TWI329637B - Compounds - Google Patents

Description

1329637 . A7 'B7 V. INSTRUCTION DESCRIPTION (1) The present invention relates to compounds which are useful for inhibiting metalloproteinases, and in particular to pharmaceutical compositions comprising the same, and uses thereof. The compounds of the invention are inhibitors of one or more metalloproteinases. Metalloproteinases are supergroups of proteases (enzymes) whose number has increased dramatically in recent years. Based on structural and functional considerations, these enzymes have been classified into several subgroups and subpopulations as described in N. M. Hooper (1994) FEBS Letters 354: 1-6. Examples of metalloproteinases include interstitial metalloproteinases (MMPs) such as collagenase (MMP1, MMP8, MMP13), gelatinase (MMP2, MMP9), matrix lysin (MMP3, MMP10, MMP11), and interstitial hormone (MMP7) ), metal elastase (MMP12), enamel lysin (MMP19), MT-MMP (MMP14, MMP15, MMP16, ΜΜΡΠ); germ lysin or enamel lysin or MDC population, including secretase and efflux enzymes, such as TNF-converting enzyme (ADAM10 and TACE); a group of astaxanthins, including enzymes such as procollagen-treated protease (PCP): and other metalloproteinases, such as aggregating pro-enzymes, endothelin-converting enzyme groups, and angiotensin-converting enzyme groups . Salt metalloproteinases are important in the blood of physiological processes, which involve tissue engineering, such as embryo development, osteophyte formation, and uterine transformation during menstruation. This is based on the ability of metalloproteinases to cleave a wide range of quality traits such as collagen, proteoglycan and fibrin. It is also known that metalloproteinases are involved in the processing or secretion of biologically important cell mediators, such as tumor necrosis factor (TNF); and biologically important membrane proteins, such as the low-affinity IgE receptor CD23 (for a more complete list, N_M. Helper et al. (1997) Biochem J. 321: 265-279) is important to translate protein water after treatment or treatment. ______^__ This paper scale General Chinese National Standard (CNS) A4 specification (210 X 297 mm > 1329637, A7 ' B7 V. Description of invention (2) Metalloproteinases are associated with many diseases or symptoms. One or more metals The inhibition of protease activity is beneficial to such diseases or symptoms, such as various inflammatory and allergic diseases, such as joint inflammation (especially rheumatoid arthritis, osteoarthritis and gout), inflammation of the gastrointestinal tract (especially It is inflammatory bowel disease, ulcerative colitis and gastritis), skin inflammation (especially psoriasis, eczema 'dermatitis); in tumor metastasis or invasion: on diseases associated with uncontrolled degradation of extracellular stroma , such as osteoarthritis; in bone debilitating diseases (such as osteoporosis and Paeder's disease); in diseases associated with vaginal angiogenesis; with diabetes, periodontal ligament disease (such as dental gingivitis),角. Membrane ulcers, skin ulcers, post-operative symptoms (such as colonic anastomosis) and skin wound healing are associated with enhanced collagen modification; myelin sheath disease in the central and peripheral nervous systems Such as multiple sclerosis; Alzheimer's disease; extracellular interstitial transformation found in cardiac and vascular diseases such as restenosis and atherosclerosis; asthma; rhinitis; and chronic obstructive pulmonary disease (COPD). Also known as macrophage elastase or metallo-elastase, which is first in mice, asexual: by Shapiro et al. [1992, J. Biol. Chem. 2: 4664] and in the human body by the same group in 1995. The MMP-12 line is preferentially expressed in activated macrophages and has been shown to be secreted by the giant cell of the smoker's lung [Shapiro et al., 1993, Biochemicals 'j, 268: 23824], And in foam cells of atherosclerotic lesions of atheroma [Matsumoto et al., 1998, Am J Pathol \53_109]. The mouse model of COPD stimulates mice with cigarette smoke. After six months, two cigarettes a day, Based on a Saturday day, wild-type mice developed emphysema after this treatment. When MMP12 knockout mice were tested in this mode, they did not develop significant gas ___ - B - This paper scale applies to Chinese national standards (CMS) A4 regulation (21〇x 297 mm) 1329637, A7 'B7 V. invention is described in (3) swelling' strongly suggests that MMP-12 is a key enzyme in the CoPt) of pathogenesis. The role of _P, such as MMP12 in COPD (emphysema and bronchitis), is discussed in Anderson and Shinagawa, 1999, current insights on anti-inflammatory and immunomodulatory research drugs 1 (1} : 29-38. Recently discovered Smoking increases macrophage infiltration and macrophage-derived MMP-12 is expressed in human carotid plaque fCangavari [Matetzky S, Pishbein MC et al., Cycle i〇2: 18, 36-39 Supplementary S, 2000 10 March 31] MMP13, or collagenase 3, is first vegetatively propagated from a cDNA gene pool derived from breast tumors [J. Μ·P. Freije et al. (1994) Biochemistry Journal 269(24): 16766- 16773]. PCR-RNA analysis from a wide range of tissues (10), showing that MMP13 expression is restricted to breast cancer because it is not found in breast fibroadenomas, normal or resting breast, placenta, liver, nest, In the uterus, prostate or parotid gland, or breast cancer cell lines (T47-D, MCF-7 and ZR75-1). After this observation, MMP13 has been transformed into epidermal keratinocytes [N. Johansson et al., (1997). Cell Growth Differ. 8(2^ : 243-250], squamous cell carcinoma [N. Johansson (1997) Am. J. Pathol. 151(2): 499-508] and epidermal tumors [K. Airola et al. (1997) J. Invest. Dermatol. 109(2)::225-231] It was detected that these results suggest that MMP13 is involved in the secretion of epithelial cells and may be involved in extracellular matrix degradation and cell-interstitial interactions associated with metastasis, especially as in invasive breast cancer lesions, And observed in the growth of malignant epithelial cells that are carcinogenic to the skin. Recently published data means that MMP13 plays a role in the transformation of other connective tissues. For example, it is consistent with the specificity of MMP13 and is preferentially used. Degradation Type II Collagen [P. G. Mitchell et al., (1996) J. Clin. Invest. 97(3): This paper scale applies to the Chinese National Standard (CMS) A4 specification (210 X 297 Public Opinion ) 1329637 . A7 B7 V. INSTRUCTIONS (4) 761-768: V. Knauper et al. (1996) J. Biochemistry 丄: 1544-1550], MMP13 has been hypothesized during primary ossification and skeletal transformation [M. Stahle -Backdahl et al., (1997) Lab. Invest. 76(5): 717-728; N. Johansson et al., (1997) Dev. Dy n. 208(3): 387-397], in destructive joint diseases such as rheumatism and osteoarthritis [D. Wernicke et al., (1996) J. Rheumatol. Benefit: 590-595; PG Mitchell et al. (1996) J. Clin. Invest. 97(3): 761-768; 0. Lindy et al., (1997) Arthritis Rheum 40(8): 1391-1399]; and during aseptic relaxation of body joint replacements [ S. Imai et al. (1998) J. Bone Joint Surg. Br. 80(4): 701-710] acts as a role. MMP13 is also implicated in chronic adult periodontitis because it has been localized in a chronic manner. Inflamed mucosa of human gingival tissue epithelium [VJ Uitto et al. (1998) Am. J. Pathol 152(6): 1489-1499] and modification of collagen stroma in chronic wounds [M. Vaalamo et al. (1997) J. Invest. Dermatol. 109(1): 96-101]. MMP9 (gelatinase B: 92kDa type IV collagenase; 92kDa gelatinase) is a secreted protein that was first purified in 1989 and then vegetatively propagated and sequenced [SM Wilhelm et al., (1989) J. Biol Chem. 264(29): 17213-17221; published an errata in j. Biol Chem. (1990) 265(36).22570]. A recent review of MMP9 provides a superior source of detailed information and references on this protease: TH Vu & Z. Werb (1998) (in: Interstitial Metalloproteinases, 1998, edited by WC Parks & Rp Mecham., p. Pages 115-148, University Press, ISBN 0-12-545090-7). The following points are taken from this review by T.H. Vu & Z. Werb (1998). The performance of MMP9 is normally limited to a few cell types, including germ layer, osteoclasts, neutrophils, and macrophages. However, the paper scale applies to the Chinese national standard (CNS> A4 specification (210 X 297 mm) 1329637 A7 B7 5. Invention description (5) The performance can be in these same cells, and in other cell types, borrowing Mediator induction, including exposure of these cells to growth factors or cytokines, which are often the same mediators associated with eliciting an inflammatory response. Like other secreted MMPs, MMP9 is an inactive zymogen. Released, which is subsequently formed by splitting. Enzyme-active enzymes. The protease required for this activation in vivo is unknown. The balance of active MMP9 to inactive enzymes is further in vivo and through a natural The interaction of the produced protein TIMP-1 (a tissue inhibitor of metalloproteinase-1) is regulated. TIMP-1 binds to the C-terminal region of _P9, resulting in inhibition of the catalytic function of MMP9. Pro_P9 is balanced by induced performance The division of ProMMP9 into active MMP9, and the presence of TIMP-1, is combined to determine the amount of catalytically active MMP9 present at a localized position. MMP9 with proteolytic activity attacks the host, Including gelatin, elastin and natural type IV and type V collagen; it is not active against native type I collagen, protein or kumbumin. There are already growing data bodies, and different physiological and pathological processes with MMP9 The role of the physiology includes the invasion of the embryonic dermal layer through the uterine epithelium in the early stages of embryo transfer; the role of growth and development in the iliac crest; and the migration of inflammatory cells from the vascular to the tissue. The release of MMP-9, measured by enzyme immunoassay, was significantly improved in fluids, and in supernatants from AM from untreated asthma patients, compared with those from other individual populations [Am. J. Resp. Ceil '& Μοί: Biol., November 1997, 17(5): 583-591]. The increased MMP9 performance has also been found in certain other pathological conditions, thus making MMP9 and disease The process is related, such as COPD, arthritis, tumor metastasis, Alzheimer's disease, multiple hard __9- This paper scale applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1329637 . A7 'B7 V. Invention (6) plaque, and plaque rupture in atherosclerosis, leading to acute coronary symptoms, such as myocardial infarction. MMP-8 (collagenase-2, neutrophil collagenase) is an interstitial metalloproteinase group 53 kD enzyme, which is preferentially expressed in neutrophils, has been shown to show that MMP-8 is also expressed in other cells, such as osteoarthritic chondrocytes [Shlopov et al., 1997, Arthritis Rheum, 40: 2065] . MMPs produced by neutrophils may cause tissue modification, so blocking _P-8 should have a positive effect in fibrotic diseases such as the lungs and in degenerative diseases such as emphysema. It has also been found that MMP-8 is up-regulated in osteoarthritis, suggesting that blocking MMP-8 may also be beneficial in this disease. MMP-3 (matrix lysin-1) is the 53 kD enzyme of the interstitial metalloproteinase group. MMP-3 activity has been implicated in fibroblasts isolated from spontaneous gingivitis [Uitto V. J_ et al., 1981, J. Periodontal Res" also: 417-424], and the enzyme content is severely associated with gum disease. Sexual association [Overa丨1 CM et al., 1987, J. Periodontal Res., benefit: 81-88]. MMP-3 is also produced by basal keratinocytes in a variety of chronic ulcers [Saarialho-Kere UK et al. 1994, J: ςΐίη. Invest·, 2^:79-88]. MMP-3 mRNA is found in the basal keratinocytes adjacent to but far from the edge of the wound, possibly at the location of the proliferative epidermis. MMP -3 therefore prevents the epidermis from getting better. Several researchers have shown that MMP-3 is consistently elevated in synovial fluid from rheumatoid and osteoarthritic patients when compared to the control group [Walakovits LA et al. 1992, Arthritis Rheum" Mutual: 35-42: Zafamllah Μ. et al., 1993, J. Rheumatol., and: 693-697]. These studies provide the basis for the belief that the inhibitor of MMP-3 will be treated ______- 1Π -__ This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1329637 A7 B7 V. Description of the invention (7) The treatment involves an inflamed disease caused by the collapse of the extracellular matrix, which is caused by the loss of structural integrity necessary for lymphocyte infiltration or organ function. A variety of interstitial metalloproteinase inhibitors are known (see, for example, the review of MMP inhibitors by Beckett RP and Whittaker M., 1998, Exp. Opin. Ther. Patents, 8(3): 259-282]. The compounds have varying degrees of efficacy and selectivity for inhibiting various metalloproteinases.

Whittaker M. et al., (1999, Chemical Review 99(9): 2735-2776] review a wide range of known MMP inhibitor compounds. It states that an effective MMP inhibitor requires a zinc binding group or ZBG (capable chelation activity). Positioning the functional group of the zinc (II) ion), at least one functional group that provides hydrogen bonding interaction with the enzyme backbone, and one or more side chains that interact with the enzyme subsite for efficient van der Waals. Knowing the zinc binding group in MMP inhibitors, including carboxylic acid groups, isohydroxy hydroxy acid groups, thiol groups or phosyl groups, etc., such as Whittaker M, et al., discuss the following MMP inhibitors: binding

The above compounds have entered clinical development. It has a sulfhydryl zinc-binding group, a trimethylhydantoin ethyl group, a P1 position, and an leucine-tertiary-t-butylglycine aryl primary bond. -11 - This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1329637 A7

This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1329637 A7 B7 V. Description of the invention (9) Enzyme. It has a non-peptidic amber-based isocyanate zinc-based base group and a cyclic quinone imine group at P1. Whittaker M. et al. also discuss other MMP inhibitors which have a P1 ring imino group and various zinc binding groups (salt, carboxylic acid, thiol, phosphorus).

The above compounds showed good inhibitors of ΜΜΡ8 and ΜΜΡ9 (PCT Patent Application: W09858925, W09858915). It has a pyrimidine-2,3,4-trione zinc binding group. The following compounds are not known as guanidine inhibitors:-

Lora-Tamayom et al. (1968, An. Quim 64(6): 591-606) describe the following synthesis of compounds as potential anticancer agents:

k m

This paper is again applicable to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1329637 • ' A7 B7 V. Inventive Note (10) Czech Patent Nos. 151744 (197311 19) and 152617 (1974022) describe the following compounds Synthesis and therapeutic activity:

CI R = 4-N02, 4-OMe, 2-N02, U.S. Patent No. 3529019 (19700915) describes the following compounds as intermediates:

F PCT Patent Application WO 00/09103 describes compounds which are useful in the treatment of visual disorders, including the following (Compounds 81 and 83, Table A, page 47):

Binding

K- Φ We have now discovered a novel class of compounds which are inhibitors of metalloproteinases and are of particular interest in inhibiting MMP such as MMP-12. These compounds are metalloproteinase inhibitors having a metal binding group which has not been found in known metalloproteinase inhibitors. In particular, I_-14 -_ This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1329637 • A7 ______ B7 ___ V. Description of invention (11) Some compounds have been discovered. It is an effective MMP12 inhibitory sword and has the desired active form. The compounds of the invention have advantageous efficacy, selectivity and/or pharmacokinetic properties. The metalloproteinase inhibitor compound of the present invention comprises a metal binding group and one or more other functional groups or side chains, characterized in that the metal binding group has the formula (k)

Wherein X is selected from the group consisting of NR1, 〇, s; Y1 and Y2 are independently selected from the group consisting of 〇, S; R1 is selected from the group consisting of hydrazine, alkyl, haloalkyl; any of the alkyl groups outlined above may be straight or branched. Any of the alkyl groups outlined above is preferably a (C1-7) alkyl group, and most preferably a (C1-6) alkyl group. A metalloproteinase inhibitor compound is a compound that inhibits the activity of a metalloproteinase (e.g., a purine). By way of non-limiting example below, the inhibitor compound can exhibit an ex vivo enthalpy: 5 〇 in the range of 0 0000 mM molar concentration, preferably 0.1-1000 nanomolar. The metal binding group is a functional group capable of binding a metal ion within the active site of the enzyme. For example, the metal binding group is a zinc binding group in the bismuth inhibitor that binds to the active site zinc (II) ion. The metal bond system of formula (8) has a five-membered ring structure -15 -

1329637 A7 B7 V. Inventive Note (12) Based on, and preferably, it is preferably a B-substrate, preferably a 5-substituted 丨·Η, 3·Η_咪° all-bit-2,4·dione. In a first aspect of the invention, we now provide a compound of formula I

Wherein X is selected from the group consisting of NR1, 0'S: Υ1 and Υ2 are independently selected from 0, S; lanthanide is selected from so, so2; m is 1 or 2; lanthanide is selected from direct bonding, (C1-6) alkane a (C1-6)haloalkyl or (C1-6)heteroalkyl group containing a hetero group selected from N, 0, S, SO, S02, or two selected from N, 0, S a hetero group of SO, S02, and separated by at least two carbon atoms: R1 is selected from the group consisting of hydrazine, (C1-3) leumino-haloalkyl: each of R2 and R3 is independently selected from the group consisting of hydrazine and halogen (preferably Is fluoro), alkyl, heterotyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, decyl, aryl, although alkyl-aryl, heteroalkyl -heteroaryl 'aryl-alkyl, aryl.heteroalkyl,heteroaryl-alkyl,heteroaryl-heteroalkyl,aryl-aryl,arylheteroaryl,heteroaryl-aryl Base, heteroaryl-heteroaryl, cycloalkyl-fluorenyl, heterogeneous paper scale applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1329637 A7 B7 V. Description of invention (13) Naphthenic Base-alkyl, alkyl-cycloalkyl, alkyl-heterocycloalkyl: each R4 is independently selected from the group consisting of hydrazine, halogen (preferably fluorine), (C1-3) pit or Alkyl; each of the R2 and R3 groups may be optionally substituted by one or more (preferably one) groups, selected from alkyl, heteroalkyl, aryl, heteroaryl, functional, haloalkyl , hydroxy, alkoxy, alkoxy thiol, alkyl thiol, aryl thiol, polyalkylene, haloalkyl fluorenyl, aryl fluorenyl, amino fluorenyl, hydrazine-alkylamine ί 风, Ν, Ν-二坑胺基基,方胺基<5 风基,胺基,Ν-plateamine, hydrazine, Ν-dialkylamino, guanylamine, Ν-alkane Base amide, hydrazine, hydrazine-dialkyl arylamino group, chaotic group, wind-based amine group, pit-based amine group, arylamino group, formazan group, fluorenyl-amino fluorenyl group- Indenyl, fluorenyl, fluorenyl-cyano-indenyl, thiodecyl, 2-nitro-ethylidene-1,1-diamino, carboxy, alkyl-carboxy, nitro, urethane R2 and R3 may optionally be joined to form a ring containing up to 7 ring atoms, or R2 and R4 may be joined to form a ring containing up to 7 ring atoms, or R3 and R4 may be joined to form a inclusion of up to 7 Ring of a ring atom; R5 is a monocyclic, bicyclic or tricyclic group, Containing one, two or three ring structures each having up to 7 ring atoms independently selected from cycloalkyl, aryl 'heterocycloalkyl or heteroaryl, wherein each ring structure is independently one or more Substituted by substituents, the substituents are independently selected from the group consisting of a hydroxyl group, a hydroxyl group, an alkyl group, an alkoxy group, a haloalkoxy group, an amine group, a fluorenyl-alkylamino group, an anthracene, a fluorenyl-dialkylamino group, a fenyl group-based amine. Base, daun, amide, ketone, nitro, thiol, thiol thiol, thiol sulfhydryl, porphyrin, aryl alcohol, tartrate, alkyl Carboxyl 'aminocarboxy, Ν-alkylamino-carboxy, hydrazine, hydrazine-dialkylamino-carboxy___-17 -_ This paper scale applies to Chinese National Standard (CNS) Α 4 specification (210X297 mm) 1329637 A7 B7 V. The invention (14), wherein any alkyl group in any substituent may itself be substituted by one or more groups selected from the group consisting of a pixel, a hydroxyl group, an alkoxy group, a alkoxy group, Amino, N-alkylamino, hydrazine, hydrazine-dialkylamino, N-alkyldecylamino, fluorenyl-alkylcarboxyamino, cyano, nitro, thiol, alkyl thiol, alkane Sulfosyl, Ν- Aminosulfonyl, carboxylate, alkylcarboxy, aminocarboxy, Ν-alkylaminocarboxy, hydrazine, fluorenyl-dialkylaminocarboxy, urethane: when R5 is bicyclic or tricyclic In the group, each ring structure is bonded by direct bonding, by -0-' borrowing (C1-6) alkyl, by (C1-6) haloalkyl, by (C1-6) heteroalkyl, by (C1- 6) alkenyl, borrowing (C1-6) alkynyl, borrowing, borrowing C0, borrowing NC0, borrowing CON, borrowing NH, borrowing S, borrowing C(0H) to join the next ring structure, or condensing to the next a ring structure; any of the heteroalkyl groups outlined above is a heteroatom-substituted alkyl group containing one or more hetero-groups independently selected from N, 0' S, SO, S02 (hetero group) Is a hetero atom or a group of atoms: any of the heterocycloalkyl or heteroaryl groups outlined above, containing one or more hetero-groups independently selected from N, 0, S, SO, S02; The alkyl, mercapto or alkynyl groups outlined may be straight or branched; any of the alkyl groups outlined above are preferably (C1-7) alkyl, and most preferably (unless otherwise stated) C1-6) alkyl group. Preferred compounds of formula I are those in which one or more of the following applies: X is NR1; Z is S02 or S0; especially Z is S02; at least one of Y1 and Y2 is 0; especially both Y1 and Y2 are 0 ; m is 1 : ___- -_ This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1329637 A7 B7 V. Description of invention (15) R1 is Η, (C1-3) alkyl (C1-3) Draw alkyl: especially R1 is Η, (C1-3) alkyl; most particularly R1 is Η; R2 is Η, alkyl 'hydroxyalkyl' alkoxyalkyl, aryloxy Alkyl, aminoalkyl, cycloalkyl-alkyl 'alkyl-cycloalkyl, aralkyl, alkylaryl, alkyl-heteroaryl, heteroalkyl, heterocycloalkyl-alkyl, Alkyl-heterocycloalkyl, heteroaryl-alkyl, heteroalkyl-aryl; especially R2 is alkyl, aminoalkyl, alkyl-heteroaryl, alkyl-heterocycloalkyl or hetero Aryl-alkyl; R3 and/or R4 are deuterium; R3 and/or R4 are f groups; R5 comprises one, two or three optionally substituted aryl or heteroaryl 5 or 6 membered rings; R5 is A bicyclic or tricyclic group containing two or three optionally substituted ring structures. Particularly preferred compounds of formula I are those wherein R5 is a bicyclic or tricyclic group containing two or three optionally substituted ring structures. The invention further provides a compound of formula II

Each of Gl ' G2 and G4 is a single ring structure containing up to 7 ring atoms. ____ 1Q -_ This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 厶) 1329637 A7 _____· _B7_____ V. INSTRUCTION DESCRIPTION (16) 'Independently selected from cycloalkyl' aryl, heterocycloalkyl or heteroaryl, wherein each ring structure is independently substituted with one or two substituents, the substituents being independently selected from halogen , hydroxy, haloalkoxy, amine, N-alkylamino, KN-dialkylamino 'cyano, nitro, alkyl, alkoxy, alkyl hydrazine, from alkyl hydrazine, alkyl amine Formate, alkanoin, wherein any alkyl group in any substituent may itself be substituted with one or more groups selected from the group consisting of a hydroxyl group, a hydroxyl group, an amine group, an N-alkylamine group, N, N. - dialkylamino 'cyano, nitro, alkoxy, alkoxy, aryloxy, heteroaryloxy, urethane: z is so2; each B and F are independently selected from direct bonds , 〇, (C1-6)alkyl, (C1-6)heteroalkyl, alkynyl, CO 'NCO, CON, NH, S; R2 is selected from the group consisting of hydrazine, alkyl, hydroxyalkyl, alkoxylated Alkyloxy Base, amine alkyl group, (Ν-hichamine group); t-based, (Ν, Ν-dihydro-amino) alkyl, amide-based, thioalkylcycloalkyl-alkyl , alkyl-cycloalkyl, aralkyl, alkylaryl, alkyl-heteroaryl, heteroalkyl, heterocycloalkyl-homo, alkyl-heterocycloalkyl, heteroaryl-alkyl , heteroalkyl-aryl: R3 and R4 are independently selected from η or (C1-3) pit group: , R2 and R3 may be joined to form a ring containing up to 7 ring atoms, or R2 and R4 may be Joining to form a ring containing up to 7 ring atoms, or R3 and R4 may be joined to form a ring containing up to 7 ring atoms: Any of the heteroalkyl groups outlined above is a heteroatom-substituted alkyl group' It contains one or more hetero-groups independently selected from Ν, 0, S, SO, S02 (the hetero group is a hetero atom or a radical): Any of the heterocycloalkyl or heteroaryl groups outlined above , contains one or more _____-20-_______- This paper size applies to @国标准(CNS) A4 specification (21Qx 297 public ^

Binding

K- 0 1329637 • A7 _____B7 V. INSTRUCTIONS (17) Hetero groups independently selected from N, 0, S, SO ' S02: Any of the alkyl, alkenyl or alkynyl groups outlined above may be straight chain or Branched; any of the alkyl groups outlined above is preferably (C1-7)alkyl, and most preferably (C1-6)alkyl, unless otherwise stated. Preferred compounds of formula II include those wherein R2 is alkyl, aminoalkyl, alkyl-heteroaryl, hydroxy-heterocycloalkyl or heteroaryl-formyl. The invention further provides a compound of the formula Ila

Wherein each of G1 and G2 is a monocyclic ring structure each containing up to 7 ring atoms, and JL alone is selected from cyclohexyl 'aryl, heterocycloalkyl or heteroaryl, wherein each ring structure is independently Or two substituents, the substituents are independently selected! |, thiol, halooxy, amino, N-hydrazine, N,N-diamine, cyano, nitro, alkyl, alkoxy, decyl, wind, pit Any of the substituents in any of the substituents may be optionally substituted with one or more groups selected from the group consisting of _, thiol, amine , Ν-alkylamino, hydrazine, hydrazine, dialkylamino, cyano, nitro, oxo, haloalkoxy, aryloxy, heteroaryloxy, urethane; Ζ is so2 ; - 21 · i Paper Wave Scale Applicable ® ® 冢 Standard (CNS) A4 Specification (21G x 297 public) ~~ ~~~

Binding

k 1329637

B is selected from the group consisting of direct bonding, fluorene, hydrazine, d6) alkyl, ((: 1-6) heteroalkyl NCO, CON, NH, S, block; CO, R2 is selected from Η, (α-6 a pit base, a mercaptoalkyl 'hydroxyalkyl group, an amine group, a pit base' (Ν-p-amino group) alkyl group, (Ν,Ν•垸垸amino)alkyl group, a % alkyl group, or R 2 is H base alkoxyalkyl, decyl alkane

C m C and D are independently selected from direct bond, H, (C1_C6) alkyl, (6), haloalkyl or (C1-C6) heteroalkyl, containing one or two selected from N, oxime or 8 An atom such that when two heteroatoms are present, they are separated by at least two carbon atoms; G3 is a monocyclic ring structure containing up to seven ring atoms, independently selected from cycloalkyl, aryl, heterocycloalkyl Or a heteroaryl group, optionally substituted by one or two substituents' substituents are independently selected from the group consisting of halogen, hydroxy, amine 'N-alkylamino, N,N-dialkylamino, cyano, nitro, alkane a group, an alkoxy group, an alkyl group, a haloalkyl group, or an alkyl group substituted by one or more groups, the substituent being selected from the group consisting of halogen, hydroxyl, amine, N-alkylamino, N, N- Dialkylamino, cyano, nitro, pitoxy, or alkoxy: R2 is optionally substituted by halo, haloalkyl, hydroxy, alkoxy, haloalkoxy 'amine, aminoalkyl , N-alkylamino, hydrazine, hydrazine-dialkylamino, (N-alkylamino)alkyl '(Ν, Ν-dialkylamino)alkyl, alkyl hydrazine, amine hydrazine, hydrazine-alkane Amine-stone, bismuth, bismuth-di-hydrogen amine, wind, amine-based, Ν-pile-based amine Ν,Ν--Alkylamino, cyano, decylamino, alkyl-decylamino, decyl, oxime-amino ____-22- This paper wave scale applies to China National Standard (CNS) Α4 size (210 X 297 mm)

Binding

Line 1329637 . A7 _____*_ B7 _____ V. Description of invention (~ι9 1 ~ 飒-甲妹基, fluorenyl, N-cyano-indenyl, thioindenyl, 2-nitroindenyl, carboxy-alkane Substituted by a carboxyl group or a urethane group; R3 and R4 are independently selected from fluorene or (C1-3) pit groups; R2 and R3 may be bonded to form a ring containing up to 7 ring atoms, or R2 and R4 may be Joining to form a ring containing up to 7 ring atoms, or R3 and R4 may be joined to form a ring containing up to 7 ring atoms; any of the heteroalkyl groups outlined above is a heteroatom-substituted alkyl group' Containing one or more hetero groups independently selected from Ν, 0, S, SO, S02 (hetero group is a hetero atom or a radical); any of the heterocycloalkyl or heteroaryl groups outlined above, Containing one or more hetero groups independently selected from N, 〇, s, SO, S02; any of the alkyl, alkenyl or alkynyl groups outlined above may be straight or branched; unless otherwise stated Or, any of the alkyl groups outlined above is preferably a (C1-7) alkyl group, and most preferably a (C1-6) pit group. Preferred compounds of the formula Ila are those in which one or more Condition: B is selected from direct bonding, 0, CO, S, alkynyl; especially B is a direct bond, 0, S or alkynyl; R2 is selected from hydrazine, (C1-6) alkyl, Aryl-(C1-6)alkyl.. or heteroaryl-(C1-6)alkyl, optionally taken from the group, haloalkyl, hydroxy, alkoxy, nonyloxy, amine, amine Alkyl, fluorenyl-alkylamino, hydrazine, hydrazine-dialkylamino, (Ν-alkylamino)alkyl, (hydrazine, fluorenyl-dialkylamino)alkyl, alkyl hydrazine, amine hydrazine , Ν-alkylamino-lithite, ruthenium, fluorenyl-dialkylamino ruthenium, ruthenium amide, ruthenium-hydroxyl-amino group, hydrazine, hydrazine-dialkyl S& amine group, amine ruthenate, cyanide Base, carbaric amine group, pit-based mercaptoamine group, carbenyl group, fluorenyl-amino fluorenyl-carbenyl group, fluorenyl group, fluorenyl-cyano-indenyl group, thio-decyl group ____-23- The scale applies to the Chinese National Standard (CNS) Α4 specification (210 X 297 mm) 1329637 A7 B7 V. Description of the invention (20, 2-nitroguanidino, 2-nitro-ethylidene-U-diamine, Carboxy, alkylcarboxyl, amino decanoate substitution: each R3 and R4 is Η; G2 is a nitrogen-containing six-membered ring; G1 is substituted by a para-position. The particularly preferred compound of Ila is each of R3 and R4. For example, a particular compound of the invention includes a compound of formula Ila wherein hydrazine is a direct bond, hydrazine, S or alkynyl group; and R2 is selected from the group consisting of hydrazine, (C1-6) alkyl, aryl (C1- 6) an alkyl or heteroaryl-(C1-6)alkyl group, optionally a cycloalkyl group, a heterocycloalkyl group, a halogen group, a decyl group, a fluorenyl group, an alkoxy group, an aryloxy group, a functional group Oxyl, amine, aminoalkyl, Ν-alkylamino, hydrazine, hydrazine-dialkylamino, (Ν-alkylamino)alkyl, (hydrazine, fluorenyl-dialkylamino)alkyl, alkane Sulfosyl, aminosulfonyl, fluorenyl-alkylamino-continudyl, hydrazine, fluorenyl-dialkylamino-sulfonyl, anthranyl, fluorenyl-alkylamino, hydrazine, hydrazine Diphthyl-based amine group, gas group, <5 wind-based amine group, pit-yl-based amine group, methyl group, fluorene-amino group-methyl fluorenyl group, fluorenyl-cyano group a thiol group, a 2-nitroguanidino group, an amino decanoate group, a carboxyl group, an alkylcarboxy group; and each of R3 and R4 is fluorene. A particularly preferred compound of the invention is the following formula lib:

B

[N:C]

Ob 〇 蒗 蒗 适用 适用 适用 适用 适用 适用 适用 适用 适用 适用 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 g 1 , B and R 2 are as described for formula Ila. In the compound of formula lib, it is preferred that G2 is unsubstituted and G1 is optionally substituted, preferably G1 is substituted by para. __- - This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1329637 A7 B7

1329637 A7 B7 V. INSTRUCTIONS (23) The appropriate meaning of R5 includes the following:

X_ = Bond, 0, CH2, CHF, CF2, S, S02, C0 X1, = Bond, CH2; CHF, CF2; S02, C0 R = F, Cl, Br, CF3, CF30, CH30, OH, CF3CH2 It will be appreciated that the number of specific substituents and substituents in the compounds of the invention are selected to avoid sterically undesirable combinations. Each of the exemplified compounds represents a particular and independent aspect of the invention. Where optically active centers are present in the compounds of the invention, we disclose all individual optically active forms and combinations thereof as individual specific embodiments of the invention, as well as the corresponding racemates thereof. The racemate can be separated into individual optics using the known ____-27 -_ paper scale using the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1329637 A7 B7 5. Inventive Note (24) Procedure Active form (see Advanced Organic Chemistry: 3rd edition: author J March, pp. 104-107), including, for example, the formation of diastereomeric derivatives with suitable optically active auxiliary species, followed by isolation and subsequent cleavage of the auxiliary species . It will be appreciated that the compounds according to the invention may contain one or more asymmetrically substituted carbon atoms. One or more of such asymmetric centers (centers of palms) are present in the compounds of the invention, which may result in stereoisomers, and in each case it will be apparent that the invention extends to all such stereoisomers, including Opposite and diastereoisomers, and mixtures thereof, including racemic mixtures thereof. Where tautomers are present in the compounds of the invention, we disclose all individual tautomeric forms and combinations thereof as individual specific embodiments of the invention. As outlined above, the compounds of the invention are metalloproteinase inhibitors, specifically, inhibitors of MMP12. Each of the above-mentioned indications, for the compounds of the present invention, represents an independent and specific embodiment of the invention. Certain compounds of the invention are particularly useful as inhibitors of MMP13 and/or MMP9 and/or MMP8 and/or _P3. The compounds of the invention exhibit a favorable selective action morphology. While we do not wish to be bound by theoretical considerations, the compounds of the invention are shown to exhibit selective inhibition of any of the above indications relative to any MMP1 inhibitory activity, as a non-limiting example, which is more potent than any MMP1 inhibition. Activity, can show 100-1000 times selectivity. The compounds of the invention may be provided as pharmaceutically acceptable salts. It includes acid addition salts such as hydrochloride, hydrobromide, citrate and maleate ___-28-_ This paper scale applies to China National Standard (CNS) A4 specification (210 X 297) 1329637 V. Description of the invention (25, and the salt formed by phosphoric acid and sulfuric acid. In another, salt, such as metal salt, such as steel or unloading, the appropriate salt for soil testing is magnesium, or organic amine salt For example, triethylamine. A salt, such as calcium, or it may be provided as a hydrolysable ester in vivo. In combination with vinegar, it is hydrolyzed in the human body to produce maternal two: sub-acceptable by, for example, intravenous The internal method is to confirm the test compound II such vinegar is tested by checking the body fluid of the test animal. It is suitable for the tongue 2 to know the animal, and for the sulfhydryl group, it includes the methoxy group to the hydrolyzable vine group and the B. A thiol group, especially an ethylenic group. The h-based system comprises a treatment with a metalloproteinase inhibitor of the present invention, a compound thereof, or a pharmaceutically acceptable salt thereof or a living body: treatment of two mammals (including humans) (including preventive treatment, which is formulated into medicine according to standard medical practice Compositions, . . . , " Therefore, in another aspect of the invention, a pharmaceutical composition comprising a compound of the invention (Formula 1 or 11, 31 or a proprietary compound) is provided as a pharmaceutical composition. Or a pharmaceutically acceptable salt or an in vivo hydrolysable ester and a pharmaceutically acceptable carrier. The pharmaceutical composition of the present invention can be administered in a standard manner to the disease or condition desired to be treated, for example, by oral, topical, parenteral, buccal 'nasal, vaginal or rectal administration or by inhalation. For such purposes, the compounds of the present invention may be formulated into, for example, tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, in a manner known per se. Gelatinous nasal sprays, suppositories, finely divided powders or aerosols for inhalation, and for parenteral use (including intravenous, intramuscular or perfusion), sterile aqueous or oily solutions or suspensions or sterile Emulsion.

1329637 A7 B7 V. INSTRUCTIONS (26) In addition to the compounds of the invention, the pharmaceutical compositions of the invention may also contain or co-administer (either simultaneously or sequentially) one or more of the treatments for one or more of the above-mentioned diseases or There are valuable pharmacological agents on the symptoms. The pharmaceutical composition of the present invention is usually administered to a human, and thus is administered at a daily dose of, for example, 0.5 to 75 mg/kg body weight (and preferably 0.5 to 30 mg/kg body weight). The daily dose may be administered in divided doses as needed. The precise amount of the compound to be administered and the route of administration will depend on the weight, age and sex of the patient being treated, and the particular disease or condition being treated, according to the skill. It depends on the known principle. Typically, the unit dosage form will contain from about 1 mg to about 500 mg of the compound of the invention. Thus, in another aspect, the invention provides a compound of formula I, or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, for use in a therapeutic treatment of a human or animal body, or as a therapeutic. I have disclosed the use in the treatment of diseases or symptoms which are mediated by one or more metalloproteinases. In particular, we disclose the use in the treatment of diseases or conditions mediated by MMP12 and/or MMP13 and/or MMP9 and/or MMP8 and/or MMP3; in particular in the treatment of diseases or symptoms mediated by _P12 or MMP9. The use; most particularly, in the treatment of diseases or symptoms that are mediated by MMP12. In particular, we provide a compound of formula II, Ila or lib, or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, for use in a therapeutic treatment of a human or animal body, or as a therapeutic agent (for example, For the treatment of diseases which are mediated by MMP12 and/or MMP13 and/or _P9 and/or _P8 and/or _P3: especially MMP12 or MMP9: most particularly MMP12 or ___-30-_ Applicable to China National Standard (CMS) A4 specification (210X297 mm) 1329637 A7 ____B7_ V. Description of invention (27) Symptoms). In yet another aspect, the invention provides a method of treating a disease or condition mediated by a metalloproteinase, which comprises administering to a warm-blooded animal a therapeutically effective amount of a compound of the formula PCT or a pharmaceutically acceptable salt thereof or in vivo Hydrolyzed ester. We also disclose the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, or an in vivo hydrolysable precursor, for the manufacture of a medicament for the treatment of a disease or condition mediated by one or more metalloproteinases. For example, we provide a method of treating a disease or condition mediated by a metalloproteinase comprising administering to a warm-blooded animal a therapeutically effective amount of a compound of the formula H, Ila or lib (or a pharmaceutically acceptable salt thereof or in vivo) Hydrolyzable ester). The invention also provides the use of a compound of formula II, Ila or lib (or a pharmaceutically acceptable salt thereof or an in vivo hydrolysable precursor) for the manufacture of a medicament for the treatment of a disease mediated by one or more metalloproteases Or symptoms. Diseases or symptoms mediated by metalloproteinases 'including asthma, rhinitis' chronic obstructive pulmonary disease (COPD), arthritis (such as rheumatoid arthritis and osteoarthritis), atherosclerosis and restenosis, cancer, invasion and metastasis Diseases involving tissue destruction, relaxation of hip substitutes, periodontal disease, squamous degenerative diseases, infarction and heart disease, liver and kidney fibrosis, endometrial tissue ectopic formation, and extracellular interstitial Weakened associated diseases, heart failure, aortic aneurysms, CNS-related diseases such as Alzheimer's disease and multiple sclerosis (MS), hematological disorders. Preparation of a Compound of the Invention In another aspect, the invention provides a process for the preparation of a compound of Formula I or n, IIa, IIb, or a pharmaceutically acceptable salt thereof or a hydrolyzable ester in vivo, such as - 31 - paper scale适财g@家鲜(CNS) A4 specification (21GX 297 public) 1329637 A7

V. INSTRUCTIONS (28 'Many associated starting materials may be synthesized by known methods, or as described in (4) to (4) below. It should be understood that they are commercially available or otherwise available, see Science (8) A compound of formula I, wherein γι and γ2 are each 盏 „ & c_ ” u 谷马 0, Z is S02, R2 is as defined in the formula, A is a direct bond, ^ and R5 contains a direct link to The nitrogen of hydrazine or hydrazine is (Cl-6) fluorenyl-alkyl, which can be prepared by reacting a compound of formula IV wherein a ruthenium compound is known as the definition of phantom, wherein χ and m are as in formula I. definition:

This reaction is preferably carried out in a suitable solvent, optionally in the presence of a base, at ambient to sludge temperature for 1 to 24 hours. Preferably, a solvent such as pyridinium, dimethylformamide, tetrahydrofuran, acetonitrile or di-methane is combined with a test such as triethylamine, N-methylmorpholine, pyridine or an alkali metal carbonate. Use 'at ambient temperature for 2 to 16 hours of reaction time, or until when the reaction has been detected by chromatography or spectroscopic methods. The reaction of the gas of the formula V with various _ grades and secondary amines has been previously described in the literature ' and the variation of the conditions is known to those skilled in the art. The synthesis of a compound of formula V is described in the literature and can be prepared from the example of smectic acid or homocysteine (M〇sher, j: j 〇rg Chem 23, 1257 (1958)). V gasification continues, where m = i, x = NR1 (R1 = H) and μ is as described in the formula ___-32- This paper scale applies to the Chinese National Standard (CMS) Α 4 specifications (210X297 public 0 1329637 A7 B7 V. Inventive Note (29), conveniently prepared by oxidative gasification of a compound of formula Va, wherein R2 is as described in Formula I (Griffith, 0. : J. Biol. Chem., 1983, 258, 3, 1591).

Va

(b) a compound of formula I, wherein Y1 and Y2 are each deuterium, Z is S, and X and R5 are both as described in formula I, by allowing a compound of formula VI wherein K is a leaving group (eg, a vapor or sulfonate) Acid ester), and R5 is as described in formula I,

It is prepared by reacting with a compound of the formula VII wherein G is a thiol group (SH) and X and m are as described in the formula I. This reaction is preferably carried out in the presence of a base such as diethylisopropylamine or cesium carbonate, and in the presence of a suitable solvent such as DMF. Alternatively, the compound of the method (b) can be produced by reacting the compound of the formula VI with the VII compound in the same manner as the method (b), but wherein the K group in the VI compound is a thiol group (SH) or a hydroxyl group. And G in the formula VII represents a leaving group. (c) a compound of formula I, wherein Y1 and Y2 are each 0, Z is S02 or S(0), and X, A and R5 are each as described in formula I, via an oxidizing agent, such as peroxide-33. This paper scale applies to the Chinese National Standard (CNS) A4 specification (21〇x 297 mm)

装

Line 1329637

Formula 1 , preferably m-gas _____ wherein z is the last product of s oxidation (Φ compound I, wherein Y1 and Y2 are each 〇, Λ. XA NRl (R1=H) » m MA 1 , and R2, R3, R4, and R5 are all in the formula j

, T. can be described by the compound of formula XI, wherein ^(3) and 八 are as described in the illusion

Reaction with ammonium and cyanide salts in a protic solvent, preferably in the presence of excess ammonium carbonate and potassium cyanide in ethanol, in a sealed container at 4 〇 8 Torr for 4-24 hours production. The ketones of formula XI may conveniently be treated with an sulfonamide of the formula wherein R3 is hydrazine and R5 is as described in formula I, and then treated with an ester, wherein R is ε or a aryl group; Residues 'and R2 are prepared as described in Formula I, in an aprotic solvent. Preferred conditions are 2 to 3 equivalents of a lithium base, such as lithium diisopropylamine or money 77 methyl crater or butyl, in an ether solvent which has been dehydrated and dried, such as tetra argon.

-34 - This paper size applies to Chinese National Standard (CNS) Α4 size (210 X 297 mm) 1329637 A7 B7

5. Description of the invention (31) A ketone of the formula XI, wherein R3 and R4 are each an alkyl group, or form a ring, R5 is an aryl or heteroaryl group, and R2 is an alkyl group or an aryl group, and may also be via a base. For example, tetrabutylammonium bromide, and a ketone of the formula XV wherein R2 is an alkyl or aryl group, is prepared by treating a sulfinic acid salt of the formula XIV, wherein R5 is an aryl or heteroaryl group, as described in Formula I ( Crandall et al, J_ Org. Chem. 1985, (8) 50, 1327-1329). R3 and R4 are then introduced by reaction with an alkyl halide or an alkyl dihalide. The reaction is preferably carried out in the presence of a base such as potassium carbonate or cesium carbonate, and in the presence of a suitable solvent, such as DMF or DMS0, at 50-100 °C.

Cl R2 H:

XIV XV The compounds of the present invention can be evaluated, for example, in the following assays: Each of the mesenchymal metalloproteinaceous groups detected, including, for example, MMP12, MMP13, is catalyzed by Parkar AA et al. (2000), protein. Performance and purification were performed as described in Purification: 152. The purified enzyme can be used to monitor active inhibitors as follows: MMP12 (50 ng/ml final concentration) in assay buffer (0.1 M Tris-HCl, pH 7.3, containing 0.1 M NaCl, 20 mM CaCl2, In 0.040 mM ZnCl and 0.05o/〇 (w/v) Brij 35), the synthetic substrate Mac-Pro-Cha-Gly-Nva-His-Ala-Dpa-NH2 was used in the presence or absence of the inhibitor in the chamber. Incubate for 30 minutes at a temperature. Activity was measured by measuring the fluorescence of Aex 328 nm and tern 393 nm. The percent inhibition is calculated as follows: % inhibition is equal to [fluorescence plus inhibitor - fluorescence 35 - this paper size applies to Chinese home standard (CMS) A4 size (210 X 297 mm) gutter 1329637 A7 B7 V. INSTRUCTIONS (32) Background] Divide by [fluorescent minus inhibitor - fluorescent background]. Recombinant human proMMP13 can be expressed and purified as described in Knauper et al. [V. Knauper et al. (1996) Biochemistry Journal: 1544-1550 (1996)]. The purified enzyme can be used to monitor active inhibitors as follows: purified proMMP13 line is activated with 1 mM aminophenylmercuric acid (ΑΡΜΑ) at 21 ° C for 20 hours; activated MMP13 ( Synthetic substrate 7 in assay buffer (0-1 MTris-HCl, pH 7.5, containing 0.1 M NaCl, 20 mM CaCl2, 0.02 mM ZnCl and 0.05o/〇 (w/v) Brij 35) - methoxycoumarin-4-yl)ethinyl.Pro.Leu.Gly.Leu.N-3-(2,4-dinitrophenyl)-L-2,3-diaminopropyl A. Arla. Arg. NH2 was incubated at 35 ° C for 4-5 hours in the presence or absence of inhibitor. Activity was determined by measuring the fluorescence of ex 328 nm and lem 393 nm. The percent inhibition is calculated as follows: Suppression 0/〇 is equal to [fluorescence plus inhibitor - light background] divided by [fluorescent minus inhibitor - fluorescent background]. Similar schemes can be used for other proMMPs that are expressed and purified, using the most suitable maturity and buffer conditions for a particular MMP, for example by C. Graham Knight et al. (1992) FEBS Lett. 296(3): 263-266 The enamel group of enamel, including, for example, the ability of a TNF-converting enzyme compound to inhibit proTNF π-converting enzyme, can be assessed using a partial purification assay by a single enzyme assay derived from a cell membrane of ΤΗΡ-1, such as K_ M. Mohler et al. (1994) Nature 370: 218-220. The purified enzyme activity and its inhibition are determined in the following manner, and the partially purified enzyme is used in the presence or absence of the test compound, and the substrate 4', 5'-dimethoxy-luciferin group is used. Ser.Pro.Leu.Ala.Gln.Ala.Val.Arg.Ser.Ser.Ser.Arg.Cys(4-(3-Amber White S&Asia__-36-_ This paper scale applies to China Standard (CNS) A4 specification (21〇x 297 mm> 1329637 A7 B7 V. Description of invention (33) Amine-1-yl)-luciferin)-NH2 in detection buffer (50 mM Tris HC1, PH 7· 4 containing 0.1 0 / 〇 (w / v) Triton X-100 and 2 mM CaCl2), cultured at 26X: 18 hours. As for MMP13, the inhibition was determined, but used; lex 490 nm and lem 530 nm The substrate is synthesized as follows. The peptide portion of the substrate is assembled on Fmoc-NH-Rink-MBHA-polyphenylene resin, either manually or on an automated peptide synthesizer. Standard method, using ?111〇(:-amino acid and hexafluorophosphate 0-benzotriazol-1-yl-:^,>^1|,>1|-tetramethyl record (HBTU) As a coupling agent, with at least a 4- or 5-fold excess of Fmoc-amino acid and HBTU. Ser1 and Pro2 are double coupled. The following side chain protection strategies are used; Seri (But), Gin5 (trityl), Arg8, 1 2 (Pmc or Pbf), Ser9, 1 0, 1 1 (three Benzyl), Cys13 (triphenylmethyl). After assembly, the Fmoc-peptidyl-resin is treated via DMF to remove the N-terminal Fmoc-protecting group. The amine-peptide thus obtained is obtained. Base-resin thiolation in the form of 1.5-2 equivalents of 4,5'-dimethoxy-fluorescein-4(5)-carboxylic acid at 70 ° C [Khanna & UUman, (1980) Anal Biochem. 196-161), which has been treated with diisopropylcarbodiimide and 1-hydroxybenzotriazole in a pre-activated treatment in DMF for 1.5-2 hours. The luciferin-peptide is treated by trifluoroacetic acid containing each 50' of water and triethylf-alkane, while removing protection and splitting from the resin. By evaporating the dimethoxyfluorescein-peptide, Trituration and filtration with diethyl ether. The isolated peptide was reacted with 4-(N-cis-butyl quinone diimido)-luciferin in DMF containing diisopropylethylamine. Purification, and finally "by freeze-drying, from acetic acid water The solution was isolated and the product was characterized by MALDI-TOF MS and amino acid analysis. Natural Acceptance _____-37- This paper size is applicable to China National Standard (CNS) A4 specification (210 x 297 mm) 1329637 A7 ______B7 V. Inventive Note (34) The compound of the present invention acts as an aggregated degradation inhibitor For activity, for example, the method based on EC Amer et al., (1998) Osteoarthritis and Cartilage Color: 214-228; (1999) Biochemistry Journal 274 (10), 6594-6601, and The antibodies described therein are tested. Compounds act as inhibitors against the efficacy of collagenase and can be assayed as described by T. Cawston and A. Barrett (1979) Anal. Biochem. 99:340-345. In a cell/group-based activity assay, as a drug to inhibit membrane efflux enzymes such as TNF-ratin, inhibiting metalloproteinase activity. The compounds of the present invention inhibit the ability of TNF-alpha producing cells to be treated in ΤΗΡ-1 cells. An ELISA assay was used to detect the released TNF, essentially as described by KM Mohler et al. (1994) Nature 370: 218-220. In a similar manner, the treatment or efflux of other membrane molecules can be tested using appropriate cell lines and detecting the efflux of the protein with appropriate antibodies, as in NM Hooper et al. (1997) Biochem. J. 32: 265-279. Said. As an agent, an invasive assay based on a grapefruit cell is capable of inhibiting cell migration in an invasive assay, as described in A. Albini et al. (1987) Cancer Research 47: 3239-3245. The measurement was carried out. As a drug to inhibit the activity of TNF efflux in whole blood, the ability of the compounds of the present invention to inhibit the production of TNFα was evaluated in human whole blood tests, in which LPS was used to stimulate the release of tNF α. Heparinized (1 〇 unit/ml) human blood from volunteers, diluted 1:5 with medium (RPMI1640 + bicarbonate, penicillin, streptomycin and glutamine) and (160 μl) 20 microliters of test compound (in triplicate). In DMSO or appropriate medium _____-38-_ This paper scale applies Chinese National Standard (CNS) Α4 specification (21〇χ 297 mm) 1329637 A7 B7 V. Invention In the (35) agent, incubate at 37 ° C in a humidified (5 ° C02 / 95 ° air) incubator for 30 minutes, then add 20 μl of LPS (E. coli 0111: B4; final concentration 10 Micrograms per milliliter). Each test line included a diluted blood control group incubated with a separate medium (6 wells/plate) or a known TNFα inhibitor as a standard. Then, the plates were incubated at 37 ° C (wet incubator) for 6 hours, centrifuged (2000 ipm, 10 minutes; 4 ° C), plasma (50-100 μl) and at -70 ° C Stored in 96 well plates and then subjected to subsequent analysis of TNF alpha concentration by ELISA. As a medicament for inhibiting in vitro cartilage degradation, the ability of the compound of the present invention to inhibit aggregation of cartilage aggregates or collagen components can be basically evaluated as described by K. M. Bottomley et al. (1997) Biochem J. 323: 483-488. Efficacy Test In order to evaluate the scavenging properties and bioavailability of the compounds of the present invention, an in vitro efficacy test was carried out using the above synthetic substrate, or HPLC or mass spectrometry. This is a general test that can be used to estimate the rate of clearance of a compound across a range of species. Animals (eg, 'white rats, baboons') take the soluble side of the compound either intravenously or orally (eg 20 〇/. w/v DMSO, 60 〇/.w/v PEG 400), and at subsequent time points (eg 5, 15, 30, 60, 120, 240, 480, 720, 1220 minutes) Blood samples were taken from appropriate blood vessels to 10 U heparin. Plasma fractions were obtained after centrifugation and plasma proteins were precipitated with acetonitrile (80% w/, ν final concentration). After 30 minutes at -20 ° C, the blood polyprotein was sedimented by centrifugation and the supernatant was evaporated to dryness using Savant speed stenciling. Reconstitute the sediment in the test buffer, and ___ -39-_ This paper scale applies to the Chinese National Standard (CNS) A4 specification (21〇x 297 mm) 1329637 A7 B7 V. Description of invention (36) Next The content of the compound was analyzed using a synthetic substrate test. In short, the compounds were evaluated for compound concentration-response curves. The activity of serial dilutions of the reconstituted plasma extract was assessed and the amount of compound present in the initial plasma sample was calculated using a concentration-response curve taking into account the total plasma dilution factor. In vivo evaluation As an anti-TNF agent test The ability of the compound of the present invention to act as an in vitro TNFα inhibitor was evaluated in rats. In short, the array of male Wistar Alderley Park (ΑΡ) rats (180-210 g) was given the compound (6 rats) or the drug vehicle (10 rats) by appropriate route, such as oral (ρ.ο) ·), intraperitoneal (ip), subcutaneous (s.c_). After ninety minutes, the rats were sacrificed using increasing concentrations of C02 and blood was collected via the posterior vena cava into 5 units of sodium heparin/ml. The blood sample was immediately placed on ice and centrifuged at 2000 rpm for 10 minutes at 4 ° C, and the collected plasma was frozen at -20 ° C for subsequent human stimulation by LPS-stimulation. Blood was tested for its effect on TNFa production. The rat plasma samples were thawed and 175 microliters of each sample was added to a 96 U well plate < a set of format drawings. Then, fifty microliters of heparinized human blood was added to each well, mixed, and the plate was incubated at 37 ° C (wet incubator) for 30 minutes. LPS (25 μl; final concentration 10 μg/ml) was added to the well and incubated for an additional 5.5 hours. Control wells were cultured using 25 microliters of culture alone. Then, the plate was centrifuged at 2000 rpm for 10 minutes, and 200 μl of the supernatant was transferred to a 96 well plate and frozen at -20 ° C for subsequent analysis of TNF concentration by ELISA. __-40-_ This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1329637 A7 B7 V. Description of invention (37) Data analysis by special software for each compound/dose Calculation: Percent inhibition percentage mean TNFα (control group) - mean TNFa (treated) Χ 1 〇〇 average TNFa (control group) The activity of the test compound as an anti-arthritic agent as an anti-arthritic agent, such as DE Trentham et al. Human, (1977) J. Exp. Med. H6: Test for collagen-induced arthritis (CIA) as defined by 857. In this model, acid-soluble natural type II collagen, when administered in Freunds' non-refined adjuvant, causes polyarthritis in the large white gas. A similar situation can be used in mice and primates to cause arthritis. The activity of the test compound as an anticancer agent as an anticancer agent can be substantially as described in IJ Fidler (1978), Cancer Research: 399-439, using, for example, the B16 cell line (described in B. Hibner et al., Summary 283, p. 75, 10th NCI-EORTC Discussion, Conference, June 1996, June 16-19 曰) Evaluation. The activity of the test compound as an anti-expanding agent as an anti-expanding agent can be basically evaluated as described in F^autamaki et al., (1997) Science, 277:2002. The invention will now be illustrated by the following examples, without limitation: an exhaustion. 1 H-NMR spectroscopy is recorded in either Varian Unity

On the Inova 400MHz or Varian Mercury-VX 300MHz instrument. A central solvent absorption peak of gas ((yH7_27ppm), dimethyl sulfonium-d6 (dH2.50ppm) or methanol-d4 (dH3.31ppm) was used as an internal reference. Low resolution mass spectrometry was used in Agilent equipped with APCI ionization chamber. Obtained on the 1100 LC-MS system. -41 The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1329637 A7 B7 V. Invention description (38) Example 1 5ι(1:[ί4- (4Ι-1 based 丨1,1'-biphenyl M-yl VI-hexahydroindole is more arable than argon, thiophene, _ 2,4-imidazolidinone

Add 1-ethylamine (〇.〇6 ml, 0.5) to a solution of 1-(4-fluorophenyl)-phenylhexahydrop-pyridinium (0125 mg, 0.48 mmol) in 5 mL of di-methane. Milliol) with gasification of 2-(2,5-dione-4-pyrimidinyl)-1-ethane (0.113 ml, 0.48 mol). The mixture was stirred for 1 hour, diluted with EtOAc EtOAc (EtOAc)EtOAc. LC-MS (APCI) m/z 446.9 (MH+). 'HNMR^ 1.95m (1H); 2.1m (1.15H), 3.2m (13.3H), 4.1m (lH), 7.05d (2H), 7.25 d (2.1H), 7.65d (2.2H), 7.80d (1.8H), 8.0bs (NH). The starting materials were prepared as follows: Gasification 2-(2,5-diketo-4 5-(2-(2-(2,5-dione-4-pyrimidinyl)ethyl]dithio}ethyl)-2, a suspension of 4-isoxazoledione (6.9 mol) in a mixture of 25 ml of AcOH and 2 ml of water, applicable to the Chinese National Standard (CNS) on three paper scales with gas inlet tubes, thermometers and short reflux condensers A4 size (210 X 297 metric tons) 1329637 A7 B7 V. Description of invention (39) In a flask, stir vigorously in an ice bath, at a maximum temperature of +5 ° C, in which foam is introduced into the gas 15 minutes (until all the precipitates are dissolved). Then, it was stirred for another 15 minutes, and evaporated to a small volume in a hollow (maximum temperature of 30 ° C), dissolved in 50 ml of di-methane, saturated with NaHC03 (about 25 ml), and then with 10Q/. Sodium thiosulfate was carefully shaken together, dehydrated, evaporated, and crystallized from THF-House (Lora-Tamayo, M. et al., 1968, An. Quim., 64(6): 591-606); 1 H NMR : ά 2.55m (1.1H), 2.65m (1.8H), 2.70m (1H), 4.55m (1H). 5-(2-{[2-(2,5-diketo-4-pyrimidinium) Ethyl]ethyl]dithio}ethyl)-2,4-imidazolidindione. Commercially available RS homocysteine (0.18 mol) was suspended in 25 ml of water with 1.5 g of potassium cyanate added. (0.2 mol), and the mixture was stirred at 100 ° C for 45 minutes. Then partially cool it and immediately add 10 ml of 10 °'. HC1, and the mixture was stirred at 100 ° C for another 50 minutes. It was placed in a refrigerator 'overnight, filtered and crystallized, washed continuously with water, and dried in the air. LC-MS (APCI) m/z 319.1 (MH+). ___-43- This paper size applies to Chinese National Standard (CMS) A4 size (210 X 297 mm) 1329637 A7 B7 V. Description of invention (4〇) Overall The general reaction pattern is shown below

Example 2 (. Speaking) -5_{丨(4·Phenyl-1-hexahydropyrrole) is determined to be a methyl p 4 azole θ 一 a" The title compound is according to the pattern shown in Example 1. Prepared by vaporizing R_(2,5-dione-4-imidazolidinyl)methanesulfonate (1 mg, 〇47 mmol) in 2.5 ml of THF, immediately via syringe, A solution of 丨Phenylhexahydropyridin (85 mg, 〇.52 mmol) and 65 μl of triethylamine (〇52 mmol) in 2.5 mL of THF was added. The mixture was stirred for 3 hours and filtered. Precipitated gasified diethylammonium, washed with two small portions of THF, evaporated, and from £t〇H and -44- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1329637 A7 B7 V. INSTRUCTIONS (41) Re-crystallization of a small amount of AcOH. LC-MS (APCI) m/z 339.1 (MH+). 1 H NMR cJ 2.5m (2H), 3. lbs (6.5H), 3.3m (2.5 H), 4.55m (1H), 6.8t (1H), 6.9d (1.88H), 7.2t (2.05H), 9.1bs (1.7H). The starting materials are prepared as follows: Gasification R- (2,5-dimercapto-4-sodium thiophene) A complete performance S stupid R-5-({[(2,5-diketo-4-imidazolidinyl)methyl]dithio) }methyl)-2,4- A suspension of oxazolidinedione (6.9 mol) in a mixture of 25 ml of AcOH and 2 ml of water, vigorously stirred in an ice bath in a three-necked flask with a gas inlet tube, a thermometer and a short reflux condenser. At the highest temperature +5 ° C, the gas was bubbled through for 15 minutes (until all the precipitates were dissolved). Then, it was stirred for another 15 minutes and evaporated in a hollow (maximum temperature 30 ° C). In a small volume, dissolved in 50 ml of di-methane, saturated with NaHC03 (about 25 ml), then with 10 ° /. sodium thiosulfate, carefully shake together, dehydrated dry 'dry, evaporated, from THF-hex Crystallization (Lora-Tamayo, M. et al., 1968, An. Quim., 64(6): 591-606); 1 H NMR (DMSO-d6): S 3.21m (1.1H), 3.3m (0.7H) 4,65m. (1H). 11-5-({[(2,5-diketo-4-imidazolidinyl)methyl]dithio}methyl:)-2,4-imidazolidinium The diketone was obtained by suspending commercially available R cystamine (0.18 mol) in 25 ml of water and adding 1.5 g (0.2 mol) of potassium cyanate, and the mixture was stirred at 100 ° C for 45 minutes. Part of it is cooled, and immediately added 10 ml 1 0% HCl, and the mixture was stirred at 100 ° C for another 50 minutes. It was placed in a refrigerator overnight, crystallized overnight, washed continuously with water, and dried in the air. LC-MS (APCI) m/z 291 (MH+). __________ - 45 -__ This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1329637 A7 B7 V. Description of invention (42) Example 3 (5S)-5-anthracene (4-phenyl-1-hexahydro]p-yl) continued Si-based 1 methyl b 2,4-imicone dione title compound according to the example 1 Made of schema. Gasification of 8-(2,5-diketo-4-pyrimidinyl) A: A complete solution of S (100 mg, 0.47 mmol) in 2.5 ml of THF, immediately via syringe, A solution of 1-phenylhexahydropyridin (85 mg, 0.52 mmol) with 65 μl of triethylamine (0.52 mmol) in 2.5 mL of THF was added. The mixture was stirred for 3 hours, and the precipitated vaporized triethylammonium was filtered, washed with two portions of THF, evaporated, and recrystallized from EtOH with a small amount of AcOH. LC-MS (APCI) m/z 339.1 (MH+). 1 H NMR : ^ 2.5 m (2 Η), 3. lbs (6.5H), 3.3m (2.5H), 4.55m (1H), 6.8t (1H) ), 6.9d (1.88H), 7.2t (2.05H), 9.1bs (1.7H) The starting materials were prepared as follows: Gasified S-(2,5-diketo-4-imidazolidinyl) Methanesulfonate will be S-5-({[(2,5-dione-4-pyrazolidyl)methyl]dithio}methyl)-2,4-imidazolidindione (6.9 mol) a suspension in a mixture of 25 ml of AcOH and 2 ml of water in a three-necked flask with a gas inlet tube, a thermometer and a short reflux condenser, placed in an ice bath and vigorously stirred at a maximum temperature of +5 ° C Next, foaming was carried out for 15 minutes (until all the precipitates were dissolved). Then, it was stirred for another 15 minutes, evaporated to a small volume in a hollow (maximum temperature 30 ° C), dissolved in 50 ml of di-methane, saturated with NaHC03 (about 25 ml), and then with 10 °7. Sodium thiosulfate, carefully shaken together, dehydrated, evaporated, crystallized from THF-pit (Lora-Tamayo, M. et al., 1968, An. Quim., 64(6): 591-606): - 46 - This paper size applies to Chinese National Standard (CMS) A4 specification (21〇x 297 mm) 1329637 A7 B7 V. Description of invention (43 ) ! H NMR (DMSO-d6) : δ 3.2m (0.9Η, 3.35m (0.9Η), 4.50m (1Η). S-5-μ丨(2,5-diketo-4-imidazolidinyl)methyl]dithio}methyl)-2,4-imidazopyridine Commercially available S cystine (0.18 mol) was suspended in 25 ml of water, and 5 g of potassium cyanate (0.2 mol) was added, and the mixture was stirred at 10 ° C for 45 minutes. Then, it was partially cooled, and 10 ml of 10% HCl was immediately added, and the mixture was further stirred at 100 ° C for 50 minutes. "It was placed in a refrigerator overnight, filtered and continuously washed with water, and Dry in the air. LC-MS (APCI) m/z 291.1 (MH+). Example 4 (R)-5-((丨4-W-Fluoroindole 1,1'-biphenyl-4-yl)-1-hexahydro Pyridinyl 1 sulfonate a) methyl) -2,4-mime 0i dandione

Gasification of [(R)-2,5-dioneimidazolidinium]methanesulfonate (〇0127g, 〇_mole), 1-(4·-fluoro[1,Γ-biphenyl] Ice-based) hexa-argon p-ratio (〇〇154 g, 〇_mole), triethylamine (0.0084 ml, 0.060 mmol) and anhydrous tetrahydrofuran (0.70 ml), stirred at room temperature overnight . Poly(phenylethene) isocyanate (0.025 g, 0.030 mmol) was added and the mixture was shaken overnight. The white suspension was carefully transferred to a round bottom flask and the resin was washed with tetrahydrofuran (2 x 1 mL) and the rinse was transferred to the whole suspension. Evaporation of solvent, -47 - Paperweight scale for S National Standard (CNS) A4 specification (210 X 297 public) 1329637 A7 B7 V. Description of invention (44) The white solid is suspended in water (5 ml) and collected in On a filter, washed with water (2 x 1 mL), water was removed by suction, and dried overnight at 45 ° C to give about 0.010 g of the title compound. LC-MS (APCI) m/z 434 (MH+). 1 H NMR (DMSO-d6) d' 10.8 (1H, bs), 7.98 (1H, d, J=2Hz), 7.63 (2H, dd, J, = 5Hz, J2=9Hz), 7.53 (2H, d, J=9Hz), 7.23 (2H, t, J=9Hz), 7.05 (2H, d, J=9Hz), 4.45 (1H, ddd, J, = 2Hz, J2=4Hz, J3=6Hz), 3.51 (1H, dd, J, =15Hz, J2=7Hz), 3.44 (1H, dd, h =15Hz, J2=4Hz), 3.35-3.25 (8H, m's ; Shielded by water signal) ppm. 13CNMR(DMSO-d6) ΰ 173.7, 161.3 (d, J=243Hz), 157.3, 149.8, 136.4 (d, J=3Hz), 130.1, 127.7 (d, J=8Hz), 127.2 , 116.2, 115.5 (d, J = 21 Hz), 53.4, 49.4, 48.0, 44.9. The starting materials were prepared as follows: gasification [(R)-2,5-dioneimidazolidinium]methanesulfonate It is made according to Mosher et al., 1958, J. Org. Chem.: 1257. 1-(4'-Fluoro[1,1'-biphenyl]-4-yl)hexahydropyrazine 4_bromo-4'-fluorobiphenyl (4_46 g, 17-8 mmol) ', N-T-butoxycarbonylhexahydropyridin (3_97 g, 21_3 mmol), sodium butoxide (2.39 g, 24.9 mmol), racemic 2,2'·double (two Phenylphosphino)-1, fluorene-hydrazine (racemic-indole) (0·082 g, 0.131 mmol), bis(dibenzylideneacetone)palladium (9) (〇.〇41 g, 0 .〇45 mmol) and anhydrous toluene (45 ml) at 80. (: Stirring under nitrogen gas for six hours. Filter the warm mixture, wash the solid twice with warm toluene) and concentrate the filtrate in the sputum to obtain a crude orange-red, which, together with ether (50 ml) Stir for two hours. Filter solids to a small volume of ether-48- This paper scale applies to the National Standard (CNS) Α4 specification (210 X 297 public) ---- 1329637 A7 B7 V. Invention description (45 Washing 'And dry overnight in the air to obtain 5 57 g (88. yield) 4_(4'-fluoro[1,Γ-biphenyl]-4-yl)-1_hexahydropyridinecarboxylic acid The third-butyl ester. This product (5-52 g, 15.5 mmol) was dissolved in dioxane (15 mL) and stirred at room temperature with 4 mL hydrochloric acid (8-1 mL) overnight. Hydrochloric acid (3 ml), stirring was continued at 45 ° C for 5 hours, and at 6 〇χ: 丨 hours. The solution was concentrated to dryness, and the solid was triturated with ether (1 mL) and filtered. Washed in a small volume puzzle and dried in the air at 45 C for two hours to obtain 5 26 g (103. yield) of 1-(4-fluoro[1,-biphenyl]yl)hexahydropyrene β well Hydrochloride , a pale yellow salt. LC-MS (APCI) m/z 257 (MH+). 1 H NMR (DMSO-d6) d 9.40 (2H, bs), 7.64 (2H, dd, J, =6Hz, J2 =9Hz ), 7.55 (2H, d, J=9Hz), 7.24 (2H, t, J=9Hz), 7.07 (2H, d, J=9Hz), 3.46-3.41 (4H, m), 3.25-3.17 (4H, m). The title compound was obtained as a pale white solid. NMR (DMSO-d6) d 7.61 (2H, dd, Jj = 6 Hz, J2 = 9 Hz), 7.49 (2H, d, J = 9 Hz), 7.22 (2H, t, J = 9 Hz), 6.98 (2H, d, J = 9 Hz), 3.10-3.06 (4H, m), 2.86-2.81 (4H, m). Example 5 Using a procedure similar to that described in Example 4, gasification of [(4R)-2,5-dione The imidazolium]methanesulfonium is reacted with a suitable primary or secondary amine to obtain the compounds listed below. The amines used are commercially available. -49 The paper size is applicable to the China National Standard (CNS) A4 size (210X 297 mm) 1329637 A7 B7 V. Description of invention (46)

The following table gives an amine group to each compound having the above structure.

Binding -50 - The scale of this sheet applies to the Chinese National Standard (CMS) A4 specification (210X 297 mm) 1329637 A7 B7 V. Description of invention (47) Example 6 (S)-5-((丨4-(4'- Fluoryl hydrazine, hydrazine-biphenyl fluorene-based) hexahydropyridinyl)methyl)-2,4-imidazolidinone

Gasification of [(S)-2,5-dioneimidazolidinium]methanesulfonate (〇〇127g, 〇〇6〇mmol), 1-(4·-fluoro[1,Γ-linked Phenyl H-yl) hexahydropyrazine (〇〇154 g, 〇060 house Moule), diethylamine (0.0084 ml '0.060 mmol) and anhydrous tetrahydrofuran (0.70 ml)' at room temperature Stir overnight. Add σ polystyrene ethyl isocyanate (0.025 g, 0.030 mmol) and shake the mixture overnight. The white suspension was carefully transferred to a round bottom flask. The resin was washed with tetrahydrofuran (2 x 1 mL) and the washings were transferred to the whole suspension. The solvent was evaporated, the white solid was suspended in water (5 mL), taken on a filter, washed with water (2×1 mL), and water was removed by suction and dried overnight at 45 ° C to give a title of about 0.010 g. Compound. LC-MS (APCI) m/z 433 (MH+). 1 H NMR (DMSO-d6) 10.8 (1H, br s), 7.98 (lH,d, J=2Hz), 7.63 (2H, del, J, = 5Hz, J2 = 9Hz), 7.53 (2H, d, J=9Hz), 7.23 (2H, t, J=9Hz), 7.05 (2H, d, J= 9Hz), 4.45 (1H, ddd, J, =2Hz) , J2 = 4 Hz, J3 = 6 Hz), 3.51 (1H, dd, J, = 15 Hz, J2 = 7 Hz), 3.44 (1H, dd, J 丨 = 15 Hz, J2 = 4 Hz), 3.35-3.25 (8H, m's; Covered by water signal _ -51 - This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) 1329637 A7 ____B7 _ V. Invention description (48 ) ))_ 13CNMR(DMSO-d6) ό 173.7, 161.3 (d, J=243Hz), 157.3, 149.8, 136.4 (d, J=3Hz), 130.1, 127.7 (d, J=8Hz), 127.2, 116.2, 115.5 (d, J=21Hz), 53.4, 49.4, 48.0 , 44.9. The starting materials are made as follows:

Gasification [(S)-2,5-dione imidazolidinium] Azepine was prepared according to M〇sher et al., 1958, J, Org. Chem. benefit: 1257. 1-(4'-Fluoro[1,1'-biphenyl]-4-yl)hexahydrosex was prepared according to Example 4. Example 7 Using a procedure similar to that described in Example 6, gasification [(4 illus, _2, bis- simi- imi) methane sulfonium was reacted with an appropriate primary or secondary amine, as shown below. Compounds. The amines used are commercially available.

Order

k The following table gives an amine group to each compound having the above structure. _ -52- This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) 1329637 A7 B7 V. Invention description (49)

Example 8 Synthesis of intramethylene urea (where E is carbon or a hetero atom) having the following general structure:

Representative synthetic route: (5R,S)-5-丨4-(4-gasosystem)-7T or 'bite-1-yield methyl j-5-methyl-sweet disease- ___-53 -_ This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1329637 A7 B7 V. Description of invention (5〇)

Reagents: a) MeS〇2 Cl, DCM, 0 C, 2.5 hours. b) i. LHMDS, THF, 45 min, ii. MeOAc, THF, 40 min. c) KCN, (NH4)2 CO3, 50°,. EtOH/H 〗 0, 70 ° C, 17 hours. -54

This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1329637 A7 B7

V. Description of the invention (51 sulfonyl-decylamine intermediate - structure _ fractionation analysis (丨) m/z 258 (MH+) m/z291 (MH+) m/z310(MH+) nc_O~〇4- m/z 267 (MH+) ρΌ~ν〇νΊ- m/z 259 (MH+) F m/z 273 (MH+) m/z 243 (MH+) c"^DKDi~ m/z 274 (MH+) (1): About NMR For the data, see the experimental section. 4-(4-Fluorophenyl)-1-methanesulfonyl-hexahydropyridine 4-(4-fluorophenyl)hexahydropyridine hydrochloride (2.16 g; 10 mmol) The ear was dissolved in DCM (60 mL) with diisopropylethylamine (4_35 mL; 25 mmol) and cooled on ice/water bath under nitrogen. 10.1 mmol was dissolved in DCM (5 mL) and was added dropwise over a period of 2 min. The reaction was carried out; the mixture was stirred on an ice/water bath for 2.5 hours. The reaction mixture was pH = 2 Dilute HC1 (aqueous solution), H2 〇 and 1M Na2 C03 wash. Make _-55- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm > 1329637 A7 B7 V. Invention description (52 The organic phase is dried (Na2SO4), filtered and evaporated to give a crude material from THF / n-heptane The crystals were recrystallized. The colorless crystals were removed by EtOAc (EtOAc) elute ^) : (ί 7.31 (m, 2Η), 7.12 (m, 2Η), 3.67 (m, 2Η), 2.80 (dt, 2H), 2.64 (m, 1H), 1.85 (m, 2H), 1.65 (m , 2H). 5-Lyryl-2-(1-methylxanthene) (bristyl-7T wind p is more than -4-yl lactyl)-^ bite the title compound by 4-(4-fluorophenyl)- 1-A was prepared as described in the synthesis of succinyl-hexahydrop to bite. 5-Alkyl-2-(hexahydropyridin-4-yloxy)-pyridine (2.13 g; 10 mmol) (The preparation of this compound was prepared as described in WO 99-GB2801), diisopropylethylamine (2.20 ml; 12.5 mmol) and gasified methanesulfonate (1.56 ml; 10.1 mmol). 2.14 g (74%) of the title compound. LC-MS (APCI) m/z 291 (MH+). 1HNMR (DMSO-d6): ά 8.20 (d, 1H), 7.81 (dd, 1H), 6.87 (d, 1H ), 5.09 (m, 1H), 3.41-3.30 (m, 2H), 3.15-3.06 (m, 2H), 2.90 (s, 3H), 2.04 (m, 2H), 1.75 (m, 2H).

1-(M-branched base>-4-[5-(trifluoromethyl)p-predated-2-yl]hexahydro-17 ratio!* Well 1-[5-(trifluoromethyl)-pyridine 2-yl]-hexahydropyrazine (1.0 g; 4.3 mmol) and diisopropylethylamine (0.9 ml; 5.4 mmol) dissolved in DCM (10 mL). Molecular sieve (4A) was added. The solution was allowed to cool on an ice/water bath. The methanesulfonate (0.9 ml; 12 mmol) was gasified and the resulting slurry was stirred for 15 minutes to allow the reaction mixture to reach room temperature and after 1 hour. The reaction was quenched by the addition of 5 ° KHCO3. The solvent was evaporated and the residue was dissolved in DCM _ - 56 - This paper scale was applied to the Chinese painter standard <CNS) A4 specification (210X 297 gong ^--- -- ' 1329637 A7 B7 5. Inventive Note (53) Between 5°〇KHC03. Separate the aqueous phase and extract (1x) with DCM. The combined organic phases are dried (MgS04), filtered and evaporated. The crude product was obtained as a yellow solid. EtOAc (EtOAc) EtOAc (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Micron) LC-MS (APCI) m/ z 310 (MH+). 1 H-NMR (DMSO-d6) : ά 8.44 (1Η, bs), 7.85 (1H, dd), 7.02 (1H, d), 3.77 (4H, bt), 3.20 (4H, bt ), 2.90 (3H, s). The following compounds were prepared as described in the synthesis of 1-(methylsulfonyl)-4-[5-(trifluoromethyl)pyridin-2-yl]hexahydropyridinium. 6-[4-(methylsulfonyl)hexahydropyrrol-1-yl]pyridine-3-carbonitrile 6-(1-hexahydropyridinyl)-pyridine-3-carbonitrile (2.07 g; 11 m Mole), diisopropylethylamine (2.4 ml; 13.8 mmol) and gasified methanesulfonate (0.86 ml; 11 mmol) in 2.5 g (86%) in DCM (20 mL) The title compound. Purity > 95°/(NMR). LC-MS (APCI) m/z 267 (MH+).; 1 H-NMR (DMSO-d6): δ 8.52 (1 Η, dd), 7.90 ( 1H, dd), 7,00 (1H, d), 3.79 (4H, brt), 3.19 (4H, bt), 2.90 (3H, s). 1-(4-fluorophenyl)-4-(A) Si-based hexahydro-p ratio 11 well 1-(4-fluorophenyl)-hexahydropyridine (1. 98 g; 11 mmol), diisopropyl 6 amine (2.4 ml; 13.8 mmol) The gasified decanesulfonium sulfonate (0.86 ml: 11 mmol) was obtained. Purity >95% (NMR). ____-57-_ This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm)

Binding

K-% 1329637 A7 B7 V. Description of the invention (54) LC-MS (APCI) m/z 259 (MH+). 1 H-NMR (DMSO-d6): Θ 7.11-6.96 (4H, m), 3.28-3.20 (4H,m), 3.20-3.14 (4H, m), 2.92 (3H, s). 1- [(4-Phenylphenyl) fluorenyl 4-(A) is a six gas p ratio p well (4-Fluoro-indenyl)-hexahydropyrazine (2.14 g; 11 mmol), diisopropylethylamine (2.4 ml; 13.8 mmol) and gasification A gg (0.86 ml) (11 mmol), 1.97 g (650 / 〇) of the title compound was obtained in DCM (20 ml). Purity &gt;95% (NMR) LC-MS (APCI) m/z 273 (MH+). 1 H-NMR (DMSO-d6): ί 7.40-7.28 (2Η, m), 7.21-7.10 (2H, m) , 3.50 (2H, bs), 3.10 (4H, m), 2.87 (3H, bs), 2.44 (4H, m). 2- [4-(Met) hexahydrop to 啩-1-yl) n 唉 唉 1-(2-pyrimidinyl)-hexahydropyrazine dihydrochloride (2.61 g; 11 mmol) with diisopropylethylamine (7.2 ml; 41.3 mmol) in DCM ( Stir in 20 ml) for 30 minutes. The precipitated salt was removed by filtration, and the solvent was evaporated,jjjjjjj 4 ml of diisopropylethylamine was added; i丄 pen and 4A molecular sieves. This yellow solution was cooled on an ice/water: bath, and gasified methanesulfonate (0.86 ml; 11 mmol) was added. The resulting red liquid was stirred for 15 minutes, the reaction mixture was allowed to reach room temperature, and after 5 hours, by adding 5. ’. KHCO3 quenched the reaction. The solvent was evaporated and the residue was dissolved between DCM and EtOAc. Because the bubble is formed, it is difficult to divide. The aqueous phase was saturated with NaCl, and the pH was adjusted to 1 (M </ </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Red solid. Recrystallized from Et0Ac / heptane (3χ), obtained -------58- This paper scale applies to Chinese National Standard (CNS) Α4 specification (21〇χ 297 mm) 1329637 A7 B7 V. Invention The title compound is obtained as a red powder. mp. NMR (DMSO-d6) : ά 8.39 (2H, d), 6.68 (1H, t), 3.85 (4H, bt), 3.17 (4H, bt), 2.88 (3H, s). 4-(4-benzene The hexahydro-p-pyrylpyryl sulphate is prepared as described in the synthesis of 4-(4-fluorophenyl)-1-methanesulfonyl-hexahydropyridine. (4-indolyl) hexahydropyridine hydrochloride (0.9 g, 3.9 mmol) 'diisopropylethylamine (1.7 mL, 9.7 mmol) and gasified methanesulfonate (0.33 mL, 4.3 mM) Mole), after recrystallization from EtOAc / heptane in DCM (30 mL) Purity &gt;95°/.. LC-MS (APCI) m/z 274 (MH+). 'HNMRCDC^ : 1.83 (2H, dd) : 1.92-2.01 (2H, m) ; 2.55-2.68 (1H , m) ; 2.79 (2H, dt) ; 2.85 (3H, s) ; 3.97 (2H, d) ; 7.16 (2H, d) ; 7.32 (2H, d). Structural analysis of ester intermediates N 0 m/z 195 (MH+) lH-NMR 0 m/z 181 (MH+) X. 丫err., m/z 158 (MH+ - boc) ___- ςα - This paper scale applies to Chinese National Standard (CNS) Α4 specification (210 x 297 mm)

Binding

1329637 A7 __B7 V. INSTRUCTIONS (56) All other esters used are commercially available or have been previously described. Ethyl 4-pyrimidin-2-yl-butyrate A 2-bromopyrimidine (1_0 g &apos; 6 -3 mmol) was slurried in dry THF (8 mL). N2 (gas) was bubbled through the slurry for 5 minutes. Add to

Pd(CH3CN)2Cl2 (8 mg, 〇.〇3 mM) with pph3 (23.6 mg, 〇.〇9 mM). To a solution of N2, 4-ethoxy-4-keto-butylzinc bromide (0-5 M/THF) (15 ml, 7.5 ml) was added. The resulting brown solution was stirred at room temperature for 2 hours. H20 (5 ml) was added and the mixture was stirred for 60 minutes before evaporation of the solvent. The residue was redissolved in DCM (150 mL) with 0.5M trisodium succinate (1 mL), η 2 Ο ( Wash 100 ml) and brine (100 ml), dehydrate dry (MgS04), filter, and evaporate to give i.3 g of orange oil. The crude product was purified on a 70 g Si-60 gel using a gradient of 100% heptane to 100% EtOAc as solvent. The fractions containing the product were collected and the solvent was evaporated to give a yellow oil. The purity was determined by NMR &gt; 95 〇. , salty enough for our needs "to obtain 1.12 grams (92 °. yield) of the title compound. LC-MS (APCI) m/z 195 (MH+). 1 H-NMR (CDC13): </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; , 2.41 (t, 2H), 2.18(q, 2H), 1.25 (t, 3H). 3-1^Bitter-2-yl-propionic acid ethyl acetonate 2-bromopyrimidine (1.0 g, 6.3 mmol) The ear was dissolved in THF (8 mL) and was bubbled with nitrogen. Add Pd(MeCN)2 Cl2 (8 mg, 0.03 mmol) and PPh3 (23.6 mg, 0.09 mmol), then: add t, add 3-ethoxy-3-ketopropyl zinc bromide ( 15 ml, 7.5 millimoles). The reaction was stirred at room temperature for several days. The crude product was purified on silica gel with heptane-EtOAc 3:1 as the eluent. _-60-__ This paper scale is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1329637 A7 B7 V. Description of invention (57. Obtained 0.60 g (52%) of the title compound. LC-MS (APCI) m/z 181 (MH+). 4-(2-methoxy-2-ketoethyl)hexahydropyridin-1- Resin acid tert-butyl ester 4-(2-decyloxy-2-ketoethylidene) hexahydropyridine-1-carboxylic acid tert-butyl ester (3.6 g, 14 mmol) and used The water-wet 10% Pd/C (0_8 g) was combined with EtOAc (EtOAc) (EtOAc)克,990/.) LC-MS (APCI) m/z 158 (MH+-boc). 1 H NMR (CDC13) : ^ 4.07 (2H, bs) ; 3.68 (3H, s) ; 2.72 (2H, t 2.25 (2H, d, J=7.1Hz); 2.01-1.86 (1H, m) ; 1.68 (2H, d) ; 1.46 (9H, s) ; 1.23-1.08 (2H, m). -61 - This paper scale applies to China National Standard (CNS) A4 specification (21〇X 297 mm> 1329637 A7 B7 V. Description of invention (58) Ketone intermediate 〇

RE R2 \ II NS / II 〇RE R2 Analysis. CH Me m/z 300 (MH+) f^C}~ CH H-NMR. See experimental section. CH m/z 394 (MH+) CH m/z406( MH+)(1) α_〇~〇\ CH Me m/z 333 (MH+)(1) a-〇~°\ CH m/z 423 (MH+)(1) a~ct°\ CH m/z 427 _+)(1) . Fraction, CH m/z 439 (MH+)(1) α~〇~°\ CH m/z 347 (MH+)(1) a~CK CH m/z 361 (MH+)(1) a_&lt;Q^〇\ CH u. m/z 375 (MH+)(1) a^Q^°\ CH m/z 425 (MH+)(1) a_&lt;Q^〇\ CH m/z 423 (MH+)(1) a~^y°\ CH m/z417(MH+)(1) - S2-Installation•s This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1329637 A7 B7 V. Invention description (59) R £ R2 Analysis CH-om/z 446 (MH+)(1) α _〇^°\ CH m/z 372 (MH+)(1) CH m/z 476 (MH+)(1) a~^cy〇\ CH 〜om/z:432 _+)(1) CH -om/z 395 (MH+)( 1&gt;a_Q&quot;°\ CH -Or m/z413 (MH+)(1) α-〇·°\ CH m/z 385 _+)(1) a^y°\ CH - a~^y°\ CH ~ 0 m/z 414(MH+)(1) F~^cy~ CH ^X) m/z 392 (MH+)(1) CH m/z 384 (MH+)(1) CH mm/z 405 (MH+)(1) f^O ~ CH m/z 352 (MH+)(1) a_0_ CH m/z 400 (MH+)(1) a^O~ CH m/z 429 (MH+)(1) F^y- F '-NN Me m/z 352 (MH+ (1) Nc~^y~ N-NN Me m/z 309 (MH+)(1) fO~ N Me m/z 301 (MH+)(1) ____- . This paper scale applies to Chinese National Standard (CMS) A4 specification (210 X 297 mm) 1329637 A7 B7 V. Invention (6〇) R Ε R2 Analysis F^0^\ Ν Me m/z315(MH+)(1) Ο Ν Me m/z 285 (MH+)(1) α_〇·°\ CH fyCr- m/z 517 (MH+)(1) (1): crude product, NMR could not be obtained, and this material was used directly in the next synthetic step. 1-[4-4(气净'基基)-7Τ Nitrogen 17 is more than 4-(4-fluorophenyl)-1-decanesulfonyl-hexahydropyridine (1〇) 〇 mg; 0.39 mmol; dissolved in anhydrous THF (3 mL) under a protective nitrogen atmosphere. A 1.0 M solution of lithium bis(trimethyldecyl)amine in THF (1.0 mL; 1.0 mmol) was added at room temperature, and the resulting yellow solution was stirred for 45 min. Ethyl acetate (50 mg; 0.68 mmol) dissolved in dry THF (0.5 mL) was added and the mixture was stirred at room temperature for 40 min. The reaction was quenched by the addition of NH4CI (s) (2 mL). The mixture was evaporated and the resulting solid was dissolved in a mixture of DCM and H20. The organic phase was separated, washed with brine, dried (MgSO4), filtered and evaporated. The crude product was purified on a 20 g Si-60 gel using 100[deg.]. Heptane to 50°'. A gradient of EtOAc was used with a flow of 20 mL/min and UV = 254 nm for detection. The title compound was obtained as a colorless solid. Obtained 7 mg of magnesium. /. Yield). TLC (Si-60; EtOAc: heptane (2: 1)): Rf = 0.65 __--^64·.- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

Binding

K- 1329637 A7 B7 V. INSTRUCTIONS (61) LC-MS (APCI) m/z 300.1 (MH+). 1 H-NMR (CDC13) : δ ΊΛΊ (m, 2H), 7.01 (m, 2H), 4.02 (s, 2H), 3.93 (m, 2H), 2.94 (dt, 2H), 2.63 (m, 1H), 2.46 (s, 3H), 1.91 (m, 2H), 1.77 (m, 2H). It is prepared as described in the synthesis of l-[4-4(fluorophenyl)-hexahydrop-biti-1- decyl]-propan-2-one. 1-[4-4(fluorophenyl)-hexahydropyridine-1-sulfonyl]-4-phenyl-butan-2-one 4-(4-fluorophenyl) 1-methanesulfonyl- Hexaar pyridine (1 〇〇 mg; 0.39 mmol), methyl 3 phenylpropionate (112 mg; 0.68 mmol) and lithium bis(trimethyldecyl)amine 1.0 M/THF (1.0 ml ; <RTIgt; </RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; m, 7H), 6.99 (m, 2H), 3.97 (s, 2H), 3.79 (m, 2H), 3.11 (t, 2H), 2.94 (t, 2H), 2.83 (dt, 2H) 2.57 (m, 1H), 1.83 (m, 2H), 1.70 (m, 2H). l-[4-4(fluorophenyl)-hexahydropyridine-1- continued S-group]-5-imidazole-pentane-2- Ketone 4-(4-fluorophenyl)-1-methanesulfonyl-hexahydropyridine (1 〇〇 mg; 0.39 mmol), 4-imidazolyl-ethyl butyrate (127 mg; 0·70 <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; z 394 (MH+). 1 H-NMR (CDCI3) : δ 7.48 (s, 1H), 7.16 (m, 2H), 7.08 (s, 1H), 7.02 (m, 2H), 6.93 (s, 2H) , 4.00 (t, 2H), 3.97 (s, 2H), 3.90 (m, 2H), 2.92 (dt, 2H), 2.77 (t, 2H), 2.63 (m, 1H), 2.12 (q, 2H), 1.92 (m, 2H), 1.77 (m, 2H). 1-(4-(4-fluorophenyl)-hexahydropyridine-1-ylidene-5-5-pyrimidin-2-yl-pentane-2 - Ketone __-65-_ This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1329637 A7 B7 V. Description of invention (62) Make 4-(4-Denphenyl)-1- Methane base-hexahydro-p-bite (150 mg: 0.39 mmol) was dissolved in dry THF (3 mL) and cooled on ice/brine mixture. Lithium bis(trimethyldecyl)amine was added in THF A 1.0 M solution (1.5 mL; 1.5 mmol) was added and the mixture was stirred for 40 min. Add 4-pyrimidin-2-yl-butyrate ethyl ester (169 mg; 0.87 mmol) in THF (0.5 mL). The mixture was stirred for 30 min and then taken to room temperature. After 2 hours, LC/MS analysis of the reaction mixture showed &lt; The conversion was carried out and the reaction was allowed to float by the addition of saturated NH4CI (aq) (2 mL). The mixture was evaporated and the solid formed was dissolved in a mixture of DCM and 5% KHC. The organic phase was separated and the aqueous phase was extracted once with DCM. The combined organic phases were washed with brine, dried (MgSO4), evaporated and evaporated. This oil was dissolved in EtOAc and isohexane was added until a solid formed. The solvent was evaporated to give a crude yellow solid. This material was analyzed using only LC/MS and used in the next step without further purification. Obtained 234 mg of the crude title compound. LC-MS (APCI) m/z 406.1 (MH+). The following compound is 1-[4-(4-fluorophenyl)-hexahydropyridin-1-sulfamoyl]-5-pyrimidin-2-ylindole Made as described in the synthesis of alkan-2-one. It was obtained as a crude product and used without further purification. 1-[4-(5-murine-precipitate-2-yloxy)-7Τ风ρ比淀小·53⁄4' brewing base]-propan-2-indole from 5-gasyl-2-(1-methylxan Fibres-hexahydropurin-4-yloxy)-σ ratio bite (15 ί) mg: 〇_51 mmol, methyl acetate (61 mg: 0.82 mmol) and lithium bis (trim) Starting with alkyl)amine 1.0M/THF (1.3 mL; 1.3 mmol). 161 mg of the crude title compound were obtained. Used without further purification. __-66-_ This paper size applies to Chinese National Standard (CNS) Α4 specification (210Χ 297 mm) 1329637 A7 B7 V. Description of invention (63) LC-MS (APCI) m/z 333.1 (MH+). l-[ 4-(5-murine than bit-2-yloxy)-ττ nitrogen f7 than precipitate-1-jing 83⁄4 base]-4-m-butyl-but-2-copper from 5-carbon-2-(1-甲坑绩g Shengji-hexahydrop-supple-4-yloxy)-p 唉 (150 mg; 0.51 mmol), methyl 3-phenylpropionate (126 mg; 0_77 mmol) Starting with lithium bis(trimethyldecyl)amine 1.0 M/THF (1.3 mL; 1.3 mmol). 258 mg of the crude title compound are obtained. Used without further purification. LC-MS (APCI) m/z 423.2 (MH+). gas ratio bit-2-yloxy)-ττ rat ρ ratio 1-performance Sj^ kib 5- miso-1-yl-pentane- 2-keto from 5-carbyl-2-(1-methyl-furanyl-hexahydro-p-bito-4-yloxy-p-bite (150 mg; 0.51 mmol), 4-imidazole-1- Starting with ethyl-butyric acid ethyl ester (140 mg; 0.77 mmol) and lithium bis(tridecyldecylalkyl)amine 1.0 M / THF (1.3 mL; 1.3 mmol). Without further purification. LC-MS (APCI) m/z 427.2 (MH+). 1_[4-(5_rhobi-2-yloxy(yl)-7Τ nitrogen 17 than precipitation-1-^^ base]- 2-yl-pentan-2-one' from 5-carbyl-2-(1-methylhu continued S-group-hexahydrop-precipitate_4_yloxy.. group)-u ratio lake (150 mg : 0.51 mmol, ethyl 4-pyrimidin-2-yl-butyrate (147 mg; 0.76 mmol) and lithium bis(trimethyldecyl)amine 1.0 M/THF (1.3 mL: 1.3 mmol) The title compound was obtained in 244 mg of crude title compound. mp. mp. mp. )-7T 风ι 17比淀-1-·®^ 牛基j-丁-2-嗣-67- This paper ruler Applicable Chinese National Standard (CNS) A4 size (210x 297 mm)

Install π

k 1329637 A7 B7 V. INSTRUCTIONS (64) LC-MS (APCI) m/z 347 (MH+) l-[4-(3-^L ratio-2-·^·乳·)-ττ 1-·^· 】-戍{充-2-613⁄4 LC-MS (APCI) m/z 361 (MH+) 1-[4-(5-gas-p ratio 0^-2-yloxy)-ττ Nitrogen 17 is more than -1 - Saki δ έ 】 -4-methyl-pentan-2-yl LC-MS (APCI) m/z 375 (MH+) 1- [4-(5-wind! _1&gt; ratio- 2-yloxy)-ττ play | ? ratio δ έ base j-4-n^f -2-yl-but-2-one ketone LC-MS (APCI) m/z 425 (MH+) l-({4- [(5-Chloropyridin-2-yl)oxy]hexahydropyridine-l-yl}sulfonyl)-3-(3-methylphenyl)propan-2-one LC-MS (APCI) m /z 423 (MH+) l-({4-[(5-murine p-biti-2-yl)oxy]ττ rat p bite-l-yl} Jing S disc base)-3-tetrazine_ 2Η-σ辰喃-4-ylpropan-2-recharge LC-MS (APCI) m/z 417 (MH+) l-({4-[(5-chloro-p-Phen-2-yl)oxy] Hexahydro-p-biti-l-yl} 醯 )))-5- 福福·#- 4-Pentyl-2-one LC-MS (APCI) m/z 446 (MH+) ' 5- ({4 -[(5-murine 11 ratio-2-yl)oxy]ττ gas ρ ratio bite-l-yl} continued peak base)-4-mercapto gamma LC-MS (APCI) m/z 372 ( MH+) 5-({4-[(5-Chloropyridin-2-yl)oxy]hexahydropyridine-l-yl}sulfonyl)-4-one 1,1-dimethylethyl pentylamino decanoate LC-MS (APCI) m/z 476 (MH+) · 1-({4-丨(5-chloropyridin-2-yl)oxyl 1 Hexahydropyridine-l-yl}sulfonyl)-4-morpholine-4-ylbutan-2-one oxime. __-68 -_ This paper scale applies to China National Standard (CNS) A4 specification (210X297 PCT) 1329637 A7 B7 V. INSTRUCTIONS (65) LC-MS (APCI) m/z 432 (MH+) 2-({4-[(5-Chloropyridin-2-yl)oxy]hexahydropyridine- 1-ylsulfonylsulfonyl) small phenylethyl ketone LC-MS (APCI) m/z 395 (MH+) 2-({4-[(5-a gas-based p is more than this-2-yl)oxy]7T Rat p-bite-l-yl)-1-(4-indolyl) ethyl ketone LC-MS (APCI) m/z 413 (MH+) 2-({4-[(5-carbylpyridine-2) -yl)oxy]hexahydropyridine-l-yl}sulfonyl)-1-(1Η-imidazol-4-yl)ethanone LC-MS (APCI) m/z 385 (MH+) 4-[({ 4-[(5-Azinopyridin-2-yl)oxy]hexahydropyridine-l-yl}sulfonyl)ethinyl]benzamide No data 1-({4-[(5-gas) 1717-p-but-2-yl)oxy]7T wind ρ----l-carbyl)-4-(1Η-1,2,4-triazol-1-yl)butan-2-one LC-MS (APCI) m/z 414 (MH+) l-{[4-(4-fluorophenyl)hexahydropyridin-1-yl]sulfonyl}-4-pyrimidin-2-ylbutane 2-ketone LC-MS (APCI) m/z 392 (MH+) ; 1- {[4-(4-fluorophenyl)hexahydro I» than bit-1-yl] -2H-11 benzo-4-ylpropan-2-one ketone LC-MS (APCI) m/z 384 (MH+) 4-({[4-(4-fluorophenyl)hexahydrop ratio -1- j 醯 } } } } } } } } } LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC }}-1-(1Η-imidazol-4-yl)ethanone LC-MS (APCI) mJz 352 (MH+) __-69-_ This paper scale applies to Chinese National Standard (CNS) A4 specification (21〇x 297 MM)

Binding

1329637 A7 B7 V. Description of invention (66) Chaotic base) 7 hurricane p ratio-1-base] continuation base}-3-tetrazol-2H-methane-4-ylpropan-2-one LC-MS (APCI) m/z 400 (MH+) 1-{[4-(4-gas                        -2-嗣LC-MS (APCI) m/z 429 (MH+)

Packing 1_({4_[5-(2-gas fluorenyl)p is more than bit-2-yl] ττ wind p than 11 well-l-base} continuation base) propan-2-indole LC-MS (APCI) m/ </ RTI> </ RTI> <RTIgt; L-{[4-(4-Fluorophenyl)hexahydropyrazine-1-ylsulfonylpyridin-2-one LC-MS (APCI) m/z 301.1 (MH+)

1-({4-[(4-Fluorophenyl)methyl)hexahydropyridin-1-yl)sulfonyl)propan-2-one LC-MS (APCI) m/z 315.1 (MH+) l- [(4-pyrimidin-2-ylhexahydropyrylene-1-yl)cansinylpropan-2-one LC-MS (APCI) m/z 285.1 (MH+) 4-[3-({4-[ (5-alkylpyridin-2-yl)oxy]hexahydropyridine-l-yl}sulfonyl)-2-oxopropyl 1 hexahydropyridine-1-acid 1,1-dimethylethyl ester LC-MS (APCI) m/z 517 (MH+).

___ - 7Π - This paper size applies to Chinese National Standard (CNS) A4 size (210 X 297 mm) 1329637 A7 B7 V. Invention description (67) R Ε R2 Analysis f_0~ CH Me m/z 370 (MH+)(1 CH m/z 460 (MH+)(1) CH-nO m/z 464 (MH+)(1) CH wO m/z 476 _+)(1) CH Me m/z 403 (MH+)(1) αΌ~. , CH m/z 493 (MH+)(1) α_〇~°\ CH - 0 m/z 497 (MH+)(1) CH m/z 509 (MH+)(1) α_〇~°\ CH m/z 417 (MH+)(1) α_〇·°\ CH m/z431 _+)(1) CH m/z 445 (MH+)(1) 〇~\ CH m/z 495 (MH+)(1) α_〇·°\ CH m/z 493 (MH+)(1) a~C^〇\ CH m/z 487 _+)(1) CH om/z 517 (MH+)(1) a^Q^°\ CH \^CN m/z 442 _+)(1) 〇^〇~°\ CH \/\/Νγ〇ν^ m/z 547, 490 (MH+),- 0 1 tBu(I) __- 71 This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1329637 A7 B7 V. INSTRUCTIONS (68) RE R2 Analysis a^Q~°\ CH 〜o. m/z 502 (MH+)(2) CH m/z 465 (MH+)(2) a_ 〇~°\ CH o . m/z 483 (MH+)(2) a^〇~°\ CH m/z 455 (MH+)(2) αΌ~°\ CH m/z 508 (MH+)&lt;2) 〇^〇~°\ CH m/z 484 (MH+)(2) CH ^X) m/z 462 _+)(1) CH m/z 454 _+)(1) CH m/z 475 (MH+) (1) CH m/z 422 (MH+)(2) CH m/z 470 (MH+)(1) CH_0. m/z 499 (MH+)(1) F)^ FNN Me m/z 422 (MH+)a) nchQ^ N Me m/z 379 _+)(1&gt; N Me m/z371 _+)(1) fO*AN Me m/z 385 (MH+)(1) r=N 〇N Me m/z 355 _+)(1) Or' CH m/z 446 (MH+)(1) σΌ~°\ CH om/z 472 (MH+) (1) ___- 72 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ·«

Binding

1329637 A7 B7 V. INSTRUCTIONS (69) RE R2 Analysis CH -〇m/z 4〇3 (MH+)(1) CH m/z 466 (MH+)(1) CH 广cv 十0 m/z 530 (MH+ - boc (1) CH m/z 486 (MH+ - boc)(1) a_o~°\ CH \ m/z 524 (MH 10)(1) (1) : NMR can be obtained, see the experimental part. (2) : Not purified.

(5R,S)-5-丨4-(4-fluorophenyl)-hexahydropyridine-1-sulfonylmethyl b 5-methyl-imidazolidin-2,4-dione

In a 22 ml sealed tube, the ketone 1-[4-4(fluorophenyl)-hexahydro-p-biter-1-g-propyl-]-propan-2-one (68 mg; 0.23 mmol), KCN (30 mg; 0.46 mmol) and (NH4)2CO (111 mg; 1.16 mmol) were suspended in 509 / 〇 EtOH / H2O (8 mL) and heated to 70 ° C to form a solution. The mixture was stirred at 70 ° C for 17 hours, a solid formed in the tube, the mixture was cooled to room temperature, and the solvent was evaporated, the residue was suspended in water, and pH was adjusted to pH = 6 using 1.0 M HCl. And remove the precipitated product by hydrazine and wash it with water. The aqueous phase was saturated with NaCl and extracted with MeCN. The solid material was combined with the MeCN solution and evaporated. Take MeCN/H2 0 + 0.1. '. The TFA was used as a dissolving agent, and the crude product was purified using a semi-prepared HPLC system and a C-18 column. The product contains the dissolved fraction of the product and is removed by evaporation to obtain the title compound __-73 -_ This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 public ·)

1329637 A7 ___B7 V. Description of invention (7〇) The substance is a colorless solid. 53 mg (62 ° / yield) was obtained. The purity was determined by NMR &gt; 98. '. LC-MS (APCI) m/z 370.0 (MH+). 1 H-NMR (DMSO-d6): 10.74 (s, 1H), 8.02 (s, 1H), 7.31 (m, 2H), 7.12 (m, 2H) ), 3.61 (m, 2H), 3.51 (d, 1H), 3.34 (d, 1H), 2.86 (m, 2H), 2.63 (m, 1H), 1.82 (m, 2H), 1.63 (m, 2H) , 1.34 (s, 3H). (5R,S)-5-丨4-(4-Fluoro-based)-tt wind p than bite-i- contigyl methyl b amp; The title compound of 2,4-dione is (5R,S)-5-[4-(4-fluorophenyl)-hexahydropyridine + sulfonylmethyl]-5-methyl·mijidiao-2 , prepared as described in the synthesis of 4-dione. H4-4(fluorophenyl)-hexahydropyridine-1·indolyl]·4_phenylbutan-2-one (93 mg; 0.24 mmol), KCN (40 mg; 0.61 mmol) and (Nh4) 2C 〇 3 (117 mg; 1 - 22 mmol) afforded 37 mg (33. LC-MS (APCI) m/z 460.1 (MH+). 1 H-NMR (DMSO-d6): ί 10.87 (s, 1 Η), 8.13 (s, 1H), 7.30 (m, 4H), 7.15 (m, 5H), 3.63 (m, 2H), 3.56 (d, 1H), 3.41 (d, 1H), 2.87 (m, 2H), 2.61 (m, 2H), 2.39 (m, 1H), 1.92 (bt, 2H) ), 1.83 (m, 2H), 1.63 (m, 2H). (5R,S)-5-丨4-(4-fluorophenyl)-hexahydropyrene than bite-1- 醯 醯 甲 甲 甲 _ 5_ (3_Mijun·^•基_propyl)-imidazolidine-2,4-dione in a sealed 22 ml tube, 1-[4-4(fluorophenyl)-hexafluoropyridinium sulfonate 5-ammonium-butan-2-one (75 mg: 0.19 mmol), KCN (30 mg: 0.46 mmol) and (NH4)2 C03 (91 mg; 0.95 mmol) in EtOH /H2 0 (1/1) (10 ml), and stirred at 70 ° C for 17.5 hours. Add another -74- garment paper size for Chinese National Standard (CNS) A4 specification (210 X 297 mm)

Binding

1329637 A7 B7 V. INSTRUCTIONS (71) KCN (40 mg; 0.61 mmol) and (NH4)C03 (250 mg; 2.60 mmol), and the mixture was stirred at 70 ° C for an additional 16 hours. The solvent was evaporated, and the residue was suspended in H.sub.2, and the precipitated crude product was removed by filtration, with MeCN/H2 Ο + 0_1Q/. TFA was used as a dissolving agent and purified using a semi-prepared HPLC system with a C-18 column. The fractions containing the product were combined and the MeCN was removed by evaporation using 5a/. KHC03, the acidic aqueous phase was tested, pH = 8-9, and the precipitated product was extracted with EtOAc. The organic phase was dried (Na2SO4). Obtained 60 mg (68% yield) LC-MS (APCI) m/z 464.2 (MH+). 1 H-NMR (DMSO-d6): ^ 10.75 (bs, 1H), 8.06 (s, 1H), 7.59 ( s, 1H), 7.30 (m, 2H), 7.16-7.08 (m, 3H), 6.88 (s, 1H), 3.95 (m, 2H), 3.60 (m, 2H), 3.47 (d, 1H), 3.35 (d, 1H), 2.86 (m, 2H), 2.62 (m, 1H), 1.86-1.50 (m, 8H). (5R,S)-5-丨4-(4-fluorophenyl)-hexahydro Pyridine-1-n-decylmethyl b 5-(3-pyrimidin-2-yl-propyl)-imidazolidin-2,4-dione in a 40 ml sealed tube to make 1-[4-(4- Fluorophenyl)-hexahydropyridine-1-sulfonyl]-5-pyrimidin-2-yl-pentan-2-one (234 mg; up to 0.58 mmol), KCN (151 mg; 2.3 mmol) And (NH4)2C03 (557 mM: gram; 5.8 mmol) suspended in EtOH/H2 0 (1/1) (26 mL). The mixture was heated to 70 ° C and the resulting yellow solution was stirred for 16 hours. LC/MS analysis showed residual 15% unreacted hydrazine, another portion of KCN (65 mg: 1 mmol) and (NH4)2C03 (245 mg; 2.55 mmol), and the mixture was heated to 70 ° C It took another 16 hours. The solvent was removed by evaporation and the residue was taken in EtOAc (25 mL). Remove the sink by filtration; the crude product of the temple -75- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

Binding

K- 1329637 A7 B7 V. Description of invention (72) with MeCN/H2 0 + 0.1. 〇 TFA was used as a dissolving agent and purified using a semi-prepared HPLC system with a C-18 column. The product-containing fractions are combined, and MeCN is removed by evaporation, using 5% KHC03 to make the acidic aqueous phase alkaline, pH = 8-9, and the precipitated product is filtered off, washed with water, and dried in a desiccator It was dried overnight at 40 ° C under reduced pressure. This gave the title compound as a colorless solid. The purity was determined by NMR &gt; 98 ° /. . Obtained 120 mg (43 ° / yield, 2 steps). LC-MS (APCI) m/z 476.2 (MH+). 1 H-NMR (DMSO-d6): ί 10.77 (s, 1H), 8.72 (d, 2H), 8.03 (s, 1H), 7.36- 7.27 ( m, 3H), 7.157.09 (m, 2H), 3.60 (m, 2H), 3.50 (d, 1H), 3.34 (d, 1H), 2.92-2.80 (m, 4H), 2.62 (m, 1H) , 1.86-1.54 (m, 8H). The following compounds are based on (5R,S)-5-[4-(4-fluorophenyl)-hexahydropyridine-1-sulfonylmethyl]-5-(3 - shouted bit-2-yl-propyl) - prepared by the synthesis of the olfactory bite-2,4-dione. (5R,S)-5-丨4-(5-Gas-pyridin-2-yloxy)-hexahydropyridine-1-n-decylmethyl b 5-methyl-imidazolidin-2,4-di After the ketone was evaporated and the water was added, without purification, it was determined by HPLC (220 nm, 254 nm) and NMR that the product was precipitated to be sufficiently pure &gt; 98 °/. . 147 mg (71% yield, 2 mp. LC-MS (APCI) m/z 403.1 (MH+). 1 H-NMR (DMSO-d6): </ RTI> </ RTI> 10.73 (bs, 1H), 8.20 (d, 1H), 8.01 (s, 1H), 7.81 (dd, 1H), 6.87 (d, 1H), 5.09 (m, 1H), 3.52 (d, 1H), 3.35 (d, 1H), 3.42-3.26 (m, 2H + H2 O), 3.18-3.06 (m, 2H ), 2.08-1.96 (m, 2H), 1.79-1.65 (m, 2H), 1.33 (s, 3H). (5S)-5-丨4-(5-Gas-pyridin-2-yloxy)- Hexahydropyridine-1, sulfonylmethyl b 5-methyl- __-76-_ This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1329637 A7 B7 V. Description of invention ( 73) Imidazolidine-2,4-dione and (5R)-5-indole 4-(5-azapirin-2-yloxy)-hexahydropyridine-1-sulfonylmethyl b-5-A The base-imidazolidine-2,4-dione was dissolved in 36 ml of isohexane/EthOH (25/75) in the corresponding racemic material (74 mg) and separated into pure pairs using the following Gilson HPLC system. Palm isomer: Column: CHIRALCEL 0D, 2.0 x 25 cm, flow = 6.0 ml/min, eluent = isohexane / EtOH (25/75), temperature = ambient temperature, detector UV = 220 nm. Collect these palmomers and analyze them in CHIRALCEL OD-H, 0.46 x 25 cm, 0.5 mL/min, isohexane/EthOH (25/75), ambient temperature, 220 nm.

Rt = ue &gt; 99°/ for faster dissolving of the palmier isomer. , 29 mg (39%).

Rt = eeiSJ for the slower dissolution of the palmomer, 11.45 minutes. /. , 27 mg (36%). LC-MS (APCI) m/z 403.1 (MH+). (5R,S)-5-丨4-(5-Gas-pyridin-2-yloxy)-hexahydropyridine-1-sulfonate, ketone Base 1-5-phenethyl-mitotoxicity-2,4-dione from crude mouse-p-precipitate-2-yloxy-1-yl)-ττ rat p bite-1-continuation base]-4- Phenylbutan-2-one (258 mg: up to 0.51 mmol) was started. Use DCM+5. . Purification of the crude product was carried out on 70 g of Si-60 gel using MeOH as a solvent. The purity was >96% by NMR and HPLC (220 nm, 254 nm). Obtained 201 mg (80 ° yield, 2 steps) of the title compound as colorless solid ___-77 -_ This paper scale applies to China National Standard (CNS) A4 size (210 X 297 mm)

Binding

K- 1329637 A7 B7 V. Description of invention (74) Body. LC-MS (APCI) m/z 493.0 (MH+). 1 H-NMR (DMSO-d6): δ 10.86 (bs, 1H), 8.21 (bd, 1H), 8.13 (s, 1H), 7.81 - (dd , (1,1H) 3.43-3.28 (m, 2H + H2 0), 3.20-3.08 (m, 2H), 2.66-2.52 (m, 1H), 2.45-2.31 (m, 1H), 2.08-1.96 (m, 2H), 1.96- 1.83 (m, 2H), 1.81-1.65 (m, 2H. (5R,S)-5-丨4-(5-a-pyridin-2-yloxy)-hexahydropyridine-l-sulfonyl Keb 5-(3-imifluor-1-yl-propyl)-middle octagonal 2,4-dioxime self-crude l-[4-(5-rat than bit-2-yl lactyl)-ττ Nitrogen was started at 151 mg (59% yield, 比 确 确 确 确 鱼 ] -5 -5 268 268 268 268 268 268 268 268 268 268 268 268 268 268 268 268 268 268 268 268 268 268 268 268 268 The title compound was obtained as a colorless solid. mp </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> LC-MS (APCI) m/z 497.2 (MH+). 1 H-NMR (DMSO-d6): ί 10.81 (bs, 1Η), 8.20 (d, 1H), 8.05 (s, 1H), 7.81 (dd, 1H), 7.59 (bs, 1H), 7.13 (bs, 1H), 6.88 (bs, 1H), 6.87 ( d, 1H), 5,08 (m, 1H), 3.47 (d, 1H), 3.40-3.28 (m, 3H + H2 O), 3.17-3.06 (m, 2H), 2.07-1.95 ( m, 2H), 1.79-1.64 (m, 3H), 1.61-1.48 (m, 3H). (5R,S)-5-丨4-(5-gas-bite-2-yloxy)-six Hydrogen p is better than bite_1_ _g fish-based methyl-bite-2-yl-propyl)-mi-bite-2,4-dione from crude 1-[4-(5-gas-acridin-2- The base oxy)-hexahydro ρ is more than the bite-丨-continuation of the base]·5· shout bite · 2·  decane-2-one (244 mg: up to 0.51 mmol). Obtained 105 mg (49% yield, 2 steps) of the title compound as colorless solid-78- This paper scale applies to Chinese National Standard (CNS) Α4 size (210 X 297 mm) 1329637 A7 _____B7___ V. Description of invention ( 75) Body. NMR was used to determine the purity &gt;98°'«^ 1 H-NMR (DMSO-d6): ά 10.77 (bs, 1H), 8.72 (d, 2H), 8.20 (d, 1H), 8.03 (s, 1H) , 7.81 (dd, 1H), 7.34 (t, 1H), 6.87 (d, 1H), 5.08 (m, 1H), 3.50 (d, 1H), 3.41- 3.29 (m, 3H + H2O), 3.16-3.07 (m, 2H), 2.83 (t, 2H), 2.06-1.96 (m, 2H), 1.81 - 1.66 (m, 5H), 1.63-1.51 (m, 1H). (5S)-5-丨4-( 5-gas ratio bite-2-base pen ^ hexamidine pyridine small sulfhydryl methyl b 5_(3·0 densely-2-yl-propyl)-imipid bite-2, succinone oxime r5RV5_ 4_(5•Chloro-pyridine: ethoxy 7T hydrogen g than lake-1-continuation methyl hydrazine-5-Π-m-butyl-2-yl-propyl)-imipid bite _2,4·2 Copper The corresponding racemic material (40 mg) was dissolved in 26 ml of isohexane / EtOH (25/75) and utilized as for separation (5R S)_5-[4_(5-gas-acrididine-2- The same conditions as described for the base oxy)-rr hydrogen leaf 1: 唉-1- 驴 曱 曱 ]]-5-methyl- olfactory-2,4-di copper, so that they are separated into pure palm Structure.

Rt = ee &gt; 990/ for faster dissolving of the palmier isomer. , 17 mg (42%).

Rt = for slower dissolution of the palmier isomer, 21.0 minutes, ee = 98.90 /. , 15 mg (37%). , LC-MS (APCI) m/z 509 (MH+). 5-[({4-丨(5-gas-based g is more than bit-2-yl)oxy 1 six gas g than biting small base} Methyl hydrazine_5_ethylimidazolidin-2,4-dione LC-MS (APCI) m/z 417 (MH+)., 1 H NMR (DMSO-d6) : ά 0.76 (3H, t); (2H, q) ; 1.66-1.76 (2H, m): 1.96-2.06 (2H, m): 3.12 (2H, bt): 3.48, 3.35 (each old, eight 39, b 14.9): 3.32-3.41 (2H ,m); 5.04-5.12 (1H, m) : 6.86 (lH;d): 7.80 (1H, dd) : 7.96 (1H, _-79-_ This paper size applies to China National Standard (CNS) A4 specification ( 210 x 297 mm) 1329637 A7 _B7_ V. Description of invention (76) s): 8.19 (1H, d): 10.73 (1H, s). LC-MS (APCI) m/z 417 (MH+). 5-[ (丨4-丨(5-chloropyridin-2-yl)oxyindole hexahydropyridin-1-yl)sulfonyl)methyl b-5-propyl imipenone-2,4-di steel LC- MS (APCI) m/z 431 (MH+). 1 H NMR (DMSO-d6): ί 0.84 (3H, t); 1.03-1.16 (1H, m); 1.20-1.35 (1H, m); 1.58 (2H , t) ; 1.65-1.77 (2H, m) ; 1.96-2.06 (2H, m) ; 3.11 (2H, t); 3.21-3.42 (3H, D20): 3.48 (1H, semi-ABq, J=14.9); 5.04-5.12 (lH,m); 6.86 (1H, d) ; 7.80 (1H, dd); 7.99 (1H, s); 8.19 (1H, d) ; 10.74 (1H, s). 5-i(丨4-丨(5-aphthyridin-2-yl)oxy-1 Hydropyridin-1-ylindolesulfonyl)methyl1-5-(2-methylpropyl)imidazolidin-2,4-dione LC-MS (APCI) m/z 445 (MH+). 1 H NMR (DMSO-d6): 0.81 (3H, d); 0.88 (3H, d): 1.50-1.59 (3H, m): 1.64-1.78 (2H, m); 1.95-2.05 (2H, m); 3.06- 3.16 (2H, m); 3.22-3.41 (3H, D20): 3.46 (1H, semi-Abq, J=15.1); 5.03-5.12 (1H, m); 6.86 (1H, d); 7.80 (lH, dd) 7.99 (lH,bs); 8.19 (lH,d); 10.71 (lH,bs). 5-[(丨4-丨(5-aphthyridin-2-yl)oxy]hexahydropyridine-1- Methyl sulfonate, benzyl) 1-5-(2-* dimethyl-2-ylethyl) imidate-2,4-dicopper LC-MS (APCI) m/z 495 (MH+). 1 H NMR (DMSO-d6) : ό 1.66-1.78 (2H, m) : 1.96-2.16 (4H, m) ; 2.64-2.76 (1H, m) ; 2.84-2.95 (1H, m): 3.08-3.18 ( Ϊ2Η, m) : 3.33-3.41 (2H, ηη); 3.43,3-57 ( 4- 1H, ABq, J=14.9) : 5.04-5.12 (1H, m) : 6.86 (1H, d) ; 7.34 (lH , t): 7.80(1H, dd): 8.12 (lH,d): 8.19(1H, d); 8.70 (1H, d) : 10.84 〇H, s) _-80-_ This paper size applies to China National Standard (CNS) A4 specification (210X 297 mm) 1329637 A7 B7 V. Invention description (77)

I 5-f(丨4-丨(5-alkyl 17-precipitate-2-yl)-milyl hexa-nitrogen g-bite-l-yl}})] methyl]-5·K3-methyl stupid Methyl 1 imidazolidin-2,4-dione \ LC-MS (APCI) m/z 493 (MH+). 'HNMR (DMSO-d6): δ 1.66-1.78 (2Η, m); 1.96-2.07 (2H, m) ; 2.23 (3H, s) ; 2.84 (2H, s) ; 3.09-3.20 (2H, m) ; 3.34-3.43 (2H, m) : 3.45,3·69 (each IH, ABq, J =14.7 Hz) : 5.06-5.13 (1H, m) : 6.87 (1H, d) ; 6.93-6.98 (2H, m); 7.01-7.06(1H, m) ; 7.10-7.17 (1H, m) ; 7.81 ( 1H, dd); 8.08 (1H, s); 8.20 (1H, d); 10.35 (lH, s). 5-f(丨4-丨(5_aphthyridin-2-yl)oxy]hexahydro Pyridyl-l-yl}sulfonyl)methyl b-5-(tetrahydro-2H-pyran-4-ylmethyl)imidate-2,4-dione LC-MS (APCI) m/z 487 (MH+). 1 H NMR (DMSO-d6): 1.06-1.26 (2H, m); 1.39-1.77 (7H, m): 1.95-2.05 (2H, m); 3.06-3.27 (4H,m); -3.41 (3H, D20) ; 3.48 (1H, semi-ABq, J=15.0Hz): 3.69-3.79 (2H, m) ; 5.03-5.12 (1H, m) ; 6.85 (lH,d); 7.80 (1H, Dd); 8.03(1H, bs); 8.19 (lH,d); 10.79 (lH,s). 5-i(M-丨(5-aphthyridin-2-yl) Oxyl 1 hexahydropyridin-1-ylindolesulfonyl)methyl1-5-(3-norfosolin-4-ylpropyl)imidazolidin-2,4-dione trifluoroacetic acid; LC-MS (APCI) m/z 517 (MH+). 1 H NMR (DMSO-d6): ά 1.40-1.78 (6H, m); Ί.96-2.06 (2H, m): 2.94-3.18 (6H, m); 3.31-3.44 (5H,m) ; 3.54 (1H semi-Abq, J=14.9 Hz); 3.60 (2H, t): 3.90-4.01 (2H, m): 4.25-6.27 (1H) ; 6.85 (1H, d) 7.80 (1H, dd):, 8.05(1H, bs): 8.19 (lH,d); 9.52(1H, bs); 10.88 (lH,s). 3-f4-丨(丨4-丨(5- Phenylpyridin-2-yl)oxyl hexahydropyridinyl sulfonyl sulfonyl)methyl 2,5-dione imidazolidin-4-ylindolepropanonitrile __-81 - __ Applicable ten national standard (CNS) A4 specification (210X 297 mm) 1329637 A7 B7 V. Description of invention (78) LC-MS (APCi) m/z 442 (MH+). 1 H NMR (DMSO-d6) : cJ 1.66-1.78 (2H, m): 1.95-2.05 (4H, m): 2.37-2.57 (2H, DMSO-d6): 3.07-3.17 (2H, m) ; 3.25-3.40 (2H, D2 O) ; 3.42, 3.52 (each lH, Abq, J = 14.7); 5.04-5.12 (lH, m); 6.86 (lH, d): 7.80 (lH, dd): 7_99 (lH, bs); 8.20 (lH, d); (lH,s). 3-{ 4-丨({4-丨(5-aphthylpyridin-2-yl)oxy]hexahydropyridine-l-yl}sulfonyl) fluorenyl 1-2,5-dione imidazolidin-4- 1,1-dimethylethyl propyl propyl carbamate LC-MS (APCI) m/z 547, 490 (MH+); (MH+)-tBu. 1 H NMR (DMSO-d6): i 1.10- 1.27 (1H, m) ; 1.27-1.43 (9H, s): .1.52- 1.77 (4H, m) ; 1.94-2.06 (2H, m): 2.80-2.90 (2H, m) ; 3.06-3.16 (2H, (m); (1H, bs); 8.19 (1H, d); 10.73 (1H, bs)_ 5-f(丨4-丨(5-chloropyridin-2-yl)oxy-1hexahydropyridin-1-ylindole Sulfomethyl)methyl1-5-(2-moffflu-4-ylethyl) minotonate-2,4-dione was not purified. LC-MS (APCI) m/z 502 (MH+). ; 5-ί({4-丨(5-chloropyridin-2-yl)oxy]hexahydropyridin-1-yl): mercapto) Methyl 5-phenylimidazolidin-2,4-dione was not purified. LC-MS (APCI) m/z 465 (MH+). 5-f (H-indole (5-chloropyridin-2-yl)oxyindole hexahydropyridine-l-yl}sulfonyl)methyl b 5-(4-Fluorophenyl)imidazolidin-2,4-dione was not purified. __-82 -_ This 尺度 尺度 applies Chinese Painter Standard (CNS) A4 Specification (210 X 297 mm) Binding

k 1329637 A7 B7 V. INSTRUCTIONS (79 ) ! LC-MS (APCI) m/z 483 (MH+). 5-『(丨4-丨(5-气基'^咬-2-yl)oxyanthracene Six winds p bite-l-based} kiln) methyl]-5_ (1H-imidazol-4-yl)imidazolidine-2,4-dione. Not purified. LC-MS (APCI) m/z 455 (MH+). 4- {4-丨({4-丨(5-lactyp-p-but-2-yl)oxy] 7T wind '^比淀-l- Methyl]_ 2,5-dione imidazolidin-4-ylindole benzamide was not purified. LC-MS (APCI) m/z 508 (MH+). 5- [(丨4-丨(5-ylpyridin-2-yl)oxy-1 hexahydropyridine-l-yl}sulfonyl)methyl Indole-5-f2-(111-1,2,4-triazol-1-yl)ethyl 1 imidazolidin-2,4-dione was not purified. LC-MS (APCI) m/z 484 (MH+). 5-Chloro 4-(4-fluorophenyl)hexahydropyridin-1-ylsulfonylmethyl)-5-(2-pyrimidine-2 -ethylidene)imidazolidine-2,4-dione LC-MS (APCI) m/z 462 (MH+). 1 H NMR (DMSO-d6): 1.62 (2H, dq); 1.77-1.86 (2H, m) : 2.07-2.19 (2H, m) ; 2.57-2.76 (2H, m) ; 2.81-2.96 (3H, m) ; 3.42,3:.56 (each 1H, ABq, J=14.6 Hz); 3.59- 3.68 (2H, m): 7.11 (2H, t) ; 7.27-7.36 (3H, m) ; 8.08 (1H, bs); 8.71 (lH,d); 10.84 (1H, bs). 5-({丨4 -(4-fluorophenyl)hexahydrofolate I: biti-1-yl] continued S-methyl}methyl)-5-(tetrahydro-2H-methane-4-ylmethyl)imidazolidin-2, 4-dione LC-MS (APCI) m/z 454 (MH+). 1 H NMR (DMSO-d6) : ^ 1.07-1.28 (2H, m) ; 1.40-1.68 (7H, m); 1.77- __- 83-_ The standard of Zhang is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1329637 A7 B7 V. Description of invention (8〇) 1.85 (2H, m) ; 2.56-2.67 (1H, m) ; 2.85 (2H, dq): 3.22 (2H, dq) ; 3.39-3.45 (1H,m); 3.48 (1H semi-ABq, J=14'5 Hz); 3.53-3.66 (2H,m); 3.75 (2H, Dt) ; 7.11 (2H, t) : 7.26-7.33 (2H, m) : 8.00 ( 1H, bs) ; 10.68 (1H, bs). 444-(丨丨4-(4-fluorophenyl)hexahydropyridin-1-ylsulfonyl}methyl)-2,5-dioneimidazole啶-4-yl benzoylamine LC-MS (APCI) m/z 475 (MH+). 1 H NMR (DMSO-d6): 1.61 (2H, dq): 1.77-1.88 (2H, m); -2.69 (1H, m) ; 2.85-3,01 (2H,m) ; 3.60 (1H semi-ABq, J=14.6 PIz); 3.60-3.69 (2H, m); 7.12 (2H, t) 7.26-7.34 ( 2H, m) ; 7.42 (1H, bs) ; 7.65 (2H, d&gt;; 7.9l· (2H, d); 8.01(1H, bs); 8.85 (1H, s) ; 10.95 (1H, bs). -(丨丨4-(4-fluorophenyl)hexahydropyridine small group]sulfonyl fluorenylmethyl)-5-(lH-imidazol-4-yl) imidazolidin-2,4-dione without purification . LC-MS (APCI) m/z 422 (MH+). 5-({丨4-(4-Phenylphenyl)hexahydropyridin-1-ylindolesulfonylmethyl)-5-(tetrahydro- 2H-Cryptyl 4- 4-methyl-imidazolidine-2,4-dione LC-MS (APCI) m/z 470 (MH+). ; 1 H NMR (DMSO-d6) : ^ 1.07-1.28 ( 2H, m) ; 1.40-1.68 (7H, m) ; 1.76- 1.85 (2H, m); 2.56-2.68 (1H, m) ; 2.85 (2H, q) ; 3.22 (2H, q) ; 3.48 (1H half ABq, J=14_5 Hz) ; 3.53-3,67 (2H,m): 3.75 (2H, t) : 7.26-7.37 (4H, m) ; 8.02(1H, bs): 10.79 (lH,bs). 5-({丨4-(4-Phenylphenyl)hexahydropyridin-1-ylindolesulfonylmethyl)-5-(3-morpholine-4-ylpropyl)imidazolidin-2, 4-Dione trifluoroacetic acid LC-MS (APCI) m/z 499 (MH+). __-84 -_ This paper size applies to Chinese National Standard (CNS) A4 size (210 x 297 mm) 1329637 A7 B7 V. DESCRIPTION OF THE INVENTION (81) 1 H NMR (DMSO-d6) : cJ 1.41-1.87 (8H, m); 2.56-2.69 (1H, m); 2.86 (2H, q): 2.95-3.14 (4H, m) ; -3.44 (3H, m) ; 3.52 (1H semi-ABq, J=14_6 Hz); 3.55-3.69 (4H, m): 3.90-4.00 (2H, m) ; 7.25-7.37 (4H, m) ; 8.07 (lH , s) ; 9.89 (1H, bs) : 10.87 (lH, s). (5R,S)-5-methyl-5-indole ({4-丨5-(dimethylmethyl) 1^bit-2-yl 17T murine mouth ratio °丼-l-yl} continued 睦)) Base imidazolidine-2,4-dione LC-MS (APCI) m/z 422.1 (MH+). Purity & 95%. 1 H-NMR (DMSO-d6): d 10.75 (1H, s); 8.44 (1H, d): 8.02 (1H, s); 7.85 (1H, dd); 7.03 (1H, d); 3.75 (4H, m) ; 3.55 (lH,d); 3.35 (1H, d); 3.21 (4H,m); 1.31 (3H,s). 6_(4-{f({4R,S}-4-methyl-2) ,5-dikecylimidazolidin-4-yl)methyl 1sulfonyl}hexahydropyrrolidin-1-yl)pyridine-3-carbonitrile LC-MS (APCI) m/z 379.1 (MH+). NMR was found to have a purity &gt; 99%. 1 H-NMR (DMSO-d6) : d 10.74 (1H, s): 8.52 (1H, d); 8.00 (1H, s); 7.90 (1H, dd); 7.00 (1H, d) ; 3.78 (4H, m) ; 3.55 (1H, d) ; .3.36 (1H, d); 3.20 (4H, m); 1.31 (3H, s). (5R,S)-5-(丨丨4-(4·fluorobenzene) )) hexahydropyrazine-1-yl 1 sulfonyl} fluorenyl)-5-methylimidazolidin-2,4-di-LC-MS (APCI) m/z 371.1 (MH+). Purity &gt; 98°. . 1 H-NMR (DMSO-d6) : ί 10.75 (1Η, s) : 8.03 (1H, s) : 7.11-6.95 (4H, m) :3.56 (lH,d): 3.36 (lH,d): 3.25 ( 4H, m) : 3.15 (4H,m); 1.33 (3H,s). ___ -85 -_ This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1329637 A7 B7 V. Description of invention ( 82 ) (5R,S)-5-indole (M-indole (4-fluorophenyl)methyl 1 hexahydropyrazine-l-yl}sulfonyl)methyl 1-5-methylimidazolidin-2 , 4-dione LC-MS (APCI) m/z 385.1 (MH+). Purity & 95%. 1 H-NMR (DMSO-d6) : δ 10.72 (1Η, s) : 7.99 (1H, s) ; 7.33 (2H, m); 7.15 (2H, m): 3.50 (2H, s): 3.49 (1H, d) ; 3.30 (1H, d): 3.12 (4H, m); 2.42 (4H, m): 1.32 (3H, s). (5R,S)-5-methyl-5·丨丨(4-pyrimidine) · 2-ylhexahydropyrrolidin-1-yl)sulfonylhydrazino}imidazolium-2,4-difluorene LC-MS (APCI) m/z 355.1 (MH+). purity by NMR&gt; 99%. 1 H-NMR (DMSO-d6): 10.74 (lH, s): 8.40 (2H, d); 8.01 (1H, s); 6.68 (lH,t); 3.83 (4H,m); 3.53 (1H, d ; 3.33 (lH,d); 3.18 (4H,m): 1.31 (3H, s). 5-(3-Aminopropyl)-5-丨 ({4-丨(5-gas base disease-2) -yl)oxyanthracene hexahydrolate bite small base}continued fluorenyl)methyl imidazolidin-2,4-dione trifluoroacetic acid 3-{4-[({4-[(5-) Bite-2-yl)oxy]hexahydro b than the small base} continued g) methyl]-2,5-keto-carbidyl-4-yl}propylaminocarbamate ι,ι_- Methyl ethyl vinegar (426 mg, 0.78 mmol) was dissolved in 10 ml of CH2 C! 2 and 4 ml of tfa was added. The reaction was stirred at room temperature for 1 hour. The solvent was removed to give 4 <RTI ID=0.0></RTI> </RTI> <RTIgt; LC-MS (APCI) m/z 446 (MH+). 1 H NMR (CD3 OD): </ RTI> 1.48-1.63 (1H, m): 1.69-1.96 (5H, m): 2.01-2.12 (2H, m); 2.93 (2H, t) ; 3.20-3.29 (2H, m) : 3.40, 3,60 (each 1H, ABq, J=14 6 a ____·86- This paper scale applies to the Chinese National Standard (CNS) A4 specification ( 210x 297 mm) ' ~~-- 1329637 A7 B7

V. Description of the invention (83

Hz): 3.44-3.54 (2H, m): 4.85 (4H, D2 Ο): 5.14-5.22 (1Η, m) : 6.7δ(1Η d) : 7.67 (1H, dd) ; 8.08 (1H, d). Jj4-(5•gas-bite-2-yloxy)·hexapyridinylmethylindole-5_-4-yl-imidazolidin-2,4-dione hydrochloride pounds 4-{ 4-[4-(5-chloro-p ratio -2-yloxy)·hexahydrop-precipitate-1-decylmethyl]_2 5 keto-imidazolidin-4-yl}-six The hydrogen pyridine small carboxylic acid tri-butyl ester (100 gram, 〇 16 mmol) was dissolved in 2M hydrogen chloride (ethyl acetate, 30 ml) and methanol (5 ml). This solution was stirred at 50 ° C for 1 hour. Evaporation afforded 90.5 mg (0.16 mmol) of the title compound 5-[4-(5-,,,,,,,,,,,,,,,,, Base]-5-hexahydropyridin-4-yl-imidazolidinium-2,4-dione hydrochloride. LC-MS (APCI) m/z 472.3 (MH+). 1 H NMR (DMSO-d6) : ά 10.88 (1H, s) ; 9.05 (1H, d) ; 8.48 (1H, m); 8.21 (1H, d 7.82 (1H, dd) ; 6.87 1H, d) ; 5.10 1H, m) : 3.47 (2H, s): 3.43-3.13 (7H, m) ; 2.78 (2H, m) : 2.02-1.39 (9H, m). 4- {4-丨4-(5-rat-bite-2-yloxy)-hexanitrogen g-bite-l-continuous-branched methyl l-2,5-•mercapto-mi Olfactory bite-4-kib six argon ο than bite-1-3⁄4 acid third-butyl vinegar for this reaction with ester, hexahydropyridine-1,4-dicarboxylic acid 1-tri-butyl ester isopropyl ester For preparation, see, for example, Albert A Carr et al., J. Org. Chem. (1990), 55 (4), 1399-401. LC-MS (APCI) m/z 472.3 (MH+-Boc). 5-f4-(5-Gas-pyridin-2-yloxyhexahydropyridine-1-sulfonylmethyl1-5-(tetrahydro) Piperazin-4-yl)-2,4-dione LC-MS (APCI) m/z 403.2 (MH+). -87- The paper size applies to the Chinese National Standard (CNS) A4 specification (21〇x 297 PCT)

Binding

k 1329637 A7 B7___ V. Description of the invention (84) 1 H NMR (DMSO-d6) : ά 10.77 (lH, s): 8.20 (1H, d): 8.19 (lH, s); 7.81 (lH, dd): 6.87 (lH,d) : 5.09(1H, m): 3.88 (2H, t) : 3.45 (2H, s): 3.38 (2H, m) ; 3.21 (2H, t) ; 3.13 (2H, m) ; 2.02 ( 2H, m) ; 1.84 (1H, t); 1.72 (2H, m) ; 1.60 (1H, d) ; 1.32 (4H, m). 5-f4-(5-chloro-leafate-2-yloxy Base) - hexahydrophyllocaine - 1 - bristol - 5 - g - -4-yl) - imidazolidin-2,4-dione trifluoroacetic acid LC-MS (APCI) m/z </ RTI> </ RTI> <RTIgt; 7.80 (1H, d) ; 6.86 (lH,d): 5.10(1H, m); 4_17(lH,m); 3.73(lH,d); 3.41(2H,m); 3.17(2H,m); 2_08 (2H,m); 1.72 (2H, m). 丨(丨4-丨(5-chloro 〃 〃 咬 基 基 基 基 基 丨 丨 T T T T T T T T T ) ) ) ) )) Keb 2,5-嗣-based bite-4-yl]•methyl)7 moles 1^ than the lake 1-竣_ fee 1,1-dimethylethyl hydrazine title compound is basically according to (5R, S)-5-[4-(4-Fluorophenyl)-hexahydropyridine-1-sulfonylmethyl]-5 Made by the synthesis of methyl-imidazolium-2,4-dione. LC-MS (APCI) m/z 530 (MH+-boc). 1 H NMR (DMSO-d6): d 0.88-1.10 (2H, m); 1.30-1.77 (16H, m); 1.94-2.06 (2H, m) ; 2.53-2.77 (2H, m) ; 3.05-3.17 (2H, m) : 3.21-3.41 (4H, D20) ; 3.48 (1H semi-ABq, J=14.7 Hz); 3.73-3.88 (2H, m) ; 5.03-5.12 (1H, m); 6.86 (lH, d); 7.80 (1H, dd); 8.04 (lH, bs); 8.19 (lH, d); 10.55 (1H, bs). 5-(~(丨4-丨(5-乱基吨吨-2-yl)oxy] hexanitrogen 17 than bite-1-based S S base) methyl]-5-(six atmosphere 1 syndrome-4-yl Methylpyrazine-2,4-dicopperyl trifluoroacetate The title compound is 5-(3-aminopropyl)-5-[({4-[(5-a)pyridinyl)oxy) ] hexahydro&gt;? 淀 -1--1-yl}}8] yl) methyl] imiban, 2,4-dione trifluoroacetic acid -88 - This paper scale is suitable for China National Standard (CNS> A4 size (210 X 297 mm) 1329637 A7 B7 V. Description of the invention (85) Prepared as described in the synthesis. LC-MS (APCI) m/z 486 (MH+). 1 H NMR (DMSO-d6): δ 1.17-1.40 (2Η, m) : 1.47-1.81 (7Η, m) : 1.94-2.07 (2H,m) ; 2.75-2.93 (2H,m) ; 3.06-3.42 (7H, m) ; 3.50 (1H half ABq, J= 15.6Hz) : 5.04-5.12 (1H, m) ; 6.85 (1H, d) ; 7.80 (1H, dd) : 8.06 (1H, s): 8.08-8.22 (2H,m) ; 8.45 (1H,bd) ; 10.85 (1H, s). N-(3-丨4-m4-丨(5-aphthylpyridin-2-yl)oxy-1 hexahydropyridyl yl)sulfonyl)methyl i -2,5-dicopper Oxazolidine-4-yl propyl propyl methacrylate hydrazine 5-(3-aminopropyl)-5-[({4-[(5-a)pyridin-2-yl)oxy] Hydrochloroacridin-1-yl}sulfonyl)methyl]imidazolidin-2,4-dione trifluoroacetic acid (100 mg, 0.18 mmol) was slurried in 2 mL DCM. Add DIPEA (62 micro Lit, 0.36 millimoles) and the slurry was stirred for a few minutes. Gasified sulfonium sulfonate (16 microliters, 0.18 millimoles) was added and the reaction was stirred at room temperature overnight. The crude product was purified by preparative HPLC. LC-MS (APCI) m/z 524 (MH+). 1 H NMR (DMSO-d6): i 1.19-1.52 (2H, m): 1.58-1.77 (4H, m); 1.95-2.06 (2H, m) 2.85 (3H, s) ; 2.83-2.93 (2H, m) ; 3.12 (2H, t) ; 3.19-3.46

〆V (3H, D20); 3.50 (1H semi-ABq, J = 15.7 Hz); 5.04-5.12 (lH, m); 6.86 (lH, d); 6.97 (lH, t); 7.80 (lH, dd): 8.01 (lH,s): 8.19 (lH,d); 10.79 (lH,s). Example 9 (5R,S)-5-丨4-(5-gas-g ratio bit-2-yl)-hexahydro Hey. Well-1_Continued g stupid methyl bromide 5-(3- shouten-2-yl-propyl)-weijun bite-2,4-two net_-89- This paper scale applies to Chinese national standards ( CNS) A4 size (210 X 297 mm)

Binding

1329637 A7 B7 V. Description of invention (86)

1-([4-(5-Gasyl-2·ρ-pyridyl)-1-hexahydro-p-ratio]-5-(2-pyrimidinyl)-2-pentene I (0.397 g, 0.936 mmol), potassium cyanide (0.122 g, 1.87 mmol), ammonium carbonate (0.500 g, 4_68 mmol) and 50% ethanol (4 ml) in sealed vials The mixture was stirred at 75 ° C (oil temperature) for 17 hours. The ethanol was removed by rotary evaporation, the pH was adjusted to 6 with 1 M HCl, the suspension was filtered, the solid was washed with a small amount of water, collected, and dried at 45 ° C in the air. Several more products were recovered from this aqueous filtrate by adding solid sodium vapor to saturation and extracting the mixture in acetonitrile (2 x 10 mL). Drying with Na2SO4, filtering and concentrating the organic phase to obtain a second portion of the product. The combined recovered product was dissolved in tetrahydrofuran (5-10 ml), adsorbed onto silica gel (3 g), and applied to a short crucible tube column. The title compound was obtained as a white crystalline solid. EtOAc (EtOAc) LC-MS (APCI) m/z 494 (MH+). 1 H NMR (DMSO-d6) δ 10.78 (1H, bs); 8.70 (2H, d, J=5Hz): 8.13 (1H, d, J=3Hz ) : 8.02 (1H, s) ; 7.63 (1H, dd, J, =3Hz, J2 =9Hz) : 7.33 (1H, t, J= 5Hz) : 6.93 (1H, d, J=10Hz) : 3.63-3.56 (4H, m) : 3.52 (1H, d, J=14Hz): 3.34 (lH,d,J=14Hz: masked by water signal),3.24-3.14 (4H,m): 2.82(2H, ___-QQ- _ This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm)

Binding

Line 1329637 A7 B7 V. Description of the invention (87) t, J=7 Hz) and 1.79-1.50 (4H, m)_ 13 C NMR (DMSO-d6) ^ 175.6, 169.5, 157.2, 157.0, 156.5, 145.6, 137.3, 119.2, 119.1, 108.8, 62.4, 52.7, 44, 5, 38.2, 36.4 and 21.2. The starting materials were prepared as follows: 1-([4-(5-Alkyl-2-pyridyl)-1- Hexahydropyridinyl]sulfonyl)-5-(2-pyrimidinyl)-2-pentanone

ZM503902 Ketone M = 423.93 1-(5-Galyyl-2-pyridinyl)]-f-sulfonylhexahydropyridin (0.64 g, 2.32 mmol) in anhydrous THF (25 mL, 40 vol.) The solution was cooled to -10 ° C under nitrogen to cause precipitation of the sulfonamide from the solution. 1 M LHMDS (4.64 ml, 4.64 mmol) in THF was added dropwise to this suspension of the sulfonamide over 4 minutes, and then the mixture was stirred for 40 minutes. Ethyl 4-(2-pyrimidinyl)-butyrate (0.68 g, 3.48 mmoles X Example 8) (6.4 mL, 10 rel vol) in dry THF was added dropwise over 4 min. minute. The mixture was quenched with saturated NH4CI (EtOAc (EtOAc) Dissolve the residue -91 - This paper size applies to the Chinese National Standard (CNS) A4 specification (21〇x 297 mm)

Binding

Line 1329637 A7 B7 V. Description of the invention (88) In DCM (20 relative volume), the organic layer was washed with water (丨5 ml, 24 rel vol), brine (15 ml, 24 rel vol), and MgS04 Dehydrated and dried. The solvent was removed by rotary evaporation to give a crude material as a white solid (0. 84 g &apos; 85 &lt; 5 &lt; The crude product was purified by flash chromatography on Biotage, using ethyl acetate/isohexane (9:: (1)) as a solvent to obtain a pure ketone as a white amorphous solid. 1-(5-Gasyl-2-toxyl)+methanesulfonylhexahydropyrrolidine with 1-(5-methyl-2-pyridyl)-hexahydropyridine (1 equivalent), To the solution in toluene (25 vol), triethylamine (11 eq.) was added and the mixture was cooled to 5 &lt;0&gt;C in an ice bath. The vaporized methanesulfonate (〇 5 volume) which had been diluted with toluene was slowly added to the cooled solution to keep the temperature below 10 °C. Once the addition was complete, the reaction was allowed to warm to room temperature. Water (6.6 vol) was added and the mixture was filtered and the cake was slurried in toluene (2 vol). The filter cake (2 vol) was then washed with a pad and dried in a hollow oven at 4 CTC overnight. 1-(5-methyl-2-pyridyl)-hexahydropyrrole

Binding

CI

DCP hexahydrogen ratio tillage ZM503902 »Bite bit M.W. 148 M.W. 86 M.W. 197.5 * Hexahydropyrazine (4 equivalents) was charged as solid in a reaction vessel. Pyridine (1.43 vol) was added to the vessel at room temperature, followed by toluene (2.14 vol) -92- ϋ 尺度 适 A Chinese National Standard (CNS) A4 size (210 X 297 mm) 1329637 A7 B7 V. Description of the invention (89). The final slurry was stirred and heated to reflux at 120 ° C to obtain a complete solution. In a separate container, 2,5-dipyridine (DCP) was charged followed by toluene (1.43 vol) to dissolve the solid. This dissolution is endothermic and the solution must be warmed to ~30 ° C to give a complete solution. Then, the solution containing DCP was slowly discharged into the reaction vessel for 5 hours. At this time, the residual amount of DCP should be about 20α/. . The reaction was left to reflux overnight to reach completion. The reaction mixture was allowed to cool to room temperature and then water (6 vol) was added. The two layers were separated and the aqueous phase was re-extracted with toluene (5 vol). The two organic layers were combined and washed again with Η2 Ο (6 vol). Finally, the organic layer was washed with brine (6 vol). (5S)-5-丨4-(5-Gas-pyridin-2-yl)-hexahydropyridin-1-sulfonylmethyl b-5-(3-pyrimidin-2-yl-propyl)-imidazole Pyridin-2,4-dione and (5R)-5-indole 4-(5-chloro-pyridin-2-yl)-hexahydropyrazole-1-continued S-methyl-2-5-(3-° Cyclosyl-2-yl-propyl)-methanolol-2,4-dione The corresponding racemate (23 mg) was dissolved in 8 mL of isohexane / EtOH (25/75) and utilized Gilson HPLC system, which is separated into pure palmomerisomers: column ·· CHIRALCEL OD, 2.0x25 cm, flow rate = 6.0 ml/min, eliminator = isohexane / EtOH (25/75), temperature = ambient temperature True, the detector UV = 230 nm. The palmier isomers were collected and analyzed in CHIRALCEL OD-H, 0.46 x 25 cm, 0.5 ml/min, isohexane/EthOH (25/75), ambient temperature, 220 nm. .

Rt = ee &gt;99°' for the faster dissolving of the palmier isomer. , 8.7 mg (37%). LC-MS (APCI) m/z 494.1 (MH+). _______-93 -_ This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm) 蝎 Binding

1329637 A7 B7 V. INSTRUCTIONS (9〇) [a]D = -26.4o (c=0_0022 g / ml, EtOH, t=2 (TC)

Rt = for slower dissolution of the palmier isomer, 14.5 minutes, ee = 980 /. , 9 mg (39%). LC-MS (APCI) m/z 494.1 (MH+).

[a] D = +24.50 (c = 0.0020 g / ml, EtOH, t = 20 ° C) Example 10 The following compounds were obtained using a procedure similar to that described in Example 8 or 9. 5-[4-(4·Phenylphenyl)-hexahydrofuran well-1-continued g-methyl-]-5-(3-^-Bitter-2-yl-propyl]-imidazole pyridine-2 , 4-dione.-〇-〇7^^. ^ m/z493 (MH+) 5-[4-(4-fluorophenyl)_hexahydropyridin-1-sulfonylmethyl]-5- [2-(5-Fluoro-»Bite-2·yl)-ethyl]-imidazolidin-2,4-dione F m/z 481 (MH+) &gt;[4-(5-Gas-pyridine- 2-yl)-hexafluoropyrazine-1-sulfonylhydrazino]-5-[2-(5-fluoro-pyrimidin-2-ylethyl)-flavored bite-2,4-dicopper 0 F m/z 498 (MH+) 5-[4-(3,4-dioxa-phenyl)-hexahydropyrazine-1-sulfonylmethyl]-5-(3-pyrimidin-2-yl- Propyl]-imidazolidin-2,4-dione ^ m/z 527(MH+) _-94 - This paper size applies to Chinese National Standard (CNS) Α4 size (210X 297 mm)

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Line 1329637 A7 B7 V. INSTRUCTIONS (91) Example 11 Compound having the following general formula

It was synthesized according to the method described in Example 8. Ketone intermediate R R2 z analysis (1) 〇~ Me s GC/MS m/z 242 〇〇Me s GC/MS m/z 267 (M^) Me s GC/MS m/z 326 〇〇〇Me S02 LC/MS m/z 275 (MH+) Me S02 - (1): For NMR data, see the experimental part. 1-(1,Γ-biphenyl-4-ylthio)propan-2-one 1-[(4-bromophenyl)thio]propan-2-one (357 mg, 1 Λ 6 mmol) , [U'-bis(diphenylphosphino)dicyclopentadienyl iron] dipalladium (11) with phenyldihydroxyborane (231 mg, 1.89 mmol) and two methane methane (1: 1) (36 mg), methyl stupid (20 ml), methanol (7.5 ml), saturated sodium carbonate solution (3.5 ml) -95 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1329637 A7 _____B7 ____ V. Inventive Note (92) Treatment 'and stirred at 80 ° C for 18 hours. After cooling, the reaction mixture was treated with dilute hydrochloric acid and extracted with ethyl acetate. The product was purified by flash chromatography on EtOAc to 250. Ethyl acetate: Isohexane was dissolved to give 277 mg of product. GC/MS m/z: 242 [M+], 1 H NMR (CDC13): d 2.33 (3 Η, s): 3.73 (2 Η, s) ; 7.37 (1H, s) ; 7.42-7.48 (4H, m) ; 7.54-7.59 (4H, m). The following compounds were prepared as described for the synthesis of bis-phenyl-4-ylthio)propan-2-one. 4·-[(2-Oxopropyl)thio]-1,1'-biphenyl-4-carbonitrile GC/MS m/z : 267 [M+]. 1 H NMR (CDCI3) : ί 2.34 ( 3Η, s) ; 3.75 (2Η, s) ; 7.44,7.54 (4H, abq, J= 8.5 Hz); 7.67, 7.74 (4H, abq, J=8.5 Hz). l-({4'-[(3 Fluoromethyl)oxy]-1,1'-biphenyl-4-yl]thio)propan-2- steel GC/MSm/z : 326 [M+]. 1H NMR (CDCI3) : ^ 2.34 (3H , s) ; 3.73 (2H, s) : 7.30 (2H, d) ; 7,43 (2H, d) ; 7.51 (2H, d); 7.58 (2H, d). ' 1-(1,Γ-联Phenyl-4-ylsulfonyl)propan-2-one with 1-(1, fluorenylbiphenyl-4-ylthio)propan-2-copper (69 mg, 〇28 mmol) Sodium bicarbonate (72 mg, 0.85 mmol), an oxygen generating agent (525 mg, 〇85 mmol), water (5 ml) and methanol (1 ml) were stirred at room temperature for 3 hours. Water (50 ml) was added and the product was extracted ethyl acetate (3×25 mL). The extract is washed with brine to dehydrate and dry the sodium, and evaporated to obtain a product of Μmg (990/.) which is of sufficient purity for use without further pure-96- paper &amp; SS Home Standard (CNS) Α 4 Specifications (21G X 297 public) ' ----

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k 1329637 A7 B7_ V. Description of invention (93). LC-MS (APCI) m/z 275 (MH+). 1 H NMR (CDC13): ci 2.47 (3H, s): 4.22 (2H, s): 7.44-7.54 (3H, m); 7.64 (2H, d 7.80, 7.97 (4H, abq, J=8.6 Hz). 4'-[(2-Oxopropyl) hydrazinyl]-1, fluorenyl-biphenyl-4-carbonitrile the title compound is 1- It is prepared as described in the synthesis of (1, fluorenyl-biphenyl-4-ylsulfonyl)propan-2-one. 1 H NMR (DMSO-d6) '· d 2.48 (3H, s) ; 4.23 (2H, s) ; 7.74 (2H, d) ; 7.81 (4H, t) : 8.02 (2H, d). The following compounds of guanidine are based on (5R, S) each [4-(4-fluorophenyl)-hexahydropyridine sulfenylmethyl&gt; 5-methyl-imidazolidin-2,4-dione (example) 8) prepared as described in the synthesis. R R2 X Analysis (1) Xr. , Me s〇2 m/z 396 (MH+) Me S(〇) ni/z4l3(MH+) 0 Me S02 m/z 345 (MH+) Me S02 m/2 370 (MH+) 〇〉About NMR data, see experiment Part. (5R,S)44-(5-Gas-pyridin-2-yloxy)-benzenesulfonylhydrazinyl]-5-methyl-methaneidine-2,4-dione LC-MS (APCI) m/z 396 (MH+). lHNMR(DMSO-d6): 1.27(3H,s); 3.71,3_78 (each lH, ABq, J=15.0); ___- Q7 ._ This paper scale applies to Chinese national standards ( CNS) A4 size (210 x 297 mm)

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Line 1329637 A7 _B7 ___ V. Description of invention (94) 7.23 (1H, d) : 7.36-7.41 (2H, m) ; 7.82-7.87 (3H, m) ; 8.04 (1H, dd) ; 8.27 (1H, d) : 10.79 (lH, s). 5_Gasyl-2-{[4-(methylsulfonyl)phenyl]oxy}pyridine 2,5-dipyridine (1.48 g; 10 mmol), 4. A total of nonylphenol (1·89 g: 11 mmol) and Cs2C03 (4.24 g; 13 mmol) were slurried in 75 ml of mash. The slurry was heated to about 170 ° C overnight. After cooling, Cs2C03 was filtered off and solvent was extracted between EtOAc and EtOAc. The organic phase was dried over Na2SO4 and evaporated. Heptane: EtOAc 2:1 was added to this residue and crystals were filtered, 1.42 g (50%). NMR CDCls: ^ 3.09 (3H, s); 7.02 (1H, d): 7.33 (2H, d); 7.76 (1H, dd); 8.00 (2H, d); 8.17 (lH, s). 5-methyl-5-fluorene (trifluoromethyl)oxyanthracene, fluorenyl-biphenyl-4-yl}sulfinyl)methylidazolidinium- 2,4-dione 5-methyl-5-[({4.-[(trifluoromethyl)oxy]-indole, fluorenyl-biphenyl-4-yl}thio)methyl]imidazole Pyridine-2,4-dione (48 mg, 0.112 mmol), with oxygen generator (50 mg), sodium bicarbonate (5 mg), water (5 ml) and methanol (10 m) Stir for 18 hours under temperature. The solid was filtered and crystallized from ethanol to give 20 mg of the title compound. LC-MS (APCI) m/z Very weak 413 (ΜΗ+). 1 H NMR (DMSO-d6) : ό 1.41 (3Η, s) : 3.04-3.27 (2H, m) : 7.47 (2H, d) : 7.67-7.73 (2H,m); 7.78-7.90 (5H,m): 8.21 and 8.37 (1H, 2s); 10.79 and 10.91 (1H, 2s) 5-methyl-5-[({4·-[( Trifluoromethyl)oxyl 1-1, fluorenyl-biphenyl-4-yl)thio)methyl]imi-98 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm)

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k 1329637 A7 B7 __ V. Description of the invention (95) Zolidine-2,4-dione LC-MS (APCI) m/z Very weak 397 (MH+). 1 H NMR (DMSO-d6) : J 1.33 (3H , s) : 3.29 (2H, s) : 7.42-7.45 (4H, m): 7.61 (2H,d): 7.77 (2H,d); 7.99 (lH,s); 10.75 (lH,s). 5- ί(1,Γ-Biphenyl-4-ylsulfonyl)methyl1-5-nonylimidazolidin-2,4-dione LC-MS (APCI) m/z 345 (MH+). 1 H NMR (DMSO-d6): cJ 1.27 (3H, s); 3.72, 3.81 (2H, abq, J = 15.3 Hz): 7.45 (1H, t); 7.52 (2H, t) ; 7.76 (2H, d): 7.82 (1H, s): 7.88, 7.94 (4H, abq, J=8.9 Hz); 10.80 (1H, bs). 4·-{ί(4-methyl-2,5-dioneimidazolidin-4 -Methyl 1 sulfonyl phenyl 1, hydrazine-biphenyl-4-carbonitrile LC-MS (APCI) m/z Very weak 370 (MH+). 1 H NMR (DMSO-d6): S 1.26 ( 3H, s): 3.74, 3.84 (2H, abq, J = 16.0 Hz): 7.81 (lH, s); 7.91-8.03 (8H, m); 10.81 (lH, s). Example 12 Synthesis of carbendazim

Representative synthetic pathways are shown on the next page. •99- The paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 1329637 A7 B7 V. Description of invention (96) (90%)

^^τ Ο + (Xs A θ

Reagents and conditions: a) KCN, ΝΗ4 C03, EtOH/H2 0, +9 (TC, 3 hours. b) for palm separation, CHIRALPAK AD with methanol as the eliminator. c) C丨2 (gas), Ac〇H/H2 〇, &lt;+丨 5»c, 25 min. d) Diisopropylethylamine, THF, 20. (:, 30 minutes. Experimental procedure (gg)-5JL({[4-(4-fluorophenyl)hexahydropyridine-i-ylindenyl)methyl)_5_methylimine bite-2, 4-Diethyl 4-(4-fluorophenyl)hydropyridine salt (6 mg, 〇29 mmol) dissolved in 3 mL of dry THF with diisopropylethylamine (5 〇 〇 29 mmoles) Neutralize and cool on an ice water bath. Add gasification [(4S)_4•methyl·2 5 diketo _ imidazolidin-4-yl]methanesulfonate (10) mg, 〇35 mmol), and after stirring for 1 minute, add diisopropyl Ethylamine (5 〇 microliters, 〇29 mmol), and the reaction mixture is stirred at ambient temperature until LC, MS (Apci) shows that the amine has been 100- the paper size applies to the Chinese National Standard (CNS) A4 Specifications (210 X 297 public) 1329637 A7 B7 V. Description of invention (97) When it is used up. The reaction mixture was evaporated, and the residue was dissolved in EtOH and warmed to 50 &lt;0&gt;C and allowed to cool&apos; then water was added. The precipitated product was collected, washed with EtOH / water, and dried in a dry space to yield 87 mg. LC-MS (APCI) m/z 370 (MH+). HNMR (DMSO-d6): cM 0.73 (1H, s); 8.01 (lH, s); 7_29 (2H, dd): 7.11 (2H, dd ): 3.61(2H,dd); 3.50,3.33 ( ^ 1H, ABq, J=14.7 Hz) : 2.91-2.80 (2H, m) ; 2.67-2.57 (1H, m) : 1.82 (2H, d) ; 1.62 (2H, ddd); 1.33 (3H, s). The starting material was prepared as follows: 5-methyl-5-{[(phenylmethyl)thiolmethyl)imidazolidin-2,4 -Dione was added to a steel vessel with ethanol and water (315 ml / 135 ml). 31.7 g (0.175 mol) of mercaptopropylthione, 22-9 g (0.351 mol) of potassium cyanide and 84.5 g (0.879 mol) of ammonium carbonate were added. The sealed reaction vessel was kept in an oil bath (bath temperature 90 C) and subjected to vigorous blasting for 3 hours. The reaction vessel was cooled (0.5 hr) with ice water, and the yellow-yield was evaporated to dryness, and the solid residue was partitioned between 400 ml of water and 700 ml of ethyl acetate, and separated. The aqueous phase was extracted with ethyl acetate (300 mL). The combined organics were washed with EtOAc (EtOAc)EtOAc. If the product did not form crystals, 300 ml of dichloromethane was added to the oil. Evaporation gave the product as a slightly yellow powder, 43.8 g (yield: 90 〇), LC-MS (APCI) m/z 251.1 (MH+). 1 H NMR (DMSO-d6) ό : 10.74 (1H, s) ; 1H, s) : 135-7.20 (5H, m) : 3_76(2H, s); 2.72, 2.62 (&amp;lH, ABq, J=14.0Hz): U9(3H,s)_ ___- 101 -____ The paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

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k 1329637 A7 B7 V. INSTRUCTIONS (98) 1 3 C NMR (DMSO-d6) δ : 177.30, 156.38, 138.11, 128.74, 128.24, 126.77, 62.93, 37.96, 36.39, 23.15. (5S)-5-methyl -5-{丨(phenylmethyl)thio]methyl}imidazolidin-2,4-dione The title compound was applied on a dynamic axial compression preparative HPLC system using a 250 mm X 50 mm column. The racemic substance is produced by separating the palms. The stationary phase used was CHIRALPAK AD, dissolving agent = methanol, flow rate = 89 ml/min, temperature = ambient temperature, UV = 220 nm, sample concentration = 150 mg/ml, injection volume = 20 ml. The retention time of the title compound = 6 minutes. Analysis of palm purity was performed using a 250 mm χ 4.6 mm CHIRALPAK-AD column from Daicel with flow = 0.5 mL/min, eluent = ethanol, UV = 220 nm, temperature = ambient temperature. The retention time of the title compound = 9.27 minutes. The purity is estimated to be &gt;99Q/. Ee. LC-MS (APCI) m/z 251.1 (MH+). 〇]D=-30_3o (c=0.01 g/ml, ?^〇^1,1'=20°(:)· 1 H NMR (DMSO -d6) J : 10.74 (lH, s); 8.00 (1H, s): 7.35-7.20 (5H, m); 3.76 (2H, s); 2.72, 2.62 (each 1H, ABq, J = 14.0 Hz); 1.29 (3H, s). 13 C NMR (DMSO-d6) ά : 177.30, 156.28, 138.11, 128.74, 128.24, 126.77, 62.93, 37.96, 36.39, 23.15. (5R)-5-methyl-5-{{ (Phenylmethyl)thiolmethyl}soxazolidine-2,4-dione The title compound is a 250 mm X 50 mm column on a dynamic axial compression preparative HPLC system with a racemic material. It is made by separating palms. The stationary phase used is CHIRALPAK AD, eliminator = methanol, flow rate = __-102-_ This paper scale applies to Chinese National Standard (CNS) A4 size (210X 297 mm) 1329637 A7 B7 V. Description of the invention (99) 89 ml/min, temperature = ambient temperature, UV = 220 nm, sample concentration = 150 mg/ml, injection volume = 20 ml. Retention time of the title compound = 10 minutes. Analysis of palm purity using a 250 mm X 4.6 mm CHIRALPAK-AD column from Daicel Line, flow rate = 0.5 ml/min, eliminator = ethanol, UV = 220 nm, temperature = ambient temperature. The retention time of the title compound = 17.81 minutes. The palm purity was estimated to be &gt;99 ° /. ee. LC- MS (APCI) m/z 251.0 (MH+). 〇]D=+30_30 (c=0.01 g/ml,]^(^, butyl = 20°(:)· 1 H NMR (DMSO-d6) δ 10.74 ( 1H, s); 8.00 (1H, s): 7.35-7.20 (5H, m); 3_76(2H, s); 2.72, 2.62 (each lH, ABq, J=14.0 Hz); l, 29 (3H, s 1 3 C NMR (DMSO-d6) d : 177.31, 156.30, 138.11, 128.74, 128.25, 126.77, 62.94, 37.97, 36.40, 23.16. Gasification [(4S)-4-methyl-2,5-dione (5S)-5-methyl-5-{[(phenylmethyl)thio]methyl}imidazolidin-2,4-dione (42.6 g: 〇·17 mol) is dissolved in a mixture of AcOH (450 ml) and Η2 Ο (50 m). The mixture was immersed in an ice/water bath, and Cl2 (gas.) was bubbled through the solution, and the gas flow rate was adjusted so that the temperature was kept below +15 °C. After 25 minutes, the solution turned yellow-green in color and a sample was taken for LC/MS and HPLC analysis. It shows that the starting material has been used up. The yellow clear solution was stirred for 30 minutes to form an opaque solution/slurry. The solvent was removed on a rotary evaporator using a water bath maintained at a temperature of +37 °C. This yellow solid was suspended in toluene (400 ml) and used in the same rotary evaporator __- 103 -_ This paper is suitable for Chinese National Standard (CNS) A4 specification (210X 297 mm) 1329637 A7 ____B7 V. Description of the invention (100) Up and down; 4 doses. Repeat it again. Then, the crude product was suspended in isohexane (400 ml) and warmed to +4 (rc, while stirring, the slurry was cooled to A / m, and then borrowed;; remove the soluble product, to dissident The house was washed (6 χι liters) and dried overnight under reduced pressure at +50 ° C. This gave product as a slightly yellow powder. 36.9 g (95%) of title compound was obtained. °', NMR supports this purity. [a] D = -12.4 〇 (c = 0.01 g / ml, N, D = 2 〇. 〇 · iHNMRCmF-ds): d9_91 (lH, bs); 7.57 (lH, s); 4.53, 4.44 (each 1H, ABq, J = 14.6 Hz); 1.52 (s, 3H, CH3). 13 C NMR (THF-d8): δ 174.96; 155.86; 70.96; 61.04: 23.66. (4R)-4-methyl-2,5-dioneimidazolidin-4-yl]methanesulfonate according to gasification [(4S)_4-methyl-2,5-dioneimidazolidin-4 -Based on the procedure described for methanesulfonyl. From (5R)-5-methyl-5-{[(phenylmethyl)thio]methyl}imidazolidin-2,4-dione (10.0 g, Starting at 40 mmol. Obtained 8.78 g (96°·y. yield) of the title compound.. Purity by NMR &gt;98..]&gt;]D = +12.8o (c=0.01)克 / ml, THF, T = 20 ° C). 1 H NMR (THF-d8): ci 9.91 (1H, br s); 7.57 (1H, s): 4.53, 4.44 (each 1H, ABq, J=14.6 Hz) ; 1.52 (s, 3H, CH3). , 13CNMR (THF-d8) : 174 174.96: 155.84; 70,97; 61.04: 23.66. Example 13 Compound of the formula _______-1 Ω4 -___ This paper The scale applies to China National Standard (CNS) Α 4 specifications (210Χ 297 mm)

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1329637 A7 B7 V. INSTRUCTION OF THE INVENTION (1,1,0, a method for the synthesis of amine intermediates according to the method described in Example 12, m/z 246 (MH+); h NMR data Q:=-〇m/z 185 ( MH+); A NMR data ra/z 198 (MH+); lH NMR data with irk. -105 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1329637 A7 B7 V. Description of invention ( 102) m/z 218/220 3 ] _+); 咕 NMR data fVcto F m/z 247 (MH+); ι NMR data NCxro m/z 204 (MH+); 4 NMR data ΧΓΟ WNMR data Wnmr data αΧΤ°Ό 4 NMR data ΧΤΌ ^NMR data 1H NMR data Wnmr data, xm m/z 225 (MH+) 0^0 m/z 240 (MH+) ΎΧΤΌ xatz 235 &lt;MH+) NCxrXi m/z 203 (MH+) ΟΓΟ m/z 208 ( MH+) τχτ°χ^ m/z 262 (MH+) Λχ) m/z214{MH+) -106 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1329637 A7 B7 V. Invention Description (103) 0ΧΤαΌ m/z2)2(MH+) m/z 203 (MH+) m/2 208 (MH+) :xro m/z 246 (MH+) ra/z2l4(MH+) Human χτο ra/z 235 (MH+ ) Know. ο m/z 220 (MH+) m/z 220 (MH+) σ~〇~0 xn/j: 197 (MH+); ^ NMR data m/z285 (MH+) , ΧτΌ m/z 195 _+); NMR data Βχτο m/z 257,259 (MH+) m/z 258 (MH+) m/z 270(MH+) °O-〇-〇m/z 274,276 (MH+) six&lt;xy&lt;ym/z 324 (MH+) 0Ό~Ο m /z 230 (MH+)

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Line -107 - This paper size applies to National Standard (CNS) A4 Specification (210 X 297 mm) 1329637 A7 B7 V. Description of Invention (104)

All other amines used are either commercially available or have been previously described. 4-{4-[(Trifluoromethyl)oxy]phenyl}hexahydropyridine trifluoroacetic acid Pd(PPh3)4 (87 mg, 0.0075 mmol), UC1 (19 mg, 4 5 mmol) Ear), 4-{[(trifluoromethyl)methyl]oxy}-3,6-dihydropyridine](2H)-sodium butyl tris-butyl ester (0.50 g 1.5 mmol), 4 (Trifluoromethoxy)phenyldihydroxyborane (0.43 g, 2.1 mmol) and Na aqueous solution of CO3 (2 mL, 2 Ν solution), mixed in 5.2 mL DME and heated at 85 ° C After 3 hours, it was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between DCM (10 mL), EtOAc (EtOAc) (EtOAc (EtOAc) The liquid layer was separated and the aqueous layer was extracted with DCM (3×10 mL). The combined organic layers were dried (Na2SO4) and concentrated. Purification by column chromatography (SiO 2 , heptane / ethyl acetate / DCM 5 : 1 : 1) to give 4-[4-(trifluoromethoxy) phenyl]-3,6-dihydropyridine-1 (2H)-dibasic acid tert-butyl ester (0.27 g, 52%). The product was mixed with 5% Pd/C (30 mg) in MeOH (3 mL). The mixture was filtered through celite and concentrated to give 4-[4-(trifluoromethoxy)phenyl]hexa- pyridine-l-carboxylic acid tri-butyl ester (0.23 g, 86%). The crude product was dissolved in EtOAc (2 mL)EtOAc. The reaction mixture was concentrated and purified with EtOAc EtOAcjjjjjj ____-108 -___ This paper size applies to @国标准(CNS) A4 size (210 X 297 mm)

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1329637 A7 B7 V. INSTRUCTIONS (1〇5) LC-MS (APCI) m/z 246 (MH+). 1 H NMR (CDG13) : β 9.38 (1H, bs) : 8.97 (1H, bs) ; 7.26 ( 2H,d); 7.20 (2H, d) ; 3.60 (2H, bd) ; 3.07 (2H, q) ; 2.88-2.72 (1H, m) ; 2.18-2.01 (4H, m). 1 9 F NMR (CDCI3 ···δ -58,35 (3F), -76.19 (3F). 4-[(4-Phenylphenyl)ethynyl]-1,2,3,6-tetrahydropyridine hydrochloride makes PdCl2 (PPh3) 2 (47 mg, 0.07 mmol) and Cul (13 mg, 0.07 mmol) were dissolved in Et3N (2.7 mL) and THF (8.4 mL) under argon and stirred for 10 min. Add 4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridine-1(2Η)-carboxylic acid tert-butyl ester (0.46 g, 1.4 mmol) and 2 a solution of ethynylpyridine (152 μL, 1.5 mmol) in 3.5 mL of THF. The reaction mixture was stirred at room temperature for 2 hr, diethyl ether was added and the precipitate was filtered. The clear solution was washed with a saturated aqueous NH4Cl solution, water, brine, and dried (Na2SO4). Concentrate and purify by column chromatography (SiO 2 , heptane / diethyl ether 1: 2) to give 4-[(4-phenylphenyl)ethynyl]-3,6-dihydropyridine-1(2H)-carboxy Acidic third-butyl ester (0.26 g, 58 °/.). The product was dissolved in THF (3 mL) and concentrated EtOAc (3 mL). The title compound (0.20 g, 98%, two steps, 57%). LC-MS (APCI) m/z 218/220 3: 1 (MH+). 1 H NMR (DMSO-d6) : cJ 9.25 (2H, bs); 7.49-7.44 (4H, m): 6.24-6.11 (1H , m) ; 3.75-3.63 (2H, m) ; 3.25-3.15 (2H, m) ; 2.48-2.42 (2H, m). The following amines are similar to 4-[(4-phenylphenyl)ethyl bromide Made in the manner described in the form of -1,2,3,6-tetrahydropyridine hydrochloride. 2-(1,2,3,6-tetrahydropyridin-4-ylethynyl)pyridine ___- 109 -_ This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm)

Binding

1329637 A7 B7 V. INSTRUCTIONS (1〇6) LC-MS (APCI) m/z 185 (MH+). 1 H NMR (CDG13): cy 8.59-8.55 (1H, m): 7.64 (1H, dt) ; 7.43-7.39 (1H, m) ; 7.20 (1H, ddd) ; 6.30 (1H, bs) ; 3.51 (2H, q) ; 3.04 (2H, t) ; 2.37-2.31 (2H, m). 4-[( 4-methylphenyl)ethynyl]-1,2,3,6-tetrahydropyridine LC-MS (APCI) m/z 198 (MH+). 1 H NMR (CDCI3) : d 8.91 (1H, bs) 7.33 (2H, d) ; 7.15 (2H, d) : 6.06 (1H, bs) ; 3.93-3.80 (2H, m) ; 3.49-3.335 (2H, m) ; 2.73-2.60 (2H, m): 2.37 (3H, s). 2-(hexahydroi1 than ylide-4-yloxy)-5-trifluoromethyl-by bite sodium hydride (0.52 g, 12 mmol, 55 ° /., in oil It was washed twice in hexane and suspended in anhydrous dimethoxyethane (30 ml). 4-Hydroxypiperidine (1.21 g, 12 mmol) and 2-chloro-5-trifluorodecylpyridine were dissolved in anhydrous dimethoxyethane (30 mL). This solution was added dropwise to the hydrogen's sodium suspension. The reaction was stirred at 80 ° C under nitrogen overnight. After cooling, water was carefully added to the mixture and the solvent was removed by rotary evaporation. The residue was dissolved in water and extracted with ethyl acetate. :. The organic phase was dried over Na2SO4 and evaporated. The residue was chromatographed on EtOAc (EtOAc:MeOHMeOHMeOHMeOH LC-MS (APCI) m/z 247.1 (MH+). 1 H NMR (CDC13): s. 8.40 (1H, s); 7.74 (1H, dd, J=2.52, 8.70 Hz); 6.78 (1H, d, J =8.74 Hz) : 5.25-517 (1H, m) : 3.19-3.08 (2H, m) : 2.83-2.73 (2H, m) ; 2.10-2.00 (2H, m) ; 1.83 (1H, s) ; 1.73- 1.62 〇2H, m). ___-110-_ This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1329637 A7 B7 V. Description of invention (107) The following amines are similar in 2 It is prepared in the manner described in the synthesis of (hexaropyridin-4-yloxy)-5-trifluoromethyl-blow. 6-(hexahydrobutyrate-4-yloxy)-acetonitrile LC-MS (APCI) m/z 204.2 (MH+). 1 H NMR (CDC13) : δ 8.45 (1Η, s) : 7.76 (1H , dd, J=2.40, 8.77 Hz); 6.78 (1H, d, J=8.77 Hz); 5.28-5.17 (1H, m) ; 3.19-3.09 (2H, m) ; 2.83-2.74 (2H, m) : 2.10-2.01 (2H, m) : 1.74-1.63 (2H, m). 5-methyl-2-(hexahydro I» than 0έ -4-yloxy)-&gt;» ratio bit H NMR (methanol) -d4) : 7.90 (1Η, s) ; 7.46 (1Η, dd, J=2.47, 8.46 Hz); 6.68 (1H, d, J=8.50 Hz); 5.07-4.98 (1H, m): 3.15-3.07 ( 2H, m) : 2.82-2.73 (2H, m) : 2.23 (3H, s) : 2.07-1.97 (2H, m) : 1.84-1.74 (2H, m). 2-methoxy-6-(hexahydro) 17-precipitate-4-yloxy)-峨1 H NMR (CDCI3): δ 7.44 (1Η, t, J=7.90 Hz); 7.25 (2H, dd, J=1.83, 7.90 Hz); 5.19-5.11 (1H, m) - gas-based nitrogen ρ ratio -4 -based basal)-? ratio bite H NMR (methanol-d4): d 7.64 (1Η, dd, J=7.60, 8.22 Hz); 6:96 (1Η, dd, J = 0.66, 7.60 Hz); 6.73 (1H, dd, J = 0.60, 8.19 Hz); 5.25-5.14 (1H, m) ; 3.28-3.18 (2H, m) : 3.05-2.94 (2H, m) ; 2.19-2.07 (2H, m) ; 1.93-1.80 (2H, m). 5-fluoro- 2-(hexahydro 1»by -4-yloxy)-&lt;# 1 H NMR (CDCI3) : β 8.36 (2H, s): 5.16-5.06 (lH, m): 3.29-3.18 (2H , m) ; 2.98-2.87 (2H, m) ; 2.21-2.08 (2H, m) ; 1.97-1.81 (2H, m). 2-(hexahydropyridin-4-yloxy)-4-trifluoromethyl Base-pyrimidine 1 H NMR (CDCI3) : 8.75 (1H, d, J=4.93 Hz) : 727 (1H, d, J=5.07 Hz); _-111 -_ This paper size applies to the Chinese National Standard (CNS) A4 size (210X297 mm)

Binding

k

1329637 A7 B7 V. INSTRUCTIONS (108) 5.39-5.30 (1H, m) : 3,44-3.33 (2H, m) ; 3.28-3.17 (2H, m) ; 2.35-2.10 (4H, m). 5- Ethyl-2-(hexahydro-p-buty-4-yloxyl-precipitated iHNMR (methanol-d4): J 8.40 (2H, s): 5.16-5.08 (lH, m): 3.16-3.06 (2 Η, m) : 2.77-2.70 (2H, m) : 2.60 (2H, dd, J=7.66, 15.28 Hz) ; 2.10-2.00 (2H, m) ;1.76-1.66 (2H, m), 1.23 (3H, t, J=7.63 Hz). 5-methoxy-2-(hexahydro I» than bita-4·yloxy)-&lt;» bis lake; hydrochloride makes 4-(5-methoxy-(» Bisino-2-yloxy)·hexahydrop ratio-1-pyruic acid third-butan (45 mg, 0.14 mmol) dissolved in THF (3 ml) with concentrated HC1 (2 mL) The reaction was stirred at room temperature for 2 hours, then the solvent was removed in the sputum and the residual water was removed by azeotropic evaporation using EtOH / toluene to afford 35 mg (97%) of LC-MS (APCI) m/z 225.1 (MH+). The starting material was obtained as follows: 2-chloro-5-methoxy-g ratio of 1-oxide to 2-carbyl-5 -Methoxy-u ratio (200 mg, 1.39 mmol) and mCPBA (360 mg, 2.09 mmol) The mixture was stirred at room temperature for 2 days. Then, the mixture was diluted with CH.sub.2Cl.sub.2 and washed with aq. The solvent was removed in vacuo to afford the title compound as a white crystal. </RTI> <RTIgt; </RTI> <RTIgt; </ RTI> NMR (DMSO-d6): ^ 8.30 (1H, d, J = 2.72 Hz); 7.68 (IH, d, J =9.23.Hz) :7.08 (1H, dd, J=2.70, 9.23 Hz): 3.31 (3H, s). 4-(5-methoxy-1-oxy-g-pyridin-2-ylhydrocarbyl) - Six remnants of P-pyridinium small acid acid third-butan so that potassium tert-butoxide (128 mg 'U4 millimolar.) is dissolved in anhydrous THF (10 _ ___ -112- This paper scale is suitable for medium solid state 揉Quasi (CNS) A4 specification (210X 297 public) ' ' 1329637 A7 B7 5, invention description (1〇9 ) liter), and under nitrogen, add 4 • hydroxyl group dissolved in anhydrous THF (5 ml) - Trihydropyridine-1-carboxylic acid tert-butyl ester (177 mg, 〇88 mmol). The mixture was stirred at room temperature for 10 minutes, then 2-yl-5-methoxypyridinium 1-oxide (14 mg, 〇88 mmol) dissolved in anhydrous (5 mL) was added. The reaction was stirred at room temperature for 3 days. The solvent was removed and the residue was partitioned between Η2 Ο and CDCI3. The organic phase was washed with brine and dried over NasSO*. The solvent was removed in vacuo to afford 245 mg (86%) 1 H NMR (CDCI3) : ό 7.95-7.93 (1Η, m) : 6.86-6.84 (2H, m) : 4.95-4.85 (1H, m) ; 3.79 (3H, s) ; 3.25-3.14 (2H, m) , 3.07-2.96 (2H, m): 1.98-1.79 (4H, m); 1.46 (9H, s). 4-(5-methoxy-indenyl-2-yloxy)-hexahydro-g ratio -i-reacidic third _ vinegar makes 4-(5-methoxy-1-oxy-ρ than dec-2-yloxy)-hexahydrou Vinegar (200 mg, 0.62 mmol) was dissolved in EtOH (5 mL). Indium (498 mg, 4.34 mmol) and a saturated aqueous NH4Cl solution (4 mL) were added to this solution, and the mixture was refluxed for 4 days. After cooling, the mixture was filtered through celite and the solvent was removed in the air. The residue was purified by chromatography eluting with EtOAc EtOAc (EtOAc) Hz) ; 7.20 (lH, 4d, J=3.07, 8.89

Hz): 6.66 (lH, d, J = 8.99 Hz); 5.14-5.07 (lH, m): 3.80 (3H, s); 3.79-3.72 (2H, m): 3.31-3.23 (2H, m): 2.00 -1.91 (2H, m) ; 1.75-1.64 (2H, m); 1.47 (9H, s). 4-(4-bite-3-yl-phenyl)hexahydro-17-pyrene; hydrochloride-113 This paper scale is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1329637 A7 __B7_ V. Invention description ("〇) 4-(4-pyridin-3-yl-phenyl)hexahydropyridinium 4 small The carboxylic acid tert-butyl ester (60 mg, 0.18 mmol) was stirred with THF (3 mL) and concentrated HClt (3 mL) for one hour. The solvent was removed in the sputum and the mixture was taken from EtOH / toluene. Obtaining 50 mg (1 〇〇〇 / 〇) of the title compound as a yellow powder. LC-MS (APCI) m/z 240.2 (MH+). The starting material was prepared as follows: 4- (4-Butylphenyl) hexahydropyridin-b-acidic _ butyl ester according to La Clair, Angew. Chem_ Int. Ed. 1998, 37(3), 325-329, to 55 0/. Rate prepared from N-phenylhexahydropyrazine (19 mM) 4-(4-g than -3-ylphenyl) hexahydrop ratio g well citrate third-butyl vinegar (Reference to Wel Lmar et al., J. Heterocycl. Chem. 32(4), 1995, 1159-1164.) 4-(4-iodophenyl)hexahydropyridinium small carboxylic acid tert-butyl ester (0.272 g, 0.70 m) Mole), 3-pyridyldihydroxyborane (0.078 g, 0.64 mmol), hydrazine (triphenylphosphine) ruthenium (0.024 g, 0.02 mmol), 1 M sodium bicarbonate (1.0 mL) and 1, 2-Dimethoxyethane (1.5 ml) was stirred under nitrogen at 84 ° C for 3 hours, dissolved in ethyl acetate and washed with water and brine. The solid was obtained by rotary evaporation of phthalocyanine (1 g), and applied to a short hard rubber column. The gas was burned with two gas; the gas was burned/ethyl acetate (4:1) and pure ethyl acetate The ester was lysed, and the title compound was obtained as a white solid as a white solid, and 0.060 g of the starting material (the iodide). The yield was calculated from the amount of converted iodide. LC-MS (APCI) m/z 340.3 (MH+). 1 H NMR (methanol-d4): d 8.75 (1H,d,J=2.0 Hz): 8.43 (1H,m) : 8.04 (1H, m ) : 7.58 (2H, d, J=8.0 Hz), 7.47 (1H, m) : 7.10 (2H, d, J=8.〇Hz) ; 3.59 _____-114-___ This paper size applies to China National Standard (CNS) A4 specification (210 x 297 mm) 1329637 A7 B7 ' V. Invention description (111) (4H, m) ; 3.22 (4H, m) ; 1.50 (9H, s). Ν-[3-(ττ风ρ比'bit-4-yloxy!-)-benzamine The salt was subjected to 4-hydroxy-hexahydropyridine-1-carboxylic acid tert-butyl ester (300 mg, 1.5 mmol) dissolved in dry CH2C12 and cooled to -10. The polymer-bound triphenylphosphine (750 mg, 2.25 mmol) was added and allowed to swell. Add N-(3-hydroxy-phenyl)-acetamide (340 mg, 2.25 mmol) dissolved in dry THF, and stir the reaction at -10 °C for 10 min then DEAD (0.35 ml, 2.25 mmol) was added dropwise to the mixture. The reaction was stirred overnight and allowed to warm to room temperature. The polymer was filtered off, using a short column of silica gel, using toluene / EtOAc (5 | 〃 1) as the solvent. The volume of the combined fractions was reduced by rotary evaporation, and the solution was washed with 5% aqueous K0H and water, dried over Na 2 S04, and solvent was removed from the air. The resulting white powder was dissolved in THF (10 mL) and concentrated EtOAc (10 mL) and stirred at ambient temperature for one hour. The solvent was removed in the sputum and the residual water was removed by aq. EtOAc (EtOAc). LC-MS (APCI) m/z 235.1 (MH+). The following amines are similar in the synthesis of N-[3-(hexahydropyridin-4-yloxy)yl-phenyl]-acetamide Made in the manner described. 3-(ττ鼠ρ比淀-4-yloxy)-本甲月贪 LC-MS (APCI) m/z 203.2 (MH+). 4- (3-methoxy-phenoxy hexahydrofolate b Bite LC-MS (APCI) m/z 208.2 (MH+). 4-(3-Trifluoromethoxy-phenoxy)-hexahydropyridine__-115 -_ This paper size applies to Chinese National Standard (CNS) A4 size (21〇x 297 mm) 1329637 A7 B7 V. Description of invention (112) LC-MS (APCI) m/z 262.1 (MH+). 4-(2,4--gas-year*milk base) -7ΤNitrogen ρ ratio bite. LC-MS (APCI) m/z 214.2 (MH+). 4-(4-Gas-phenoxy)-hexahydro ι» bite LC-MS (APCI) m/z 212.2 ( MH+) 4-(hexahydropyridin-4-yloxy)-benzonitrile LC-MS (APCI) m/z 203.2 (MH+). 4-(4-methoxy-phenoxy)-hexahydro峨 LC-MS (APCI) m/z 208.2 (MH+). 4-(3,4-di- phenoxy)-hexa-argon precipitation LC-MS (APCI) m/z 246.1 (MH+). 4 -(3,4--murine-local oxy)-ττ wind 1^ ratio LC-MS (APCI) m/z 214.2 (MH+). Ν~[4-(ττ氮ρ比咬-4-基氧1 base)--winter base--acetamide LC-MS (APCI) m/z 235.1 (MH+). 4-{[(3,4-dimethylphenyl)methyl]oxy}hexahydropyridinium salt Acid salt LC-MS (APCI) m/z 220 (MH+). ' 4- {[(2,5-Dimethylphenyl)methyl]oxy } Hexahydropyridine hydrochloride LC-MS (APCI) m/z 220 (MH+). 5-Phenyl-2-hexa-1 p butyl-4-yl p-bitate hydrochloride Zn powder (225 mg, 3.5 mmoles in THF (1 mL), stirred under ar, and then, at room temperature, 1,2-dibromoethane (50 liters). The mixture was heated to 65 ° C for 3 minutes. And allowed to cool to room temperature, then add vaporized trimethyl decane (70 μl), and the mixture was stirred at room temperature for 30 minutes. Slow-116- This paper scale is applicable to China National Standard (CNS) A4 specification ( 210 X 297 mm)

Binding

K- 1329637 A7 B7 V. INSTRUCTIONS (113) Slowly add a solution of 4-iodo-N-Boc-hexahydropyridine (840 mg, 2.7 mmol) in THF (1.5 mL) and the reaction mixture at 40 Stir at ° C for 2 hours. Pd2(dba)3 (22 mg, 0.024 mmol) was combined with P(2-furyl)3 (23 mg, 0.10 mmol) in THF (0.5 mL). Minutes were then added to the capsule zinc reagent solution followed by 2-bromo-5-pyridine (624 mg, 3.24 mmol) in THF (1 mL) and DMA (4 mL). The reaction mixture was heated at 80 &lt;0&gt;C for 3 h then cooled to rt then filtered over EtOAc EtOAc. The filtrate was washed with aq. aq. EtOAc (aq.) and brine, dried over Na.sub. The third-butyl hexahydropyridine-1-carboxylate is a yellow oil (128 mg, 160.). This oil was dissolved in THF (1.5 mL) and concentrated EtOAc (1 mL). The title compound (89 mg, 890 /) was obtained. LC-MS (APCI) m/z 197 (MH+). 1 H NMR (MeOD-d4): J 8.54 (1H, d); 7.86 (1H, dd); 7.38 (1H, d) ; 3.55 -3-45 (2H, m) ; 3.22-3.06 (3H, m) ; 2.19-2.09 (2H, m) ; 2.08-1.98 (2H, m). 5-yloxy-2-(hexahydrop ratio -4- The hydroxy group)-p is a salt; the hydrochloric acid is prepared in the same manner as described in the synthesis of 5-methoxy-2-(hexahydropyridin-4-yloxy)-pyridine. LC-MS (APCI) m/z 285 (MH+). The starting material was obtained as follows: 2-carbo-5-methoxy pyridine as sodium hydride (55 °, in oil, 236 mg, 5,40 millimoles in hexane -117 - This paper size applies to Chinese National Standard (CNS) A4 size (210 X 297 mm) Binding

K- 1329637 A7 B7 V. INSTRUCTION DESCRIPTION (114) Washing was carried out and 2-ylidene-5-hydroxypyridine (350 mg, 2.70 mmol) was suspended in anhydrous DMF (20 mL). After 10 minutes at room temperature, a sulphate (0.32 mL, 2.70 mmol) was added and the mixture was stirred for a further 2 hours. The reaction was diluted with water and extracted with EtOAc (3 <RTIgt; The combined organic layers were washed with water and brine and dried over Na 2 EtOAc. The solvent was removed by rotary evaporation to afford 520 mg (yiel. LC-MS (APCI) m/z 220 (MH+). 1 H NMR (CDC13): ί 8.19 (1H, d, J = 3.00 Hz); 7.55 (1H, dd, J = 3.15, 8.81 Hz); 7.48- 7.31 (6H, m): 5.19 (2H, s). 2-Chloro-5-nonyloxy-pyridine 1-vaporate This amine is such as 2-alco-5-methoxy-ι» It is made in the same manner as described in the synthesis of 1-oxide. LC-MS (APCI) m/z 236 (MH+). 1 H NMR (DMSO-d6): δ 8.38 (1H, d, J = 2.61 Hz); 7.69 (1H, d, J = 9.28 Hz); 7.47- 7.33 (5H, m): 7.15 (1H, dd, J=2.69, 9.15 Hz); 5.19 (2H, s). 4-(5-decyl-1-oxypyridin-2-yloxy) - hexahydropyridine-polycarboxylic acid tert-butyl ester This compound is based on 4-(5-methoxy-1-oxy-pyridin-2-yloxy)-hexahydropyridin-1-carboxylic acid Made as described in the synthesis of tri-butyl ester. LC-MS (APCI) m/z 401 (MH+). 1 H NMR (DMSO-d6) : δ 8.12 (1H, d, J = 2.79 Hz): 7.48-7.32 (5H, m); 7.19 (1H, d , J=9.16Hz) : 7.07 (1H, dd, J=2.88, 9.18 Hz) : 5.13 (2H, s) : 4.84 -4.76 (1H, m) : 3.20-3.11 (2H, m) : 3.00-2.87 ( 2H, m) : 1.86-1.78 (2H, m) ; 1.59-1.49 (2H, m); 1.40 (9H, s). 4-(5-+milyl-bito-2-yloxy)·six Argon p ratio bite-i-poic acid third-butan r-118 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm)

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1329637 A7 _B7_ V. INSTRUCTION DESCRIPTION (115) This compound is described in the synthesis of 4-(5-methoxy-pyridin-2-yloxy)-hexahydropyridine-1-carboxylic acid tert-butyl ester. production. LC-MS (APCI) m/z 385 (MH+). 1 H NMR (CDC13) ·· ί 7.86 (1Η, d, J=3.10 Hz) : 7.46-7.32 (5H, m) : 728 (1H, dd, J=3.16, 9.04 Hz) : 6.67 (1H, d, J=9.04 Hz) : 5.16-5.08 (1H, m); 5.05 (2H, s) ; 3.84-3.72 (2H, : m) : 3.33-3.25 ( 2H, m) ; 2.02-1.93 (2H, m); 1.76-1.66 (2H, m): 1.49 (9H, s). 5-yl-2-(hexahydrop-biti-4-yloxy) -p-pyridyl tricarboxylic acid to give 4-(5-benzyloxy-1-oxy-acridin-2-yloxy)-hexahydropyrazole-1-carboxylic acid tert-butyl ester (476 mg , 1.19 mmoles, dissolved in methanol (20 mL) and added Pd(OH) 2 (30 mg). The mixture was hydrogenated at 1 atm and room temperature for 24 hours. The catalyst was decanted and the mixture was purified using preparative HPLC to give 110 mg (30%) of the title compound as the intermediate of the TFA salt and 34 mg (10%) of neutral Boc-protected. LC-MS (APCI) m/z 195 (MH+). 1 H NMR (DMSO-d6): ί 7.66 (1H, d, J = 2.94 Hz); 7.20 (1H, dd, J = 3.07, 8.82 Hz); 6.68 (1H, d, J=8.93 Hz) : 5.12-5.00 (1H, m) : 3.29-3.00 (4H, m) ; 2.16-2.02 (2H,m); 1.93-1.75 (2H,m). 5- Bromo-2-(hexahydro 1» than butyl-4-yloxy)-hydrochloric acid hydrazine bite this amine such as 5-methyllacyl-2-(7T 〃 〃 -4--4-yloxy)- (7) Prepared in the same manner as described in the synthesis of the bite. LC-MS (APCI) m/z 257 + 259 (MH+) Starting material is 4-(5-methoxypyridin-2-yloxy) Made from the synthesis of hexahydropyridine small carboxylic acid tert-butyl ester: -119 - This paper scale applies to Chinese National Standard (CNS) Α4 specification (210 X 297 mm) 1329637 A7 B7 V. Description of invention ( 116) 4-(5-bromo-o-precipitate-2-yloxy)-hexahydrofolate I: bite-1-acid acid third-butyric acid LC-MS (APCI) m/z 357 + 359 (MH+ 1 H NMR (DMSO-d6 ) : δ 8.26 (1H, dd, J = 0.53, 2.67 Hz); 7.88 (1H, dd, J = 2.66, 8.81 Hz); 6.80 (1H, dd, J = 0.53, 8.79 Hz) ; 5.15-5.07 (1H, m) : 3.72-3.64 (2H, m) : 3.20-3.09 (2H, m) ; 1.97-1.88 (2H, m) ; 1.58-1.48 (2H, m); 1.40 (9H, s). 4-(5-(4-fluorophenyl)-p ratio-2-yl)-hexahydropyrene ratio p-well hydrochloride makes 4-(5-(4-gas-based) -p ratio-2-yl)-ττ chloride ρ ** well-1-reductive guanidine (98 mg, 0.34 mmol) dissolved in MeOH (5 ml), and concentrated HCl (12M, 5 ml) The mixture was stirred overnight at room temperature. The solvent was removed in the sputum and the residual water was removed by azeotropic evaporation using EtOH / benzene to afford the title compound (1 s. Yellow powder. LC-MS (APCI) m/z 258 (MH+). The starting material was prepared as follows: 4-(5-4-fluoro-phenyl-pyridin-2-yl)-hexahydropyrazine 1-carboxycarboxaldehyde 4-(5-bromo-pyridin-2-yl)-hexahydropyridin-1-carboxycarboxaldehyde (100 mg, 0.37 mmol), 4-fluorobenzodiazepine shed (55 mg, 0.39 mmol,), (ι,ι'·bis(diphenylphosphino)dicyclopentadienyl iron) digas palladium (11) (10 mg, 〇_〇1 mmol), A solution of stupid (2 ml), EtOH (0.5 ml) and 2M Na.sub.2CO.sub.3 (5 mL, 1 mmol) was heated at 80 ° C under N2 overnight. After cooling, the mixture was diluted with toluene and allowed to separate. The organic phase was washed with water and brine, filtered over celite and dried over Naz. The solvent was removed in the air to provide 100 mg (94 y.) of the title product as a beige powder. LC-MS (APCI) m/z 286 (MH+). -120 - This paper size is applicable to national standard (CNS) of country t. A4 specification (21〇X 297 mm) ~ 1329637 A7 B7 V. Description of invention (117) 1 H NMR (DMSO-d6) : ί 8.44 (1H, d, J = 2.66 Hz): 8.10 (lH, s): 7.97 (1H, dd, J=2.52, 8.82 Hz); 7.70-7.31 (2H, m 7.31-7.21 (2H, m); 6.97 (1H, d, J=8.97Hz); 3.65-3.43 (8H,m). The following compounds are based on 4-(5-(4-fluorophenyl)-pyridine Synthesis in the synthesis of 2-yl)-hexahydropyridine hydrochloride: .^ 4-(5-(4-methoxy-styl)-p-predated-2-yl)-hexahydrop ratio 11 Well Hydrochloride LC-MS (APCI) m/z 270 (MH+). 4-(5-(4-Phenylphenyl)-pyridin-2-yl)-hexahydropyridine hydrochloride LC-MS (APCI m/z 274, 276 (MH+). 4-(5-(4-Trifluoromethoxy-phenyl)-pyridin-2-yl)-hexahydropyridine hydrochloride LC-MS (APCI) m /z 324 (MH+). 4-(5-Indol-2-yl-ι»p-but-2-yl)-hexahydropyp-11 well hydrochloride LC-MS (APCI) m/z 230 (MH+) 4-(5-(1Η-pyrrol-2-yl)-pyridin-2-yl)-hexahydropyrazine dihydrochloride The title compound is prepared from 2-(6-(4-carbamidylhexahydropyridinium). Tung-1-yl)-pyridin-3-yl)-pyrrole-b-carboxylic acid tert-butyl ester. LC-MS (APCI) m/z 229 (MH+). ' 4-[3,3']-bipyridyl-6-yl-hexahydropyrazine hydrochloride LC-MS (APCI) m/z 241 ( MH+). 4-(6-Hexahydropyrrol-1-yl-pyridin-3-yl)-benzonitrile hydrochloride LC-MS (APCI) m/z 265 (MH+). _- 121 - paper Zhang scale applies to China National Standard (CNS) A4 specification (21〇x 297 mm)

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k 1329637 A7 B7 V. INSTRUCTION DESCRIPTION (118) Analysis of the urepene carbendazim of formula I (1 &gt; m/z 380 (MH+) mJz 382 (MH+) m/z 402/403 3:1 (MH+) /° m/z 382 (MH+) m/z420(MH+) fm/z 420 (MH+) P^o-h9° \ m/z 488 (MH+) m/z 384/386 3:1 (MH+) F ta /z 370 (MH+) binding

Line -122 - This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1329637 A7 B7

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Line 1329637 A7 B7 V. Description of invention (120) m/z 408 (MH+) 夕 O#r. ' m/z 393 (MH+) m/z 375 (MH+) m/2 388 (MH+) m/z 408 (MH+) m/z436 (MH+) Fy〇rm/z 437 (MH+) m/z 394 (MH+ ) xrx^rm/z382(MH+) m/z 436 (MH+) m/z 393 (MH+). ^wm/z 398 (MH-r) m/z 404 (MH+) -124- This paper is the standard Chinese National Standard (CNS) A4 specification (210 X 297 public) 1329637 A7 B7 V. Invention description (121 ) taJz 402 (MH+) m/z 398 (MH+) VII. Interpretation. m/z 438 (MH+) Money CF. m/z 383 (MH+) m/z 398 (MH+) m/z 388 (MH+) m/z 399 (MH+) atJXW m/z 403 (MH+) Nxr〇xF. m/z 393 (MH+) 'xx ΌΆ丫m/z 398 (MH+) m/z 425 (MH+) m/z 402 (MH+) winter money π taJz 452 (MH+) m/z 452 (MH+) _- 125 - The paper size applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 1329637 A7 B7 V. Description of invention (122) m/z 404 (MH+) m/z 386 (MH+) m/z 386 (MH+) Hey. chat. m/z 386 (ΜΗ十),. Less money. m/z 399 (ΜΗ*+·) 〇r〇~&lt;ySH m/z 430 (MH+) m/z 369 (MH+) m/z 410 (MH+) σχ^τ m/z 368 (MH+) m/ z 413 (MH+) m/z 410 (MH+) m/z 387 (MH+) α. Chest price m/z 475 (MH+) -126 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 public love) 1329637 A7 B7 V. Invention description (123) m/z 403 (MH+) m /z 385 (MH+) m/z 418 (MH+) m/z 450 (MH+) m/z 385 (MH+) s s s s s s s s s s s s s s s s s s s s s s 449 (MH+) m/z 448 (MH+) rOOOi^ m/z 460 (MH 10) ^&lt;y&lt;y〇-^rm/z 464, 466 (MH+) m/z 514 (MH+)

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Line-127 - This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1329637 A7 B7 V. Invention description (124) m/z 420 (MH+) OO-Oi^0 m/z419 (MH+) m/z 431 (MH+) m/z 455 (MH+) (1): For the NMR data, see the experimental part. The following compounds were prepared in the same manner as in the examples of fluorophenyl)hexahydropyridyl/sulfonyl/methylmercapazolidin-2-indoledione, and whether by precipitation and//// Wash with water, or by preparative / / LC, to purify. (5S)-5-mercapto-5-(丨丨4-丨4-(methoxy)phenyl-3,6-dihydropyridine -1(2Η)-yl]sulfonyl}methyl)mididine-2,4-dione LC-MS (APCI) m/z 380 (MH+). 1 H NMR (methanol-d4): &lt; S 7.35 (2H, d, J = 8.9 Hz); 6.87 (2H, d, J = 8.9 Hz): 6.01 (lH, dd): 3.92 (2H, dd); 3.78 (3H, s); 3.56, 3.41 ( Each lH, ABq, J = 14.6 Hz); 3.51-3.46 (2H, m); 2.62-2.57 (2H, m): 1.47 (3H, s). (5S)-5-methyl-5-丨 (丨) 4-丨4-(decyloxy)phenyl 1 hexahydropyridin-1-ylsulfonyl)methyl 1 imidazolyl-2,4-dibenzyl LC-MS (APCI) m/z 382 (MH+) 1 H NMR (DMSO-d6) : ^10.73(1^5): 8.01 (1H, s) : 7.17(2H, d); 6.85 -128 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 x 297 mm) binding

Line 1329637 A7 B7 V. Description of invention (125) (2H,d); 3.71(3H, s); 3_60(2H, dd): 3.50 (1H, part ABq, J=14.8Hz); 2.85 (2H, q ; 2.54 (1H, t) : 1.79 (2H, d) : 1.64-1.53 (2H, m) ; 1.33 (3H, s). (5S)-5-(丨丨4-(4-气phenyl) -4-Sodium hexahydropyridin-1-ylsulfonyl fluorenyl)-5-methyl imiline-2,4-dione LC-MS (APCI) m/z 402/4043 : 1 ( MH+). 1 H NMR (DMSO-d6): J 10.72 (1H, s): 8.01 (1H, s): 7.51 (2H,d): 7.37 (2H,d): 5.22 (1H, s): 3.49, 3.34 (each 1H, ABq, J = 14.9 Hz); 3.47-3.35 (2H, m); 3.15 (2H, q): 1.93 (2H, t): 1.64 (2H, d) ; 1.33 (3H, s). (5S)-5-methyl-5-indole ({4-丨2-(methoxy)phenyl]hexahydropyridine-l-yl}sulfonyl)methyl 1 imidazolidin-2,4-di Ketone LC-MS (APCI) m/z 382 (MH+). 1 H NMR (DMSO-d6): δ 10.72 (1 Η, s) ; 8.01 (1H, s): 7.24-7.14 (2H, m); 6.96 (lH) , d); 6.90 (lH, t); 3.78 (3H, s); 3.60 (2H, dd); 3.51, 3.33 (each 1H, ABq, J = 14.7 Hz); 3.02-2.94 (1H, m); 2.88 (2H,q) ; 1·77 (2H,d); 1.66-1.56 (2H,m); 1.33 (3H,s). (5S)-5- 5-(丨4-丨4-(trifluoromethyl)phenyl]hexahydropyridin-1-ylindolesulfonyl)methyl 1 imidazolidin-2,4-dione* LC-MS ( APCI) m/z 420 (MH+). 1 H NMR (DMSO-d6) : δ 10.73 (1H, s) ; 8.01 (1H, s) ; 7.66 (2H, d) ; 7.50 (2H, d) ; 3_63 (2H , dd) ; 3.52, 3.34 (each 1H, ABq, J = 14.9 Hz); 2.88 (2H, ddd); 2.79-2.68 (1H, m); 1.86 (2H, d) ; 1.67 (2H, ddd) ; 1.33 (3H, s). (5S)-5-Methyl-5-J({4-J3-(trifluoromethyl)phenyl 1 hexahydropyridine-l-yl}sulfonyl)methylimidazolium -2,4-D嗣LC-MS (APCI) m/z 420 (MH+). -129- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1329637 A7 B7 _ V. Invention (126) 1 H NMR (DMSO-d6) : δ 10.74 (lH, s); 8.02 (IH.s): 7.63-7.52 (4H, m): 3.63 (2H, dd): 3.52 (1H, part八89,]=14.91^); 2.87(211,3廿〇1): 2.79-2.70 (lH,m): 1.87 (2H,d): 1.75-1.63 (2H, m) ; 1.33 (3H, s) (5S)-5-丨(丨4-丨3,5-bis(trifluoromethyl)phenylphosphonium hexahydropyridin-1-ylindolesulfonyl)methyl1-5-methylimidazolidinium- 2,4-dione LC-MS (APCI) m/z 488 (MH +). 1 H NMR (DMSO-d6): d 10.74 (1H, s); 8.02 (1H, s); 8.00 (2H, s); 7.93 (1H, s); 3_64 (2H, dd); 3.52 ( 1H, part ABq, J=14_9 Hz); 2.95-2.81 (3H, m); 1.89 (2H, d) : 1.83-1.69 (2H, m) ; 1.34 (3H, s). (58)-5- (丨丨4-(4-Chlorophenyl)-3,6-dihydropyridine-1(211)-yl 1 sulfonyl}methyl)-5-methylimidazolidin-2,4-dione LC -MS (APCI) m/z 384/386 3 : 1 (MH+). 1 H NMR (DMSO-d6): S 10.74 (1H, s): 8.03 (1H, s): 7.47 (2H, d) ; 7.40 (2H, d); 6.23 (1H, app s); 3.85 (2H, app s) ; 3_52, 3.39 (each 1H, ABq, J = 14.7 Hz); 3.39-3.32 (2H, m) ; 2.55 (2H, Brs); 1.32 (3H, s). (5S)-5-(丨丨4-(3-fluorophenyl)hexahydropyridin-1-yl 1sulfonyl}methyl)-5-methylimidazole bite -2,4-two steel 'LC-MS (APCI) m/z 370 (MH+). 1 H NMR (DMSO-d6) : ^ 10.73 (lH,s): 8.01 (lH,s): 7.38-7.31 ( 1H, m) :7.15-7.08 (2H, m) ; 7.05-6.98 (1H,m) ; 3.62 (2H, dd) ; 3_51,3.33 (each 1H, ABq, J=14.7 Hz); 2.95-2.80 (2H , m) ; 2.68-2.60 (1H, m) ; 1.82 (2H, brd) ; 1.69-1.58 (2H, m) : 1.33 (3H, s (5S)-5-(丨丨4-(2-fluorophenyl)hexahydropyridin-1-ylindolesulfonylmethyl)-5-methylimidazole. 2,4-dione -130- The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1329637 A7 B7 V. Description of invention (127) LC-MS (APCI) m/z 370 (MH+). 1 H NMR (DMSO-d6) : ci 10.73 (1H, s) ; '8.01 (1H, s) : 7.36 (1H, t) : 7.30-7.20 (1H, m): 7.18-7.12 (2H'm); 3_63(2H , dd): 3.52, 3.33 (each lH, ABq); 2.96-2.85 (3H, m); 1.80 (2H, brd): 1.69 (2H, ddd): 1.33 (3H, s). (5S)-5- Methyl-5-({丨4-(4-methylphenyl)hexahydropyridin-1-ylsulfonyl}methyl)imidate-2,4-dicopper LC-MS (APCI) m/ z 366 (MH+). 1 H NMR (DMSO-d6): ί 10.73 (1H, s); 8.01 (1H, s); 7.15-7.07 (4H, m); 3.60 (2H, dd); 3.50, 3_32 ( Each lH, ABq); 2.85 (2H, q); 2·59-2_51 (1H, m); 2.25 (3H, s); 1.79 (2H, brd); 1.60 (2H, ddd). (5S)-5 -methyl-5-(indol-4-(phenylmethyl)hexahydropyridin-1-ylindolesulfonyl}methyl)imidazole bite-2,4-dione LC-MS (APCI) m/z 366 (MH+). 1 H NMR (DMSO-d6): d 10.70 (1H, s): 7.96 (1H, s) ; 7.29-7.15 (5H, m) ; 3.46 (2H, t) ; 3.41, 3.24 (each 1H, ABq, J = 14.9 Hz); 2.68 (2H, dt) ; 2_52 (2H, d 1.54-1.51 (3H, m) ; 1.30 (3H, s). (5S)-5-丨(H-bishexahydropyridine-decylsulfonyl)methyl b 5-methylimidazolidin-2 , 4-dione trifluoroacetic acid LC-MS (APCI) m/z 359 (MH+). 1 H NMR (DMSO-d6) : J 10.74 (1H, s) : 9.25 (1H, brs) : 8.02 (1H, s) : 3.63 (2H,t) : 3.51, 3.34 (each 1H, ABq, J=14_8 Hz); 3.39 (2H,d) : 3.24 (1H,t); 2.92 (2H, q) ; 2.81 (2H, t) : 2.07 (2H, d) ; 1.82 (2H, d) ; 1.74-1.58 (5H, m) :1.45-1.34 (1H, m) ; 1.31 (3H, s). 1 9 F NMR (DMSO-d6 ) : J -74.48. -131 - This paper size is suitable for China National Standard (CNS) A4 specification (21〇x 297 mm) 1329637 A7 B7 V. Invention description (128 ) (5S)-5-(丨丨4-(3-furan-2-yl-1H-pyrazole-5-yl)hexahydropyridin-1-ylsulfonyl}methyl)-5-methylimidazolidin-2,4-dione LC -MS (APCI) m/z 408 (MH+). 'HNMR (DMSO-d6): d 10.73 (lH, s); 8.01 (lH, s): 7.66 (lH, s): 6.64 (lH, s); 6.53 (lH, s); 6.34 (lH, s); 3.61-3.49 (2H, m 3.49 (1H, semi-ABq, J = 14.9 Hz); 2.94-2.84 (2H, m): 2.81-2.72 (1H, m); 1.98 (2H, brd); 1.70-1.58 (2H, m); 1.32 (3H, s). (5S)-5-Methyl-5-{丨(4-{4-『(difluoromethyl)oxy)phenyl}hexahydrop-precipitate-i-yl) Methyl phthalimidazole pyridine-2,4-dione LC-MS (APCI) m/z 436 (MH+). 1 H NMR (DMSO-d6) : 10.73 (1H, s) ; 8.01 (1H, s) ;740 (2H, d) -2.61 (2H, m) ; 1.86 (2H, d) : 1.71-1.57 (2H, m) ; 1.33 (3H, s). (5S)-5-(丨丨4-(4-鼠束基鼠鼠1-2-1-yl 1 chloromethyl)-5-methyl-pyridin-2,4-dione LC-MS (APCI) m/z 386/388 3 : 1 (MH+). , 1 H NMR (DMSO-d6): 10.73 (1H, s): 8.01 (1H, s); 7.36-7.28 (4H, m); 3.66-3.54 (2H, m); 3.51, 3.33 (each 1H, ABq, J= 14.9 Hz) ; 2.92-2.80 (2H, m) ; 2.67-2.58 (1H, m) ; 1.81 (2H, brd) ; 1.68-1.56 (2H, m) : 1.33 (3H, s). ( (5S)- 5-methyl-5-(anthracene (4-tetrahydro)-pyrrolidyl hexahydropyrene-precipitate-l-yl) Oxazolidine-2,4-dione trifluoroacetic acid LC-MS (APCI) m/z 345 (MH+). -132 This paper size applies to Chinese National Standard (CNS) A4 size (210 x 297 mm) 1329637 A7 B7___ V. Description of invention (129) 1 H NMR (DMSO-d6) : δ 10.74 (IH, s) : 9.61 (1Η, brs) ; 8.01 (1H, s); 3.60 (2H, t) ; 3.51, 3_36 ( Each 1H, ABq, J=14_8 Hz); 3.55-3.47 (2H, m) ; 3.27 -3.15 (1H, m) ; 3.13-3.02 (2H, m) : 2.80 (2H, t) : 2.12 (2H, brd ) : 2.07-1.94 (2H, m) ; 1.86-1.77 (2H, m) : 1.62-1.49 (2H, m) ; 1.32 (3H, s). 1 9 F NMR (DMSO-d6) : d -74.02 ( 5S)-5-Methyl-5-({丨4-(tetrahydrofuran-2-ylcarbonyl)hexahydropyrrolidin-1-yl 1sulfonyl}methyl)imidazolidine-2,4-dione LC- MS (APCI) m/z 375 (MH+). 1H NMR (DMSO-d6): δ 10.73 (1H, s): 8.01 (1H, s); 4.65 (1H, dd); 3.80-3.68 (2H, m ; 3.60-3.42 (3H with water, m); 3.33 (1H, semi-ABq, J = 14.9 Hz); 3.19-3.00 (4H, m); 2.09-1.92 (2H, m); 1.87-1.75 (2H, m) ; 1.30 (3H, s). N-丨1-((丨(4S)-4-methyl-2,5-dioneimidazolidin-4-yl 1methyl}sulfonyl) hexahydro Pyridine-4-丨 醯 醯 LC LC-MS (APCI) m/z 395 (MH+). 1 H NMR (DMSO-d6) : ό 10.72 (1H, s) ; 8.30 (1H, d) ; 8.01 (1H, s): 7.82 (2H, d); 7.51 (lH, t); 7.45 (2H, t) ; 3.96-3.85 (1H, m) : 3.52 (2H, t); 3.50, 3.32 (each 1H, ABq, J=14_7 Hz ; 2.92 (2H, t) ; 1.88 (2H, d) ; 1.55 (2H, q) ; 1.33 (3H, s). (5S)-5-丨丨(4_{丨2-(1,1_二Methyl ethyl)·1Η-4丨哚-5-yl)amino}hexahydropyridin-1-yl) hydrazinyl 1 methyl b 5-methylimidazolidinyl 2,4-dione LC-MS (APCI) m/z 462 (MH+). 1 H NMR (DMSO-d6) : ά 10.72 (1H, s) : 10.37 (1H, s) : 8.00 (1H, s) : 7.02 (1H, d, J= 8.4 Hz): 6.58 (1H, s); 6.45 (1H, d, J=8.4 Hz): 5.86 (lH, s): 4.65 (1H, Br s) ; 3.48, 3.29 (each 1H, ABq, J=14.7 Hz) : 3.46 (2H,t) : 2.93 _-133-___ This paper and scale apply to the national standard (CNS) A4 size &lt;210 x 297 mm) rI329637 , A7 B7_ V. Invention description ()

I (2H, t) ; 1.95 (2H, t) ; 1.45-1.35 (2H, m) ; 1.33 (3H, s) ; 1.29 (9H, s). (5S)-5-methyl-5-丨 ( Hexahydropyridin-1-yl hydrazine methylimidazole pyridine-2,4-dione LC-MS (APCI) m/z 276 (MH+). 1 H NMR (DMSO-d6) : β 10.70 (1H, s 7.97 (1H, s); 3.44, 3.23 (each 1H, ABq, J=14.8 Hz); 3.13-3.01 (4H, m); 1.58-1,42 (6H, m) ; 1.30 (3H, s) (5SV5-丨(3,6-dihydropyridine-1(2H)-ylsulfonyl)methyl M-methylimidazolidin-2,4-dione LC-MS (APCI) m/z 274 ( MH+). 1 H NMR (DMSO-d6) : δ 10.72 (1H, s) : 8.00 (ΪΗ, s) : 5.85-5.78. (1H, m) ; 5.74-5.68 (1H, m) ; 3.67-3.62 ( 2H, m) ; 3.47, 3.33 (each 1H, ABq, J=14.7 Hz); 3.22 (2H, dd); 2.14-2.10 (2H, m) ; 1.31 (3H, s). (5S)-5-曱5-({4-(2-oxy, keto-2,3-dihydro-1H-benzimidazol-1-yl)hexahydropyridin-1-yl) hydrazinylmethyl) Imidazopyridine-2,4-dione LC-MS (APCI) m/z 408 (MH+). 1 H NMR (DMSO-d6): 10.86 (lH, s); 10.75 (lH, s); 8.02 (1H, (7), 7.27-7.17 (1H, m) (each 1H, ABq, J=14.8 Hz); 3.03-2.90 (2H,m); 2.f 1-2.24 (2H,m) ;1.76 (2H,d); 1.34 (3H,s). ., ( 58)-5-(lamp 4-(111-1,2,3-benzotriazol-1-yl)hexahydropyridin-1-yl 1sulfonyl}methyl)-5-methylimidazolidin- 2,4-Diketone LC-MS (APCI) m/z 393 (MH+). 1 H NMR (DMSO-d6) : ό 10.77 (1H, s) : 8.05 (1H, s) : 8.05 (1H, d) : 7.93 (lH,d); 7.56 (lH,t); 7.41 (lH,t); 5.12-4.97 (lH,m); 3-71 (2H,t); 3.58, 3.43 (each 1H, ABq, J =14.7 Hz) : 3.19-3.03 (2H,m) : 2.29-2.16 (4H,m) • 134- The paper size is based on the national standard (CNS&gt; A4 size (210X297 mm) 1329637 A7 B7 , invention description (131): l_35(3H, s)_(5S)-5-mercapto-5-({ί4-(pyridin-2-ylethynyl)-3,6-dihydropyridine-1 (2H --I sulfonyl hydrazine methyl} imidazolidin-2,4-dione trifluoroacetic acid LC-MS (APCI) m/z 375 (MH+). 1 H NMR (DMSO-d6) : δ 10.57 (1H , s); 8.56 (lH, d); 8.03 (1H, s); 7.82 (lH, t); 7.53 (lH, d); 7.38 (1H, dd); 6.31 (1H, brs); 3.83 (2H, d) : 3.54, 3.41 (each 1H, ABq, J=14.8 Hz); 3.36-3.25 (2H,m) ; 2.42- 2.34 (2H, m); 1.32 (3H, s). 1 9 F NMR (DMSO-d6) : J -75.10 (58)-5-methyl-5-({丨4-丨(4-methylbenzene) Ethyl acetyl]-3,6-dihydropyridine-; 1 (2-in-1 sulfonyl fluorenylmethyl) imidazolidin-2,4-dione LC-MS (APCI) m/z 388 (MH+ 1 H NMR (DMSO-d6): i 10.74 (1H, s); 8.02 (1H, s); 7.32 (2H, d); 7.19 (2H, d); 6.17 (1H, brs) ; 3.80 (2H , d) ; 3.52, 3.39 (each 1H, ABq, J = 14.8 Hz): 3.29 (2H, t) ; 2.39-2.32 (2H, m) ; 2.30 (3H, s) ; 1.32 (3H, s). 5S)-5-(丨丨4-丨(4-Phenylphenyl)ethynyldi 3,6-dihydropyridine-1(2H)-yl Isulfonyl}methyl)-5-methylimidazolidinium -2,4-dione LC-MS (APCI) m/z 408 (MH+). 1 H NMR (DMSO-d6) : ά 10.74 (1H, s) ; 8.02 (1H, s) ; 7.54-7.38 (4H , m) ; 6.23 (1H, brs) ; 3.87-3.76 (2H, m) ; 3.53, 3.41 (each 1H, ABq, J = 14.9 Hz); 3.34 - 2.25 (2H, m): 2.42-2.29 (2H, m) ; 1.32 (3H, s). (5S)-5-丨4-(3,4-dioxa-phenoxy)-hexahydropyridine-1-sulfonylmethyl b 5-methyl-imidazole Disease-2,4-dione LC-MS (APCI) m/z (APCI) m/z 436.1 (MH+). -135 - This paper scale applies to Chinese national standards ( CNS) A4 size (210X 297 mm) 1329637 A7 _B7____ V. Description of invention (132) 1 H NMR (DMSO-d6) : δ 10.74 (lH, s): 8.01 (lH, s); 7.53 (1H, d, J=9.2 Hz) : 7.31 (1H, d, J=2.9 Hz) : 7.02 (1H, dd, J=9.2, 2.9 Hz); 4.65-4.57 (1H, m); 3.51, 3.34 (each lH, ABq, J = 15.2 Hz): 3.39-3.27 (2H, m); 3.17-3.08 (2H, m); 2.00-1.90 (2H, m); 1.75-1.65 (2H, m); 1.33 (3H, s). 38)-5-[4-(5_气比淀-2-yloxy!yl)-77 nitrogen π ratio bite-l-insult 1 arylmethyl hydrazine-5-methyl·imipididine-2, 4-Dione LC-MS (APCI) m/z 403.3 (MH+). 1 H NMR (DMSO-d6): 10.74 (1H, s); 8.20 (1H, d, J=2.7 Hz): 7.81 (1H, Dd, J=8.7, 2.7 Hz); 6.87 (1H, d, J=2.7 Hz): 5.16-5.03 (1H, m) ; 3.52, 3.35 (each out, eight 81 households 15.0 along); 3.43-3.28 (2 111); 3.19-3.07 (2 za 111); 2_08-1.95 (2H, m); 1.80-1.65 (2H, m); 1.33 (3H, s). (5SV5-methyl-5-丨4-( 5-trifluoromethyl-pyridin-2-yloxy)-piperidine-1-sulfonylfluorenyl-imidazolidine-2,4-dione LC-MS (APCI) m/z 437 (MH+ 1 H NMR (CDC13) : S 8.95 (1H, s) ; 8.42-8.38 (1H, m) 7.79 (1H, dd, J= 8.8, 2.5 Hz); 6.81 (lH,d, J=8.8Hz); 6.71 (lH,s): 5.40-5.28 (1H, m): 3.52-3.39 (2H, m) : 3.40-3.28 (2H, m) : 3.32 (2H, ABq, J=24.6, 14.0 Hz): 2.16-2.02 (2H, m) : 2.02-1.84 (2H, m) : 1.67 (3H, s). 6 -[l-((4S)-4-methyl-2,5-dione-imidazolidin-4-ylnonanesulfonyl)-hexahydropyridin-4-yloxy-1-nicotinonitrile LC -MS (APCI) m/z 394.3 (MH+). 'H NMR (DMSO-d6): ά 10.72 (lH, s): 8.68 (1H, d, J = 2.3 Hz); 8.14 (1H, dd, J= 8.7, 2.3 Hz) : 8.00 (1H, s) ; 6.98 (1H, d, J=8.7 Hz) : 5.27-5.14 (1H, m) :3.56-3.28 (4H, m) : 3.18-3.06 (2H, m ) : 2.08-1.96 (2H, m) : 1.81-1.66 -136- ________ This paper wave scale applies to Chinese National Standard (CMS) A4 specification (210 x 297 mm) Binding

k 1329637 A7 _B7___ V. DESCRIPTION OF THE INVENTION (133 ) (2H, m): 1.31 (3H, s). (5S)-5-Methyl-5-(4-p-tolyloxy-hexahydropyridine-1-醯 甲基 methyl)-imidazolidine-2,4-dione LC-MS (APCI) m/z 382.5 (MH+). 1 H NMR (DMSO-d6): d 10.73 (1H, s) ; 8.01 (1H , s) : 7.09 (2H, d, J=8.4 Hz) : 6.87 (2H, d, J=8.4 Hz) ; 4.50-4.42 (1H, m) ; 3.50, 3.34 (each 1H, ABq, J=14.8 Hz ) : 3.38-3.29 (2H, m) ; 3.17-3.09 (2H, m) ; 2.23 (3H, s) ; 1.99-1.89 (2H, m) ; 1.73-1.63 (2H, m) ; 1.33 (3H, s (5S)-5-Methyl-5-anthracene 4-(4-trifluoromethyl-phenoxy)-hexahydropyridine-1-dimethyl-methyl-miproza-2,4- Diketone LC-MS (APCI) m/z 436.3 (MH+). 1 H NMR (DMSO-d6): d 10.71 (1H, brs); 8.02 (1H, s): 7.65 (2H, d, J = 8.8 Hz ) : 7.17 (2H,d,J=8.8 Hz) ; 4.72-4.64 (1H,m) : 3.52, 3.35 (each 1H, ABq, J=14.7 Hz); 3.40-3.28 (2H, m) ; 3.19-3.10 (2H, m) : 2.05-1.95 (2H, m) ; 1.78-1.68 (2H,m); 1.33 (3H,s). 4-『1-(48)-4-methyl-2,5-II Keto-imidazolidin-4-ylmethanesulfonyl)-hexahydropyridine·4-yloxybenzonitrile” LC-M S (APCI) M/Z 393.2 (MH+). 1 H NMR (DMSO-d6) : δ 10.73 (1H, s) : 8.00 (1H, s) : 7.76 (2H, d, J = 8.8 Hz) : 7.15 ( 2H, d, J=8.8 Hz) : 4.74-4.65 (1H, m) : 3.51, 3.34 (each 1H, ABq, J=14.9Hz): 3.40-3.27 (2H, τη) : 3.17-3.07 (2H, m ) : 2.03-1.94 (2H, m).: 1.77-1.66 (2H,m) : 1.32 (3H,s). (5S)-5-丨4-(4-methoxy-phenoxy)-six Hydrogen p-precipitate----------------------------------------------------------------------------------- The paper size applies to China's S standard (CNS) A4 specification (210X 297) 1329637 A7 B7 _ V. Inventive Note (134 ) LC-MS (APCI) m/z 398.2 (MH+). 1 H NMR (DMSO-d6) : ό 10.73 (1H, s) : '8.01 (1H, s) : 6.89 (4H, ABq, J=29.1, 9.1 Hz) ; 4.43-4.34 (1H, m) : 3.70 (3H, m) : 3.51, 3.33 (1H, ABq, J=15.0 Hz) : 3.38-3.28 (2H, m) ; 3.16-3.05 (2H, m) : 1.97-1.87 (2H, m); 1.73- 1.62 (2H, m) ; 1.33 (3H, s). (5S)-5-丨4-( 3,4-Difluoro-phenoxy)-hexahydropyridin-1- sureinylmethyl b 5-methylmiprozol-2,4-dione LC-MS (APCI) m/z 404.2 (MH+ 1 H NMR (DMSO-d6) : δ 10.74 (1H, s 8.01 (1H, s); 7.35 (1H, q, J=19.6, 9.2 Hz); 7.19-7.11 (1H, m); 6.86-6.80 (1H, m); 4.57-4.48 (1H, m); 3.51, 3.34 (each 1H, ABq, J= 14.9 Hz); 3.38-3.28 (2H, m): 2.16-2.06 (2H, m); 2.00-1.90 (2H,m) ; 1.74-1.64 (2H,m) ; 1.33 (3H, s). (5S)-5-丨4-(4-Gas-phenoxy)-hexahydropyridine-1-sulfonylmethyl b 5-methyl-imidazolidin-2,4 -diketone LC-MS (APCI) m/z 402 (MH+). 1 H NMR (DMSO-d6) : ά 10.73 (1H, s); 8.00 (1H, s); 7.32 (2H, d, J=8.8 Hz) ; 7.00 (2H,d, J=8.8 Hz) ; 4.56-4.48 (1H,m) ; 3.50,3.33:. (each 1H, ABq, J=14.8 Hz): 3.37-3.28 (2H, m) : 3.16-3.06 (2H, m): 2.00-1.90 (2H, m): 1.73- 1.63 (2H, m) ; 1.32 (3H, s). (5S)-5-丨4-(5-ethyl-pyrimidine -2-yloxy)-hexahydropyridine-1-sulfonylmethyl b 5-methyl-imidon-2,4-dione LC-MS (APCI) m/z 398 (MH+). H NMR (DMSO-d6) : δ 10.74 (1H, s): 8.47 (2H, s): 8.02 (lH, s): 5.11 -5.03 (1H, m): 3.52, 3_35 (1H, ABq, J= 14.8 Hz) : 3.42-3.28 (2H, m); -138- This paper scale applies to China National Standard (CNS) A4 (210 X 297 mm) 1329637 A7 B7 V. INSTRUCTIONS (135) 3.19-3.10 (2H, m) : 2.54 (2H, q, J=15.2, 7.6 Hz) : 2.06-1.98 (2H, m) : 1.81 -1.71 (2H, m) ; 1.33 (3H, s): 1.17 (3H, t, J = 7.2 Hz). (5SV5-methyl-5-indole 4-(4-trifluoromethyl-pyrimidine-2- Benzyl)-hexahydropyridin-1- sure Si-methylimidazole pyridine-2,4-dione LC-MS (APCI) m/z 438 (MH+). 1 H NMR (CDC13): 8.84-8.76 (1Η, m) ; 8.02(lH,s): 7.31(lH,d,J= 4.8 Hz) - 6.33 (lH,s); 5.41-5.34 (1H, m) ; 4.54-4.42 (4H, m) : 3.35, 3.24 (each 1H, ABq, J = 12.9 Hz); 2.17-2.07 (4H, m); 2.02 (3H, s). (5S)-5-methyl-5-(4-(5-methyl) -g is more than 2-aminooxy)-hexahydrophyllum sulphate -1- 酿 曱 曱 卜 吐 这 -2 This-2,4-dione LC-MS (APCI) m / z 383 (MH +). 1 H NMR (CDCi3): β 8.14 (1H, s); 8.06-7.99 (2H, m); 7.19 (1H, s); 7.09 (1H, d, J = 11.6 Hz); 5.28-5.21 (1H, m ;3.70 (3H, m): Mercapto)-hexahydropyridine-1-sulfonylmethyl b 5-methyl-imidazole bite-2,4-diindole LC-MS (APCI) m/z 398 (MH+). ; 1 H NMR (DMSO-d6) : ά 8.06 (2H, q, J=9.2, 6.0 Hz): 7.40 (2H, t, J=8.8 Hz): 3.61-3.41 (4H , m) : 3.00-2.91 (2H, m) : 1.90-1.81 (2H, m) : 1.62-1.50 (2H, m): 1.33 (3H, s). (5S)-5-丨4-(5- Fluoro-pyrimidin-2-yloxy)-hexahydropyridine-1-sulfonylmethyl1-5-methyl_imidazolidine-2,4-dione LC-MS (APCI) m/z 388 (MH+ 1 H NMR (CDCI3) : ά 8.42 (2H, s); 8.30 (lH, s).: 6.40 (lH, s): 5.30- __- 139-_ This paper scale applies to China's fixed house ( CNS) A4 size (21〇x 297 mm) 1329637 A7 B7_ V. Description of invention (136) 5.23 (1H,m): 3.53-3.35 (4H, m): 3.36, 3.21 (each IH, ABq, J=14.4 Hz): 2.10-2.02 (4H, m): 1.70 (3H,s)_ (5S)-5·丨4-(6-methyl-pyridin-2-yloxy)-hexahydropyridine-1-醯Methyl 1-5-methyl-imidazolidinium-2.4-dione LC-MS (APCI) m/z 399 (MH+). 1 H NMR (MeOD) : ά 7.54 (1H, t, J=8.4 Hz) ; 6.33-6.28 (2H, m) ; 5.24-5.14(lH,m); 3.86(3H, s): 3_53-3_42(2H,m); 3_58,3.39 (each 1 八八七J=1=1 Hz) ; 3.30-3.22 (2H, m) ; 2.13-2.02 (2H, m) ; 1.96-1.82 (2 H, m); 1.47 (3H, s). (5S)-5-丨4_(6-gas-g ratio bit-2-yloxy)-hexahydrofolate I: bite-1-continuation methyl 5-Methyl-imidazolidine-2,4-dione LC-MS (APCI) m/z 403 (MH+). 1 H NMR (MeOD): ί 7.65 (1H, t, J-7.8 Hz); (1H, d, J=7.2 Hz); 6.73 (1H, d, J=7.2 Hz); 5.25-5.14 (1H,m) ; 3_55-3·44 (2H, m) ; 3.58, 3.39 (each 1H, ABq, J=14.4 Hz) ; 3.28-3.19 (2H, m) ; 2.14-2.02 (2H, m) ; 1.92-1.79 (2H,m); 1.47 (3H,s). 3-fl-((4S) -4-methyl-2,5-dione-imidazolidin-4-ylmethanesulfonyl)-hexahydropyridin-4-yloxy]benzonitrile LC-MS (APCI) m/z 393 ( MH+). 1 H NMR (DMSO-d6): ^ 10.74 (1H, s): 8.02 (1H, s); 7.52-7.47 (2H, m):7.42-7.38 (1H, m): 7.36-7.31 (1H , m) ; 4.69-4.61 (1H, m) ; 3.52, 3.35 (&amp;lH, ABq, J = 17.2 Hz): 3.18-3.07 (2H, m): 2.02-1.95 (2H, m): 1.79-1.65 (2H,m): 1.33 (3H, s). (5S)-5-(4-(3-Methoxy-phenoxy)-hexahydropyridine-1-sulfo S-ylmethylhydrazine-5- Methyl-micrometer__- 140 -___ This paper scale applies to t S national standard (CNS) A4 specification (21〇x 297 public) 1329637 A7 B7__ Description (137) Olfactory bite-2,4-dione LC-MS (APCI) m/z 398 (MH+). 1 H NMR (DMSO-d6) : δ 10.74 (1H, s): 8.01 (lH, s) ; 7.21-7.15 (1H, m) ; 6.58-6.50 (3H, m) ; 4.57-4.49 (1H,m) ; 3_73 (3H,s) ; 3.51,3_34 (each IH, ABq, J=14.4 Hz): 3.17-3.08 (2H, m) : 2.01-1.91 (2H, m) ; 1.74-1.64 (2H, m): 1.33 (3H, s). 1^-{4-丨1-((48)-4- Methyl-2,5-dione-imidazolidin-4-ylmethanesulfonyl)-hexahydrog-butyl-4-yloxy-1-dipylamine-LC-MS (APCI) m/ z 425 (MH+). 1 H NMR (DMSO-d6): δ 10.69 (1H, brs): 9.78 (1H, s); 8.00 (1H, s); 7.47 (2H, d, J = 9.2 Hz); (2H, d, J=9.2 Hz); 4.48-4.41 (1H, m): 3.51 (1H, ABq, J=14.4 Hz); 3.16-3.06 (2H, m) ; 2.00 (3H, s); 1.98- 1.90 (2H, m) ; 1.73-1.63 (2H, m) ; 1.33 (3H, s). (5S)-5-丨4-(3-Gas-phenoxy)-hexahydropyridine-1- 醯Methyl]-5-methyl-imidazolidine 2,4•dione LC-MS (APCI) m/z 402 (MH+). 1 H NMR (DMSO-d6) : δ 10.76 (1H, brs) ; 7.99 (1H, s) ; 7.31 (1H, t, J= 8.4 Hz) : 7.08 (1H, t, J=2.2 Hz) ; 7.02-6.95 (2H , m) ; 4.64-4.56 (1H, m); 3.51 (1H, ABq, J = 14.4Hz); 3.17-3.09 (2H, m) ; 2.00-1.91 (2H, m) ; 1.75-1.65 (2H, m ): 1.33 (3H, s). (5S)-5-Methyl-5-indole 4-(4-trifluoromethoxy-phenoxy hexahydropyridin-1- surely decyl methyl bimide bite -2,4-Bronze LC-MS (APCI) m/z 452 (MH+). 1 H NMR (DMSO-d6) : δ 10.74 (1H, s) ; 8.01 (1H, s): 7.29 (2H, d , J=8.8 _ -141 - _ This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

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Line 1329637 A7 B7_ V. Description of invention (138)

Hz): 7.08 (2H, d, J=9.2 Hz): 4.60-4.52 (1H, m): 3.51 (1H, ABq, J=14.8 Hz): 3.17-3.08 (2H, m) ; 2.02-1.93 (2H , m) ;' 1.75-1.65 (2H, m) : 1.33 (3H, s). (5S)-5_methyl-5-丨4-(3·trifluoromethoxy-phenoxy)-six Hydropyridine-1-sulfonylmethylpyridinium-2,4-dione LC-MS (APCI) m/z 452 (MH+). 1 H NMR (DMSO-d6) : ^ 10.74 (1H, s) ; 8.01 (1H, s) : 7.41 (1H, t, J=8.4 Hz) ; 7:06-6.91 (3H, m) ; 4.65-4.58 (1H, m) ; 3.51 (1H, ABq, J=14.8 Hz ); 3.18-3.08 (2H, m) ; 2.02-1.93 (2H, m) : 1.76-1.65 (2H, m) : 1.33 (3H, s). (5S)-5-丨4-(2,4- Difluoro-phenoxy)-hexahydropyridine-1-sulfonylmethylindole-5-methyl-imidazolidin-2,4-dione LC-MS (APCI) m/z 404 (MH+). H NMR (DMSO-d6): ό 10.74 (1H, s); 8.02 (1H, s); 7.34-7.23 (2H, m): 7.06-6.97 (1H, m); 4.50-4.41 (1H, m): 3.50 (1H, ABq) ; 3.17-3.06 (2H, m) ; 2.02-1.90 (2H, m) ; 1.78-1.65 (2H, m) : 1.33 (3H, s). (5S)-5-丨4- (4-Fluoro-phenoxy)-hexahydropyridine-1-methyl-methyl bromide 5-methyl-imidazolidin-2,4-dione LC-MS (AP CI) m/z 386 (MH+). 1 H NMR (DMSO-d6) : δ 10.75 (1H, s) ; 8.02 (1H, s): 7.17-6.97 (2H, m); 4.52-4.43 (1H, m ) : 3.17-3.06 (2H, m) : 2.00-1.89 (2H, m) : 1.75-1.62 (2H, m); 1.33 (3H, s). (5S)-5-丨4-(3-Fluorine- Phenoxy)-hexahydropyridine-1-decylmethyl 1-5-methyl-imidazolidin-2,4-dione LC-MS (APCI) m/z 38ΰ (ΜΗ+). 1 H NMR (DMSO-d6) : δ 10.72 (1H, s) : 8.02 (IH, s) : 7.36-7.26 (1H, m) _ -142 -__ This paper size applies to the Chinese National Standard (CNS) A4 specification (210X 297 PCT) 1329637 A7 B7_ V. INSTRUCTIONS (139) : 6.91-6.71 (3H, m) : 4.62-4.52 (1H, m) ; 3.18-3.06 (2H, m) : 2.02-1.91 (2H, m) : 1.78 -1.63 (2H, m): 1.33 (3H, s). (5S)-5-丨4-(2-Fluoro-phenoxy)-hexahydropyridine-1-sulfonylmethyl b-5-methyl - Imidazolidin-2,4-dione LC-MS (APCI) m/z 386 (MH+). 1 H NMR (DMSO-d6) : s: 10.74 (lH, s); 8.01 (lH, s): 7.28- 7.17 (2H, m) :7.17-7.08(1H, m) ; 7.02-6.97 (1H, m) ; 4.59-4.47 (1H, m) ; 2.04-1.92 (2H, m) ; 1.80-1.67 (2H, m ) : 1.33 (3H, s). (5S)-5-丨4-(5-A -Pyryl-2-yloxy)-hexahydropyridine-1-sulfonylmethyl-5-methyl-imidazolidin-2,4-dione LC-MS (APCI) m/z 399 (MH+ 1 H NMR (DMSO-d6) : ά 10.74 (lH, s); 8.01 (lH, s); 7.89 (1H, d, J = 3.16 Hz); 7.39 (1H, dd, J=3.18, 9.07 Hz 6.77 (1H, d, J=8.95 Hz) : 5.08-4.96 (1H,m) ; 3.76 (3H,s) ; 3.51,3.34 (8 屮 each 8 屮) ==14.7 he); 3.43-3.29 ( 2H, m) ; 3.18-3.05 (2H, m) : 2.05-1.94 (2H, m) ; 1.77-1.61 (2H, m): 1.33 (3H, s). (5S)-5-methyl-5-丨4-(4-Pyridin-3-yl-phenyl)-hexahydropyrazine-1-sulfonylmethyl bumi bite-2,4-dicopper LC-MS (APCI) m/z 430 ( MH+). 1 H NMR (DMSO-d6): δ 10.76 (lH, s); 8.99 (1H, s): 8.60 (1H, d, J = 4.91 Hz); 8.35 (1H, d, J = 7.81 Hz) : 8.04 (lH, s) : 7.70 (2H, d, J=8.87 Hz) :7.12 (2H, d, J=8.91 Hz) : 3.57 (1H, ABq) : 3.35 (4H, m) : 3.27 (4H, m) : 1.33 (3H, s). (5S)-5-Methyl-5-({丨4-(pyridin-2-yloxy}hexahydropyridin-1-ylindolesulfonyl 1 methyl) _-143-_ This paper size applies to China National Standard (CNS) A4 specification (210 X 297 public attack) 1329637 A7 B7 V. Description of the invention (14〇) Imididine-2,4-dione LC-MS (APCI) m/z 369 (MH+). 1 H NMR (CDC13): d 1.73 (3H, s) , 1.96-2.04 (2H, m) ; 2.04-2.13 (2H, m) : 3.21 (lH,d): 3.36-3.42 (3H, m) : 3.45-3.50 (2H, m) : 5.29-5.33 (1H, m ) : 6.30 (1H, bs); 6.78 (lH, d): 6.93 (1H, t) : 7.65 (1H, t) ; 7.70 (1H, bs) : 8.16 (13⁄4 d). (5S)-5-丨(丨4-丨(3,4-dimethylbenzyl)oxy-1hexahydropyridin-1-yl)sulfonyl)methyl b-5-methylimidazolidin-2,4-dione (NB. Contains 30% 2,3-dimethyl isomer in the starting material). LC-MS (APCI) m/z 410 (MH+). 1 H NMR (DMSO-d6): ί 1.3 (3Η , s) ; 1.53-1.64 (2Η, m) ; 1.83-1.89 (2H, m) ; 2.18 (3H, s); 2.20 (3H, s) ; 2.95-3.33 (2H, m) ; 3.25-3.31 (3H , m); 3.45 (1H, d) ; 3.45-3.53 (1H, m) ; 4.42 (2H, s) : 7.01-7.15 (3H, m) ; 7.97 (1H, s); 10.70 (lH, s). (5S)-5-Methyl-5-{indole(4-phenoxyhexahydropyridin-1-yl)sulfonyl-1methyl}imidazolidine-2,4-dione LC-MS (APCI) m /z 368 (MH+). ' • s 1 H NMR (DMSO-d6) : 1.30 (3H, s) : 1.64-1.7 3 (2H, m) ; 1.92-2.00 (2H, vm) : 3.08-3.15 (2H, m) ; 3.28-3.44 (4H, m) : 4.49-4.54 (1H, m) ; 6.92 (1H, t) : 6.96 (2H, d) ; 7.28 (2H, t) : 7.69 (1H, bs) ; 10.7 (1H, bs). 4-fluoro-N-丨l-((4S)-4-mercapto-2,5 -diketo-imidazridin-4-ylmethanesulfonyl)-hexahydropyridin-4-ylbufenamide LC-MS (APCI) m/z 413 (MH+). 1 H NMR (DMSO-d6 ) : δ 10.73 (lH, s): 8.34 (1H, d, J=7.50 Hz) : 8.02 _- 144 -___ This paper is the standard Chinese National Standard (CMS) A4 specification (210 X 297 mm)

Binding

1329637 A7 B7 V. INSTRUCTIONS (141) (1H, s): 7.94-7.88 (2H, m): 7.33-7.26 (2H, m) ; 3.96-3.86 (1H, m) : 3.58-3.47 (2H,m ) : 3.51, 3.32 (each 1H, ABq, J=i4_81 Hz): 2.97-2.88 (2H, m): 1.92-1.84 (2H, m) : 1.62-1.48 (2H, m) ; 1.33 (3H, s) (5S)-5-丨(M-丨(2,5-dimethylindenyl)oxyindole hexahydropyridine-l-yl}sulfonyl, a certain 1-5-methyl imiline bite_ 2,4_dione LC-MS (APCI) m/z 410 (MH+). 1 H NMR (DMSO-d6): ci 1.30 (3H, s); 1.54-1.62 (2H, m): 1.85-1.91 ( 2H, m) ; 2.21 (3H, s) ; 2.24 (3H, s) ; 2.97-3.03 (2H, m) ; 3.27-3.34 (3H, m); 3.45 (lH, d); 3.49-3.55 (1H, m); 6.97-7.04 (2H, m); 7.11 (lH, s).; 7.98 (1H, s); 10.70 (lH, s). (5S)-5-(T4-(5-alkylpyridine- 2-yl)hexahydropyridin-1-ylindolesulfonyl)-5-methylimidazolium 2,4-di-LC-MS (APCI) m/z 387 (MH+). 1 H NMR (DMSO- D6) : δ 10.72 (1H, s) ; 8.54 (1H, d) ; 8.01 (1H, s): 7.86 (1H, dd) ; 7.38 (1H, d) ; 3.61 (2H, bt) ; 3.50, 3.32 ( Each 1H, ABq, J = 14.9 Hz); 2.96-2.76 (3H, m): 1.92 (2H, brd): 1. 77-1.62 (2H, m): 1.33 (3H, s). '(5S)-5-丨4-(5-decyloxy-pyridin-2-yloxy)-hexahydropyridine-1-sulfonate Methyl 1-5-methyl-imidazolidin-2,4-dione LC-MS (APCI) m/z 475 (MH+). 1 H NMR (DMSO-d6): c? 10.73 (lH, s) ; 8.01 (1H, s) : 7.90 (1H, d, J = 3.13 Hz) : 7.48-7.30 (6H, m) ; 6.76 (1H, d, J=8.97 Hz) : 5.10 (2H, s) ; 5.05 - 4.98 (1H,m) ; 3_51 (IH (from ABq), J=14.84 Hz); 3.40-3.30 (3H, m): 3.15-3.07 (2H, m) : 2.07-1.95 (2H, m) : 1.74 -1.64 (2H, m) : 1.33 (3H, s). -145 - This paper size is applicable to China National Standard (CNS) A4 specification (210 x 297 mm)

Binding

1329637 A7 B7 V. INSTRUCTIONS (142 ) (5S)-3-f4-(6-Mouse-Lepidoptera-3-yloxy)-7 Hurricane 17 to bite-l-continuation 1 S-sodium methyl] -3-methyl miso bite-2,4-dihydropurine LC-iMS (APCI) m/z 403 (MH+). 1 H NMR (DMSO-d6) : ^ 10.74 (lH, s): 8.17 (1H, d, J=3.10 Hz); 8.01 (1H, s); 7.56 (1H, dd, J=3.18, 8.80 Hz); 7.44 (1H, d, J=8.77 Hz): 4.67-4.59 (1H, m) ; 3.52, 3.35 (2H, ABq, J=15.22 Hz); 3.39-3.28 (2H, m) ; 3.17-3.08 (2H, m) : 2.03-1.93 (2H, m) : 1.77-1.67 (2H, m) : 1.33 (3H, s). (5S)-5-丨4-(5-Hydroxy-pyridin-2-yloxy)-hexahydropyridine-1-sulfonylmethyl b 5-methyl-microbite -2,4-dione LC-MS (APCI) m/z 385 (MH+). 1 H NMR (methanol-d4): ??? 7.73 (1H, d, J = 3.01 Hz); 7.53 (1H, dd, J =3.11, 9.03 Hz) ; 7.04 (1H, d, J=9.04 Hz) ; 3.80-3.67 (1H, m) ; 3.58, 3.41 (2H, ABq, J=15.04 Hz) : 3.53-3.42 (2H, m) ;3.36 (2H, m) Thio)-hexahydropyridine-1-methyl-methyl bromide 5-methyl-imidazolidin-2,4-dione LC-MS (APCI) m/z 418 (MH+). &lt;1&gt;H NMR (DMSO-d6): 10.74 (1H, s); 8.00 (1H, s); .7.45-7.39 (4H, m): 2.97- 2.89 (2H, m) : 2.00-1.91 (2H, m) ; 1.56-1.45 (2H, m) : 1.31 (3H, s). (5S)-5-f4-(4-Gas-Benzenesulfonyl) -Hexahydropyridine oxime methyl]-5-methyl-imidazole bite 2,4·diindole LC-MS (APCI) m/z 450 (MH+). 1 H NMR (DMSO-d6) : ΰ 10.73 (lH, s): 7.99 (1H, s); 7.86 (2H, d, J = 8.77 Hz); 111 (2H, d, J=8.75 Hz): 3.66-3.54 (2H, m): 3.50-3.41 (1H, m) -146-__ This paper size applies to China National Standard (CNS) A4 specification (210X 297 mm)

Binding

k 1329637 A7 B7 V. Description of invention (143); 3.44, 3.32 (each 1H, ABq, J = 14.63 Hz): 2.82-2.73 (2H, m): 1.97-1.88 (2H, m) ; 1.57-1.42 (2H , m) ; 1.30 (3H, s). (5S)-5-丨4-(4-fluorophenylamino)-hexahydropyridine-1-sulfonylmethylhydrazine·5-methyl-imidazole bite -2,4-di_LC-MS (APCI) m/z 385 (MH+). 1 H NMR (methanol-(14): &lt;^7.20-7.11 (4 claws); 3_84-3.71 (2's 111 ); 3.60-3.48 (1Η,m) ; 3.56, 3.39 (each 1Η, ABq, J=14.96 Hz); 2.97-2.84 (2Η,m); 2.10-2.00 (2H, m); 1.69-1.53 (2H, m); 1.46 (3H, s). N-{3-丨l-((4S)-4-methyl-2,5-dione-imidazolidin-4-ylmethanesulfonyl)-hexahydro H 基 基 基 基 基 基 LC LC LC LC-MS (APCI) m / z 425 (MH+). 1 H NMR (DMSO-d6) : ά 10.74 (lH, s): 9.89 (lH, s); 8.01 (lH, s); 7.37-7.33 (1H, m): 7.21-7.14 (1H, m) ; 7.08-7.03 (1H, m) ; 6.65 (1H, dd, J=1.89, 8.04 Hz) 4.49-4.42 (1H, m) ; 3.51, 3.34 (each 1H, ABq, J=14.73 Hz); 3.39-3.28 (2H, m): 3.18-3.08 (2H, m): 2.02 (3H, s) ; 2.00-1.92 (2H, m) ; 1.76-1.65 (2H, m) ; 1.33 (3H, s) (5S)-5-丨4-(4-Gas-Benzyl decyl)-hexahydropyrimidin-1-Continuomethylmethyl 5-methyl-imidazole 2-3,4_Bronze LC- MS (APCI) m/z 415 (MH+). 1 H NMR (DMSO-d6): 0 10.75 (1H, s): 8.04 (1H, s): 7.54 (2H, d, J = 8.38 Hz); 45 (2H,d,J=8.38 Hz); 3.79-3.55 (2H, bs) ; 3.56, 3.35 (each JH, ABq, J=14.84 Hz): 3.51-3.31 (2H, bs): 3.27-3.06 (4H , bs); 1.33 (3H, s). 1-((48)-4-methyl-2,5-dione-imidazolidin-4-ylmethanesulfonyl)-hexahydropyridine-4- Acid (4-fluorophenyl)-nonylamine-147 - This 尺度 尺度 适用 适用 ( ( ( (CNS) A4 specification (210 X 297 mm) ♦

Binding

1329637 A7 B7 V. Description of invention (Like LC-MS (APCI) m/z 413 (MH+). 1 H NMR (DMSO-d6) : δ 10.74 (1Η, s) : '9.97 (1Η, s) ; 8.02 ( lH, s); 7.65-7.58 (2H, m): 7.16-7.09 (2H, m) ; 3.62-3.52 (2H, m): 3.49, 3.33 (each 1H, ABq, J=14.94 Hz); 2.87-2.77 (2H, m) : 2.48-2.39 (1H, m) : 1.91-1.84 (2H, m) : 1.70-1.57 (2H, m) ; 1.33 (3H, s). (5S)-5-丨4-( 5-bromo-pyridin-2-yloxy)-hexahydropyridine-1-methylhydrazinemethyl-5-methyl-imidazole bite-2,4-dione LC-MS (APCI) m/z 447,449 (MH+). 1 H NMR (DMSO-d6): ό 10.73 (1H, s); 8.28 (1H, d, J = 2.64 Hz); 8.01 (1H, s): 7.91 (lH,dd,J=2.60 , 8.84 Hz): 6.83 (1H, d, J=8.79 Hz); 5.12-5.05 (1H, m) ; 3.52, 3.35 (each 1H, ABq, J=14.85 Hz); 3.41-3.34 (2H, m); 3.17-3.08 (2H, m); 2.06-1.97 (2H, m); 1.78-1.67 (2H, m) ; 1.33 (3H, s). (5S)-5-丨4-(5-(4-Fluorine Phenyl)-pyridin-2-yl)-hexahydropyrrol-1·sulfonylmethyl b 5-methyl-imidazolidin-2,4-dione LC-MS (APCI) m/z 448 (MH+ 1 H NMR (DMSO-d6): 10.75 (1H, s); 8.45 (1H, d, J = 2.51 Hz): 8.02 (1H, s); 7.88 (1H, dd, J=2.57, 8.86 Hz); 7.70-7.62 (2H, m) 7.30-7.22 (2H, m); 6.98 (1H, d, J = 8.94 Hz); 3.70-3.62 (4H,m): 3.55, 3.36 (each 1H, ABq, J=14.73 Hz); 3.26-3.19 (4H, m): 1·32 (3H,s) (5S)-5-丨4- (5-(4-Methoxy-phenyl)-pyridin-2-yl)-hexahydropyridin-1-sulfonylmethyl 1 -5-methyl-imidazolidin-2,4-dione LC -MS (APCI) m/z 460 (MH+). (5S)-5-i4-(5-(4-Phenylphenyl)-pyridin-2-yl)-hexahydropyridinium-1-sulfonyl Methyl]-5-methyl-imidazolidin-2,4-dione-148- This paper is used in the standard (CNS) A4 size (210X 297 mm) ψ binding

1329637 A7 B7 V. INSTRUCTIONS (145) LC-MS (APCI) m/z 464, 466 (MH+). (5S)-5-丨4-(5-(4-trifluoromethoxy-phenyl) -pyridin-2-yl)-hexahydropyrazine-1-ylidenemethyl 1-5-methyl-imidazolidin-2,4-dione LC-MS (APCI) m/z 514 (MH+). (5S)-5-丨4-(5-17fan-2-yl-p ratio -2-yl)-7 hurricane 1** well -1- bromomethyl]-5-methyl- Imidazolium-2,4-dione LC-MS (APCI) m/z 420 (MH+). (5S)-5-methyl-5-(4-丨5-(1Η-pyrrol-2-yl)- Pyridin-2-ylhexahydropyrazine-1-sulfonylmethyl)imidazolidin-2,4-dione LC-MS (APCI) m/z 419 (MH+). Pack (58)-5-( 4-丨3,3'-dipyridyl-6-yl-hexahydropyrrol-1-sulfonylmethyl)-5-methyl-imidazolidin-2,4-dione LC-MS (APCI) m/z 431 (MH+). I1&quot; k (4S)-4-(6-丨4-(4-methyl-2,5-dione-imidazolidin-4-ylmethanesulfonyl)-six Hydrogen pyridin-1-yl]-pyridin-3-yl)-benzamide f LC-MS (APCI) m/z 455 (MH+). Example 14 Compounds 0, R2

, S Ο 合成 was synthesized according to the method described in Example 12. Ο -149 This paper scale is applicable to China National Standard (CNS) Α4 specification (210 X 297 mm) 1329637 A7 B7 V. Invention description (146) R R2 analysis rr°Y^ α&gt;^Ν 1Ν m/z 543 (ΜΗ +)(1) κκ&gt; m/z 562 (ΜΗ+)α) m/z511(MH+)(1) m/z 523 (MH+)(1) m/z 443 (MH+)(1) 蟋

Packing (1): NMR can be obtained, see the experimental section. Order

线5-ί(丨4-丨(5-aphthylpyridin-2-yl)oxyindole hexafluoride small } sulfonyl)methyl b 5-f (3,4,4-trimethyl- 2,5-Diketopylimidazolidin-1yl)methylimidazolyl-2,4-dione The title compound was purified from the racemic {2,5-dione group as described in Example 12. 4-[(3,4,4-trimethyl-2,5-dioneimidazolidin-1-yl)methyl]imidazolyl-4-yl}methine Si; with 5-carbon group- 2-(hexahydro, than bit -4-yloxy)-» is made by bite.礞LC-MS (APCI) m/z 543 (MH+). 1 H NMR (DMSO-d6): 1.28 (6H, s): 1.63-1.74 (2H, m): 1.95-2.05 (2H, m): 2.77 (3H, s) : 3.14 (4H, d) ; 3.53-3.73 (3H, m) : 4.14 (1H, q) : 5.04-5.11 (lH,m): 6.85 (lH,d): 7.80 (1H, dd : 7.94 (lH, s): 8.19(1H, d): 10.83 (1H, s). The starting materials are made as follows: -150- This paper is used in the standard of the country (CNS) A4 size (210X 297 public property) 1329637

Twist #thio-)-2-oxo-supplemented methylimidazolidine-2.4-dione oxime thiol (256 μl, 2.2 mmol) with cesium carbonate (712 mg, 2 2 mM) in two Methylformamide (5 ml) was stirred at room temperature for a few hours. Add 3-(3-bromo-2-oxopropylpyridinium)·trimethylimidazolium-2'4-dione (5W gram, 1.99 mmol) prepared according to W0 99/06361, and The mixture was stirred at room temperature for 18 hours. The reaction mixture was taken with EtOAc (EtOAc)EtOAc. The product was purified by silica gel chromatography eluting with 50 EtOAc / EtOAc. LC-MS (APCI) m/z 321 (MH+). 1 H NMR (CDC13): δ 1.45 (6 Η, s); 2.91 (3 Η, s) ; 3.16 (2H, s) ; 3.70 (2H, s); 4.53 (2H, s) '&gt; 7.22-7.33 (5H, m). H·(thiol)methyl]-5-f(3,4,4-trimethyl-2,5-dione The imidazolidinyl-1,4-methylidazolidin-2,4-dione title compound is 5-methyl-5-{[(phenylmethyl)thio]indolyl}imidazole according to Example 12. Made by the synthesis of pyridine-2,4-dione. LC-MS (APCI) m/z 391 (MH+). « 1 H NMR (DMSO-d6) : d 1.28 (6H, s) ; 2.64 and 2.76 (23⁄4 abq, J = 14.2 Hz): 2.78 (3H, s ; 3.54 &amp; 3.64 (2H, abq, J = 14.2 Hz); 3.73 (2H, s); 7.20-7.32 (5H, m); 7.98 (1H, s): 10.83 (1H, s). 2,5-diketyl-4-"(3,4,4-trimethyl-2,5-di; g with certain imidazolidinyl-bu)methyl 1 imidazolyl-4-yl}decanesulfonate The title compound was prepared as described in the synthesis of gasification [(4S) and (4R)-4-methyl-2,5-dione imidate-4-yl] formazan in Example 12. -151 This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) 1329637 A7 _____B7____ V. Invention description (148) lHNMR(CD3OD): J 1.38(6H, s): 2.89(3H, s) : 3.81 and 3.92 (2H, abq, J = 14.3 Hz); 4.61 (2H, s). The following compounds are based on 5-[({4-[(5-chloropyridin-2-yl)oxy]hexahydro) Pyridin-1-yl}sulfonyl)methyl]-5-[(3,4,4-trimethyl-2,5-dioneimidazolidin-1-yl)methyl]mitudin-2 , prepared as described in the synthesis of 4-di- 5-f((445-(trifluoromethyl)pyridin-2-ylindole hexahydropyrazine-1-ylsulfonyl)methyl b-5- f(3,4,4- Methyl-2,5-dione imidazolidin-1-yl)methyl]imidazolyl-2,4-dione LC-MS (APCI) m/z 562 (MH+). 1 H NMR (DMSO-d6 ) : d 1.26 (6H, s) ; 2.76 (3H, s) ; 3.16-3.22 (4H, m); 3.48-3.76 (8H, m) ; 7.02 (1H, d) ; 7.81-7.76 (2H, m) 8.43 (1H, s) : 10.83 (1H, s). 544-(4-Fluorophenyl-hexahydropyrazine-1-dimethylcarbazide-5-indole (3,4,4-trimethyl) -2,5-diketopylimidin-1-yl)methylimidazolyl-2,4-dione LC-MS (APCI) m/z 511 (MH+). 1 H NMR (DMSO-d6): ^ 1.28(6H, s); 2.77 (3Η, s); 3.10-3.16 (4Η, m); 3.21-3.26 (4HS m); 3.48-3.71 (4H, m); 6.95-7.09 (4H, m); 7.88 (1H, s); 10.84 (1H, bs). ; 5-i({4-丨(5-gas-based 〇 than bit-2-yl)oxy] hexahydro-p-precipitate-1 ., fluorenyl)methyl]-5-{2-丨(stylmethyl)decyl 1ethyl} miso-2,4-dione title compound by 5-[({4-[( 5-chloropyridin-2-yl)oxy]hexahydropyridin-1-yl}sulfonyl)methyl]-5-[(3,4,4-trimethyl-2,5-trione) 5-imido-2-(hexahydropyridin-4-yloxy)-pyridinium as described in the synthesis of imidazolidin-1-yl)methyl]imidazolyl-2,4-dione Salts with gasification (2,5-diketo-4- {2 - [(phenylmethyl) oxy] ethyl} imidazol-4-yl) methanesulfonamide Prepared starting XI. ____-152-___ This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1329637 A7 B7 V. Description of invention (149) LC-MS (APCI) m/z 523 (MH+). ' HNMR (DMSO-d6): ί 1.37-1.79 (3Η, m) ; 1.83-2.08 (4H, m) ; 3.00-3.56 (7H, m is partially obscured by D20); 4.33-4_44(2H,m); 5.01 -5.12(lH,m) ; 6.85 (lH,d); 7.21-7.36 (5H, m) ; 7.80(lH,dd); 8.02 (lH,s); 8.19 (lH,d): 10.70 (1H, bs 6-({4-丨(5-aphthyridin-2-yl)oxy-1hexahydropyridin-1-ylindolesulfonyl)-i,3-diindole 丨4.51癸虎-2, 4-Dione LC-MS. (APCI) m/z 443 (MH+). Starting material 桉 制成: 6-Γ(phenylmethyl)thio 1-1,3-diazaspiro 4.51 decane-2,4-dione was dissolved in 70 ml of THF by hydrazine thiol (937 mg, 7.5 mmol). NaH (362 mg, 60%, 9.0 mmol) was added and the slurry was stirred for a few minutes. 2-Vycyclocyclohexanone (1-0 g, 7.5 mmol) was added and the reaction was stirred at room temperature overnight. The solid was filtered and the solvent was removed by rotary evaporation. Potassium cyanide (4 equivalents), (NH4) 2C03 (8 equivalents) and 25 ml of ethanol were added. The reaction was stirred in a sealed vial at 80 °C overnight. The suspension was filtered and the title compound was crystallised from white crystals LC-MS (APCI) m/z 291 (MH+). 1HNMR (DMSO-d6): δ 1.2 Μ.81 (8 Η, m): 2.79 (1H, dd); 3.67-3.76 (2H, m); 7.18- 7.32 (5H, m): 8.43 (lH, s); 10.68 (1H, s). Example 15

-----U ___- 153- The paper size is the common Chinese national standard (CNS) A4 specification (21〇X297 mm) 1329637 A7 _____B7 _5, invention description (150) 3-methyl-5-α彳茇 茇 -4- 醯 ) ) · 夂呔 夂呔 夂呔 夂呔 夂呔 夂呔 夂呔 夂呔 夂呔 夂呔 夂呔 夂呔 夂呔 夂呔 夂呔 夂呔 夂呔 夂呔 夂呔 夂呔 夂呔 夂呔 夂呔 夂呔 夂呔 夂呔 夂呔 夂呔 夂呔 夂呔 1- 1- 1- 1- 1- · 〇 gram, 〇 · 38 millimoles), potassium cyanide (0.049 grams, 0.75 millimoles), ammonium carbonate (0.18 grams, 1.9 millimoles), 50% ethanol in water (1_6 ml), sealed In a tube (2 ml volume), stir at 90 C for 70 hours. "This solution was taken at 1 Torr. /. Acetic acid, acidified to ρ Η 6, and concentrated by condensation to one half of its original volume, at which point a portion of the product is produced. This solution and its solid content were dissolved in ethyl acetate, and the aqueous phase was separated and washed twice with acetic acid. The combined organic phases were washed with brine <RTI ID=0.0>: </RTI> dried <RTI ID=0.0> The crude product was dissolved in MeOH (5 mL). EtOAc (EtOAc) Dissolve in ethyl acetate/n-heptane (1:2 and 2:1) to give the title product as a colorless needle. LC-MS (APCI) m/z 337 (MH+). 1 H NMR (DMSO-d6) : ί 0.96-1.10 (1H, m) : 1.32-1.44 (1H, m) : 1.36 (3H, s) ; 1.47 -1.58 (2H, m) : 2.10-2.30 (4H, m) : 2.40 (3H, s) : 7.41 (2H, d, J= 8 Hz); 7.72 (2H, d, J=8 Hz) : 7.80 ( 1H, bs) J5L 10.7 (1H, bs): 13 C NMR (DMSO-d6) : δ 21.0, 22.60, 22.64, 26.1, 26.3, 30.8, 31.5, 64.1, 78.9, 129.2, 130.3, 135.3, 144.2, 156.0 and 176.2· The starting materials are prepared as follows: 1-(methyl 4-sulfonyl)-propan-2-one according to Crandall et al., J. Org Chem. 1985, (8) 50, 1327-1329 , self-aligned sodium toluenesulfinate dihydrate (4.2 g, 18 mmol), acetone (1.0 ml, 12 mmol), n-tetrabutylammonium bromide (0.30 g) and water-benzene -Acetone 4 : 3_-154-___ This paper wave scale uses Chinese National Standard (CNS) A4 specification &lt;210 X 297 public)

Binding

k 1329637 A7 _ B7 ____ V. Invention description (151): 3 (10 ml). The crude product was treated with ethyl acetate / hexanes /hexanes (1.sup.3 to 1:2) as eluting solvent to afford 2.4 g (95 °. It crystallizes when it is placed in a refrigerator. LC-MS (APCI) m/z 213 (MH+). 1 H NMR (CDC13) : δ 2.38 (3 Η, s) ; 2.42 (3H, s) ; 4.10 (2H, s) ; 7.35 (d2H, d, J =8 Hz); 7.74 (d2H, d, J=8 Hz). 13CNMR(CDC13): β 21.7, 31.4, 67.7, 128.0, 129.8, 135.5, 145.3 and 195.9. 1-(1-(Toluene-4) Si-based)-cyclopentyl))-ethyl m 1-(Tolyl-4-sulfonyl)-propan-2-one (0.10 g, 0.47 mmol), 1,4-dimobutidine ( 0.068 ml, 0.52 mmol, finely ground potassium carbonate (0.14 g, 1_0 mmol) and anhydrous dimethylhydrazine (0.80 ml) were stirred at 50 ° C (oil bath temperature) for 22 hours. The heating was turned off and stirring was continued for 22 hours at 22 °C. The crude product was dissolved in ethyl acetate. EtOAc (EtOAc m. The oily residue was purified by chromatography eluting eluting eluting eluting eluting eluting LC-MS (APCI) m/z 266 (MH+). 1 H NMR (CDCI3): </ RTI> </ RTI> <RTIgt; 2.42 (3H, s): 2.48 (3H, s); 7.30 (2H, d, J = 8 Hz) and 7.60 (2H, d, J = 8 Hz). , 1 3 C NMR (CDCI3) · ό 21.7, 25.4, 28.0, 31.3, 83.9, 129.4, 129.5, 133.2, 145.0 and 202.5. _.-155- This paper scale applies to the national standard (CNS) A4 specification (210 x 297 public) 1329637 '. This application date

hJT Case No. A4 C4 Category U4 cp^yt Manual replacement page (93 years i〇 month) (The above columns are filled by this Bureau) Invention t{G\, s name invention III, applicant's patent specification novel metalloproteinase Inhibitor and pharmaceutical composition thereof

Chinese English

NOVEL METALLOPROTEINASE INHIBITORS AND PHARMACEUTICAL COMPOSITIONS THEREOF Name Nationality residence, residence name (name) Nationality residence, residence (office) Representative name 1. Anders Ilikson 2. Madi Le Pisto 3. McLurd Fes special

ANDERS ERIKSSON MATTI LEPISTO MICHAEL LUNDKVIST

1. Sweden SWEDEN 2. Sweden SWEDEN 3. Sweden SWEDEN 1. Sweden's Ruth S-22187 ASTRAZENECA R&amp;D LUND S-221 87 LUND, SWEDEN 2. Ruth, Sweden S-22187 ASTRAZENECA R&amp;D LUND S-221 87 LUND, SWEDEN 3. S-22187 ASTRAZENECA R&amp;D LUND S-221 87 LUND, SWEDEN Binding

Swedish company AstraZeneca AB ASTRAZENECA AB Sweden SWEDEN Sweden Sudeto S-15185 S-151 85 SODERTALJE, SWEDEN Joanne Margaret JOANNE MARGARET MARSHALL Paper scales in the middle ® S standard (CNS) A4 Specifications (plus x 297 public) line

Claims (1)

1329637 A B c D 2 14 Patent Application No. 091104934 Chinese Patent Application Substitution (April, 1999) Patent Application Announcement—Ten---&quot; A compound of formula I or a pharmaceutically acceptable salt thereof or an in vivo hydrolysable ester, R5——A wherein X is NR1; Y1 and Y2 are independently selected from Ο and S; Z is selected from SO and S02; m is 1; A is selected from direct bonding, (C1-6) alkyl, and a (C1-6)heteroalkyl group selected from a hetero group of N, hydrazine or S; R1 is selected from the group consisting of hydrazine and (C1-3) alkyl; R2 and R3 are independently selected from hydrazine, (C1-6) Alkyl, heterocycloalkyl, phenyl, heteroaryl, phenyl-alkyl, phenyl-heteroalkyl, heteroaryl-alkyl, and heterocycloalkyl-alkyl; R4 system; each R2 And the R3 group may be optionally substituted by one or more groups, the substituent being selected from the group consisting of alkyl, halo, haloalkyl, (C1-C6) alkoxy, amine, fluorenyl-alkylamine, hydrazine, Ν-Dialkylamino 'amine', Ν-alkyl guanamine, gas base and alkyl sulfhydryl amine; This paper scale applies to China National Standard (CNS) A4 specification (2l 〇 x 297 mm) 1329637 A8 B8 C8 D8 6. The patent application R2 and R3 may be joined to form a ring containing up to 7 ring atoms, or R3 and R4 may be joined to form a ring containing up to 7 ring atoms; 'R5 is a single ring, double a cyclic or tricyclic group comprising _, _ or three ring structures each having up to 7 ring atoms independently selected from ((:3·7)cycloalkyl, phenyl, heterocycloalkyl or a heteroaryl group, wherein each ring structure is independently substituted with one or more substituents, the substituents being independently selected from the group consisting of dentin, hydroxyl, alkyl, alkoxy, haloalkoxy, acetamido, an aryl group, And an alkylsulfonyl group, wherein any of the substituents in any of the substituents may be optionally substituted with one or more groups selected from the group consisting of s, thio, and alkoxy; when R5 is bicyclic or In the case of a tricyclic group, each ring structure is bonded by direct bonding, borrowing - Ο-, borrowing (C1-6) alkyl, borrowing (C1-6) heteroalkyl, borrowing (C1_6) alkenyl, borrowing (C1) -6) alkynyl, by means of 'by CO' by NCO, by CON, by NH, by S to join to the next ring structure, or by condensing to the next ring structure; The alkyl group is a (C1-6) alkyl group; the heterocyclic group is a feeding, a bite, a triterpene, a P bite, a sputum, a scorpion, a leaf oxazole, an isoindole. And heterocycloalkyl are hexahydropyridine, morpholine, hexahydropyrrolidine, pyrrolidine, 3,4 · de-IL ° bottom bite, tetrahydrofuran, tetrahydropyran, tetrahydropyrene, and oxime Lynch or imidazolium-2,4-dione ring 2. The compound of formula I according to claim 1 or its pharmaceutically acceptable paper scale applies to the Chinese National Standard (CNS) A4 specification (210X 297 1329637 ABCD 6. A salt or in vivo hydrolysable ester of a patent application, wherein Y1 and γ2 are each 〇. 3. A compound of formula j or a pharmaceutically acceptable salt or living body thereof according to the scope of claim 2 or 3. Hydrolyzable ester, wherein the phantom is 11, ((: 1_6) alkyl, amino (C1-6) alkyl, phenyl (C1_6) alkyl, heterocycloalkyl-alkyl or heteroaryl-alkane 4. A compound according to the formula or the formula 2, or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, wherein the indole or methyl group and R4 are hydrazine. Or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, wherein the milk comprises one, two or three optionally substituted phenyl or heteroaryl 5 or 6 membered rings. The formula compound, or a pharmaceutically acceptable salt thereof, or an in vivo hydrolyzable vinegar according to any one of the preceding claims, wherein R5 is a tricyclic or tricyclic group, comprising two or three as appropriate Substituted ring structure. 7. - a compound of formula II or a pharmaceutically acceptable salt thereof or a hydrolyzable vinegar in vivo Wherein each of Gi, G2 and G4 is a single cyclic structure each containing up to 7 ring atoms 'independently selected from (C3·7) ring-based, phenyl, heterocycloalkyl or heteroaryl, wherein each ring structure Independent her brother is taken by one or two substituents -3- 1329637 A8 B8 C8 D8 VI. The patent application Fan Yuandai 'substituent is independently selected from halogen, hydroxyl, halogen (C1-6) alkoxy, acetamide, A cyano group, a (C1-6)alkyl group, a (C1-6) alkoxy group, and an alkylsulfonyl group, wherein any alkyl group of t in any of the substituents may be optionally substituted by one or more groups. The group is selected from the group consisting of halogen, hydroxy and (C1_6) oxime oxy; Z is so2; each B and F is independently selected from the group consisting of direct bonding, hydrazine, (C1_6) alkyl, (C1_6) heteroalkyl, (C1-6) Alkynyl, CO, NCO, CON, NH and S; R2 is selected from the group consisting of hydrazine, (C1-6) alkyl, alkoxyalkyl, aminoalkyl, (Ν-alkylamino)alkyl, (Ν) , Ν-dialkylamino)alkyl, decylamino, phenyl (C1-6) alkyl, heterocycloalkyl-alkyl and heteroaryl yl; R3 is hydrazine or (C1-3 ) alkyl and R 4 are Η; R2 and R3 may optionally be joined to form a ring containing up to 7 The sub-ring 'or R3 and R4 may be joined to form a ring containing a high 7 ring atoms. 8. A compound of formula η according to claim 7 or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, wherein R2 is (ci-6)alkyl, aminoalkyl, heterocycloalkyl- Alkyl or heteroaryl-alkyl. 9. A compound of the formula Ila or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof -4- The paper scale itffi China National Standard (CNS) ΜSpecifications (21()x 297 DON) - 1329637 A Be D VI. Applying for the patent garden, each of G1 and G2 contains up to 7 ring atoms. The monocyclic ring structure 'is independently selected from (C3-7)cycloalkyl, phenyl, heterocycloalkyl or heteroaryl' wherein each ring structure is independently substituted with one or two substituents, the substituents being independently selected from Halogen, hydroxy, halo-(Cl_6)alkoxy, ethyl acetamido, cyano, (C1-6)alkyl, (C1-6) alkoxy and alkyl </ RTI> </ RTI> in any of the substituents Any alkyl group may be optionally substituted by one or more groups. The substituent is selected from the group consisting of halogen, hydroxy and (C1_6) alkoxy; Z is so2; B is selected from direct bonding, hydrazine, (C1_6) alkyl (C1_6)heteroalkyl, CO, NCO, CON, NH, s and (C1-6) alkynyl; R2 is selected from the group consisting of hydrazine, (C1-6) alkyl, alkoxyalkyl, aminoalkyl, (N_Acetylamino)alkyl, (N,N-dialkylamino)alkyl and decylalkyl, or R2 is a group of formula III C and D are independently selected from direct bond, H, (C1_C6) alkyl or (C1_C6) heteroalkyl; G3 is a monocyclic ring structure containing up to 7 ring atoms, independently selected from phenyl, heterocyclic The base and heteroaryl group 'optionally substituted with one or two substituents' are independently selected from halogen, amine carbonyl and (C1_6) alkyl; -5- This paper scale applies to the Chinese National Standard (CNS) A4 specification ( 210 X 297 藿) 1329637 A8 B8 C8 D8 Patent application scope R3 is Η or (C1-3) alkyl and R4 is Η; R2 and R3 may be joined to form a ring containing up to 7 ring atoms, or R3 It can be joined to R4 to form a ring containing up to 7 ring atoms. A compound of the formula Ila according to claim 9 or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, wherein the B group is selected from the group consisting of a direct bond, a hydrazine, a C0, an S, and a (C1-6) alkynyl group. The compound of the formula IIa, or a pharmaceutically acceptable salt thereof or an in vivo hydrolysable ester thereof, according to any one of claims 9 or 5, wherein the one is selected from the group consisting of hydrazine, (C1-6) alkyl, phenyl _ (C1_6) alkyl and heteroaryl·(α_6) alkyl. The compound of formula na, or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, according to any one of claims 9 or 1 wherein each of the phantoms and R4 is hydrazine. H a compound of formula lib or a pharmaceutically acceptable salt thereof or a hydrolyzable ester in vivo Hb wherein G1 is a monocyclic ring structure each containing up to 7 ring atoms independently selected from (C3-7)cycloalkyl, phenyl, heterocycloalkyl or heteroaryl, wherein each coat is independent of the case Substituted by one or two substituents, the substituents are independently selected from the group consisting of halogen, hydroxy, halo(C1-6)alkoxy, acetamido-cyano 1329637 A8 B8 C8 D8 6. Patent application base, (C1-6) alkyl, (C1-6) alkoxy and alkylsulfonyl, wherein any alkyl in any substituent may itself be Or a plurality of groups substituted, the substituent is selected from the group consisting of halogen, hydroxy, and (C1-6) alkoxy; G2 is optionally substituted with hexa-argon 1» than bite or hexahydrop; B is selected from direct Bonding, 0, (C1-6) alkyl, (C1-6) heteroalkyl, CO, NCO, CON, NH, S and (C1-6) alkynyl; R2 is selected from hydrazine, (C1-6 An alkyl group, an alkoxyalkyl group, an aminoalkyl group, an (N-alkylamino)alkyl group, an anthracene, a fluorenyl-dialkylamino group and a decylamino group, or R2 is a group of the formula III The C and D groups are independently selected from the group consisting of a direct bond, H, (C1_C6) alkyl and (C1C6) heteroalkyl; G3 is a monocyclic ring structure containing up to 7 ring atoms, independently selected from phenyl, heterocycloalkane And heteroaryl, optionally substituted by one or two substituents, independently selected from halo, amine carbonyl and (C16)alkyl; R3 is deuterium or (C1-3)alkyl and R4 is deuterium; R2 R3 can be joined to form a ring containing up to 7 ring atoms, or R3 and R4 can be joined to form a ring containing up to 7 ring atoms. 14_ A medicine for treating diseases or symptoms of metalloproteinases, which contains a compound of formula 1 according to the scope of the patent application or according to the Chinese National Standard (CNS) Α4 specification (210X 297 public) according to the paper ruler j ) --- ^29637 Patent application scope patent range § § compound of formula 7 or according to the scope of application patent = formula, or according to the scope of claim 13 of the patent application &amp; or its pharmaceutically acceptable Accepted salts or in vivo hydrolyzable esters, and a musically acceptable carrier. 15—A compound of the formula I or II or a Ha or lib compound or a pharmaceutically acceptable compound thereof as shown in U.S. Patent Application Serial No. 1, + ττ Spear 7 9 or U, or a pharmaceutically acceptable salt or in vivo The use of a water-soluble precursor for the preparation of a disease or condition for the treatment of one or more metalloproteinases. 16 a compound of formula j or a pharmaceutically acceptable salt thereof or a hydrolyzable in vivo according to the scope of claim patent, which is (5S)_5_[4_(5•chloro-pyridine-2-yloxy)-hexa Hydropyridine-indolesulfonylhydrazin-5methyl-imidazolidinyl-2,4-di-class or a pharmaceutically acceptable salt thereof. -8- This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm)