL) was added to a microwave reaction tube, sealed, and heated in a microwave oven for 60 minutes at 10 °C. The reaction mixture was concentrated in vacuo <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI> </RTI> <RTIgt; (isopropyl(methyl)amino)-2-((S)-2-keto-3-(6-(trifluoromethyl)quinazolin-4-ylamino)tetrahydropyrrole-1 Methyl-cyclohexanecarboxylate is a white solid. MS found: (M+H)+= 508.24. Example Ubh: (1R,2S,5S)·5·(T-butylamino)-2-((s)·2·keto-3·( Synthesis Example of 3-((Trifluoromethyl)-benzoicyl)tetrahydropyrrol-1-yl)cyclohexanthracene methyl ester Ilbh Step 1: Will (lR, 2S, 5S)-2- ((S)-3-(Benzyloxycarbonylamino) 2 ketotetrahydropyrrol-1-yl)-5-(Third-butylamino)cyclohexane carboxylic acid oxime ester (2 〇〇 mg , 0_4 moles, obtained from the solution of step 6b of Example 12b above, in methanol, treated with 60 g of 10% Pd/C and hydrogenated in a Parr shaker at 55 psi overnight. The catalyst was filtered and the filtrate was concentrated in vacuo to give mg (1R, 2S, 5S)-2-((S)-3-amino-2- ketotetrahydropyrrol-1-yl)-5- (Third-butylamino)-methyl cyclohexanecarboxylate as a white solid. Used without further purification 95318 • 251 - I354664. MS found: (m+H)+= 312.3. Example i2bh Step 2: bis(pm- 2 keto-tetrahydropyridinyl)-5-(tri-butylamino)-ring A sample of methyl hexanecarboxylate is carried out by the procedure outlined in Step 8 of Example i2b. After flash chromatography, the title compound (nUS, 5S)-5 (tris-butylamino) -2-((S)-2-keto-3-(3-(trifluoromethyl)·

Benzoguanidino) tetrahydropyrrole small) methyl cyclohexanecarboxylate as a white solid. MS found: (m+h)+ = 4842 Table 12-A The compounds in the table below were prepared using the methods exemplified above. See Table 1-A for a complete description of the header.

95318 252· 1354664

Example R5 R2

12a i-Pr(Me)N

MS data step to change n/a 484.2

n/a 484.2

12c t-Bu(Me)N

12d i-Pr(Me)N

n/a 498.4 n/a 508.2

12e i-Pr(Me)N

\^N 12d 524.2 Step 1

12f i-Pr(Me)N

OH 12a 488.3 Step 7 95318 -253 - 1354664

12g i-Pr(Me)N

0 12a 502.2 Step 7

12h i-Pr (Me)N

12a 473.3 Step 7 o

OH O 12b 488.3 Step 8

O X2b 472.4 Step 8

12k t-Bu (H)N

121 t-Bu(H)N

O

o 12b 474.3 Step 8 12b 473.3 Step 8

12m t-Bu (H)N

12b 492.5Step 8 95318 -254 - 0 1354664 12η

Ph

0 12b Step 8 494.5 12ο

t-Bu(Me)N 12bStep 8 502.4 12ρ 12q

t-Bu(Me)N

12c step 3 530.3

12r

t-Bu(Me)N

12s

t-Bu(H) N

12c Step 3 (see 12d) 12c Step 3 (see 12d) 12b Step 8 538.4 522.4 541.4

12t

12b step 8 479.5 12u

12b step 8 567.4 95318 -255 - 1354664 12v

12b step 8 499.4 12w 12x

12b step 8 12b step 8 533.4 556.4 12y 12z

12b step 8 12b step 8 502.2 502.2 12aa

12b step 8 557.2 95318 -256- 0 1354664 12ab

0 12b. Step 8 500.2 12ac 12ad 12ae 12af

t-Bu(H)N 12ag

t-Bu(H)N 12ah

t-Bu (8) N 12ai

t-Bu(H)N

t-Bu(H)N t-Bu(H)N t-Bu(H)N

12b Step 8 12b. Step 8 12b Step 8 12b Step 8 12b Step 8 12b Step 8 12b Step 8 499.4 533.3 476.5 474.4 516.1 550.3 584.2 95318 257 - 1354664 12aj 12ak 12al 12am

t-Bu(H)N t-Bu(H)N t-Bu(Η)N t-Bu(H)N

12an 12ao

t-Bu (H)N

12ap 12aq

t-Bu (8) N t-Bu(Η)N

12ar 12as

t-Bu(H)N

12b Step 8 12b Step 8 12b Step 8 12b Step 8 12b Step 8 12b Step 8 12b Step 8 12b Step 8 12b Step 8 12b Step 8 550.2 524.4 500.4 482.4 500.3 507.4 512.5 507.3 518.3 550.4

95318 -258 - 1354664 12at 12au 12av

t-Bu(H)N 12aw 12ax 12ay 12az 12ba

12b Step 8 12b Step 8 12b Step 8 12b Step 8 12b Step 8 12b Step 8 12b Step 8 12b Step 8 512.2 550.2 482.4 498.3 499.4 504.3 492.4 528.4

95318 -259 - 1354664

Ο 12b, step 496.2

12b, step 483.4

-cf3

12bh t-BuN (S)-stereochemistry

12b, step 8 (see 12d) 12b, step 8 (see 12d) 12b, step 8 (see 12d) 12b, step 8 (see 12d) n/a 508.2 498.4 474 .: 524.2 484.2

95318 -260- 1354664

The chemical name 12-A series of the specific examples shown in Table 12-B is shown below. Example name 12a (1 Min 2S, 5R)-5-(isopropyl(methyl)amino)-2-((S)-2-keto-3-(3-(trifluoromethyl)benzene Amidino)tetrahydropyrrole-1_yl)cyclohexanecarboxylic acid methyl ester 12b (1R,2S,5R)·5·(tri-butylamino)_2_((3)_2-keto_3_(3_( Trifluoromethyl)benzamide amino)tetrahydropyrrol-1-yl)cyclohexanecarboxylic acid methyl ester 12c tert-butyl(methyl)amino)_2_((3)_2_费基-3-(3- (Trifluoromethyl)benzamide amino)tetrahydropyrrole-indole-yl)cyclohexanecarboxylate 12d (lR,2S,5R)-5-(isopropyl(methyl)amino)- 2-((s)-2-keto-3-(6.(trifluoromethyl) quinazolin-4-ylamino)tetrahydropyrrole-yl) cyclohexanecarboxylic acid methyl ester 12e (jR, 2S, 5R)-5-(isopropyl(indenyl)amino)_2-((S)-2-keto-3-(6-(trifluorodecyloxy) quinazoline- 4-ylamino)tetrahydropyrrole-i-yl)cyclohexanecarboxylate 12f (lR,2S,5R)-2-((3)-3-(3-tert-butyl-4-hydroxybenzoate Acrylamino)-2-ketotetrahydropyrrole-1-yl)-5-(isopropyl (methyl)aminocyclohexanecarboxylic acid methyl ester 12g (lR, 2S, 5R)-2-(( S)-3-(3-Fluoro-5-(trifluoromethyl)benzene Methylamino)-2-ketotetrahydropyrrol-1-yl)-5-(isopropyl (methyl)aminocyclohexanecarboxylic acid methyl ester 12h (1 Min 2S, 5R)-2-( (S)-3-(2-Third-butyl p-Bisylamino)_2_ketotetrahydropyrrole-1-yl)-5-(isopropyl(methyl)amino)-cyclohexane Methyl carboxylate 12i (lR, 2S, 5R)-2-((S)-3-(3-tert-butyl-4-ylphenylbenzylamino)-2-yltetrahydropyrrole- 1-yl)-5-(t-butylamino)cyclohexanecarboxylic acid methyl ester 12j (lR,2S,5R)-2-((S)-3-(3-tert-butylbenzene Methylamino)-2-g-isotetrahydropyrrole-1-yl)-5-(tri-butylamino)cyclohexanecarboxylic acid methyl ester 12k tert-butylamino)-2- ((S)-3-(2-Third-butylpyrimidine-4-carboxyguanidino)-2-mercaptotetrahydropyrrole-li) Methyl cyclohexanecarboxylate 95318 -261 - 1354664 121 (1 28,511)-5-(Third-butylamino)-2-((S)-3-(2-Third-butylpyrylamino)-2-indenyltetrahydro-p-pillo -1-yl) Cyclohexanoic acid methyl ester 12m (lR, 2S, 5R)-5-(tris-butylamino)-2-((S)-3-(3-phenylbenzhydrazide) Amino)-2-copperyltetrahydropyrrol-1-yl)cyclohexanecarboxylic acid methyl ester 12η (1艮28,51〇-5-(third- Amino)-2-((S)-2-keto-3((2-phenyl-Bist 1 -6-branched amino) tetrahydro-p-l-yl) cyclohexyl酸甲酉的12ο (1民23,51〇-5-(T-butylamino)-2-((S)-3-(4-fluoroyl-3_(trifluoromethyl)-benzene) Amidino)-2-ketotetrahydrop 嘻 ιι_yl) cyclohexane carboxylic acid methyl ester 12ρ (lR^SJRX tert-butyl(methyl)amino)_2-((S)- 3-(2-(4-Chlorophenyl)pyran-5-octanylamino)-2-copperyltetrahydropbilo-ι_yl) cyclohexane carboxylic acid methyl ester 12q tert-butyl (Methyl)amino)_2-((S)-2-yl-3-(6-(trifluoromethoxy)&gt; quinone-4-ylamino)tetrahydroppyr-i_ Methyl cyclohexanecarboxylate 12r (lR, 2S, 5R)-5-(tris-butyl(methyl)amino): ((s)-2-mercapto-3-(6-( Trifluoromethyl&gt;»Querone-4-ylamino)tetrahydro (7-haha-I)-methyl cyclohexanecarboxylate 12s (lR, 2S, 5R)-5- (third- Butylamino)-2-((S)-2-indolyl-3-(4-(perfluoroethyl)&quot;sut-2-pyramino)tetrahydropyrazol-1-yl) Cyclohexanol oxalate 12t (lR, 2S, 5R)-5-(tri-butylamino)-2-((S)-3-(4-t-butyl-pyrazole-2 -Rebel Amidoxime&gt;2-ketotetrahydropyrrole-ii) Cyclohexane retinoic acid methyl ester 12u (lR, 2S, 5R)-5-(tri-butylamino)-2-((8)-2- Ketopropyl-3-(4-(3-(trifluoromethyl)-phenyl)p-sept-2-adenylamino)tetrahydro-saltyl-1-yl)cyclohexane-indolizine 12v ( lR,2S,5R)-5-(Third-butylamino)-2-((S)-2-keto-3-(4-phenylpyrazole-2-remenoyl)tetrahydrogen Pyrrole small group) methyl cyclohexanecarboxylate 12w (lR, 2S, 5R)-5-(tri-butylamino)-2-((S)-3-(4-(4-chlorophenyl) &gt; Retazodin-2-ylideneamino)-2-ketotetrahydropyrrole_ι_yl) Cyclohexylcarboxylate 12x (lR, 2S, 5R)-2-((S)-3- (4-(Benzo[d&gt; plug π sitting_2_yl) p plug _2_ apocytosyl)-2-ketotetrahydrop-ha-1-yl)-5-(third- Methyl butylamino)cyclohexanecarboxylate 95318-262· 1354664 12y (l;^2S,5R)-5-(second-butylamino)·2_((8)2 copper base·3 (4 seven plugs) Benz-3-yl) oxime-2-repoprene amino) tetrahydropyrrole small) methyl cyclohexanecarboxylate 12z (lR, 2S, 5R)-5-(second-butylamino) 2_((8)_2 keto-3 (4-7-secen-2-yl)&gt; Methyl cyclohexanecarboxylate 12aa (1Min 23,511)-2-((8)-3-(4-(金铁烷_ι·基)ρ-propazole·2·Resinyl)-2-one Methyl tetrahydropyrrol-1-yl)·5·(t-butylamino)cyclohexanecarboxylic acid methyl ester 12ab (lR, 2S, 5R)-5-(di-dibutylamino)_2_( (s)-2-Dyphosyl-3-(4-(ρ ratio-2-yl)&gt;sedyl-2-resinylamino)tetrahydropyrrole-diyl)methyl cyclohexanecarboxylate 12ac (lR, 2S, 5R)-5-(Third-butylamino): ((8)_2_indolyl_3_(2-phenylthiazole-4-tresineamino)tetrahydropyrrole-yl) Methyl hexanecarboxylate 12ad (1R, 2S丨5 Magic-5-(Third-butylamino)_2_((s)_3_(2_(4_chlorophenyl)&gt; Methyl)-2-ketotetrahydropyrrole) cyclohexanecarboxylic acid methyl ester 12ae (lR, 2S, 5R)-2_((S)-3-(2-t-butylbutyl-5-methylfuran Rebel amino)-2-ketotetrahydropyrrolidine)·5_(Third-butylamino)cyclohexanyl-methyl ester 12af (lR, 2S, 5R)-5- (third -butylamino)-2-((S)-2-S-yl-3-(2-(trifluoromethyl) s-ol-5- ruminyl) tetrahydropyrrole-i-yl) ring Methyl Hexanecarboxylate 12ag (lR, 2S, 5R)-5-(Thr. )-2-((S)-3-(2-(4-chlorophenyl)-anthracene-5-arene amino)-2-ketotetrahydrop-pyr-1-yl) Methyl ester 12ah (1R, 2S, 5R)-5-(tris-butylamino)-2-((S)-2-keto-3-(2-(3-(trifluoromethyl)) Phenyl)furan-5-carboxyguanidino)tetrahydropyrrol-1-yl)cyclohexanecarboxylic acid methyl ester 12ai (lR,2S,5R)-5-(tri-butylamino)-2- ((S)-3-(2-(2-Chloro-5-(trifluoromethyl)phenyl)furan-5-carboxyindenyl)-2-ketotetrahydropyrrole-1·yl) ring Methyl hexanecarboxylate 12aj (lR, 2S, 5R)-5-(tri-butylamino)-2-((S)-3_(2_(2,5-diphenyl)furan-5 - Carboxylamido)-2-ketotetrahydropyrrol-1-yl)cyclohexanecarboxylic acid methyl ester 95318 -263- 12ak (lR, 2S, 5R)-5-(tri-butylamino) 2-((S)-3-(2-(4-isopropylphenyl)furan-5-carboxyindenyl)-2-ketotetrahydropyrrol-1-yl)cyclohexanecarboxylate Ester 12al (lR, 2S, 5R)-5-(t-butylamino)-2-((S)-3-(2-(4-fluorophenyl)pyran-5-treaminyl Methyl 2-ketotetrahydropyrrol-1-yl)cyclohexanecarboxylate 12am (lR^SJRW-C tert-butylamino)-2-((S)-2-indolyl-3 -(2-phenylfuran -5-treazone amino) tetrahydropyrrol-1-yl)cyclohexanecarboxylic acid oxime ester 12an (lR, 2S, 5R)-5-(tri-butylamino)-2-((S) Methyl 3-(2-(3-fluorophenyl)furan-5-carboxyindenyl)-2-ketotetrahydropyrrol-1-yl)cyclohexanecarboxylate 12ao (lR, 2S, 5R) -5-(dis-butylamino)-2-((S)-3-(2-(3-aminophenyl)furan-5-carboxyguanidino)-2-ketotetrahydropyrrole -Ι-i) methyl cyclohexanecarboxylate 12ap (lR, 2S, 5R)-5-(tri-butylamino)-2-((S)-3-(2_(3-methoxybenzene) Ethyl-5-rebel-amino)-2-ketotetrahydropyrrole-indole-i) methyl cyclohexanecarboxylate 12aq (lR, 2S, 5R)-5-(tri-butylamine Benzyl-2-(()-3-(2-(4-cyanophenyl)pyran-5-alginyl)-2-ketotetrahydropyran-1-yl)cyclohexene Methyl ester 12ar (lR, 2S, 5R)-5·(tri-butylamino)-2-((S)-3-(2-(3,4-difluorophenyl)furan-5 - Carboxylamido)-2-ketotetrahydropyrrol-1-yl)cyclohexanecarboxylate 12as (lR,2S,5R)-5-(tri-butylamino)-2-( (S)-2-keto-3-(2-(4-(trifluoromethyl)phenyl)furan-5-rebelamino)tetrahydropyrrole-1-yl)cyclohexanecarboxylic acid 12at (lR, 2S, 5R)-5-(t-butylamino)-2-((S)-3-(3-(4-indolylphenyl)furan-5-carboxyguanidino) Methyl-2-ketotetrahydropyrrol-1-yl)cyclohexanecarboxylate 12au (lR,2S,5R)-5-(tri-butylamino)-2-((S)-2- Keto-3-(3-(4-(trifluoromethyl)phenyl)furan-5-carboxyguanidino)tetrahydropyrrol-1-yl)cyclohexanecarboxylate 12av (lR, 2S, 5R)-5-(T-butylamino)-2-((S)-2-keto-3-(3-phenylfuran-5-anthraquinone)tetrahydropyrrole-1-yl Methyl cyclohexanecarboxylate 12aw (lR, 2S, 5R)-5-(tri-butylamino)-2-((S)-2-keto-3-(3-phenyl porphin) -5-Carboxynonylamino) tetraapyrrole small) methyl cyclohexanecarboxylate 1354464 12ax tert-butylamino)-2-((s)-2-keto-3-(2-( Pyridin-2-yl&gt;cephen-5-rebelamino)tetrahydropyrrole small)methyl cyclohexanecarboxylate 12ay (1R,2S,5R)_5_(tri-butylamino)-2 -((S)-2-keto-3-(2-7-secen-2-yl)(cephen-5-rebelamido)tetrahydropyrrole·ι·yl)methyl cyclohexanecarboxylate 12az (1艮23,511)-5-(T-butylamino)-2-((S)-2-keto-3-(2-phenyl porphin-5- Amidino)tetrahydropyrrole-i-yl)cyclohexanecarboxylic acid methyl ester 12ba (lR,2S,5R)-5-(tris-butylamino)_2-((S)-3-(2- (4-methoxyphenyl) cephen-5-rebel amidino)-2-ketotetrahydropyrrol-1-yl)cyclohexanecarboxylic acid methyl ester 12bb (lR, 2S, 5R)-5-( Third-butylamino)-2-((S)-3-(l-methyl-3-phenyl-1H-pyrazole-5-carboxyguanidino)-2-onetetrahydropyrrole Methyl cyclohexanecarboxylate 12bc (lR, 2S, 5R)-5·(tri-butylamino)-2-((S)-2-keto-3-(3-phenyliso) 4jun-5-rebel-amino)tetrahydro-p-l-l-yl) methyl cyclohexanecarboxylate 12bd (lR, 2S, 5R)-5-(tri-butylamino)-2- ((S)-2-_yl-3-(6-(trifluoromethyl)oxazolin-4-ylamino)tetrahydropyrrol-1-yl)cyclohexanecarboxylic acid methyl ester 12be (1R, 2S,5R)_5_(Third-butylamino)-2-((S)-3-(6-tris-butylpyrimido[5,4-d]pyrimidin-4-ylamino)- Methyl 2-ketotetrahydropyrrol-1-yl)cyclohexanecarboxylate 12bf (lR,2S,5R)-5·(T-butylamino)-2-((S)-3-( 6-Chloroquinazolin-4-ylamino)-2-self-isodentyltetrahydrop-pyrid-1-yl)cyclohexanic acid formazan 12bg (1R, 2S, 5R )_5_(Third-butylamino)-2_((S)·2·keto-3-(6-(trifluoromethoxy)-quinazolin-4-ylamino)tetrahydropyrrole- 1-yl)methyl cyclohexanecarboxylate 12bh (1R, 2S, 5S)_5_(tri-butylamino)-2-((S)-2-keto-3-(3-(trifluoro) Mercapto)-benzylaminoamino)tetrahydropyrrole-1-yl) Cyclohexanecarboxylate Example 13a-13f Example 13a: (lS, 2S, 5R)-5-(isopropyl(methyl)amine Synthesis of methyl 2-((S)-2-keto-3-(3-(trifluoromethyl)phenylhydrazino) tetrahydropyrrole small) cyclohexanecarboxylate 95318 • 265 · 1354664 Complex D 13a Step 1 (isomerization of cis ester to the corresponding trans ester): (1{^,5 magic-2-((8)-3-(oxiranyloxycarbonyl))_2 Ketotetrahydropyrrole-yl)-5-(2nd-butoxycarbonylamino)-cyclohexanecarboxylate (281 mg, 0.573 mmol, see Example 12a, step 3) in anhydrous DMF To the solution, cesium carbonate (747 mg, 2.29 Torr) was added and the mixture was stirred at room temperature for 16 hours. At the end of the mixing, the mixture was poured into water and extracted with Et 〇Ac (3 Torr). The combined extracts were washed with water, dried and dried, then filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with Et 〇Ac to give the pure trans isomer (1S,2S,5R)-2-((S)-3-(yloxycarbonyl)amine 2-ketotetrahydropyrrol-1-yl)-5-(tris-butoxycarbonyl)amino-cyclohexanecarboxylate (214 mg) as an oil. Step 13: Step 2: (lS, 2S, 5R)-2-((S)-3-(indolyl)amino-2-ketotetrahydroindol-1-yl)·5· (Third-butoxycarbonyl)amino-cyclohexanecarboxylic acid methyl ester (677 mg ' 1.383 mmol) in CH2C12 (7 mL), trifluoroacetic acid (1.07 mL, 13.83 mmol) ), and the mixture was stirred at room temperature for 75 minutes. Evaporating the acid and the solvent' and drying the residue under vacuum to give (1S,2S,5R)-5-amino-2((S)-3-(- yloxycarbonyl)amino-2-one-4- Hydropyrryl small group) Trifluoroacetate salt of methyl cyclohexanecarboxylate as an oil. Example 13a, Step 3: The crude product of Step 2 was stirred with EtOAc (EtOAc (EtOAc) Sodium borohydride (880 mg ' 4.15 mmol). After stirring at room temperature for 2.5 hours, a 37% aqueous HCl solution (1 mL) was added, and the mixture was stirred for 1 hour, then an additional sodium triethoxysulfonate (44 mg, 2.07 mmol) was added. The mixture was kept stirring for another 3 hours. With saturation 95318 - 266 - 1354664

The reaction was quenched with EtOAc (EtOAc) The combined extracts were washed with brine, dried (NzSO4), filtered and evaporated. The mass spectrum of the crude product showed that the product was mainly (lS,2S,5R)-2-((S)-3·((-) oxycarbonyl)amino-2-ketotetrahydropyrrole small)_5-(isopropylamine Ethyl ester of cyclohexanecarboxylate with (lS,2S,5R)-2-((S)-3-(^r milyl)amino ketotetrahydropbiha_ι_yl)·5_ ( _ Amidino) a mixture of cyclohexane carboxylic acid methyl ester. The product was redissolved in CH.sub.2Cl.sub.2 (8 mL). The mixture was stirred for 30 minutes and sodium triacetoxyborohydride (66 mg, 31 mmol) was added. It was then stirred for 16 hours and treated as described above. After concentration, the residue was purified by flash chromatography on silica gel eluting with 5:45:% cNH4OH-MeOH-CH2Cl2 followed by 0.7: 6.3:93 cNH4 〇H-MeOH_CH2Cl2 (1S, 2S, 5R)-2-((S)-3-(octyloxycarbonyl)-2·ketotetrahydropyrroleyl)amino-5-(isopropyl(methyl)amino)cyclohexanecarboxylic acid Ester (2244 mg), MS found: (M+H)+ = 446.2, and (lS,2S,5R)-2-((S)-3-(:f oxycarbonyl)amino-2-yl ketone Hydrogen ratio -1 -yl)-5-(didecylamino)cyclohexanol oxalate (238 mg), MS found: (m+H)+ = 418.2. Example 13 &amp; Step _ Li·1L By way of example, as described in Step 5, (1S, 2S, 5R) 2- 2-((S)-3-(indolylcarbonyl)-2-keto-tetrahydropyrrole-1-yl)amino group _5 Methyl (isopropyl(methyl)amino)cyclohexanecarboxylate (224 mg) was converted to (is,2S,5R)-2-((S)-3-amino-2-keto-4 Hydrogen pyrrolidinyl)-5-(isopropyl(indenyl)amino)cyclohexanecarboxylic acid methyl ester (134 mg). Example 13a ϋΐ - by the method described in Example 6c, to give (lS, 2S, 5R)-2-((S)-3-amino-2-yltetrahydropyrrole small group)_5_(isopropyl Conversion of the base (indenyl)amino)cyclohexanecarboxylic acid methyl vinegar (33.5 mg) to the title compound (1S,2S,5R)-5-(isopropyl(methyl) 95318 -267·1354664 amine )-2-((S)-2-keto-3-(3-(trifluoromethyl)benzhydrylamino)tetrahydropyrrole-1-yl)methyl cyclohexanecarboxylate (19.3 mg) . MS found: (M+H)+= 484.4. Example 13d: (lS,2S,5R)-2-((S)-3-(2-(4-Phenylphenyl)pyran-5- Rebel Synthesis of ethylamino)-2-imyltetrahydropyrrol-1-yl)-5-(isopropyl(methyl)amino)cyclohexanecarboxylate _Ud Step 1: Will (lR, 2S , 5R)-2-((S)-3-(indolylcarbonylamino)-2-ketotetrahydropbi-l-yl)-7-keto-6-nitro-bicyclo[3.2. 1] Xin Xuan &lt; -6-Resorcinated third-butyl ester (0.80 g, 1_75 mol) in EtOH, treated with NaH (84 mg, 2.1 mol) in fractions while stirring at room temperature . After stirring for 1 minute, the reaction was diluted with water and extracted with CH2C12. The extract was washed with water and brine, concentrated, and the residue was chromatographed on silica gel to give 81 gram of isomerized ester. (lS,2S,5R)-2-((S)-3-(oximeoxycarbonylamino)_2-g-iso-tetrahydropyrrole-1-yl)-5-(tris-butoxycarbonylamino) ring Ethyl hexanecarboxylate. MS found: (M+H)+ = 504.46; (M+H-B0C)+ = 404.46. Preferably J column 13d step 2: (lS, 2S, 5R)-2-((S)-3-( Benzyloxycarbonylamino)-2-ketotetrahydropurine-1-yl)-5-(t-butoxycarbonylamino)cyclohexanecarboxylate (81 mg, 1.61 mol) The solution in CH.sub.2Cl.sub.2 (1 mL) was taken in <RTIgt; The reaction mixture was concentrated in vacuo and the residue was dissolved in CH2 C12. The solution was concentrated in vacuo and this was repeated several times. Using this final crude (1S,2S,5R)-5-amino-2-((S)-3-(nonoxycarbonylamino)-2-ketotetrahydropyrrole-yl)cyclohexanecarboxylate Ethyl acetate, without further purification. Example 13d Step 3: Will be obtained from Step 2 of (lS,2S,5R)-5-amino-2-((S)-3-(oxycarbonylcarbonylamino)-2 term homotetrahydropyrrole A solution of ethyl cyclohexanecarboxylate in CH.sub.2Cl.sub.2 (10 mL), EtOAc (EtOAc) (EtOAc) . A 37% aqueous solution of formaldehyde (2 95318 • 268 · 1354664 ml) was added and stirred at room temperature for 1 hour. The solution was diluted with CH.sub.2Cl.sub.2 (50 mL). , 2S,5R)-2-((S)-3-(indolylcarbonylamino)-2-g-isotetrahydropyrrole-yl)-5-(isopropyl(indenyl)amino)-cyclo Ethyl hexane hexanoate is a white foam. MS found: (M+H)+ = 460.51 实_创13d Step 4: (lS,2S,5R)-2-((S)-3-(芊-oxycarbonylamino)-2-one-tetrahydrol A solution of ethyl pyrrol-1-yl)-5-(isopropyl(methyl)amino)-cyclohexanecarboxylate (53 〇 mg '1.1 mmol) in methanol to 150 mg 10 % Pd/C treatment and hydrogenation overnight at 55 psi Hz in a Parr oscillator. Filter the catalyst and concentrate the filtrate in vacuo to give 360 mg (13,23,511)-2-((3)-3-amino-2-ketotetrahydroindol-1-yl)-5- Ethyl (isopropyl(methyl)amino)cyclohexanecarboxylate. Used without further purification. MS found: (M+H)+= 326.3 煑 M. 13d Step 5: Using the method outlined in Step 7 of Example 12a (and replacing 5-(4-chlorophenyl)pyran-2-1 Acid ('S,2S,5R)-2-((S)-3-amino-2-ketotetrahydroindol-1-yl)-5-(isopropyl(methyl)amino A sample of ethyl cyclohexanecarboxylate was converted to the title compound (18,23,511)-2-((3)-3-(2-(4-chlorophenyl)furan-5-carboxyguanidino)- Ethyl 2-ketotetrahydropyrrole]-yl)_5-(isopropyl(methyl)amino)cyclohexanecarboxylate. MS found: (m+H)+= 530.4. Example 13e: 3-((lS,2S,5R)-5-(isopropyl(methyl)amino)_2_((s)-2-fluorenyl Synthesis of ethyl 3-(3-(trifluoromethyl)benzylideneamino)tetrahydropyrrolesyl)cyclohexyl)propionate Straight Example 13e Rabbit Star Chloride Grasshopper (2.0 Μ, in dichloromethane A solution of 370 μl of '735 micromoles' in dichloromethane (1.6 mL) was stirred at -78 °C. Dimethyl hydrazine (1 〇 8 μl, 151 mmol 95318 1354664 ears) was added dropwise over about 2 minutes and the mixture was stirred for 35 minutes. Addition of (11^31^48)-4-((5)-3-dioxocarbonylamino-2-ketotetrahydropyrroleyl)_3_(monomethyl)cyclohexylaminocarbamic acid tert-butyl ester (219 mg, 475 micromolar, see step 1 of Example 4a) in solution of methylene chloride (L5 mL) and the solution was stirred at _78 〇c for 65 minutes. Triethylamine (215 μL, 1.54 mmol) was added, and after 1 min, the mixture was warmed to 0 ° C and stirred for 2 h. The mixture was diluted with dichloromethane to a saturated aqueous solution of ammonium chloride and then washed with water and dried over sodium sulfate and concentrated under vacuum to afford (1Rj4S) _4·((8)_3·-oxycarbonylamino group·2· Keto-tetrahydro-p-pyridin-1-yl)_3_nonylcyclohexylamino decanoic acid tert-butyl ester is a brownish glassy foam (220 mg). MS found: (M+Na)+ = 482.37. _ Example 13e Step 2: Sodium hydride (60% in mineral oil, 67 mg, 1.66 mmol) suspended in tetrahydroethane (1 mL) And treated dropwise with triethyl phosphonate acetate (330 μl ' 1.66 mmol). After stirring for 2 minutes, the mixture was cooled to (TC ' and taken as (1R,4S)-4_((s)_3_-yloxycarbonylamino-2-carbonyl-4-indol-1-yl)-3 - a solution of the third-butyl carbaryl hexylaminocarbamate (22 mg, 475 micromoles) in tetrahydrofuran (2 ml). The mixture was stirred at room / m for 21 h then added Saturated gasification The reaction was quenched with aqueous solution. The mixture was extracted with ethyl acetate three times, and the combined organic phases were dried over silica gel, and concentrated, and the residue was purified by flash column chromatography. Dissolve in 3:7 hexane-ethyl acetate to provide (E)_3_((2S,5R)_ 2-((S)-3-yloxycarbonylamino 2 keto-tetrahydropyrrole small group) -5_(Third-butoxycarbonyl)cyclohexyl)ethyl acrylate with (111,23,5,7-bonded 2-((3)((3)-(())-(tetrahydropyrrole-1)- a mixture of 7-(2-ethoxy-2-ketoethyl)-6-nitro-bicyclo[3.2.1]octane-6-carboxylic acid third vinegar (56 mg) as a white glassy bubble 95318 • 270- 1354664 foam. MS measured value: (M+H)+= 530.48. Example 13e Step 3: Follow The procedure of Step 3 of Example 5a was carried out to give (E)-3-((2S,5R)-2-((S)-3-methoxycarbonylamino-2-ketotetrahydropyrrole as prepared in Step 2 above. -1-yl)-5-(tris-butoxycarbonyl)cyclohexyl)ethyl acrylate with (ir,2S,5R,7R)-2-((S)-3-(indolyloxycarbonyl)-2- Ketotetrahydropyrrol-1-yl)-7-(2-ethoxy-2-ketoethyl)-6-nitro-bicyclo[3.2.1]octane-6-carboxylic acid tert-butyl a mixture of esters, converted to 3-((2S,5R)-2-((S)-3-amino-2-S-iso-tetrazine p-rho-1-yl)-5-(third-butoxy) Ethylamino)cyclohexyl)propionic acid ethyl ester with (lR,2S,5R,7R)-2-((S)-3-amino-2-ketotetrahydroindol-1-yl)_7_(2 a mixture of -ethoxy-2-mercaptoethyl)-6-aza-bicyclo[3.2.1]octane-6-carboxylic acid tert-butyl ester (48 mg) as an off-white solid. :(M+H)+= 398.36, 396.36. Example 13e Step 4: 3-((2S,5R)-2 made in step 3 above, following the procedure outlined in steps 6 and 7 of Example 2a -((S)-3-Amino-2-ketotetrahydropyrrol-1-yl)-5-(tris-butoxycarbonylamino)cyclohexyl)propionic acid ethyl ester with (ir, 2S, 5R ,7R)-2-((S)-3-Amino-2-keto-4 Mixture of pyrrol-1-yl)-7-(2-ethoxy-2-ketoethyl)-6-aza-bicyclo[3.2.1]octane-6-tagamic acid tert-butyl ester ( 48 mg), after reverse phase HPLC and lyophilization, converted to the title product 3-((lS,2S,5R)-5-(isopropyl(methyl)amino)-2-((S)-2 A TFA salt of ethyl keto-3-(3-(trifluoromethyl)phenylhydrazino)tetrahydropyrrole-1-yl)cyclohexyl)propanoate as a white powder (12 mg). MS found: (M+H)+= 526.37. Example 13:: 3-((18,28,51〇-5_(isopropyl(methyl)amino)-2-((8)_2-one Synthesis of 3-(3-(trifluoromethyl)benzylideneamino)tetrahydropyrrole-1-yl)cyclohexyl)propanoic acid Example 13f Step 1: 3-((2S,5R)-5 -(isopropyl(methyl)amino)-2-((S)-2-keto-3-(3-(trifluoromethyl)benzylideneamino)tetrahydropyrrole-1-yl) -cyclohexyl)propionic acid 95318 -271 - 1354664 Ethyl trifluoroacetate (10 mg, 15 micromoles) in tetrahydrofuran (〇 5 ml) in a solution of lithium argon oxide in water, Treat with 5 ml, 〇5 mmol, and stir the mixture at room temperature for 18 hours. The mixture was treated with 1.0 NHC1 (0.5 mL) and concentrated in vacuo. The residue was purified by reverse phase HPLC to afford title product: 3-((1S,2S,5R)_5-(isopropyl(methyl)amino)-2-((S)-2- keto-3 TFA salt of (3-(trifluoromethyl)benzylideneamino)tetrahydropyrrole small)cyclohexyl)propanoic acid as a white powder (7 mg). MS measured value: (M+H)+ = 498.41.

J〇3-A The compounds in the table below were prepared using the methods exemplified above. See Table 1-eight for a complete description of the header. Instance

Rl

R2 13a C〇2Me Change step n/a 13b C02Me 13c C〇2Me

O

MS Data 484.4

13a Step 5 13a Step 5 516.3 488.4 95318 -272- 1354664 13d C02Et

n/a 530.4 Cl n/a 526.4 n/a 498.4 13e (CH2)2C〇2Et 〇 13f (CH2)2C02H 〇

.^CFS

Table 13-B The list of chemical names for the specific examples shown in Table 13-A is given below. Example name 13a (lS, 2S, 5R)-5-(isopropyl(indenyl)amino)_2•((3)·2(trifluoromethyl}benzamide) tetrahydrogen, than two rings Methyl alkanoate 13b (lS, 2S, 5R)-2-((S)-3-(2-(4-chlorophenyl)pyran-5-carboxyguanidino)_2_ketotetrahydropyrrole- 1-yl)-5-(isopropyl(methyl)amino)methyl cyclohexanecarboxylate 13c (lS,2S,5R)-2-((S)-3-(3-third-butyl Methyl benzylamino amidino) 2-ketotetrahydropyrrole-1-yl)·5-(isopropyl(indenyl)amino) methyl cyclohexanecarboxylate 13d (lS, 2S, 5R)- 2-((S)-3-(2-(4-Chlorophenyl) succinyl-5-carboxyguanidino)_2-ketotetrahydropyrrole-1-yl)_5-(isopropyl (methyl) Amino) ethyl cyclohexanecarboxylate 13e 3-((1 S,2S,5R)-5-(isopropyl(f-)amino)-2-((S)-2-keto- 3-(3-(Trifluoromethyl)phenylhydrazinyl)tetrahydropyrrole-1-yl)cyclohexyl)ethyl propionate 13f 3-((lS,2S,5R)-5-(isopropyl (Methyl)amino) 2 -((S)-2-keto-3-(3-(trifluoromethyl)benzylideneamino)tetrahydropyrrol-1-yl)cyclohexyl)propionic acid 14a-14e Example 14a: (S)-l_((lS,2R,4R)-4-isopropyl 2-(isopropylsulfonylmethyl) ring 95318-273 · 1354664 hexyl)-3-(6-(trifluoromethyl)quinazolin-4-ylamino)tetrahydropyrrole-2 Synthesis Example 14a. Step a: A sodium hydride (60% dispersion; 45 g, 1.17 mol) was washed with 500 ml of hexane (2X), suspended in 750 ml of THF and taken with diethyl carbonate ( 112.5 g of '0.94 moles.) This suspension was heated to reflux and was added dropwise 1,4-cyclohexanedione monoethyl ketal (6 g, 384 mM) in THF (250 The solution in ML). After the addition is completed, the suspension is heated to reflux for another 4 hours to cool the mixture to 〇C in an ice bath, then pour to ice (1 liter) when it is severely disturbed. In a mixture of water (1 ml) and citric acid (100 ml), the resulting mixture was extracted with hexane (2 liters total) and the extract was washed with water and brine. , filtered, and concentrated to give ethyl </RTI> </RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; MHz, C DC13 ) 6 (TMS) : 12.25 (s, 1H), 4.20 (q, J = 7 Hz, 2H), 4.06-3.96 (m, 4H), 2.53-2.48 (m, 4H), 1.84 (t, J = 6.6 Hz, 2H), 1.29 (t, J = 7 Hz, 3H). Example 14a Step b: Step 1 crude ester (0.384 mol) in benzene (375 ml) in solution A to (5)-1 -Phenyl-ethylamine (46.4 g, 0.384 mol) and Y^(〇Tf)3 catalyst (0.6 g) were treated with 'heated to reflux for 2-3 hours and water was removed using a Dean-Stark gas cylinder . The resulting solution was concentrated on a rotary evaporator. The residue was passed through a pad of silica gel, using 4:6 EtOAc-hexane, and the solvent was evaporated to give an oily residue, which was crystallized from hexanes to give s. Base 4,4-dioxo-spiro[4.5]dec-7-ene-7-oleic acid ethyl ester.

1H NMR (300 MHz, CDC13) δ (TMS): 9.41 (d, J = 7.4 Hz, 1H)S 7.35-7.20 (m, 9531E • 274·1354664 5H), 4.64-4.58 (m, IH), 4.14 ( q, J = 7 Hz, 2H), 4.02-3.88 (m, 4H), 2.57-2.49 (m, 3H), 2.25-2.15 (m, 1H), 1.72-1.65 (m, 2H), 1.48 (d, J = 7.4 Hz, 3H), 1.28 (t, J = 7Hz, 3H). Example 14a, step c: to make 8-(S1-phenyl-ethylamino)-i,4-dioxo-spiro[4.5] A solution of 癸-7-ene-7-carboxylate (59 g '0.178 mol) in 110 ml of acetonitrile and 54 ml of acetic acid' was cooled in an ice bath with NaBH(OAc)3 (55.9 g, 0.263 The mixture was stirred and stirred for 30 minutes, the ice bath was removed and stirred at room temperature overnight. The solution was concentrated on a rotary evaporator and the residue was dissolved in CH2Cl2. The solution was tested as solid NaHC03 and partitioned between ch2Cl2 and water. The organic layer was washed with water and brine, dried over Na.sub.2, filtered, and concentrated on a rotary evaporator. The residue was filtered through a pad of silica gel, using 4: 6 EtOAc-hexanes and evaporated to give 28.7 g of (7R,8S)-8-(Sl-phenyl-ethylamino)-i, 4- Oxy-spiro[4.5]decane-7-carboxylic acid ethyl ester. 1H NMR (300 MHz, CDC13) ^ (TMS): 7.34-7.21 (m, 5H), 4.18 (q, J = 7 Hz, 2H), 3.95-3.88 (m, 4H), 3.73 (q} J = 7 Hz, 1H), 3.14 (m, 1H), 2.81 (m, 1H), 2.08 (m, 1H), 1.80-1.38 (m, 6H), 1.32-1.25 (m, 6H). Step d: 7R,8S)-8-(Sl-styl-ethylamino)-1,4-dioxo-spiro[4.5]decane, ethyl 7-carboxylate (28.7 g, 0.086 mol) in THF (400 The solution in ML) was cooled to 〇 ° C in an ice bath and slowly treated with 1 om_lah (86 mL '0.086 m) in ether, and the mixture was stirred for 2 hours, and Naz was added in portions. SO4 ·10Η2 0 quenched the reaction. The mixture was filtered through celite and concentrated to give [(7R,8S)_8-(S-1-phenylethylamine)-1,4-dioxo-spiro[4.5]癸-7-yl. ]_Methanol (quantitative yield) of a colorless syrup was used without further purification. Step 14a will be crude [(7R,8S)-8-(Sl-phenyl-ethylamino)-i,4-dioxo. 95318 -275- 1354664 spiro[4.5]癸-7-yl]-methanol (0.086 Moore) 1 ^ Guandou) A solution of 250 liters of Me〇H, treated with 4 grams of 20% Pd(〇H) 2/C and deuterated overnight at 55 psi. The mixture was filtered through celite and concentrated on a rotary evaporator to give ((7R,8S)-8-amino-U4-dioxos[4.5]癸_7_yl)-methanol , for liquid. Used without further purification.哗师:: A solution of crude ((10)S) amido-1,4.dioxaspiro[4·5]癸·7_yl>methanol_6 mol in milliliters of CH2Cl2' (3) mL of saturated Na2C 〇3 was treated 'and cooled in an ice bath. The mixture was vigorously stirred while slowly adding chloroformic acid to the liter of mic, (4) 8 mol). After the addition was completed, the mixture was stirred for another 30 minutes. The organic layer was separated, washed with water and brine, and concentrated to give 33 g of crude material. Recrystallization of its own alkane gave pure (lS'2R&gt; 2-(methyl)- 4_(1,3-dioxosulfonate) cyclohexylaminocarboxylic acid vinegar. 1H NMR (300 MHz, CDC13) δ (TMS): ± _ 14a step hard before adding triethylamine (9.4 ml), make (1S, 2R)_2_(! mercapto)-4-(1,3-dioxosyl) cyclohexylamino The decylformate was dissolved in anhydrous hydrazine 12 〇 2. The solution was cooled to 〇〇c, and gasified methanesulfonate (34 ml) was added. The resulting solution was stirred for 2 hours, then saturated sodium bicarbonate was added. The organic layer was re-extracted with CH 2 Cl 2 . The combined organic layers were washed with brine and dried and dried, then filtered, concentrated, and dried in EtOAc to afford methanesulfonic acid (1R, 2S) _2 ( Benzyloxycarbonyl)_5_(1,3-dioxosulfanyl)-m-hexyl)methyl ester as a pale yellow oil. No further purification was carried out without using it. Step 14a is applied to a solution of isopropane thiol (6.3 ml, 67.72 mmol) in anhydrous DMF. Under the nitrogen, a small amount of 95318 * 276 - 1354664 plus sodium hydride is added under a nitrogen overflow. (2.7 grams, 67.72 millimoles). After the foaming subsides, the cooling is removed and stirring is continued for 90 minutes at room temperature, and then the methane is acid-renewed ((1R^2S)_2_(芊oxycarbonyl)-5-(1,3-dioxolan) Methyl cyclohexyl) (33 86 mmol) was dissolved in DMF (50 mL) and slowly added to the reaction. After 4 hours, saturated NH4 C1 was added to the reaction. The liquid separation treatment was carried out between ethyl acetate and water. The aqueous layer was re-extracted with ethyl acetate. The combined organic layers were washed with brine and dried (MgSO.sub.4). After filtration and concentration, the flash column produces (lS, 2R)-2-(isopropylthiomethyl)-4-(1,3-dioxosulfonate) cyclohexylamine decanoate, as Light oil (8.16 g, 63% yield, in two steps). Example 14a Step 3 • Prior to the addition of 1NHC1 (50 mL), (is, 2R)-2-(isopropylthiomethyl)-4-(l,3-dioxacin)cyclohexylaminocarbamic acid A sample of benzyl ester (8.15 g) was dissolved in acetonitrile (50 mL). After 30 hours, the reaction was made basic by the addition of saturated NaHC〇3 in portions. Then, it was subjected to a liquid separation treatment between Et 〇 Ac and water. The aqueous layer was re-extracted with EtOAc. The combined organic layers were washed with brine and dried (MgSO.sub.4). filtered, concentrated and dried in vacuo to afford (lS,2R)-2-(isopropylthiomethyl). Cyclohexylamino formate vinegar 'as a clear oil (6.57 g, quantitative yield). MS found: (m+H)+= 336.1. Yiyi 14a Step 4: Sample of dS,2R)-2-(isopropylthiomethyl) ketocyclohexylaminocarbamate (8.66) Gram, 25.81 mmol, dissolved in a mixture of iPrOH (50 mL) and triisopropyl orthoformate (50 mL), and then a portion of the mixture of decyl sulfonic acid (1.2 g, 5.16 mmol). After stirring overnight at room temperature, the reaction was quenched by the addition of saturated aqueous sodium bicarbonate. The aqueous layer was re-extracted with EtOAc. The combined organic layers were washed with brine and dried (MgSO.sub.4). Filtration 'concentration, and flash chromatography to give (1's 2r)_4,4-95318 -277-1354664 diisopropoxy-2·(isopropylthiomethyl)cyclohexylaminocarbazate, Foamy solid (8.376 g, yield = 74%). Example 14a Example of a sample of (lS,2R)-4,4·diisopropoxy-2-(isopropylthiomethyl)cyclohexylamino decanoate (8.376 g, 19.16 mmol) ) Dissolved in CH2C12 (75 ml). Before adding triethyldecane (46 ml, 28 J4 mmol), it was allowed to cool in an ice bath, followed by 3· Et 2 〇 (4 96 ml, 40.23 mmol). After 2 hours, the resulting solution was quenched with saturated aqueous NaHCO3. Dispensing between water and 03⁄4⁄4. The aqueous layer was re-extracted with CH2Cl2. The combined organic layers were washed with brine, dried (MgSO.sub.4), filtered, and concentrated to give (1S,2R)-4-isopropoxy-2-(isopropylthiomethyl)cyclohexylamine Benzyl phthalate, used as a clear oil, was not subjected to any further purification. Example: fU and step 6: _ a sample of (lS, 2R)-4-isopropoxy-2-(isopropylthiodecyl)cyclohexylaminocarbazate (27.59 mmol) In ipr〇H (2 〇〇 ml) ' Then add Oxone® (33.92 g, 55.18 mmol) as a solution in 300 ml of water. The reaction was stirred at room temperature overnight. Dispensing between Et0Ac and water. The aqueous layer was re-extracted with EtOAc, and the combined organic layers were washed with brine and dried (MgSO.sub.4). Filtration, concentration and flash chromatography to give (lS,2R)-4-isopropoxy-2-(isopropyl succinylmethyl)cyclohexylamine decanoate decyl ester as a transparent oil (7-73 g , 68%, after steps 5 and 6). MS found: (M+H)+ = 412.35. Example 1_Pack, Step 7: (lS,2R)-4-isopropoxy-2-(isopropylsulfonylhydrazino)cyclohexylamine A sample of decyl carbamate (7.73 g, 18.8 mmol) and Pd/C (2 g) were dissolved in MeOH (250 mL) and stirred at room temperature under 50 psi of hydrogen. 2 5 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The resulting solution was concentrated and dried under vacuum to give (1S,2R)-4-isopropoxy-2-[(isopropyl-decylmethyl)cyclohexylamine as a transparent oil. No further purification was carried out without using it. Real name 丄4a Step 8: A sample of (lS,2R)-4-isopropoxy-2-(isopropylsulfonylmethyl)cyclohexylamine (18_8 mmol) was dissolved in MeCN (60 In milliliters, then diisopropylamine (6.55 ml, 37.6 mmol), N. oxacarbonylcarbonyl-1-oxothioate (5.86 g, 20.68 mmol) and TBTU (7.8 g, 24.44 millimoles). The resulting pale solution was stirred for 2 h. EtOAc was diluted with EtOAc EtOAc. Dehydration and drying such as 〇4), filtration, concentration and flash chromatography to obtain (5) small ((ls, 2R) 4j propoxy-2_(isopropylsulfonylmethyl)cyclohexylamino)_4-( Methionyl ketone ketobutan-2-ylaminocarbamate is a white solid (8·76 g, 86%). MS found: (M+H)+ = 543.2. 14a Step 9: (S)-l-((lS,2R)-4-Isopropoxy-2-(isopropylsulfonylmethyl)cyclohexylamino)-4-(decylthio) A solution of _i_g with benzyl butyl 2-aminocarbamate (28 g, 5.16 mmol) was stirred at room temperature. After 24 hours, the solution was evaporated. The residue was redissolved in CHzCl2 and evaporated. This procedure was repeated for a further four more times. The residue was dried in vacuo to give a yellow foamy solid, which was taken from &lt;RTI ID=0.0&gt;&gt; After stirring for 4 hours, the reaction was quenched with EtOAc EtOAc EtOAc (EtOAc)EtOAc. , concentration and chromatography to obtain (S)-l-((lS, 2R , 4R)-4-isopropoxy-2-(isopropylsulfonylhydrazino) 95318 1354664 Cyclohexyl)-2-ketotetrahydropyrrole-3-ylaminocarbazate A (faster isomerization) , 0.41 g, oil) and isopropoxy-2-(isopropylsulfonylhydrazinyl)cyclohexyl)-2-i-iso-tetrahydropyrrole-3-ylaminocarbazate B (slower) Fe isomer '0.62 g, white solid). Example 14a, step 1 使2 (SH-aiSJMRM-isopropoxy-2-(isopropylsulfonylmethyl) 1⁄4-hexyl)-2-ketotetrahydropyrrole-3-ylaminocarbamate A sample (faster isomer, 0.41 g) and Pd/c (〇. 8 g) were dissolved in MeOH (20 mL) and stirred at room temperature under 50 psi hydrogen. After stirring overnight, the reaction mixture was filtered through Celite using EtOAc. After concentration and drying in vacuo, (3)-3-amino-i-((is, 2R,4R)-4-isopropoxy-2-(isopropylsulfonylmethyl)% hexyl) tetragas is obtained. ? Same as Biha-2-S, it is a transparent viscous oil.

Example 14a Step 11: _ (S)-3-Amino-l-((lS,2R,4R)-4-isopropoxy-2-(isopropylsulfonylmethyl)cyclohexyl Tetrahydropyrrole-2-one (〇.〇4 g, 0.128 mmol), triethylamine (71 μl, 0.512 mmol) and 4·gas-6-(trifluoromethyl), quinine A mixture of oxazoline (0.035 g, 0.192 mmol) was dissolved in EtOH and microwaved at 1 °C for 45 minutes. The reaction mixture is concentrated and chromatographed to give (8) small ((lS,2R,4R)-4-isopropoxy-2-(isopropylsulfonylmethyl)cyclohexyl)·3_(6_(trifluoromethyl) Base 4:oxazolin-4-ylamino)tetrahydropyrrole-2-one as a white solid (〇. 〇 4 g). MS found: (Μ+Η)+= 557.2 Example 14b: (5)-l-((lS,2R,4R)-4-methoxy-2-(methylsulfonylmethyl)cyclohexyl)-3- Synthesis of (6-(Trifluoromethyl)»»Qutula-4-ylamino)tetrahydropbilo-2-indole Example 14b Step 1: A was added in a portion of LiBH4 (0.44 g) before ( A sample (2.8 g) of lR, 2S, 5R)-7-keto-6-oxo-bicyclo[3.2.1]octyl-2-ylaminocarbamate was dissolved in anhydrous THF. The reaction mixture was stirred at room temperature overnight at 95318 - 280 - 1354664. The reaction was quenched with saturated aq. The organic layer was washed with brine and dried (MgSO.sub.4). Filtration, concentration and chromatography gave (1S,2R,4R)-4-hydroxy-2m-methyl) decylaminocarbazinate as a white foamy solid. Example lik#Step 2: A sample of (lSJIMRH-hydroxy-2-(hydroxymethyl)cyclohexylcarbamate benzyl ester (8.78 g, 31.42 mmol) was dissolved in anhydrous CH2C12, followed by the addition of triethylamine ( 11 ml '78·55 mmol>, followed by ^&gt; (0.05 g), then add a portion of triphenylmethane chloride (1 〇·52 g, 37.7 mmol) in one portion. After stirring overnight, the reaction mixture was partitioned between CH 2 Cl 2 and water. The organic layer was washed with brine, dried and dried (MgS 〇 4), filtered, concentrated and chromatographed (IS, 2R, 4R) Benzyl 4-methyl-2-(trityloxymethyl)cyclohexylcarbamate was a white foamy solid (9 85 g, yield = 60%). Example 14b was free of 3 吏(lS, 2R, 4R)-4-Phenyl-2-(triphenylphosphonium decyl) decyl carbamic acid methacrylate (6.9 g, 13.24 mmol) dissolved in Mel (12.4 ml) , in a mixture of 198.6 mmoles and anhydrous DMF (15 ml), then add Ag2 hydrazine (6.1 g, 26.48 mmol) in one portion under argon overflow. Set the reaction at room temperature. Stir in the dark. Stir After 3 hours (reaction is not complete), it is diluted with CH2Cl2 and filtered through Shixiazao. Filtered, concentrated to a yellow oil, and flash chromatographed to obtain (1S, 2R, 4R)_4_ A Benzyl oxy-2-(triphenylphosphonyloxymethyl)cyclohexylcarbamate (3.48 g) as a white foamy solid, and the starting material was recovered. J: Example 14b Step 4: J 吏 (lS , 2R, 4R)-4-decyloxy-2-(triptymethyloxymethyl) benzyl cyclohexylamine decanoate (〇·53 g) was dissolved in 7〇% acetic acid aqueous solution 95318 - Mix 281 - 1354664 (10 ml) with MeCN (10 ml) and stir at 6 ° C for 2 h. The reaction mixture was cooled and evaporated, dissolved in Et0Ac and washed with sat. NaHC. 'then dehydrated (MgSO*) ^ filtered, concentrated and chromatographed to give (lS, 2R, 4R)-2-(monomethyl)-4-methylcyclohexylaminocarbamate (0.24 g, yield Rate = 83%), as a clear oil. MS found: (M+H) + = 294.29 Example Hb Step 5: Using (lS, 2R, 4R)-2- (by the same procedure as in Step 1 of Example 14a) Methyl-free)-4-methoxycyclohexane A sample of decyl carbamate (0.298 g) was synthesized to synthesize methanesulfonic acid ((ιϊ^28,5ιι)·2_(芊 oxycarbonyl)·5 methoxycyclohexyl) methyl ester. The product was in the form of a yellow foam. The solid was obtained without any further purification. Example 14b Step 6: A sodium thiomethoxide sample (0.28 g, 4.04 mmol) was dissolved in DMF (4 mL) Water was added dropwise thereto until the suspension became a homogeneous mixture. A sample of methanesulfonic acid ((11^,511)-2-(loyed oxycarbonyl)·5-methoxycyclohexyl)methyl ester in DMF (6 ml) (1〇1 mmol) Slowly added to the sulfur acid mixture. The mixture was continuously stirred at 〇 ° C for 1 hour, and then the reaction was quenched with saturated NaHC03. Extract twice with EtOAc. The combined organic layers were washed twice with water and then brine. Dehydration and drying (MSs 〇 4), filtration, and concentration to give (13,211,411)-4-methoxy-2-(methylthiomethyl)cyclohexylaminocarbamate as a pale solid. : (M+H)+ = 324.27 Example _ljb. Step _7: according to the procedure of step 6 of Example 14a; with (lS, 2R, 4R)-4-methoxy·2·(methylthio fluorenyl) A sample of cyclohexylamino decyl decanoate (1.01 mmol) was started as the desired product (13, 2 min 4 ft) 4-methoxy-2-(methylsulfonylmethyl) 95318 • 282· 1354664 Benzyl cyclohexylamine decanoate (0.318 g 'yield = 89%) was obtained as a white solid. MS found: (M+H)+=356.1 f Example 14b Step 8: according to the procedure of step 7 of Example 14a; to (18, 2 min 4 ft)-4-decyloxy-2-(sulfonyl) a sample of decylaminocarbazate carboxylate (〇318 g) to start the desired product (lSJMRM-decyloxy-2-(methylsulfonylhydrazino)cyclohexylamine (0.2 g 'quantitative yield Obtained as oil. MS found: (M+H)+= 222.19 Example 14b Step 9: according to the procedure of Example 14a, step 8; with (is, 2R, 4R)-4-methoxy-2- Starting with a sample of (methanesulfonylmethyl)cyclohexylamine (51 mmol), the desired product (S)-l-((lS,2R,4R)-4-methoxy-2-(methane) Mercaptomethyl)cyclohexylamino)-4-(methylthio)-lg-yl-butan-2-ylaminocarbazate (15 g, yield = 6〇5%) is translucent sticky tung oil Obtained. MS found: (M+H)+ = 487.38 Example 14b: 10: according to the procedure of step 9 of Example 14a; (5) small ((lS,2R,4R)-4-methoxy-2-(A Starting with a sample of benzyl sulfonylmethyl)cyclohexylamino)-4-methylsulfonyl ketobutan-2-ylcarbamate (1.5 g), the desired product (S)-l-( (lS, 2R, 4R)-4-methoxy-2-(methylsulfonyl) Benzyl)cyclohexyl)-2-ketotetrahydropyrrol-3-ylcarbamate (1.15 g, yield = 8%) was obtained as a foamy solid. MS found: (m+H)+ 439.4 Example 14b Step 11: According to the procedure of Step 1 of Example 14a; to (5)·Bu((lS,2R,4R)-4-methoxy-2-((methylsulfonylmethyl)cyclohexyl)_2• Starting with a steel benzyl tetrahydropyrrol-3-ylcarbamate sample (〇.65 g), the desired product (5) s-amino-l-((lS'2R,4R)-4.methoxy 2 · ((4) f-based) cyclohexyl) tetrachloropyridin-2-one (0.44 g, quantitative yield) was obtained as a viscous oil. The more the _111_ procedure according to Example 14a; the (8) amines Small ((1S, 2R, 4RM-methoxy winter (methyl chloromethyl) cyclohexyl) tetracentric _2_ 95318 -283 - 1354664 ketone sample (0.0364 g) begins with the desired product methoxy -2-(曱 驴 甲基 methyl)cyclohexyl)-3-(6-(trifluoromethyl)p-quinone _4_ylamino)tetrahydropyrrole-2-one (0.0462 g, yield =77%) was obtained as a white solid. Ms found: (M+H)+ = 501.39 Example 1: 2-t-butyl-n-ksh^isjr^rh-methoxy winter Synthesis of methyl)cyclohexyl)-2-ketotetrahydroindolebi-3-yl) shouting-4-treazone Example 14c Step 13: Procedure according to Example Step 8; with (6)-3-amino group -l-((lS,2R,4R)-4-methoxy-2-(fluorenylmethyl)cyclohexyl)tetrahydrop-pyridone sample (0.0364 g) and 2-third-butyl The base "I-precipitate-4-deoxy acid begins, the desired product 2-tri-butyl-N-((S)-l-((lS,2R,4R)-4-methoxy-2-( Methyl decylmethyl)cyclohexyl)-2-g-isotetrahydropyrrol-3-yl)-hydan-4-carboxamide (0.0403 g, yield = 74%) was obtained as a white solid. MS found: (M+H)+ = 467.42 Example 1 Buckle: (8)-1-((18,2 Min 48)_4-isopropoxy-2-(isopropylsulfonylmethyl) ring Synthesis of hexyl)-3-(6-(trifluoromethyl)junethin-4-ylamino)tetrahydronbipir-2-one Example 14e Step 1: By way of Example 14a, steps 10-11 The slower isomer (S)-l-((lS,2R,4S)-4-isopropoxy-2-(isopropyl decylmethyl) ring of step 9 of Example 14a. Conversion of the hexyl)-2-ketotetrahydropyran-3-ylcarbamic acid carboxylic acid ester to the title (S)-l-((lS,2R,4S)-4-isopropoxy-2-( Isopropyl sulfonylmethyl)cyclohexyl)-3-(6-(trifluoromethyl) quinone-4-ylamino) tetrahydro-p-pyrene. MS found: (Μ+Η) += 557.2. Example 14g: 5-(3_(((S), 2R), 4-methoxy-2-(nonylsulfonylmethyl)cyclohexyl)-2-one Synthesis of tetrahydropyrrol-3-yl)aminecarboxamido)phenyl)phenyl-3-derivatives in 5-(3-(((3) 411)-4 -Methoxy-2-(methylsulfonylmethyl)cyclohexyl)-2-onetetrahydropyrrole-3-yl)aminecarboxyl)phenyl)phenyl-3-carboxylic acid methyl ester (27 MG 95318 • 284. 1354664, Example 14 In a solution of MeOH (3.5 mL), EtOAc (EtOAc &lt;RTI ID=0.0&gt; The mixture was extracted twice with EtOAc EtOAc EtOAc. +H)+= 529.4.

Table 14-A The compounds in the table below were prepared using the methods exemplified above. See Table 1-A for a complete description of the header.

Η / Ν R2 Example R5 R6 R2 Change Step MS Data 14a iPrO iPr n/a 557.2 14b MeO Me «/ww n/a 501.3£

95318 • 285 - 1354664

14c MeO

Me 14d

MeO Me 〇

n/a 467.42

14e 14c. 509.36 α Step 13

iPrO ipr (S)- diastereomer 14f MeO Me 0=^C MeOaC 14c Step 13 543.4 MeO Me 0=K ho2c ao n/a 529.4 Table 14-芎Special examples of chemistry shown in Table 14-A The list of names is listed below. Example ------ Name 14a 14b~~~ (S)-l-((lS,2R,4R)-4-Isopropoxy_2-(isopropylsulfonylmethyl)cyclohexyl) -3-(6-(trifluoromethyl)&gt; quinazolin-4-ylamino)tetrahydropyrrole _-2-one (S)-1-((1 S,2R,4R)-4 -Methoxy-2-(methylsulfonylmethyl)cyclohexyl)-3-(6-(trifluoromethyl)p-salt-4-ylamino)tetrahydroindole-2-one 14c 2-Terti-butyl-N-((S)-1-((1S,2R,4R)_4-methoxy-2-(indolyl)------ylmethyl)cyclohexyl )-2-mercaptotetrahydro ρ, bilo-3-yl)p-dense-4-treazone 14d 5-(4-chlorophenyl)-N-((S)-l-((lS,2R , 4R)-4-methoxy-2-(methylsulfonyl--*-----ylmethyl)cyclohexyl)-2-self-synonym tetrahydrop-specific-3-yl)»» -2--2-Rebel amine 14e (S)-l-((lS,2R,4S)-4-isopropoxy-2-(isopropylsulfonylmethyl)cyclohexyl)-3-(6 -(trifluoromethyl&gt; quinazolin-4-ylamino)tetrahydropyrrole-2-indole 95518-286·1354664 14f 5-(3-(((8)-1-((18)) 411)-4-Methoxy-2-(indolyl sulfhydryl)cyclohexyl)-2-ketotetrahydropyrrol-3-yl)aminecarboxamido)phenyl)phenyl-3-carboxylic acid Methyl ester 14g 5-(3-(((3)-1-((13, 2)艮)-4-methoxy-2-(nonylsulfonylmethyl)cyclohexyl)-2-ketotetrahydropyrrol-3-yl)amine fluorenyl)phenyl)phenyl-3-carboxylic acid Examples 15a-15h Example 15a: (3S)-1-((3R,4S)-1_isopropyl-3-propylhexahydropyridin-4-yl)-3-(6-(trifluoromethyl) Synthesis of quinazolin-4-ylamino)tetrahydropyrrole-2-ketone Example 15a Step a: (3R,4S)-4-((S)-l-phenylethylamino)hexahydroindole Bite·ι,3_ dicarboxylic acid 1-tris-butyl 3-methyl ester (47 g '0.13 mol, see: s. S. Κο et al, WO PCT 2002002525, for this compound against palm isomers Preparation) iM_LAH (1 mL, 0.1 mol) was added dropwise (y&gt;c) in a solution in anhydrous water (500 ml), and the mixture was stirred at 〇15 &lt;t for 3 hours. Naz SO4 · 10H2 0 (excess) was added in portions to quench the reaction' and allowed to stir for 1 hour at room temperature. It was filtered through a rare earth and evaporated to give (3R, 4S) _3 _ s. -4-((S)-l.Phenylethylamino)hexahydrou is called succinic acid (quantitative yield). Actually._15a invites JL to (3R,4S)-3-(hydroxyindenyl)-4-((S)-l-phenylethylamino)hexahydropyridine-1-carboxylic acid tert-butyl ester A mixture of (38 g, 113.6 mmol) and Pd(〇H) 2 (5 g) was stirred in methanol (250 mL) at room temperature under 5 psi of hydrogen. After stirring overnight, the reaction mixture was filtered through celite. The solution was concentrated to give the desired product (3,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, Really ashamed 5 & 111-free (3R,4S)-4-amino-3-(hydroxymethyl)hexahydropyridine small acid-depleted third-butyl vinegar sample (113.6 millimolar) dissolved in CH2Cl2 Medium, then add saturated 95318 • 287· 丄: sodium carbonate / 80 ml). The mixture was allowed to cool to this point, and then the ruthenium acid was added slowly (21.76 liters, 136.32 millimoles). Remove the cooling and continue to mix overnight. The mixture was subjected to a liquid separation treatment between water and CH 2 Cl 2 . The aqueous layer and CH2C12 were re-extracted. The organic layer was combined and washed with brine, and dehydrated and dried (MgS04). After the 'concentrated end' and dried in a vacuum, the desired product (3R, 4S)-4-(yano-a) is suspected to be methyl) hexachloro-p is the third bit of diced acid, which is yellow oil. . ΐ 15a ^ . In an anhydrous DMSO (U ml, 25.36 mmol) in = Η 2α 2 (40 $ liter) in a positive mixed solution, slowly add chlorinated grass I. (2 liters, 23.78 Millions of ears). After 20 minutes, a sample of I (3R,4S)-4-(word oxycarbonyl)_3_read methyl)hexahydropyridine small carboxylic acid tri-butyl ester was dissolved in CH2Cl2 (such as pen liter) (5.78 Gram, 丨5 85 mils) was slowly added to the reaction. Stirring was continued for 1 hour. Triethylamine (6. 6 ml, 4755 mmol) was added dropwise. Stirring is then continued and gradually warmed to 〇t for a few hours. The mixture was subjected to a liquid separation treatment between water and CH2%. The aqueous layer was re-extracted with CH 2 Cl 2 . The combined organic layers were washed with brine and dried with EtOAc EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 1-carboxylic acid tert-butyl ester as a pale oil (38 g, yield = 67%). Example 15a Step 11 - EtPPh3 Br (4.7 g, 12.59 mmol) in anhydrous THF (70 liters) is being stirred in a suspension, in a _5 〇c (approximately) bath, slowly Add KHMDS (13.12 millimolar). The resulting reddish solution was stirred for 20 minutes. While maintaining the same low temperature, a solution of (3Rj4s)_4•(ythoxycarbonylmethylmercaptohexahydro-&quot;-precipitated small carboxylic acid tri-butyl ester in anhydrous THF (30 ml) was added to the reaction mixture. After the addition was completed, the reaction was stirred EtOAc EtOAc EtOAc EtOAc (EtOAc) Concentration and chromatography to give the desired product (4S, E)-4-(-(oxycarbonyl)-3-(prop-1-enyl) hexahydropyridin-1-carboxylic acid tert-butyl ester, diastereomer Apparent mixture of isomers, light oil (3.2 g, yield = 82%). Example 15a Step 5: (3艮43忑)-4-(benzyloxycarbonyl)_3·(propylamine) A mixture of hexahydropyridine-1-carboxylic acid, third butyl ester (2.85 g), Pd/C (0.28 g) in MeOH (75 mL) was stirred at room temperature under 50 psi of hydrogen. The reaction mixture was filtered through celite to give the desired product (4 s), 4-amino-3-propyl hexahydropyridin-1-carboxylic acid, tert-butyl ester (172 g, yield = 93%). It is a light oil. It is used. Any further purification was carried out. Example 15a Step 6: According to the procedure of Step 8 of Example 14a, the desired product was obtained using (4S)-4-amino-3-propyl hexahydropyridine· The ester (1 72 g) was obtained as the starting material. The desired product (4S) _4_((8)_2-(H. ethoxycarbonyl) _4(methylthio)butylamino)-3-propylhexahydropyridine: [_ The acidified third-butyl ester, an apparent mixture of diastereomers, was obtained as a white solid (3.174 g, yield = 88%) after flash column chromatography.丨4a, step 9 of the procedure, the desired product is (4S)-4-((S)-2-(竿oxycarbonyl)····(曱thio)butaninyl)_3•propylhexahydroindole The third product of the carboxylic acid + carboxylic acid (3. 174 g) was obtained as the starting material. The crude product mixture was chromatographed. Two products were obtained, which were found to be isomers. Based on TLC, it will Here, it is called squat,]: (3R, 4s) _4 • Ovate Oxygen Group > 2-ketotetrahydro (tetra) (4-)]-based &gt; 3- propyl hexahydro hydrazine bite acid third · Ding The purpose of (faster) and (3 families of 4-((8)·咐 oxycarbonyl) side groups tetrachloroguanidine small traitors 9 5318 -289- 1354664 propyl hexahydropyridin-1-tert-acid third-butyl ester (slower). Example 15a Step 8: PMS)-4-((S)-3-(anthraceneoxy) A sample of _2_ketotetrahydropyrrol-1-yl)-3-propylhexahydropyridine-1·succinic acid tri-butyl ester (faster, 〇341 g) was dissolved in CH2 CL (10 ml) Then, trifluoroacetic acid (〇82 ml, 11.14 mmol) was added. After 2.5 hours, the reaction was evaporated and redissolved in CH2CI2. This solution was washed with saturated NaHC(R), then brine. Dehydrated (NajSO4) was filtered, concentrated and dried in vacuo to give the desired amine (25 g, yield = 94%) as a transparent oil. Preferably, Example 15a, Step 9: The amine sample from Step 8 (0.25 g) was dissolved in 1,2-dichloroethane, followed by the addition of acetone (0-26 mL, 3.475 mmol). Stirring was continued for 1 hour at room temperature, then sodium triethoxysulfonate (0.29 g, 1.39 mmol) was added to the reaction. The reaction was stirred for 5 hours and then quenched with saturated NaHC. The liquid separation treatment is carried out between CH2 Cl2 and water. The organic layer was washed with brine and dried (MgS04). Filtration, concentration, and drying in vacuo to give the desired product (S)-1-((3R,4S)-1-isopropyl-3-propyls. Ketohydrotetrahydro&gt;»Bilo-3-ylaminocarbamic acid (faster) (0.262 g, yield = 94%), as a clear oil MS found: (M+H)+ = 402.2 f Example 15a Step: 胳 (S)-1-((3R,4S)-1-isopropyl-3-propylhexahydropyridin-4-yl)-2-onetetrahydropyrrol-3-yl A mixture of benzyl carbamate (faster) (0.262 g) and Pd/C (0.056 g) in MeOH was stirred at room temperature under 50 psi of hydrogen. After stirring overnight, the reaction was filtered through celite. Concentration and drying in vacuo to give the desired product (3S)-3-amino-1-((3R,4S)-1-isopropyl-3-propylhexahydro-P. Tetrahydropyrheptin-2-one (faster) (0.166 g, yield = 95%) was a clear oil. 95318 • 290· 1354664 Example I5a Step 11: In accordance with the procedure of Step 11 of Example 14a, using (3s)-3-amino-1-((3Rj4S)-1-isopropyl-3-propyl:hydrogen p-biting- 4-yl)tetrahydro-p-Bilo 2_嗣 (faster) (0.0399 g) as starting material, desired product (3s)·b ((3R,4S)-l-isopropyl-3-propyl Hexahydropyridine 4-4-yl)-3-(6-(trifluoromethyl)quinazoline·4.ylamino)tetrahydrofuran-2-one (faster) is a white solid (〇〇45 Gram, yield = 65%) obtained. MS found: (μ + Η) + = 464.2 Example 15c: 5-(4-phenylphenyl (tetra)-(10) small (6) to give isopropyl isopropyl propyl hexahydropyridin-4-yl)-2- primate Synthesis of Hydropyrrole_3_yl)furan-2-treazone Example 15c Step 1: According to the procedure of Step 8 of Example 14a, using (3S)-3-amino-1-((3R,4S)-1- Isopropyl-3-propylhexahydroindole τ than _4·yl) tetrahydro-p-Bilo_2_g with (faster) (0.036 g) and 5-(4·chlorophenyl)pyran-2- Acid (0.027 g, 0.148 mmol) as the starting material 'product 5' (4-chlorophenyl)-indole-((3)-1·((3ΙΙ,43)-1·isopropyl-3 -propylhexahydropyridin-4-yl)-2-ketotetrahydropyrrol-3-yl)furan-2-carboxylate (faster) as a white solid (0.0401 g, yield = 63%) obtain. MS found: (M+H)+ = 472_2 Example 1: (3)-1-((3S,4S)-1-isopropyl-3-propylhexahydropyridin-4-yl)-3-(6 Synthesis of -(trifluoromethyl)oxazolin-4-ylamino)tetrahydropyrrole-2-one f Example 15e step @ 1 ··Oxycarbonyl)-2-ketotetrahydropyrrole-1-yl) A sample of -3-propylhexahydropyridine-1-carboxylic acid tert-butyl ester (derive slower isomer from step 15 of Example 15a) was subjected to the procedure outlined in steps 8-11 of Example 15a above. get on. Example 15i: (3R,4S)-1-Isopropyl-4-((S)-2-keto-3-(6-(trifluoromethyl)&gt; quinazolinylamino)tetrahydropyrrole _1_Base) Synthesis of Hexahydropyridine_3_Resinolate Step 1: # 4-Ketylhexahydropyridine-3-carboxylic acid methyl ester hydrochloride (10.0 95318 -291 · 1354664 g ' 51.6 mmol The ear, i equivalent) was dissolved in water (6 mM) at room temperature and then cooled to 〇 ° C ^ sodium carbonate (6.02 g, 56 8 mmol, 1 〇 5 equivalent), followed by a funnel Add bTHFc anhydride (1) 84 g '51_6 mmol, ! equivalent) in THF (5 mL). Here. Stir the mouth for an hour. The treatment was carried out by extracting 3 times with an ethyl bond (50 ml). Combine the B-key extract and rinse once with saline (5 mL). The ether layer was dried over sodium sulfate and stripped to give 4-[pi][pi] </RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; Yield = 100% . 1H NMR (400 MHz) (CDCl3) 5 4 〇 2 (s, 2H); 3.77 (s, 3H); 3.59 (s, 2H); 2.37 (s, 2H); 1.47 (s, 9H). 彳15i Step 2. 4. 4-Ketyl hexahydro ι» 淀-i,3-di-acid citrate tri-butyl 3- decyl ester (13.29 g, 51.6 mmol, 1 equivalent) , (8) seven) _ 〇; _ methylbenzylamine (6 66 pen liters, 51.63⁄4 mol, 1 equivalent), acetic acid (5.91 ml, 103.0 mmol, 2 equivalents) and benzene (200 ml) at room temperature Mix and then reflow using a Dean_Stark gas cylinder for 4 hours. Cool to 〇. (; ^ Add acetic acid (23 66 ml, 412 8 mM '8 equivalents), followed by sodium triethyl sulfonium borohydride (21 9 gram, 1 〇 3 〇 millimoles ' 2 equivalents) ^ at ( Stir at TC for 20 minutes, then allow the reaction to warm to room temperature and stir for 20 hours. Add sodium carbonate by careful (foaming) until pH = 10 '. This aqueous solution was extracted with ethyl acetate three times. The ethyl acetate layers were combined, washed once with brine, dried over sodium sulfate and stripped to give (31^43)-4-((13)-1-phenylethylamino)-hexahydropyridine- 1-1,3-dicarboxylic acid 1-tris-butyl 3-methyl ester (18.7 g) oil as product. Yield = 100%. MS (ESI) (M+H)+ = 363.2. Example 15i Step 3: Chiang 20% palladium hydroxide (1.87 g) was carefully wetting down with isopropanol (50 ml) under nitrogen, then adding 95318 • 292- 1354664 (311) in isopropanol (50 ml) ^)-4-((18)-1-phenylethylamino)-hexahydropyridine-1,3-diglutamate·t-butyl 3-decyl ester (18.7 g ' 51.6 mmol, 1 Equivalent). The mixture was hydrogenated on a Parr for 20 hours. After passing through the glass fiber filter paper, the catalyst is treated by decanting the catalyst. The filtrate is stripped to obtain an oil, which is made on the crushed rubber, with 1:1 hexane/ethyl acetate to 100% ethyl acetate to 4 : 1 dichloromethane / methanol purification. Obtained (31^48)-4-amino hexahydrop than yttrium, yttrium yttrium tris-butyl 3-methyl ester (11.2 g), Colorless oil. Yield = 84%. Mass spectrometry (ESI) extraction (M+H)+= 259.1. Example 15if._. Suspended. 4: (31^48)-4-Amino hexahydropyrene -i,3-diacid acid 1_third_butyl 3-methyl ester (10.0 g, 38.7 mmol, 1 equivalent), CBZ_L•methionine (13.16 g '46.5 when mol, 1.2 equivalent) , 1-Phenylbenzotriene hydrate (hobt) (6.28 g, 46.5 mmol, 1.2 eq.), 1-[3-(dimethylamino)propyl]_3_ethylcarbodiimide HC1 (EDCI) (8.91 g, 46.5 mmol, 1.2 eq.), triethylamine (10.79 liters, 77.4 mmol, 2 eq.) and dioxane (1 mM) were stirred at room temperature under nitrogen. Overnight was treated by rinsing with water 3 times. The organic layer was dried over sodium sulfate and stripped to give an oil. Purified to 1:1 hexane/ethyl acetate to obtain (3R,4S)_4_((2S)_2_((2)-(())-(yloxy)-ylamino)-4-hexahydro- Bismuth 丨, 3_2 bismuth acid μ second-butyl 3-methyl ester (19.7 g), white glass. Yield = 97% . LCMS detection (M+Na)+ = 546.26. U'l 15i ΨΜ11.Μ (3R,4S)-4-((2S)-2-(芊氧谈基基基)_4- (Methylthio) butylamino)-acupoint argon pyridine 丨, _ 3 - dicarboxylate 丨 _ _ _ butyl 3 _ methyl ester (19 7 grams, 37.6 millimoles '1 equivalent) and methyl iodide ( 23 5 ml, 376 〇 millimolar, 1 〇 equivalent) was stirred under nitrogen at room temperature for 20 hours. The reactant 95318 1354664 was stripped 5 times from chloroform (50 mL). Obtained 27.1 g of bismuth salt, which was off-white glass. Yield = 100%. LCMS detected (M+H) + = 538.38. This bismuth salt (1 gram, j 5 〇耄 mol, 1 equivalent) and cesium carbonate (1.96 g '6.01 mmol, 4 equivalents) were stirred at room temperature under nitrogen for 20 hours in dmf (1 mL). Treatment was carried out by adding ethyl acetate (25 ml) and rinsing three times with brine (25 ml). The organic layer was dried over sodium sulfate and stripped to give an amber oil. It was purified on celite in 3.1 to 1.1 hexane/acetic acid vinegar. Obtaining (3r,4§)_4_((3s)_3-(+oxy-neylamino)-2-copperyltetrahydrop-pylor-1-yl)hexa-p-p-bito-1,3-diacid 1_ Third-butyl 3-methyl ester (450 mg) 'is a white glass material. Yield = 63% LCMS detection (M+H) + = 476.30. Example 15i Step 6: (3R,4S)-4-((3S)-3-(benzyloxycarbonylamino)&gt; Tetrahydropterin p--1-yl) hexahydro-p-precipitate-1,3-dipo-l-tert-butyl 3-methyl ester (7.45 g) was dissolved in dichloromethane at room temperature under nitrogen. (20 ml), then TFA (10 mL) was added. After 3h, the reaction was taken from dichloromethane (25 mL). Rinse 4 times with 1.000 N NaOH (25 ml). The ethyl acetate layer was dried over sodium sulfate and stripped to give (3R,4S)-4-((3S)-3-(benzyloxycarbonylamino) --2-ketotetrahydropyrrole-fluorenyl) hexahydropyridine-3-carboxylic acid decyl ester (4.30 g) as a white glass material. Yield = 73%. LCMS detection (M+H)+= 376.1 .

Example 15i Step 7: Methyl (3R,4S)-4-((3S)-H芊oxycarbonylamino)-2-ketotetrahydropyrrol-1-yl)hexahydropyridine-3-carboxylate (1.00 g, 2_66 mmol, 1 equivalent), sodium triethoxysulfonate (0.85 g, 4.00 mmol, 1.5 equivalents) and acetone (0.59 mL, 7.99 mmol, 3 equivalents) mixed in two Methyl chloride (15 ml) was stirred at room temperature for 20 hours. Treatment was carried out by adding 20 ml of 1.000 N NaOH 95318 • 294 · 1354664. Stir for 10 minutes and then extract 3 times with dichloromethane. The organic layers were combined, dried over sodium sulfate and evaporated to give 4-((3S)-3-(indoleylamino)-2-indolyl tetraphos p-ha-1-yl)-i- Isopropyl-hexahydro-p is a bit of a little bit of acid methyl vinegar (1.10 g), white glass material. Yield = 99%. LCMS detection (M+H)+ = 418.41. Example 15i Step 8: Under nitrogen, '20% palladium hydroxide (〇.3 gram) carefully with isopropanol (10 ml) ) Wetting down' and then adding (3's 4S)-4-((3S)-3-(_oxycarbonylamino)-2-keto-tetrahydro^ ratio in isopropanol (1 mL) Ha_1_base) small isopropyl hexahydro-p is more than bite--3-reacid methyl ester (1·1 gram). The mixture was hydrogenated on a Parr shaker for 20 hours. The glass fiber filter paper was passed through under nitrogen and treated by filtering out the catalyst. The filtrate was stripped to obtain (3R,4S)-4-((3S)-3-amino-2-ketotetrahydropyrrole-1-yl)-1-isopropylhexahydropyridin-3-one acid Ester (695 mg) as an oil. Yield = 93% · LCMS detection (M+H) + = 284.34. Example 15i Step 9: # (3R,4S)-4-((3S)-3-Amino-2-ketotetrahydropyrrole- 1-yl) • 1-isopropylhexahydropyridine-3-methylated acid methyl ester (50 mg, 0.176 mmol, 1 equivalent), 4-chloro-6-(trifluoromethyl)-P-razole Levage (45 mg, 0.194 mmol, 1.1 equivalents) and triethylamine (98 μL, 0.706 mmol, 4 equivalents) in ethanol (3 mL) at room temperature, then microwave at 100 ° C 1 hour. Purification by HPLC to obtain (3R,4S)-1-isopropyl-4-(2-keto-(3S)-3-(6-(trifluoromethyloxazolin-4-ylamino)tetra Hydrochloropyrrol-1-yl) hexahydropyridine-3-carboxylic acid methyl ester double TFA salt (88 mg) as a white solid. LCMS (1^+11)+ = 480.39.1 H NMR (400 MHz) CD3OD) δ 8.82 (s, 1H, J = 7Hz); 8.20 (s, 1H, J = 7 Hz); 8.78 (s, 1H, J = 7 Hz); 7.91 (d, 1H, J = 7 Hz); 7.30-7.10 (m, 1H); 5.37 (m, 1H); 4.3-4.05 (m, 1H); 3.80-3.00 (m, 9H); 2.60-2.45 (m, 1H); 2.45-2.10 (m, 2H) ; 2.10-1.80 (m, 2H) ; 1.27 (m, 6H). 95318 • 295· 1354664 Example 13⁄4 : (3S,4S)-1-isopropyl-4_((8)_2· germination·3 life (trifluoro Synthesis of methylazoline "4-aminoamino" tetrahydropyrrole-1-yl) hexahydropyridine _3_ retinoic acid methyl ester. Example 15j Step 1: _ 15i step 5 in the synthesis of decylamine, Proportionally increased by 21.5 times. A white solid was obtained as a white solid instead of amber oil. The white solid was stirred in diethyl ether (50 ml) and filtered to yield 7 g of white solid. In the step 5, the indoleamine (3R, 4S)-4-( (3S)-3_(benzyloxycarbonylamino)-2-ketotetrahydropyrrol-1-yl)hexahydropyridine_ι,3-dicarboxylic acid 1-tris-butyl 3-oxime ester the same. The filtrate was extracted and purified on silica gel in 3:1 to 1:1 hexanes / ethyl acetate to give 2.77 g of diastereomers (3S,4S)-4-((3S)-3-( Euylcarbonylamino)-2-ketotetrahydropyrrol-1-yl)hexahydropyridine-1,3-dicarboxylic acid 1-tris-butyl 3-methyl ester. Example 15j Step 2: (3S , 4S)-4-((3S)-3-(indolylcarbonylamino)-2-ketotetrahydropyha-1-yl)hexahydropyridine-1,3·dicarboxylic acid 1-third- Butyl 3-methyl ester is subjected to the reaction sequence described in i5i steps 6-9 to give (3S, 4S) small isopropyl hopper (2-keto-(3S)-3-(6-(trifluoro) Methyl &gt; Kudtton _4_ylamino) tetrahydrogen ratio p small base) hexahydropyridine-3-carboxylic acid methyl ester double TFA salt. LCMS detection (M+H)+ = 480.39. WNMR (400 MHz) (CD3 OD) δ 8.79 (s, 2H); 8.27 (d, 1H, J = 7 Hz; 7.96 (d, 1H, J = 7 Hz); 5.50-5.25 (m, 1H); 4.30- 4.10 (m, 1H) ; 3.74 (s, 3H) ; 3.70-3.50 (m, 3H)

&gt; 3.40-3.20 (m, 1H); 2.80-2.60 (m, 1H); 2.50-2.00 (m, 3H); 1.37 (Sj 6H). Table 15-A The compounds in the table below use the above examples Made by the method. See Table A for a complete description of the header. 95318 •296 - 1354664

Example 15a 15b 15c 15d 15e

Rl R2 change step {R)-nPr . n/a

MS data 464.2 480.2 472.2 440.2 464.43 95318 297- 1354664 15f 15g 15h (S)-nPr

(^)- C02Me 15e steps 480.38 15i

I5e step 1 (see 15c) Ue step 1 (see 15c) n/a &lt;40.41 472·37 480.4 15j (S)- C02Me

n/a 480.4

Table 15-B Table 6-A shows the chemical name series of the special examples. The following example name is ^--- 15a (S)-l-((jR,4S)-l-isopropyl-3- Propyl hexahydro = fluoromethyl &gt; quinoxaline-4-ylamino) tetrahydropyrrole % - lion- 15b 1-pR^SH-isopropyl-3-1,3-propyl hexahydropyridine 4 Fluoromethoxy&gt; quetporin-4-ylamino)tetrahydropyrrol_2_嗣15c 5-(4-phenylphenyl)-N-((S)-l-((3R,4S) 1-isopropyl 3-propyl hexahydropyridin-4-yl)-2-ketotetrahydropyrrol-3-yl)pyran-2-ylcarboxamide 15d N-((S)-1 -((3R,4S)-1-isopropyl-3-propylhexahydroindole _4_yl)_2-indolyltetrahydropyrrol-3-yl)-3-(trifluoromethyl) Benzylamine 15e (8)-1-((3S,4S)-1-isopropyl-3-propylhexahydrop-p-but-4-yl)-3-(6-(trifluoromethyl)&gt; Olanzal-ylamino)tetrazolium p-r-but-2-one 15f (S)-1-((3S,4S)-1-isopropyl-3-propyl acupoint P ratio-4 -yl)-3-(6-(trifluoromethoxy)&gt; quinoxalin-4-ylamino)tetrahydroppirin-2-one 95318 •298- Ϊ354664 I5g N-((S)-1 -((3S,4S)-1-isopropyl-3-propylhexahydropyridin-4-yl)-2-indolyltetrahydropyrrol-3-yl)-3-(trifluoromethyl)benzene Indole 15h ----- 5-(4-chlorophenyl)-N-((S)-l-((3S,4S)-l-isopropyl-3-propylhexahydropyridin-4 -yl)_2·copper-based four gas p pir-3-yl) gnat-2-decarbamide 15i (3 min 43)-1·isopropyl-4-(2-keto-(3S)- 3-(6-(Trifluoromethyl)oxazolin-4-ylamino)tetrahydropyrrole-1-yl)hexahydropyridine_3_monomethyl ester 15j (3S,4S)-1-isopropyl —4-(2·keto-(3S)-3-(6-(trifluoromethyl)thiazolin-4-ylamino)tetrahydropyrrol-1-yl)hexahydropyridine_3·Rebel Methyl ester examples 16a-16c Example 16a: N-((S)-1-((3R,4S)-1-isopropyl-3-(isopropylsulfonylmethyl)hexahydropurine bite-4 Synthesis of -yl)-2-ketotetrahydropyrrole_3_yl)_3_(trifluoromethyl)benzamide 直|^| 16a step 1 : According to the procedure in step 1 of Example 14a, the desired product (3Rj4S&gt;4_(word oxycarbonyl)_3·((sulfonyloxy)indolyl)-hexahydropyridine-1-acid acid second-butyl ester using (3R,4S)-4-(benzyloxy) Carbonyl)_3_(hydroxymethyl)hexahydropyridine + carboxylic acid tert-butyl ester (5.38 g) was obtained as a starting material. The desired product was obtained as a pale yellow oil which was dried in vacuo and used without further purification. According to the procedure in the second step of Example 14a, the desired product is (3R, 4S)-4-(Eloxycarbonyl)&gt;3_((Alanineoxy)methyl)hexahydrate The carboxylic acid third · butyl vinegar (14.76 millimolar) was obtained as the starting material. The desired product (3R, 4S) -4- (anthoxycarbonyl) _3_ (isopropylthiomethyl) six gas blowing small The acid-reducing third-TS is obtained as a yellow oil, which is dried in a vacuum and used without any further purification. According to the procedure in step 6 of Example 14a, the desired product is used (3R, 4S). _4-(Usooxycarbonyl)_3_(isopropylthiomethyl)hexachloroindole precipitation acid (... 14.15 mmol) was obtained as the starting material. The crude product was obtained as a product (95318 1354664). 43)-4-(Hanoxycarbonyl)-3-(isopropylsulfonylmethyl)hexahydroindole-1-carboxylic acid The third-butyl ester was obtained as a white foamy solid. The net yield over three steps was 3.16 g (yield = 47%). (3MS)-4-(indolylcarbonyl)·3-(isopropylsulfonylmethyl)hexahydropyridine-1·carboxylic acid 3rd-butyr (3 15g) and pd/c(〇 A mixture of 6 g) in 2 mL of EtOAc was stirred at room temperature under stirring. After stirring for 24 hours, the reaction was filtered through celite and concentrated to a pale brown oil. It is assumed to be a quantitative yield. The desired product (3R, 4S)_4_amino-3-(isopropylsulfonylmethyl)hexahydropyridine-1-carboxylic acid tert-butyl ester was used without any further purification. J: Example 16a, step 5: According to the procedure in Step 8 of Example 14a, the desired product (3R, 4S)-4-((S)-2-(- yloxycarbonyl)·4·(methylthio)butane Amino)_3·(isopropylsulfonylmethyl)hexahydropyridine-1-carboxylic acid tert-butyl ester (3r&gt;4S)_4_amino group _3•(isopropyl benzyl group Base) hexahydropyridine small carboxylic acid tert-butyl ester as starting material (6.929 mmol), obtained as "glassy" solid (3.46 g, yield = 85%). Re-scraping 16a step 6: _ According to the procedure in Step 9 of Example 14a, the desired product (3R,4S)-4-((S)-3-(indolyloxycarbonyl)-2-ketotetrahydropyrrole·ι·yl)_3_(isopropyl (3R,4S)_4_((S)_2(benzyloxycarbonyl)-4-(methylthio)butanamine) is used as the butyl sulfonylmethyl) hexahydropyridine-1-carboxylic acid tert-butyl ester. 3-(Isopropylsulfonylmethyl)hexahydropyridine-1-teric acid tri-butyl ester (3.46 g, 5.9 mmol), obtained as a white crystalline solid (1.92 g, yield = 60%)岂_Example 16atA!L will be (3R,4S)-4-((5)-3-(benzyloxycarbonyl)-2-onetetraapyrrolidin-1-yl)-3-(isopropylsulfonyl) Methyl) hexahydropyridine 丨 叛 · tartrate third butyl butyl ester (〇7g), a mixture of Pd/C (0_14g) in MeOH (20 mL), EtOAc EtOAc EtOAc EtOAc. 300· 1354664 Concentrate it and dry in vacuo to give the desired product (3R^s)_4_((s)-3-amino-2-ketotetrahydropyrroleyl) winter (isopropylsulfonate) Mercaptomethyl) hexahydropyridine-1-tert-acid third-butyl ester (assumed to be a quantitative yield), is a transparent &quot;glassy&quot; solid. No further purification was carried out using this material. 16a. Step: Step 8: According to the procedure in Step 8 of Example 14a, the desired product (3IMS)-3-(isopropylsulfonylhydrazino)_4_((s)_2-keto_3 (3 ( Trifluoromethyl)benzamide amino)tetrahydropyrrole 1 -yl)hexahydropyridine small carboxylic acid tert-butyl ester using (3R,4S)-4-((S)-3-amino- 2-mercaptotetrahydropyrrole small)·3·(isopropylsulfonylmethyl)hexahydropyridine-1-carboxylic acid tert-butyl ester (1.3 mmol) and 3-(trifluoromethyl) Benzoic acid (0.26 g, 1.365 mmol) was used as the starting material, obtained as a reddish foamy solid (0.688 g. =92%). Example 16a Step 9: Adding trifluoroacetic acid (0.92 ml, ιι·9 mmol) to the month 'J, making (3R, 4S)-3-(isopropyl succinylmethyl) )_4_((s)_2_g同基_3_(3_(trifluoromethyl) fluorenylamino) tetrahydro-p-ha_1_yl) hexahydro hydrazine bite small acidated third _ vinegar sample 0,688 g) was dissolved in CH2C12 (10 mL). After 4 hours, the reaction was taken up in saturated NaHC03 to extract with CH2C12. The organic layer was washed with brine and dried (MgSO.sub.4). Concentration and drying in vacuo to give the desired product N-((S)-l-((3MS)-3_(isopropylsulfonylmethyl)hexahydropyridin-4-yl)-2-one Tetrahydrop-rho-3-yl)-3-(trifluoromethyl)benzamide (〇482 g, yield = 85%). MS found: (m+H)+ = 476.31 Example 16a Step 10: A before adding acetone (0.38 ml, 0.525 mmol) before making 'N-((3)-l-((3R,4S)-3-( Isopropyl hydrazinyl) hexahydrop to bite _4·yl)_2· fluorenyltetrahydropyrrole-3·yl)-3-(trifluoromethyl)benzamide sample (〇〇 5 g) was dissolved in it in dichloroethane (3 ml). After stirring at room temperature for 1 hour, triethylsulfonium 95318 -301 · 1354664 sodium borohydride (0.445 g &lt; 0.21 mmol) was added to the mixture. When quenching with saturated NaHC03 &lt; 吏 reaction, stirring was continued for 2 hours. Do not liquid between Yu Yu· and water. The organic layer was washed with brine and dried (Natal 4). Filtration, concentration, and chromatography. The desired product N•((8)_H(3R,4SH_isopropyl-3-(isopropylsulfonyl yl)hexahydropyridyl)·2•ketotetrahydropyrroleyl)_3_(trifluoromethyl) Benzobenzamide (0.0086 g, yield = 16%) θ octagonal white solid obtained. MS found: (μ+Η)+= 518.2 Refer to the table The compounds in the table below were prepared using the method exemplified above to give a complete description of the header. 95318 Example 16a 16b 16c

Steps to change n/a MS data 518, 2 16a Step l〇 16a Step 10 5〇4.33 -302- 1354664

Table 16-B The list of chemical names for the specific examples shown in Table 16-A is given below. -Example~~ ----- Name 16a, 1^((8)-1-((31^48)-1-isopropyl-3-(isopropyl succinylmethyl) π hydroacridine -4-yl)-2-ketotetrahydroindolyl_3_yl)·3·(trifluoromethyl)benzamide-1b, N^SH.MS)isoisobutyl-3-(iso) ^^ylmethyl) octapeptide p than -4-yl)-2-ketotetrahydropp ratio p·3·yl) winter (trifluoromethyl) benzoguanamine- 16c &lt;i-( (S)-l-((3R,4S)-l-ethyl-3-(isopropyl succinylmethyl) π hydrogen p to 凌-4-yl)-2-steel-based tetrahydro-p-Bilo _3_yl)_3_(trifluoromethyl)benzamide - Example 17a-17b Example 17a: 1-((18,2 Min 4 and -4-(isopropyl(ethyl)amino))_2 Synthesis of (isopropylsulfonylmethyl)cyclohexyl)-4-(3-(trifluoromethyl)phenyl)-5,6-dihydropyridine-2(1Η)-one, preferably 17a, step 1 : a solution of 3-trifluoromethylbenzaldehyde (6.7 ml) in tetrahydrofuran (40 ml), which was stirred on ice-bath, and a solution of vinylmagnesium bromide in tetrahydrofuran (1.0 Μ, 60 ml) Drip treatment for 25 minutes" The mixture was stirred for 2 hours while slowly warming to room temperature and then treated with a saturated aqueous solution of ammonium chloride. The mixture is extracted, and the organic extract is washed with water and brine, then dried over sodium sulfate, and concentrated under vacuum. Purified by flash column chromatography, eluted with 10% ethyl acetate in hexane to provide 1 -(3-Trifluoromethylphenyl)propan-2-en-1-ol (2.33 g) as a colorless oil. MS found: (M+H-H20)+=185.19. Example 17a Step 2: Card A solution of 1-(3-trifluoromethylphenyl)prop-2-en-1-ol (1.0 g) in acetone (10 ml) was applied to an ice bath and was taken with a jones reagent (1.4 m 95318 - 303·1354664 liters). After 30 minutes, add isopropanol to discharge yellow orange, and filter the mixture through crushed soil. The filtrate was concentrated under vacuum and the residue was purified by flash column chromatography. Dissolved in 1% by weight of ethyl acetate in hexane to provide 1-(3-trifluoromethylphenyl)propenone (672 mg) as a colorless liquid. 1H-NMR (CDC13): 58.21 (s) 1H ), 8.15 (d, J = 7.6 Hz, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.66 (t, J = 7.6 Hz, 1H), 7.18 (dd, J = 17.3, 10.4 Hz, 1H ), 6.51 (dd, J = 17.3, 1.5 Hz, 1H) 6.04 (dd, J = 10.4, 1.5 Hz, 1H) Example 17a Free House 3: (lR,3R,4S)-4-amino-3-(isopropylsulfonylmethyl)cyclohexylaminocarboxylic acid tert-butyl ester (1·〇9 g, Refer to Procedure i〇a Step 3) Stir in a solution of methanol (10 mL) on ice-bath, and 丨-(3-trifluoromethylphenyl)propanium copper (655 mg) in decyl alcohol (5 ml) The solution in the solution was treated dropwise for $ minutes. The mixture was stirred at room temperature for 4.75 hours and then concentrated under vacuum. Purification by flash column chromatography, eluted with 75% ethyl acetate in hexane to provide (lIUR'4SH4-[3-keto-3-(3-trifluoromethylphenyl)propylamino]_3· (propane·2·j-methylmethyl)cyclohexyl]-amine methyl acid, third butyl ester (1. gram), as a white glassy solid. MS found: (Μ+Η)+=535.3. _Example 17a Step 4: A suspension of sodium hydride (60%, 82 mg) in tetrahydrocethane (25 ml) was stirred on an ice bath and dimethyl-phosphonic acid-acetic acid- Ding vinegar (0.37 liters) was treated dropwise for 5 minutes. The mixture was dropped at room temperature for 15 minutes, then cooled on ice, and (1R, 3R, 4S)-[4-[3-ketotrifluoro -Methylphenyl)propylamino]-3-(propane-2-sulfonylmethyl)-cyclohexyl] aminic acid tert-butyl ester (500 mg) in tetrahydrofuran (2.5 mL) . The resulting mixture was stirred at room temperature for 2.5 hours, then treated with an aqueous solution with saturated gasification. The mixture was extracted with ethyl acetate and the organic phase was dried with &lt;RTI ID=0.0&gt;&gt; Rapid column chromatography, eluting with 50% ethyl acetate in hexane to provide 5-[(1艮2min43)-4-tris-butoxypyranyl-2·(propane-2- Sulfhydryl decyl)-cyclohexylamino]-3-(3-trifluoromethylphenyl)penta-2- decanoic acid E-isomer (300 mg) as a white glassy solid . MS found: (M+H)+ = 633.37. Further dissociation provides the z isomer of the same compound (232 mg) as a white glassy solid. Example 17a Step 5: 5-[(lR,2R,4S)-4-T-butoxycarbonylamino) 2_(propane-2-sulfonylmethyl)-cyclohexylamino]-3-(3-trifluoromethylphenyl)pent-2-enoic acid, third butyl ester, E isomer (293 mg The solution was taken up in dichloromethane (3 mL)EtOAcEtOAc After 2 hours, the mixture was concentrated in vacuo to afford 5-[(l,,,,,,,,,,,,,,,,,,,,, 3-E-trifluoromethylphenyl)pent-2-enoic acid bis-trifluoroacetate E isomer (387 mg) as a white glassy powder. MS found: (M+H)+= 477.35. Example 17a Step 6: None 5-[(1艮2艮43)-4-amino-2-(propan-2-sulfonylmethyl)cyclohexane a solution of the E isomer of amido]-3-(3-trifluoromethylphenyl)pent-2-enoate in bis-trifluoroacetate (387 mg) in dioxane (3 mL). Treatment with diisopropylethylamine (0.323 mL), 4-(N,N-dimethylamino)pyridine (57 mg) and TBTU (164 mg). The mixture was stirred at room temperature for 4.75 hours, then washed with a saturated aqueous solution of sodium hydrogen carbonate, water and brine and dried over sodium sulfate. The solution was concentrated under vacuum and the residue was purified by reverse phase HPLC to afford l-[(l,,,,,,,,,,,,,,,,,,,, Cyclohexyl]·4_(3-dilacylmethylphenyl)-5,6-dihydro-indole-ί» is a white powder as a bit of 2-pyridyl trifluoroacetate (143 mg). MS found: (Μ+Η)+=459.35· 95318 -305- 1354664 Example 17a Step 7: From 1-[(1艮2艮43)-4-amino-2-(propane-2-sulfonate) Free radical base (94 mg) of mercaptomethyl)cyclohexyl]-4-(3-trifluoro-methylphenyl)-5,6,dihydro-1H-pyridine-2-one trifluoroacetate This was treated with a solution of acetone (0.045 mL) &lt;RTI ID=0.0&gt;&gt; The mixture was stirred at room temperature for 4.5 hours and then concentrated under actual conditions. The residue is subjected to liquid separation between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution and the organic phase is dehydrated and dried with sodium sulfate, and the condensed product provides 1-[(1,211,48)-4-iso Propylamino·2_(propane-2-sulfonylmethyl)annyl]trifluoromethylphenyl)-5,6-dihydro-1indole-pyridin-2-one (103 mg) 'for white glass State solid. MS found: (m+H)+= 501.37. I, step 17a, Ali--isopropylamino-2-(propan-2-yl)methylhexyl]- 4-(3-trifluoromethyl) A solution of phenyl phenyl) _5,6-dihydro-m-pyridin-2-one (43 cc) in MeOH (1 mL). After 35 minutes, sodium cyanoborohydride (8 mg) was added, and the mixture was stirred at room temperature for 22.5 hours. The mixture was concentrated and partitioned between water and ethyl acetate. The aqueous phase was extracted with additional ethyl acetate and the combined organics were dried with sodium sulfate and concentrated in vacuo to afford 1 ((lS,2R,4R)-4 -(isopropyl(ethyl)amine 2·(isopropylsulfonylmethyl)cyclohexyl) 4 (3 (-fluoromethyl)phenyl)-5,6-dihydroindanone (41 mg) as a white glassy solid. MS measured value: (m + H) + = 529.39.

Table 17-A The compounds in the table below were prepared using the methods exemplified above. See Table 1-A for a complete description of the header. 95318 - 306- 1354664

CF, i-Pr(Me)N 17a Step 8 MS data 529.4 515.4 Example 17a 17b

Table 17-B The chemical name series of the specific examples shown in Table 17-A is shown below in the example name 17a l-((lS,2R,4R)-4-(isopropyl(ethyl)amino)_2_(different Propylsulfomethyl)cyclohexyl)-4-(3-(trifluoromethyl)phenyl&gt;5,6_di\2--2(1H)-oxime with 17b l-((lS,2R, 4R)-4-(isopropyl(methyl)amino)_2_(isopropylsulfonylmethyl)cyclohexyl)-4-(3-(trifluoromethyl)phenyl-2(1H)- Ketone Examples 18a and 18b Example 18a: (S)-l-((lR,2S,4S)-4-(isopropyl(methyl)amino)_2-methoxycyclohexyl)-3-(6- Synthesis of (difluoromethyl olyl-4-ylamino)tetrahydrop-bilo_2_嗣 complex _ Example 18a step 1 : racemic 4-cis-(benzyloxy)·2-anti Stirring a solution of methoxycyclohexanol (3-24 g, see / C&amp;m. 1990, 55, 4265) with triethylamine (5.73 ml) in dioxane (35 mL) on ice bath And the mixture was treated with a gasification of formazan for about 1 minute. The mixture was stirred on an ice bath for 2 hours, and then treated with a saturated aqueous solution of NI^Cl. The liquid layer was separated and the organic layer was saturated with NaHC 3 aqueous solution. Then wash with salt water and then dehydrate with Ν々3〇4 Dry and concentrated under vacuum 'provides the use of racemic methacrylate 4_cis _ (; oxy 95318 -307-1546664 trans-methoxycyclohexyl ester, orange gum (4.36 g), used Without further purification. MS found: (M+H)+=315.1. f. Example 18a Step 2: Cyclos-methanesulfonic acid 4-cis-(yanooxy)_2_trans-methoxyl ring A solution of hexyl ester (1 gram) in dimethyl hydrazine (12 ml), treated with sodium azide (1_03 g) and heated at 60 ° C for 16 hours and then for 4 5 days. Cool to room temperature, dilute with ethyl acetate, wash with water five times, and wash once with brine. Dilute the solution with Na2SO4 and concentrate under vacuum for 'k for racemic 1-((4- Trans-azido-_3_trans-methoxy-cyclohexyloxy)indenyl)benzene was a brown oil (756 mg) which was used without further purification. MS found: (M+Na)+ =284.5. Example 18a, step 3: racemic 1-((4-trans-azido-3-trans-indolyloxycyclohexyloxy)methyl)benzene (750 mg) in ethanol ( 20 ml) solution to Pearlman's catalyst (20% Pd) (OH) 2 / charcoal, 150 mg) was treated and stirred under a hydrogen atmosphere (maintained by a cylinder filled with hydrogen) for 2.5 hours. The mixture was filtered through pulverized soil and the solid was washed with ethanol. Concentration under vacuum to provide racemic 4-trans-(benzyloxy)-2-cis-methoxycyclohexylamine as an oil (678 mg). : (M+H)+= 236.1. Example 1 Shame Step 4: _ Racemic 4-trans-(decyloxy)-2-cis-methoxycyclohexylamine (675 mg) with (S)-2-(Tertiary-butoxycarbonyl)-4-(methylthio)butanoic acid (787 mg) in a die-cast (153⁄4 L) solution as diisopropylethylamine ( I liters) with TBTU (1,01 g). The mixture was stirred at room temperature for 35 hours and then diluted with dichloromethane. The mixture was washed with a 1.0 M aqueous solution of MH.sub.3, saturated aqueous NaH.sub.3, and water, then dried over Na.sub.2.sub.4, and concentrated under EtOAc. The residue was purified by flash column chromatography on silica gel, eluted with 6:4 v/v hexane·acetic acid ethyl acetate to provide (3) small ((13, 2 s 4 _4 (yloxy)·2_ Methoxycyclohexylamino)-4-(methylthio) ketobutylbutan-2-ylaminocarboxylic acid third-butyl vinegar and (3)-1-((1民23'411)-4- (Benzyloxy) 2 - methoxycyclohexylamino) 4 - (methylthio) 1 ketobutan-2-ylaminocarbamate - butyl vinegar mixture, viscous white solid (893 mg) MS found: (m+H)+ = 467.4. Example 5: (S)-l-((lS,2R,4S)-4-(benzyloxy)- 2-methoxy-hydroxyhexylamino)_4·(methylthio)_1_indole-butyryl-2-ylaminocarbamic acid tert-butyl ester with (S)-l-((lR, 2S, 4R) 4-((yloxy)-2-methoxycyclohexylamino)·4_(mixture of decylthio-ketobutan-2-ylaminocarbamic acid tert-butyl ester (87〇 mg) The solution in methylene chloride (2 mL) was taken in EtOAc (EtOAc) (EtOAc) And concentrated under vacuum This was dissolved in dichloromethane and concentrated, and repeated four times to provide (S)_4_((1S,2R,4S)_4_(yloxy)-2-methoxycyclohexylamino)_3_ (third -butoxycarbonylamino)butanylbutane-1-dimethyliodide and (8)·4·((1κ,28,4Κ)_4_(yloxy)_2•methoxycyclohexylamino) a mixture of -3-(tris-butoxycarbonylamino)- 4 ketobutane dimethyl sulfonium iodide as a pale yellow powder (1.019 g). MS found: (M-Me2S) + = 419.4. iU8a 歩 Hui will be obtained from Example 18a Step 5 of (8) _4_((1S, 2R 4SM•(Yooxy)-2-methoxycyclohexylamino)_3-(T-butoxycarbonylamino) _4_ketobutane-1-dimethyliodonium iodide with (S)-4-((lR,2S,4RM-(hydroxyl)_2-methoxycyclohexylamino)-3-( A mixture of tris-butoxycarbonylamino)-4_g-butyryl-7-dimethyliodonium iodide (1.013 g) in tetrahydrofuran (10 ml) was stirred on an ice bath and taken in NaH 60% of the oil, 266 mg). If it is minute, move back 95318 • 309- 1354664 except for the bath' and stir the mixture at room temperature. After 22 hours, the mixture is Dilute with ethyl acetate. Separate the liquid layer and extract the aqueous layer three times with ethyl acetate. The combined organic layer is dried with N^SO4, and concentrated under vacuum to make the residue on the silica gel. Purify by chromatography and elute with 35: 65 v/v hexane-ethyl acetate to provide (S)-l-((lS,2R,4S)-4-(yloxy), 2-methoxycyclohexyl -2-ketotetrahydropyrrole_3_ylaminocarbamic acid tert-butyl ester with (S)-l-((lR'2S,4R)-4-(decyloxy)_2-methoxy ring A mixture of hexyl)_2-ketotetrahydropyrrole-3-ylamino-tris-butyl ester as a white glassy foam (386 mg). MS found: (m + H) + = 419.4. i. Example 18a Step 7: Following the procedure of Example 18, Step 3, such that (S)-l-((lS, 2R, 4S)- 4-(Benzyloxy)-2-methoxycyclohexyl>2·decyltetrahydropyrrol-3-ylcarbamic acid tert-butyl ester and (8)benzyloxy)_2·methoxycyclohexyl) a mixture of 2-ketotetrahydropyrrole-3-ylaminocarboxylic acid tert-butyl ester (374 g), converted into (3)^hydroxy-2_methoxycyclohexyl)-2-one in two batches Tetrahydropyrrole·3_ylaminocarbamic acid tert-butyl ester and (S)-l-((lR,2S,4R)-4-hydroxy-2-decyloxycyclohexyl)_2-ketotetrahydropyrrole A mixture of d-butyl butyl carbamate was a white glassy foam (293 mg). MS measured value: (M+H)+=329.2. f Example 18a Step 8: According to the procedure of step 1 of Example 18a, (S)-l-((lS, 2R, 4S)-4 from step i8a step 7 -#Mexyl-2-methoxycyclohexyl)_2-ketotetrahydropyrrol-3-ylcarbamic acid tert-butyl ester with (s)-i-((1R,2S,4R)-4-hydroxyl a mixture of -2-methoxycyclohexyl)-2-one tetrahydropyrrole-3-ylamino decanoic acid tert-butyl ester (165 mg), converted to methanesulfonic acid (iS, 3R, 4S)- 4-((S)-3-(Third-butoxycarbonylamino)-2-one-tetrahydropyrrole_1-yl)_3_methoxycyclohexyl ester with methanesulfonic acid 95318 •310-1354664 ( lWS,4R)-4-((S)-3-(Third-butoxyamino)·2-mercaptotetrahydrop-bilo-ι·基)-3_methoxycyclohexane The mixture was a pale yellow-brown orange glassy foam (198 mg). MS found: (M+H)+ = 407.1. Example 18a Step 9. Following the procedure of Step 2 of Example 18a, methanesulfonic acid (1S,3MS)-4-((S) from Example iga Step 8. -3-(Third-butoxycarbonyl)_2·ketotetrahydropurine-1-yl)-3-methoxycyclohexyl ester with methyl benzoate (1Rj3S4r)4_((s)_3_(third a mixture of -butoxycarbonyl)-2-ketotetrahydropyrrole small)-3-decyloxycyclohexyl ester (193 oz)' converted to (S)-l-((lS, 2R, 4R)- 4-azido-2-methoxycyclohexyl)-2-ketotetradecene piro-3-ylaminocarbamic acid third-butan with (s)_l_((2R, 2s, 4s)_4 · A mixture of a gas-based 2-methyl-n-cyclohexyl)-2-mercaptotetrahydro-u-lo-3-ylaminocarbamic acid tert-butyl vinegar as a solid (H5 mg). MS found: (M+Na)+=376.4. Example 18a Step 10: According to the procedure of Step 3 of Example 18a, (8)-2-((18,211,411)-4-azide from step 9 of the example version. Ratio of tert-butyl ester of benzyl-2-methoxycyclohexyl)_2-ketotetrahydropyrrol-3-ylcarbamate to azide-2-ylcyclohexyl)-2-indenyltetrahydropyran a mixture of 第三·3_ylamino decanoic acid tert-butyl ester (145 mg), converted to (S) small ((1S, 2R, 4R)_4_amino-2 _ methoxycyclohexyl)-2 -keto-tetrahydropyrrole.3-ylaminocarbamic acid tert-butyl ester with (S)-l-((lR,2S,4S)-4-amino-2-methoxycyclohexyl)_2-one A mixture of tetrahydropyrrole. &lt;RTI ID=0.0&gt;&gt;&gt;&gt; MS found: (M+H)+= 328 2. (3)·丨-(10) precipitated from Example 18a, step 10), carbamido-2-methoxycyclohexyl)_2-g, iso-tetrahydropyrrole _3_ylaminocarbamic acid tert-butyl ester and (S)-l-((lR,2S,4S)-4-amino-2-indolylcyclohexyl)-2-ketotetrahydropyrrole- a mixture of 3-triaminocarbamic acid tert-butyl ester (145 mg) in a solution of -dichloroethane 95318 •311 - 1354664 (2 ml), followed by acetone (90 μl) of acetic acid (117 μm)升) and diethyl ethoxylated shed hydrogenated (348 mg). The mixture was stirred at room temperature for 5 hours, then treated with 37% aqueous formaldehyde (153 μL) and stirred at room temperature. After 17 hours, the mixture was treated with saturated aqueous NaHCO.sub.3 and stirred for 10 min and extracted with ethyl acetate five times. The combined organic layers were dried over NazSO4 and concentrated. The residue was dissolved in dichloromethane to filter <RTI ID=0.0> -2-ketotetrahydropyrrole-3-ylaminocarbamic acid tert-butyl ester with (3)-K(lR,2S,4S)-4-(isopropyl(indenyl)amino)2-a A crude mixture of the oxycyclohexyl)-2-ketotetrahydropyrrole-3-ylaminocarbamic acid tert-butyl ester (67 mg) was used without further purification. MS found: (M+H)+= 384.5. Example 18a Step 12: (S)-l-((lS,2R,4R)-4-(isopropyl) Amino)-2-methoxycyclohexyl)_2-ketotetrahydropyrrolylcarbamic acid tert-butyl ester with (8) small ((1R,2S,4S)_4_(isopropyl(methyl)amine a solution of a mixture of the third &lt;2-decyloxycyclohexyl)-2-ketotetrahydropyrrole-3-ylaminocarboxylic acid tri-butyl ester (67 mg) in dichloromethane (2 ml) Treated with fluoroacetic acid (2 ml), allowed to stand at room temperature for a few hours, then concentrated under vacuum, dissolved in toluene and concentrated in vacuo again. Providing (3) amino-isopropyl-(meth)amino)-2-methoxycyclohexyl)tetrahydro-p-bi-2-one bis-trifluoroacetate and (5)-3.amino-l a mixture of -((lR,2S,4S)-4-(isopropyl(methyl)amino>&gt;2-methoxycyclohexyl)tetrahydropyrrol-2-one bis-trifluoroacetate Powdered glass material (94 mg), used without further purification. MS found: +h) + = 95318 -312 - 1354664 284.3 Example 1 package_Step 13 \(S)-3·Amino-l-((lS,2R'4R)-4-(isopropyl(methyl)amino) will be obtained from Example 18a, Step 12. _2-methoxycyclohexyl)tetrahydropyrrole 2-one bis-trifluoroacetate and (8) amine group small ((1 284 phor 4 (isopropyl)methyl) methoxy) a mixture of cyclohexyl)tetrahydropbibromo-2-ketobis-trifluoroacetate (94 mg), 4-chloro-6-trifluoromethyloxazoline (81 mg), triethylamine (97) A solution of microliters and ethanol (1 ml) was heated under reflux for 25 hours, then cooled to room temperature and concentrated under vacuum. The residue was purified by reverse phase j^PLC. The substance in the first elution of the product spike provides the compound designated as the title structure isopropyl(methyl)amino)-2-methoxyJ-hexyl)-3-(6-(trifluoromethyl) ) tiqualine _4-ylamino) tetrahydropyrrol-2-one bis-trifluoroacetate as a white powder (15 mg). MS found: (m+H)+= 480.4. Example 181?: (8)-1-((18,2,4拗-4-(isopropyl)methyl)amino) Synthesis of cyclohexyl)-3-(6-(trifluoromethyl)quinazolin-4-ylamino)tetrahydropyrrole-2-one Purified by reverse phase HPLC of Step 13 of Example 18a, by freeze drying The substance in the second dissociation of the two product spikes, providing the compound, designated as the title structure of bis-trifluoroacetate, as a white powder (9 mg) ^ ]^8 found: (M+H) + = 480.4. Table 18-+ The compounds in the table below were prepared using the methods exemplified above. See Table 1-A for a complete description of the header. 95318 •313- 丄354664

The chemical name series of the specific examples shown in Table 18-A is shown below in the example name 18a isopropyl (methyl}amino peak oxiranyl cyclohexyl)-3-(6-(trifluoromethyl) pyridine Benzyl-4-ylamino)tetrahydropyrrol_?_cluster 18b^)-1-((18,2's 411)-4-(isopropyl(methyl)amino)_2-methoxy ring Hexyl)-3-(6-(trifluoromethyl)pyrazolylamino)tetrahydropyrrole-2-one is a compound of formula I which is known to be known by the art. Modulators of cytokine receptor activity. In this paragraph, we describe these speculations and give references to their literature. By in vivo detection of MCP-1 antagonism, the compound of the expected formula It can be used to treat human diseases associated with chemical cytokines and their cognate. In these tests, active sputum is the compound exhibiting iC5 30 30 but V [or lower] when measured in a specific assay. Concentration. 9531$ -314- 1354664 Antagonism of MCP-1 binding to human PBMC (Yoshimura et al., /. /wwwimo/.1990, /45,292) The compounds of the present invention bind to humans as described herein. PBMC (human peripheral blood mononuclear cells) is active in antagonism. Microporous filter plate (#MABVN1250) at room temperature with 100 μl of binding buffer (0.5% bovine serum albumin, 20 mM HEPES buffer) And 5 mM magnesium chloride in RPMI 1640 medium) for thirty minutes. To measure binding, 50 μl of binding buffer with or without a known concentration of compound, and 50 μl of 125-1 labeled human MCP-1 (To obtain a final concentration of 150 pM radioligand) and 50 μl of binding buffer containing 5 x 105 cells. Cells for such binding assays may include human peripheral blood samples isolated by Ficoll-Hypaque gradient centrifugation Nuclear cells, human single cells (Weiner et al, /mmwwo/. 1980, 3 (5,89) or THP-1 cells expressing endogenous receptors. Mixing compounds, cells and radioligands at room temperature The plates were incubated for thirty minutes. The plates were placed on a vacuum manifold, vacuum was applied, and the plates were washed three times with a binding buffer containing 0.5 M NaCl. The edges of the plastic were removed from the plates, the plates were air dried, the wells were perforated and counted. Percentage of inhibition , using the total count obtained in the absence of any competing compound, and the background binding measured by adding ΙΟΟηΜ MCP-1 instead of the test compound. The antagonism of MCP-1-induced calcium influx (Sullivan et al, Methods Mol. Biol. 114, 125-133 (1999)) The compounds of the invention are active in the antagonism of the MCP-1-induced calcium influx assay described herein. Calcium movement was measured using the fluorescent Ca2+ indicator dye Fluo-3. The cells were incubated at 95318 -315 - 1354664 8 x 105 cells/ml with 0.1% bovine serum albumin, 20 mM HEPES buffer, 5 mM glucose, 1% fetal bovine serum, 4 mM 1 Fluo-3 AM and 2.5 mM carboxybenzenesulfonamide in phosphate buffered saline, incubated at 37 ° C for 60 minutes. Cells for such #5 detection may include human single cells, as described by Weiner et al, J. Immunol. Methods, 36, 89-97 (1980), or exhibit endogenous CCR2 receptors. Cell lines, such as THP-1 and single Mac-6. These cells were then washed three times in phosphate buffered saline containing 0.1% bovine serum albumin, 20 mM HEPES, 5 mM glucose, and 2.5 mM carboxybenzenesulfonamide. The cells were resuspended in phosphate buffered saline containing 0.5% bovine serum albumin, 20 mM HEPES and 2.5 mM carboxybenzenesulfonamide at a final concentration of 2-4 x 106 cells/ml. The cells were covered in 96-well black wall microplates (100 μL/well) and the plates were centrifuged at 200 X for 5 minutes. Compounds of different concentrations were added to the well (50 μl/well), and after 5 minutes, 50 μl/well of MCP-1 was added to obtain a final concentration of 10 nM. Use a fluorescent imaging plate reader to detect calcium movement. The cell monolayer was stimulated with an argon laser (488 nM) and the cell-bound fluorescence was measured for 3 minutes (per second for the first 90 seconds and every 10 seconds for the last 90 seconds). The data is generated in arbitrary fluorescent units, and the fluorescence changes for each well are measured as the highest-lowest difference. Compound-dependent inhibition was calculated relative to the response of MCP-1 alone. Antagonism of human PBMC chemotaxis induced by MCP-1- (Bacon et al., price &quot;_ «/· PAamaco/· 1988, 95, 966) The compounds of the invention are caused by MCP-1- described herein Human PBMC is active in the antagonism of the chemotaxis assay. Neuroprobe MBA96-96-well-to-chemical chamber, Polyfiltronics MPC 96 well plate and 95318 -316-1354664

Neuroprobe does not contain polyethylidene tetrahydro-&gt; pirone-polycarbonate PFD5 8-micron filter and is warmed in a 37 ° C incubator. Human peripheral blood mononuclear cells (PBMC) (Boyum et al., Scand. J. Clin. Lab Invest. Suppl. 1968, 97, 31) that were isolated by standard polysucrose density separation method at 1 X 107 c / ml Next, suspend in DMEM and warm at 37 °C. The 60 nM solution of human MCP-1 was also warmed at 37 °C. The dilution of the test compound is made up to 2x of the desired concentration in DMEM. The PBMC suspension was mixed with a 60 nm MCP-1 solution in i:1 in a polypropylene tube with pre-warmed DMEM with or without dilution of the test compound. These mixtures were allowed to warm in a 37 ° C tube heater. To initiate the assay, the MCP-1 / compound mixture was added to a well of a Polyfiltronics MPC 96 well plate that had been placed in the bottom of the Neuroprobe cheming chamber. Each well has an approximate volume of 400 microliters and should have a positive meniscus after dispensing. An 8 micron filter was gently placed on top of the 96 well plate, the rubber gasket was attached to the bottom of the upper chamber, and the chamber was assembled. A 200 microliter volume of cell suspension/compound mixture was added to the appropriate well in the upper chamber. The upper chamber was covered with a plate stopper and the assembled unit was placed in a 37 ° C incubator for 45 minutes. After incubation, the plate stopper was removed and all residual cell suspension was aspirated. Disassemble the chamber and gently remove the filter. While maintaining the crucible at a 90 degree angle, use a gentle flow of phosphate buffered saline to wash away the unmigrated cells and wipe the top of the filter with the tip of the rubber scraper. This wash was repeated twice more. The filter was allowed to air dry and then completely submerged in Wright Geimsa stain for 45 seconds. Then, the second filter was washed for 15 seconds by soaking in distilled water for 7 minutes, followed by water in the freshly distilled water. Allow the filter to air dry again. The submerged fine 95318 •317-1456664 cells on the filter were quantified by visual microscopy. Mammalian Chemical Fine &amp; Active Factor is provided by the system for the function of immune cells in animals (such as humans). A compound that acts as a suppressor receptor, and is particularly useful for modulating immune details to provide a therapeutic effect. Therefore, the present invention can be used for the prevention and/or treatment of a wide variety of compounds for inflammatory, infectious and immunomodulatory disorders, including asthma and allergic diseases, by pathogenic microorganisms (which are customized) Including viruses) (iv), as well as autoimmune pathological diseases such as rheumatoid arthritis and atheroma hardening. For example, a compound of the invention which inhibits the mammalian chemical cytokine receptor (e.g., human chemical cytokine receptor) - or a plurality of functions, can be administered to inhibit (i.e., reduce or prevent) inflammation or infectious disease. . As a result, more than one inflammatory process, such as leukocyte migration, adhesion, chemokinet, cytosolic efflux (eg, cytosolic efflux of enzymes, histamine) or inflammatory mediator release, is inhibited. Similarly, a compound of the invention that promotes one or more functions of a mammalian chemical cytokine receptor (eg, human chemical cytokine), when administered to stimulate (inducing or potentiate) an immune or inflammatory response, such as a white blood cell tour Exudation, adhesion, 'chemotactic' cleavage efflux (such as enzyme, histamine cleavage efflux) or inflammatory mediator release, will cause favorable stimulation of the inflammatory process. For example, you can add 啥 red blood cells to fight parasitic infections. In addition, the treatment of the aforementioned inflammatory, allergic and autoimmune diseases may also be intended for the compounds of the present invention, if we intend to transmit a sufficient amount of a compound to cause a receptor via internalization of the chemical cytokine receptor. Loss of expression on the cell, or transmission of the compound in a manner that causes the cell to migrate in the wrong direction, promotes one or more functions of the mammalian cytokine receptor. In addition to primates such as humans, a variety of other mammals can be treated in accordance with the methods of the present invention. For example, mammals, including but not limited to cows, sheep, goats, horses, dogs, cats, guinea pigs, rats, or other cattle, sheep, horses, dogs, felines, rodents or mouse species, can be treated . However, this method can also be implemented on other species, such as bird species. The patient treated in the above method is a male or female mammal in which the activity of the chemical cytokine receptor is desired to be regulated. As used herein, "modulation" is intended to encompass antagonism, partial antagonism, and/or partial motility. CCR5 Binding and Functional Detection of Cell Derivation and Cell Culture: A stable expression of endogenous CC chemical cytokine receptor 5 (CCR5) in the ΗΤ1080 cell pool's system using methods outlined by Harrington, Sherf and Rundlett (see US Patent US 6,361 972 and us 6 41〇266) development. Repeated flow cytometry was used to isolate the highest performing asexual reproduction line followed by secondary asexual reproduction. Then, these cells were cultured in a 6 well culture dish at 3 x 1〇5 cells/well, and DNA vector containing the chimeric HA-tagged G protein Gqi5 (Molecular Device Company; at 15 μl 5 micrograms of linearized vector DNA from Fermentes' Ex-Gen was used for transfer infection) transfection. Two days after the transfer of infection, the wells were combined and covered into a P100 plate. Seven days after the cover, colonies were selected, expanded, and Gqi5 content was analyzed by Western blotting. "Select a cloned line with high expression of Gqi5 (derived from metastatic infection) and CCR5 (endogenous) (referred to as 3559.1. 6) and used in the experiments below. HT1080 cells (clonal reproduction line 3559.1.6) were made at 37. (: and 5% 95318 -319- 1354664 C〇2 under 'in the humid gas layer, to supplement 1%% dialysis bovine fetal serum, 2% penicillin / streptomycin / glutamine and 500 μg / ml of M. BB (final concentration) of α-ΜΕΜ culture. Preparation: 细胞 Cell pellet containing 1×108 HT1080 cells (clonal reproduction line 3559.1.6) was resuspended in 5 ml of ice-cold cell membrane preparation buffer (50 mM HEPES, 5 mM MgCl2, 1 mM CaCl 2 ), and homogenized on ice on a p〇丨ytron homogenizer for 20 seconds on ice. The homogenate was diluted with another 25 ml of cell membrane preparation buffer and centrifuged for 12 minutes. (48,000 X g at 4 ° C.) Resuspend the cell pellet in 5 ml of cell membrane preparation buffer before rehomogenization as described above. Dilute the homogenate in 5 ml cell membrane preparation buffer and test CCR5 Protein concentration. The test was performed: the homogenate was obtained from the above cell membrane preparation, and combined with a buffer (50 mM HEPES, 5 mM MgCl2, 1 mM CaCl2, 0.1% BSA; a complete protease inhibition was added before the assay). Dilute in tablets to achieve a final protein concentration of 10 μg/well (Solid white 96-well plate, available from Coming). This cell membrane preparation was mixed with WGA-SPA beads (Amerhsam; pre-soaked in binding buffer) to obtain a concentration of 200 μg/well. Then, the cell membrane/SPA Bead mixture (1 〇〇 microliter/well), added to a plate that has been pre-spotted with 2 μl of DMSO containing different concentrations of the analyte to be tested (pure DMSO for the negative control group with 'different concentrations of this invention example) For the object to be tested; 5〇〇MIP-1 /3 as the positive control group. By adding 5〇微升召 (PerkinBlmer; the substance is diluted in the binding buffer, so that the addition of 5〇 microliter/well will get the last The binding assay was initiated at a concentration of 0.1 nM [I25I]-MIP-1 /5. Prior to counting on the Packard TopCount, the plates were sealed and allowed to stand at room 95318 • 320-1354664 for 4-6 hours. The percentage of the combination of objects to be tested is calculated using negative and positive controls to define the window of each experiment. Fluorescence imaging plate reader (FLIPR)-based functional assay: HT1080 cells (clonal reproduction line 355916) ) over 10,000 cells/well (30 microliters) Cover in a 384-well plate (black/clear bottom Biocoat PDL, Beckton Dickinson) and add 30 μl/well of Fluro-4 AM Rao dye (by dissolving 1 mg of Fluro-4 AM in 440 μl of DMSO, It was diluted with 100 μl of Pluronic solution and further diluted with 10 ml of Hanks buffer). The cells were incubated at 37 ° C and 5% CO 2 for 30 minutes, then washed three times and suspended in assay buffer (20 mM HEPES, 1.2 mM CaCl 2 , 5 mM MgCl 2 , 2.5 mM probenecid, 0.5% BSA, lx Hanks) in. The test article was serially diluted in DMS0, then diluted with a detection buffer, 10:1, and then added to the cells (10 μl/well). Use FLIPR to read (10-70 seconds) plate flux (meaning agonist activity). Then, in the cells, further add a mobilizer solution (30 μl/well; made by diluting 30 μl of 100 μmol concentration MIP-1 in 100 ml of detection buffer; this is The final concentration of 5 nM MIP-1 was transmitted during the assay and the plate was read using FLIPR for one minute. The antagonist activity of the analyte was measured relative to the 0.4% DMSO/buffer negative control. A disease or condition of a human or other species treated by a body function inhibitor, including but not limited to: inflammatory or allergic diseases and symptoms, including respiratory allergic diseases such as asthma, allergic rhinitis, allergic lung disease, allergic pneumonia, Eosinophilic plague (such as Well's syndrome), sputum red pneumonia (such as Loeffler's syndrome, chronic eosinophilic pneumonia), fascination 95318 -321 · 1354664 eosinophilic fasciitis (such as Shulman's syndrome) Delayed allergic, interstitial lung disease (ILD) (eg, spontaneous pulmonary fibrosis or rheumatoid arthritis associated with ILD, systemic lupus erythematosus, joint adhesion spondylitis, systemic sclerosis, Sjog) Ren's syndrome, polymyositis or dermatomyositis; systemic allergies or allergic reactions, drug allergic reactions (eg for penicillin heads, spores), excessive eosinophils due to ingestion of contaminated tryptophan - Myalgia syndrome, allergic reactions to insects and bruises; autoimmune diseases such as rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, systemic lupus erythematosus, myasthenia gravis, juvenile onset diabetes; spheroid nephritis, Autoimmune Hashimoto's disease, Behcet's disease; transplant rejection (eg at the time of transplantation), including allograft rejection or graft-to-host disease; inflammatory bowel disease, such as Crohn's disease and ulcerative colitis; spondyloarthropathy Scleroderma; psoriasis (including psoriasis by T-cells), and inflammatory skin diseases such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis (eg Necrotic, cutaneous and allergic vasculitis; eosinophilic, eosinophilic fasciitis; cancer with white blood cells immersed in the skin or organs. Other diseases or symptoms that are sexually responsive to inhibition may be treated, including but not limited to reperfusion injury, atherosclerosis, and toxicity caused by certain blood-threatening cells/tongues (eg, septic shock) , endotoxin shock), polymyositis, dermatomyositis. Infectious diseases or symptoms of human or other species that can be treated with chemical cells and activator receptors, including but not limited to HIV. A disease or symptom of a human or other species treated by a receptor receptor function enhancer', including but not limited to, immunosuppression, such as in individuals with an immunodeficiency syndrome of 95318 1354664, such as aids or other viral infections, receiving radiation therapy, chemistry Treatment, individuals with autoimmune diseases or medications (eg corticosteroid therapy), which cause immunosuppression; immunosuppression due to congenital defects in receptor function or other causes; and infectious diseases such as parasitism Diseases, including but not limited to helminth infections, such as nematodes (roundworms), (whipworm disease, tsutsugamushi disease, worms) Disease, hookworm, roundworm disease, trichinosis, filariasis; trematode (schistosomiasis) (schistosomiasis, branched tsutsugamushi), mites (worm) (cytic worm disease, obese tsutsugamushi, Cysticercosis" visceral worms, visceral larva migraine (such as Toxoplasma), eosinophilic gastroenteritis (such as the genus Heterodera, phocanema), skin larva migraine (Brazil hookworm, canine worm). The compounds of the invention are therefore useful in the prevention and treatment of a wide variety of inflammatory, infectious and immunomodulatory disorders and diseases. In addition, if we intend to transmit a sufficient amount of compound to cause loss of expression of the receptor on the cell by causing internalization of the chemical cytokine receptor, or to cause the cell to migrate in the wrong direction, the above-mentioned compound is transmitted. Inflammatory, allergic and self-immunity = treatment of disease can also be a specific factor for the chemical cytokine receptor function promoter. The invention can be used to evaluate the inferred y-protein conjugate or the antagonist. . The present invention (4) m... ^ ^ JU m. 'Using these compounds in the regulation and regulation of chemical cytokines receptors in preparation and implementation. Furthermore, too ▲ "the substance (the compound selected by the teacher to test the chemical cytokines receptors by other competitive inhibition or as a reference, in the detection of the activity of the compound # t ^, sex and possession When I develop a new test or (4)^(4) 95318 -323· UM664 This month's sigma can be used to test its validity &quot;May sure, this compound can be provided in a commercially available kit, for example For use in pharmaceutical research involving the aforementioned diseases, the compounds of the present invention can also be used to evaluate inferential-modulating agents for chemical cytokine receptors. Furthermore, we can use the compounds of the present invention to verify that they are not considered to be chemical cytokines. The G protein coupling of the body is also specific to m, either by charging as an example of a compound that does not bind, or as a structural variant of a compound that is active at a receptor that can define a specific position of the interaction. Preferably, it is used for treating or preventing a disease selected from the group consisting of: "1. arthritis, osteoarthritis, septic shock, atherosclerosis, aneurysm, fever, heart and blood vessel action" Hemorrhagic shock, septic disease, injury after reperfusion, dysentery, Crohn's disease, inflammatory bowel disease, mycobacterial infection, meningitis, psoriasis, septic heart failure, fibrotic disease , cachexia, transplanted sputum, autoimmune disease, inflammatory disease of the skin, multiple sclerosis, radiation damage, hyperoxic lung injury, Ηιγ HIV dementia, non-insulin-dependent diabetes, asthma, allergic rhinitis, atopic dermatitis , spontaneous pulmonary fibrosis, large vesicular pemphigoid, helminth parasitic infection, allergic colitis, eczema, conjunctivitis, transplantation, familial eosinophilia, eosinophilic plague, irritability Red pneumonia, eosinophilic fasciitis, eosinophilic gastroenteritis, drug-induced eosinophilia, gallbladder fibrosis, Churg-strauss syndrome, lymphoma, Hodgkin's disease, colon cancer , Felty's syndrome, sarcoidosis, uveitis, Alzheimer's disease, spheroid nephritis, and systemic lupus erythematosus. On the other hand, these compounds are used to treat or prevent Inflammatory disorder, 95318 •324· From rheumatoid arthritis, A —, serovar stagnation, atherosclerosis, aneurysm, fever, heart and blood vessels

Action, Crohn's disease, inflammatory bowel disease, psoriasis, blood stasis heart failure, multiple I multiple sclerosis, autoimmune disease 'skin inflammatory disease. Μ 另 面 ’ These compounds are used to treat or prevent inflammatory conditions, from rheumatism to inflammation, 'osteoarthritis', atherosclerosis, Crohn's disease, inflammatory bowel disease and multiple sclerosis. Oral/oral therapy for the prevention and treatment of inflammatory, infectious and immunomodulatory disorders and diseases 'including breast and allergic diseases' and autoimmune pathological diseases such as rheumatoid arthritis and atherosclerosis, and The pathological disease indicated by the text is illustrated by the cooperation of a compound of the invention with other groups known to be useful for such use. For example, in the treatment or prevention of inflammation, the prosthetic may be combined with an anti-inflammatory or analgesic agent, such as an opioid stimulant, a lipoxygenase inhibitor, a cyclooxygenase-2 inhibitor, an interleukocytokinin inhibitor ( Such as interleukin-1 inhibitor, tumor necrosis factor inhibitor, NMDA antagonist, inhibitor of nitric oxide or inhibitor of nitric oxide synthesis 'Non-steroidal anti-inflammatory agent, bis-diacetate inhibitor or cytokine Inhibition of anti-inflammatory agents, for example, the following compounds, such as acetamin〇phen, aspirin, codeine, fentanol, ibuprofen (9) 叩 η, 吲哚 萨 辛 辛(indomethacin), ketorolac, morphine, naproxen, fenacetin, piroxicam, steroid analgesics, sufentanyl, forest SunHndac, interferon alpha, etc. Similarly, the compounds of the invention may be administered with the following drugs, pain relievers; enhancers, such as caffeine, Η2_antagonists, polydimethyl hydrazine 95318-325 · 1354664 alkane, aluminum hydroxide or magnesium; decongestants Such as phenylephrine, phenylpropanolamine, pseudoephedrine, oxymetazoline, ephedra, naphazoline, difenzin, hydrogenated deoxygenated or deoxygenated - ephedrine; and antitussives, such as codeine, hydrocodone, caramiphen, carbepentine &lt; (carbetapentane) or dextramethorphan; diuretic And sedative or non-sedating antihistamines. Similarly, the compounds of the present invention may be used in combination with other drugs for the treatment/prevention/inhibition or amelioration of diseases or conditions for which the compounds of the present invention are useful. Such other drugs may be administered simultaneously or sequentially with the compounds of the invention by their usual routes and amounts. When the compound of the present invention is used together with one or more other drugs, a pharmaceutical composition containing such other drug is preferred in addition to the compound of the present invention. Accordingly, the pharmaceutical composition of the present invention includes one or more other active ingredients in addition to the compound of the present invention. Examples of other active ingredients which may be combined with a compound of the invention, whether administered individually or in the same pharmaceutical composition, include, but are not limited to: (8) integrin antagonists, such as the alternatives ICAM and VLA-4 users; b) steroids such as bermamexone, methylprednisolone, mesacon, prednisone, dexamethasone and hydrocortisone; (c) immunosuppressive agents such as cyclosporine, Tacrolimus, rapamycin and other FK-506 immunosuppressive agents; (6) antihistamines (H1-histamine antagonists), such as bromopheniramine, phenoxyphene Chlorpheniramine, dexchlorpheniramine, triprolidine, kleimas, clemastine, diphenhydramine, diphenyl ρ bidin 95318 - 326- 1354664

(diphenylpyraline), p than tripelennamine, hydroxyzine, methdilazine, promethazine, trimeprazine, azatadine, west Plomon; cyproheptadine, antaline, fennelamine, neostigmine, astemizole, terfenadine, loratadin, cetirizine Well (cetirizine), fexofenadine, deoxyacetate, raloxifene, etc.; (e) non-steroidal anti-asthmatic agents, such as b2-activator (meta-adrenalin, dextran) Alcohol (metaproterenol), fentanol, neoisoproterenol, albuteral, bitolterol and pirbuterol, tea, sodium cromoglycate, atropine, bromine Ipratropium bromide, leucotriene antagonist (zafirlukast, montelukast, pranlukast, clothing) Iralukast, pobilukast, SKB- 102,203), leukotriene biosynthesis inhibitors (zileuton, BAY-1005); (f) non-steroidal anti-inflammatory agents (NSAIDs), such as propionic acid derivatives (aminoxene, benzalkonium) (benxaprofen), buclocil, c-propionyl, acetobutanoic acid, fenoprofen, fluprofen, fluorodipropion, ibuprofen, Indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, p-propylidene, and puppamine Pranoprofen), supprofen, tiaprofenic acid and oxypropylation, acid derivatives (4 indomethacin, acemetacin) , Alclofenac, clidanac, diclofenac, phenophene, benzene petacetin, fentiazac, fluoride If phenac, p-isobutyl phenylacetic acid, isoxqpac, 11th 95318 -327-1354664 oxpinac, sarnink Sulindac), tamarind, tolmetin, domomitacin and zomepirac, chlorinated derivatives (flufenic acid, meclofenac, mefenamic acid, Nitoric acid and toluene acid), biphenylcarboxylic acid derivatives (diflufenic acid and flufenisal), oxicams (isoxicam, pyroxibamine) Piroxicam), sudoxicam and tenoxicam, salicylate (sulfasalazine, sulfasalazine), and scented 57 genus Erqi, Wuxi Baotaisong, mofebutazone, oxyphenyl phenylbutazone, phenyl phenylbutazone; (g) cyclooxygenase-2 (COX-2) inhibitor; h) phosphodiesterase type IV (PDE-IV) inhibitor; (i) other antagonists of chemical cytokine receptors; (j) cholesterol lowering agents, such as HMG-COA reductase inhibitors (Lovamycin) Lovastatin, simvastatin, and pravastatin, fluvastatin, atorvsatatin, and other bacteriocins Sequestering agent (cholestamine and colestipol), nicotonic acid, non-fibric acid derivatives (gemfibrozil, clofibrat, Non-fibrate (fenofibrate) and benzfibrate, and probucol; (k) anti-diabetic agents, such as adenosine, sulfonyl urea, bismuth (metformin), a-glycosidase inhibitor (acarbose) and glitazone (troglitazone and pioglitazone); (1) interference Preparations (interferon a-2a, interferon-2B, interferon a-N3, interferon, interferon lb, interferon ylb); (m) antiviral compounds, such as efavirenz ), nevirapine, indinavir, ganciclovir, lamivudine, famciclovir, and jiaxiitabin 95318 • 328- 1354664 Species, age, gender, health status, medical symptoms and weight; nature and extent of symptoms; types of co-treatment; frequency of treatment Rate; route of administration, kidney and liver function of the patient&apos; The physician or veterinarian can determine and initiate the effective treatment of the drug to prevent, counter or arrest the development of a blood-thawing disorder.

In the following general guidelines, the daily oral dose of each active ingredient, when used for the indicated effect, will range from about 丨1 to 丨(8)〇mg/kg body weight, preferably about daily. 〇〇 1 to 1 〇〇 mg / kg body weight, and the best system is between about 1_0 to 20 mg / kg / day. The optimal dosage range for the intravenous mode is from about 〇 to about 1 氅 g/kg/min during constant rate perfusion. The compounds of the invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses of two, three or four times daily. The compounds of the invention may be administered in intranasal form by topical application of a suitable intranasal vehicle, or via transdermal delivery, using a transdermal skin patch. When administered in the form of a transdermal delivery system, the dose administration is consistent throughout the dosage regimen, and is not continuous.

These compounds are typically administered in admixture with a suitable pharmaceutical diluent, excipient or agent (herein collectively referred to as a pharmaceutical carrier), which is suitably selected for the intended mode of administration, i. , capsules, sputum, syrup, etc., and consistent with the practice of medicinal medicine. For example, for oral administration in the form of tablets or porpoise and sacs, the active ingredient can be combined with an oral, non-toxic, and inert carrier that can be burned on the funeral, such as lactose, starch, and ale. ",", sugar glucose, methyl cellulose, stearic acid 'dicalcium phosphate, aluminum sulfate, calcium mannose, sterol, etc.; for oral administration of liquid form 95318 • 330 · U54664 and t, Oral pharmaceutical ingredients can be combined with any oral, non-toxic pharmaceutically acceptable inert carrier, such as ethanol, glycerol, water, etc.: Again, if necessary or necessary, appropriate adhesives, lubricants, disintegration Agents and coloring agents are incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars, such as glucose or lactose, corn sweeteners, natural and synthetic gums such as gum arabic, scutellaria or (4) acid steel, rebellious Methylcellulose, 4 ethylene glycol, ants, etc. Lubricants used in these dosage forms include sodium oleate, sodium stearate, barium stearate 'sodium benzoate sodium acetate, sodium chloride Etc. Disintegrators include but It is limited to starch, methyl cellulose, agar, bentonite, Sanxian gum, etc. The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small single-layered vesicles, large single-layered vesicles, and multi-layered vesicles. Liposomes can be prepared from a variety of phospholipids, such as cholesterol, stearylamine or phospholipid choline. The compounds of the invention can also be coupled to soluble polymers which are pharmaceutical carriers which can be used as labels. Such polymers can include polyvinyl Tetrahydropyrrolidone, piper copolymer, polyhydroxypropylmethylpropionamide-phenol, polyhydroxyethylaspartamide, or polyoxyethylene-polylysine substituted by palmitoyl residues Furthermore, the compound of the present invention can be coupled to a biodegradable polymer species which can be used to achieve controlled release of a drug, such as polylactic acid, polyglycolic acid, a copolymer of polylactic acid and polyglycolic acid, and poly-caprolactone. , a combination of polyhydroxybutyric acid, poly-orthoacetic acid, polyacetal, polydihydropyran, polycyanohydrazine and hydrogel, or amphoteric block copolymer. Suitable for dosage forms (pharmaceutical combinations) ()), each dosage unit can There are from about 1 mg to about 100 mg of active ingredient. In such pharmaceutical compositions, the active ingredient will usually be present in an amount of from about 0.5% to about 95% by weight of 95318-331 - 1354664 in the total weight of the composition. It may contain active ingredients and powdered carriers, powders, cellulose derivatives, stearic acid, stearic acid, etc. to produce compressed tablets. Tablets and capsules can be made into thinner In order to provide continuous release of the drug, the release period of the drug is released. The tablet is compressed, and the sugar coating or film coating is applied to cover up any V. 7 unpleasant taste and film (4) from the atmosphere. Or coated with an enteric substance to be selectively selected in the gastrointestinal tract. A liquid dosage form for oral administration may have a coloring and flavoring agent to increase patient acceptance. - Generally speaking, water, oil, Sleeping water, aqueous dextrose (glucose) and related sugar solutions, and disaccharides, such as propylene glycol or polyethylene glycol, are suitable carriers for parenteral solutions. The solution for parenteral administration is preferably a water-soluble salt of the active ingredient, a suitable decoction, and, if necessary, a buffer f. Antioxidants, such as sodium bisulfite, sodium sulfite or ascorbic acid, either alone or in combination, are suitable stabilizers. Also users are citric acid and its salts, as well as sodium EDM. In addition, parenteral solutions may contain preservatives such as benzalkonium chloride, methyl or propylparaben and chlorobutanol. Appropriate pharmaceutical carriers are described in Remington's Pharmacopoeia Publishing Company, which is a standard reference book in this field. A representative useful pharmaceutical dosage form for administration of a compound of the present invention can be illustrated as follows: A large number of capsules of the capsule can be made by filling a standard two-piece hard gelatin capsule with '100 mg of powdered active ingredient each, 15 〇 mg Lactose, 5 mg of cellulose and 6 mg of magnesium stearate. 95318 332 · 1354664

Ijg can prepare a mixture of active ingredients in digestible oil such as soybean oil, cottonseed oil or eucalyptus oil, and inject it into gelatin using a positive displacement pump to form soft gelatin gum containing 100 mg of active ingredient. It should be warp and dried.片剂. Tablets can be prepared by customary procedures, so the dosage unit is 1 mg of active ingredient, 0.2 mg of colloidal cerium oxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch and 98.8 Millions of lactose. Appropriate coatings can be applied to increase palatability or delay absorption. Inter-injection The parenteral composition suitable for administration by injection can be prepared by stirring 1.5% by weight of the active ingredient in 10% by volume of propylene glycol with water. The solution should be isotonic with sodium vaporated and sterilized. An aqueous suspension can be prepared for oral administration by suspension, so each 5 ml contains mg of finely divided active ingredient, 200 mg of sodium carboxymethylcellulose, 5 mg of sodium benzoate, 1.0 g of camphorol solution (United States Pharmacopoeia) and 〇〇25 ML vanillin. In the case where the compound of the present invention is combined with, for example, other anticoagulant agents, the daily dose may be from about 〇1 to about 1 mg of formula compound per kg of patient body weight, and about 2 to 7.5 g of the second antibiotic. Coagulant. For tablet dosage forms, the compound will generally be present in an amount of from about 5 to about 1 mg per dosage unit, and the second anticoagulant is present in an amount of from about 5 mg to about 5 mg per dosage unit. In the case where two or more of the foregoing second therapeutic agents are administered together with a compound of formula I, usually the amount of each component in a typical daily dosage form and a typical dosage form is relative to the preparation of '^ 95318 -333 · 丄jj leaves常用ο斗 commonly used doses when the drug is used in combination with the treatment agent: or = can be reduced, when a single dose unit can be = 'Γ active ingredients between, there is a chemical interaction. So, when! The compound is combined with the second therapeutic agent in a single agent::=#, which is formulated so that although the active ingredient is combined in a single-in-one injury, the physical contact system is minimized ( : Ρ reduction, for example, Dissolving an active ingredient in an enteric material to coat its active ingredient can not only minimize the contact between the combined parts, but also control the release of the gastrointestinal tract. Among them, these ingredients will not be released in the intestines. One of the active ingredients can also be coated with a 4.. Continuous release in the entire gastrointestinal tract, and also used to make (4) Physical contact is minimized. In addition, this performance can be additionally coated with enteric substances, so that the release of this ingredient is only in the intestine. Another way is to involve the combination of the products, (4) A polymer that is sustained and/or enteric-released, and the other polymer, such as a low-viscosity grade, is propylated cellulose or other suitable material known in the art to further separate the activity. Ingredients. This polymer coating is used to shape For additional barriers that interact with the other. Wind cuts minimize the contact between the components of the combination of the invention and its: it is either in the form of a single dose or in a single form but simultaneously in the same way In the case of the disclosure of the present invention, it will be apparent to those skilled in the art. 95318 - 334 - 1354664 Obviously, many modifications and variations of the present invention, after It is therefore to be understood that the invention may be embodied in other ways as described herein in the context of the appended claims. 95318 -335 -

Claims (1)

ΙΟΟ. 9. 2 7 ^ Patent application No. 093124980 Chinese patent application scope replacement (September 100) X. Patent application scope: 1. A compound of formula (la), Wherein: Z is selected from the group consisting of a bond, _nr8 c(9)_, -NR8 and -NR9-; R1 is selected from Η, R6, Cl_3 R6 substituted Cl_6 alkyl, substituted by 〇3 R6 (: 2·6 alkenyl, c2_6 alkynyl substituted by 〇-3 R6, C6-10 aryl substituted by 〇-5 R6, and 5-10 membered heteroaryl system substituted by 〇3 R6' Containing 1-4 heteroatoms selected from N, oxime and S; with the proviso that if R1 is Η, then R5 is (CRR)rNR5aR5a; and another condition is that if R5 is Η, then R1 is not R2 is selected from C6-1() aryl substituted by 0-5 R7, and 5-10 membered heteroaryl system substituted by 0-3 R7, containing 1-4 selected from N,杂 and S heteroatoms; R5 is independently selected from Η, =0, (: 6 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, (CRR) rOH, (CRR) rSH, (CRR)rOR5d, (CRR)rSR5d, (CRR)rNR5aR5a, (CRR)rN(0)R5aR5a, (CRR)rC(0)OH, (CRR)rC(0)R5b, (CRR)rC(0)NR5aR5a (CRR)rNR5aC(0)R5b, (CRR)r0C(0)NR5aR5a, (CRR)rNR5aC(0)0R5d, (CRR)rNR5aC(0)NR5aR5a, (CRR)rNR5aC(0)H,(CRR)rC (0)0R5d, (CRR)rOC(0)R5b, 95318-100092 7.doc (CRR)rS(0)pR5b, (CRR)rS(0)2NR5aR5a, (CRR)rNR5aS(〇)2R5b, (CRR)rNR5aS(0)2NR5aR5a, Ch haloalkyl, bedding_3 r5c Substituted (CRR)r-C3· l 〇Carbocyclic residue' and (CRR)r-5-10 member heterocyclic ring system containing 1-4 heteroatoms selected from N, Ο and S, 2 R5c substitutions; R5 a in each presence 'separate from Η, methyl substituted by 0-1 RSg, C2-6 alkyl substituted by 0-2 R5e, 〇_2 R5e a substituted C3 ·8 alkenyl group, a c3 -8 alkynyl group substituted by 0-2 R5 e, a (CH2)r-C3-1Q carbocyclic group residue substituted by 〇5 R5 e, and a beryllium_ Three R5e-substituted (CH2)r-5-10 member heterocyclic ring systems containing 1-4 heteroatoms selected from N, 0 and S; wherein, when R5 is (CRR)rN(0)R5aR5a, R5a is not R5b, in each presence, is selected from the group consisting of 〇3 substituted Ci 6 alkyl, C-2-8 alkenyl substituted by 0-2 R5e, 〇3-8 alkyne substituted by 〇-2 R5e a (CH2)r-C3.6 carbocyclic residue substituted by 0-2 R5e, and a (CH2)r-5-6 heterocyclic ring system substituted by 〇-3 R5e, containing 1-4 One hetero atom selected from N, 0 and S; R5e in each Wherein, selected from C -6 alkyl, C 2-8 alkenyl, (: 2-8 alkynyl, (CH 2 ) r C 3.6 cycloalkyl, Cl, Br, I, F, (CF 2 ) r CF 3 , NO ], CN, (CH2)rNR5fR5f, (CH2)rOH, (CHAOCh alkyl, (CHdSCH alkyl, (CH2)rC(0)0H, (CH2)rC(0)R5b, (CH2)r C(0) NR5 fR5 f, (CH2)r 0C(0)NR5 fR5 f, (CH2)rNR5fC(0)R5b, (CH2)rC(0)OCHalkyl, (CHANRHCCCOOCw alkyl, (CH2)r0C(0)R5b, 95318-1000927.doc 1354664 (CH2)rC(=NR5f)NR5fR5f, (CH2)rS(0)pR5b, (CH2)rNHC(=NR5f)NR5fR5f ' (CH2 )r S(0)2 NR5 fR5 f ' (CH2 Rr NR5 f S(0)2 R5 b and (CH2)r stupid substituted by 0-3 R5 e; R5d is selected from thiol, CF3, 0-2 1^ in each presence Substituted _2_6 alkyl, C3-8 alkenyl substituted by 0-2 R5e, C3-8 alkynyl substituted by 0-2 R5e, and C3-1G carbon ring substituted by 0-3 R5e Residue; R5e is selected from the group consisting of q 6 alkyl, & 8 alkenyl, C28 alkynyl, C3.6 cycloalkyl, Cl, F, Br, I, CN, N〇2, CF2)rCF3, (CHAOCu alkyl, OH, SH, (CHASCu alkyl, (012\ see 15 死1^ and ((:112)) benzene R5f is selected from the group consisting of hydrazine, Ci-6 alkyl and C3.6 cycloalkyl at each position; R5g is independently selected from -C(0)R5b, -C(0)0R5d, -C(0 NR5fR5f &amp; (CH2)r phenyl; R in each presence, selected from Η, substituted by R5e (^_6 alkyl, C2.8 alkenyl, C2-8 alkynyl, (CH2)rC3_6 ring Alkyl and (CH2)1•phenyl substituted by R5e; R6 is selected from the group consisting of Ch alkyl, (CH2)rC3_6 cycloalkyl, Cl 'Br &gt; I 'F 'N〇2 ' CN ' (CR'R')rNR6aR6a &gt; (CR'R')rOH ' (CR'R'^OCCR'R'XR^ ' (CR'R')rSH ' (CR'R')r C(0 ) H ' (CR'R')rS(CR,R,)rR6d, (CR,R,)rSC(0)(CR,R,)rR6b, (CR,R,)rC(0)0H, (CR 'ROrCXOXCR'R%!^, (CR'R,)rC(0)NR6aR6a, (CR,R,)rNR6fC(0)(CR,R,)rR6b, (CR,R')rC(0)0( CR,R')rR6d,(CR'R^OqOXCR'R'XR615, 95318-1000927.doc (CR,R')rOC(0)NR6a(CR'R')rR6d, (CR'R'^NR^ C^^^CR'R'XR641 ' (CR,R,)rNR6aC(S)NR6a(CR'R')rR6d, (CR'R')rNR6aC(S)NR6aR6d, (CR'R'XNI^CXCOCKCRiROrR611, (CR, R')rC(=NR6f)NR6aR6a, (CR'R,)r NHC(=NR6 f)NR6 fR6 f, (CR,R|)r S(0)p (CR R,)r R6 b, (CR'R')rS(0)2NR6aR6a &gt; (CR'R')rNR6fS(0)2NR6aR6a ^ (CR'R')rNR6fS(0)2(CR'R')rR6b , Cu haloalkyl, C2-8 alkenyl substituted by 0-3 R, C2-8 alkynyl substituted by 0-3 R', (CR'R')r benzene substituted by 0-3 R6e And a (CH2)r-5-6 heterocyclic ring system substituted by 0-2 R6e, containing 1-2 heteroatoms selected from N, fluorene and S; or two on adjacent atoms on R1 R6 can be joined to form a cyclic acetal; R6a is selected from the group consisting of hydrazine, a methyl group substituted by 0-1 R6g, and a 〇2·6 alkyl group substituted by 0-2 R6e. 0-2 R6e substituted (: 3-8 alkenyl and C3-8 alkynyl substituted by 0-2 R6e; R6b in each presence, selected from Η, replaced by 0-2 R6e, Ci -6 alkyl, C3-8 alkenyl substituted by 0-2 R6e, and C3 · 8 substituent substituted by 〇-2 R6e; R6d, in each presence, selected from C3 substituted by 0-2 R6e 8 alkenyl, C3-8 alkynyl substituted by 0-2 R6e, methyl, CF3, C2-6 alkyl substituted by 0-3 R6e and C2-4 haloalkyl; R6e in each presence , selected from (^-6 alkyl, C2.8 alkenyl, C2-8 alkynyl, (CH2)rC3.6 naphthenic , Cl, F, Br, I, CN, N〇2, (CF2)rCF3, (CHAOCu alkyl, OH, SH, (CHJSCu alkane 95318-1000927.doc -4- 1354664 base, ((^2\]^ 1616€ and (012\phenyl; R6f in each presence, selected from hydrazine, Cm alkyl, C3-6 cycloalkyl, and phenyl; R6g is independently selected from -C(0)R6b, -C (0) 0R6d, -C(0)NR6fR6f &amp; (CH2\ phenyl; R7 is selected from CVs alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3_6 cycloalkyl, Cl, Br, I, F, N02, CN, (CR.R.)rNR7aR7a, in each presence. (CR'R'XOH, (CR'R,)rO(CR,R')rR7d, (CR'R')rSH ' (CR'R')rC(0)H ' (CR'R')r S (CR'R')rR7d ' (CR'R')rC(0)0H ' (CR'R'X^OXCR'R'^R715 ' (CR,R,)rC(0)NR7aR7a,(CR'R 'XNRKCCOXCR'RIRn, (CR'R'^C^O^R'R'XR70 ' (CR'R'^OC^CCR'R'XR715 ' (CR,R,)rOC(0)NR7a(CR'R ,)rR7a, (CR'R')rNR7aC(0)NR7a(CR'R')rR7a, (CR'R'^NR^CCOPCCR'R'^R70 ' (CR'R')rNR7aC(0)OR7d ^ (CR, R')rC(=NR7f)NR7aR7a, (CR|R,)rNHC(=NR7f)NR7fR7f, (CR'R')rS(0)p(CR'R')rR7b, (CR'R' rS(0)2NR7aR7a, (CR'R')rNR7aS(0)2NR7aR7a, (CR'R')rNR7fS(0)2(CR'R')rR7b, (:6-dentate alkyl, 0-3 a C2-8 alkenyl group substituted by R', a C2-8 alkynyl group substituted by 0-3 R. and a (CRll')r phenyl group substituted by 0-3 R7e; or two of adjacent atoms on R2 R7 can be joined to form a cyclic acetal&gt; R7a is independently selected from the group consisting of hydrazine, a methyl group substituted by 0-1 R7g, a C2-6 alkyl group substituted by 0-2 R7e, Be 0-2 R7e substituted 95318-1000927.doc C3_8 alkenyl, C3.8 alkynyl substituted by 0-2 R7e, (CH2)r-C3-1{) carbocyclic ring substituted by 0-5 1176 a family residue, and a (CH2)r-5-10 member heterocyclic ring system substituted with 〇-2 R7e, containing 1-4 heteroatoms selected from N, Ο and S; R7b at each presence, Substituted from 0-2 R7e (: 6 alkyl, C3-8 alkenyl substituted by 0-2 R7e, 03_8 alkynyl substituted by 〇-2 R7e, replaced by 0-3 R7e a (CH2)rC3_6 carbocyclic residue, and a (CH2)r-5-6 member heterocyclic ring system substituted by 0-2 R7e, containing 1-4 heteroatoms selected from N, fluorene and S; R7d In each presence, it is selected from C3-8 alkenyl substituted by 0-2 R7e, C3-8 alkynyl substituted by 0-2 R7e, methyl, CF3, C2-4 haloalkyl, 0-3 R7e substituted C2_6 alkyl, substituted by 〇3 R7e (匸^^^-(7) carbocyclic residue ' and ^2 取代~substituted ^%) 〆-6 member heterocyclic ring a system comprising from 1 to 4 heteroatoms selected from the group consisting of ruthenium, osmium and S; wherein each R7e is selected from the group consisting of Cl-6 alkyl, C28 alkenyl, C28 alkynyl, (CH2)rC3.6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2)rCF3 (CHJrOC!-5 alkyl, 〇H, SH, (:(0)0(^ ·5 alkyl, (CHASCu alkyl, (CH2)rNR7fR7f and (CH2)r phenyl; R7f in each presence, It is selected from the group consisting of hydrazine, (^_5 alkyl, C3_6 cycloalkyl, and phenyl; the oxime is independently selected from -C(0)R7b, -C(C〇〇R7d, [and (αΐ2χ phenyl; R· Each presence is selected from the group consisting of c 'c^6 alkyl substituted by R6e, c2.8 alkenyl, C2_8 alkynyl and (CH2)rC3-6 cycloalkyl; 95318-1000927.doc -6 - R8 Selected from Η, C _4 alkyl and C34 cycloalkyl; R is selected from η, Ch alkyl, C 3 4 cycloalkyl, _c(〇)H&_c(0)_Ci 4 alkyl; P in each Where present is 'independently selected from 0, 1 and 2; r is in each occurrence' is independently selected from 0, 1, 2, 3 and 4; or a stereoisomer or pharmaceutically acceptable salt thereof. 2. A compound according to claim 1 wherein R5, at each occurrence, is independently selected from the group consisting of hydrazine, C丨.6 alkyl, C2-8 alkenyl, C2-8 fast radical, (CRR)r〇H, (CRR) rSH, (CRR) 〇R5d, (CRR)rSR5d, (CRR)rNR5aR5a(CRR)rc(〇)OH, (CRR)rc(〇)R5b (CRR)rC(0)NR5aR5a , (CRR)rNR5aC(0) (5) 〇 ( ( ( (CRR)r〇c(〇)R5b, (CRR)rS(〇)pR5b, (CRR)rS(0)2NR5aR5a, (CRR)rNR5aS(〇)2R51^Ci-6 haloalkyl; R5a in each Where present is selected independently from hydrazine, methyl, substituted by 0-2 R5e (: 2-6 alkyl (wherein alkyl is selected from ethyl, propyl, isopropyl, butyl, isobutyl, pentyl) And a hexyl group, a c3 alkenyl group substituted by (7) 尺 (the alkenyl group is selected from a propenyl group), a c3 alkynyl group substituted by 04 R5 e (wherein the alkynyl group is selected from a propynyl group), and a ruthenium _5 R5e substituted (CH2)r-C3·4 carbocyclic residue (wherein the carbocyclic residue is selected from cyclopropyl and cyclobutyl); R5b is selected from the group in each presence _ 2 RSe substituted Ci 6 alkyl groups (where The base is selected from the group consisting of decyl, ethyl, propyl, isopropyl, butyl, iso 95318-1000927.doc 1354664 butyl, pentyl and hexyl) and substituted by 0-2 R5e (CH2)r-C3. a 4 carbocyclic residue (wherein the carbocyclic residue is selected from the group consisting of a cyclopropyl group and a cyclobutyl group); and R5d is selected from the group consisting of methyl, CF3, and C2_6 alkyl substituted by 〇_2 R5e a base (which is selected from the group consisting of ethyl, propyl, isopropyl, butyl, isobutyl, pentyl and hexyl), C3.8 alkenyl, C3-8 alkynyl, and 0-3 R5e Substituting the c3-1() carbocyclic residue. 3. The compound of claim 1, wherein: R is independently selected from the group consisting of hydrazine, methyl, ethyl, propyl, allyl, Propynyl, (CH2)rC3-6 cycloalkyl and (CH2)r phenyl substituted by R5e; R5 is independently selected from the group consisting of hydrazine, methyl, ethyl, propyl, iso-prop Base, butyl, iso-butyl, allyl, propynyl, (CH2)r〇H, (CH2)r〇R5d, (CH2)rNR5aR5a, (CH2)rC(0)0H, (CH2)rC (0) R5b, (CH2)rC(0)NR5aR5a, (CH2)rNR5aC(0)R5b, (CH2)r0C(0)NR5aR5a, (CH2)rNR5aC(0)0R5d, (CH2)rC(0)0R5d (CH2)r0C(0)R5b, (CH2)rNR5aS(0)2R5b, C!·6 tooth-burning group, (CH2)r phenyl substituted by 0-2 R5c, and (CRR)r· 5-10 The heterocyclic ring system 'containing ι_4 heteroatoms selected from n, oxime and S, substituted by 0-2 R5c, wherein the heterocyclic ring system is selected from the group consisting of tetrahydropyrrolyl, hexahydropyridyl and whalipid; R5 a in each presence, independently selected from the group consisting of hydrazine, methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, pentyl, hexyl'cyclopropyl and cyclobutyl; At each occurrence, it is selected from 〇, 1 and 2. 95318-1000927.doc, 8 8 1354664 4. The compound of claim 3, wherein: R1 is selected from the group consisting of ruthenium, R6, substituted by 0-3 R6, substituted by 〇-3 R6. a C2_6 alkenyl group, a C2_6 alkynyl group substituted by 0-3 R6, a C6-1() aryl group substituted by 〇5 R6, wherein the aryl group is selected from a stupid group and a fluorenyl group, and a 5-10 member An aryl system containing i_4 heteroatoms selected from n, fluorene and S substituted by 0-3 R6, wherein the heteroaryl is selected from the group consisting of fluorenyl, benzimidazolyl, benzofuranyl, benzothiofuran Benzo, benzofluorenyl, benzo-P-beta, benzotriazene, benzotetrachisyl, benzoisoxazolyl, benzisothiazolyl, benzimidazolone, temple Φ Base, fluorenyl, milanosyl, oxime, thiol, iso-indentation, iso- 4: phenyl, isopyrazolyl, iso-dihydrocarbazolyl, iso-alpha sulphate, carbazolyl , argon-based, methyl pyridyl, pyridinyl, pyrazolyl,.荅耕基, pyridine base, thiol base, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, pyrazolyl, ρ exemplyl, tri-negative and tetrazolyl; R 2 is selected from a phenyl group substituted by 0-2 R7, and a 5-10 membered heteroaryl system containing 1-4 heteroatoms selected from ruthenium, 0 and S, substituted by 〇3 r7, 0 wherein heteroaryl Is selected from the group consisting of 4-mercapto, benzimidazolyl, benzindene, benzothiopyranyl, benzoxanthyl, benzoxyl, benzotriazolyl, benzotetrazolyl, Benzoiso-α-azolyl, benzo-iso-[beta]-based, benzopyro-β-keto-keto, _-linyl, fluorenyl, π-m-sodium, carbazolyl, fluorenyl, iso-quine Ortholinyl, isopyrazolyl, iso-r-oxazolyl, carbazolyl, hydrazine, pyridinyl, pyrazolyl, 嗒ρ well base, 咬bite base, bite base, ring bite, Ρ ratio Loki, υ比略和三喷基95318-1000927.doc, oxazoline, porphyrin, pyrazolyl, thienyl and tetrazolyl. 5. The compound of claim 3 or 4, wherein: R6 is selected from the group consisting of (^8 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3.6 cycloalkyl, Cl , Br, I, F, N〇2, CN, (CH2)rNR6aR6a ' (CH2)rOH, (CH2)rO(CH2)rR6d, (CH2)rSH, (CH2)rC(0)H, (CH2)rS (CH2)rR6d, (CH2)rC(0)0H, (CH2)rC(0)(CH2)rR6b, (CH2)rC(0)NR6aR6a, (CH2)rNR6fC(0)R6b,(CH2)rC(〇 )0(CH2)rR6d, (CH2)rNR6aC(0)NR6aR6d, (CH2)rNR6aC(S)NR6aR6d, (CH2)r0C(0)(CH2)rR6b, (CH2)rS(0)pR6b, (CH2)rS (0) 2NR6aR6a, (CH2)rNR6fS(〇)2(CH2)rR6b, (CH2)rNR6fS(0)2NR6aR6a, Cu haloalkyl, (CH2)rphenyl substituted by 0-3 1^, and CH2)r-5-6 member heterocyclic ring system containing 1-2 heteroatoms selected from N, 0 and S, substituted by 0-2 R6e, wherein the heterocyclic system is selected from the group consisting of rosin and hexahydro I » 唆 唆 及 and whufolin; R6a is independently selected from the group consisting of hydrazine, methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl , pentyl and hexyl; R6b is selected from the group consisting of hydrazine, methyl, ethyl, propyl, _ propyl, butyl, iso-butyl, tert-butyl, pentyl and hexyl; R6d in each presence, selected from thiol, CF3, ethyl, propyl, iso-propyl, butyl Base, iso-butyl, tert-butyl, pentyl and hexyl; R6f, in each presence, is selected from the group consisting of H, methyl, ethyl 'propyl, iso-propyl, butyl, iso-butyl Base, tri-butyl, pentyl, hexyl, cyclopropyl and phenyl; 95318-1000927.doc • 10· 1354664 R7 is selected from the group consisting of decyl, ethyl, propyl, iso-propyl, butyl, Iso-butyl, second-butyl, tert-butyl, pentyl, (CH2)rC3.6 cycloalkyl, Cl, Br, I, F, N〇2, CN, (CH2)rNR7aR7a, ( CH2)rOH, (CH2)rO(CH2)rR7d, (CH2)rSH, (CH2)rC(0)H, (CH2)rS(CH2)rR7d, (CH2)rC(0)OH, (CH2)rC( 0) (CH2)rR7b, (CH2)rC(0)NR7aR7a &gt; (CH2)rNR7fC(0)(CH2)rR7b ' (CH2)rC(0)0(CH2)rR7d ' (CH2)r0C(0)( CH2)rR7b, (CH2)r0C(0)NR7aR7a, (CH2)rNR7aC(0)NR7aR7a, (CH2)rNR7aC(0)0(CH2)rR7d, (CH2)rS(0)p(CH2)rR7b, (CH2 rS(0)2NR7aR7a, (CH2)rNR7fS(0)2(CH2)rR7b, Cu haloalkyl and replaced by 0-3 R7e (CH2)rphenyl; R7a is selected from the group consisting of hydrazine, hydrazino, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, Hexyl, prop-2-enyl, 2-methyl-2-propenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, CH2 cyclopropyl and benzyl; R7b in each presence, Selected from methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl, cyclopropyl, cyclopentyl, CH2-cyclopentyl, ring a hexyl group, a CH2-cyclohexyl group, and a heterocyclic group selected from the group consisting of a tetrahydro-external b-yl group, a hydrazone, and a hexahydro-p-menthyl group, are substituted by Ο-ΐR7e; and each R7d is selected from each of Sulfhydryl, CF3, CF2CF3, CHF2, CH2F, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl and cyclopropyl; Where present, selected from the group consisting of hydrazine, methyl, ethyl, propyl, iso- 95318-1000927.doc • 11- 1354664 propyl, butyl, iso-butyl, tert-butyl, pentyl, cyclopropane And phenyl; and r is 0 or 1. 6. The compound of claim 5, wherein: R6, at each occurrence, is selected from the group consisting of Cm alkyl, C2-8 alkenyl, (: 2-8 alkynyl, alkyl, Cl, Br, I, F, N〇2, CN, (CH2)rNR6aR6a, (CH2)rOH, (CH2)rOR6d, (CH2)rSH, (CH2)rC(0)H, (CH2)rSR6d, (CH2)rC(0)0H, ( CH2)rC(0)R6b ' (CH2)rC(0)NR6aR6a ' (CH2)rNR6fC(0)R6b ' (CH2)rC(0)0R6d, (CH2)rNR6aC(0)NR6aR6d, (CH2)rNR6aC(S )NR6aR6d, (CH2)rOC(0)R6b, (CH2)rS(0)pR6b ' (CH2)rS(0)2NR6aR6a ' (CH2)rNR6fS(0)2R6b ' (CH2)rNR6fS(〇)2NR6aR6a, C, _6 haloalkyl and (CH2)r phenyl substituted by 0-3 R6e; R7 is selected from decyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, second-butyl Base, pentyl, hexyl, Cl, Br, I, F, CN, Ν02, NR7aR7a, NHC(0)NHR7a, NR7fC(0)R7b, NR7aC(0)R7b, NR7aC(0)0R7d, CF3, CF2CF3, CHF2 , CH2F ' OCF3 ' C(0)R7b ' C(0)0R7d ' NR7 a C(0)NR7 a R7 a &gt; NHS(0)2R7b, -12· 95318-1000927.doc 8 1354664 \c(o)o+butyl and . -NR7fC(0)\ \n 7. The compound of claim 1, wherein: Z is -NR9-; R1 is selected from the group consisting of oxime, Cu alkyl substituted by 0-3 R6, wherein the alkyl group is selected from the group consisting of Base, ethyl, propyl, iso-propyl, butyl, pentyl and hexyl, C2-6 alkenyl substituted by 0-3 R6 and C2-6 alkynyl substituted by 0-3 R6; R2 a stupid group substituted with 0-2 R7; R6 is selected from the group consisting of decyl, ethyl, propyl, iso-propyl, butyl, F, C1, Br, I, N〇2, CN, (CH2) rOR6d, C(0)R6b, SR6d 'NR6aR6a, C(0)NR6aR6a, NR6fC(0)R6b, OC(0)R6b, S(0)pR6b, (012)4(0)21^631163 and 0?3圮3 is H, methyl, ethyl, propyl, iso-propyl or butyl; R6b is hydrazine, fluorenyl, ethyl, propyl, iso-propyl or butyl; 116 (1 is fluorenyl) Or CF3; and r is 0 or 1. 8. The compound of claim 1, wherein: R7, at each occurrence, is selected from the group consisting of methyl, ethyl, propyl, iso-propyl 'butyl, iso- Butyl, second-butyl, tert-butyl, pentyl, hexyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, N02, CN, (CH2)rNR7aR7a, (CH2) rOH, (CH2)rOR7d, (CH2)rSH, (CH2)r C(0)H, (CH2)rSR7d, (CH2)rC(0)0H, (CH2)rC(0)R7b 95318-1000927.doc •13· ' (CH2)rC(0)NR7aR7a ^ (CH2)rNR7fC (0) R7b &gt; (CH2)rC(0)0R7d, (CH2)r0C(0)R7b, (CH2)rOC(0)NR7aR7a, (CH2)rNR7aC(0)NR7aR7a ^ (CH2)rNR7aC(0)0R7d ^(CH2)rS(0)pR7b, (CH2)rS(0)2S(0)2NR7aR7a, (CH2)rNR7aS(0)2NR7aR7a, (CH2)rNR7fS(0)2R7b, (:Bu 2 haloalkyl and 0-3 R7e substituted (CH2)r phenyl. 9. The compound of claim 1, wherein: Z is -NH-; R1 is selected from R6, q_6 alkyl substituted by 0-1 R6 and - C(0)0-CV6 alkyl; R2 is selected from the group consisting of 0-2 R7 substituted phenyl and 5-10 membered heteroaryl systems containing 1-4 heteroatoms selected from N, fluorene and S, Substituted by 0-3 R7, wherein the heteroaryl system is selected from the group consisting of oxazoline, tri, well, pyrimidinyl, methylpyridyl, iso-intestinal, p-folyl, fluorenyl, p Specific butyl, pyrazolyl, pyridinyl, pyrazolyl, thiophenyl and iso-oxazolyl; R5 in each presence, independently selected from methyl, ethyl, propyl, iso-propyl , butyl, iso-butyl, allyl, propynyl, (CH2)rOH, (C H2)rOR5d, (CH2)rNR5aR5a, (CH2)rC(0)0H, (CH2)rC(0)R5b, (CH2)rC(0)NR5aR5a, (CH2)rNR5aC(0)R5b, (CH2)r0C( 0) NR5aR5a, (CH2)rNR5aC(0)0R5d, (CH2)r0C(0)R5b, (CH2)rNR5aS(0)2R5b, Cb6 haloalkyl, and (CRR)r-5-10 heterocycle The system, containing from 1 to 4 heteroatoms selected from N, O and S, is substituted by 0-2 R5c, wherein the heterocyclic ring system is selected from the group consisting of tetrahydropyrrolyl, hexahydropyridyl and morpholinyl. </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> </ RTI> <RTIgt; In each presence, it is independently selected from the group consisting of (CH2\OH, (CH2)rOR5d, (CH2)rNR5aR5a, and (CRR)r_5_1 杂环 heterocyclic ring system, containing M heteroatoms selected from N, 〇 and S, Substituted by 0-2 R5c, wherein the heterocyclic ring system is selected from the group consisting of tetrahydropyrrolyl, hexahydropyridyl and morpholinyl. The compound of claim 1, wherein: Z is -NR9. , R6, a Ci_6 leukolide substituted by 0-3 R6, wherein the alkyl group is a thiol group, an ethyl group, a propyl group, an iso-propyl group, a butyl group, a decyl group and a hexyl group, which are substituted by 0-3 R6 groups. C2.6 alkenyl, C2-6 alkynyl substituted by 3 R6; R2 is a 5-10 membered heteroaryl system containing 1 4 heteroatoms selected from n, fluorene and S - 3 R7 substitutions in which the heteroaryl is selected from the group consisting of fluorenyl, benzimidyl, benzoxanthyl, benzothioindolyl, benzopyrene, benzopyrazole Base, benzotriazolyl, benzotetrazolyl, benzoiso-quot; oxazolyl, benzoisopyrazolyl , benzimidazolone, porphyrin, furyl, imidazolyl, oxazolyl, fluorenyl, isoquinolyl, isopyrazolyl, iso- 1*°, stagnation, stagnation, °, too 51 well foundation, Ρ ratio, well foundation, Ρ ratio β seat base, tower ρ well base, Ρ bite base, ρ ratio bite base, mouth bite base, Ρ 哈 基 base, n 奎 嗤Ρ base, porphyrin base , pyrazolyl, pyrenyl, tetrazolyl, tri-negative, methylpyridyl and isoniarine; and R5 is NR5aR5a. 95318-1000927.doc -15· 1354664 12_Compound of claim 1 Wherein: R6 is selected from the group consisting of Ci.8 alkyl, C2.8 alkenyl, C2.8 alkynyl, (CH2)rC3_6 cycloalkyl, Cl, Br, I, F, N〇2 in each presence. , CN, (CH2)rNR6aR6a, (CH2)rOH, (CH2)rOR6d, (CH2)rSH, (CH2)rC(0)H, (CH2)rSR6d, (CH2)rC(0)0H, (CH2)rC (0) R6b, (CH2)rC(0)NR6aR6a, (CH2)rNR6fC(0)R6b, (CH2)rC(0)0R6d, (CH2)rNR6aC(0)NR6aR6d, (CH2)rNR6aC(S)NR6aR6d, (CH2)rOC(0)R6b, •(CH2)rS(0)pR6b, (CH2)rS(0)2NR6aR6a, (CH2)rNR6fS(0)2R6b, (CH2)rNR6fS(0)2NR6aR6a, (^_6 halogen Alkyl and 0-3 R6e (CHR')r phenyl; R7 is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, second-butyl, pentyl, hexyl Cl, Br, I NR7fC(0)R7b C(0)0R7d NHS(0)2R-NR7fC(0) 7b F, N02, NR7aR7a, NHC(0)NHR7a, NR7fC(0)0R7d, CF3, OCF3 C(0)R7b, NR7aC (0)NR7aR7a -NR7fC(0) -NR7fC{0), ,N,C(0)0-N butyl and -NR7fC(0), Ό 13. The compound of claim 1, which has the structure: 95318-1000927.doc -16 - 8 1354664 Or a pharmaceutically acceptable salt thereof. 14. The compound of claim 1 which has the structure: Or a pharmaceutically acceptable salt thereof. 15. The compound of claim 1 which has the structure: Or a pharmaceutically acceptable salt thereof. 16.  A pharmaceutical composition comprising a pharmaceutically acceptable carrier, and a therapeutically effective amount of a compound according to any one of claims 1 to 15. 17.  The use of a compound according to any one of claims 1 to 5 for the preparation of a condition in which a patient is modulating the activity of MCP-1, MCP-2, MCP-3 and MCP-4 and MCP-5 drug. 18.  The use of a compound according to any one of claims 1 to 5 for the preparation of a medicament for modulating MCP-1 activity in a patient in need thereof. 19.  A use of a compound according to any one of claims 1 to 5, which is 95318-1000927. Doc -17- 1354664 for the preparation of a medicament for the treatment of a condition selected from the group consisting of osteoarthritis, aneurysm, fever, cardiovascular action, Crohn's disease, fulminant heart failure, autoimmune disease, HIV infection, and Ηΐν associated dementia, psoriasis, spontaneous pulmonary fibrosis, graft arteriosclerosis, physical or chemical brain trauma, inflammatory bowel disease, pulmonary cytopathitis, colitis, systemic lupus erythematosus, toxic kidney blood _ Qing nephritis, spheroid nephritis, asthma, multiple sclerosis, atherosclerosis, rheumatoid arthritis, restenosis, organ transplantation and cancer. Lu 20. The use of claim 19 wherein the condition is selected from the group consisting of pneumocytitis, colitis, systemic lupus erythematosus, venous nephritis, spheroid nephritis, asthma, multiple sclerosis, atherosclerosis, rheumatoid arthritis, Restenosis, organ transplantation and cancer. twenty one.  The use of claim 19, wherein the condition is selected from the group consisting of asthma, multiple sclerosis, atherosclerosis, and rheumatoid arthritis. twenty two.  The compound of claim 1, which has the structure: cis-(3S)-l-(4-(tri-butylamino)cyclohexyl)-3-(6-(trifluoromethyl)) p Quinol-4-ylamino)tetrahydropyrrol-2-one; trans-(3S)-1-(4-(t-butylamino)cyclohexyl)-3-(6- (trifluoromethyl) *» 奎唆琳-4-ylamino)tetrahydroindan-2-one; cis-(3S)-1-(4-(tri-butylamino)cyclohexyl -3-(6-Third-butylpyrrolo[1,2-f][l,2,4]trin-4-ylamino)tetrahydropyrrole_2-one; trans-(3S )-l-(4-(Third-butylamino)cyclohexyl)-3-(6-tris-butylpyrrolo[l,2-f][l,2,4]three tillage-4 · arylamino)tetrahydropyrrole-2-one; cis-(3S)-3-tri-butyl-N-(l-(4-(tri-butylamino)cyclohexane 95318-1000927 . Doc -18- 8 1354664 yl)-2-yl-based tetrahydro-p-pyridyl-3-yl)-4-light-based abbreviated amine; trans-(3S)-3-second-butyl-N- (l-(4-(Third-butylamino)cyclohexyl)-2-one-tetrahydro I»biha-3-yl)-4-yl-based acetaminophen; cis-and trans -(3S)-4-tris-butyl-N-(1-(4-(t-butylamino)-]-yl-yl)-2-branched 1 yl-tetram-p-ha-3-yl)- 1Η-ρ比嘻-2 - Atherosamine; cis- and trans-(3S)-4-tri-butyl-N-(1-(4-(tri-butylamino)cyclohexyl) )-2-ketotetrahydrop-pyrylene-3·yl)-1·methyl-_ιη-ι» 嘻-2-carboxylamine; cis- and trans-(3S)-4-gold steel Alkan-1-yl-N-(l-(4-(tris-butylamine-yl)cyclohexyl)-2-oneyltetrahydrop-pyrrol-3-yl)-1Η-ρbilo-2 Carboxylamine; cis- and trans-(3S)-4-gold alkyl-1-yl-N-(l-(4-(tri-butylamino)cyclohexyl)-2-one Tetrahydropyridin-3-yl)-1-mercapto-1H-P ratio slightly-2-amine amine; N-{(3S)-l-[(lS,2R,4R)-4-(iso Propyl-fluorenyl-amino)_2-propyl-cyclohexyl]-2-mercapto-tetrahydropbilo-3-yl}-2-(3-isopropyl-glycosyl)-5-trifluoromethane Benzo-benzoguanamine 1-carboxylic acid (2-{(38)-1-[(18,2 ft, 4 ft)-4-(isopropyl-methyl- _amino)-2-propyl-cyclohexyl]- 2-mercapto-tetrahydro-p-pyrrol-3-ylamine oxime 4-trifluoromethyl-phenyl)-guanamine; l-{2-[((S)-l-((lS,2R ,4R)-4-(isopropyl(indenyl)amino)_2-propylcyclohexyl)-2-onetetrahydropyrrol-3-yl)aminecarboxyl]-4-(trifluoromethyl Phenyl} 3 -ethyl month urine, l-(2-(((S), 2R,4R)-4-(isopropyl(methyl)amino)))) Hexyl)-2-ketotetrahydropyrrol-3-yl)amine fluorenyl)-4-(trifluoromethyl)benzene 95318-1000927. Doc -19- teli)-3-cyclopropylurea; 仏((3)-1-((18,211,411)-4-(isopropyl(indenyl)amino)-2-propylcyclohexyl )-2-ketotetrahydro I»bilo-3-yl)-3-(trifluoromethyl)benzamide; 3-t-butyl-N-((S)-l-(( lS,2R,4R)-4-(isopropyl(methyl)amino)-2-propylcyclohexyl)-2-one-tetrahydropyrrol-3-yl)benzamide; 2-third -butyl-N-((S)-l-((lS,2R,4R)-4-(isopropyl(indolyl)amino)-2-propylcyclohexyl)-2-indenyl four wind I»Bilo-3-yl) Bite-4-Rebel amine; 3-Terve-butyl-4-hydroxy-N-((S)-l-((S,2R,4R)-4 -(isopropyl(methyl)amino)-2-propylcyclohexyl)-2-branched I-based tetrahydro-p-allo-3 _yl)benzamide; 6-tris-butyl-N -((S)-l-((lS,2R,4R)-4-(isopropyl(methyl)amino)-2-propylcyclohexyl)-2-one-tetrahydropyrrole_3·yl曱 p p 比 比 2- 2- 2- 2- 2- Propylcyclohexyl)_2-ketotetrahydropyrrole_3_yl)isonicotinium amide; (8)-1-[(18,2 ft, 411)-4-(isopropyl (methyl) ) 丙基 环 环 环 己 3- 3- 3- (6-(trifluoromethyl)oxazoline _4. 4 ft) 4-(isopropyl(methyl)amino)_2-propylcyclohexyl) 3-(6-(trifluoromethoxy)quinazoline-4 an amine) tetrahydropyrrole _2 ketone; (S)-3-(6-chlorooxazoline·4-ylaminoisopropyl(methyl)amino)-2-propylcyclohexyl)tetrahydropyrrole-2-one; (S)-3-(6-Fluorocarbazole _4-ylaminoisopropyl(methyl)amino)-2-propylcyclohexyl)tetrahydropyrrole·2 ketone; 95318-1000927. Doc •20· (S)-3-(6-Third-butyl occlude [5,4-d] shouting 4-ylamino)] ((lS,2R,4R)-4-(different Propyl (fluorenyl)amino) 2 - propylcyclohexyl) tetrahydrofuran-2-one; (S)-1-((1 S,2R,4R)-4-(isopropyl (methyl) Amino) 2 - propylcyclohexyl) 3-(6-(2-methoxyphenyl)oxazolin-4-ylamino)tetrahydropyrrole_2_ steel; 3-(4-(( S)-l-((lS,2R,4R)-4-(isopropyl(methyl)amino)_2·propylcyclohexyl)-2-one-tetrahydropyrrol-3-ylamino) (Z)-3-(6-Chloroquinazolin-4-ylamino)-i_((is,2R,4R)-4-(isopropylamino)-2 -propylcyclohexyl)tetrahydro? (B)-3-(6-Chlorooxazolin-4-ylamino)-i-((is,2R,4S)-4-(ethyl(isopropyl)amine (2-)-propylcyclohexyl)tetrahydro-p-bi·2·_ ; (S)-l-((lS,2R,4R)-4-(tris-butylamino)_2-propyl Cyclohexyl)_3·(6-(trifluoromethyl)oxazolin-4-ylamino)tetrahydropyrrole-2·one; (S)-l-((lS,2R,4S)-4-( Tris-butylamino)_2-propylcyclohexyl)_3_(6-(trifluoromethyl)quinazolin-4-ylamino)tetrahydro-P belo- 2 ketone; (S)-l- ((lS, 2R, 4R)-4-(diamido)_2-propylcyclohexyl)-3-(6-(trifluoromethyl)*&gt; 嗤··········· Tetrahydrop-pyrrol-2-stuffed; (8)-1-((13,211,411)-4-(dimethylamino)_2-propylcyclohexyl)-3-(6-(trifluorodecyloxy) Quinazolin-4-ylamino)tetrahydroindol-2-yl; 3-tris-butyl-:^-((8)-1-((18,211,411)-4-(diamine) ))-2-propylcyclohexyl)-2-ketotetrahydropyrrol-3-yl)-4-hydroxybenzamide; n-((S)-1-((1S,2R,4R)- 4-(diamino) 2, propylcyclohexyl)-2-one tetrahydropyran-3-yl)-3-(trifluoromethyl)benzamide; N-((S)- L-((lS,2R,4R)-4-(dimethyl Yl) _2_ propylcyclohexyl) -2-one 95318-1000927. Doc •21· 1354664 base four wind pbi-3-yl)-2-(trifluorof-yl) bite-4-rebel amine; (S)-l-((lS,2R,4R)-4 -(Diammonium)-2-propylcyclohexyl)-3-(6-(2-oxophenyl)&gt; quetia-4-ylamino)tetrahydroppyrole 2-hole; 6 -Third-butyl-1^-((5) small((15,211,411)-4-(dimethylamino)-2-propylcyclohexyl)-2-onetetrahydropyrrol-3-yl曱pyridinium amide; 5-(4-chlorophenyl)-N-((S)-l-((lS,2R,4R)-4-(diguanyl)-2-propylcyclohexyl -2-ketotetrahydropyrrole-3-yl)furan-2-carboxamide; (S)-3-(6-tri-butylpyrimidine[5,4-d]pyrimidine-4 -ylamino)-l-((lS,2R,4R)-4-(didecylamino)-2-propylcyclohexyl)tetrahydropyrrole-2-one; (S)-l-((lS , 2R, 4R) -4-(diethylamino)·2_ propylcyclohexyl)_3_(6-(trifluoromethyl) quinine. sitting *#-4-ylamino)tetrahydro ρ pylon_2 (S)-1-((1 S,2R,4R)-4-(diethylamino)_2-propylcyclohexyl)-3-(6-(trifluoromethoxy)p-razole Phenyl-4-ylamino)tetrahydropyrrole-2-one; N-((S)-1-((1S,2R,4R)-4·(diethylamino)_2-propylcyclohexyl)_2_ Ketotetrahydropyrrole-3- 3-(trifluoromethyl)benzamide; 2-tri-butyl-1^-((3)-1-((13,211,411)-4-(diethylamino)- 2-propyl-dopylhexyl)-2-yltetrahydro) mouth bite _4-enylamine; l-((S)-l-((lS,2R,4R)-4-(isopropyl ( Mercapto)amino)_2-propylcyclohexyl)-2-ketotetrahydropyrrole-3yl)-3-(3-(trifluoromethyl)phenyl)urea; (S)-l-( (lS,2R,4R)-4-(isopropyl(methyl)amino)_2-propylcyclohexyl 3-(6-(dimethylmethyl)p-quinegyl-4-ylamino)tetra Nitrogen p piroxime__阙; (R)-l-((lS,2R,4R)-4-(isopropyl(indolyl)amino)_2propylcyclohexyl)_ 3-(6-( Trifluoroindolyl)-indolyl-4-ylamino)tetrahydropyridin-2-one; 95318-1000927. Doc ·22· 8 1354664 N-((S)-l-((lS,2R,4R)-4-(isopropyl(methyl)amino)-2-propylcyclohexyl)-2-one Tetrahydropyrrol-3-yl)-3-(3-trifluoromethylsulfonylaminophenyl)_ acesulfame; 4-hydroxy-1^-((5)-1-((18,211,41) 〇-4-(isopropyl(indenyl)amino)_2-propylcyclohexyl)-2-onetetrahydropyrrol-3-yl)-3-phenyl-benzoamidamine; N-(( S)-l-((lS,2R,4R)-4-(isopropyl(methyl)amino)-2-propylcyclohexyl)-2-onetetrahydroindol-3-yl)- 3-phenyl-benzoguanamine; N-((S)-l-((lS,2R,4R)-4-(isopropyl(methyl)amino)_2-propylcyclohexyl)-2 -keto-tetrahydro-p-indol-3-yl)-2-phenyl-iso-hydrogenated N-oxide; N-((S)-1-((1 S,2R,4R)-4- (isopropyl(methyl)amino)-2-propylcyclohexyl)-2-indenyltetrazolium-pyrrol-3-yl)-1-indolyl-3-arene; N- ((S)-l-((lS,2R,4R)-4-(isopropyl(indenyl)amino)-2-propylcyclohexyl)-2-indenyl tetraphos pbi-3- N-((S)-l-((lS,2R,4R)-4-(isopropyl(methyl)amino)-2 -propylcyclohexyl)-2- Ketotetrahydropyrrol-3-yl)-2-(indolylsulfonylamino)-5-(trifluoromethyl)benzoguanamine; 3-tert-butyl-N-((S)- L-((lS,2R,4R)-4-(isopropyl(indenyl)amino)-2-propylcyclohexyl)-2-one-tetrahydropyrrol-3-yl)-5-( 1H -tetrazol-5-yl)benzamide; N-((S)-l-((lS,2R,4R)-4-(isopropyl(methyl)amino)-2-propylcyclo Hexyl)-2-ketotetrahydropyrrol-3-yl)-3-(4-methyl p-conazole-2-yl)benzamide; N-((S)-l-((lS,2R) , 4R) -4-(isopropyl(indenyl)amino)-2-propylcyclohexane 95318-1000927. Doc -23-yl)-2-copperyltetrahydrom»bilo-3-yl)-5-(tris-methyl)-2-(trifluoro)-benzoguanamine phenylamine; -isopropyl-N-((S)-l-((lS,2R,4R)-4-(isopropyl(indolyl)amino)-2-propylcyclohexyl)-2-oneyl four Hydropyrrol-3-yl)-2-(trifluoromethylsulfonylamino)benzamide; 2-chloro-N-((S)-bu((13,211,411)-4-(isopropyl) (Methyl)amino)-2-propylcyclohexyl)-2-ketotetrahydropyrrol-3-yl)-5-(trifluoromethyl)benzamide; N-((S)-l -((lS,2R,4R)-4-(isopropyl(methyl)amino)_2-propylcyclohexyl)-2-one-tetrahydropyrrol-3-yl)-3-oxazole- 2-yl)benzamide; methyl 3-(((S)-l-((lS,2R,4R)-4-(isopropyl(methyl)amino)-2-propylcyclohexyl) -2'-ketotetrahydropyrrol-3-yl)amine fluorenyl)_5_tris-butyl benzoate; 3-(((S)-l-((lS,2R,4R)) -4-(isopropyl(indenyl)amino)-2-propanylcyclo)-2-ketotetrahydropyrrol-3-yl)amine-branched)-5-tert-butylacetoic acid; 2-Terti-butyl-1-keto-N-((S)-l-((lS,2R,4R)-4-(isopropyl(methyl)amino) -2-propylcyclohexyl)-2-ketotetrahydropbilo-3-yl) shouting 4-sulfoximine; (S)-l-((lS,2S,4R)-2-iso Propyl 4-(isopropyl(indenyl)amino)cyclohexyl)-3-(6-(trifluorof-yl)quinazolin-4-ylamino)tetrahydropyrrole-2-one; (S)-l-((lS,2S,4S)-2-isopropyl-4(isopropyl(methyl)amino)cyclohexyl)-3-(6-(trifluorof-) quinquin (Z)-l-((lS,2S,4R)-2-isopropyl-4-(isopropyl)methylamino Cyclohexyl)-3-(6-(trifluoromethoxy)oxazoline. 4-ylamino)tetrahydropyrrole-2·one; 95318-1000927. Doc •24· 1354664 (S)-3-(6-Chlorooxazolin-4-ylamino)-l-((lS,2S,4R)-2-isopropyl-4-(isopropyl) (methyl)amino)cyclohexyl)tetrahydropyrrole-2-one; 6-tris-butyl-N-((S)-1-((1 S,2S,4R)-2-isopropyl 4-(isopropyl(methyl)amino)cyclohexyl)-2-ketotetrahydropyrrol-3-yl)decylpyridiniumamine; N-((S)-l-((lS,2R) ,4R)-4-(isopropyl(methyl)amino)_2-decylcyclohexyl)-2-yltetrahydropyrrol-3-yl)-3-(trifluoromethyl)benzate Amine; (S)-1-((1 S,2R,4R)-4-(isopropyl(indenyl)amino)_2-methylcyclohexyl)_ 3-(6-(tri-Imethyl)奎 基 基 基 -4- -4- 基 基 基 基 基 基 基 基 基 基 基 S S S S S S S S S S S S S S S S S S S S S S S S S S S S S _2·Methylcyclohexyl)_ 3-(6-(tri-Imethoxy)»»奎°全〇MU-4-ylamino)tetrahydrou-biha_2·one; (S)-l -((lS,2R,4R)-2-ethyl-4-(isopropyl(methyl)amino)-cyclohexyl)-3-(6-(trifluoromethyl)"» sets" Lin-4-ylamino)tetrahydrop-pyrrol-2-_ ; N-((S)-1-((1 S,2R,4R)-4-(isopropyl(indenyl)amino) _2_(曱oxy Base) cyclohexyl)-2-ketotetrahydrop-pyridinyl-3-yl)-3-(trifluoromethyl)benzamide; lp-iXOl-iXlS,2!^,4!^4^ Isopropyl (fluorenyl)amino)_2·(methoxy-based fluorenyl)cyclohexyl)-2-oneyltetrahydropyrrol-3-yl)amineyl).4·(三氤甲(phenyl)-3-ethylurea; (S)-l-((lS,:2R,4R)-4-(isopropyl(f-)amino)_2_(methylidylmethyl)cyclohexyl -(6-(Trifluoromethyl)oxazoline-4-ylamino)tetrahydropyr/2-one; (S)-3-(6-chloroquinazolin-4-ylamine Small ((1 s,2R,4R)-4-(isopropyl(indenyl)amino)-2-(methoxymethyl)cyclohexyl)tetrahydrop ratio _2· ketone; 95318 -1000927. Doc -25- (S)-l-((lS,2R,4R)-4-(isopropyl(indolyl)amino)_2_(decyloxy)cyclohexyl)-3-(6-( Trifluoromethoxy)p-quinazoline- 4-ylamino)tetrahydro-pyrrol-2-one; (S)-1-((1 S,2R,4R)-4-(isopropyl (A) Amino) 2,2-(methoxyindenyl)cyclohexyl)-3-(6-(2-methoxyphenyl)p-salt _4_ylamino)tetrahydro? Bilo 2 ketone; N-((S)-Bu((lS,2R,4R)-2-(ethoxyindolyl)_4-(isopropyl(methyl)amino)cyclohexyl)-2 -ketotetrahydropyrrol-3-yl)-3-(trifluoromethyl)benzoguanamine; (S)-l-((lS,2R,4R)-2-(ethoxymethyl)_4 ·(isopropyl(indenyl)amino)cyclohexyl)-3-(6-(trifluoromethyl)oxazolidine-4-ylamino)tetrahydroindolebiha-2-one; M2- (((S)-l-((lS,2R,4R)-2-(ethoxymethyl)-4-(isopropyl(methyl)amino)cyclohexyl)-2-oneyltetrahydro) Pyrrol-3-yl)amine indolyl)-4-(trifluoromethyl)phenyl)-3-ethylurea; N-((S)-l-((lS,2S,4R)-4-( Isopropyl (indenyl)amino)-2-(2-methoxyethyl)cyclohexyl)-2-onetetrahydropyrrol-3-yl)-3-(trifluoromethyl)phenylhydrazine (S)-l-((lS,2S,4R)-4-(isopropyl(methyl)amino)-2-(2-decyloxyethyl)cyclohexyl)-3-(6 -(trifluoromethyl)quinazolin-4-ylamino)tetrahydropyrrole-2-one; l-(2-(((S),2R)-4-((lS,2S,4R)-4-( Isopropyl (fluorenyl)amino)-2-(2-decyloxyethyl)cyclohexyl)-2-one tetrahydropyrrole-3-yl)aminecarboxyl)_ 4·(trifluoromethyl) stupid)-3-ethylurea; 95318-1000927. Doc -26- 1354664 1-((1 S,2R,4R)-2-(l-hydroxypropyl)_4-(isopropyl(methyl)amino)cyclohexyl)-3-(6-(three Fluoromethyl&gt;quinazolin-4-ylamino)tetrahydropyrrole-2-one; 1-((1 S,2R,4R)-2-(l-hydroxypropyl)_4_(isopropyl Mercapto)amino)cyclohexyl)-3-(6-(trifluoromethyl)oxazolin-4-ylamino)tetrahydropyrrole-2-one; 1^-(b ((18,211,41〇) -2-(1-hydroxypropyl)-4-(isopropyl(methyl)amino)cyclohexyl)-2-ketotetrahydropyrrol-3-yl)-3·(trifluoromethyl)benzene Methionamine; N-(l-((lS,2R,4R)-2-(l-hydroxypropyl)_4_(isopropyl(methyl)amino)cyclohexyl)-2-one tetrahydropyrrole 3-yl)-2-(tert-butyl)pyrimidine-4-carboxamide; 5-(4-phenylphenyl)-N-(l-((lS,2R,4R)-2-() l-Hydroxypropyl)-4-(isopropyl(methyl)amino)cyclohexyl)-2-ketotetrahydroindole-3-yl)furan-2-carboxyindole; Bu ((lS, 2R,4R)-2-(l-Hydroxyethyl)-4-(isopropyl(indenyl)amino)cyclohexyl)-3-(6-(trifluoromethyl)-oxazolin-4-yl Amino) tetrahydropyrrole-2-one; N-(1-((1S,2R,411)-2-(1-hydroxyethyl)-4-(isopropyl) Amino)cyclohexyl)-2-ketotetrahydropyrrol-3-yl)-3-(trifluoromethyl)benzamide; l-((lS,2R,4R)-2-(hydroxyl Methyl)-4-(isopropyl(indenyl)amino)cyclohexyl)-3-(6-(trifluoromethyl)4α-sodium-4-ylamino)tetrahydrofuran-2-one ; l-((lS,2R,4R)-2-(2-hydroxypropan-2-yl)-4-(isopropyl(indenyl)amino)cyclohexyl)-3-(6-(three| L-mercapto) quinazolin-4-ylamino)tetrahydropyrrole-2-one; N-((S)-l-((lS,2R,4R)-2-(2-hydroxyprop-2- 4-(isopropyl(indenyl)amino)cyclohexyl)-2-onetetrahydropyrrol-3-yl)-3-(trifluoromethyl)benzamide; 6-third -butyl-N-((S)-l-((lS,2R,4R)-2-(2-hydroxypropan-2-yl)-4-(iso 95318-1000927. Doc -27·propyl (indenyl)amino)cyclohexyl)-2-ketotetrahydropyrrole_3_yl)methylpyridinium; isobutyric acid ((lR, 2S, 5R)-5-(( Isopropyl (methyl)amino)_2_(2-keto_3_(6-(trifluoromethyl)p- quinazoline-4-ylamino)tetrahydropyrrole-丨-yl)cyclohexyl) A Ester; isobutyric acid ((111,28,511)-5-(isopropyl(methyl)amino)_2_(2-keto_3_(3-(trifluoromethyl)benzamide) tetrahydrogen Pyrrole-fluorenyl-cyclohexyl) decyl ester; isobutyric acid ((111,23,511)-2-(3-(3-tri-butyl-1-methyl-1-s-oxazol-5-carboxyindole) Amino)-2-ketotetrahydropyrrole_1-yl)_5-(isopropyl(methyl)amino)cyclohexyl)methyl ester; isobutyric acid ((1 R,2S,5R)-5-( Monomethylamino)-2-(2-methyl-3-(6-(trifluoromethyl)P-pyrene-4-sulfonylamino)tetrahydro-p-l-l-yl)cyclohexyl) Acetate; isobutyric acid ((lR, 2S, 5R)-5-(dimethylamino)_2·(2-keto-3-(3-(trifluoromethyl)benzamide) tetrahydrogen Pyrrol-1-yl)cyclohexyl)methanine; isobutyric acid ((lR,2S,5R)-2-(3-(3-tris-butyl-i-mercaptozol-5-sulfanylamino) 2-keto-tetrahydro-p-l-yl-1-yl)-5(dimethylamino)cyclohexyl)methyl ester; N-((S)-l-((lS,2R,4R)-4-( Isopropyl(fluorenyl)amino)_2_(methyl succinylmethyl)cyclohexyl)-2-indenyltetrahydroubilo-3-yl)_3_(trifluoromethyl)benzamide; 2 - Amino-:^-((3)-1-((18,211,411)-4-(isopropyl(methyl)amino)_2-(methyl-enriched methyl)3⁄4-hexyl)-2- Net-based tetrazolium p-indenyl)_5·(tri-gaso-oxy)benzene f-amine; 3-tri-butyl-N-((S)-l-((lS,2R,4R)-4 -(isopropyl(indenyl)amino group 95318-100O927. Doc -28- 1354664 )-2-(曱26-ylylmethyl)3⁄4-hexyl)-2-yl-based four gas p ratio _3_yl)_1_mercapto-1H-pyrazole-5-carboxamide 6-Terti-butyl-N-((S)-l-((lS,2R,4R)-4-(isopropyl(methyl)amino)-2-(methyl aryl) Cyclohexyl)-2-yltetrahydrop to each _3_yl)methylpyridiniumamine; N-((S)-l-((lS,2R,4R)-4-(isopropyl ( Methyl)amino)_2 • (曱 酿 甲基 methyl) cyclohexyl)-2-network tetrahydropbilo-3-yl)-6-(trimethyl)methylpyridinium; 1 ^-((3)-1-((18,211,411)-4-(isopropyl(indenyl)amino)_2_(indolyl® methyl)cyclohexyl)-2-ketotetrahydrop比 · -3-yl)-6- 曱 曱 说 说 醯 ; ; ;; N-((S)-l-((lS,2R,4R)-4-(ethyl(isopropyl)amine )_2_(曱(酿)methyl)cyclohexyl)-2-ketotetrahydroindol-3-yl)-3-(trimethyl)benzamide; N-((S)-l- ((lS,2R,4R)-2-(nonylsulfonylmethyl)·4·(neopentylamino)cyclohexyl)-2-ketotetrahydropyrrol-3-yl)-3-(three Fluoromethyl)phenylamine; N-((S)-l-((lS,2R,4R)-4-(isopropyl(indenyl)amine) _2_(曱 sulfoxime® fluorenyl)cyclohexyl)-2-ketotetrahydropyrrol-3-yl)-4-methyl-3-(trifluoromethyl)benzamide; 4-gas 氺- ((5)-1-((13,211,411)-4-(isopropyl(methyl)amino)_2-(oxasulfonyl)-cyclohexyl)-2-one-tetrahydropyrrole-3 -yl)-3-(trifluoromethyl) benzoate; 3-tert-butyl-N-((S)-l-((lS,2R,4R)-4-(isopropyl ( Methyl)amino)-2-(methylsulfonylmethyl)cyclohexyl)-2-ketotetrahydropyrrol-3-yl)benzene 95318-1000927. Doc •29· 1354664 guanamine; 3-phenyl_N-((S)-l((lS,2R,4R)-4-(isopropyl(indenyl)amino)-2-(methylsulfonate) Methyl)cyclohexyl)-2-ketotetrahydropyrrole-3yl)benzamide; N-((S)-l-((lS,2R,4R)-4-(isopropyl ( Methyl)amino)-2-(methylsulfonylmethyl)cyclohexyl)-2-ketotetrahydropyrrol-3-yl)-6-phenylpyrazine-2-carboxamide; 3-fluoro -N-((S)-l-((lS,2R,4R)-4-(isopropyl(indolyl)amino)-2-(methylsulfonylmethyl)cyclohexyl)-2-one Tetrahydropyrrol-3-yl)-5-(trifluoromethyl)benzamide; N-((S)-l-((lS,2R,4R)-4-(isopropyl(fluorenyl) Amino)-2-(indolylmethyl)cyclohexyl)-2-onetetrahydropyrrol-3-yl)-3-(trifluoromethoxy)benzoin; (S)- L-((lS,2R,4R)-4-(isopropyl(indenyl)amino)_2-(decylsulfonyl)cyclohexyl)-3-(6-(trifluoromethyl) Olsin-4-ylamino)tetrahydropyridin-2-one; (S)-3-(6-chloroquinazolin-4-ylamino)_1_((15,211,411)-4- (isopropyl(methyl)amino)-2-(methyl succinylmethyl)cyclohexyl)tetrahydropyrhoal-2-one; N-((S )-l-((lS,2R,4R)-4-(isopropyl(indenyl)amino)·2_(sulfonylhydrazinyl)cyclohexyl)·2-ketotetrahydropyrrole_3_ -3,5-bis(trifluoromethyl)benzamide; 3,5-dichloro-&gt; 1-((8)-:1-((18,211,411)-4-(isopropyl (M)amino)-2-(indolylmethyl)cyclohexyl)-2-ketotetrahydropyrrol-3-yl)benzamide; 95318-1000927. Doc •30· 8 1354664 N-((S)-l-((lS,2R,4R)-2-(T-butylsulfonylmethyl)-4-(isopropyl(methyl)amine) Cyclo)-cyclohexyl)-2-ketotetrahydropyrrol-3-yl)- 4-fluoro-3-(trifluoromethyl)benzoamidamine; N-((S)-l-((lS, 2R,4R)-2-(Tertiary-butylsulfonylmethyl)-4-(isopropyl(methyl)amino)cyclohexyl)-2-onetetrahydropyrrol-3-yl)- 6-(Trifluoromethyl)methylpyridinium; N-((S)-l-((lS,2R,4R)-2-(T-butylsulfonylmethyl)-4-( Isopropyl (methyl)amino)cyclohexyl)-2-ketotetrahydropyrrol-3-yl)-3-(trifluoromethyl)benzamide; 6-tertiary-butyl-N- ((S)-l-((lS,2R,4R)-2-(Tertiary-butylsulfonylmethyl)-4-(isopropyl(indenyl)amino)cyclohexyl)-2- Ketotetrahydropyrrol-3-yl)methylpyridiniumamine; N-((S)-l-((lS,2R,4R)-2-(tris-butylsulfonylmethyl)-4 -(isopropyl(methyl)amino)cyclohexyl)-2-onetetrahydropyrrol-3-yl)-3-(trifluoromethoxy)benzamide; N-((S) -l-((lS,2R,4R)-2-(T-butylsulfonylfluorenyl)-4-(isopropyl(fluorenyl) Amino)cyclohexyl)_2-yl-tetraphos pbi-3-yl)-3-disorganized- 5-(trifluoromethyl) stanylamine; 2-amino-N-((S) -l-((lS,2R,4R)-2-(Tertiary-butylsulfonylfluorenyl)-4-(isopropyl(methyl)amino)cyclohexyl)-2-oneyltetrahydrol Pyrrol-3-yl)-5-(trifluoromethoxy)benzamide; 3-amino-((8)-1-((18,211,411)-2-(tri-butylsulfonate)醯-mercapto)- 4-(isopropyl(indenyl)amino)cyclohexyl)-2-onetetrahydropyrrol-3-yl)-5-(trifluoromethyl)benzamide; 95318 -1000927. Doc •31 - 1354664 N-((S)-l-((lS,2R,4R)-2·(T-butylsulfonylmethyl)·4-(isopropyl(methyl)amine) Cyclohexyl)-2-ketotetrahydropyrrol-3-yl)-5-phenyl in the base decylamine N-oxide; (8)-1-((18,2 ana, 411)-2-( Tris-butylsulfonylhydrazino)-4-(isopropyl(methyl)amino)cyclohexyl)-3-(6-(trifluoromethyl)quinazolin-4-ylamino)tetra Hydrogen p ratio slightly-2-oxime; (5)-1-((18,211,411)-2-(tris-butylsulfonylhydrazino)-4-(isopropyl(methyl)amino) Cyclohexyl)-3-(6-chlorobenzylidene-4-ylamino)tetrahydroppyr-2-one; 3-tris-butyl-1^-((5)-1-( (18, 2 heart 411)-2-(t-butylsulfonylmethyl)-4-(isopropyl(methyl)amino)cyclohexyl)-2.ketotetrahydropyha_3_ ))-4-hydroxybenzamide; N-((S)-l-((lS,2R,4R)-2·(T-butylsulfonylmethyl)·4_(isopropyl) Methyl)amino)cyclohexyl)-2-ketotetrahydropyrrol-3-yl)-5-phenyl in the amine; N-((S)-l-((lS,2R,4R)-4 -(isopropyl(indenyl)amino)-2.(isopropyl(indolyl)indolyl)cyclohexyl)-2-oneyltetra Hydrogen I»Bilo-3-yl)-3-(trifluoromethyl)benzamide; (S)-l-((lS,2R,4R)-4-(isopropyl(methyl)amine Benzyl-2-(isopropylsulfonylhydrazinyl)cyclohexyl)-3-(6-(trifluoromethyl)»»奎嗤淋-4-ylamino)tetrahydro-p-bi-2- Cave; 3-tert-butyl-1^-((8)-1-((18,211,411)-4-(isopropyl(methyl)amino)-2-(isopropyl) Mercapto)cyclohexyl)-2-holeyltetrahydropyrrole-_3_yl)·1-methyl-1H-pyrazole-5-carboxyguanamine; 95318-1000927. Doc -32- 8 1354664 N-((S)-l-((lS,2R,4R)-2-(isopropyl hydrazinyl)_4_(tetrahydroexoindole-1-yl)cyclohexyl --2-feeding tetrahydrop-p 嘻_3_yl)·3_(trifluoromethyl)benzamide; 3-tris-butyl-N-((S)-l-((lS, 2R,4R)-4-(isopropyl(methyl)amino)-2-(isopropylsulfonylmethyl)cyclohexyl)-2-onetetrahydropyrrole_3_yl) phenylhydrazine (S)-l-((lS,2R,4R)-4-(ethyl(isopropyl)amino)_2-(isopropyl cyanomethyl)cyclohexyl)-3-( 6-(Trifluoromethyl) 4 β gulin _4_ ylamino) tetrahydropyrrole-2-one; · 3-Terve-butyl-N-((S)-l-((lS, 2R , 4R)-4-(ethyl(isopropyl)amino)-2-(isopropyl succinylmethyl)cyclohexyl)_2-fluorenyltetrahydrop ratio _3_yl) phenylhydrazine Amine; 3 - second-butyl-N-((S) - l-((lS,2R,4R)-4-(isopropyl(propyl)amino)-2-(isopropyl hydrazine Benzyl)cyclohexyl)_2-ketotetrahydropbilol-3-yl) benzoguanamine; (8)-1-((18,211,411)-4-(isopropyl(indenyl)amine) )-(isopropyl hydrazinyl)cyclohexyl)-3-(6-(trifluoromethoxy)V» 奎嗤琳_4·ylamino)tetrahydrogen p to 11 each-2-ketone; (S)-l-((lS,2R,4R)-4-(ethyl(isopropyl)amino)_2·(different Propylsulfonyl fluorenyl)cyclohexyl)-3-(6-(trifluoromethoxy)thiazolidine _4_ylamino)tetrahydrop ratio c each -2-( ; (S)-l -((lS,2R,4R)-4-(ethyl(isopropyl)amino)_2-(isopropyl chloromethyl)cyclohexyl)-3-(6.(trifluoromethyl) ♦ oxazolyl-4·ylamino) tetrahydrogen ring 鸣* - 2 - class, 95318-1000927. Doc •33- 1354664 N-((S)-l-((lS,2R,4R)-4-(isopropyl(indenyl)amino)-2-(isopropylsulfonylmethyl) ring Hexyl)-2-ketotetrahydropyrrol-3-yl)-1-indenyl-1H_P-indole-2-carboxamide; N-((S)-l-((lS,2R,4R)- 4-(Ethyl(isopropyl)amino)-2-(isopropyl hydrazinyl)cyclohexyl)-2-ketotetrahydropyrrole-3-yl)-3·(2Η-tetrazole -5-yl)benzamide; N-((S)-l-((lS,2R,4R)-2-(ethylsulfonylmethyl)-4-(isopropyl (methyl)) Amino)m-hexyl)_2-ketotetrahydropyridyl-3-yl)-3-(trimethylmethyl)benzamide; (8)-1-((13,211,411)-2-( Ethylsulfonylmethyl)-4-(isopropyl(indenyl)amino)cyclohexyl)-3_(6-(trifluoromethyl)oxazolin-4-ylamino)tetrahydropyrrole- 2-ketone; N-((S)'l-((lS,2R,4R)-2-(ethyl aryl fluorenyl)-4-(isopropyl(indenyl)amino)cyclohexyl) 2-ketotetrahydropyrrol-3-yl)-3-(phenyl)benzamide; N-((S)-l-((lS,2R,4R)-2-(ethylsulfonate) Benzyl)-4-(isopropyl(methyl)amino)cyclohexyl)-2-one-tetrahydropyrrol-3-yl)-3-(4-A Benzyl-2-phenyl)benzamide; 3-(((S)-l-((lS,2R,4R)-2-(ethylsulfonylmethyl)-4-(isopropyl) (indenyl)amino)cyclohexyl)-2·ketotetrahydropyrrol-3-yl)aminecarboxylidene-5-tris-butylbenzoic acid; (111,23,511)-5-(isopropyl (meth)amino)-2-((8)-2-keto-3-(3-(trifluoromethyl)benzylideneamino)tetrahydropyrrol-1-yl)cyclohexanecarboxylate Methyl ester; (111,28,511)-5-(second-butylamino)-2-((8)-2-yl-3-(3-(三敦95318-1000927. Doc -34- 8 1354664 methyl) benzylamino) tetrahydropyrrole-1-yl) oxime carboxylic acid oxime ester; (1R, 2S, 5R) _5_ (tris-butyl (methyl) amine Base)_2_((s)_2-keto_3_(3-(trifluoromethyl) amidino) tetrahydropyrrole-indole-yl) cyclohexanecarboxylic acid methyl ester; (lR, 2S, 5R -5-(isopropyl(methyl)amino)-2-((S)-2-keto-3-(6-(trifluoromethyl)oxazolin-4-ylamino)tetra Hydroxyl pyridyl-1 -yl)cyclohexanecarboxylate; (lR,2S,5R)-5-(isopropyl(methyl)amino)_2-((S)-2-keto-3- Methyl (6-(trifluoromethoxy)oxazolin-4-ylamino)tetrahydropyrrole-1 -yl)cyclohexanecarboxylate; (lR,2S,5R)-2-((S) -3-(3-Terti-butyl-4-hydroxybenzoguanidino)-2-ketotetrahydropyrrol-1-yl)-5-(isopropyl(indenyl)amino)-cyclo Methyl hexanecarboxylate; (lR, 2S, 5R)-2-((S)-3-(3-fluoro-5-(trifluoromethyl)phenylhydrazinyl)-2-one-4- Hydrogen pyrrol-1-yl)-5-(isopropyl(indenyl)amino)-cyclohexanecarboxylic acid methyl ester; (lR,2S,5R)-2-((S)-3-(2- Tertiary-butylpyridinium)-2-ketotetrahydropyrrole-1-yl)-5-(isopropyl Methyl (decyl)amino)-cyclohexanecarboxylate; (111,25,5 ft)-2-((3)-3-(3-tert-butyl-4-hydroxybenzhydrazide Methylamino)-2-ketotetrahydropyrrol-1-yl)-5-(tris-butylamino)cyclohexanecarboxylate; (lR, 2S, 5R)-2-((S) 3-(3-tert-butylbenzylidinium)-2-ketotetrahydropyrrol-1-yl)-5-(tri-butylamino)cyclohexanecarboxylate; (lR, 2S, 5R)-5-(T-butylamino)-2-((S)-3-(2-tri-butylsulfanyl 95318-1000927. Doc-35-Acridino-4-carboxyindolyl)-2-ketotetrahydropyrrole_methane) Cyclohexanecarboxylic acid methyl ester (lR, 2S, 5R)-5-(tri-butylamine Methyl)-2-((S)-3-(2-tert-butylpyridinium)-2-ketotetrahydropyrrol-1-yl)cyclohexanecarboxylate; (lR, 2S , 5R)-5-(t-butylamino)-2-((S)-3-(3-phenylbenzylidinium)-2-indenyltetrazine p-specific -1-yl环 院 院 缓 缓 ;; (1 尺, 28, 5 尺) -5-(T-butylamino)-2-((8)-2- benzyl-3-(2-phenyl) Pyridin-6-carboxyguanidino)tetrahydroindol-1-yl) cyclohexanone methyl ester; (1 ft, 23,511)-5-(tri-butylamino)-2-(( 8) methyl 3-(4-fluoro-3-(trifluoromethyl)-benzoguanidino)-2-ketotetrahydropyrrol-1-yl)cyclohexanecarboxylate; (lR, 2S,5R)-5-(Third-butyl(methyl)amino)-2-((S)-3-(2-(4-chlorophenyl)pyran-5-amidyl) -2-_yltetrahydrop-bi-l-yl) cyclohexanone methyl ester; (lR, 2S, 5R)-5-(tris-butyl(methyl)amino)_2-(( S) 2-1-keto-3-(6-(trifluoromethoxy)oxazoline-4-ylamino)tetrahydropyrrol-1-yl)cyclohexanecarboxylic acid methyl ester; (lR, 2S, 5R ) -5-(Third-butyl(methyl)amino)_2-((S)-2-keto-3-(6-(trifluoromethyl)quinazolin-4-ylamino)tetra Ethyl pyrrolyr-1-yl)cyclohexanecarboxylate; (lR, 2S, 5R)-5·(tri-butylamino)-2-((S)-2-keto-3-( 4-(perfluoroethyl)pyrazole-2-carboxyguanidino)tetrahydropyrrole-fluorenyl-cyclohexanecarboxylic acid oxime ester; (111,23,51〇-5-(tri-butyl) Amino)-2-((8)-3-(4-tri-butyl 95318-1000927. Doc -36 - 1354664 pyrimidine-2-carboxyguanidino)-2-mercaptotetrahydropyrrol-1-yl)cyclohexanecarboxylic acid methyl vinegar; (lR, 2S, 5R)-5- (third- Butylamino)-2-((S)-2-keto-3-(4-(3-(trifluoromethyl)-phenyl)pyrazole-2-carboxyguanidino)tetrahydropyrrole- 1-yl)cyclohexanecarboxylic acid oxime ester; (1 ft, 28,511)-5-(tri-butylamino)-2-((8)-2-keto-3-(4-phenyl) Thiazole-2-carboxyguanidino)tetrahydropyrrole_1-yl)cyclohexanecarboxylic acid oxime ester; (lR,2S,5R)-5-(tri-butylamino)-2-((S )-3-(4-(4-Phenylphenyl)oxazol-2-carboxyindenyl)-2. ketotetrahydropyrrol-1-yl)cyclohexanecarboxylic acid methyl ester; (lR, 2S, 5R)-2-((S)-3-(4-(benzo[d]pyrazol-2-yl)oxazol-2-carboxyindolyl)-2-ketotetrahydropyrrole-1-yl -5-(T-butylamino)cyclohexanecarboxylic acid methyl ester; (lR, 2S, 5R)-5-(2-butylamino)-2-((S)-2 - Alkyl-3-(4-(p-cephen-3-yl)thiazole-2-carboxyguanidino)tetrahydropyrrole-1-yl)cyclohexanecarboxylic acid methyl vinegar; (lR, 2S, 5R)- 5-(Third-butylamino)-2-((S)-2-keto-3-(4-(4 phen-2-yl)pyrazole-2-carboxyguanidino)tetrahydropyrrole -1-base) ring Methyl alkanoate; (lR, 2S, 5R)-2-((S)-3-(4-(金铁烷-1·yl)pyrazole-2-carboxyguanidino)-2-keto Methyl tetrahydropyrrol-1-yl)-5-(t-butylamino)cyclohexanecarboxylate; (lR,2S,5R)-5-(tri-butylamino)-2-(( S)-2-mercapto-3-(4-(pyridin-2-yl)pyrazole-2-carboxyguanidino)tetrahydropyrrol-1-yl)cyclohexanecarboxylic acid 95318-1000927. Doc •37- 1354664 methyl ester; (lR,2S,5R)-5-(tris-butylamino)-2_((s)_2-keto·3_(2·phenylthiazole-4-carboxyindole Amino)tetrahydropyrrole_ι_yl) cyclohexane carboxylic acid methyl ester; (1 ft, 25,511)-5-(tri-butylamino)_2_((8)_3_(2_(4_ benzene) (喽嗤) 曱-4-carboxyindoleyl)-2-ketotetrahydropyrrol-1-yl)cyclohexanecarboxylic acid oxime ester; (lR, 2S, 5R)-2-((S)-3- (2-Terve-butyl-5-methylfuran-4-carboxyindenyl)-2-ketotetrahydropyrrol-1-yl)-5-(tri-butylamino)cyclohexane -carboxylic acid methyl ester; (1 ft, 23,511)-5-(tris-butylamino)-2-((3)-2-keto-3-(2-(trifluoromethyl)furan- 5-Carboxynonylamino)tetrahydropyrrol-1-yl)cyclohexanecarboxylate; (1R,2S,5R)_5_(Third-butylamino)-2-((S)-3- (2-(4-Chlorophenyl)furan-5-carboxyguanidino)-2-ketotetrahydropyrrol-1-yl)cyclohexanecarboxylate; (lR, 2S, 5R)-5- (Third-butylamino)-2-((S)-2-yl-3-(2-(3-(trifluoromethyl)phenyl)furan-5-carboxyguanidino) tetrahydrogen Methyl pyrrol-1-yl)cyclohexanecarboxylate; (lR,2S,5R)-5-(tris-butylamino)-2-((S) 3-(2-(2-carbyl-5-(trifluoromethyl)phenyl)furan-5-carboxyindenyl)-2-ketotetrahydropyrrole-i-yl)cyclohexanecarboxylic acid Methyl ester; (lR, 2S, 5R)-5-(t-butylamino)-2-((S)-3-(2-(2,5·dichlorophenyl)pyran-5- Carboxylamido)-2-ketotetrahydropyrrole-1-yl) cyclohexane carboxylic acid methyl ester; 95318-1000927. Doc -38· 8 1354664 (lR,2S,5R)-5-(Third-butylamino)_2_((8)_3_(2_(4-isopropylphenyl)furan-5-carboxyguanidino ) 2 - keto-tetrahydropyrrole-1 -yl) cyclohexanecarboxylic acid methyl ester; (111,25,511)-5-(third-butylamino)_2_((5)-3-(2_(4) _Fluorophenyl)furan-5-carboxy-bromoamino)-2-ketotetrahydropyrrol-1-yl)cyclohexanecarboxylic acid oxime ester; (lR, 2S, 5R)-5- (third · butyl Methylamino)_2_((S)_2-keto-3-(2-phenylfuran-5-carboxyguanidino)tetrahydropyrrole-yl)cyclohexanecarboxylic acid methyl ester; (lR, 2S , 5R)-5·(Third-butylamino)_2_((S)-3-(2-(3-fluorophenyl)furan-5-carboxyguanidino)_2-ketotetrahydropyrrole- 1-yl)cyclohexanecarboxylic acid oxime ester; (111,28,511)-5-(tri-butylamino)_2_(〇3-(2_(3-cyanophenyl)furan-5-carboxyindole Ethyl)-2-keto-tetrahydropyrrol-1-yl)cyclohexanecarboxylic acid decyl ester; (lR, 2S, 5R)-5-(t-butylamino)_2_((8)_3_(2_(3• Methoxyphenyl)furan-5-carboxyindenyl)-2-ketotetrahydropyrrol-1-yl)cyclohexanecarboxylic acid oxime ester; (lR, 2S, 5R)-5- (third · butyl Amino) 2 - ((S)-3-(2-(4-cyano) Methyl)furan-5-carboxyindenyl)-2-ketotetrahydropyrrol-1-yl)cyclohexanecarboxylate; (lR, 2S, 5R)-5-(tri-butylamino) ) 2-((S)-3-(2-(3,4-difluorophenyl)furan-5-carbamoylamino)-2-one-tetrahydropyrrole-1-yl)cyclohexanecarboxylic acid Anthracene ester; (lR, 2S, 5R)-5·(T-butylamino)-2-((S)-2-keto-3-(2-(4-(三95318-1000927. Doc -39- 1354664 fluoromethyl)phenyl)pyran-5-rebel-amino)tetrahydro-p-bi-oxime-yl) cyclohexanyl acid; (lR, 2S, 5R)-5· (Third-butylamino)_2-((S)-3-(3-(4-methoxyphenyl)indole-5-carboxyindolyl)-2-ketotetrahydropyrrolidyl) Cyclohexane carboxylic acid methyl ester; (111,23,511)-5-(tris-butylamino)_2-((3)-2-yl-3-(3-(4-(trimethyl)methyl) Phenyl)furan-5-carboxyguanidino)tetrahydropyrrole_1-yl) cyclohexane carboxylic acid methyl ester; (lR, 2S, 5R)-5-(tri-butylamino)_2_( (s)_2_keto-3·(3_phenylpyran-5-treaminyl)tetrahydrop ratio _ι_yl) cyclohexanol oxalate; (lR, 2S, 5R)-5 -(Third-butylamino)_2_((s)-2-keto-3-(3-phenyl4phen-5-carboxyguanidino)tetrahydropyrrolyl)cyclohexanecarboxylic acid methyl ester (lR,2S,5R)-5-(Thr-butylamino)_2-((s)_2-keto-3-(2·(pyridin-2-yl)porphin-5-carboxyindole Amino) tetrahydropyrrole-indole-yl) cyclohexanecarboxylic acid methyl ester; (111,28,511)-5-(tris-butylamino)_2_((8)_2-keto-3-(2) - oxenophen-2-yl)thiophene-5-carboxyguanidino)tetrahydropyrrole-丨-yl)cyclohexane Methyl carboxylate; (lR, 2S, 5R)-5-(tris-butylamino)_2_((s)_2-keto-3-(2-phenylsep-5-arubic amine a tetrahydro-p-bi_1-yl) cyclohexyl sulphate methyl ester;  (lR, 2S, 5R)-5-(Third-butylamino)_2_((s)_3-(2-(4-methoxyphenyl)thiophene-5-carboxyguanidino)-2-one Methyl tetrahydropyrrole-丨-yl) cyclohexanecarboxylate; (lR, 2S, 5R)-5-(tri-butylamino)_2_((s)_3-(l-methyl-3 -Phenyl·95318-1000927. Doc •40· 8 1354664 1H-Pyrazole-5-carboxyguanidino)-2-ketotetrahydropyrrol-1-yl)cyclohexanecarboxylic acid methyl ester; (lR, 2S, 5R)-5-( Tert-butylamino)-2-((S)-2-keto-3-(3-phenylisoxazole-5-carboxyguanidino)tetrahydropyrrol-1-yl)cyclohexane Ethyl carboxylate; (lR, 2S, 5R)-5-(tri-butylamino)-2-((S)-2-keto-3-(6-(trifluoromethyl)carbazole (4,23,511)-5-(tris-butylamino)-2-((8)-3 -(6-Third-butylpyrimido[5,4-d]pyrimidin-4-ylamino)-2-one-tetrahydropyrrole-1-yl)cyclohexanecarboxylate; (1 foot) ,28,511)-5-(Third-butylamino)-2-((8)-3-(6-oxaquinazolin-4-ylamino)-2-onetetrahydropyrrole-1 -yl)methyl cyclohexanecarboxylate; (111,28,511)-5-(tris-butylamino)-2-((8)-2-keto-3-(6-(trifluoromethyl) Methyl)-4-oxazolyl-4,ylamino)tetrahydropyrrole-1-yl)cyclohexanecarboxylate; (lR,2S,5S)-5-(tri-butylamino)- Methyl 2-((S)-2-keto-3-(3-(trifluoromethyl)-benzoguanidino)tetrahydropyrrole-1-yl)cyclohexanecarboxylate; (lS,2S,5R)-5-(isopropyl(methyl)amino)-2-((S)-2-keto-3-(3-(trifluoromethyl)benzenef-aminol Ethyl tetrahydropyrrole-1-yl)cyclohexanecarboxylate; (lS,2S,5R)-2-((S)-3-(2-(4.chlorophenyl)furan-5-carboxyindole Methylamino)-2-ketotetrahydropyrrol-1-yl)-5-(isopropyl(indenyl)amino)cyclohexanecarboxylic acid methyl ester; (lS,2S,5R)-2-(( S)-3-(3-Terti-butyl-4-hydroxybenzamide)-2-ketotetrahydropyrrole-bu)-5-(isopropyl(indenyl)amino) ring Hexanecarboxylic acid 95318-1000927. Doc •41 - 1354664 methyl ester; (lS,2S,5R)-2-((S)-3-(2-(4-phenylphenyl)furan-5-carboxyguanidino)-2-keto-4 Ethyl pyrrol-1-yl)-5-(isopropyl(methyl)amino)cyclohexanecarboxylate; 3-((lS,2S,5R)-5-(isopropyl(methyl)) Ethyl)-2-((S)-2-keto-3-(3-(trifluoromethyl)benzhydrylamino)tetrahydropyrrole-1-yl)cyclohexyl)propionic acid ethyl ester; 3 -((lS,2S,5R)-5-(isopropyl(methyl)amino)-2-((S)-2-keto-3-(3-(trifluoromethyl)benzamide Amino)tetrahydropyrrol-1-yl)cyclohexyl)propionic acid; (S)-l-((lS,2R,4R)-4-isopropoxy-2-(isopropylsulfonylmethyl) Cyclohexyl)-3-(6-(trifluoromethyl)oxazolin-4-ylamino)tetrahydropyrrole-2-one; (S)-1-((1 S,2R,4R)- 4-methoxy-2-(methylsulfonylmethyl)cyclohexyl)-3-(6-(trifluoromethyl)&gt;»奎0下-4-amino-amino)tetrahydro-p-pyrene 2-ketone; 2-tert-butyl-N-((S)-1-((1S,2R,4R)·4-methoxy-2-(nonylsulfonylmethyl)cyclohexyl) -2 - mercapto tetrahydro ρ ratio σ each -3-yl) ° 3⁄4 bite-4-encaptoamine; 5-(4-chlorophenyl)-N-((S)-1-((1 S, 2R,4R)-4-decyloxy-2-( Sulfomethyl)cyclohexyl)-2-ketotetrahydropyrrol-3-yl)pyran-2-carboxyindole; (S)-l-((lS,2R,4S)-4-isopropyl Oxy-2-(isopropylsulfonylmethyl)cyclohexyl)-3-(6-(trifluoromethyloxazolyl-4-ylamino)tetrahydro-p-ha-2-one; 5- (3-(((S)-l-((lS,2R,4R)-4-methoxy-2-(methylsulfonylmethyl)cyclohexyl)-2-one-tetrahydropyrrole-3- Ethyl mercapto)phenyl)phenyl-3-carboxylic acid decyl ester; 95318-l000927. Doc -42- 8 1354664 5-(3-((3)-1-((13,2 ft,411)-4-methoxy-2-(methylsulfonylmethyl)cyclohexyl)-2 -ketotetrahydropyrrol-3-yl)amine fluorenyl)phenyl)phenyl-3-carboxylic acid; (S)-1-((3R,4S)-1-isopropyl-3-propyl Hexahydropurine is more than -4-yl)-3-(6-(trifluoromethyl)p-doxazol-4-ylamino)tetrahydro-p-butan-2-one; (S)-1-( (3R,4S)-1-isopropyl-3-propylhexahydrop-butyl-4-yl)-3-(6-(tri- 1 decyloxy) &lt;»Set of salivary? Forest-4-ylamino) Four moxibustion ^Bilo 2 -_ ; 5-(4-chlorophenyl)-N-((S)-l-((3R,4S)- L-Isopropyl-3-propylhexahydropyridin-4-yl)-2-ketotetrahydrop-pyrimidin-3-yl)indole-2-treazone; N-((S)- 1-((3R,4S)-1-isopropyl-3-propylhexanitro-p-buty-4-yl)-2-indolyltetrahydropyrrol-3-yl)-3-(trifluoromethyl) Benzoguanamine; (S)-1-((3S,4S)-1-isopropyl-3-propylhexahydrop-biti-4-yl)-3-(6-(trifluoromethyl) V 0 0 坐 -4- ylamino) tetrahydrogen (^ -2- ketone; (S)-1-((3S,4S)-diisopropyl-3-propylhexahydropyridine-4 -yl)-3-(6-(trifluorodecyloxy)°azate-4-ylamino)tetrahydrop to slightly-2-copper; N-((S)-1-((3S,4S) )-1-isopropyl-3-propylhexanitro-p-precipitate-4-yl)-2-copperyltetrahydropyrrol-3-yl)-3-(trifluoromethyl)benzamide; 5 -(4-chlorophenyl)-N-((S)-l-((3S,4S)-l-isopropyl-3-propylhexahydropyridin-4-yl)-2-yl-4- Hydroquinone is more specific than indole-3-yl)pyran-2-amine; (3R,4S)-1-isopropyl-4-(2-keto-(3S)-3-(6-(trifluoro) Methyl)carbazolyl-4-ylamino)tetrahydropyrolo-1_yl)hexahydropyridine-3-ylcarboxylate; (3S,4S)-1-isopropyl 4-(2-keto-(3S)-3-(6-(trifluoromethyl)oxazolidine-4-ylamino)tetrahydropyrrole-indole-yl)hexahydropyridine_3_carboxylic acid hydrazine Ester; ((8)-1-((31^,48)-1-isopropyl-3-(isopropylsulfonylmethyl)hexahydro 95318-1000927.doc 43· 1354664 0 7 pyridine 4-yl)_2-ketotetrahydropyrrole_3_yl)-3-(trifluoromethyl)benzamide; N-((S)-1-((3R,4S)-1-iso) Butyl-3-(isopropyl succinylmethyl)hexahydrop-butyt-4-yl)-2-ketotetrahydropbilo-3-yl)-3-(trifluoromethyl)benzene Brewing amine; N-((S)-1-((3R,4S)-1-ethyl-3-(isopropyl aryl fluorenyl) hexahydro ρ than -4-yl)-2- Ketotetrahydrop to 嘻-3·yl)-3-(trifluoromethyl)benzamide; Spring (S)-l-((lR,2S,4S)-4-(isopropyl (A) Amino)-2-methoxycyclohexyl)-3-(6-(trifluoromethyl)carbazole, lin-4-ylamino)tetrahydropyha 2 嗣; or drama: 彳:丨^ » ··. &lt;&quot; (S)-l-((lS,2R,4R)-4-(isopropyl(methyl)amino)-2-decyloxycyclohexyl)-3-(6-(trifluoro) Indenyl)oxazolin-4-ylamino)tetrahydropyrrole. 95318-1000927.doc -44- 8