TW580491B - Aryl-S(O)n-substituted hydroxamic acids, and their preparation and use - Google Patents

Abstract

Compounds of the formula, wherein: n is 0, 1 or 2; Y is hydroxy or XONH-, where X is hydrogen or lower alkyl; R1 is hydrogen or lower alkyl; R2 is hydrogen, lower alkyl, heteroalkyl, aryl, aralkyl, arylheteroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heteroarylheteroalkyl, heterocyclo, heterocylo-lower alkyl, heterocyclo-lower heteroalkyl or -NR6R7, wherein: R6 is hydrogen, lower alkyl, cycloalkyl or cycloalkylalkyl, aryl, heteroaryl and heteroaralkyl; R7 is hydrogen, lower alkyl, cycloalkyl or cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -C(O)R8, -C(O)NR8R9, -SO2NR8R9, -SO2R10, aryloxycarbonyl, or alkoxycarbonyl; or R6 and R7 together with the nitrogen atom to which they are attached represent a heterocyclo group; wherein R8 and R9 are independently hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl or heteroalkyl; and R10 is lower alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heteroalkyl or heterocyclo; or R1 and R2 together with the carbon atom to which they are attached represent a cycloalkyl or heterocyclo group; R3 is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heteroalkyl or lower alkoxy; R4 is hydrogen, lower alkyl, cycloalkyl or cycloalkylalkyl; or R2 and R3 together with the carbons to which they are attached represent a cycloalkyl or heterocyclo group; or R3 and R4 together with the carbon to which they are attached represent a cycloalkyl or heterocyclo group; and R5 is lower alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or pharmaceutically acceptable salts or esters thereof exhibit useful pharmacological properties, in particular for use as matrix metalloprotease inhibitors, particularly for interstitial collagenases.

Description

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 580491 A7 —-_ β 7 V. Description of the Invention (1) —— ~ This invention is about formulas; [of the compounds, and their pharmaceutically acceptable salts or esters It inhibits matrix metalloproteinases, especially interstitial collagenases, and can therefore be used to treat mammals suffering from diseases. By inhibiting such matrix metalloproteinases, the disease state is slowed down. Kibes proteases ("MMPs") are a family of proteases (enzymes) that are involved in the degradation and modification of connective tissue. A member of the endonuclease family exists in various cell types belonging to or associated with connective tissues, such as fibroblasts, monocytes, macrophages, endothelial cells, and invasive or metastatic tumor cells. By the growth factors and cytokinins in the local tissue environment to stimulate the performance of M MP, these enzymes work there, specifically degrading the protein components of the extracellular matrix, such as collagen, proteoglycan (protein core), fiber Reticulin and Kunbunic Acid. These ubiquitous extracellular basal negative components' appear on the inner surface of joints, interstitial connective tissue, basement membrane and right month. The excessive degradation of extracellular matrix caused by MMPs is involved in the pathogenesis of many diseases, including rheumatoid arthritis, osteoarthritis, multiple sclerosis, chronic obstructive pulmonary disease, stroke-related cerebral hemorrhage, periodontal Complications of membrane disease, labyrinthic angiogenesis, tumor invasion and metastasis, corneal ulcers and diabetes. Therefore, it is believed that the inhibitory effect of M μP can be an excellent target for therapeutic intervention. MMPs share many characteristics, including zinc and calcium dependence, enzyme-like secretion, and homology of 40-50% amino acid sequences. Currently the MMP family consists of at least 11 enzymes, and includes collagenase, stromelysin, gelatinase, matrilysin, metal elastase, and membrane-type M MP, as described below Discuss in more detail _____ 4 _ This paper size is suitable for financial and family care standards (CNS) Α4 size (21 () χ297 male sauce) (Please read the precautions on the back before filling this page)

580491 V. Description of the invention (: printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. Interstitial collagenase catalyzes the initiation and rate-limiting incision of natural collagen 胶原, n * In type. Collagen, mammals The main structural protein is the essential components of the matrix of midnight tissues, such as cartilage, bone, tendons, and skin. Interstitial collagenase is a very special matrix metalloproteinase. It cuts collagen to get two fragments. It naturally degenerates at physiological temperature, and therefore becomes easily cut by less specific enzymes. Digestion by collagenase causes the target tissue to lose its structural integrity, which is essentially an irreversible process. There are currently three known humans Collagenase. The first is human fibroblast-type collagenase (HFC, MMP- and collagenase), which is produced by various cells including fibroblasts and macrophages. The second is human Neutrophil-type collagenase (HNC, MMP_8 or collagenase_ 2) 'So far it has only been confirmed that it is produced by neutrophils. The MMPs family was recently revealed The member of the line, human collagenase-3 (熥 1 ^ [1 > _13), was originally found in breast cancer, but has been shown to be produced by chondrocytes. It is known // present in table teeth The collagenase in is a homologue of human collagenase 3. Gelatinase includes two different but highly related enzymes: the 72-kD enzyme (Gelatinase A, HFG, M) secreted by fibroblasts and various other cell types MP-2) 'and 92-kD enzymes (gelatinase B, HNG, MMP-9) released by monocytes, neutrophils, keratinocytes, tumor cells, trophoblast cells and keratinocytes ). It has been shown that these gelatinases can degrade gelatin (denatured collagen), collagen 1 ¥ type (basement membrane) and V type, fibronectin and insoluble elastin. -5- This paper size applies to Chinese national standards (CNS) A4 size (210 X 297 mm) (Please read the precautions on the back before filling in this page) t Γ- 580491 A7

Please read the memorandum before writing this page t

580491 A7 B7 V. Effect of the invention (4), bleeding, coagulation and acute phase reaction, cachexia and loss of appetite, acute infection, shock state, restenosis after surgery, aneurysm disease, response to transplantation to the host and Autoimmune response. In addition to its effect on the release of TNF from cells, MMP inhibitors have also been shown to inhibit the release of other biologically active molecules from cells, including soluble receptors (CD30 and TNF (pages 55 and 75), iL -6, IL-1 and TSH receptors), adhesion molecules (such as l-selection, [Cam_1, fibronectin), and other growth factors and cytokinins, including Fas ligand, TGF · Han, EGF , HB-EGF, SCF, and M-CSF. Inhibition of the release or shedding of such proteins may be beneficial for various disease states' including rheumatoid arthritis, multiple sclerosis, vascular disease, type 11 diabetes, ΗIV, cachexia, psoriasis, allergies, hepatitis, Inflammatory bowel disease and cancer. Because the non-specific inhibitory effect of shedding enzymes (sheddases) may have opposite pharmaceutical effects, the selectivity will be particularly advantageous. For example, the inhibitory effect of TNF release is not the same as the inhibitory effect of TNF receptor release. simultaneously exist. The design and use of MMP inhibitors are described, for example in j. Enzyme Inhibition 9 2 9 1-22 (1987); Drug News & Prospectives 9 3 (8), 453-458 (1990); Arthritis and Rheumatism, 36 ( 2), 181-189 (1993); Arthritis and Rheumatism, 34 (9), 1073-1075 (1991); Seminars in Arthritis and Rheumatism, 19 (4), Appendix 1 (February), 16-20 (1990) Drugs of the Future, 15 (5), 495-508 (1990); and J. Enzyme Inhibition, 2, 1-22 This paper is sized to the Chinese National Standard (CNS) A4 (210X 297 mm) (please first (Read the notes on the back and fill in this page)

1T Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 580491 A7 —_____ ^ _ B7___ V. Description of Invention (5) (1987). MMP inhibitors are also the subject of various patents and patent applications, for example, U.S. Patent Nos. 5,189,178 and 5,183,900, European Published Patent Applications Nos. 438 223, 606 426, and 276 436, as well as publications International applications for patent cooperation clauses WO 92/21360, WO 92/06966-VWO 92/09563 and WO 94/25434. One aspect of this issue is about compounds represented by formula Ϊ: p1 r2: WR5. O R3 R4 where n is 0, 1 or 2; Υ is hydroxy or XONY-, where X is hydrogen or lower alkyl; R1 is hydrogen or lower alkyl; R2 is hydrogen, lower alkyl, heteroaryl, aryl, aralkyl, arylheteroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, hetero Aralkyl, heteroarylheteroalkyl, heterocyclic, heterocyclic-lower alkyl, heterocyclic-lower alkyl, or -NR6R7, where R6 is hydrogen, lower alkyl, cycloalkyl, or Cycloalkylalkyl, aryl, heteroaryl, and heteroaralkyl; R7 is hydrogen, lower alkyl, cycloalkane, or cycloalkylalkyl, aryl, aryl, heteroaryl, heteroaryl Alkyl, _C (〇) R8, -c (〇) nr8r9, -S02NR8R9, -S02R1 (), aryloxycarbonyl or oxoyl; or

I -8- & Zhang scale is applicable to Chinese National Standard (CNS) M specification (21 () > < 297 public director) " ^ '(Please read the precautions on the back before filling this page). # 衣. Revision 580491 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 __ V. Description of the Invention (6) R6 and R7 are attached together with a nitrogen atom to represent a heterocyclic group; where R8 and R9 are hydrogen, low Carboalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heteroalkyl; and R 1 G is lower alkyl, cycloalkyl, or cycloalkane Alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heteroalkyl, or heterocyclic ring; or R1 and R2 are attached together by carbon atom, representing a cycloalkyl or heterocyclic group ; R3 is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heteroalkyl, or lower alkoxy; R4 is hydrogen, Lower alkyl, cycloalkyl, or cycloalkylalkyl; or attaching R2 and R3 together as a carbon atom to represent a cycloalkyl or heterocyclic group; or attaching R3 and R4 as a stone counter atom Linked together to represent a cycloalkyl or heterocyclic ring And R5 is a lower alkyl group, a cycloalkyl group, a cycloalkylalkyl group, an aryl group, an aralkyl group, a heteroaryl group, or a heteroaryl group; or a pharmaceutically acceptable salt or ester thereof. • A second aspect of the present invention relates to a pharmaceutical composition containing a compound of formula I having a therapeutic efficacy I content, or a pharmaceutically acceptable salt or ester thereof, mixed with at least one pharmaceutically acceptable excipient. A third aspect of the present invention relates to a method for suffering from a mammal whose disease state can be alleviated by inhibiting matrix metalloproteinases, by administering to the mammal an effective amount of a compound of formula, or a pharmaceutical combination thereof Thing. Such diseases include joint disease, multiple sclerosis, bone reabsorption diseases (such as osteoporosis), diabetes-related collagen destruction promotion, more obstructive pulmonary disease, deficiency, and appetite. / 、 A form of cardio-cerebral hemorrhage and periodontal membrane disease. The paper size is applicable to Chinese national standard PcNS) A4 specification (--- Γ-: ------- (Please read the precautions on the back before filling in this Page), π 580491 A7 B7 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (7 Disease, corneal or gastric ulcer, skin ulcer and tumor metastasis. The fourth aspect of the present invention relates to the preparation of compounds of formula I In the family of compounds of the present invention as described above, a particular family of compounds of formula I includes η is 0, 1 or 2; Y is hydroxyl or XONH ·, where X is hydrogen or lower alkyl; R 1 is Hydrogen or a lower alkyl group; r 2 is hydrogen, a lower alkyl group, an aralkyl group, a cycloalkyl group, a cycloalkylalkyl group, a heterocyclic ring, or -NR6R7; or R1 and R2 are attached together by a carbon atom, Represents a cycloalkyl or heterocyclic group; wherein R6 is hydrogen, lower alkyl or phenyl; R7 is hydrogen, lower alkyl, benzyl, C (0) R8, -C (0) NR8R9, -so2nr8r9, -so2r10, benzyloxycarbonyl or alkoxycarbonyl, or the nitrogen atom is {{/ Attach together with H7, which represents a heterocyclic group; where R8 and R9 are hydrogen or lower alkyl, respectively; and Rio is low-carbon alkyl, aryl, heteroaryl, or heterocyclic; R3 is hydrogen, low Carboalkyl, cyclopentyl, cycloalkylalkyl, aralkyl, heteroaryl, or lower alkoxy; R4 is hydrogen or lower alkyl; or R2 and R3 are attached together by carbon atom , Represents a cycloalkyl or heterocyclic group; or R3 and R4 are attached together by a carbon atom, represents a cyclofluorenyl or heterocyclic group; and R5 is a lower alkyl, aryl, aralkyl, Heteroaryl or heteroaralkyl. Among these families, the preferred classes include compounds where η is 2 and Y is -NHOH. Among these classes, the preferred group includes those in which hydrogen is hydrogen and R5 is aryl. Compounds. Preferred subgroups in this group include those in which R2 is hydrogen and R3 is aryl ', especially benzyl, and R4 is hydrogen and R5 is optionally substituted phenyl or naphthyl compounds. Especially among them R5 It is a 4-methoxyphenyl, phenylthiophenyl, phenoxyphenyl, or diphenyl compound. 10- The paper size is applicable to the Chinese National Standard (CNS) A4 specification (21〇 > < 297mm) n -ΓΙ n LI II n III (Please read the notes on the back before filling this page) Order 580491 Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (8) Other better ones in this group Subgroups, including compounds in which R3 and R4 are attached together with carbon atoms to form a cycloalkyl group, especially cyclopentyl and cyclohexyl, and more particularly where R5 is 4-methoxyphenyl or 4-benzene Combination of oxyphenyl. Another preferred subgroup in this group includes compounds in which R3 and R4 are attached together with carbon atoms to form a heterocyclic group, especially substituted hexahydropyridyl or tetrahydropiperanyl, if necessary , Especially hexahydropyridin-4 · yl, 1-methyl cryptic outer 1: yodo-4 · yl, 1- (cyclopropylmethyl) hexahydrop is more than yodo-4-yl or tetrahydropiperanyl In particular, R5 is 4-phenoxyphenyl, 4- (4-phenoxy) phenyl, 4- (bromophenoxy) phenyl or 4- (4-fluorophenoxy) phenyl combination. Other preferred groups in this category include compounds where R2 is -NR6R7, R1, R3 and R4 are hydrogen and R5 is aryl. In this group, preferred subgroups include compounds in which R5 is 4-phenoxyphenyl, 4- (chlorophenoxy) phenyl or 4- (4-fluorophenoxy) phenyl, especially among them R6 is hydrogen and H7 is CBZ-valineamine, valineamine, or dimethylaminosulfamonium. In this category, another preferred group includes compounds in which R 1 and R 2 are attached together with a carbon atom to form a heterocyclic group. Among this group, the preferred subgroups include compounds in which R3 and R4 are hydrogen and R1 and R2 are attached together by a carbon atom to form a heterocyclic group, especially substituted ryumate, if necessary. Or tetrahydropyranyl, especially hexahydrop-pyridin-4-yl, 1-methylhexahydropyridine · 4-yl, 1_ (cyclopropylmethyl) hexahydropyridin-4-yl, or most Tetrahydropiperanyl is preferred, with R5 being 4-phenoxyphenyl, 4- (4-chlorophenoxy) phenyl, 4- (bromophenoxy) phenyl, 4- (4 -Fluorophenoxy) phenyl, ______ -11- This paper size applies Chinese National Standard (CNS) A4 (210 X 297 mm) (Please read the precautions on the back before filling this page) Order 580491 Central Ministry of Economic Affairs A7 _______B7 printed by the Bureau of Consumer Standards of the Bureau of Standards (9 butyl ~ ~~ —— 4-(thiothio-2 _yl) phenoxy) phenyl, 4-(thiothio_ 3 _yl) phenoxy) benzene , 4- (oxazol-2-yl) phenoxy) phenyl, 4- (2-pyridyloxy) phenyl, or 4 (5-chloro-2-pyridyloxy) phenyl. Other preferred groups in this category include compounds where Ri and R2 are both alkyl and R and R4 are hydrogen. A preferred subpopulation includes where & $ is 4-oxophenyl, 4- (4-phenoxy) phenyl, 4- (4-phenoxy) phenyl, or 4- (4- Fluorophenoxy) phenyl. In this category, other groups include compounds in which R2 and R3 are attached together with carbon atoms to form a cycloalkyl group, and R5 is an aryl group. Preferably, the cycloalkyl or cyclopentyl or cyclohexyl, and R5 is 4-phenoxyphenyl, 4-(; 4-bromophenoxy) phenyl, 4- (4-chlorophenoxy) Phenyl or 4- (4-fluorophenoxy) phenyl. The preferred compounds are: N-unityl-2- [4- (4-phenoxyphenylfluorenyl) -tetrahydroxan-4-yl] -acetamidine; 2_ {4- [4- (4 · chlorophenoxy) -benzoic acid group] · tetraazepine-4-yl} -1 ^ -light ethylacetamide; 2- {4- [4- (4-fluorophenoxy) -Benzyl group] -tetrazolidine-4-yl}-] \ 1-kisylacetamidinyl; N_lightyl- 2- [4- (4-phenoxyphenylidene) -hexa Hydroxypyridine_4_yl] -acetamidinium; 2- {4- [4- (4- (chlorochlorophenoxy) -benzenesulfonyl]]-hexahydropyridine-4. ; 2 · {4- [4- (4 • fluorophenoxy) -phenylphenanthryl] -hexahydropyridine_4 · kib N -hydroxy ____- 12- This paper size applies to Chinese National Standards (CNS) Α4 Specification (210 × 297 mm) (Please read the precautions on the back before filling out this page)-Order 580491 A7 B7 V. Description of the Invention (1Q) Aminoacetic acid; N-hydroxy- 2- [l-methyl- 4- (4-Phenoxybenzenesulfonyl) -hexahydropyridyl] -amine acetate; N-lightyl-2- {1_methyl_4- [4- (4-chlorophenoxy) phenylphenone []] &Quot; Hydroxypyridin-4_yl} -acetamidinium; N-Cycloyl-2 · {1 · methyl-4- [4- (4-fluorophenoxy) phenylfluorenyl ]-六六 外 刀 爪 · 4-Kibb Amidoamine; 2- [1-Cyclopropylmethyl- 4- (4-phenoxybenzenesulfonyl) -hexahydropyridine-4_ylb-N-hydroxyacetamide; 2- {1-cyclopropylmethyl 4--4- (4- (4-chlorophenoxy) benzenesulfonyl] hydropyridine ^ 4-ylb-N-hydroxyacetamidamine; 2- {1-cyclopropanyl-4_ [4- ( 4-fluorophenoxy) benzenesulfonyl hexahydropyridine hydroxyacetamidamine; N-hydroxy · 2 · [4 · (4-phenoxyphenylsulfinyl) -tetrahydrosulfan-yl] • Acetylamine; 2 .- [Phoenyl- [4- (4-chlorophenoxy) -benzenesulfenyl-1-tetrahydropyranyl-N-hydroxyacetamidine; .2- [f_ [4- ( 4-fluorophenoxy) _benzenesulfenyl] -tetrahydropiperanyl group N · Hydroxyacetamide; Ν-hydroxy-2_ [4- (4-phenoxyphenylthio) _tetrahydropipe 4-Amino-4-amine, 2 {4-[4-(4-chlorophenoxy) phenylthio] -tetrahydropiran_4-, 3-Niobutanamide; 2 — {4 -[4- (4-Fluorophenoxy) · phenylthio] -tetrahydrofuran_4-kibu N_! Group-13-This paper size applies to China National Standard (CNS) A4 (210X297 mm) (Please read the notes on the back before filling out this page)

、 1T printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 580491 A7 B7 --------------------- 5. Description of the Invention (11) Acetamide; (Please read the notes on the back first Fill out this page again) 4- [4- (4-chlorophenoxy) benzenesulfonylmethyl] -tetrahydrofuran-4_ ^, supercarboxamidine); 4_ [4 · (4 · Bromophenoxy Phenylbenzenesulfonyl] -tetrahydropiperan-4_ (N · hydroxycarboxamide); 4- [4- (4-fluorophenoxy) benzenesulfonylmethyl] -tetrahydropiperan_4 · (N · hydroxycarboxamidine); 3 · [4- (4 · chlorophenoxy) benzenesulfonylmethyl] -2,2-dimethyl 4-hydroxypropanamine; 4- [4 · ( 4-Gasphenoxy) benzenesulfonylmethyl] -1- (cyclopropylmethyl) hexahydropyridine-4-(N _ per slender amine); 4- [4 · (4_chlorophenoxy Phenylbenzenesulfonylmethyl] -1- (nicotinylfluorenyl) hexahydrohydrogenated _ 4 _ (N-Cetylfluorenamine); 4- [4- (phenoxy) benzenesulfonylmethyl] • Tetrahydropiperan- 4- (N -hydroxycarboxamidine); 4- [4- (4- (p-phenen-2-yl) -phenoxy) benzene continued to be methyl] -tetrahydroan _4_ (N-hydroxycarboxamidine); printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 4_ [4- (4- (thiophen-3-yl) -phenoxy) benzenesulfonylmethyl]- Hydropiperan-4 · (N-boryl bisammonium amine); 4- [4- (4- (furan-2-yl) -phenoxy) benzenesulfonyl tetrahydropiperan-4 · ( N-Hydroxyfluorenamine); 4- [4- (4- (Benzosulfuran-2-yl) -phenoxy) phenyl transverse methyl] -tetrahydroxanthene 4- (N_ meridyl Acanthamine); 4- [4- (4 · 〇Sejun-2-yl) -phenoxy) phenyl transverse sulfanyl] -tetrahydroan- 4- 4- ____- 14-_ This paper is suitable for wealth Guanjia County (CNS) A4 Specification (21Gx; 297 mm) '580491 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the Invention (12) (N-hydroxycarboxamide); 4- [4- (4- (pyrazol-4-yl) _phenoxy) benzenesulfonylmethyltetrahydrofuran-4_ (N-hydroxycarboxamidine); 4- [4- (4- (pyrazol-5 -Group > phenoxy) benzenesulfonylmethyltetrahydrofuran-4 · " (N · hydroxycarboxamide); 4- [4_ (4- (imidazol-1-yl) -phenoxy ) Benzenesulfonylmethyl] -tetrahydropyran_4- (N-hydroxycarboxamidine); 4- [4_ (4- (imidazole · 2-yl) · phenoxy) benzenesulfonylmethyl]- Tetrahydrofuran · 4- (N · Hydroxycarboxamide); 4- [4 · (5-Gas-2-pyridinyloxy) benzenesulfonylmethyl] -tetrahydrofuran_4_ (N -Roxy Chloramine); 3- [4_ ( 5 · Chloro-2 · Pyridyloxy) benzenesulfonyl] -2,2-dimethyl- >^-hydroxypropylammonium; (R) -2- (CBZ-valamine) · Hydroxy-3- (4-phenoxyphenyl-sulfonyl) propanilamine; (R) -N-hydroxy-2 -valaminesulfonyl-3-(4-phenoxyphenylbenzenesulfonyl) ) -Propanamide; (To) 2-Dimethylamino-N-hydroxy-3- (4-phenoxyphenylbenzenesulfonylpropanamidine); (R) -2-Dimethylaminosulfonyl Amino_N_hydroxy_3_ (4-phenoxyphenylbenzenesulfonyl) -propanamide; and pharmaceutically acceptable salts thereof. Define the following definitions of 7F to explain and define each of the ____ 15_ used in the present invention. ^ The paper size applies the Chinese National Standard (CNS) A4 specification (2ιχχ297 mm) '---- (Please read the back first Notes before filling out this page) Order J # 580491

The meaning and scope of a noun. "Amidino" means a branched or unbranched saturated hydrocarbon chain containing ... carbon atoms, such as methyl, ethyl, propyl, tertiary.butyl, n-hexyl, n-octyl, and the like . " Lower alkyl, which means a branched or unbranched saturated hydrocarbon chain containing 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, third butyl, n-butyl Base, n-hexyl and the like, unless otherwise specified. The term "heteroalkyl" means a branched or unbranched, cyclic or acyclic saturated organic group containing carbon, hydrogen, and one or more heteroatoms, and containing a group selected from the group consisting of 0Ra, NRaRb, and S, respectively. (0) a substituent of nRa (where n is 0, 142), and Ra is hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroarylfluorenyl or acid group, and Rb is hydrogen , Alkyl, cycloalkyl, aryl, aralkyl, fluorenyl, fluorenyl, fluorenyl, ammonium, or mono- or di-carbylaminocarboxylic acid. Representative examples include hydroxyalkyl, amidino, alkoxyalkyl, aryloxymethyl, N-fluorenylamino, farphenothiomethyl, and the like. "&Quot; Methyl " means the group -C (0) -R, where R is a lower alkyl group. Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs "Extended Alkyl Groups" means straight-chain or branched-chain divalent groups consisting of only carbon and hydrogen that are 'unsaturated' and have from 1 to 6 broken atoms For example, methylene, ethylidene, propylidene, 2-methylidene, butylidene, 2-ethylidene, hexamethylene and the like. "Lower alkoxy" means the group -O-R ', where R' is a lower alkyl group. "Alkoxycarbonyl" means the group R 0-C (Ο) _, where R is as As defined herein, it is a base. "Alkoxycarbonylalkyl" means the group ROC (0) (CH2) n-, where R is as in this -16- this paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 580491 A7 B7 five Description of the invention (14 alkyl groups as defined in the text, and η is 1, 2 or 3. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page). Refers to a monovalent aromatic carbocyclic group having a single ring (such as phenyl) or two condensed rings (such as fluorenyl), and optionally, a hydroxyl group, a carboxyl group, a lower alkyl group, a cycloalkyl group, a cycloalkoxy group, Lower-carbon alkoxy, chlorine, fluorine, trifluoromethyl and / or cyano are mono-, di ·, or tri-substituted. Alternatively, the ring may be mono-substituted with the group Ra-Z ·, where ζ is Oxygen, sulfur, -CH = CH ·, -C Η 2, a carbonyl group, a covalent bond, or a nitrogen substituted with a lower alkyl group as required, and Ra is a monovalent aromatic carbocyclic ring having 1 or 2 rings, Heteroaryl or heterocyclic groups, or mixtures thereof, such as phenyl, p-phenylyl, phenyl, imidyl, furyl, pyrimidinyl, phenylpyrimidine, azafluorene, fluorene Indyl, phenyl- (furan_2_yl), phenyl- (fluoren-2-yl), phenyl- (pyrimphen-3-yl), phenyl- (imidazol-2yl), phenyl -〇Sezo 2-yl), phenyl- (morpholin-2 -yl), and phenyl · (saki-2 -yl) (rings represented by Ra, may be light-based, carboxyl, low-carbon if necessary Alkyl, lower alkoxy, triphenyl, trifluoromethyl and / or cyano are mono- or di-substituted). Examples of aryl substituted with Ra-z are benzyl, Winter-based methanol, mono- winter-based, 6-methoxydiphenyl, 4- (4-methylphenoxy) phenyl, 4-phenoxyphenyl, 2-thiophenoxyphenyl, 4-pyridine Ethacryl fluorenyl, 4- (p-secen-2-yl) epioxyphenyl, 4- (u-secenyl) phenoxyphenyl, 4- (2.pyridinyloxy) phenyl, 4- (5-chloro-2-pyridyloxy) phenyl, 4- (thiazol-5-yl) phenoxyphenyl, 4- (imidazol-2-yl) phenoxyphenyl, and the like. "Heteroaryl" Means a monovalent aromatic carbocyclic ring having one or two rings in which one, two or three heteroatoms (selected from N, 0 or s) are combined, such as pyrazole, oxazole, imidazole, pyrimidine, Quinolinyl, benzofuranyl, pyridine And -17-

580491 A7 B7 V. Description of the invention (15) An indolyl group, which may be separately OH, COOH, lower alkyl, lower alkoxy, functional element, trifluoromethyl and / or cyano mono, two Or tri-substituted. (Please read the notes on the back before filling this page) "Aralkyl" means a group of the formula Rb-Rc ·, where Rb is an aryl group as defined above, and Re is an alkylene group as defined above , Such as benzyl, phenethylenyl, 3-phenylpropyl or diphenylpropyl. "" Methoxycarbonyl "means a group of the formula RdCH20C (0)-, where Rd is phenyl." Benzyloxycarbonylamino "means a group of the formula RdCH20C (0) NH-, where Rd is phenyl. "Cycloalkyl" means a saturated monovalent monocyclic hydrocarbon group containing 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. "Cycloalkylalkyl" means a cycloalkyl group, as defined above, attached to a dialkyl group, as defined above. "Halogen" means bromine, chlorine, or fluorine. "Heteroaralkyl" means A group of the formula ReRe-, where Re is a heteroaryl group as defined above, and Re is an alkylene group as defined above. The "Cyclocycle" printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economics means monovalent saturated carbon A ring group consisting of a single ring of 5 to 7 members or a bicyclic ring of 9 to 14 members, which is replaced by one, two or three heteroatoms selected from N, 0 or S, and can be fused into A substituted or unsubstituted benzene ring. Examples of heterocyclic groups are morpholinyl, hexahydropyridyl, hexahydropyridyl, erodolide, tetrahydrofaryl, tetrahydropyranyl, 1,1-dioxide, Tetrahydropiperanyl and its analogs, which may be substituted with one or more substituents as required, the substituents being selected from the group consisting of lower alkyl, lower alkyl, carbamoyl, and fluorenylamino , Fluorenyl, valinyl fluorenyl, pit-based dibasic acid, di __- 18 -______ This paper size applies to China National Standard (CNS) A4 (210X297 mm1 " 580491 employee consumption of the Central Standards Bureau of the Ministry of Economic Affairs Cooperative printed A7 B7 V. Description of the invention (16) Alkylamino, heteroarylfluorenyl, alkoxycarbonylalkyl and appropriate amine protecting groups (such as CBZ, such as 1-CBZ-hexahydroe < -4_ However, the definition of "attaching R6 and R7 together with a nitrogen atom to represent a heterocyclic group" explicitly means only a heterocyclic group containing at least one nitrogen atom. "Hydroxyamino" means a group The group -NHOH. "BOC" means tertiary-butoxycarbonyl. "CBZ" means oxocarbonyl. N DCC "means 1,3-dicyclohexylcarbodiimide. 'Valamine', means the group (C Η 3) 2 CHCH (NH2) C (Ο) Ν Η-. "As necessary" or "optionally" means the condition of the event described later, can Occurs or may not occur, and the description includes instances where the event or state appears, as well as instances where it does not occur. For example, a substituted phenyl or aryl group as necessary "means the phenyl or aryl moiety May be substituted or may be unsubstituted, and the description includes substituted and unsubstituted phenyl groups. The phrase "pharmaceutical excipients as needed" refers to a composition or dosage form so described that may contain or Pharmaceutical excipients different from those specifically required to be present may not be included, and the formulations or dosage forms thus described include examples of excipients where there is a need, as well as those in which the excipients are not present. Examples When the term "amino-protecting group" is used herein, it means those organic groups that are intended to protect nitrogen atoms from unwanted reactions in synthetic procedures, and includes, but is not limited to, benzyl, fluorenyl, Benzyl Carbonyl (benzyloxycarbonyl), p-methoxylactylcarbonyl, p-nitrohenylfluorenyl, tertiary-butoxycarbonyl, trifluoroacetamidine, and the like. Applicable to China National Standard (CNS) M specifications (2 丨 〇 < 297 mm) (Please read the precautions on the back before filling out this page) Order 580491 A7 B7 17 V. Description of the invention ((Please read the first on the back Note: Please fill in this page again.) When the term "base" is used in this article, it includes strong inorganic bases such as sodium hydroxide, lithium hydroxide, ammonium hydroxide, potassium carbonate and the like, and p-ratio Organic bases such as sodium carbonate, diisopropylethylamine, 4-methylmorphine, triethylamine, dimethylaminopyridine, and the like. The "Pharmaceutically acceptable salts" printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs refer to those freely tested or free acid salts that retain biological potency and characteristics, and are not biologically or otherwise Unwanted. If the compound exists in the form of a free base, the desired acid salt can be prepared by methods known to those skilled in the art, such as those such as hydrogen acid, hydrobromic acid, Treat the compound with classical acids such as sulfuric acid, nitric acid, phosphoric acid, and the like; or with acetic acid, propionic acid, glycolic acid, pyruvate, oxalic acid, maleic acid, malonic acid, succinic acid, Organic acids such as fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like are treated. If the compound exists in the form of a free acid, the desired basic salt can also be prepared by methods known to those skilled in the art, such as treating the compound with an inorganic or organic base. Derived from an inorganic base Salts, including but not limited to sodium, , Lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases, including but not limited to primary, secondary and tertiary amines, including naturally occurring Substituted amines, substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, dimethylamine, monoethylamine, triethylamine, tripropylamine, ethanolamine, octamethylaminoethanol, 2 · 2 Ethanol, trimethylamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, bile, betaine, ethylenediamine, glucose Sugar amines, methyl glucosamine, cocoa • 20 580491 A7 B7 V. Description of the invention (18) ~ Alkali, purine, pyrocene, hexahydropyridine, N • ethylhexahydropyridine, polyamine resins and the like Salts. When the term "pharmaceutically acceptable ester" is used herein, it means, for example, those non-toxic esters of the formula where R1 is a hydroxy! Compound, and through this compound, through this technique Well-known methods, formed by reaction with a suitable alkanol having 1 to 8 carbon atoms Such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tertiary-butanol, iso-butanol (or 2-methylpropanol), n-pentanol, n-hexanol and the like The term "inert organic solvent" or "inert solvent" means that the solvent is inert under the reaction conditions described together, including, for example, benzene, toluene, ethidium, tetrahydrofuran ("THF,"), N, N_dimethylformamide (,, dmf ,,), chloroform ("CHC13"), dichloromethane (or dichloromethane or, CH2Cl2 "), diethylamine, ethyl acetate, acetone, Methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, tert-butanol, dioxane, pyridine, and the like. Unless specified to the contrary, all solvents used in the reactions of the present invention are It is an inert bulking agent. The compound of the present invention may have one or more asymmetric centers; therefore, it can be produced as a mixture of stereoisomers or as individual (R) _ * (S) _ stereoisomers. Compound. Individual enantiomers can be obtained by resolving the racemic or un-racemic mixture of the intermediates in some appropriate synthetic states. It is understood that the individual (R) _ or (S) _ stereoisomers, as well as racemic mixtures and other mixtures of stereoisomers, are all included within the scope of the present invention. Use the symbol "(R)" or "(S)" before the substituents, according to Caingo-21-This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) iKIl · ---- Φ (Please read the notes on the back before filling this page) Order the printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 580491 Α7 Β7 V. Description of the invention (19) Cahn-Ingold-Prelog rules [See Cahn et al. Person, the person's name is 6 \ ¥ · Chem. Inter · Edit., 5,385 (1996), errata page 511;

Cahn et al., Angew. Chem. 78, 413 (1966); Cahn and

Ingold, J. Chem. Soc.? (London), 612 (1951); Cahn et al., Experientia, 12, 81 (1956); Cahn J. 9 Chem.

Educ., 41, 116 (1964)] to indicate the absolute stereochemistry of the substituent. Because the interrelationship between the specified substituents and other substituents in this compound has an alpha or a prefix, the name of the absolute configuration of a substituent determines the absolute configuration of all substituents in the compound, and The absolute configuration of the compound is therefore summarized. "Stereoisomers" are isomers that differ only in the way the atoms are arranged in space. "Enantiomers" are a pair of stereoisomers that are non-overlapping mirror images of each other. The enantiomer rotates the plane of polarized light in the opposite direction. The enantiomer that rotates this plane to the left is called the L-isomer and named it (-). The enantiomer that rotates this plane to the right is called the dextroisomer and named it (+). "Diastereoisomers" are stereoisomers that are not mirror-images of each other. Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the notes on the back before filling out this page) "Racemic mixture" means a mixture containing the same equal number of individual enantiomers. "Non-racemic mixture" It is a mixture of individual enantiomers containing different aliquots. "Mammal" includes humans and all domestic and wild animals, including but not limited to cattle, horses, horses, sheep, goats, dogs, and the like. When the word "treatment" or "disposal" is used in this article, it covers the treatment of breastfeeding _-22-_ This paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 580491 V. Description of the invention ( 20 'disease-states in animals, especially in humans, and include; (0 prevent the disease-states from occurring in mammals, especially those mammals that are susceptible to the disease-state, but have not yet At the time of diagnosis; ~ (1 i) inhibit the disease-state, that is, prevent its development; or (iii) reduce the disease-state, that is, trigger the regression of the disease state. "There is a therapeutic effect "Content" means the content of the compound of formula I, when administered to a mammal in need of such treatment, is sufficient to achieve an effective treatment as defined above. The therapeutically effective content will depend on the patient to be treated and the symptoms of the disease, The severity of the pain and the manner in which it is administered can be changed and can routinely be determined by those skilled in the art. Nomenclature—The compounds of formula I, explained below, will be designated using a designated numbering system. Name: (Please read the notes on the back before filling out this page)

Y

R Ο R3 R4 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs where Υ is N-hydroxylamine; R1 and R2 are hydrogen; r3 is benzyl; R4 is hydrogen; R5 is 4-methoxyphenyl; and η is 2 The compound of formula I is named 3-methyl-3- (4-methoxybenzenesulfonyl) hydroxypropylammonium. · Where Y is N-hydroxylamino; R1 and R2 are hydrogen; R3 and R4 are attached together by carbon atom, representing tetrahydroouran-4-group; R5 is 4-(4-fluorophenoxy)- 23- This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 580491 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (21) Phenyl; and compound of formula I where η is 2 , Named in the form of an acetic acid derivative, that is, 2- {4- [4- (4-fluorophenoxy) -benzo-xanthenyl] -tetrahydroxan-4-ylacetamidamine. Wherein Y is N-hydroxyamine group; R1 and R2 are methyl groups; R3 and R4 are attached together by a carbon atom, representing 1-methylhexahydrou-bito-4-yl; R5 is a diphenyl group; and η The compound of formula I which is 1 is designated as 2- [4- (diphenyl-4-sulfinyl-8sup- phenyl) -1 · methylhexahydrop-pyridin-4-yl] -propionic acid. Where Υ is N-hydroxyamine group; R1 and R2 are attached together with carbon atoms, representing tetrahydropiperan-4 · yl; R3 and R4 are hydrogen; R5 is 4- (4-chlorophenoxy) phenyl ; And η is 2, a compound of formula I, named 4- [4 · (4-Gaphenoxy) -benzenesulfonylmethyl] -tetrahydroxan-4-(N · ammonium hydroxy acid). Synthetic reaction parameters Unless specified to the contrary, the reactions described herein are performed at atmospheric pressure and at a temperature range from 5 C to 100 C (preferably from 10 ° C to 50 ° C; most The preferred temperature is "room temperature" or "ambient", such as 20 ° C). Furthermore, unless otherwise specified, attempts are made to bring the reaction time and conditions close to a period of about i hours to about 10 hours (preferably about 5 hours), at about atmospheric pressure, at about 5 ° C to about 100 ° It is performed in a temperature range of C (preferably from about 10 ° C to about 50 ° C, and most preferably about 20 ° C). The parameters provided in the examples are intended to be specific, not approximate. The hydrazine coupling used to form compounds of formula I is usually carried out by the carbodiimide method using, for example, 1,3-dicyclohexylcarbodiimide or N'.ethyl-N,-(3-dimethyl Aminopropyl) _Reagents such as carbodiimide hydrochloride, or 1- (3 · dimethylaminopropyl) · 3-ethylcarbodiimide hydrocarbide-24- Applicable to this paper standard China National Standard (CNS) Α4 Specification (210 X 297 mm) (Please read the precautions on the back before filling out this page) Clothing · 580491 、 Invention Description (Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (EDCI) 'in 1. In the presence of hydroxyphenylhydrazone triturate hydrate (HOBT), it is done in an inert detergent such as N, N-dimethylformamide (DMF) or dichloromethane (CH2C12). Others Methods for forming amidine or peptide bonds include, but are not limited to, synthetic pathways via fluorenyl chloride, fluorenyl azide, mixed anhydrides, or reactive esters such as p-nitrophenyl esters. Generally, this is done with or without Peptide-based solutions are coupled with amidine. The amine protecting group used in the preparation of the compound of formula I is selected, in part by specificity Amine coupling conditions, and part of them are specified by the components involved in the coupling. Frequently used amine-protecting groups include those well known in the art, such as benzyloxycarbonyl (benzyloxycarbonyl) ) (CBZ), p-methoxy; oxycarbonyl, p-nitrobenzyloxycarbonyl, N-tert-butoxycarbonyl (Boc) and the like. For amino groups, Boc or CBZ is preferably used. As a protecting group, because in the case of B 0 C, it is relatively easy to remove it with a weak acid, such as triethylacetic acid (TFA) or hydrochloric acid in ethyl acetate; or In the case of CBZ, it is removed by catalytic hydrogenation. Preparation of a compound of formula I A method of preparing a compound of formula I, especially where η is 1 or 2; Y is light or XONY-, where X is hydrogen or Lower alkyl; R1 is hydrogen or lower alkyl; R2 is hydrogen, lower alkyl, aralkyl, cycloalkyl, cycloalkylalkyl, or heterocyclic ring; or R1 is attached to R2 as a carbon atom Together, represents a cycloalkyl or heterocyclic group; R3 is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, heteroaralkyl or Carboalkoxy; R4 is hydrogen or lower alkyl, or R2 and R3 are attached together by a carbon atom to represent a cycloalkyl or heterocyclic group; or R3 and R4 are carbon atoms. Attached together, it represents cycloalkyl or heterocyclyl-25 This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) (Please read the precautions on the back before filling this page)

I, ν " Γ 580491 A7 ________ B7 V. Description of the invention (23) group; and R5 is a lower alkyl group, aryl group, aralkyl group, heteroaryl group or heteroaryl group V; the method includes the following formula: Compound

〇 R3 R4 is in contact with the oxidant. Appropriate oxidation conditions are outlined in the description of the scripture reaction VIII. A method for preparing a compound of formula I, wherein η is 0, R1 is hydrogen and ruler 2 is not _NR6R7 but is derived from the unsaturated acid corresponding to formula (4). ;

Reaction Formula I R3 0 = < R4 ⑴ R2: > = PPhG Brother III-Bu〇2C, (2) Step 1 R2 R3-Third-Bu〇2C r4 ⑶ Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs ( 3) Step 2 R2 R3 Η〇2〇pj4 (4) Starting material ______ -26- This paper size applies Chinese National Standard (CNS) A4 specification (21〇297297 mm) ~ Formula (1), _ and _ It is commercially available, such as Alddehchemieaic, or prepared as described below, or according to methods well known to those skilled in the art. The osmium salt of formula (2) is commercially available, for example ^ Aldrich (tertiary butoxycarbonylmethylene) triphenylphosphorane, or by standard methods known to the artisan. To prepare it, for example, by reacting a bromine derivative of the formula R CHBrC02- (second-butyl) with triphenylphosphine, and then reacting the obtained triphenyl bromide scale with a strong test. Step 1-Preparation of the compound of formula (3) Generally, a solution of the compound of formula (1) or a solution of the compound of formula (1) in an inert organic solvent, such as benzene, and the compound of formula (2) (or another corresponding phosphate ester, such as phosphonic acid) Triacetate), 151 to 3 (TC (aldehyde), preferably 20.0, or 70 ° C to 9CTC (_), preferably 8 (rc, reaction 8 to 48 hours, Until the starting material is exhausted. The reaction product is isolated and purified by the traditional method, which is the olefinic ester of formula (3). &Quot; Child step 2-Preparation of compound of formula (4) The compound of formula (3) below can be hydrolyzed if necessary in the presence of an inert solvent, for example, treated with trifluoroacetic acid in dichloromethane for about 20 minutes to 3 hours. At a temperature range of about (TCf, j4 (rc, The reaction is preferably carried out at about room temperature. In the case of using trimethyl phosphonate acetate in step 丨, the methyl ester produced can be hydrolyzed in a conventional manner under basic conditions, such as in Sodium hydroxide in aqueous methanol or ethanol. The actinic acid of formula (4) is separated and purified by conventional methods. Formula (1) Preparation of the product, in which R3 and R4 are attached together, which represents the hexapeptide p ratio derivative 580491 A7 B7 V. Description of the invention (25) v Preparation In the following, the formula (4) is represented by formula (4) A compound in which R3 and R4 are attached together with a carbon atom, which represents a dehydropyridine derivative, usually requires protection of the NΗ group. An example is shown in the following reaction formula π. Reaction formula 11 Η I Μ

OH ⑻ step

CBZ I N

Step 2 CBZ I Μ

〇 (1a)

(Please read the notes on the back before filling out this IC 0H (b)

1T Step 1

CBZ step 2

CBZ

R2 ^ XC02H (4a) The third butyl (3a) printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. Compounds of formula (b) · Zining j 偌 · Solutions of hydroxyhexahydropyridine compounds of formula (a) are usually protected By reacting (a) in an inert solvent, such as tetrahydrofuran, in the presence of an excess tertiary base, such as triethylamine, with an equimolar amount of benzyl formate. This reaction-28 This paper size is in accordance with Chinese National Standard (CNS) A4 specifications (210X297 mm 580491 A7 B7 V. Description of the invention (26 is in the temperature range from about 0 ° C to 40 ° C, preferably about 25T, The reaction is carried out for about 10 to 30 hours, preferably about 8 hours. The reaction product of formula (b) is isolated and purified by conventional methods. A compound is a compound of formula (丨) in which ... and 4 are attached together with carbon atoms to represent a protected hexahydropyridine derivative. A solution of a compound of formula (b) is oxidized to formula (1 & ), Is to react (b) with an oxidizing agent, such as chloric acid ton ingot, in an inert solvent, such as dichloromethane, preferably in the presence of an inert support, such as chopping algae. It is carried out at a temperature range from about 0 ° C: to 40 ° C, preferably about 25 ° C, for about 10 to 30 hours, preferably about 8 hours. By conventional methods Isolate and purify the reaction product of formula (1a). Alternatively, commercially available 4-hexahydropyridone monohydrate may be used. The compound hydrochloride is reacted with benzyl chloroformate under Schotten-Baumann conditions to obtain a compound of formula (1 a) in a single step. Preparation of a compound in which R3 is attached to a carbon atom Together, the hexahydropyridine derivative is represented by a compound of formula (4a) in which R3 * R4 is attached together with a carbon atom, which represents a compound of formula (4) that represents a hexahydroxanthene derivative. a) The protected hexahydropyridone is converted to (3a), which is hydrolyzed to (4a) as described in steps 1 and 2 of reaction formula (I). The compound of formula (4a) is then converted to As described in the following reaction formula in, wherein η is 0, a compound of formula I. The benzyloxycarboxyl (c BZ) protecting group is removed by catalytic hydrogenation to give R 3 and R 4 with carbon atoms attached Together, on behalf of -29- this paper size applies Chinese National Standard (CNS) Α4 specification (210 × 297 mm) (please read the precautions on the back before filling out this page)-Order printed by the Central Consumers Bureau of the Ministry of Economic Affairs and Consumer Cooperatives 580491 A7 B7 V. Description of the invention (27 Table hexahydropyridine derivatives of formula I The compound "prepared, the base, t, and ^ ^ 3 ^ 4 ^ 4 brothers together, on behalf of Lunan Street peaks" is expressed by the formula (4b) where the carbon atom is attached to the ruler 3 and ruler 4 Together, the compounds of formula (4), which represent tetrahydropiperan derivatives, start with the corresponding 4-oxotetrahydropiperan, and are prepared by a procedure similar to the one shown above. The following reaction formula III To show the reaction and describe it in Example 3. Scheme 111 〇.co2h

cr (1b)

(Please read the precautions on the back before filling out this page.) Clothing · Order Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs -30 and then convert the tetrahydropiran derivative of formula (4b) to the corresponding formula r The compound is a compound as described in Reaction Scheme VII where 11 is 0. ,.. The preparation of arsenic compounds, in which carbon atoms Chiang P3 and R4 are attached together 丄 A epitetrahydro 喽 piran-1,1 digas derivative · Start with 4-oxotetrahydropyrimidine A procedure similar to the above is used to prepare a compound of formula (4) in which R3 and R4 are attached together with a carbon atom and represents a tetrahydrothipiperan-1,1-dioxide derivative. . Then, the tetrahydropiperidine-1, 1 -dioxide derivative of formula (4) is converted into a paper standard applicable to the Chinese National Standard (CNS) A4 specification (21〇297297) 580491 A7 B7 V. Description of the invention (28 Correspondingly, as described in Reaction Formula III, wherein n is 0. Compound of Formula I. Another method of preparing compounds of Formula I is to prepare Formula I in which R2 is not -NR6R7, and R3 and R4 are both hydrogen. Another method for the compounds is derived from the corresponding ester of formula (iO), and the preparation method is shown in the following reaction formula IV.

Reaction Formula IV EKX R1, R2 R -Et0V rV0Et Step 1 〇〇⑺ 11 10: 〇H cast 2 (Please read the precautions on the back before filling this page) (8) R1 R2 H〇? ≪ ^ 〇H 〇⑼ 0) Step 3 rV ^ r2

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (10) Step 1-Preparation of compound of formula (8) The starting compound of formula (7) is commercially available, or can be known by this technique The method begins with the production of diethyl malonate, such as Dagger and Johnson 'J. Chem. Soc., Page 2525 (193 °) (other diesters can be used instead of diethyl ester if necessary). Generally, a solution of the compound of formula (7) is dissolved in an inert aromatic solvent, preferably benzene or toluene, and cooled to about · 40 ° C to -20 ° C, and preferably about -3 (rc). · Into this ice-cold solution, add 31-This paper applies to Chinese National Standard (CNS) A4 specifications (210X297 mm) as far as possible. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 580491 A7 _______________ B7_ V. Description of the Invention (29) ~ -Tian's hydrazone hinders rhenium agents, preferably diisobutyl hydrogenated in an inert aromatic solvent, and maintained at a temperature not higher than about 25X: After the addition is complete, the reaction is maintained at about ^^, until the starting material is consumed. After about 10 minutes, the reaction is stopped by adding a protic solvent, preferably ethanol, and the temperature is maintained so that it is not higher than about 5 t. As required Sodium borohydride is added, but it is best to simply warm the reaction to about ▲ / dish. The reaction product of formula (8) is isolated and purified by conventional methods. The preparation of a compound of Moulis is usually carried out by using a base to formula (8). ) Compounds are hydrolyzed to form (9) Hydroxymethyl acid. The compound of formula (8) is dissolved in an aqueous protic solvent, preferably aqueous methanol, and reacted with about 3 mole equivalents of a base, such as potassium hydroxide or lithium iodide ' It is then reacted with sodium cyanide. The reaction is carried out at a temperature ranging from about 80 t to about t, preferably at about the reflux temperature of the solvent mixture, for about 8 hours. Isolation and purification of the formula (9) by conventional methods Reaction product 0) Step 3-Preparation of compound of formula Π 01 The compound of formula (9) is usually dehydrated to form a lactone of formula (10). At the compound of formula (9) and about 2 mole equivalents of a tertiary base, Preferably, it is a mixture of triethylamine. If necessary, in the presence of 4-dimethylaminopyridine, in an inert solvent, such as diethyl ether or dichloromethane, add about 1 Mo. Ear equivalents of dehydrating agents, such as trifluoromethanesulfonic anhydride, methanesulfonic anhydride, methanesulfonyl chloride, p-toluenesulfonyl chloride, benzenesulfonyl chloride, preferably benzenesulfonyl chloride. The reaction is at about -10 . (: It takes about 10 minutes to 4 small -32- This paper size applies to Chinese national standards (CNS) A4 size (210χΥ97 mm) - (Please read the Notes on the back page and then fill in}

580491 A7 B7 5. In the invention description (30), it is preferably about 30 minutes. The reaction product of formula (10) is separated by conventional synthesis without further purification. "Attached together" represents a tetrahydrofuran derivative. To provide a specific example, a carbon atom is used to attach ... and trans 2 together to represent a compound of formula (10) (represented by the formula (Shown) in the preparation, shown in the following reaction formula ", and in fact :; February.

Et〇

(8a)

OH (9a) Step 3 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

(10a) The starting compound of formula (7a) is commercially available ^, 1 ,, 丄 丄, or q can be prepared according to the methods described in Example 31A to react with step 1-3 in reaction formula IV. ‘Same method as shown to complete the $ 's Zhang scale for Chinese countries ^^ (Please read the precautions on the back before filling this page)

580491 A7 B7 V. Description of the invention (31 K1 〇) compound preparation, wherein R3 and R4 are as defined in the formula J and the meaning is represented by formula (10b), where R3 and R4 are as defined in the compound of formula I (1 0) The method for preparing the compounds is shown in Reaction Formula VI below and illustrated in Example 5.

Reaction Formula Step 1 R1 R; R2 BO. V, 〇Et

〇 〇 ⑺ R〇 R2 (Please read the precautions on the back before filling this page) Clothing _ (11) (11) +

Step 2 R4

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs Step 3 (9b) 〇

R1x .R2, R3 〇, R4 ′ (1〇b) Step 1 The compound of formula (1 u is a compound of formula (n) in which R is Et, which can be decarboxylated by formula (7) Compounds are prepared. Usually a diester is mixed with a mixture of lithium iodide and sodium cyanide at about 130 X: to 140 ° C in a suitable solvent such as N, N-dimethylformamide. The reaction takes about 24 hours. -34 This paper size is applicable to the Chinese national sample f CNS, the project / 楱, 580491 A7 B7 V. Description of the invention (32 Step 2-Preparation of compound of formula (9b) Usually, let R be Η An anion of a compound of formula (11) or a lower alkyl group reacts with a compound of formula R3R4C = 0 to form a hydroxy acid or hydroxy ester of formula (9b). In an anhydrous ether solvent containing a compound of formula (1 1), Preferably, in a tetrahydrofuran solution, an anhydrous ether solvent is added at 0 ° C, preferably about 1.1 mole equivalents (in this case R is a lower alkyl group) or about 2 mole equivalents (in this case, tetrahydrofuran). When R is hydrogen) hindered base. When the addition is completed, a small amount of a polar solvent may be added as required, preferably Rokko Phosphobenzamine. To this mixture is added an excess of a compound of formula R3R4C = 0. The addition is carried out at a temperature range of about _78 to 10 ° C. When R3 and R4 are 氲, preferably • 78 ° C, or preferably for ketones, followed by a reaction at room temperature for about 2 to 24 hours, preferably about 1 hour. When R in the starting material formula In the case of hydrogen, the reaction product of formula (9 b) is separated and purified by conventional methods. When r in the starting material formula (11) is a lower alkyl group, where R = H of formula (9b) The reaction product is obtained by hydrolyzing the ester product using a base, preferably lithium hydroxide, as described above, and then separating and purifying it by conventional methods. Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (Please (Read the notes on the back before filling out this page)

1T Step 3—Sword of the compound of formula (10b) Then, in a similar manner to that described in reaction formula IV, the compound of formula (9b) is converted to the compound of formula (10b). The method of Reaction Formula VI can be used, for example, to start with 4-carboxytetrahydropiperan or its esters, such as ethyl ester, to prepare a compound in which r1 * r2 is attached together with carbon atoms to form tetrahydropiperan-4. -A compound of formula (10). Similarly, -35-

580491 A7 B7 V. Description of the invention (33 can also be from 1-fluorenyloxycarbonyl-4-carboxyhexahydropyridine, N- (tertiary butoxycarbonyl) 4-yl /, lice p bite or its purpose, such as Ethyl alcohol is used to prepare compounds of formula (10) in which R1 and R2 are attached together with carbon atoms to form hexahydropyridin-4-yl or a derivative thereof. Another method for preparing compounds of formula I is also The compound of formula (13) can be prepared from the compound of formula (13), and the preparation method is shown in the following reaction formula VIA and illustrated in Example 5A. R1

RO male 丨 \ (11) 0 R2 + χχχ Reaction Formula VI A R3 R4 Step 1

(Please read the notes on the back before filling this page)

I Γ Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, where R is hydrogen or a lower alkyl group, and X is halogen or _ • p-toluenesulfonyl. Step 1-Preparation of the compound of formula (13) from (11) The starting compound of formula (13) is commercially available, for example, a conventional method for preparing gaseous pivalic acid can be prepared. Esters, or compounds of formula (13) can be prepared by methods known to those skilled in the art, such as Gibson and Johnson, j. Chem. Soc., Page 2525 (1930). Generally, the anion of the compound of the formula (η) is reacted with an alkyl dioxide to form a halogen-substituted hydroxy acid ester of the formula (13). In a solution of water-soluble ether; cereals' is preferably a compound of formula (1 1) in tetrahydrobutan, at a temperature of about _100 to 0 ° C, preferably below, adding Paper size Common Chinese National Standard (CNS) A4 specification (210X297 mm) 580491 A7 ____ ._B7 _______ V. Description of the invention (34) ·

I water ether solvent, preferably tetrahydrofuran, is hindered by about i 1 mole equivalent (in this case R is a low-carbon fe group) or about 2 mole equivalent (in this case R is hydrogen). Lithium diisopropylamidine. To this mixture is added an excess of alkyl dihalide, preferably diiodomethane. This addition is performed at a temperature range of about _5 to 50 for about 1 to 5 hours. The reaction product of formula (13) is isolated by a conventional method and can be used in the next synthesis step without further purification. It should be noted that the compound of formula (13) in which X is p-toluenesulfonyl is obtained by continually fluorinating a compound of formula (8) or (9b) with toluene. '' The preparation of compounds of formula I can transform the intermediates of formulas (4), (10) and (13) to compounds of formula I in which γ is a hydroxyl group and η is 0, which is named a compound of formula 1 & It is shown in Reaction Formula V11.

Reaction Formula VII (Please read the precautions on the back before filling this page). 11 [11 or (10) or (13)] R5SH —

Step J Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

Where R is hydrogen or a low-carbon alkyl group. Compounds of formula (4) are commercially available, such as from Aldrich, or can be prepared by methods known to those skilled in the art, such as the

580491, invention description (35 dihydro acids, according to the description of MannichMister, chem., 57, 6 (1924), or can be prepared as described. Compound ⑺ of formula ^ ^ as described in Example 3仵, such as from Alddch, Fluka Shouji 'or can be prepared according to the slang term ... Call the method known to the person, for example as described in Example 4 below. The compound will be n The compound of formula I, which is 0 and γ is a light group, is named as a compound of formula. By the presence of a molar amount of a secondary amine equal to τ, preferably hexahydropyridine, the compound of formula (4) The enoic acid is prepared by heating with an equivalent amount of a thiol of the formula (5). The reaction is carried out at a temperature range of about 70 ° (: to 12 °., Preferably about 10 ( It is carried out at TC for about 1 to 24 hours, preferably about 3 hours. The sulfide reaction product, which is a compound of formula I a, is isolated and purified by a conventional method. The compound of formula la is prepared from (10) Central Ministry of Economic Affairs Printed by the quasi-station employee consumer cooperative named the compound of formula I in which η is 0 and Y is hydroxyl It can be obtained by making the lactone of formula (10) and anion of about 1.1 mol equivalent of thiol of formula (5) (the production is made in a polar solvent, preferably N, N · Dimethylformamide is prepared by reacting (5) with an alkali metal hydride, preferably sodium hydride). The reaction is in a polar solvent, preferably N, N · dimethyl Formamidine is carried out at a temperature range of about 0 ° C to 70 ° C, preferably about 0 to 25 ° C. The sulfide reaction product, which is a compound of formula Ia, is isolated and purified by conventional methods. The compound of formula la is exempted from (13). The compound of formula I in which η is 0 and Y is a hydroxyl group or a lower alkoxy group is named -38.-This paper applies the Chinese National Standard (CNS) A4 specification (210X 297). (Mm) 580491 A7 B7 V. Description of the invention (36) The compound of formula la can be obtained by combining the thioester of formula (13) with about ^ mole equivalent of the anion of thiol of formula (5) By reacting (5) with an alkali metal hydride in a polar solvent, preferably N, N · dimethylformamide, more preferably hydrogen Sodium) is prepared by a reaction. The reaction is performed in a polar solvent, preferably N, N-dimethylformamide, at a temperature of about 30 ° C to about 120 ° C, preferably About 800, for about 10 minutes. Isolate and purify the sulfide reaction product, which is the compound of formula u, by conventional methods. The compound of formula I a is transformed into other compounds of formula I, and the compound of formula I a is transformed into other The method of the compound of formula I is shown in the following reaction formula V111.

Reaction Formula VIII (Please read the notes on the back before filling in this page j

Order Third butyl 〇νη2 · ηοι Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economy lc Step 3

Step 1 Third butyl 〇ΝΝ Step 2 Third butyl 〇OH

HOHN

-39- This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 580491 A7 ___ B7 V. Description of the Invention (37) I ~~~ Step 1_ Formula lb The production of compounds is usually a compound of formula in which η is 0 and γ is a third _Bu〇NH •, and is named a compound of formula lb by the formula "compound with an excess of third butyl) -hydroxyl Amine hydrochloride and N_ethyl-N, _ (3-dimethylaminopropylcarbodiimide hydrocarbide (or other carbodiimide derivatives, such as 1,3_dicyclohexylcarbodiimide Amine), prepared in the presence of __hydroxybenzotriazole hydrate and a primary base, the tertiary test such as dimethylaminopyrene, triethylamine, 4-methylmorpholine, pyridine or this A base-like mixture. The reaction is carried out in an inert solvent, preferably digas methane, at a temperature ranging from about 0t to 40 ° C, preferably at about 25t, for about 丨0 to 30 hours, preferably about 18 hours. The N_third · butoxy reaction product is isolated and purified by a conventional method, that is, A compound of formula b. Step 2-Preparation of a compound of formula ic in which η is 1 Generally a compound of formula I (ie subclass) in which η is 1 and Y is third_Bu〇NH- is named as formula I c The compound is prepared by reacting the compound of formula b with a mild oxidant such as sodium periodate or one equivalent of "OXONE" τ μ (potassium permonosulfate, Aldrich Chemieal

Co ·) until the starting material cannot be detected. The reaction is carried out in an inert solvent, preferably aqueous acetone, from about 0.01 to 40. (: At a temperature range of about 25 ° C, preferably about 10 minutes to 4 hours, and preferably about 30 minutes. Isolation and purification of the subarsenic product by conventional methods, ie Compounds of formula Ic in which η is 1. Step 2. Preparation of compounds of formula Ic in which η is 2 Compounds of formula I in which η is 2 and Y is third-BuONH China National Standard (CNS) A4 specification (210 '乂 297 mm) (Please read the notes on the back before filling out this page) ^^ Clothes · Order 580491 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

V. Description of the invention (38) is a stone wind type), named as the personalization of the formula I c. Mouth, is a compound of the formula lb, by making it with about 1-3 Mordan fleas, p ^ w It is better to have Chevre in Yetian to react with 1.5 mol equivalent of strong oxidant, such as m-chloroperbenzoic acid or 0x〇ne. The reaction is performed in an inert solvent, preferably a protic solvent, most preferably water-containing methyl alcohol, at a temperature range τ from about (TC to 40 ° C, preferably about 25τ) for about 10 minutes to 4xiaoxiao, preferably about 2 小 #. Isolation and purification of the hydrazone product, that is, the compound of formula B in which η is 2, by the traditional method. Step 3-Formula I Wherein Y is a compound of formula HONH-, named as a compound of formula Id, which is based on acidic conditions, under conditions similar to the preparation of the compound of formula (4) described above, the formula Ib * IcwN_third · Butoxy compounds are prepared by hydrolysis, or in sealed test tubes, in inert solvents, such as 1,2-chloroform, and prepared using hydrogen acid gas. Isolation and purification of side groups by traditional methods The reaction product of an amine, which is a compound of formula I d where Y is HONH-. Another method of introducing R3 and R4 into a compound of formula I. Another method of introducing R3 and R4 into a compound of formula I, shown in the reaction below In Formula V111A. Reaction Formula VIIIA

s〇2ft step 1

L —. Clothing-(Please read the notes on the back before filling in this page) Order 41-This paper size applies to China National Standard (CNS) A4 specification (21 × 297 mm) 580491 A7 B7 V. Description of the invention ( 39 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs where R is hydrogen or a lower alkyl group. Step 1 Prepare a compound of formula I, where η is 7 hi P 3 ^ 1, --t is the same as defined in the compound of formula I But it is not hydrogen ^ where η is 2, Υ is rityl or alkoxy, the same as defined in magic compounds, but not hydrogen, and R1, R2, and R4 are the same as the compounds of formula I defined in magic compounds, named Compounds of formula Iw are prepared by alkylation of compounds of formula I in which R3 and M are both hydrogen. In a manner similar to that shown in reaction formula VIA above, the hindered base, preferably two Isopropylammonium amine is added to a solution of a compound of formula Iw in an ether solvent, preferably tetrahydrofuran. To this mixture is added approximately a molar equivalent of an alkyl or aralkyl compound. At room temperature Stir the addition reaction for about 1-3 hours, then stir for an additional 1-5 hours, preferably 3 hours. Isolate and purify the reaction product by conventional methods. R4 can be introduced similarly to the method described above. • Compounds of formula IW can be converted to other compounds of formula I as shown previously. The preferred procedure for compounds of d. The preferred method for converting a compound of formula I a to another compound of formula I is shown in the following reaction formula IX. -42- Private scale applies the Zhongguan Family Standard (CNS) A4 specification (21〇χ297 public envy) (Please read the notes on the back before filling out this page) Order 580491 A7 B7 V. Description of the invention (4〇

Formula IX Step 1 R1 R2aW: 5 〇 R3 R4 (12) (12) Step 2 R1 R2 HOHN. X / SR5

(Please read the notes on the back before filling this page)

Iba Step 3 R1 R2 H0HN ^ X.S (0) nR5 Or3 R4

1T printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs of the People's Republic of China 1-Production of compounds of formula Iba Chutong 'often names the fluorenyl halides of compounds of formula la as compounds of formula (12), It is prepared by reacting a halogenating agent. The compound of formula I a with an excess of a halogenating agent, such as grass hydrazone gas, grass bromide, lindenium chloride, phosphorus trichloride, pentafluorine, sulfite hydrazone, preferably oxadiazine, is used as The catalyst is reacted in the presence of a small amount of N, N-dimethylformamide. The reaction is performed in an inert solvent / preferably dichloromethane, and at a temperature ranging from about 0 ° C to 40 ° C, more preferably about 2 5 X: for about 10 to 30. Hours, preferably about 18 hours. The fluorenyl halide reaction product, which is a compound of formula (12), is isolated by conventional methods. Step 2-Preparation of the compound of formula Iba 43- The paper size is in accordance with Chinese National Standard (CNS) A4 (210X 297 mm) 580491 A7

V. Description of the Invention (41) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, the compound of formula I in which η is 0 and ah is HONH-is named a compound of formula Ba. -5 mol equivalent, preferably about 3.5 mol equivalent of N, 0-bis (trimethylsilyl) -hydroxylamine reaction, or more preferably dissolved in a suitable solvent, such as tertiary butyl alcohol / Reaction of aqueous hydroxylamine in tetrahydrocrack. The reaction is performed in an inert solvent, preferably dichloromethane, at a temperature ranging from about 0 ° C to 25 ° C, preferably about 25 t, for about 1-10 hours. For N, 0-bis (trimethylsilyl) -hydroxylamine is preferably about 3 hours, and hydrous hydroxylamine is preferably about 1.5 hours. The N-hydroxyamino acid product, i.e. the compound of formula Iba, is isolated and purified by conventional methods. fStep 3-Preparation of Compounds of Formula Id In a manner similar to that shown in the above Reaction Formula Vin, Step 2 or 3, the compound of Formula Iba is converted to a compound of Formula Id where ^ is 1 or 2. It should be noted that the method of preparing the compound of formula I should be noted that the order of the steps in the reaction formula of formula 1 (1) above can be changed. That is to say, the compound of formula "can be oxidized to sulfone first, The above-mentioned conversion of a carboxyl group to a hydroxylamine group. Preparation of a compound of formula I with poor and five diphenyl groups, wherein R5 is a diphenyl compound of formula I, optionally substituted, preferably from which R5 is optionally substituted For example, a compound of the formula Ia of bromophenyl is prepared by $. For example, a compound of which R5 is 4-diphenyl can be represented by the following formula of Iaa, wherein R5 is 4-bromophenyl of formula Ia. Prepared as shown in the following reaction formula X. -44-This paper size is applicable to the Chinese National Standard (CNS) A4 size (210X 297 mm) (Please read the precautions on the back before filling this page). # 衣 _

1T 580491 Α7 Β7 V. Description of the invention (42 dead 2 H〇l…

Br

0 R3 R4 laa

Formula X Step 1 Ιθ + σ Β (〇Η), Step 2

(Please read the notes on the back before filling this page)

If Step 3

Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs, where n is 2, Y is hydroxyl, eR5 is 4-bromophenyl, and R1, R2, R3, and R4 are all as in the formula The defined compound of formula H is named a compound of formula Ie, which is prepared from a compound of formula raa by reacting it with a strong oxygenating agent similarly to the method shown in the above reaction formula V111 and step 2. . Step 2 _ The preparation of the compound of formula I f usually includes η is 2, Y is a warp group, R5 is a diphenyl group, and R1, R2, -45- This paper size applies the Chinese National Standard (CNS) A4 specification (210 × 297) (%) 580491 43 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs -46 A7 B7 V. Description of the invention (R3 and R4 are the same as those defined in the compound of formula I. The compound of formula Z is named as a compound of formula I f. A compound of formula I e is prepared by reacting a phenylacid and a valence | barium catalyst, preferably tetravalent (triphenylphosphine), with this reaction in a protic solvent, preferably The mixture of ethanol and benzene is carried out at a temperature range from about 30 ° C to 100 ° C, preferably about 80 ° C. When the desired temperature is reached, 2 M sodium carbonate in water is added and continued Reflux for about 1 to 8 hours, preferably about 2 hours. The reaction product is isolated by conventional methods, that is, the compound of formula If, and further purified by preparative TLC. Step 3-Preparation of the compound of formula Ih η is 2, Y is HONH-, R5 is diphenyl, and R1, R2, R3, and R4 are all A compound of formula I as defined in a compound of formula I is named a compound of formula Ih. The corresponding compound of formula if can be used in a similar manner to that shown in reaction formula VIII above, or preferably according to reaction formula lx. Or X. To prepare a compound of formula I in which R5 is a substituted diphenyl group, the same method as shown above allows a formula substituted on the 4-bromophenyl ring if necessary. I aa compounds are reacted with boric acid optionally substituted. ΆΛΛ 5 is the preparation of compounds of formula I where diphenylsulfide is substituted, where R5 is a compound of formula I which is optionally substituted with diphenylsulfide, preferably from the corresponding formula I e Compounds are prepared, that is, compounds of formula I in which R5 is 4-bromophenyl optionally substituted in reaction formula X. For example, compounds in which R5 is 4-diphenylsulfide can be prepared as shown below. The reaction formula XI is prepared from the compound of formula Ie. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm C, please read the precautions on the back before filling this page)

580491 A7 B7 V. Description of the invention (44

Reaction XI

Id step 1

3 ^ 0 Step 2

HOHN

3 ^ 0 (Please read the notes on the back before filling in this page) Preparation of U-free compounds of type I i Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs • Usually η is 2:, Y is the base, R5 Is diphenylsulfide, and Ri, R2, R3, and r4 are all the same as those in the compound of formula I, and the compound of formula I is named as the compound of formula 11. The anion of thiophenol can be heated by heating (E.g., in a polar solvent, preferably N, N dimethylformamide) to treat sodium sulfide or benzylbenzene, preferably potassium hydride), from formula I e Compounds. The reaction is carried out in a polar solvent, preferably N, N-dimethylformamide, at a temperature range from about 100 ° C to 10 ° C, preferably 75 ° C, for about 4- 48 hours, preferably about 18 hours. Isolate the reaction product by the traditional method, which is the compound of formula, and it will be used in the National Standard for Winter (CNS) M specifications (21〇297). Gongqing 580491 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

A7 B7 V. Description of the invention (45) It is further purified by preparative TLC. Step 2-Preparation of Compounds of Formula Ij 'Generally, where η is 2, γ is HONH-, and R5 is 4-diphenylsulfide, and

I R1, R2, R3, and R4 are all the compounds of formula I as defined in the formula compounds. They are named compounds of formula Ij, which can be similar to the method described in reaction formula V111 above, or more preferably as shown in reaction formula χ or The method shown is prepared from the corresponding compound of formula Ii. To prepare a compound of formula I in which R5 is a substituted 4-diphenylsulfide, in a manner similar to that shown above, the compound of formula Ie may be optionally substituted on the 4-bromobenzene ring, and may be substituted as necessary. The anion of thiol is reacted. ， ΙίΑ5ΑΑ · [4- (喽 phen_, 1 ^) phenoxy 1phenyl group; Preparation of compounds of formula I in which R5 is 4 [[4- (4 • phenphenyl) phenoxy group ] A phenyl compound of formula I is prepared from a corresponding compound of formula I in which R5 is optionally substituted with 4- (4-bromophenoxy) phenyl. This reaction is shown in anti-anaesthesia XIA. ; Reaction Formula XIA ’

h〇Vr2 person J Y ^ cs〇2 〇r3 r4 Ifa -48- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) (Please read the precautions on the back and save this page)

1T 580491 A7 ________ ΒΊ 5. Description of the invention (46) Preparation of compounds of formula Ifb The 4 · bromo group of the compound of formula (Ifa) can be prepared by methods similar to those shown previously, or according to Example 16 The description in D was replaced by a procedure similar to that described in Reaction Formula X, Step 2 to obtain a compound of formula Lfb. The compound of formula (Ifa) is likewise reacted in order to introduce another aryl or heteroaryl group. Reduction of compounds of formula Ifa by palladium and hydrogen, replacing the bromine group with hydrogen. Where R5 is 1,2-dibenzyl ethylene compound of formula I error correction where R5 is 1,2-stilbene compound of formula I which may be substituted as needed, preferably prepared according to reaction formula X, where R5 It is prepared for the corresponding compound of formula I, optionally substituted 4-bromophenyl. For example, a compound in which R5 is 4-diphenylethylhydrazone can be prepared from a compound of formula Ie, as shown in reaction formula XII below.

Reactive XII (Please read the notes on the back before filling out this page).-Order

Step 1-Preparation of compound of formula I k _________- 49-This paper size applies Chinese National Standard (CNS) A4 (210X 297 mm) 580491 Α7 Β7 V. Description of the invention (47) (Fill in this page again) Generally, 将 is hydroxy, R5 is 4- (1,2-stilbene), and R1, R2, R3 and R4 are all the compounds of formula I as defined in the compounds of formula I, and are named Compounds of formula Ik, in the presence of hindered tertiary organic bases, such as diisopropylethylamine, and palladium diacetate, and trimethylphenylphosphine, or other triphenylphosphine derivatives, Preferably, trimethylphenylphosphine or tetravalent (triphenylphosphine) -palladium (0) is used to react the compound of formula Ie with styrene which may be substituted if necessary. The reaction is carried out in the absence of a solvent at a temperature ranging from about 30 ° C to 100 ° C, preferably at about 80 ° C, for 4 to 48 hours, and more preferably for 16 hours. The reaction product, i.e. the compound of formula Ik, is isolated by conventional methods and is further purified by means of preparative TLC. The conversion of the carboxylic acid of formula Ik to its hydroxylamine equivalent is accomplished in a similar manner to that shown in reaction formula V111 above, or preferably according to the method shown in reaction formula IX or X. Preparation of compounds in which R3 and R4 are attached together with end atoms, representing N-substituted hexahydropyridine derivatives, are printed by the Consumer Cooperative of the Central Standards Bureau, Ministry of Economic Affairs • Preparation of the compounds in which R1 and R2 are carbon atoms, Alternatively, R3 and R4 are attached together, and the compound of formula I, which represents N-substituted anaerobic compounds, is prepared from the corresponding unsubstituted hexahydropyridine derivative. This procedure cites a compound of formula I in which R3 and R4 are attached together with carbon atoms and represents an N-substituted hexahydropyridine derivative as an example, and is named a compound of formula η, as shown in the following reaction formula XIII As shown. -50- This paper size applies Chinese National Standard (CNS) A4 (210X297 mm) 580491 A7 B7 V. Description of the invention (48. R2 third butyl, > 〇S (〇) nR5

N — H

Reaction Formula XIII

Step 1 third butyl OHN

R Step 2

R1 R2 HOHN

(Please read the precautions on the back before filling this page.) Step 1-Preparation of Compound of Formula Im 'Where Y is the third -BuONH-, Rose 1 and R2 are as defined in the compound of Formula I, and A carbon atom attaches R3 and R4. Together, and represents a compound of formula I, which is an N-substituted hexahydroeodo derivative, and is named a compound of formula Im. Generally, the compound of formula Im is prepared by reacting a compound of formula II in the presence of a test such as triethylamine or potassium carbonate and a compound of formula RX, where R is lower alkyl, cycloalkylalkyl, Fluorenyl, oxycarbonylalkyl, pyridyl, -S02Ra, where Ra is lower alkyl or -NRbRc, where Rb and Re are hydrogen or lower alkyl, respectively; and the like, and X is chlorine, Bromine or iodine; for example, RX may be methyl iodide, cyclopropyl methyl bromide, 3-pyridylmethyl gas, ethyl bromide acetate, acetamidinium bromide, acetamidine gas, dimethylaminosulfonyl chloride. The reaction is in a polar solvent, preferably N, N_dimethylformamidine 51-this paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) Order-Staff Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs Printed 580491

V. Description of the invention (49 The printed amines are produced by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs at a temperature range from about 0 ° C: to 5 ° C, preferably about 25 ° C, for about 4 to 48 hours. It is preferably about 16 hours. The reaction product, that is, the compound of formula Im, is isolated by conventional methods and used without further purification. In addition, reductive alkylation of formula II can also be performed to form compounds of H to formula. For example, In the presence of a catalyst, such as palladium on carbon, under a hydrogen atmosphere, the compound of formula II in acetone is reduced to obtain a SImiN-isopropyl derivative. FStep 2-Preparation of the compound of formula In R2 is as defined in the compound of formula I and attaches R and R4 together with a carbon atom, and represents a compound of formula I, which is an N-substituted hexahydropyridine derivative, and is named a compound of formula ^. Generally formula In compound, the compound of formula Im is reacted with a strong acid, preferably hydrochloric acid. The reaction is in a sealed test tube, in the inert solvent, 'preferably 1,2,3 — gas radon' in the range from about Under the temperature range of 0 ° C to 4 5 ° C 'preferably is about 2 0 C, The reaction time is about 10 to 72 hours, preferably about 48 hours. The reaction product is isolated and purified by a conventional method, that is, a compound of formula In, and chromatography is preferred. The base soil I2 is -NR ^ IL7 Preparation of the compound of formula I In the compound of formula I, R2 is _NR6R7, where R6 is hydrogen and R7 is CBZ, where CBZ represents benzyloxycarbonyl, and R1, R3, and R / are hydrogen. In the following, for example, formula Ip and It is represented by the formula I q, which is prepared by different routes, as shown in the reaction formulas XIV, XV, and XVI. This route provides the compound of formula lab, which is a purely optical or racemic mixture,- 52- The paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling this page)

580491 A7 B7 V. Description of the invention (50 is based on the palmity of the starting lactone

Reaction XIV. NHCBZ. Square ⑹ + r5sh ⑸, Step 1 NHCBZ SR5 lab Printed by the Consumer Cooperatives of the Central Associated Bureau of the Ministry of Economic Affairs 丄: The preparation of 丄 -type lab compounds usually uses Y as hydroxyl, R2 as-NR6R7, where R6 is hydrogen and R7. It is CBZ, where CBZ represents: T oxo carboxyl, and R1, R3 and R4 are hydrogen. The compound of formula la is named compound of formula Iab. ) Of thiol (· It is best to prepare in situ, for example by treating in a polar solvent, preferably N, N dimethylformamidine, with sodium or potassium hydride (5 ), Preferably potassium hydride). The reaction is carried out in a polar solvent, preferably N, N-dimethylformamide, at a temperature ranging from about 0 ° C to 40 ° C, and preferably at about 25 ° C. 5 minutes: minutes to 10 hours, preferably about 30 minutes to 6 hours. The sulfide reaction product, the compound of formula lab, is isolated by conventional methods and is preferably used directly in the next step. In the compound of formula I, R2 is -NR6r7, where R6 is hydrogen and R7 is CBZ ', where CBZ represents fluorenyloxycarbonyl, and Ri and R3 * R4 are hydrogen. Shown in the reaction formula XV, prepared from the compound of the formula Iab --- _ -53- This paper rule is obscured by Φ blueprints all over / \ ~ λ ..— u ί I "!-Μ (Please read the notes on the back before filling out this page}-Order · J · 580491 A7 B7 V. Description of the invention (51 of them. Lab Step 1

XV

Tertiary butyl GHN

NHCBZ SR 5 NHCBZ Step 2 Third butyl 〇ΗΝγΛ ^ 3 (〇) η | ^ (Please read the precautions on the back before filling out this page) ip Step 3 〇ip NHCBZ 〇lq,,?! Central Bureau of Standards, Ministry of Economic Affairs Employee Consumer Cooperative Printing Step 1-Preparation of Compound of Formula I The compound of formula 1 where γ is third-BuONH-, R2 is-NHCBZ, where CBZ represents benzyloxycarbonyl, and R1, R? * R4 is hydrogen is named The compound of Formula 10 is prepared by the same method as shown in Reaction Formula V111, or is preferably prepared by the method shown in Reaction Formula IX or X. Step 2-Preparation of Compound of Formula I Compounds of formula I in which η is 2, Y is third -BuONH-, and R2 is -NHCBZ, where CBZ represents fluorenyloxycarbonyl, and R1, R3, and R4 are hydrogen are named Formula Ip Compounds were prepared according to the same method as shown in Reaction Formula VIII. -54 This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 580491 A7 B7 V. Description of the invention (52) Prepared 'or better It is prepared according to the method shown in Reaction Formula IX or X. 'Step 3-Preparation of a compound of formula Iq where η is 2, Y is ΗΝΝΗ-, R2 is -NHCBZ, where CBZ represents benzyloxycarbonyl, and R1, R3 and R4 are as defined for the compound of formula I in the compound of formula I The compound named Formula Iq is prepared by the same method as shown in Reaction Formula VIII, or, more preferably, by the method of 'hydrolyzing the compound of Formula I p according to the method shown in Reaction Formula IX or X. In the compound of formula I, R2 M-NR6 R7, in the compound of formula I, R2 is -NR6 R7, where R6 and R7 are both hydrogen, and R1, R3 and R4 are hydrogen, according to / text in the reaction formula XVI As shown, it is prepared from a compound of formula Ip. ^! -I ..----- ΨΤΙ (Please read the notes on the back before filling this page) Order

Ip step 1

XVI

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs lr Step 2

Step 1—The preparation of the compound of formula Ir is usually in which η is 2, Y is third-BuONH-, R2 is · ΝΗ2, and -55- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) ) 580491 A7 B7 V. Description of the invention (53 Compounds of formula R1, R3 and R4 printed by hydrogen are printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. Compounds of the formula Ir are named compounds of formula Ir. By using a metal catalyst, palladium carbon is preferred. The reaction is prepared by reducing the compound of formula Ip. The reaction is carried out under about one atmosphere of hydrogen in a protic solvent, preferably ethanol, and at a temperature ranging from about 0.0 to 40 t. Che Fujia is about 2 5 ° C, and is carried out for about 4 to 48 hours, preferably about 8 hours. The N-third-butoxy reaction product is isolated and purified by conventional methods, that is, the formula Ir Compounds of compounds of formula I are generally named compounds of formula Is in which η is 2, AH is HONH-, R2 is · NΗ2, and Ri, r3, and R4 are hydrogen. The formula "the reaction between ubiquitination and strong defeat" is preferably hydrochloric acid. The reaction is sealed In a test tube, in an inert solvent, 丨, 2-dichloroformamidine is preferred, and at a temperature range from about -10 ° C to 40 ° C, preferably about 25x :, for about 4 To 48 hours, preferably about 18 hours. The hydroxylamine reaction product is isolated and purified by conventional methods, that is, the compound of the formula] [s, preferably in the form of its hydrochloride salt. Where R2 is -NR / gJ compounds of formula I In addition, compounds of formula Ir can also be used to produce ... and / or other compounds of formula VII as defined in the abstract of the present invention but not all hydrogen. For example, where R2 is The preparation of the compound of formula I of valamine is shown in the following reaction formula X V11. (Please read the notes on the back before filling this page)

、 1T > f-I · -56- The paper size is applicable to China National Standard (CNS) A4 (210X297 mm) 580491 A7 Β7 V. Description of the invention (54)

Reaction XVII

CBZHN

lr Step 1 O ^ NH third butyl OHN, ^ A ^ S (〇) nR5 〇 It

It step 2

S (〇) nR5 〇 lu (Please read the note ^^ on the back before filling this page) Ιυ Step 3

S (〇) nR £ 〇Ιν Printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs, Step 1. The preparation of the compound of formula Tt is usually where n is 2 and Y is the third _BuONH-… CBZ_valamine amine A compound of formula I in which R6 is hydrogen and R7 is 2- (S) _CBZ 3-methyl-1-butanyl, wherein CBZ represents benzyloxycarbonyl, and R1, R3, and R4 are all hydrogen are named compounds of formula 11. By making the compound of formula I, N-ethyl-N'-3 · (dimethylaminopropyl) carbodiimide and 1 R2 are 2- (S) 57- This paper size applies Chinese National Standard (CNS ) A4 size (210X297 mm) 580491 A7 B7 Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. 5. Description of the invention (55 Light phenyl hydrazone trijune, and a slight excess of tertiary amine, preferably triethylamine It is prepared by reacting with c BZ-(S)-valine acid in the presence. The reaction is in an inert solvent, preferably dichloromethane, at a temperature range from about 0.00 to 40.0. Then, it is preferably about 25 ° C for about 6 to 48 hours, and preferably about 16 hours. The reaction product is isolated by a conventional method, that is, a compound of formula u ' It can be used directly in the next step without further purification. Step 2-The preparation of the compound of formula Iu usually takes η as 2, Y is the third -Bu0NH ·, and r2 is 2_ (s) -CBZ · valamine. That is, a compound of formula J in which R6 is hydrogen and & 7 is 2_ (§) _amino · 3-methyl · 1-butyryl, and R1, R3, and R4 are all hydrogen, and is named a compound of formula Iu, which is borrowed It is prepared by using a metal catalyst, preferably palladium on carbon, to reduce the compound of formula It. The reaction is carried out under about one atmosphere of hydrogen in a protic solvent, preferably a mixture of methanol and ethanol ' In a temperature range from about 0 C to 40 C, preferably about 25 ° C, for about 1 to 8 hours, preferably about 3 hours. Isolate and purify the reaction product by conventional methods, That is, the compound of the formula IU is preferably a chromatography method. Step 3. The preparation of the compound of the formula Iv is generally wherein η is 2, Y is HONH-, and R2 is 2- (S) -amino-valamine. An amine, that is, a compound of formula I in which R6 is hydrogen and R7 is 2- (S) -amino_3_methyl_1-butyryl, and R1, R3, and R4 are all hydrogen is named a compound of formula B. borrow It is prepared by reacting a compound of formula Iu with a strong base, preferably hydrogen acid. The reaction is in a sealed test tube, in an inert solvent, preferably 1,2-digas methane, from about -20 Temperature range from ° C to 40 ° C -58- This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page), 1T 580491 A7 B7 Central Ministry of Economic Affairs Printed by the Consumer Bureau of the Standards Bureau 5. Under the description of invention (56), it is preferably about 2 5 C for about 4 to 48 hours, and preferably about 24 hours. The hydroxylamine reaction product, i.e. the compound of formula Iv, is isolated and purified by conventional methods, preferably in the form of its hydrochloride. The compound is similar to the method shown above, so that the compound of formula Ir is in a polar solvent, preferably N, N-dimethylformamidine, and about 2 equivalents of methyl iodide in the presence of a base. For the reaction, the preferred base is potassium carbonate, and then the product is reacted with hydrochloric acid gas as shown in step 3 above to prepare a compound in which R2 is _NR6R7, wherein H6 and H7 are both methyl. The compound of formula I is similar to the method shown above by using a compound of formula Ir with about 1 equivalent of dimethylaminesulfonyl chloride in an inert solvent, preferably two Chloromethane is reacted in the presence of a base. The preferred base is pyridine, and then the product is reacted with hydrochloric acid gas as shown in step 3 above to prepare R2 is _NR6R7, where R6 is Hydrogen and R7 is a compound of formula I of NHS〇2_N (CH). Similarly, in the same manner as shown in the above reaction formula XVII, a compound of formula Ir can be used to produce R6 and / or R7 as in In the abstract of the present invention, other compounds of formula I are not 'but hydrogen'.

Ui # can be separated and separated by any appropriate separation or purification procedures, such as, for example, filtration, extraction, crystallization, column chromatography, thin layer chromatography, thick layer chromatography, Preparing low or high pressure liquid chromatography, or a mixture of these procedures' to complete the separation and purification of the compounds and intermediates described in this article (please read the precautions on the back before filling this page). _

TT

57 V. Description of the invention (Chemistry. By referring to the following examples, proper separation = explanation can be obtained. However, of course, other equivalent separations can also be used :: Salts of compounds of formula I due to the presence of experimental nitrogen atoms, Some of the corresponding acid addition salts can be added. The transformation can be accomplished by treating with at least one equivalent of an appropriate acid, such as hydrochloric acid, chloroauric acid, sulfuric acid, acid, scale Acids and their analogs, and organic acids such as acetic acid, propionic acid, glycolic acid, propane, keto acid, oxalic acid, glutamic acid, malonic acid 'succinic acid, maleic acid, fumaric acid Acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, taranic acid, formic acid, acetic acid, p-toluene, acetic acid, salicylic acid and the like. Usually free base is dissolved in In an inert organic solvent, such as diethyl ether, ethyl acetate, chloroform, ethanol, or methanol and the like, an acid in the same solvent is added thereto. The temperature is maintained at ❹ ^ to "^. The resulting salt naturally precipitates out , Or a small amount of polar solvent can be used to make the solution appear. The compound of the present invention is prepared by the procedure outlined below: 1. Preparation of a compound of formula I in which R1 is hydrogen: Let the compound of formula:, R2 R3 u > = < • H〇2C, (4) Among them, R2, R3 and R4 are the same as those defined in the compound of formula I, except R: -60- This paper size is applicable to the Chinese national standard (⑽) M specification (Biemag 97 public director) 580491 A7 B7 V. Description of the invention _NH6R7; react with a compound of formula R5SH in the presence of a first order test, where R5 is as defined in a compound of formula I. 2 Another method of preparing a compound of formula j, comprising: making a compound of formula:

O R3 R4: one R1 R2 third butyl oHN, Y-SR5 wherein R1, R2, R3, and r5 are as defined in the compound of formula I, and react with a mild oxidizing agent, such as sodium homogene. 3. Another method for preparing a compound of formula I, comprising: making a compound of formula: R1 R2

O r3 R4 Third butyl OHN. / SR5 Printed by the Consumer Cooperative of the Central Sample Bureau of the Ministry of Economic Affairs where R1, R2, R3, R4 and r5 are as defined in the compound of formula I, and react with strong oxidants, such as OXONE or M-chloroperbenzoic acid. 4. Another method for preparing a compound of the formula Γ where η is 2, including: 61-This paper size applies the Chinese National Standard (CNS) A4 specification (210 × 297 mm) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 580491 A7 · -------- B7 V. Description of the invention (59) ^ ^^ Let the compound of the following formula: 一一 R; R2 罘 二 butyl〇HN ^ > ^ S (0) nR5 〇R3 R4 耆 八 中RR, R, R4 and R5 ', as defined in the compounds of formula I, react with a strong oxidizing agent, such as OXONE or m-chloroperbenzoic acid. 5. Another method for preparing a compound of formula I, comprising: making a compound of formula:

Ft ;, 'H〇U> ^ S (〇) nR5. 〇R3 R4 wherein η, Ri, r2, r3, r4, and r5 are as defined in the compound of Formula 1. In carbodiimide, such as N-ethyl The group -N,-(3-dimethylaminopropyl) -carbodiimide hydrogenate, and a tertiary amine are reacted with 0- (tertiary-butyl) hydroxylamine hydrogenate. 6. Another method for preparing the compound of formula I includes: making the compound of the following formula: -62- This paper size applies to China National Standard (CNS) A4 specification (2 丨 〇297mm) (Please read the precautions on the back before Fill out this page} 衣. 580491 V. Description of the invention (60 where η, and are defined as,

R2, R3, R4 and R5 are as if in a compound of formula I! Amine or Ν, 〇 · bistrimethyllithium sulfonium hydrazone reaction 7. Another method for preparing a compound of formula I includes the compound of formula: third butyl

〇, R3 R4 (Please read the precautions on the back before filling in this page) Clothing · Order Among them η, Ri, R2, R3, R4 * R5 are like formulas! In compounds • Definition, i is hydrolyzed under acidic conditions, such as using hydrochloric acid or trifluoroacetic acid. 8 · Another method for preparing compounds of formula I, including: printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

Third butyl OHN

-63- This paper size applies Chinese National Standard (CNS) A4 (210X297 mm) 580491 A7 B7 V. Description of the invention (61 where η, R1, R2 and R5 are as defined in the compound of formula I, except that R2 is not allowed Is other than -NR6R7; reacts with a compound of the formula RX, wherein R is a lower alkyl group, a cycloalkylalkyl group, an octadecyl group, a carbamoyl group, an acetamido group, an amidyl group, and -s. 2 R a, wherein Ra is lower alkyl or -NRbRc, wherein R and R are fluorene or lower alkyl, respectively; and X is gas, bromine or iodine. 9. Another method for preparing a compound of formula I includes: Compound of formula:

R1 R2 Third butyl OOH

Η (Please read the notes on the back before filling in this page) It is other than -NR6R7; • Under hydrogen in the presence of a catalyst, such as palladium on carbon, and acetone to give an N-isopropyl derivative. 10. Another method for preparing a compound of formula I, comprising: making a compound of the formula: NHCBZ -64-this paper size applies the Chinese National Standard (CNS) A4 specification (21〇 > < 297 mm) 580491 A7 B7 V. DESCRIPTION OF THE INVENTION (62) reacts with the anion of a compound of formula R5S Η, where R5 is as defined in the compound of formula I. 1 1. Another method for preparing a compound of formula I, comprising: making a compound of the formula: νη2 a third butyl group where R5 is as defined in the compound of formula I Methylaminopropyl) -carbodibenzylamine and b-hydroxyphenylammonium trioxide, and the presence of tertiary amines, reacted with a halogenating agent, such as CBZ- (S) -valine, or in a base It is reacted with an alkylating agent such as methyl iodide or in the presence of a base with an amine sulfonyl chloride such as dimethylamine sulfonyl chloride. 12. Another method for preparing a compound of formula I, including: Making a compound of the following formula: (Please read the notes on the back before filling this page).

R1, R2, R3, and R4 are as defined in the compound of formula I, except that R2 cannot be -NR6R7; in the presence of a secondary base, react with a compound of formula R5SH, where R5 is -65- · This paper size applies the Chinese National Standard (CNS) A4 specification (210X297). 580491 A7 B7 V. Description of the invention (63 Same as defined in the compound of formula I. I3. Another method for preparing the compound of formula I includes the following: Compound of formula:

R, 1 R2 RQ

X Or3 R4 reacts with the anion of a compound of formula R5SH, where R5 is as defined in the compound of formula I. 14. Another method for preparing a compound of formula includes: Making a compound of the following formula: (Please read the precautions on the back before filling out this page)

, R2 R〇, meaning / S〇2R 〇 in the presence of a hindered base, and alkyl or aralkyl autogenate 15 5 Another method of preparing a compound of formula I, comprising: making a compound of the formula:

Br

-66 This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 580491 Α7 Β7 V. Description of the invention (64) ^ ~ — In the presence of tetravalent (triphenylphosphine) | bar (〇) And react with a compound of formula RiiB (OH) 2i, wherein R11 is aryl or heteroaryl. (Please read the notes on the back before filling this page.) The compounds of formula I inhibit mammalian matrix metalloproteinases such as stromolysin, gelatinase, stromelysin and collagenase, so they can be used as therapeutically active Substances, in particular for the treatment of mammalian diseases related to excessive degradation of matrix and connective tissue caused by MMP-such as joint diseases (rheumatoid arthritis and osteoarthritis), multiple sclerosis, scallop Resorbable diseases (such as osteoporosis), diabetes-promoting collagen destruction, chronic obstructive pulmonary disease, stroke-related cerebral hemorrhage, periodontitis, corneal ulcers, skin ulcers, tumor invasion and metastasis , And labyrinthic angiogenesis. Compounds of formula I substantially inhibit the release of tumor growth factors (TNF) from cells and are therefore useful in the treatment of conditions regulated by TNF, such as inflammation, fever, cardiovascular effects, bleeding, coagulation and acute phase reactions, cachexia and Loss of appetite, acute infection, shock status, postoperative restenosis, aneurysm disease, transplantation response to the host, and autoimmune response. Compounds of Formula I printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs also inhibit the release of other bioactive molecules from cells, including soluble receptors (CD30 and TNF (pages 55 and 75), IL-6, IL-1, and TS Η receptors), adhesion molecules (such as l-selection, ic AM-1, fibronectin) and other growth factors and cytokinins, including Fas ligand, TGF-han, EGF, HB-EGF, SCF And M-CSF. Inhibition of the release or shedding of these proteins can therefore be used to treat various disease states, such as rheumatoid arthritis, multiple sclerosis, vascular disease, type π diabetes, ΗIV, cachexia, psoriasis, allergies, hepatitis, inflammation Sex-67- This paper size applies Chinese National Standard (CNS) A4 size (210x297 mm) 580491 A7 B7 V. Description of invention (65 bowel disease and cancer. (Please read the precautions on the back before filling this page) Formula I The ability of compounds to inhibit matrix metalloproteinases, such as collagenases -1, -2, and -3, stromalysin · i, gelatinases a and B, and stromalysins, etc. It is well known to confirm this by in vitro analysis, such as the analysis of MMP Enzymatic Assay described in FEBS, 296, 263 (1992), or a modification thereof. The ability of a compound of formula I to inhibit the MM P regulatory process in vivo It can be tested using interleukin- stimulated cartilage colonization analysis and cartilage plug colonization analysis. The ability of a compound of formula I to inhibit TNF release is shown in Examples 45 and 47. The present invention is also relevant. Pharmaceutical composition comprising pharmaceutically acceptable non-toxic excipients and a therapeutically effective amount of a compound of formula I. Printed in pure form or in an appropriate pharmaceutical combination by the Consumer Cooperatives of the Central Standards Bureau, Ministry of Economic Affairs The administration of a compound of formula j or a pharmaceutically acceptable salt thereof in the form of a substance can be accomplished by any of the accepted modes of administration or formulations that provide similar political utility. Therefore, it can be, for example, oral, nasal, non-menstrual Enteral, topical, transdermal or rectal means, in solid, semi-solid form, lyophilized powder or liquid dosage form, such as, for example, lozenges, troches, pills, soft elastic and hard gelatin capsules, Powders, solutions, suspensions or sprays, or the like, are preferably administered in a unit dosage form suitable for a single dose at the correct dosage. The composition will contain traditional pharmaceutical carriers or excipients and as an active agent In addition, it may also contain other pharmaceutical preparations, pharmaceutical preparations, carriers, adjuvants, etc. Generally, depending on the desired mode of administration, Agriculturally acceptable composition 68-580491

Description of the invention (66 Printed by the Consumer Cooperatives of the Central Government Bureau of the Ministry of Economic Affairs of the People's Republic of China, containing compounds of formula ί, or their pharmaceutically acceptable salts, containing about 1% to about 99% by weight, and 99% to 1% % By weight of suitable pharmaceutical ingredients > > ι]. Preferably, the offending composition will contain from about 5 to 75% by weight of a compound of formula I, or a pharmaceutically acceptable salt thereof, and the rest It is an appropriate pharmaceutical excipient. The preferred route of administration is oral, which uses a convenient daily dose of phototherapy, which can be adjusted according to the severity of the disease state to be treated. In order to 'such oral administration, borrow It can be combined with any daily-used excipient to form a pharmaceutically acceptable composition containing a compound of formula I, or a pharmaceutically acceptable salt thereof, such as, for example, pharmaceutical grades of mannitol, lactose , Starch, pregelatinized starch magnesium stearate, sodium saccharin, talc, cellulose ether derivatives, glucose, gelatin, sucrose, citrate, propyl gallate and the like. Such a composition system Use solvent , Suspensions, tablets, pills, capsules, powders, sustained release formulations and the like. It is preferred that such compositions will be in the form of capsules, sachets or lozenges, and will therefore also be Contains diluents, such as lactose, sucrose, diphosphoric acid, and the like. 'Disintegrants, such as croccamellose sodium or derivatives thereof; lubricants, such as magnesium stearate and the like; and Binders, such as starch, gum arabic, polyvinylpyrrolidone, gelatin, cellulose ether derivatives, and the like. Formula! Compounds or pharmaceutically acceptable salts thereof can also be formulated into formulations, for example, using about 0.5 % To about 50% of active ingredient, dispose it in a carrier that slowly dissolves in the body, such as polyethylene glycol and polyethylene glycol and calcium (please read the precautions on the back before filling this page) ) > Packing · -Order Φ -69- This paper size is suitable for towels_Home Standard (CNS) A4 Specification (21Gx297 ^ j- 580491 Printed by A7 B7 of the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs V. Description of the Invention (67) (PEG), such as PEG1000 (96 %) And PEG4000 (4%). Liquid compositions that can be administered pharmacologically, for example, by compound of formula I (about 0.5% to about 20%) or a pharmaceutically acceptable salt thereof, and if necessary The selected pharmaceutical adjuvant is prepared by dissolving or dispersing in a carrier such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like, thereby forming a solution or suspension. If desired, The pharmaceutical composition of the present invention can also be used to contain a small amount of auxiliary substances, such as wetting or emulsifying agents, buffers, antioxidants and the like, such as, for example, citric acid, sorbitol monolauric acid, etc. , Triethanolamine oleate, butylated hydroxytoluene, etc. The exact method for preparing such dosage forms is known or apparent to those skilled in the art; see, for example,

Pharmaceutical Sciences, 18th edition, Mack Publishing Company ’Easton, Pennsylvania (1990). In any event, the composition to be administered will contain a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in order to treat the 'inhibition of matrix metalloproteinase activity' according to the invention To alleviate the disease-state. A compound of formula I or a pharmaceutically acceptable salt thereof administered in a therapeutically effective amount will vary depending on various factors including the activity of the particular compound used, the metabolic stability and effect of the compound Length 'Age, weight, general health, gender, diet, mode and timing of administration, route of excretion, composition of medication, severity of specific disease condition', and treatment the host has undergone. Generally, the daily dose with therapeutic effect is from about 0.014 mg to about 14 3 mg / kg body weight -70-this paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) t --- r .------ Install ------ Order ------ (Please read the notes on the back before filling this page) 580491 A7

Order 4 580491 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs V. Invention Description (69-N-CBZ · Hexazone (18g '76.5 亳 Mor) solution, followed by pyridinium achromate (33 g, 153 moles). The mixture was stirred overnight and then isopropanol (2 liters) was added over a period of 3 hours. The reaction mixture was filtered through silica gel and repeated with dichloromethane and ethyl acetate. Rinse the filter cake gently. Evaporate the mixed filtrate under reduced pressure. Silica gel chromatography uses 50% ethyl acetate / hexane to give a yellow oily oxo_n_CBZ · hexahydroρ bidian. Example 2 Preparation of the compound of formula (3) 2 A · Huanghui where R2 is hydrogen, and r 3 and r4 are attached with carbon atoms at the same time, representing N-CBZ-hexahydropyridine of the formula (3, the third (but Oxycarbonylmethylene) triphenylphosphorane (28 g, 74.4 mmol) added to 4 · oxo-N-CBZ-hexahydropyridine (14.2 g, 61.3 mmol) in benzene (150 ml) And the solution was stirred under reflux overnight. The solution was concentrated and the residue was triturated with hexane (500 ml). The filtrate was concentrated to obtain 4-tertiary-butoxyfluorenyl · methylene-N-CBZ-hexahydropyridine as a colorless oil. 2B · Preparation Changing the formulas of R2, R3, and R4 Similarly, based on Example 2 A procedure, but with: formic acid; acetone; propanal; cyclopentanone; cyclohexanone; -72- This paper size applies the Chinese National Standard (CNS) A4 specification (210X 297 mm) (Please read the note on the back first Please fill in this page again. Order-Φ 580491 Α7 Β7 V. Description of the invention (70) 1,4 _cyclohexanedione monoethyl ketal; 4-methylcyclohexanone; phenylacetaldehyde; 4 -(Dibenzyl-4-yl) butane 6 ^; cyclopentylacetaldehyde; tetrahydrobranone; and tetrahydrofuran; instead of 4-oxo-N-CBZ-hexahydropyridine, and if necessary With: tertiary-butyl_3-phenylpropanoic acid-2-triphenylphosphorane; tertiary-butylpropionic acid_2 · triphenylphosphorane; and tertiary-butyl-3-methylpropane Acid-2-triphenylphosphorane; instead of tertiary- (butoxycarbonylmethylene) triphenylphosphorane, the following compound of formula (3) is prepared: 1- (tertiary-butoxycarbonyl) 1-fluorene Ethylene; 1 · (tertiary-butoxycarbonyl) · 2,2-dimethylethylene; 1_ (third · butoxycarbonyl) _1_methyl-2 · ethylacetamidine; third-butoxymethylenecyclopentane; third-butoxycarbonylmethylenecyclohexane; Ministry of Economic Affairs Printed by the Consumer Standards Cooperative of the Central Bureau of Standards (please read the precautions on the back before filling out this page) Third · Butoxycarbonylamidino-4 · methylcyclohexane; 1_ (Third-butoxycarbonyl)- 2-benzylethylene; 1- (third · butoxycarbonyl) -1_isopropyl-2-benzylethylene; 1_ (third-butoxycarbonyl) · 2_ [3 · (diphenyl_4 · yl)] -Propyl ethylene; 1-(third butoxycarbonyl) -2 -cyclopentyl methyl ethylene; -73- This paper size applies Chinese National Standard (CNS) A4 specification (210 × 297 mm) 580491 A7 B7 Central Ministry of Economic Affairs Printed by the Bureau of Consumer Standards of the Standards Bureau 5. Description of the invention (4 · (Third-butoxycarbonylmethylene) _tetrahydropiran; and 4- (Third-butoxycarbonylmethylene) _tetrahydropiper Mum. "2C" can be changed in the same way, according to the procedure of Example 2a above, but other compounds of formula (1) can be used instead of 4-oxo-N-CBZ_hexahydropyridine, and other Instead of (tertiary-butoxycarbonylmethylene) triphenylphosphine, the compound of formula (2) was used to prepare other compounds of formula (3). Example 3 Preparation of compound 3A.1 of formula (4), wherein R2 agrohydrogen, and R3 * R4 are attached together with carbon atoms, also shown in formula (4) of N-CBZ · hexahydropyridine, namely formula (4a Compound) Trifluoroacetic acid (10 ml) was added to 4-tert-butoxycarbonylmethylene-N_CBZ-hexahydropyridine (20 g, 60.3 mmol) in dichloromethane (30 ml). 'And stir the solution for 1.5 hours at room temperature. After the solvent was evaporated off, the residue was triturated with diethyl ether to obtain 4-carboxymethylene_N-CBz.hexahydropyridine as a crystalline white solid. 3B · 1 where R2 is hydrogen, and carbon atoms are used to attach ... and ... together, which expresses the formula (4) of tetrahydropiperan, that is, formula (4b) Ml) was slowly added to a suspension of sodium hydride (5.48 g, 228.2 mmol) in tetrahydrodecan (204 ml). When the addition was complete, the temperature could be maintained below 1 2 Ό To the mixture, trimethyl phosphonic acid acetate (34.22 ml, 211.4 mmol) was added at a constant rate. Stirring was continued: stirring for 10 minutes. To the reaction mixture was added tetrahydrofuran (2. Ml) of 2,3,5,6-tetrahydropiperan-4_one (16.28 g, 163.0 mmol) -74- This paper size applies to China National Standard (CNS) Α4 specification (2 丨 〇 > < 297 mm) l ·, r .----------- IT -----. φ (Please read the notes on the back before filling out this page) 580491 Employees of the Central Standards Bureau of the Ministry of Economic Affairs Consumption cooperative prints A7 «_____B7_____ V. Description of the invention (72) Solution and keep the temperature below 30. (:. After the addition is complete, continue stirring at room temperature for 30 minutes, then add methanol (1 0 ml) and 2M sodium hydroxide (326 ml), and the mixture was stirred at room temperature overnight. The resulting solution was concentrated to half of the original volume and it was diluted with 6M hydrochloric acid (108 ml) Acidified to pH 1 · 2. The reaction mixture was distributed between ethyl acetate and water, the mixed organic extracts were dehydrated with magnesium sulfate, and the solvent was removed under reduced pressure to give 4- (carboxymethylene) Based) -2,3,5,6-tetrahydrofuran (22.62 g), can be used directly without further purification. 3C. Preparation of changing formula (4) of r2, r3 * r4 Similarly, according to the above example 3A Procedure, but replacing 4- (third · butoxycarbonylmethylene) -N-CBZ_hexahydropyridine with another compound of formula (3) to prepare the following compound of formula (4): Methyl-1 acetofluorene; 1-carboxy-2,2-dimethylethylene; 1-carboxy-2 -ethyl-1 -methylacetamidine; Hexane; carboxymethylene- (4-methylcyclohexane); 4-carboxymethylene cyclohexanone mono-ethylidene ketal; 2 · yl group fluorenyl acetoacetone; 2- [ 3_ (diphenyl-4 · yl) propyl] -1-carboxyl Acetamidine; 2- (1-methyl) -1-isopropyl-1-ethylidene; 1-carboxy-2-cyclopentylmethylethylene; 4-slimethylene-tetrahydrothiosulfan; and -75- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) _ installed-(Please read the precautions on the back and fill in this page) Order printed by the Central Consumers Bureau of the Ministry of Economic Affairs, Consumer Cooperatives 580491 A7 _____ B7 V. Description of the invention (73) 4 Carboxymethylene- (tetrahydropiperan-1, 1-dioxide). 3D · Preparation to change the formula (4) of R2 and RypR4 Similarly, according to the procedure of Example 3 A above, but using another compound of formula (3) instead of 4 · (third butoxycarbonylmethylene) -N_CBZ_hexa Hydropyridine 'can be used to prepare other compounds of formula (4), or it can be prepared by methods known to those skilled in the art. In addition, they are also commercially available. For example, 1-cyclopentenecarboxylic acid and 1-cyclohexenecarboxylic acid can be purchased from Lancaster Synthesis Inc. Example 4 Preparation of compound 4 A of formula (5) • Preparation of formula (5) in which R5 is 4-phenoxyphenyl. Thiomethyl in Ν, Ν · dimethylamidamine (DMF) (150 ml) A solution of sodium oxide (25 g) and 4-bromodiphenyl ether (25 g) was refluxed overnight. The mixture was cooled and added to diluted aqueous sodium hydroxide. The aqueous layer was rinsed with ether to remove by-products and acidified with hydrogen acid. The product was extracted with ether 4_ (benzyloxy) sulphur, and the acid layer was dehydrated and evaporated to give 4- (phenoxy) thiophenol (19-20 g) as a red oil. This material was used without further purification. 4 B · Inter-preparation of 4-bromodiphenyl ether (50 g, in which R5 is 4- (4-bromophenoxy) phenyl) 200.7 mmol) solution was cooled to 0 ° C, and chlorosulfonic acid (14.7 liters, 220.8 mmol) was added dropwise over a period of 20 minutes. The solution was stirred for an additional 10 minutes and warmed to room temperature. Warm, and stir for an additional hour. In this mixture _ -76- This paper size applies Chinese National Standard (CNS) A4 specifications (210 X 297 mm j '(Please read the precautions on the back before filling this page ) Order 580491 Printed by A7 B7, Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs 5. Description of the invention (74) Add chlorammonium chloride (23.6 ml, 270.9 mmol), and then add N, N-dimethylamidine as a catalyst Amidine (1.5 ml), and the mixture was refluxed for 2 hours. The mixture was cooled to room temperature, and additional chlorpyrrolidine (23 6 ml, 270.9 mmol) was added, and the mixture was refluxed for 3 hours, Cool to room temperature and stir for an additional 12 hours. The solution was concentrated to an oil and stagnated with dichloromethane. And place under high airspace (1 Torr (mmHg)) for several hours until the mixture is completely cured. Dissolve the mixture directly in dichloromethane (160 ¾ liters) 'Add it dropwise to the containing n, N-dimethylformamide (4 ml, 52.2 mmol) in a solution of triphenylphosphine (157 g, 602 mmol) in methane (160 ml). Stir the mixture 2 hours, diluted with 1 M aqueous hydrochloric acid (300 ml), and expanded; stirred for 1 hour. The liquid layer was separated, extracted with dichloromethane (200 ml), and the organic layer was mixed with 200 ml Brine was washed, dehydrated (MgSCU) and concentrated in the air. The resulting solid was further purified by trituration with 7500 ml of hexane. The solid was then dissolved in 750 ml of diethyl ether and 2M aqueous sodium hydroxide (2 X 350 亳 L) extraction and back extraction of the basic liquid layer with diethyl ether (2 X 400 ml). Adjust the liquid layer to pH 2, extract with diethyl ether (3 X 200 ml), and mix the organic layers Dehydrate (MgSCU) and concentrate it to give 4_ (4_bromophenoxy) thiophenol (4 5.6 g, 81%). 4 NMR (CDC13) d 3.43 (s, ιΗ), 6.86 (d, J = 8.9 Hz, 2H), 6.89 (d, J = 8.6 Hz, 2H) 5 7.28 (d, J = 8.6 Hz, 2H), 7.43 (d, J = 8.9 Hz, 2H). In a similar manner, the corresponding 4-gases and 4-gases were obtained from commercially available 4-halogen diphenyl ethers, respectively. analog.

4- (4-chlorophenoxy) thiophenol: NMR (CDCl〇β 3.43 1HL _____- 77-_ This paper size applies to China National Standard (CNS) A4 size (27 ^ x297 mm) '-(please first (Read the notes on the back and fill out this page)

580491 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (75 6 · 90 (me, 4H), 7.27 (me, 4H). 4 · (4_fluorophenoxy) thiophenol: 4 NMR (CDC13) J3.41 (s, 1H), 6.85 (d, J = 8.7 Hz, 2H), 7.00 (mc, 4H), 7.26 (d, J = 8.7 Hz, 2H) 〇4- (4-eridine (Oxy) thiophenol: 1HNMR (CDCl3) β7.05 (d, J = 9.0 Hz, 2H), 7.29 (d, J = 7.3 Hz, 2H), 7.44 (d, J = 8.8 Hz, 2H) , 8.70 (d, J = 7.3 Hz, 2H); EIMS (M +): 203. 4- (5-Gas-2-pyridyloxy) thiophenol: j NMR (CDC13) d 6.87 (d, J = 8.5 Hz, 1H), 7.01 (d5 J = 8.7 Hz, 2H), 7.32 (d, J = 8.7 Hz, 2H), 7.63 (d, J = 8.6 Hz, 1H), 8.15 (d, J = 2.8 Hertz, 1H). Example 5 Preparation of a compound of formula (10) 5 A. Huang Bei where R 1 and R 2 are attached together with carbon atoms, representing tetrahydrogen ^ formula (8), that is, the formula (8aH) Add a 1.5M solution of diisobutyl hydrogen (DIBal-H) (419 ml, 629 mmol) in toluene at a rate capable of maintaining the internal temperature at no more than _ 2 5 ° C. Nitrogen inlet Mechanical stirrer, low temperature thermometer, 500 ml pressure equalizing funnel, and containing -4 (rc, diethyl tetrahydrofuran-4,4-dicarboxylic acid in toluene (600 ml) (7078 g, 30%) 74 millimoles) in a 3 liter Morton flask. Stir the mixture for an additional 10 minutes and add dropwise absolute ethanol (595 ml) dropwise over 20 minutes while maintaining the internal temperature to not exceed- 15 ° C. Over a period of 15 minutes, solid rotten hydrogenated steel (11.6 g '307.4 millimoles) was added in three batches and the ice bath was removed to allow the mixture to warm to room temperature within i hours. And within 5 minutes -78- Participate in paper standards (CNS) A4 size 717 ^ 797mm HI ml · ^ Bn Hi · — aMMMMMmm i · ϋι (Please read the precautions on the back before filling in this Page), 11 580491 A7 B7 76 V. Description of the invention (add saturated aqueous sodium sulfate (325 亳 liters). Cool the mixture to _5 ° C, add ethyl acetate (250 ml), and place in diatomaceous earth Filter the flocculent white precipitate. Rinse the diatomaceous earth pad with ethyl acetate (7 X 450 ml) and rinse with brine ( 200 ml), the filtrate was washed with magnesium sulfate, dehydrated, and concentrated in the air. This residue was dissolved in a small amount of ethyl acetate, filtered through a sintered glass funnel containing silica gel (40 g), and the filtrate was concentrated in the air to obtain the base 4-( Ethyl) tetrahydrobranthane 4-carboxylic acid ethyl ester (48.5 g, 84%). 5 Β · ^ —A method for preparing a compound of formula (8) in which R 1 and R 2 are attached together with carbon atoms, and 1) Lithium iodide (1.16 g, 8.66 mol) Add to a solution of tetrahydropiperan-4,4 · dicarboxylic acid diethyl ester (400 g, 1.74 mol) in n, N-dimethylformamide (4 ml), then Then add sodium cyanide (94 mg, ΐ 9ιmol). The mixture was heated to 130 ° C. for 7 hours, and 140 to 25 hours. After GC analysis, the reaction was shown to be complete> 95%. The mixture was distributed between 33% diethyl ether / hexane (100 ml) and brine (25 ml). The organic layer (25 ml) was washed with additional brine, dehydrated (MgS04) and concentrated in the air to obtain tetrahydropiperanecarboxylic acid ethyl ester (253 mg, 92%). Note: In the M reaction, 2 equivalents of sodium acetate were used instead of 丨 j equivalents of sodium cyanide 'and heated for more than 12 hours to obtain the same result. 2. By adding 2.5 M N-butyllithium in hexane (30.3 liters, 75.6 mi) at 0 ° C; add spring liquid to tetrahydrocran (M # ml) Diisopropylamine (10.6¾ liters, 75.6 millimoles) in solution and stirred for 20 minutes to prepare lithium diisopropylamine. Then at _78 ^ τ, within 15 minutes will be in tetrahydro t——r .----------- IT ------ φ (Please read the precautions on the back before filling in this (Page) Printed by the Consumer Cooperatives of the Central Procurement Bureau of the Ministry of Economic Affairs

580491 A7 B7 V. Description of the invention (77) Tetrahydropiperan in furan (50 liters) 4 • Ethyl carboxylate (丨 0 g, 63 2 mmol) was added to diisopropyl Lithium Amine solution. The resulting solution was stirred for an additional 50 minutes, and solid formaldehyde (0 g) was added in one batch. Allow the mixture to slowly warm to room temperature within 9 hours, dilute with 2M water-containing hydrogen chloride (100 liters), filter on celite chop, rinse with diethyl ether (2 X 200 strokes) Of it. The filtrate was washed with an additional portion of diethyl ether (2 x 200 ml). The mixed organic layer was washed once with 2M aqueous hydrochloric acid (100 ml), saturated aqueous sodium bicarbonate (100 ml), dehydrated with magnesium sulfate, and concentrated in the air to obtain a slightly impure product 4 _ ((Hydroxymethyl) tetrahydroan-4-carboxylic acid ethyl ester (11.5 g, 97%)) was directly included in the next reaction without further purification. IR (pure) 3433 (br), 1726 cm; lfi NMR (CDC13) d 1.30 (t5 J = 7.1 Hz, 3H), 1.57 (ddd, J 2 13.8, 10.1, 4.4 Hz, 2J), 2.07 ( dm, J = 13.8 Hz, 2H), 2.30-2.45 (br s, 1H), 3.56 (ddd, J = ll.9, 10.3, 2.7 Hz, 2H), 3.66 (s, 2H), 3.82 ( dt, J = 11.9, 4.2 Hz, 2H), 4.24 (q, J = 7.2 Hz, 2H); 13C NMR (CDC13) d 14.25 (q), 30.54 (t), 46.63 (s), 61.04 (t), 64.79 (t), 69.02 (t), 175.24 (s); HRMS, calculation for C19H1604 (188.1049, experiment): 1881105. 5. ... Where R 1 and R 2 are attached together with a carbon atom, which represents a compound of formula (8), which is a compound of formula (8), that is, the compound of formula (8) 1 · 6ΜΝ_ Butyl lithium (29.1 ml, 46.6 mol) was added to a solution of diisopropylamine (65 ml, 46.6 mmol) in tetrahydrofuran (150 ml) and stirred at -78 ° C for 2 For 0 minutes, prepare an isopropylamine bell. Then add pure n _ within 5 minutes (No .: r · -80- This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling in, write this page ) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 580491 A7 B7 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs , 38.9 mmol), and the resulting solution was stirred for an additional 50 minutes. Solid dynein (13.5 g, 1S5.4 mmol) was added in one batch, and the mixture was allowed to slowly warm to room temperature within 9 hours. The mixture was diluted with 2M aqueous hydrochloric acid (100 ml), filtered over crushed, celite, and washed with diethyl ether (2 x 2000 ml). The mixed organic layer was washed once with 2 M aqueous hydrochloric acid (100 ml), saturated aqueous sodium bicarbonate (100 ml), covered with hydrazone sulfate, dehydrated, and concentrated in the air. Chromatography on silica gel and elution with 50% ethyl acetate / hexane gave slightly impure N- (third-butoxycarbonyl) _4- (hydroxymethyl) hexahydropyridine_4_carboxylic acid Ethyl ester (10.57 g, 95%) as a pale yellow oil, which was directly incorporated into the hydrolysis reaction (LiOH): 1 H NMR (CDC13) ^ 126 (t, J = 7.4 Hz, 3H), 1.40 -1.53 (m, 2H), 1.46 (s, 9H), 2 00-2.12 (m, 2Η), 3.05-3.16 (m, 2Η), 3.65 (s, 2Η), 3.70-3.83 (m, 2H) ), 4.23 (q, J 2 7.2 Hz, 2H). 5 D · Complex ^ wherein R 1 and r 2 are attached together with carbon atoms, representing four g of rabbit compound of formula (9), that is, compound of formula (9a) will be lithium hydroxide monohydrate (16.7 g, 398.5 mmol Mol) was added to a solution of ethyl 4- (hydroxymethyl) tetrahydropiperan-4-carboxylic acid (25.0 g, 132.8 mol) in 4.5: 1 methanol / water (220 ml). The mixture was heated to reflux for 40 minutes, and the methanol was removed by concentration in a vacuum using a water bath temperature not higher than 45 ° C. The liquid layer was then extracted into diethyl ether (4 × 100 ml), and the ether layer of the mixture was washed twice with 2M sodium hydroxide (15 ml). The mixed aqueous alkaline layer was cooled to 0 ° C, acidified to pH 3.0 with 8M aqueous hydrogen acid, saturated with solid sodium chloride, and ethyl acetate (8 X 250 _ -81-- -^^ 装-(Please read the notes on the back before filling this page)

mL

、 1T 4 This paper size applies Chinese National Standard (CNS) A4 specification (210 X297 mm) 580491 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economy Dehydrated with magnesium sulfate and concentrated in the air. The white fluffy powder residue was recrystallized from a small amount of dichloromethane / hexane to obtain pure 4 _ (# methyl) tetrahydropiran_4 • carboxylic acid (PM G, 80%) 〇 Atoms will be attached to the ancient method of a compound of formula (9) in a cyanocyanine ~ by 0. (: 2 45 M butyllithium in hexane (ΐό 5 ml) was added to a solution of diisopropylamine (5.80 ml, 41.4 mmol) in tetrahydrofuran (40 ml) and stirred for 20 minutes to prepare lithium diisopropylamine. Then in Within 15 minutes, tetrahydropiperan-4-carboxylic acid (2.5 g, 19.2 mmol) in tetrahydrofuran (10 ml) was added to a solution of lithium diisopropylamide, and formed into a slurry. Then add hexamethylphosphamide (2 ml). Stir the resulting solution for 2 5 minutes and let the gaseous formaldehyde vapor (borrow After heating 4 g of secondary formic acid to 175-20 (rc to prepare) within 5 minutes, the solution was immediately warmed to room temperature. The slurry was carefully concentrated at ambient temperature to '8 Hydrochloric acid was used to acidify it to pH 3, saturated with solid sodium chloride, and extracted with ethyl acetate (8 x 100 ml). The mixed organic layer was dehydrated with magnesium sulfate and airborne Concentrated. Chromatographed on silica gel (80 g) and eluted with 10% methanol / dichloromethane to give 4- (hydroxymethyl) tetrahydropiperan-4-carboxylic acid (1.80 g) as a white solid. , 5 8%). Melting point 113.7-115 ° C; IR (KBr) 3420 (br), 1724 cm 1,4 NMR (DMSO-d6) d 1.43 (ddd, J = 13.5, 11.0, 4.4 Hz, 2H), 1.85 (dm, J = 13.4 Hz, 2H), 3.37 (td, J = 11.3, 3.0 Hz, 2H), 3.43 (s, 2H), 3.71 (dt, J = 11.6, 3.9 Hz, 2H), 4.81 (br s, 1H), 12.24 (s, 1H); 82 wood paper size applies Chinese National Standard (CNS) A4 specification (210XM7 mm) (Please read the precautions on the back before filling this page) Order Φ 580491 Ministry of Economic Affairs Printed by the Consumer Standards Cooperative of the Central Bureau of Standards Α7 Β7 V. Description of the invention (80)

13C NMR (DMSO-d6) β 30.42 (t), 46.38〇), 64.35 (t), 68.15 (t), 69.02 (t), 176.08 (s); HRMS about C7H12〇3: c, 52.49; H 7.55; Experiment 値: C, 52.50; H, 7.62. 5 f · Prepare a formula in which r1 and r2 are changed to hexahydropyridine with a carbon atom (9 H dagger compound, that is, a compound of formula (9 b)) If hydroxide monohydrate (6.95 g, 165.5 mol) is added N- (third-butoxycarbonyl) _4- (hydroxymethyl) hexahydropyridine-4-carboxylic acid ethyl ester (9.52 g, 33.1 mmol) in 2 ·· 1 methanol / water (100 ml) ) Solution. The mixture was heated to reflux for 30 minutes, and the methanol was removed in the air by concentration using a water bath temperature not higher than 4 5. The liquid layer was cooled to 0 ° C, and 6M aqueous hydrochloric acid was used. It was acidified to pH 3.0 and extracted with ethyl acetate (4x75 ml). The mixed organic layer was dehydrated with magnesium sulfate, concentrated in the air, and recrystallized from methylene chloride / hexane. N_ (tertiary-butoxycarboxyl) -4_ (hydroxymethyl) hexahydropyridine-4-carboxylic acid (8.59 g, 100%) was obtained. One of 50 preparations in which R1 and R2 were attached together with broken atoms The method of representing a compound of the formula f 9) of hydropyridine is at 0. (: Add 2.45MN · butyllithium (69 ml, 168.8 mmol) in hexane to a solution of diisopropylamine (24 ml, 171.2 mmol) in tetrahydrofuran (40 ml) , And stirred for 20 minutes to prepare a diisopropylated amination bell. Then within 15 minutes, the N- (third_butoxycarbonylpyridine_4_carboxylic acid in tetrahydrofuran (35 ml) G, 78.5 mmol) was added to a solution of lithium diisopropylamide to form a slurry, followed by the addition of hexamethylphosphamide (2 ml). The resulting solution was stirred for 25 minutes, and then the gaseous formic acid was allowed to evaporate. Vapor (by removing paraformaldehyde (16.4 g, 189 millimeters) in 5.1 minutes-83-This paper size applies Chinese National Standard (CNS) A4 specifications (21〇 > < 297 mm_ I n I —Til —Li -—— IIIII (Please read the precautions on the back before filling out this page) • Φ 580491 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (81) 1 Moore) Heat to i75 -20 (prepared by TC) through the solution, immediately allowed to warm to room temperature. The slurry was concentrated at ambient temperature , Acidify it to pH 4 with 6 "hydrochloric acid, saturate it with solid sodium chloride, and extract it with ethyl acetate (8 X 100 liters). Dehydrate the mixed organic layer with magnesium sulfate, Concentrated in tritium. Chromatographed on silica gel and eluted with 10/0 methanol / dichloromethane to give N_ (third-butoxycarbonyl group 4_ (hydroxymethyl) π-hydropyridine- 4_ Metabolic acid (4 g, 20%). Melting point i56.6_157.3 ° C; h NMR (DMSO-d6) d 1 · 25 · 1 · 37 (m, 2H), 1 · 38 (s, 9H), 1.85 (dm, J = 13.7 Hz, 2H), 2.78-2.94 (br m, 2H), 3.41 (s, 1H), 3.70 (dm, J = 12.8 Hz, 2H), 4.87 (br s, 1H), 12.34 (S, 1H); Analytical calculations for C12H21N05: C, 55.58; H, 8.16; N, 5.40; Experiment: C, 55.72; H, 8.10; N, 5.53. Attach R1 and R2 together with a carbon atom to represent a compound of formula (1 0), which is a compound of formula (10a). Add trifluoromethanesulfonic anhydride (111 g, 66 2 mmol). To 4 · (light methyl) tetrahydrolanan · 4 · carboxylic acid in anhydrous diethyl ether (115 ml) cooled to 0 ° C 10.20 g, 63.68 mmol) slurry, followed by triethylamine (17.8 mL, 127.4 mmol). Beat the two-phase solution for 2 hours, warm to room temperature, and stir for an additional 2 hours. The layers were separated by decantation, and the lower layer was diluted with a 2% aqueous solution of sodium bicarbonate (50 ml), and extracted with dichloromethane (4 x 200 ml). The mixed organic extracts were washed with an additional 2% aqueous sodium bicarbonate (100 ml), dried over magnesium sulfate and concentrated in the air to give 2,7-dioxa-spiro [3.5 as a pale yellow oil. ] Ren roast-1-tan | (10.8 g). IR (KBr) 1821 cm 1; 4 NMR (CD3C13) d 1.92 -84- This paper size applies to China National Standard (CNS) A4 (210X 297 mm) ^ —— r .--------- --IT ----- Meeting (Please read the notes on the back before filling out this page) 580491 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 _____ B7_ V. Invention Description (82) ~ " — (ddd, J = 13.4, 8.1, 4.0 Hz, 2H), 2.10 (ddd, J = 13.4, 1.1, 3.4, 0.8 Hz, 2H), 3.70 (ddd, J = 11.8, 6.3, 3.9 Hz, 2H), 3.92 (ddd, J = 11.8, 7.9, 3.4 Hz, 2H), 4.15 (s, 2H); 13C NMR (CD3CI3) d 30.78 (t), 55.78 (s), 64.46 (t), 71.50⑴, 173.42 (s), MS (EI) m / e = 142. MS (CI) M + = H m / e = i43, M + + HNH4 m / e = 160 0 5 1 · Preparation in which R1 and R2 are attached with two carbon atoms, representing hexanitrogen, which is represented by the formula (1 0) Compound, that is, compound of formula (10b). Trifluoromethanesulfonic anhydride (2.60 ml, 15.39 mol) was added to N- (third) in anhydrous diethyl ether (27 ml) cooled to 0 ° C. • Butoxycarbonyl) _4-methylhexahydropyridine-4-carboxylic acid (3.80 g, 14.65 mol) in a slurry, followed by triethylamine (4.30 ml, 30.78 mmol). The two-phase solution was taught for 23 hours, warmed to room temperature, and stirred for an additional hour, and the upper diethyl ether layer was separated by decantation. The lower layer was extracted with an additional portion of diacetic acid X 100 ml), and the mixed organic extracts were washed with an aqueous solution of sodium bicarbonate (2 X 50 ml), dried over magnesium sulfate, and concentrated in the air to give a pale yellow oil. 7- (butoxycarbonyl) -2-oxa-azaspiro [3.5] nonan-1-one (2.88 g, 82%). iH NMR (CDCl3) ji 48 (s, 9H), 1.79-1.89 (m, 2H), 2.02-2.10 (m5 2H), 3.48_3 66 (m, 4H), 4.13 (s, 2H). Example 6 Preparation Compound 6A * of formula (1 3) covers the base with carbon atom, and R1 is tetrahydrofuran: South 'and x is iodine. Mv (Please read the precautions on the back first nn I n I n It- -pack- • Please fill in this page again) Order Φ -85- This paper size is applicable to Chinese National Standard (CNS) A4 (210X 297 mm) 580491 A7 B7 2.5M N-butyllithium in hexane (56 ml, Ϊ3.9 mol) was added to diisopropylamine 四.% Ml in tetrahydrofuran (30 ml) at 0 ° C, 13.9 mmol Ear) solution and stir for 20 minutes to prepare a diisopropylated amidated bell. Then a solution of ethyl tetrahydropiperan-4-carboxylate (2 g, 12.7 mmol) in tetrahydrocondensate (8 liters) was added to two at -78 ° C over 15 minutes. Lithium isopropylamide solution. The resulting solution was stirred for an additional 50 minutes, and diiodomethane (114 mL, 14.2 mmol) was added. Stir the known solution for an additional 50 minutes, warm to room temperature within 30 minutes, and then cool to 0 ° C again. The mixture was diluted with 1 M aqueous hydrogen acid (25 ml), extracted with diethyl ether (2 x 100 ml), and rinsed with an additional portion of diethyl ether (2 x 50 ml). The mixed organic layer was washed once with 1 μ of aqueous hydrochloric acid (100 mL), saturated aqueous sodium bisulfite (100 mL), and saturated aqueous sodium bicarbonate (100 mL), and covered with sulfuric acid. Magnesium is dehydrated and concentrated in the air. The residue was filtered on a silicone plug, and successively eluted with hexane and ethyl acetate, and the excess alkylating agent was removed by washing with hexane to obtain pure 4-(brokenyl) tetrahydrofuran. Ethyl hydrogen 4-carboxylate, which can be directly included in the next reaction without further purification (3.20 g '85%). IR (KBr) 1732 cm 1 4 NMR (CDC13) 1.31 (q, J = 7.3 Hz, 3H), 1.56 (ddd, J = 14.6, 10, 4.5, 2H), 2.17 (ddd, J = 14.6 , 5.7, 3.3, 2H), 3.31 (s, 2H), 3.51 (ddd, J = 11.7, 11.1, 2.5 Hz, 2H), 3.51 (td, J = ll.7, 4.3 Hz, 2H), 4 24 (q, J = 7.1 Hz, 2H); 13C NMR (CDC13) ^ 14.33 (q), 15.04 (t), 34.70 (t), 45.26 (s), 61.34 ⑴, 65.22 (t), 172.89 (s) ) ： EIHRMS calculation of C9H15I03 (M +) 値: -86- This paper size is applicable to Chinese National Standard (CNS) A4 specification (21 OX 297 mm) (Please read the precautions on the back before filling this page) Printed by the Consumer Standards Cooperative of the Ministry of Standards of the People's Republic of China 580491 A7 ____ B7 V. Description of the Invention (84) — ^ 298.0066 'Experiment 値: 298.0066. Analysis and calculation of c9H15I03: C: C, 36.26; H, 5.07 'Experiment 値: c, 36.56; H, 509. 6 B · To prepare ..., in which carbon atoms are used to combine R.1 color and R2 together to represent tetrafuran, and change the formula (1 3) of X. Similarly, dibromomethane or bromochloromethane is used instead of two. Methyl iodide to prepare the following compound of formula (1 3): '4 _ (bromomethyl) tetrahydrotripan-4 _ carboxylic acid ethyl ester: I r (pure) i732 cm _ 1; 1h NMR (CDC13) 1.30 (q5 J = 7.1 Hz, 3H), 1.59 (ddd J = 14.6, 10.9, 4.5, 2H), 2.17 (dm, J = 14.7, 2H), 3.48 (s, 2H) 3.53 (dt, J = 11.9, 4.5 Hertz, 2H), 3.84 (dt, J = 11.9, 4.5 Hertz, 2H), 4.23 (q, J = 7.1 Hertz, 2H), 13C NMR (CDC13), 14.27 (q), 33.17 (t), 40.16 (t ), 46.05 (s), 61.29 (t), 64.97 (t), 172.9m (s); CIMS (M ++ H): 251, (M. + NH4 +) 268. 4- (Gasmethyl) tetrahydropiperan-4-carboxylic acid ethyl ester: ir (pure) 1734 cm-1; 4 NMR (CDC13) 1.30 (q5 J = 7.1 Hz, 3H), 1.59 (ddd, J 14.6, 10.9, 4.5, 2H), 2.16 (dm, J = 14.7, 2H), 3.53 (dt,) = 11.9, 4.5 Hz, 2 India, 3.61 (8,211), 3.84 (< ^,] = 11.9, 4.5 Hz, 2H), 4.24 (q, Bu 7.1 Hz, 2H), 13 C NMR (CDC13) d 14.24 (q), 32.14 (t), 46.69 (s), 51.40 (t), 61.29 (t ), 64.85 ⑴, 173.01 (s); CIMS (M ++ H): 207. Analysis and calculation of C9H15C103 値: C, 52.31; Η, 7.32, experimental 値 · C, 52.51; H, 7.30. 6 c · AjzAM A method in which r1 and r2 are attached together with carbon atoms to represent t-disulfan, and X is p-toluenesulfonyl group of compound of formula (i 3) _______- 87- Home County (CNS) A4 Specification (21Gx297mm) {Please read the notes on the back before filling in this page]: w · φ. 580491 A7 B7 V. Description of the invention (85) The p-toluene will be added with chlorine (997 mg, 5.23 mmol) to ethyl tetrahydrofuran 4-chitoate (82 mg) in pyridine (10 ml) at 0 ° C. 4.356 mmol), and allow the mixture to warm to room temperature over a period of 1 hour. Stir; stir the mixture for 36 hours and distribute it in dichloromethane (150 ml) and 3N Between aqueous hydrogen acid (50 liters). The organic layer was washed with 25 ml of saturated aqueous sodium bicarbonate, dehydrated (MgSO), concentrated, and the residue was chromatographed on 45 g of silica gel to Eluted with 30% ethyl acetate / hexane to give the tosylate salt as a white solid (03 g, 69%). Melting point 87.7-88.6 ° C; IR (KBr) 1717 cm 1; j NMR ( CDC13) 1.21 (q, J = 17.1 Hz, 3H), 1.52 (ddd, J = 13.4, 10.6, 4.1 Hz, 2H), 2.00 (dm, J = 13.4 Hz, 2H), 2.46 (s, 3H ), 3.49 (ddd? J = 11.7 > 10.6, 2.5 Hz, 2H), 3.76 (dt, J = 11.9, 4.1 Hz, 2H), 4.03 (s, 2H), 4.13 (q, J = 7.1 Hz , 2H), 7.35; 13C NMR (CDCls) ά 14.10 (q), 21.67 (q)? 30.43 (t)? 44.93 (s), 61.37 (t), 64.43 (t), 74.65 (t), 127.95 (d ), 129.89 (d), 132.67 (s), 145.05 (s), 172.57 (s); HRMS calculation on C16H22〇6: 343.1215 , Experiment 値: 343.1217. Analysis and calculation of C16H22〇6 値: C, 56.12; H, 6.48, Experiment ，: C, 56.22; H, 6.46. Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs Example 7 Preparation of compounds of formula la 7 A · Fish-type (4) compounds where R1 and R2 are hydrogen, and carbon atoms are connected together—and—to 4 to represent hexahydrop Bi Lai, and R 5 is a diphenyl ether of the formula La. 1 · Stir 4-phenoxyphenylsulfide in a sealed flask at 100-110 ° C ___- 88- This paper size applies to Chinese national standards (CNS) A4 specification Y210X297 mm) " " 580491 A7 B7 V. Description of the invention (86) Phenol (7.4 g, 36.3 mmol), 4-carboxymethylene-N_CBZ-hexahydropyridine (10 g, 36.3 mmol) and hexahydropyridine (1.8 ml, 36.3 mmol) overnight. After cooling, the crude reaction mixture was distributed between ethyl acetate and 1 N hydrochloric acid. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated in the air to give a yellow solid. This solid was triturated with 1: 丨 (vol / vol) ethyl acetate / hexane (500 ml) to obtain 2- [4 · (4-phenoxyphenylthio) -N-CBZ -hexa as a white solid. Hydropyridin-4-yl] -acetic acid.

2. 2- [4- (4-phenoxyphenylthio) -N-CBZ-hexahydropyridine · 4-yl] -acetic acid in anhydrous 2,2-dichloroethane (3 ml) under nitrogen The solution (150 mg '0.29 Emole) was cooled to · 10 ° C and saturated with a hydrochloric acid gas for 15 minutes. The reaction vessel was then sealed and the solution was stirred at 25 for 2 days. Before opening to release gaseous hydrochloric acid, the test tube was cooled to -10 ° C and allowed to warm to room temperature. The solvent was removed in the air and the product was triturated with ethyl picrate to obtain 2- [4_ (4-phenoxyphenylthiohexahydropyridine_4) yl] acetic acid hydrogenate as a white powder. lH NMR (CD3OD): 7.93 (d, 2H), 7.45 (t, 2H), 7.27 (t, 1H), 7.14 (t, 4H), 3.52 (m, 2H), 3.25 (m, 2H), 2.70 (s, 2H), 2.35 (m5 4H). Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 7 B. Also prepared for the preparation of 11 compounds in which R 1 and R 2 are hydrogen, and the carbon atom will — see option I — start epicyclopentyl, and R 5 is diphenyl ether Formula la under cyclohexylpyridine (2 mol) and p- (phenoxy) -thiophenol (2 mmol) in the presence of hexahydropyridine (100 μl) under nitrogen. Ear) mixture was heated to 110 C 2 for 4 hours. Dissolve the residue in ethyl acetate, and use 89- (Please read the notes on the back before filling this page) Private paper size applies Chinese National Standard (CNS) mm) 580491 A7 B7 V. Description of the invention (87) Printed with dilute hydrochloric acid by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. Separate the organic layer, dehydrate it under reduced pressure and evaporate it to the crude 2-[1-(4 -phenoxyphenylthio) · cyclopentyl 丨 丨 kibacetic acid, which can be used directly in the next reaction No further purification was required. 7 C.t R112 company 3 is hydrogen, R4 is benzyl and R5 is 4-bromo-phenyl. Formula I a is stirred in the presence of hexahydropyridine (300 microliters) under u〇r. A mixture of benzylpropionic acid (1 g) and p-bromothiophenol (i 12 g) was overnight. The residue was distributed between ethyl acetate and dilute hydrochloric acid. The organic layer was separated, dehydrated under reduced pressure, and concentrated to obtain benzyl-3 · (4-bromophenylthio) -propionic acid (Iaa), which can be used directly in the next reaction without further purification. . 7 D · A compound of formula (10) to prepare a formula in which Ri and R2 are attached to a carbon atom by IniLfL. Tetrahydrothran 'R3 and R4 are hydrogen and R5 is 4. I a Immediately, 2,7-dioxa-spiro [3.5] nonan-1-one (1,08 g) obtained as described in Example 5 (1) was dissolved in ν, ν_dimethylformamide ( 95 ml) and slowly add it to a solution containing 4- (4-chlorophenoxy) thiophenol salts (by using Add sodium hydride powder (2.14 g '89.2 mmol) to 4_ (4 · chlorophenoxy) benzenesulfur test in ν, N · dimethylformamide (19 ml) (15.83 g, 66.8 Millimolar) into the liquid and stir for 30 minutes to produce), then stir for an additional 15 minutes. The resulting slurry was heated to 4 ° C, stirred for 5 minutes, tertiary-butanol (2 ml) was added, and the mixture was cooled to room temperature within 20 minutes. Most of the N was removed from the paniculata, N-dimethylformamidine, adjust p Η 値 to -90, and the scale is applicable to Chinese National Standard (CNS) A4 specification (210 × 297 mm) (Please read the precautions on the back before filling this page)

In! Ι · Λ, installed. -Order- Φ Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 580491 A7 B7 I—— ___ V. Description of the Invention (88) 9.2, 30% diethyl ether-hexane (120 ml) The resulting slurry was diluted and filtered. The filter cake was rinsed with an additional portion of diethyl ether (3 X 700 ml), acidified to pH 3.5 with 2 N aqueous hydrochloric acid, and extracted into dichloromethane (4 X 350 ml). The mixed organic layer was dehydrated with magnesium sulfate, and concentrated in the air. Recrystallizing the solid residue from a small amount of di-methane-hexane to obtain pure 4- [4- (4-chlorophenoxy) phenylthiomethyl] tetrahydropiperan · 4-carboxylic acid, White solid (19.50 g). Melting point 140.6-141.9 ° C; IR (KBr) 3429 (br), 1732 cm 1 4 NMR (DMSO-d6) d 1.54 (ddd, J = 14.2, 10.0 > 4.2 Hz, 211), 1.95 (4111, "1 = 14.2 Hz, 211), 3.19 (s, 2H), 3.56 (ddd, J = 11.8, 10.0, 4.2 Hz, 2H), 3.70 (dt, J = 11.8, 4.2 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 7.02 (d, J = 8.9 Hz, 2H), 7.02 (d, J = 8.9 Hz, 2H), 7.42 (d, J = 9.0 Hz, 4H), 12.66 (s, 1H) ; 13C NMR (DMSO_d6) d 33.06 (t), 43.56 (t), 45.03 (s), 64.13 (t), 119.43 (d), 120.11 (d), 110.43 (d), 127.35 (s) 9 129.80 (d ), 131.09 (s) 9 131.59 (d) 9 154.90 (s); 155.50 (s), 175.25 (s); HRMS calculation of ChHhSC ^ CI 値: 378.0693, experiment 値: 378.0685. Analytical calculations for Ci9H19S04Cl. 0.25. H20:,: c, 59.53; H, 5.13, experimental 値: c, 59.53; Η, 5.07. Similarly, by replacing 4- (4-chlorophenoxy) thiophenol with 4- (4-bromophenoxy) benzenethiophene and 4- (4-fluorophenoxy) thiophenol, the following was prepared Compound: 4- [4- (4-Bromobenzyloxy) phenylthiomethyl] tetrahydrobran-4-metanoic acid: melting point 143.7-144.5 C, IR (KBr) 3434 (br), 1732 cm 1 -91 This paper size applies to Chinese National Standard (CNS) A4 (21 × 297 mm) (Please read the precautions on the back before filling this page)

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 580491 A7 B7 V. Description of the Invention (89) NMR (DMSO-d6) d 1.54 (ddd, J = 13.8, 10.1, 4.3 Hz, 2H), 1.94 (dm, J = 13.5 Hertz, 2Η), 3.19 (s, 2Η), 3.37 (ddd, J = 11.8,

10.1, 2.5 Hz, 2H), 3.70 (dt, J = 11.8, 4.0 Hz, 2H), 6.96 (d, J = 9.2 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 7.41 ( d, J = 8.8 Hz, 2H), 7.55 (d, J = 9.0 Hz, 2H), 12.68 (s, 1H); 13 C NMR (DMSO-d6) β 33.04 (t), 43.34 (t), 45.00 (s), 64.10 (t), 115.14 (s), 119.59 (d), 120.53 (d), 131.15 (s), 131.51 (d), 132.77 (s), 154.71 (s), 156.06 (s), 175.28 (s); EIMS (M +): 424. Analysis and calculation of C19H19S04Br 値 · C, 53.91; H, 4.52, experiment 値: C, 53.53; H, 4.54. 4_ [4 · (4-fluorophenoxy) phenylthiomethyl] tetrahydropiperan · 4-carboxylic acid: melting point 143.0 143.4 ° C; IR (KBr) 3436 (br), 1721 cm-1; 4 NMR (DMSO-d6) d 1.54 (ddd, J = 13.5, 10 · ΐ, 4.0 Hz, 2H), 1.94 (dm, J = 13.5 Hz, 2H), 3.17 (s, 2H), 3.38 (td, J2 11.8, 2.5 Hz, 2H), 3.70 (dt, J = 11.8, 4.0 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 7.05 (dd, J = 9.2, 4.6 Hz, 2H ), 7.21 (dd, J = 9.1, 8.4 Hz, 2H), 7.40 (d, J = 8.8 Hz, 2H), 12.65 (s, 1H); 13 C NMR (CDC13) d 33.05 (t), 43.65 (t ), 45.49 (s), 64.12 (t), 116.53 (dd, Jc_f = 23.2 Hz), 118.71 (d), 120.63 (dd, Jc_f = 8.5 Hz), 130.31 (s), 131.69 (d), 152.38 (s) ), 155.85 (s), 158.29 (d, Jc_f 239.9 Hz) 5 175.28 (s); EIMS (M +): 362. Analytical calculations for C19H19S04F 値: c, 62.97; H, 5.28, experimental 値: C5 62.79; H, 5.26 〇7 E. J A preparation in which both R1 and R2 are methyl and R4 is hydrogen, and __- 92- This paper size applies to China National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling this page)

580491 A7 B7 V. Description of the invention (90) Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economics—Pen 4- (4-Gasoxy) phenyl Formula 1 & The ancient method of sodium hydride powder at 0C (0 86 g, 35.8 mmol) to 4- (4-chlorophenoxy) thiophenol (3.55 g '15 mmol) in N, N-dimethylamidamine (12 ml) ) In the mixture. The mixture was allowed to warm to room temperature over 5 minutes, stirred for an additional 20 minutes, and Gubital's chloropivalic acid (1.64 g, 12.0 mmol) was added in one batch. The mixture was heated to 80 C for 8 hours, cooled to room temperature, and water (1 mL) was added. The residue was distributed between dichloromethane (50 ml) and 2N hydrochloric acid (25 ml). The layers were separated and washed with additional dichloromethane (2 X 2 5 liters). The combined organic extracts were dried over magnesium sulfate and concentrated in the air. Chromatography was performed on Shi Xijiao, and 50%. Methanol / dichloromethane eluted to give 3 · [4- (4-chlorophenoxy) phenylthio] _2,2-dimethylpropionic acid (4 g '99%) which was slightly impure. This material was recrystallized from a small amount of diethyl ether / hexane, to give 20 g of analytical grade pure acid as a white solid. Melting point 84.4-84.9 ° C; IR (KBr) 3433 (br), 1732 cm 1; ιΗ NMR (DMSO-d6) d 1.19 (s, 6H), 3.14 (s, 2H), 6.97 (d, J = 8.7 Hz, 2H), 7.01 (d, J = 8.9, 2H), 7.40 (d, J = 8.8 Hz, 2H), 12.36 (br s, 1H). EIMS (M +): 378. Analytical calculations for C17H17S03C1 値: C, 60.62; H, 5.09, Experiment 値: C, 60.31; H, 4.96. 7 F · Fish-type (10b) compounds are prepared in which R1 ^ R2 is attached to a carbon atom Together, it represents N-BOC · hexahydropyridine, R3 and R4 are hydrogen, and are 4- 4- (4-chlorophenoxy) phenyl. Carbonyl) -2-oxa-7- 93 Private paper size is applicable to Chinese National Standard (CNS) A4 (210 X 297 mm) (Please read the notes on the back of the 4 items before filling and loading II: write this page) Order Φ

-IK 580491 A7 '* ............ Qing B7 V. Description of Invention (91) — ~ — (Please read the precautions on the back before (Fill in this page) The snail [3.5] nonane-b ketone is immediately dissolved in N, N_dimethylformamide (4 ml), and it is added slowly over a period of 10-1 5 minutes To a solution containing the sodium salt of 4- (4-chlorophenoxy) thiophenol (by adding sodium hydride powder (340 mg, 14.17 mmol) at 0 ×: to Ν, Ν_ 二4 · (4 · chlorophenoxy) benzenethione (300 g, 12 7 mmol) in methylformamide (19 ml) / valley solution 'and prepared by stirring for 30 minutes), Stir additional. Minutes. The resulting slurry was heated to 80 ° C., stirred for 5 minutes, tertiary butanol (2 ml) was added, and the mixture was cooled to room temperature over 20 minutes. Remove the large amount of N, N-dimethylformamide in hydrazone, adjust the pH to 3.5 with 2 M aqueous hydrochloric acid, and extract it into ethyl acetate (4 × 150). Liters). The mixed organic layer was dehydrated with magnesium sulfate, concentrated in the air, and the residue was chromatographed on silica gel, eluting with i% to 100% methanol / dichloromethane to give hexahydropic acid, pale yellow 4_ [4-Ga 4_chlorophenoxy) phenylthiomethyl] _N- (third-butoxycarbonyl) hexahydropyridine-4-ylcarboxylic acid (5 g, 89%) as an oil. 4 NMR (OH not observed; CDC13) d 1.37 (s, 9H), 1.55 (mC5 2H), 2.10 (mc, 2H), 3.05 (mc, 2H), 3.06 (s, 2H), 3.72 (mc, 2H), 6.81 (d, J = 8.8 Hz, 2H), 6.85 (d, 8.9 Hz, 211), 7.21 汍] = 8.9 Hz, 211), 7.30 ((1,] = 8.7 Hz, Central Ministry of Economic Affairs Printed by the Consumer Bureau of Standards Bureau, 4H)., 7 G · In worms, R is ethyl and the compound of formula la is prepared in which the 1 color -r2_attach_ is bonded together with carbon atoms to represent tetrahydropiran, R3 And R4 is hydrogen and R5 is 4- (4-chlorophenoxy) phenyl. Formula ia Potassium hydroxide (58.3 mg, 1.04 mmol) is added to 4 containing two drops of water in ethanol (2 ml). · [4_ (4-chlorophenoxy) phenylthiomethyl] tetrahydro-94- This paper size applies to China National Standard (CNS) A4 specification (210X ^ 97 mm) '' — 580491 A7 B7 Central Ministry of Economic Affairs Printed by the Bureau of Standards Consumer Cooperatives V. A description of the invention (92 piperan-4-carboxylic acid ethyl ester (70 mg, 0.17 mmol) in a solution. The mixture was refluxed for 13 hours, cooled to room temperature, and acidified to pH 4 And extracted with ethyl acetate (4 X 50 ml) The mixed organic layer was dehydrated with magnesium sulfate and concentrated to obtain 4- [4- (4-chlorophenoxy) phenylthiomethyl] tetrahydropiperan-4-carboxylic acid (66 mg, 100%), It is spectrally the same as that isolated from the procedure of the previous Example 70. 7H. The formula in the skin where R is ethyl is U compound _ ^ _ ^ where the carbon atom is used to represent the tetrahydropiperan , R3M4 is hydrogen, R5 is 4 · Li-bromophenoxy) stupid formula of la ~ 'Similarly, according to the procedure of Example 7G above, 4_ [4_ (4_bromophenoxy) dongthio Methyl] tetrahydrofuran-4 · carboxylic acid and 4_ [4_ (4_fluorophenoxy) phenylthiomethyl] tetrahydrofuran-4-carboxylic acid. Preparation of fish acid where R1: 2 The attached magnetogen early group is R, and R is methyl ether Ia. • Oxalyl chloride (0.33 ml, 3.83 mmol) is added in 10 minutes, dropwise = 4- [4- (4 • Chlorophenoxy) phenylthiomethyl] tetrahydropiperan-4-carboxylic acid (580 ¾: g, 1.53 mol) & N, N-dimethylformamide catalyst (M microliter) A solution of 0.0% in air methane (15 ml). The mixture was warmed to room temperature H, and the semi-slurry was stirred for another 12 hours, and Concentrate in air until the theoretical mass of acid chloride is obtained. Suspend the residue in tetrahydrofuran (7.5 ml), add methanol (0 19 ml, winter 59 mmol), and add triethylamine (0.64 ml, 4.59 Mol). The mixture was heated to reflux for 14 hours, concentrated, and the resulting residue was taken up in dichloromethane (150 ml). 95-'Paper size applicable to China Standard (CNS) A4 specifications (21〇297297 meals)-1 pack- (Please read the notes on the back before filling out this page} -Ordered by IAW. 580491 Α7 Β7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. The description of the invention is strict and the 1 M hydrochloric acid aqueous solution (50 ml) is delaminated. The aqueous layer was extracted with another dichloromethane fraction (2 X 30 ml), and the combined extracts were dehydrated on magnesium sulfate, and then concentrated to produce 4 · [4 · (4 · chlorophenoxy) benzene. The crude product of thiomethyl] tetrahydropiperan-4-carboxylic acid methyl ester was used directly in the next reaction without further purification. 1H NMR (CDC13) d 1.62 (mc, 2Η), 2.15 (dm ≫ 13.6 Hz, 2H), 3.13 (s, 2H), 3.47 (td, J = 11.9, 2.4 Hz, 2H), 3.59 (s, 3H), 3.81 (dt, J = 12.0, 4.1 Hz, 2H), 6.92 (d, J = 8.9 Hz, 2H), 7.29 (d, J = 8.8 Hz, 2H), 7.36 (d, J = 8.8 Hz, 2H). 7 J. Fish formula (1 3) Preparation in which R 1 R2 is attached to two for tetrahydropiperan, R3 and R4 are j, and R5 is 4- (4-nitrobenzene, phenyl, and R is ethyl. The formula la is 4 · (iodomethyl) tetrahydro Piperan_4_ leptate ethyl ester (300 mg, 1 mmol) was added to the sodium salt containing 4- (4-phenoxyphenoxy) thiophenol (by powdering sodium hydride at 0 ° C ( 36 mg, 1.5 mmoles) added to 4- (4-chlorophenoxy) phenylsulfan (262 mg, 1.1 mmoles) in Ν, Ν · dimethylformamide (2 ml) Solution, and stirred for 30 minutes to produce) solution. Allow the mixture to warm to room temperature within 5 minutes, stir for an additional 20 minutes, cool to room temperature, and add 1 M aqueous hydrogen chloride Acid (5 mL). The mixture was then distributed between ethyl acetate (100 mL) and 2M hydrogen acid (25 mL). The layers were separated and rinsed with additional ethyl acetate (2 X 50 mL). The organic extracts were mixed, rinsed with 1 M sodium hydroxide (2 x 30 ml), dried over magnesium sulfate, and concentrated in the air. Chromatography on silica gel, eluting with 20% ethyl acetate / hexane, Produces pure 4-[4-(4 -chloro Phenoxy) phenylthiomethyl] Tetrahydroan · 4 · Ethyl leptate (370 mg, 91%) 'Next is impure 4_ 96- This paper size applies Chinese National Standard (CNS) A4 specification (210X297 (Mm) (Please read the precautions on the back before filling this page) ▼ Binding and printing printed by the Central Consumers Bureau of the Ministry of Economic Affairs, printed by the Consumer Cooperative 580491 A7 —______ B7__ 5. Description of the invention (94) [4- (4-chlorobenzene (Oxy) phenylthiomethyl] tetrahydrolanan-4 leptate (40 mg). IR (KBr) 1728 cm 1; 4 NMR (CDC13) 1.23 (q, J = 7.1 Hz, 3H), 1.56 (ddd, J = 14.6, 10.9, 4. · 4, 2H), 1.63 (ddd, J = 14.6, 5.7, 3.3, 2H), 3.13 (s, 2H), 3.51 (ddd, J = 11.8, 11.1, 2.4 Hz, 2H), 3.80 (dt5 J = 11.8, 4.1 Hz, 2H), 4.07 (q, J = 7.1 Hz, 2H), 6.91 (d, J = 8.9 Hz, 2H), 6.92 (d, J = 8.9 Hz, 2H), 7.29 (d, J = 9.0 Hz, 2H), 7.39 (d, J = 8.9 Hertz, 2H); 13C NMR (CDC13) d 14.20 (q), 33.72 ⑴, 45.72 ⑴, 46.07 (s), 60.92 ⑴, 65.06 ⑴, 119.29 (d), 120.20 (d), 128.43 (s), 129.85 (129) d), 130.57 (s), 133.05 (s), 155.40 (s), 156.21 (s), 174.02 (s); EIHRMS calculation of C21H23S04C1 (M +): 406.1006, experiment: 406.1008. Analytical calculations for C21H23S04C1 61: C, 61.98; H, 5.70, experimental C: C, 61.86; H, 5.68 〇7 K · Prepared from a compound of formula (13) in which R1 and R2 are attached with two carbon atoms Represents tetrahydropiperan, R3 and R4 are hydrogen, and R5 is 4- (4-bromophenoxy) phenyl, and R is ethyl. Formula la Samely, 4- (bromophenoxy) phenylsulfide Alcohol instead of 4- (4-chlorophenoxy) phenyl mercaptan, and 4-[4-(4-bromophenoxy) phenylthiomethyl] tetrahydropiperidine was prepared according to the procedure of Example 7 J above. Ethane 4-carboxylic acid ethyl ester (2.10 g, 93%). IR (KBr) 1728 cm 1; 4 NMR (CDC13) d 1.22 (q, J = 7.1 Hz, 3H), 1.60 (ddd, J = 14.6, 10.9, 4.5, 2H), 2.14 (ddd, J = 14.6, 5.7 , 3.3, 2H), 3.13 (s, 2H), 3.81 (ddd, J = 11.8, 11.1, 2.4 Hz, 2H), 4.07 (q, J = 7.1 Hz, 2H), 6.87 (d, J = 9.0 & Again applicable to China National Standard (CNS) A4 specification (21 OX297 mm) " " (Please read the precautions on the back before filling this page) Order Φ 580491 A7 B7 V. Description of Invention (95

Hertz, 2H), 6.92 (d5 J = 8.8 Hz, 2H), 7.37 (d, J = 8.8 Hz, 2H), 7 43 (d, J = 9.0 Hz, 2H); 13C NMR (CDC13) β 14.20 (q ), 33.71 (t), 45.69 (t), 46.05 (s), 60.92 (t), 65.05 (t), 116.06 (s), 119.40 (d), 120.59 (d), 130.69 (s), 132.81 (d ), 133.03 (s), 156.04 (s), 156.16 (s), 174.01 (s); EIHRMS calculation for C21H23S04Br (M +) 値: 450.0500, experimental 値: 450.0505. Analytical calculations for C21H23S04C1: C, 55.88; H, 5.14, Experiment: C, 55.52; H, 5.09. A similar reaction was performed, starting with compounds of formula (1 3) where X is iodine, bromine and gas, and moderate to good yields were obtained in all cases. 7L. Prepare the formula la for changing R R2, R3, R4 and R5: j S--1 II ». —-> Γϋ 11 I ...... ..... ϋ (Please read the note on the back first Please fill in this page again.) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. Similarly, other N-protected compounds of formula (4) can be used to replace 4-methylene-N-CBZ-hexahydroedian if necessary. And according to the procedure of Example 7A (1) and (2) above, or if necessary, other compounds of formula (4) can be used instead of cyclopentyleneacetic acid, and according to the procedure of Example 7B above, and can be visualized It is necessary to replace p-phenoxyphenylthiol with other compounds of formula (5) to prepare the following compounds of formula Ia: 2_ [4_ (4-methoxymethoxythio) _N-CBZ-hexahydropyridine_ 4-yl] · acetic acid; 2- [4- (4-methoxyphenylsulfanyl) -hexahydropyridin-4-yl] · acetic acid; 2 ^ yl_3 · (3-methoxyphenylsulfenyl) -propyl 2-benzyl- 3- (4-methoxyphenylthio) -propionic acid; 3-benzyl-3- (4-methoxyphenylthio) -propionic acid; 3,3-dimethyl-3 -[(4-chlorophenoxy) phenylthio] · propionic acid; 2- {4- [4- (4-fluorophenoxy) phenylthio] -hexahydropyridin-4-ylbenzene Paper Degree applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) Order _ it ^ 〇〇49ι Α7 Β7 V. Description of the invention (96) Jun; (Please read the precautions on the back before filling this page) h {4 -[4- (4-fluorophenoxy) phenylthio] -N-CBZ · hexahydropyridine-4-yl} -acetic acid; 3-benzyl-3-[(4-phenylthiophenyl) thio ] Propanoic acid; 3-benzyl-3 (phenylthio) -propionic acid; 3-lamtyl-3 (4-phenoxyphenylthio) -propane & >, 3-benzyl-3 -[(4-Diphenyl) thio] -propionic acid; 3-benzyl-3- (2 • fluorenylthio) -propionic acid; benzyl-3- (4-methoxyphenethylfluorenylbenzene Thio) -propionic acid; 3-cyclopentylmethyl-3- (4-methoxyphenylthio) -propionic acid; 3-cyclopentylmethyl-2 · isopropyl-3- (4-methyl Oxyphenylthio) -propionic acid; 3-ethyl-2-methyl-3 (4-methoxymethoxythio) -prop '3,3-dimethyl- (4-methoxyphenylthio) · Propionic acid; 2- [1- (4-methoxyphenylthio) -cyclopent-1-yl] -acetic acid; 2_ [4- (4-methoxyphenylthio) -cyclohexanone-4-yl ] • Vinyl acetate ketal; 2_ [1_ (4-methoxyphenylthio) _ (4-methylcyclohexyl-1 · kibacetic acid; 2_ [1_ (4 · phenoxyphenylthio) -cyclohexyl- 1-based] -B ; 2- [4- (4phenoxyphenylthio) -tetrahydropiperan-4-yl] -acetic acid; printed by 4- [4- (4_benzo [b] Stilbene-2_yl-phenoxy) tetrahydropiperan-4-ylacetic acid; 2- {4- [4_ (benzyl) phenylthio] · tetrahydroxan 4_yl} _ethane '2- {4 · [4- (4-Fluorophenoxy) phenylthio] tetrahydropiranyl-glycolic acid; 2-{4 [4 (4 chlorophenoxy) phenylthio] tetrahydropipe Nam-4-Kibb

This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 580491 Α7 Β7 V. Description of the invention (97) Acid; Melting point 13 8.5-13 8.8 ° C; ill NMR (CDC13, OH not seen) d 1.73 (d, J = 14.7, 2H), 1.91 (ddd, J = 14.7, 10.1, 4.3 Hz, 2H), 2.58 (s, 2H), 3.76 (dt, J = 11.8, 4.1 Hz, 2H), 4.02 (dt, J = 11.8, 2.6 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.9 Hz, 2H), 7.33 (d, J = 8.9 Hz, 2H), 7.53 (d, J = 8.8 Hz, 4H); FABMS (M +): 379.2. Analysis and calculation of C19H19S04C104: C, 60.23; H, 5.05; Experiment 値: C, 60.39; H, 5.01; 2 · {4- [4 · (4-chlorophenoxy) phenylthio] -tetrahydropipe Lan-4-yl} acetic acid; 2- {4- [4 · (4-bromophenoxy) phenylthio] tetrahydropiperan-4-yl} _acetic acid; 2- [4_ (4_phenoxybenzene Thio) tetrahydropiperan-1,1-dioxide- 4-yl] -acetic acid; trans-2 (4-methoxyphenylthio) cyclopentanecarboxylic acid; and 2- (4-methyl Oxyphenylthio) _cyclohexanecarboxylic acid. 7M · Preparation to change the formula la of R1, R2, R3, R4 and R5 Similarly, 2,7_dioxa-spiro [3 · 5] nonane- 1-ketone, and following the procedure of Example 7D above, and optionally replacing 4- (4-gasphenoxy) phenyl mercaptan with another compound of formula (5) to prepare the following compound of formula Ia : 4_ [4- (4-fluorophenoxy) phenylthiomethyl] tetrahydropiperan_4_carboxylic acid; 4- [4- (4-bromophenoxy) phenylthiomethyl] tetrahydro Travelan-4-carboxylic acid; 3- (4-benzylphenylphenylthio) _2,2-dimethylpropanoic acid; 3_ [4- (4-chlorophenoxy) phenylthio] _2,2 · Dimethylpropionic acid; -100- This paper standard is in accordance with Chinese National Standard (CNS) A4 specification (210 × 297mm) mn--1-I —8— il. 1 --- —ir I I--. .... »nnnnm --- Order n. M in m (Please read the precautions on the back before filling out this page) 580491 A7 B7 Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of Invention (98) 4_ [ (4 · phenoxypyridin-4-yl) thiomethyl] tetrahydropiperan-4-carboxylic acid; ιΗ NMR (OH not observed, CDC13) β 1.65 (mc, 2Η), 2.16 ( dm, J 2 14.2 Hz, 2H), 3.20 (s, 2H), 3.57 (tm, J = 11.4 Hz, 2H), 3.84 (dm, J = 12.0 Hz, 2H), 6.87 (d, J = 6.2 Hertz, 2H), 7.00 (d, J = 8.6 Hz, 2H), 7.47 (d, J = 8.9 Hz, 2H), 8.43 (d, J = 6.0 Hz, 2H). 7 N · MM3: There are various formulas la, R2, R3, R4, and R5. Similarly, according to the procedure of Example 7 above, other compounds of formula 丨 a are prepared. Example 8 Preparation of compound 8A · ridge of formula Iba i where R1 and R2 are attached together with carbon atoms, representing tetrahydropiperazine and 3 gold and hydrogen, R5 is 4_ (4_Gabenzene gas) molybdenum formula Iba within 10 minutes, Chlorchlor (37.5 ml, 429.5 mmol) was added dropwise to 0. (Bottom, 4- [4- (4-Gaphenoxy) phenylthiomethyl] -tetrahydropiperan-4-carboxylic acid (65.1 g, 171.8 mmol) in dichloromethane (1 liter) Ear) and Ν, Ν · dimethylformamide (2 ml). The mixture was allowed to warm to room temperature within 1 hour and the resulting portion of the slurry was stirred for an additional 20 minutes' Concentrated under reduced pressure until a theoretically large amount of hydrazone was obtained. The mixture was dissolved in dichloromethane (600 ml), cooled to 0 ° C, and v was added dropwise over 10 minutes Bis (trimethylsilyl) hydroxylamine (109.1 ml, 510.45 mmol). The mixture was immediately warmed to room temperature and stirred for 3 hours, and then cooled to 0 ° C again. To this solution was added 2.4M Aqueous solution of hydrochloric acid (400ml, 960mmol), minutes after adding -101-(Please read the notes on the back before filling this page) * 131 —4., Order-4 This paper size applies to China Standard (CNS) A4 specification (210X297 mm) 580491 A7 B7 5. In the description of the invention ("), it will cause the precipitation of the amino acid product. The slurry was filtered for an additional 30 minutes and filtered. Rinse with water (3X30 mL) and 50% diethyl ether hexane (2X25 mL) and dehydrate at 70 ° C to obtain 4 · [4-(4- gas Phenoxy) phenylthiomethyl] tetrahydropiperan · 4- (N-hydroxycarboxamide) (61.8 g, 92%). Melting point 146.6 148.0 ° C; IR (KBr) 3426 (br), 1636 cm― 1; iH NMR (DMSO-d6) ^ 1.54 (ddd, J-13.8-10.2, 4.0 Hz, 2H), 2.00 (dm, J = 13.8 Hz, 2H), 3.16 (s, 2H), 3.39 (m, 2H ), 3.66 (dt, J = 11.7, 3.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 7.02 (d, J = 9.0 Hz, 2H), 7.40 (d, J = 8.8 Hz, 2H) ), 7,41 (d, J = 8.9 Hz, 2H), 8.78 (s, 1H), 10.63 (s, 1H); 13C NMR (CDC13) d 32.79 (t), 43.60 (s), 43.70 (t) , 63.93 (t), 119.56 (d), 120.07 (d), 127.19 (s), 129.85 (d), 131.24 (d), 131.34 (s), 154.62 (s), 155.59 (s), 169.69 (s) ; FABHRMS calculation of C19H21NS04C1 (M + + H)): 394.0880, experiment 値: 378.0872. Analysis and calculation of C19H2 () NS04C1 値: c, 57.94; H, 5.12; N, 3.56, Experiment 値: C, 57.98; H, 5.04; N, 3.68. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) 8B. Preparation where carbon atoms are used to attach R1 and R2, representing tetrahydrocyanine I4 are hydrogen, R5 Chlorhexyl chloride (37.5 ml, 429.5 mmol) was added dropwise over 4 minutes to i-ba in the form of 4- (4-chlorophenoxy) phenyl to dichloromethane (1 Liters) of 4- [4- (4-Gaphenoxy) phenylthiofluorenyl] tetrahydropiperan-4-carboxylic acid (65.1 g, 171.8 mmol) and N, N dimethylformamidine Amine catalyst (2 ml). The mixture was allowed to warm to room temperature over 1 hour, and the resulting portion of the slurry was stirred for an additional 20 hours and concentrated in the air until a theoretically large amount of tritium base gas was obtained. In 2 _ -102- This paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) 580491 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 ______B7 15. The description of the invention (_) A solution of amidino chloride mixture (650 mg, 1.68 mmol) in methyl chloride (3.4 ml) 50% aqueous hydroxylamine (556 mg) in 2: 1 tetrahydrofuran / tertiary-butanol (5.1 ml) ) In solution. The mixture was stirred for 1.5 hours and concentrated to the extent that approximately 1 ml of the aqueous solution remained. The slurry was filtered, rinsed with 1: 1 diethyl ether-hexane (3 X 15 ml), and the solid was dehydrated overnight at 70 ° C in an empty oven to obtain 4-[4-(4-chloro Phenoxy) phenylthiomethyl] tetrahydropiperan-4- (N-hydroxycarboxamide) (584 mg, 91%). Melting point 146.6 _ 148.0 ° C; IR (KBr) 3426 (br), 1636 cm1; iH NMR (DMSO-d6) β 1.54 (ddd, 13.8, 10_2, 4.0 Hz, 2H), 2.00 (dm, J = 13.8 Hz, 2H), 3.16 (s, 2H), 3.39 (m, 2H), 3.66 (dt, J = 11.7, 3.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 7.02 ( d, J = 9.0 Hz, 2H), 7.40 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 8.9 Hz, 2H), 8.78 (s, 1H), 10.63 (s, 1H); 13C NMR (CDC13) ά 32.79 (t), 43.60 (s), 43.70 (t), 63.93 (t), 119.56 (d), 120.07 (d), 127.19 (s), 129.85 (d), 131.24 (d) , 131.34 (s), 154.62 (s), 155.59 (s), 169.69 (s); FABHRMS calculation of C19H21NS04C1 (M + + H) 値: 394.0880, experimental 値: 378.0872. Analysis and calculation of C19H2〇NS04C1 C: C, 57 · 94; Η, 5.12; N, 3.56, experimental 値: C, 57.98; H, 5.04; N, 3.68 0 8C. Preparation changes R1, R2, R3, R4 and R5 of formula Iba Similarly, 4- [4- (4-chlorophenoxy) phenylthio] -tetrahydrolanan-4-carboxylic acid is replaced by other compounds of formula la, and according to the above The procedure of Example 8 A prepared the following compound of the formula Iba: -103- The paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) ~ 1-^-ί .........- ----II 1 tji. Iij- Γϋ m —ii I-Hi in I (Please read the notes on the back before filling this page) ·-· mi mm -ϋϋ ϋϋ _ _ eJJW ....... ........ = i -1 = -----1- -l —HI In 1 — i- 580491 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (1Q1) 4- [4- (4-Fluorophenoxy) phenylthiomethyl] • tetrahydropiperan · 4- (N-hydroxycarboxamide): melting point 146.2-146.5 ° C; IR (KBr) 343 l (br ), 162 8 cm 1 4 NMR (NH and OH were not observed in CDC13) d 1.35 (ddd, J = 13.8, 10.2, 4.0 Hz, 2H), 1.83 (dm, J = 13.8 Here, 2H), 2.85 (5,211), 3.23 (111,211), 3.46 ((^, 1 = 11.9, 3.9 Hz, 211), 6.58 (d, J = 8.8 Hz, 2H), 6.57 (d, J = 8.8 Hz, 2H), 6.65-6.67 (m, 4H), 7.06 (d, J 8.8 Hz, 2H); 13C NMR (CDC13) β 32.99 (t), 44.27 (s), 45.49 (t), 64.63 ( t), 116.28 (dd, JC_F = 23.2 Hz), 118.64 (d), 120.49 (dd, JC_F = 8.5 Hz), 130.41 (s), 132.49 (d), 152.46 (s), 156.49 (s), 160.29 ( d, JC_F = 241.9 Hz), 170.23 (s); FABMS (M + + H)): 378 〇 Analysis and calculation of C19H2iNS04F 値: C, 60.46; H, 5.34; 3.73.71, experimental 値 ·· C5 60.08; H , 5.29; N, 3.65 〇4- [4- (4-bromophenoxy) phenylthiomethylbutanhydropiperan- 4- (N-hydroxycarboxamidine) ·· Melting point 153.1-154.0X:; IR (KBr) 3434 (br), 1634 cm1; iH NMR (no NH and OH observed in CDC13) Θ 1.68 (ddd5 J = 14.0, 10.0, 4.0 Hz, 2H), 2.13 (dm, J = 14.0 Hz, 2H), 3.15 (s, 2Η), 3.55 (ddd, J = 12.0, 10.2, 2.5 Hz, 2H), 3.76 (dt, J = 12.0 Hz, 4.1 Hz, 2H), 6.87 (d, J = 9.0 Hz, 2H), 6 .90 (d, J = 8.8 Hz, 2Η), 7.37 (d, J = 8.8 Hz, 2Η), 7.43 (d, J = 9.0 Hz, 2H); 13C NMR (CDCls) ^ 33.01 (t ), 44.32 (s), 45.40 (t), 64.65 (t), 115.95 (s), 119.50 (d) 5 120.53 (d), 130.67 (s), 132.76 (d), 132.80 (d), 155.92 (s) ), 156.16 (s), 170.60 (s); FABMS (M + + H)): 438. Analysis and calculation of C19H2〇NS04Br 値: C, -104- This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) i 'Binding (please read the precautions on the back first to complete this page) 580491 A7 B7 V. Description of the invention (102 Printed by the Consumer Cooperatives of the Central Government Bureau of the Ministry of Economic Affairs of the People's Republic of China; 52.06; Η, 4.60; N, 3.20, Experiment 値: C, 51.84; Η, 4.52; N, 3.54 〇3- ( 4-Benzyldonylphenylthio) -2,2-dimethyl-N-caproylamine; 3- [4- (4 · chlorophenoxy) phenylthio] -2,2-di Methyl-! ^-Hydroxy-propylamidine; melting point 114.7-115.3. (:; IH NMR (CDC13) β 1.30 (s, 6H), 3.14 (s, 2Η), 6.90 (d, J = 8.8 Hz, 2Η ), 6.92 (d, J = 8.8 Hz, 2Η), 7.29 (d, J = 8.9 Hz, 2H), 7.37 (d, J = 8.8 Hz, 1H); FABHRMS Calculation of C17H18NS03C1 (M + + H) 値: 352.0772, Experiment 値: 352.0774. Analysis and calculation of C17H18NS03C1 ，: C, 58.03; Η, 5. · 16; N, 3.98, Experiment 値: C, 57.85; H, 5.10; N, 4.12 〇3,3-1A -3-[(4-Chlorophenyllactyl) phenylthio] _N-caproylamine; {4 -[4- (4 -Phenylhydrazine [b] p-phenphen-2-yl-phenoxy) phenylthio] tetrazine τ »diran · 4-yl} _N • hydroxyacetamidine; 2- {4 -[4 · (phenylphenyl) phenylthio] tetrahydrofuran · base-yl}-! ^ · Hydroxyacetamide; 2_ {4_ [4- (4-Gaphenoxy) phenylthio] tetrahydro Piperan-hydroxyacetamidamine; and 2. {4- [4_ (4 · bromophenoxy) phenylthio] tetrahydrobran-4-yl-pyridylacetamide. 8 D. ^ R1 R2, R3, R4 and R5 of formula I ba Similarly, the other compounds of formula I a are used instead of 4 _ [4-(4 _ phenoxy) benzylbenzene tetrahydropiperan-4 · carboxylic acid, And according to the procedure of Example 8A above to prepare other compounds of formula Iba, for example:

(CNS) A4 specification (210 X297 mm) III (Please read the notes on the back before filling out this page) Order Φ 580491 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Description (1Q3) 4- ( 4-phenoxyphenylthiomethyl) tetrahydropr, 4 · (N · # to sulfamethoxamine); 4- [4- (4-fluorophenoxy) phenylthiomethyl] tetra Hydrogen sulfan-4-((N-#-aminopyridylamine); 4- [4- (4-chlorophenoxy) phenylthiomethyl] tetrahydro to sulfan-4 · (N- ^ methylbenzylamine) ); 4- [4- (4-chlorophenoxy) phenylthiomethyl] -p-methylhexahydropyridine-4_ (N _ unsubstituted benzylamine); 4- [4- (4_aminophenoxy) ) Phenylthiofluorenyl] -1- (cyclopropylmethyl) hexahydropyridine_4- (N · zhongylbenzylamine); 4- [4 · (4-chlorophenoxy) phenylthio Methyl] -1-ethenylhexahydropyridine_4_ (N-hydroxycarboxamidine); 4-[4-(4-chlorophenoxy) phenylthiomethyl pi 1 · (3-pyridyl) Hexahydropyridine-4- (N-hydroxycarboxamidine); 4-[4-(4-chlorophenoxy) phenylthiomethyl] -1 _ (3 -pyridinyl) hexahydropyridine-4- (N-hydroxycarboxamidine); 2- [4- (4-methoxyphenylthio) -N-CBZ-hexahydropyridin-4-yl ] -N-hydroxyacetamidamine; 2-[4-(4-methoxyphenylthio) -hexahydropyridin-4-yl] -N -hydroxyacetamidine; 2-fluorenyl-3- (3- Methoxyphenylthio) -N-hydroxypropylamidamine; 2-benzyl-3- (4-methoxyphenylthio) _N-hydroxypropylamidamine; 3-benzyl-3- (4_ 曱Oxyphenylthio) -N_hydroxypropylamidamine; 2-{4-[4-(4-fluorophenoxy) phenylthio] hexahydropyridine-4 -yl}-N _hydroxy-106-benzyl Paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) (please read the notes on the back before filling this page), τ 580491 A7 B7 V. Description of the invention (104) Acetamide; 2- {4- [4- (4-Fluorophenoxy) phenylthio] _N-CBZ_Hexahydroedian_4-ylb N-hydroxyacetamidamine; 3_benzyl · 3 · [(4-phenylthiophenyl ) Thio] -N-hydroxypropylammonium; 3-benzyl-3- (phenylthio) -N-hydroxypropylammonium; 3-methyl-3- (4-phenoxyphenylthiopropylpropanyl) Acid amines; 3-benzyl-3-[(4-diphenyl) thio] -N-hydroxypropionamine; 3-benzyl-3 · (2-fluorenylthio) · N-hydroxypropionamine ; 3-benzyl-3- (4-methoxystyrylphenylthio) -N-hydroxypropanamide; 3-cyclopentylmethyl-3- (4-methoxy Phenylthio) -N-hydroxypropylammonium; 3-cyclopentylmethyl-2-isopropyl-3- (4-methoxyphenylthio) -N-hydroxypropylammonium; 3-ethyl- 2-methyl-3- (4-methyloxanylthio) -N-hydroxypropionamine; 3,3-dimethyl- (4-methoxyphenylsulfanyl) -N-methylpropionate; 2_ [1- (4-methoxyphenylthio) -cyclopent-1-yl] -N · hydroxyacetamidoamine; • 2 · [4- (4-methoxyphenylthio) -cyclohexanone-4 -Yl] _N_hydroxyacetamidine ethyl ketal; 2 · [1- (4-methoxyphenylthio) _4 · methylcyclohexyl-1_yl] _N-hydroxyacetamidine; Central Ministry of Economic Affairs Printed by the Consumer Bureau of Standards Bureau (please read the precautions on the back before filling out this page) 2- [1- (4-phenoxyphenylthio) -cyclohex-1-yl] hydroxyacetamide; 2- [ 4- (4-phenoxyphenylthio) -tetrahydroxan-4-yl] ylacetamidamine; 2 · {4 [4-(4-fluorophenoxy) phenylthio] tetrahydropiperan- 4 -based} _ Ν _hydroxyacetamidine; __- 107- ______ This & Zhang scale is applicable to the Chinese National Standard (CNS) Α4 specification (210X297 mm ^ " 580491 A7 B7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Preparation of the fifth, description of the invention (105 2-[4 _ (4 -phenoxybenzene Thio) -tetrahydrothiopiperan-1,1-dioxide-4 -yl] -N-hydroxyacetamidamine; trans-2 · (4-methoxyphenylthio) -cyclopentanecarboxylic acid; And 2 · (4 · methoxyphenylthio) cyclohexanecarboxylic acid. Example 9 Preparation of a compound of formula lb 9A. Preparation where R1 and R2 are hydrogen, R3 and R4 are attached together with a carbon atom, representing cyclopentyl, and R5 is 4-phenoxyphenyl. The obtained 2 · [1- (4-phenoxyphenylthio) -cyclopent-1-yl] acetic acid was dissolved in dichlorofluorene pit (8 ml) and treated with 4_dimethylaminophenylene (180 mg ), 0- (tertiary-butyl) -hydroxylamine hydrogenate (360 mg), triethylamine (540 μl), pyridine (400 μl), and 1- (3-dimethylaminopropyl) -3 • Ethylcarbodiimide hydrochloride (750 mg). After stirring overnight, the reaction mixture was distributed between ethyl acetate and water, the organic layer was separated and the solvent was removed under reduced pressure. Preparation of the residue by TLC and eluting with 2: 1 hexane / ethyl acetate to give N- (di-butoxy) -2 · [1 · (4-phenoxyphenylsulfide) as a white foam Group) · Pentam-1-yl] acetamidine (270 mg), which can be used directly in the next reaction without further purification. 9 Β Preparation where R 1 and R 2 are hydrogen, and R 3 and R 4 are attached to a tetrahydropiperanine with carbon atoms, and R 5 is 4-phenoxyphenyl. · Butyl) hydroxylamine hydrochloride (9.57 g), 4-methylmorpholine (15.64 ml), hydroxybenzotriazole (6.87 g) and 1- (3-dimethylaminopropyl) -3 -ethyl Base carbodiimide hydrochloride (19.5 g) is added to 108-sheet paper in digas methane. Applicable to China National Standard (CNS) M specifications (210 > < 297 mm)

Hr ----- --- 1 --I-1 I---I (Please read the precautions on the back before filling this page)

, 1T

Jt 580491 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. 2- [4- (4-phenoxyphenylthio) -tetrahydropiperan_4 · radical in the description of the invention (106) (200 ml) ] Acetamide (17.5 g) in solution. After stirring at room temperature for 3 hours, 0.5M hydrogen acid was added to the mixture, and the mixture was extracted with dioxane. The solvent was removed from the mixed extract under reduced pressure. Chromatography of the residue with silica gel, eluting with 35.80% ethyl acetate / hexane, gave N-tert-butoxy_2- [4_ (4 as an oil -Phenoxyphenylthio) · tetrahydropiperan-4-yl] acetamidine (15.3 g), which can be used directly in the next reaction without further purification. 9C · Li Bei where R1 and R2 are hydrogen, carbon atoms are used to attach R3 and r4 to a fL table N-BOC-hexahydropyridine, and R5 is 4_ (4_ lb. 4 · Methylmorpholine (2.60 ml, 23.68 mmol) was added dropwise to the 2- {4 obtained in Example 6 cooled to 0 ° C in anhydrous dichloromethane (25 ml). -[4- (4-chlorophenoxy) -phenylsulfanylmethylbenzene, 60 (:-hexahydropyridin-4-yl} -carboxylic acid (2.83 g, 5.92 mmol), Tri-butyl) hydroxylamine (2.23 g, 17.76 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.27 g, 11.84 mmol). Within 1 hour, the resulting mixture was allowed to warm to room temperature and stirred for an additional 12 hours to distribute the mixture between diethyl ether / 1N aqueous hydrogen acid (300 mL). Diethyl ether (2 X 100 ml) back extraction of the acidic liquid layer, and the mixed ether extract was dehydrated with magnesium sulfate and concentrated. Chromatography on silica gel, eluting with 25% ethyl acetate / hexane, to obtain N- (No. Tri-butoxy) -2- {4- [4- (4-chlorophenoxy) phenylthiomethyl] -N-BOC -hexa Hydrogen p ratio -4-yl} · carboxamide (2.88 g, 89%). 1HNMR (CDCl3) cM · 31 (s, -109- This paper size applies to China National Standard (CNS) M specifications (210X297 mm) ) (Please read the notes on the back before filling this page)

Order I 畚 580491 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the Invention (1Q7) 9H), 1.45 (s, 9H), 1.58 (mc, 2H), 2.10 (br d, J = 14.2 Hertz, 2H), 3.13 (s, 2H), 3.19 (mc, 2H), 3.73 (mC5 2H), 6.93 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.9 Hz, 2H), 7.30 (d, J 2 8.9 Hz, 2H), 7.38 (d, J = 8.7 Hz, 2H), 8.15 (br s, 1H) 〇9 D. Preparation of changing the formula lb of R 1, R2, R3, R4 and R5 is the same In accordance with the procedure of Example 9A above, but replacing 2- [1- (4-phenoxyphenylthio) -cyclopent-1-yl] acetic acid with another compound of formula la, the following compound of formula lb was prepared: N-third · butoxy-2- [4- (4-phenoxyphenylthio) _N_CBZ_hexahydropyridine-4--yl] -ethylamine; N-third · butoxy · 2- [4- (4 · methoxyphenylthio) -N_CBZ-hexahydropyrazol-4-yl] -ethylamine; N-third-butoxy- 2- {4_ [4- (4-fluorobenzene Oxy) phenylthio] -N_ CBZ -hexahydropyridine-4_ylbuethamine; • N -third-butoxy_2- {4- [4_ (4-fluorophenoxy) phenylthio Phenyl] -hexahydropyridine-4-yl} -ethylamine; N-tertiary-butyl _2_ [4- (4-phenoxyphenylthio) -hexahydropyridin-4-yl] -acetamidamine; N_third-butoxy-2_ [4- (3-methoxyphenylthio ) -Hydroxypyridine_4_yl] _. Acetylamine; N -Third-butoxy-2- 2- [4- (4-methoxyphenylthio) · Hydroxypyridine_4_yl] _ethyl Amidoamine; N-tertiary · butoxy-2-fluorenyl · 3 · (phenylthio) -propanamide; -110- ___ This paper size applies to China National Standard (CNS) A4 (210X 297 mm) ) L -------- ^ Installation ------ Order ------ A__w (Please read the notes on the back before filling this page) Printed by the Employees' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 580491 A7 B7_____ V. Description of the invention (108) N-Third-butoxy-3-benzyl-3- (phenylthio) _propanamide; N-Third-butoxy-3 · benzyl-3 -(4-Methoxyphenylsulfanyl) _propanamide; N_Third-butoxy-3-fluorenyl-3- 3-((4-phenylthiophenyl) thio] • propanamine; N -Third-butoxy_3-benzyl- 3- (4-phenoxyphenylthio) · propanamidine; N -Third · butoxy_3 · fluorenyl- 3-[(4-二Phenyl) thio] -propanamide; N-third-butoxy-3_fluorenyl-3- (2 · fluorenylthio) -propanamide; Ν-third · butoxy- 3_fluorenyl 3- (4-methoxystyrylphenylthio) -propanamide; N-tertiary-butoxy · 3-cyclopentylmethyl-3- (4 · fluorenylphenylthio) ) _Propionic acid amine; Ν -third-butoxy-3_cyclopentylmethyl-2-isopropyl-3- (4-methoxyphenylthio) -propanamine; N -third · Butoxy-3 -ethyl-2 -methyl_3- (4-methoxyphenylthio) _propanamide; N -third-butoxy_3,3 · dimethyl- (4 · Methoxyphenylsulfanyl) _propanamide; N_Third-butoxy-2-[[(4-methoxyphenylsulfanyl) _cyclopentyl-butyl] ethanamide; N-Third-butyl Oxy_2- [1- (4-fluorenyloxyphenylthio) -4 -methylcyclohexyl-1 · yl] -acetic acid amine; N-tertiary-butoxy- 2- [4- (4--benzene Oxyphenylthio) -cyclohexanone_4-yl] -acetamidinyl ketal; N-third-butoxy-2- [l- (4-phenoxyphenylthio) -cyclohexan -Bu Ji] -Ethylamine; 111-This paper size applies to Chinese National Standard (CNS) A4 (210 X 297 mm) (Please read the precautions on the back before filling this page)

580491 A7 B7 V. Description of the invention (1Q9) N -Third-butoxy-2_ [4- (4-methoxyphenylthio) _N-CBZ-hexahydropyridin-4-yl] -acetamidamine; N · Third-butoxy-2_ [4- (4-methoxyphenylthio) -hexahydropyridine · 4_ylbuethamine; N -Third · butoxy-2_ {4- [4- (4 • fluorophenoxy) phenylsulfanyl] tetrahydropiperan-4-ylbutanamide; N-tertiary-butoxy-2- {4- [4_ (4_Gaphenoxy) benzene Thio] tetrahydropiperan_4-yl} -acetamidine; N-tertiary-butoxy · 2 · [4- (4_phenoxyphenylthio) _tetrahydrop-septan-1, 1-dioxide-4-yl] acetamidine; N-tert-butoxy-4_ [4- (4-pyridyloxy) phenylthiomethyl] tetrahydropiperan-carboxamidine; 4 NMR (CDC13) d 1.31 (s, 9Η), 1.70 (mc, 2Η), 2.14 (dm5 J = 11.8 Hz, 2H), 3.21 (s, 2H), 3.63 (mc, 2H), 3.82 (mc, 2H), 6.84 (d, J = 6.4 Hz, 2H), 7.03 (d, J = 8.6 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 8.20 (s, 1H), 8.48 ( d, J = 5.8 Hz, 2H) 〇 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) N -Third-butoxy · 4 · [4- (5 -2_pyridyloxy) phenylthiomethyl] tetrahydropiperanocarboxamide; melting point 100.5-102.7 ° C; IR (KBr) 3438 (br) 1657 cm; iH NMR (DMSO-d6) β 1.19 ( s, 9H), 1.57 (ddd, J = 13.5, 10.1, 4.0 Hz, 2H), 2.05 (dm, J = 13.5 Hz, 2H), 3.34 (s, 2H), 3.42 (mc, 2H), 3.65 (dm, J = 11.6 Hz, 2H), 7.09 (d, J = 8.8 Hz, 2H), 7.10 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 8.7 Hz, 2H), 7.95 (dd , J = 8.8, 2.7 Hz, 1H), 8.19 (d, J = 2.7 Hz, 1H), 10.37 (s, 1H); 13C NMR (DMSO-d6) β 26.66 (q), -112- Applicable to this paper standard China National Standard (CNS) A4 specification (210X297 mm) 580491 A7 __B7 V. Description of invention (11Q) 33.03 ⑴, 43.20 ⑴, 44.25 (s), 64.10 (t), 80.78 (s), 113.00 (d), 121.88 (d), 124.88 (s), 130.43 (d), 132.67 (s), 139.93 (d), 145.51 (d), 151.89 (s), 161.58 (s), 171.64 (s); FABHRMS About C22H28N2S04C1 (M + + H) Calculated 値: 451.1458, Experimental 値: 451.1461. Analysis and calculation of C22H27N2S04C1 値 · C, 58.59; H, 6.03; N, 6.21, Experiment 値: C, 58 · 70; H, 6.05; N, 6.43. Ν -Third-butoxy-3- [4- (5-chloro_2_pyridyloxy) phenylthio] -2,2_dimethyl_N · hydroxypropylamidine; melting point 90.8-91.9 ° C ; IR (KBr) 3438 (br) 1651 cm 1; iH NMR (DMSO-d6) d 1.18 (s, 9H), 1.21 (s, 6H), 3.20 (s, 2H), 7.08 (mc, 3H), 7.40 (d, J = 8.7 Hz, 2H), 7.93 (dd, J = 8.7, 2.7 Hz, 1H), 8.17 (d, J = 2.7 Hz, 1H), 10.17 (s, 1H); 13C NMR (DMSO -d6) d 24.67 (q), 26.48 (q), 42.54 (s), 44.31 (t), 80.62 (s), 112.95 (d), 121.79 (d), 125.28 (s), 130.32 (d), 133.31 (s), 139.86 (d), 145.48 (d), 151.77 (s), 161.58 (s), 173.77 (s); FABHRMS calculation of C20H26N2SO3Cl (M + + H)): 409.1353, experiment 値: 409.1354. Analytical calculations for C20H25N2S03C1: C, 58.74; H, 6.16; N, 6.85, Experiment 値 · C, 58.91; H, 6.13; N, 7.07. Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) N -Third-butoxy-2- (4-methoxyphenylfluorenyl) · Cyclohexanecarboxyl Fluorenamine; and N-tert-butoxy · trans-2- (4-methoxyphenylfluorenyl) -cyclopentanecarboxamide. 9E. Preparation of changing the formula of R2, R3, R4 and R5 lb -113- This paper size applies Chinese National Standard (CNS) A4 specifications (210X297 mm) 580491 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Α7 Β7 V. Invention Explanation (111) Similarly, according to the procedure of Example 9A above, instead of 2- [1- (4 · phenoxyphenylthio) -cyclopent-1-yl] acetic acid, a compound of formula la was used instead. Other compounds of formula Ib. Example 1 0 Preparation of a compound of formula I d 1 A · Lai Bei where η is 0, R1 and R2 are hydrogen, R3 and R41 are joined together to represent a cyclopentyl group, and r5 is a 4-phenoxyphenyl group. The formula Id dissolves N-third-butoxy_2 · [1_ (4-phenoxyphenylthio) -cyclopent_1_1yl] -acetic acid amine in trifluoroacetic acid (6 ml), and allows the It was left for 24 hours. The acid was evaporated under reduced pressure, and the product was purified by preparative TLC, eluting with 6.5% methanol / dichloromethane to give N-hydroxy · 2- [ΙΟ-orthoepoxythio) · cyclopentane • Imidamidine (100 mg). 1 0 Β · Prepare the formula Id where η is 0 and change R1, R2, R3, R4, and R5. Similarly, follow the procedure of Example 10A above, but replace N-third- with another compound of formula lb. Butoxy-2- [1- (4 · phenoxyphenylthio) -cyclopent-1-yl] -acetamidamine to prepare a compound of the following formula Id where η is 0:-N -hydroxyl 2- [ 4 · (4 -phenoxyphenylthio) _N-CBZ -hexahydropyridine-4-yl] -acetamidamine; N -hydroxy-2- [4_ (4_ (phenoxyphenylthio) _N-CBZ • six Hydropyridine- 4-yl] -acetic acid amine; 2- {4- [4 · (4-fluorophenoxy) phenylthio] -N-CBZ -hexahydropyridin-4-yl}-Ν- Ethylamine; 2- {4- [4 · (4 · fluorophenoxy) phenylthio] -hexahydropyridine_4-yl} _. Hydroxy-acetamidine; -114- This paper size applies to China Standard (CNS) Α4 specification (210X297 mm) (Please read the precautions on the back before filling out this page) ▼ Binding and printing Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 580491 A7 __ B7 .— 1m 5. Description of the invention () 3-Methenyl-N-hydroxy · 3- (3-methoxyphenylthio) -propanilamide; Ν- 乐 基-2- [4- (4-phenoxyphenylthio) -hexahydrogen Yt-4-yl] -acetamide; Ν -Rocky- 2 · [4- (4 · methoxyphenylthio) -hexahydroρ biden-4-yl] -ethyl amine; 2-fluorenyl-N-hydroxy_3_ (phenylthio)- Promethazine; 3-Methenyl-N-hydroxy-3-(phenylthio) -propanamide; 3-Methynylhydroxy-3- (4-methoxymethoxythio) -propanamide; 3-amidine N-Hydroxy_ 3-[(4-phenylthiophenyl) thio] -propanilamine; 3-Pingyl-N- # amino- 3- (4-phenoxyphenylthio) -propyl Acid amines; 3-fluorenyl-N-hydroxy- 3-[(4-diphenyl] thio] -propanamide; 3-fluorenyl_N · hydroxy-3_ (4-fluorenylthio) -propanil Amine; 3-Amidino-N-hydroxy-3- (4-methoxystyrylphenylthio) · propanamide; 3-cyclopentylmethyl-N-hydroxy-3- (4-methoxybenzene Thio) -propanilamine; 3-cyclopentylmethyl-N-hydroxy-2 -isopropyl-3- (4-methoxyphenylthio) -propanilamine; 3-ethyl · N-hydroxy- 2-methyl-3- (4-methoxyphenylthio) -propanilamine; 3,3-dimethyl-N-hydroxy- (4-methoxyphenylthio) · propanilamine; N-hydroxyl -2- [1- (4 • fluorenylphenylthio) -cyclopent-1-yl] -acetamidine; N_hydroxy-2 · [1- (4-methoxyphenylsulfanyl) -4-methyl Cyclohexyl_1-yl] -acetamidamine; N_hydroxy-2_ [l- (4-phenoxyphenylthio) -cyclohexyl-1 -Yl] -acetamidine; N -hydroxy · 2- [4 · (4-methoxyphenylthio) -N-CBZ -hexahydropyridine_4 · -115- The paper size applies to the Chinese National Standard (CNS) M specifications (210X297 mm) I equipment-(Please read the precautions on the back before filling out this page) Order 580491 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economics A7 _________B7 V. Description of the invention (113) basis] • 醯Amine; N- # Wangyl- 2- [4- (4--oxophenylthio) -hexahydro p-pyridine-4_yl] -acetamidine; N- # 里 基 _2- [4- ( 4 -phenoxyphenylthio) _tetrahydropiperan_4 -yl] • acetamidine; 2 · {4-[4-(4-chlorophenoxy) phenylthio] tetrahydropiperan-4- }-N -hydroxy-acetamidamine; 2- {4- [4- (4- · fluorophenoxy) phenylthio] tetrahydropiperanyl N-hydroxy-acetamidine; melting point 5 0 _ 5 5 ° C; and N_ # 里 基 -2_ [4- (4-phenoxyphenylthio) -tetrahydropiperan- 丨, _ dioxide_4_yl] _ ethyl donkey amine. 1 〇C · 〇, change the formula Id of R1, R2, R3, R4 and R5 Similarly, according to the procedure of Example 10A above, but replace N_third-butoxy d with other compounds of formula lb — Phenoxyphenylthio) -cyclopent-1-yl] -acetamidinide to prepare other compounds of formula 1 (1 where η is 0. Example 1 1 Preparation of a compound of formula I d, Rij ^ R2 is hydrogen, with carbon atom Jiang R3 * R4 with pentyl, and R5 is 4-phenoxybenzyl, 66 times TH was treated with sodium periodate (26 mg) in water (2 liters) in acetone (4 liters) N_Hydroxy-2- [1 · (4-phenoxyphenylthio) _cyclopentyl-1βylbuthamine (45 mg) solution. In the course of 24 hours, add two additional portions of high iodine Sodium (260 mg). After the starting material has completely disappeared, the solution is diluted with dichloromethane, filtered, dehydrated and evaporated under reduced pressure. _-______- 116- This paper applies Chinese National Standards (CNS) 8 7 specifications (210xT97 ^ F) --- * ~~ --- (Please read the notes on the back before filling in this page) Order 4 -nn Printed by the Central Consumers Bureau of the Ministry of Economic Affairs Consumer Cooperatives 580491 A7 _____ B7 ____ _ V. Description of the invention (114) agent. Preparation of TLC on silica gel, and elution with 10% methanol / dichloromethane to obtain N-hydroxy-2- [1- (4 • phenoxybenzenesulfenic acid) Fluorenyl) _Cyclopentylpyridamide (15 mg), 4 NMR (CDC13) 7.64 (d, 2 fluorene), 7.44 (t, 2H), 7.30_7.05 (m, 5H), 2.97 (d , LH), 2.53 (d, lH), 2.15- 1.65 (m, 8H). &Quot; B. Where n is 1 ', R1 and R2 are hydrogen, and r3 and ruler 4 are attached to the carbon source j to represent four. Hydropiperan-4-yl, and fluorophenoxy and fluorenyl groups of formula I d will be 2- {4_ [4_ (4-fluorophenoxy) phenylthio] tetrahydropiperan · 4_ylb N_ super Methylacetamide (500 mg) was dissolved in methanol (25 ml). OXONE (400 mg) in water (5 ml) was added. After stirring for 30 minutes, the mixture was distributed over dichloromethane and Between water. Preparative TLC was performed on Shixi gum, and eluted with 10% methanol / dichloromethane to give 2_ {4_ [4 · (4_fluorobenzyl) benzylidene]] tetrahydrobromide Alan-4-yl} ·] ^ Acetoacetic acid amine (402 mg, melting point i20 ° C). 1 1C · Laibei where η is 1, which competes with R1, R2, r3, H 4 and H 5 Formula Id is the same , According to the procedure of Example ii A or 1 1 b above, but replacing N-hydroxy-2 · [1- (4-phenoxyphenylthio) -cyclopentane-1 with other compounds of formula id in which n is 0 _Yl] _acetamidine, to prepare other compounds of formula d where η is 1 For example: group-2- [4- (4-phenoxyphenylsulfinamidino) _N-CBZ -hexahydropyridine-4 -Yl] -acetamidamine; N-light group_2- [4- (4-phenoxyphenylsulfinamido) _hexahydropyridin-4 · yl] -acetamidamine; __ —_- 117- This paper standard is suitable for financial and family care standards (CNS) A4 ^ (21 () > < 297) (Please read the precautions on the back before filling this page)-Order 580491 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (115) to the radical 2- 2- [4- (4-methoxyphenylarsonyl) -N-CBZ-hexahydroepi-4-yl] -acetamidamine; 2- {4- [4- (4-said phenoxy) benzylidene] • Hexahydropapido-4-yl} · N-light ethylamine; N-Cyclo-2-[4- (4-Methoxybenzoylidene) -hexahydroeodo-4-yl] -acetamidinium; 2-Methenyl-NJ% -based 3- (4-methoxybenzoylidene) ) -Propanamine; 3 -N-yl-N-per-yl- 3- (3-methoxyphenylene Fluorenyl) -propanilamine; 3- fluorenyl-N-peryl-3- (4-methoxyphenylphenylene) -propylamine; 3-methyl-N-peryl-3 · [ (4-Phenylthiophenyl) hydrous acid] -propanamide; 3-benzyl-N-hydroxy-3- (4-phenoxyphenylsulfinyl) -propanilamide; 3-fluorene -N_Hydroxy_3-[(4-diphenyl) sulfenamidino] -propanamidinide; 3-Nanthyl-N_ # presenting group-3- (4-fluorenylarylene acid) -propanyl 8¾ amine; 3 · benzyl-N-hydroxy-3_ (4-methoxyphenethylfluorenylbenzenesulfenyl) · propanamide; '3-cyclopentylmethyl-N_hydroxy-3-(4 -Methoxymethoxysulfenyl) -propanamide; 3-cyclopentylmethyl-N_hydroxy-2-isopropyl-3- (4-methoxyphenylsulfinyl) -propanamide ; 3-ethyl-N-hydroxy-2 · methyl-3 (4-methoxyphenylsulfinyl) -propanamide; 3,3-dimethyl-^^ hydroxy- (4-methyl Oxybenzenesulfenyl) -propanamide; N_hydroxy- 2- [l- (4- (oxyphenylsulfenyl) sulfonyl) -cyclopent-1-ylbutanamide; -118- Paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) h —-^ -----------, 玎 ----- 0 (Please read the precautions on the back before filling in this (Page) 580491 Printed by the Consumer Standards Cooperative of the Ministry of Standards of the People's Republic of China A7 B7 V. Description of the invention () N -Hydroxy-2 · [1- (4-methoxyphenylsulfinyl) _4_methylcyclohexyl_1 · yl]- Acetylamine; Ν · # 枝 基 -2- [1- (4-phenoxyphenylidene) -cyclohex-1-yl] -ethynamine; N-hydroxy-2- [4- (4-Methoxybenzenesulfenyl) -N-CBZ-hexahydropyridin-4-yl] -acetamidinium; N-Hydroxy-2- 2- [4- (4-methoxyphenylsulfinyl) -Hexahydropyridin-4-yl] -acetamidamine; 'N-hydroxy- 2- [4 · (4-phenoxyphenylsulfinamido) _tetrahydropiperan · 4-yl] -acetic acid amine; 4 · [4 · (4-Gaphenoxy) benzylidenemethyl] tetrahydroxan-4- (N- # present carboxycarbamidine): melting point 141.3 -142.1. (:; IR (KBr) 3436 (br), 1649 cm 1 NMR (DMSO-d6) β 1.67 (dm, J = 13.9 Hz, 1H), 1.79 (dm, J = 13.9 Hz, 1H), 1.97 (dm, J = 13.9 Hz, 1H), 2.24 (dm, J = 13.9 Hz, 1H), 2.97 (d, J = 13.7 Hz, 1H), 3.07 (d, J = 13.7 Hz, 1H), 3.33- 3.54 (m5 2H), 3.69 (mc, 2H), 7.12 (d, J = 8.9 Hz, 2H), 7.21 (d5 J = 8.8 Hz, 2H), 7.48 (d5 J = 8.9 Hz, 2H), 7.66 (d , J = 8.8 Hz, 2H), 8.87 (br s, 1H), 10.76 (s, 1H), 13C NMR (DMSO-d6) 32.43 (t), 33.71 (t), 42.69 (s), 63.65 (t) , 67.12 (t) 5 118.90 (d), 121.07 (d), 126.11 (d), 12819 (s)? 130.07 (d), 139.51 (s), 154.62 (s), 158.72 (s), 169.68 (s) ;

I FABHRMS Calculation of C19H21NS05C1 (M + + H) 41: 410.0829, Experiment 値: 426.0825. Analysis and calculation of C19H2〇NS05C1 値: C, 55.68; Η, 4.92; Ν, 3.42, experiment 値: C, -119- This paper size applies to China National Standard (CNS) A4 (210X297 mm) h ^ -----------, τ ---- Φ (Please read the notes on the back before filling out this page) 580491 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention ( 117) 55.70; H, 4.93; N, 3.64. 2- {4 · [4- (4 · chlorophenoxy) -benzylidene] tetrahydrobran-4 · yl} -N · lightylacetamide; and N-benzyl- 2- [ 4- (4-Phenoxyphenylidene) -tetrahydro-p-Serane-pyridine, ι · monoxide 4 -yl] -ethanamine. Example 1 2 Preparation of a compound of the formula Id 1 2 A · Preparation where η is 2, R1 and R2 are hydrogen, R3 and R4 are attached together with a carbon atom to represent a cyclopentyl group, and R5 is 4 · phenoxyphenyl Id. Treatment of N · hydroxy-2- [1- (4-phenoxyphenylthio) -cyclopentane-1 in methanol (4 ml) with a solution of OXONE (260 mg) in water (2 ml). -A solution of ketamine (45 mg). Stir the mixture for 1 hour and then distribute it between methane and water. The organic layer was separated and the solvent was removed under reduced pressure. Preparative TLC was performed on silica gel and eluted with 10% methanol / dichloromethane to give N-hydroxy-2_ [l- (4-phenoxybenzenesulfonyl) _cyclopent-1-yl] · acetamidine Amine (20 mg), m / e = 393 (MNH4 +, CIMS). 12B. Preparation where η is 2, R1 and R2 are attached together with carbon atoms, hydrogen hydrogen ran, R3 and R4 are hydrogen, and R5 is 4- (4-gas phenoxy). ^ Ld is cooled to 5 ° C, 20 ° C tetrahydrofuran · methanol (1570 ml), mechanically; 4- [4 · (4-chlorophenoxy) phenylthiomethyl] tetrahydrotripan_ 4 -(N · hydroxycarboxamide) (59.8 g, 151.8 mmol) was added dropwise to a solution of OXONE (152 g, 247 mmol) in water (1 liter), maintaining the internal temperature at 15-2 0 ° C. Stir the mixture for 5.5 hours, then -120- This paper size applies Chinese National Standard (CNS) Α4 specification (210 × 297 mm) (Please read the precautions on the back before filling out this page} Order_φ 580491 Staff of Central Standards Bureau, Ministry of Economic Affairs Printed by the consumer cooperative A7 B7 V. Description of the invention (118) Distribute the mixture between 30% ethyl acetate / water (3 liters). Rinse the liquid layer with ethyl acetate (2 X 300 liters) and mix the mixed The ethyl acetate layer was dehydrated with magnesium sulfate, concentrated under reduced pressure, and the residue was recrystallized from a small amount of monochloromethane / hexane to obtain 4— [4 _ (4 _chlorophenoxy) of analytical grade purity. Phenylbenzenesulfenylfluorenyl] tetrahydropiperan_4_ (N_hydroxycarboxamide), as a white powder (54.2 g '84%). Melting point 147.7 148.9 ° C; IR (KBr) 3429 (br ), 1636 cm.1; iHNMR (DMSO-d6) J 1.70 (dm, J = 13.9 Hz, 2H), 1.96 (dm, J = 13.9 Hz, 2H), 3.38-3.48 (m, 2H), 3.58-3.68 (m, 2H), 3.58-3.68 (m, 2H), 3.66 (m, 2H), 7.19 (d, J = 8.9 Hz, 2H), 7.19 (d, J = 8.9 Hz, 2H), 7.52 (d, BU 8.9 Hz, 2H), 7.85 (d, J = 8.9 Hz, 2H), 8.68 (d, J = 2.0 Hz, 1H), 10.54 (d, J = 2.0 Hz, 1H), 13C NMR (DMSO-d6) 32.83 (t), 41.70 ( s), 61.02 (t), 63.19 ⑴, 118.01 (d), 121.71 (d), 128.73 (s), 130.08 (d), 139.19 (d), 135.20 (s), 158.83 (s), 160.86 (s) 168.96 (s); FABHRMS calculation of C19H20NSO6Cl 42 426.0778, experiment 値: 426.0774. Analysis and calculation of Ci9H2 NS06Cl c: c, 53.59; H, 4.73; N, 3.29, experiment 値: C5 53.58; H, 4.70; N, 3.40. 1 2 C · Preparation where n is 2 and R1 and R2 are attached with a carbon atom—generation of hydropiperan 'R3 is hydrogen, R4 is benzyl, and R5 is 4 · ( 4-Hydroxybenzyl-H-based formula Id In 10 minutes, chlorpyrrolidine (200 μl, 2.20 mmol) was added dropwise to methylene chloride (6 ml) at 0 ° C. 3-Benzyl-4- [4- (4- (phenoxy) benzenesulfonylmethyl) tetrahydropiperan-4-carboxylic acid (316 mg, 0.63 mmol_ -121-paper size) Applicable Chinese National Standard (CNS) Α4 specification (210 × 297 mm) (Please read the precautions on the back before filling out this page)-Order — 58049 1 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the Invention (119) Moore) and N, N-dimethylformamide (10 microliters). The mixture was allowed to warm to room temperature within 1 hour, and a portion of the slurry was stirred for an additional 8 hours, and concentrated in the radon air until theoretically obtaining agglomerates of the radon base gas. This mixture was dissolved in dichloromethane (8 ml), cooled to 0 t, and pure N, 0-bis (trimethylsilyl) hydroxylamine (0.56 g '3.15 *) was added dropwise over 5 minutes. Mol) solution. The mixture was immediately warmed to room temperature, stirred for 48 hours' and cooled again to 0 °. To this solution was added aqueous 1 μ hydrochloric acid (5 耄 '150 mmol), and the solution was stirred for an additional 30 minutes to distribute between ethyl acetate (150 mL) and brine (500 mL). )between. The organic layer was dehydrated with magnesium sulfate, concentrated in the air, and chromatographed on silica gel, eluting with 4% methanol / ethyl acetate, to obtain 280 mg (86%) of 3 + radicals 4- [4_ ( 4-Chlorophenoxy) phenylpentamidylmethyl] -tetrahydroan- 4- (N · hydroxyurea) hydroxylamine. Melting point 108 113 ×:; IR (KBr) 3422 (br), 1653 cm. 1; iH NMR (CDC13) β 1.76 _ 1.86 (m, 1H), 2.08-2.27 (m, 2Η), 2.34 (dm, J = 13.8 Hz, 1Η), 2.91 (dd, J = 16.5, 7.2 Hz, 1H), 3.17 (dd, J = 16.4, 4.0 Hz, 1H), 3.19-3.23 (tm5 > 9.0 Hz, 1H), 3.43 (td, J 2 11.9, 2.4 Hz, 2H), 6.65-6.72 (m, 2H), 6.76 (d, J = 8.9 Hz, 2H), 6.88 (d, J = 8.8 Hz, 211), 6.98 · 7.0 · 4 (m, 3H), 7.30 (d, J = 8.9 Hz, 2H), 7.49 (d, J = 8.8 Hz, 2H); 13C NMR (CDC13) d 31.76 (t ), 34.23 (t), 47.30 (s), 64.07 (t), 64.66 (t), 72.68 (d), 117.50 (d), 121.64 (d), 126.47 (d), 127.96 (d), 128.53 (d ), 130.31 (d), 130.69 (d), 132.91 (s), 137.83 (s), 153.34 (s), 162.12 (s), 171_30 (s); FABHMS (M + + H): 516; About C26H26NS06C1 Analysis and calculation 値: C, 60.52; H, -122- This paper size applies to Chinese national standards (CNS> A4 size (210X297 mm) (Please read the precautions on the back before filling out this page) Order 580491 Central Bureau of Standards, Ministry of Economic Affairs Printed by employees' consumer cooperatives A7 B7 Note (12Q) 5.08; N, 2.71, experiment 値 ·· C, 60.45; H, 5.10; N, 2.55. 12D · Preparation where η is 2, change the formula of jade 1, ruler 4 and ruler 5 Id samely According to the procedure of Example i 2 C above, but replacing 4- [4- (4-chlorophenoxy) phenylthiomethyl] tetrahydropiperan-4-(N -hydroxyl with other compounds of formula Iba Carboxamidine) to prepare a compound of the formula I d wherein η is 2: 4- [4- (4-fluorophenoxy) benzenesulfonylmethyl] tetrahydropiperanylhydroxycarboxamide): melting point 153.1 153.9. (:; IR (KBr) 3434 (br), 1636 cm 1; 4 NMR (CDC13) d 1.87 (ddd, J = 13.6, 8.8, 4.0 Hz, 2H), 2.22 (dm, J = 13.6 Hz, 211), 3.52-3.78 (111,411), 7.00-7.16 (m, 6H), 7.84 (d, J = 8.9 Hz, 2H); 13 C NMR (CDC13) β 33.12 (t), 42.19 (s), 62.52 (t ), 63.96 (t), 116.88 (dd, JC_F = 21.3 Hz), 117.30 (d), 121.97 (dd, JC_F = 8.4 Hz), 130.18 (s), 134.21 (d), 150.66 (d, Jc- F = 2.6 Hz), 159.73 (d, Jc_f = 243.8 Hz) 162.61 (s), 1 69.73 (s); FABMS (M + + H): 410. Analysis and calculation of CmHwNSC ^ F 値: c, 55.74; H , 4.92; N, 3.42, Experiment 値: C, 55.45; H, 4.91; N, 3.38. 4- [4- (4-Bromophenoxy) benzene and gf-based methyl] tetrahydrotripan_4_ (n _Cyclosylamine): melting point 150.1-151.0 ° C; IR (KBr) 3432 (br), 1636 cm_ 1; 4 NMR (CDC13; NH and OH are not observed) d 1.87 (ddd, J = 13.6, 8.7, 3.9 Hz, 2H), 2.12 (dm, J2 13.6 Hz, 2H), 3.52 (s, 2H), 3.62-3.80 (m, 4H), 6.97 (d, J = 8.8 Hz, 2H), 7.06 ( d, J = 8.8 Hz, 2H), 7.52 (d, J = 8.8 1H, 2H), 7.85 (d5 J = 8.8 Hz, 2H); 13C NMR (CDCls) ^ 33.10 (t), 42.16 (s), 62.49⑴, _ -123- This paper standard applies to China National Standard (CNS) A4 Specifications (210X 297mm) '~ (Please read the precautions on the back before filling this page) ▼ pack.

1T " ml 580491 A7 B7_ V. Description of the invention (121) 63.93 (t), 117.66 (s), 117.83 ⑷, 121.93 (d), 130.20 (d), 133.17 (d), 134.61 (s), 154.13 ( s), 161.79 (s), 169.53 (s); FABHMS calculation for C19H20NS06Br (M + + H) 値: 470.0273, experimental 値: 470.0268. Analytical calculations for CwHnNSC ^ Br: C, 48.51; H, 4.28; N, 2.98, Experiment 値: C, 48.29; H, 4.02; N, 2.94. 3- (4_benzylfluorenylbenzenesulfonyl) _2,2_dimethyl-N · hydroxypropylhydrazine; 3- [4_ (4 · chlorophenoxy) benzenesulfonyl] _2,2_ Dimethyl-N-hydroxypropylamidine; melting point 154.9 156.1 ° C; iH NMR (CDC13) d 1.45 (s, 6H), 3.48 (s, 2Η), 7.02 (d, J = 8.9 Hz, 2Η), 7.04 (d, J = 8.9 Hz, 2Η), 7.38 (d, J = 8.9 Hz, 2H), 7.85 (d, J = 8.9 Hz, 2H); FABMS (M + + H): 384.0. Analytical calculations for C17H18NS05C1 値: C, 53 · 19; Η, 4.73; Ν, 3.65, experimental 値: C, 52.98; Η, 4.69; Ν, 3.73 〇4_ (4-phenoxybenzene Transmethyl-methyl) -tetrachloromethane-Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Development (Please read the precautions on the back before filling this page) Amine): Melting point 141.8 142.9 ° C; IR (KBr ) 3432 (br), 1636 cm-1; iHNMRfDMSO-dO d 1.74 (ddd, J = 13.8, 10.0, 3.9 Hz, 2H), 1.98 (dm, J = 13.8 Hz, 2H), 3.45 (mc, 2H), 3.64 (mc, 2H), 3.65 (s, 2H), 7.15 (d, J = 8.8 Hz, 2H), 7.26 (d, J = 7.5 Hz, 2H), 7.47 (t, J = 7.5 Hz, 1H), 7.85 (d, J = 8.8 Hz, 2H), 8.68 (s, 1H), 10.52 (s, 1H); 13C NMR (DMSO-d6) d 32.87 (t), 41.76 (s), 61.19 (t) , 63.28 (t), 117.71 (d), 119.99 (d), 124.91 (d), 130.04 (d), 130.34 (d), 134.85 (s), 154.85 (s), 161.39 (s), 168.97; FABHRMS About Calculation of C19H22NS06 (M + + H)): __- 124-_ This paper size is applicable to China National Standard (CNS) A4 (210X297 mm) 580491 Printed by the Central Standards Bureau's Consumer Cooperatives A7 B7 V. Invention Description (122) 392.1168, Experiment 値: 392.1162. Analysis and calculation of C19H21NS06 · 0.5H2O O: C, 56.99; H, 5.54; N, 3.50, Experiment 値: C, 57.06; Η, 5.35; N, 3.93. 4- [4- (4- · phenphen-2-yl) phenoxybenzenesulfonylmethyl) -tetrahydropiperan-4 · (N · hydroxycarboxamide): melting point 172.2 176.5 ° C; IR ( KBr) 3248 (br), 1636 cm / 1; iH NMR (DMSO-d6) d 1.72 (dm, J = 14.5 Hz, 2H), 1.99 (dm, J = 14.5 Hz, 2H), 3.46 (mc, 2H) , 3.65 (mc, 2H), 3.66 (s, 2H), 7.14 (dd, J = 4.9, 3.6 Hz, 1H), 7.19 (d, J = 8.7 Hz, 211), 7.20 ((1,) 2 8.9 Hz , 211), 7.48 ((1 (1, == 3.6, 1.2 Hz, 1H), 7.52 (dd, J = 4.9, 1.2 Hz, 1H), 7.73 (d, J = 8.8 Hz, 2H), 7.86 (d, J = 8.8 Hz, 2H), 8.68 (s, 1H), 12.58 (s, 1H); 13C NMR (DMSO-d6) β 32.89 (t), 41.78 (s), 61.20 (t), 63.28 ( t), 117.88 (d), 120.55 (d), 123.66 (d), 125.56 (d), 127.34 (d), 128.45 (d), 130.07 (d), 130.62 (s), 135.04 (s), 142.45 ( s), 154.30 (s), 161.16 (s), 169.03 (s); FABHRMS calculation on C23H24NS206 (M + + H): 474.1045, experiment: 474.1050; analysis on C23H23NS 2 06: C, 58.33 H, 4.90; N, 3.00, Experiment 値: C5 58.18; Η, 4.84; Ν, 3 · 19. 4- [4- (4-Fenphen-3-yl) phenoxybenzene (continued 8methyl) -tetrachlorosulfan-4- (N-hydroxycarboxamide: M melting point 183.5-184.4 ° C; IR (KBr) 3432 (br), 1636 cm 1; iH NMR (DMSO-d6) d 1.72 (me, 2H), 1.98 (mc, 2H), 3.48 (mc, 2H), 3.65 (mc , 4H), 7.18 (mc, 4H), 7.55 (dd, J = 5.1 Hz, 1H), 7.62 (d, J = 4.9, 3.7 Hz, 2H), 7.80 (d, J = 8.6 Hz, 2H), 7.86 (mc, 3H), 8.69 (s, 1H), 10.58 (s, 1H); 13C ___- 125-_ This paper size applies to China National Standard (CNS) A4 (210X 297 mm) (Please read the back Please fill in this page again for attention) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 580491 A7 —_B7 ___ V. Invention Description (123) NMR (DMSO-d6) Θ 32.88 ⑴, 41.79 (s), 61.19 (t), 63.28 ( 〇, 117.71 (d), 120.42 (d), 120.81 (d), 126.09 (d), 127.10 (d), 127.97 (d), 130.06 (d), 132.10 (s), 134.89 (s), 140.54 (s) ), 153.86 (s), 168.85 (s); FABHRMS calculation of C23H24NS206 (M + + H)): 474.1045, experiment 値: 474.1049; analysis of C23H23NS206 · 0.75H2O Zhi: c, 56.72; H, 5.07; N, 2.88, experimental Zhi: C, 56 · 74; H, 4 · 78; N, 3 · 22. 3,3-Difluorenyl-3-[(4-chlorophenoxy) benzenesulfonyl] -N-hydroxy-propanamide; {4 · [4- (4 · phenylhydrazine [b] fluorene- 2-ylphenoxy) benzenesulfonyl] -tetrahydropiperan-4-yl] -N-light acetic acid amine; 2_ {4_ [4 · (benzyl) phenazinyl] -tetrachlorobromide Nan-4-yl] -N-benzylacetamide; 2_ {4- [4- (4- (4 • chlorophenoxy) benzenesulfonyl tetrahydropiperan-4-yl] -N-hydroxyacetamidine Amines; and 2- {4- [4- (4-bromophenoxy) benzenesulfonamidotetrahydropiperan-4-yl] -N-hydroxyacetamidamine. 12E. Prepare the formula Id where η is 2 and change R1, R2, l3_ ^ R4, and R5. Similarly, follow the procedure of Example 1 2 A or 1 2 B above, but use the other formula 1 (1 where η is 0) Compound instead of N-hydroxy-2- [l- (4-phenoxyphenylthio) · cyclopent-1-yl] · acetamidine to prepare a compound of the formula Id in which n is 2, for example: 4- ( 4 -phenoxybenzenesulfonylmethyl) tetrahydropiran- 4- (N -hydroxycarboxamidine); ___ 126- This paper size applies to China National Standard (CNS) A4 (210X297 mm) (Please (Read the notes on the back before filling out this page)

580491 A7 — ^ ____ ^ ------- 5. Description of the invention (124) 4- [4- (4-Fluorophenoxy) benzenesulfonylmethyl] tetrahydropiperan-4_ (N_hydroxyl S all amines); 4 · [4- (4-chlorophenoxy) benzenesulfonylmethyl] hexahydropyridine-4_ (N-hydroxychimonamine); 4- [4- (4-chlorophenoxy) Group) benzenesulfonylmethyl] -bumethyl-hexahydropyridine-4 · (N-hydroxycarboxamidine); 4- [4- (4-chlorophenoxy) benzenesulfonylmethyl] · 1 · Cyclopropyl-methylhexahydropyridine-4- (N-hydroxycarboxamidine); 4- [4- (4-chlorophenoxy) benzenesulfonylmethyl] -1-ethenyl-hexahydro Pyridine-4- (N-hydroxycarboxamidine); 4- [4- (4-chlorophenoxy) benzenesulfonylmethyl] -1- (3-pyridyl) -hexahydropyridine-4- (NR · Hydroxycarboxamide); 4-[4-((4-Gaphenoxy) benzenesulfonylmethyl] -1-(3 · pyridinyl) -hexahydropyridine_4_ (N-hydroxycarboxamidine) ); Ν-hydroxy-2 · [4- (4 · phenoxybenzenesulfonyl) -N-CBZ-hexahydropyridin-4-ylpyridamidine; Ν-hydroxy-2 2- [4- (4 -Methoxybenzenesulfonyl) -N-CBZ -Hexahydropyridin-4-yl] -acetamidinium; printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs ·· -------- Aw% .-- (please Read the notes on the back and fill in this page again) 2- {4_ [4- (4- (Phenylphenoxy) phenylphenone group] _N-CBZ-: rc rat's mole ratio lake 4 -based} -1 ^ -Luo Zhi Ethylethyl S &amine; 2_ {4- [4_ (4-Gaphenoxy) benzene continuation group] -7T chloropyridine-4-yl} -N-hydroxyacetamidine; N-hydroxy-2- [4- (4-Methoxybenzenesulfonyl) -hexahydropyridine-4-ylbuthylamine; _____ 127-_ This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) Economy Printed by the Consumer Standards Cooperative of the Ministry of Standards of the People's Republic of China 580491 A7 ^ _________ V. Description of the Invention (125) N-Hydroxy-2- 2- [4_ (4-phenoxybenzylsulfonyl) -hexahydropyridin-4-yl] • B Amidoamine; 2-benzyl-N-hydroxy-3- (4-methoxybenzenesulfonyl) -propanamide; 3-benzyl-N-hydroxy-3- (3.methoxyphenylsulfonyl) -Propanamide; 3-benzyl-N-hydroxy-3- (4-methoxybenzenesulfonyl) -propanamide; 3-benzyl-N-hydroxy · 3-[(4-phenylthiobenzene Group) sulfofluorenyl) -propanamide; 3-benzyl-N-hydroxy-3- (benzenesulfonyl) -propanamide; 3.benzyl-N · hydroxy-3 · (phenoxybenzenesulfonyl) ) -Propanamide; 3-benzyl-3-[(4-diphenyl) sulfonamido] -N-hydroxypropanamine; 3 _Yeyl-N-per-yl- 3- (2-Fanyl) -Propanylamine; 3-benzyl · N_hydroxy-3 · (4-methoxystyrylbenzenesulfonyl) · Propylamidine; 3- (cyclopentylmethyl) -N · hydroxy-3- (4 · methoxybenzenesulfonyl) -propanilamine; 3- (cyclopentylmethyl) hydroxy-2-isopropyl- 3- (4-methoxyphenyl-sulfonyl) -propane 6 &amine; 3-ethyl-1 ^ _protecting group-3- (4-methoxybenzoic acid) -2-methylpropane Amine; 3,3-dimethyl-N-hydroxy- (4-methoxybenzenesulfonyl) · propanamide; N-hydroxy_2 · [1- (4-methoxybenzenesulfonyl) -cyclo Pentamyl-1 · methylbutyrimidine; N-hydroxy-2- [1- (4-methoxybenzenesulfonyl) -tetramethylcyclohex-1-yl] acetamide; Ν · hydroxy · 2_ [ 1 · (4-phenoxybenzenesulfonyl) -cyclopent-1-yl] -acetamidamine; N-hydroxy · 2- [4- (4-phenoxybenzenesulfonyl) -tetrahydropiperan_ 4-yl] -acetamidamine; 2_ {4- [4- (4-chlorophenoxy) benzenesulfonyl] tetrahydropiperanine This paper is sized to the Chinese National Standard (CNS) A4 (210 X 297 Mm) (Please read the notes on the back before filling in this page)

、 1T -128- ______ 580491 A7 ______ _B7 V. Description of the invention (126) Acetylamine; 2- {4- [4- (4-fluorophenoxy) benzenesulfonyl] tetrahydropiperan- "group } -... several acetoacetamides; N · hydroxy_2- [4 · (4-phenoxybenzenesulfonyl) -tetrahydropiperidine ·: [, dioxide-4-yl] -ethanamine 1 2 F · Prepare the formula id where η is 2 and change R 1, R2, R3, R4, and R5. Similarly, follow the procedure of Example 12A above, but replace other compounds of formula Id where n is 0. -Hydroxy- 2- [1- (4-phenoxyphenylthio) -cyclopent-1-yl] -acetamidine to prepare other compounds of formula Id where η is 2. Example 1 3 Preparation of Y where third is -BuONE- Compound I of Formula I 3 A · Preparation where η is 2, R1 and R2 are hydrogen, R3 and R4 are attached together with carbon atoms to represent tetrahydropiperan, and R5 is 4-phenoxyphenyl Tc Printed by the Consumers Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs will add 〇χ〇ΝΕ (33.9 grams) solution in water (170 ml), added to the cooled NH in methanol (340 ml)-the third -Butoxy-2- [4- (4-phenoxyphenylthio) -tetrahydroouran-4-yl] -acetamidamine (14.1 g, 33 .9 millimoles) / valley fluid. The mixture was dropped at room temperature for 5 hours, concentrated under reduced pressure to half of the original volume, and the residue was then distributed between ethyl acetate and water. The solvent was removed from the ethyl acetate extract under reduced pressure. The residue was chromatographed on Shi Xijiao and eluted with 10% methanol / dichloromethane to give N_th as a white foam. Tri-butoxy_2- [4_ (4_phenoxybenzenesulfonyl) -tetrahydrotripan-4-yl] ethylamine. 1 3 Β · Wherein η is 2, R3 and R4 are Hydrogen, with carbon atoms and r2 1 connected together to represent N-BOC-hexahydropyridine, and R5 produces soil 丄 4-chlorobenzyl) 129- This paper size applies to China National Standard (CNS) A4 specifications (210X297 mm) ) 580491 Printed by A7 ____— B7 instructions from the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (i27y '^ ~~~ Phenyl formula I c is cooled to 0 ° C in anhydrous methylene chloride (70 ml) -Third-butoxy- 2 · [4- (4-phenoxyphenylthiofluorenyl) _n-BOC_hexahydroanidine_4yl] -carboxamide (4.96 g, 9.03 mmol) To the solution, add 60% 3_ chloroperbenzoic acid (4 .96g). Allow the resulting mixture to warm to room temperature within 30 minutes and then stir for 5 minutes. Add 36% aqueous dimethylsulfide (1 ml, 13.62 mmol) in one batch. The mixture was stirred for 10 minutes, distributed with saturated aqueous sodium bicarbonate (2 x 50 ml), dried over magnesium sulfate, and concentrated in the air. Chromatography on silica gel, eluting with 25% ethyl acetate / hexane, gave N · Third-butoxy · 2- [4- (4-phenoxybenzoylhydrazone) as a white foam ) -N-BOC-Hexahydroanodo-4-yl] -carboxamide (4.70 g, 90%). 4 NMR (CDC13) d 1.31 (s, 9H), 1.46 (s, 9H), 1.59 (mc, 2H), 2.18 (mc, 2H), 3.42 (mc, 2H), 3.45 (s, 2H), 3. · 62 (mc, 2H), 7.01 (d, J = 8.9 Hz, 2H), 7.04 (d, J = 8.8 Hz, 2H), 7.38 (d, J = 8.8 Hz, 2H), 7.84 (d, J = 8.8 Hertz, 2H), 8.44 (br s, 1H) 〇13C. Preparation of formula Ic in which n is 2, Y is third -BuONH-, change R1, R2, K3, R4 and R5 Similarly, according to Example 1 above 3 B procedure, but replacing N-third-butoxy-2- [4- (4-phenoxyphenylthiomethyl) -N-BOC · hexahydropyridine-4- with another compound of formula lb []] Carboxamidine to prepare a compound of the following formula Ic in which η is 2 and Y is third_BuONH-: N-third-butoxy · 4 [[4- (4 · pyridyloxy) benzenesulfonate Fluorenylmethyl l · tetrahydropiperan-carboxamide: IR (KBr) 3434 (br), 1684 cm 1; ANMK -130- __ One paper size applies Chinese National Standard (CNS) A4 specifications (210 X297 Mm)----m--In · m 丨 Tf-三 ·· I Jg Γ · —--= i III (Please read the notes on the back before filling this page) Ordering ·

-LT 580491 Μ ____ Β7_ V. Description of the invention (128) (CDCI3) 4 1.33 (s, 9H), 2.01 (mc, 2H), 2.24 (mc, 2H), 3_55 (s, 2H), 3.79 (mc, 4H), 6.93 (d, J = 6.3 Hz, 2H), 7.22 (d, J = 8.8 Hz, 2H), 7.96 (d, J = 8.8 Hz, 2H), 8.38 (s, 1H), 8.57 (d, J 2 6.3 Hz, 2H); FABHRMS calculation of C22H28N2S06 (M + + H) 値: 449.1746, Experiment 値: 449.1757. N_Third-butoxy-4- [4- (5 · Ga-2-pyridyloxy) benzenesulfonylmethyl] -tetrahydropiran · carboxamide: melting point (wide) 100.8_135. 8 ° C; IR (KBr) 3436 (br), 1684 cm1; iH NMR (DMSO-d6) d 1.20 (s, 9H), 1.72 (mc, 2H), 2.03 (mc, 2H), 3.48 (mc, 2H), 3.67 (mc, 2H), 3.76 (s, 2H), 7.23 (dd, J = 8.8, 0.5 Hz, 1H), 7.41 (d, J = 8.8 Hz 5 2H), 7.91 (d, J = 8.8 Hertz, 2H), 8.03 (dd, J = 8.8, 2.7 Hertz, 1H), 8.25 (dd, J = 2.7, 0.5 Hertz, 2H), 8.30 (s, 1H), 10.23 (s, 1H); 13C NMR (DMSO-d6) d 26.66 (q), 33.09 (t), 42.37 (s), 61.03 (t), 63.36 (t), 80.64 (s), 113.89 (d), 121.38 (d), 126.33 (s) ), 129.53 (d), 137.00 (s), 140.34 (d), 145.74 (d), 157.87 (s), 160.66 (s), 171.25 (s); FABHMS calculation for C22H28N2S06C1: 483.1357, experiment: 483.1354 . Analysis and calculation of C22H27N2S06C1: C, 54.71; H, 5.63; N, 5.80, Experiment: C, 54.46; K, 5.60; Ν, 5.98. Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the notes on the back before filling this page) Ν -third-butoxy_3- [4- (5-chloro-2-pyridyloxy) benzenesulfonate Fluorenyl] · 2,2-dimethyl-propanamide: melting point (extensive) 64.5-70.5 ° C; iH NMR (DMSO-d6) β 1.19 (s, 9H), 1.29 (s, 6H), 3.65 (s, 2H), 7.24 (d, J = 8.7 Hz, 1H), 7.41 (d, J = 8.8 Hz, 2H), 7.91 (d, J = 8.8 Hz, 2H), 8.04 (dd, J = 8.8, 2 · 7 Hz, 1H), 8.26 (d, J 2 · 7 Hz, 1H), -131-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 580491 A7 B7 5 Description of the invention (129) 10.17 (s'lH); 13C NMR (DMSO_d6) β 25.01 (q) 5 26.47 ⑷, 40.74 (s), 63.03 ⑴, 80.79 (s), 113.91 (d), 121.38 (d), 126.32 (s), 129.35 (d), 130.66 (s), 140.36 (d), 145.75 (d), 157.72 (s)? 160.68 (s), 173.14 (s); FABHMS about C20H26N2SO5Cl (M + + H) Calculated 値: 441.1251, Experimental 値: 441.1248. Analysis and calculation of C20H25N2S05C1: C, 54.48; H, 5.71; N, 6.35, Experiment: C, 54.37; H, 5.69; N, 6.57. 1 3 D. Formula Ic in which η is 2 and Y is third -BuONH-, and R1, R2, K3, R4, and R5 are changed. Similarly, according to the procedure of Example 1 3 A above, but with other compounds of formula lb Instead of N-tertiary, butoxy-2 · [4 · (4-phenoxyphenylthio) -tetrahydropiperan-4-yl] · acetamidine, where η is 2 and fluorene is third -BuONH a compound of the formula I c of the following: N -Third-butoxy-2- [4- (4-phenoxybenzenesulfonyl) -N-CBZ -Hexane-4 -yl] ethylamine; N-Third · Butoxy-2 · [4- (4-Methoxybenzenesulfonyl) -N-CBZ-Hexahydrodagger_ 4 -yl] Ethylamine; Consumption by Employees of Central Bureau of Standards, Ministry of Economic Affairs Printed by the cooperative (please read the notes on the back before filling this page) N-Third-butoxy_2- {4- [4_ (4_fluorophenoxy) benzenesulfonyl] -hexahydro outer dagger Yodo-4_yl] amine; N · third-butoxy-2 · [4- (4-methoxybenzenesulfonyl) _hexahydropyridine-4 · yl] acetamide; Ν-third _ Butoxy-2- [4- (4-phenoxybenzenesulfonyl) -hexahydropyridine-4 · yl] acetamidamine; 2-benzyl-N · third-butoxy-3- ( 4-Methoxybenzenesulfonyl) -Propanamide; ____- 132 -__ This paper size is applicable National Standard (CNS) A4 specification (210X297 mm) 580491 Α7 B7 V. Description of the invention (13)} 3-benzyl-N-tertiary butoxy-3- (3-methoxybenzenesulfonyl) -Propanylamine; 3-benzyl-N-third-butoxy-3- (4-methoxybenzenesulfonyl) -propanamide; 3-benzyl-N-third-butoxy- 3-[(4 · phenylthiophenyl) sulfonyl] propanilamine; 3. · benzyl-N -third-butoxy-3_ (benzenesulfonyl) -propanilamine; 3 -fluorene -N-di-di-butoxyi-yl-3-(4-bromolactamyl) -propanamine; 3-benzyl-N-third-butoxy- 3-[(4-di Phenyl) sulfonyl] -propanylamine; 3-pyridyl-N-di-di-butoxy-3-(2-naphthyl) -2-propanamine; 3-benzyl-N-tertiary · Butoxy-3- (4-methoxymethoxystyrylbenzenesulfonyl) -propionic acid amine; N-Third-butoxy-3- (cyclopentylmethyl) -3_ (4_methyl Oxybenzenesulfonyl) _propanamide; N-tertiary-butoxy-3 · (cyclopentylmethyl) -2 -isopropyl-3 · (4-methoxyphenylbenzene S & yl) -Propionic acid amine; Ν-third-butoxy-3_ethyl_2 · methyl-3_ (4-methoxybenzenesulfonyl) -propanamine; NR-third-butoxy-3 , 3-dimethyl-3_ (4 -Methoxybenzenesulfonyl) -Propanamide; Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) Ν -third-butoxy- 2- [1- (4-Methoxybenzenesulfonyl) -cyclopent-1-ylbuethamine; N-tertiary-butoxy-2 · [1- (4-methoxyphenylsulfonyl) -4 · methyl Cyclohexan-1 _yl] • Ethylamine; Ν -Third-butoxy-2 · [4- (4-phenoxybenzenesulfonyl) -cyclohexanone-4_ -133- Applicable to this paper size China National Standard (CNS) A4 specification (210 × 297 mm) 580491 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (131); l. Acetylamine ethyl ketal; N. Third -Butoxy-2_ [1- (4-phenoxybenzenesulfonyl) -cyclohexyl-butyl] -acetamidine; N -third-butoxy · 2_ [4_ (4 · phenoxyphenylene Alkyl) -tetrazol- 4-yl] -acetamidamine; Ν -third-butoxy- 2- {4 · [4 · (4 -chlorophenoxy) phenythryl] -tetra Azapiran-4 -yl} -acetamidine; N · " Third-butoxy- 2- {4- [4_ (4-fluorophenoxy) benzoic acid group] -tetrahydropiperan- 4 _yl} -acetamidamine; Ν-didi · butoxy_2- [4_ (4_ Phenoxybenzene hydrazone) _tetrachloroρ, cetoran 1,1-dioxide-4 _yl] acetamidine; tert-butoxy-2- (4-methoxybenzenesulfonyl)- Cyclohexanecarboxamide, and N-di-di-butoxy-trans-2- (4-methyllactylbenzene), cyclopentadienyl amine. 1 3 E · Huang Bei where η is 2 and the formula ic of R1, R2, R3, R4, and R5 is changed. Similarly, according to the procedure of Example 1 3 A above, but using other compounds of formula lb instead of N-third -Butoxy_2- [4_ (4 • phenoxyphenylthio) _n_ CBZ -hexahydrot? Bito_4 · yl] · acetamidine, where η is 2 and Y is third_ BuONH- Compound of formula B. Example 1 4 A compound of the formula Ic in which Y is the third -BuONE_ is prepared. 4 A · In which η is 2, R1 and R2 are hydrogen, R3 and ^ 4 are attached to the carbon atom, and R5 is 4-benzene 气 笨 | The formula Tr. ~ FI. — ^ N!: W_ n ml In · ϋι —ϋ ϋ— · ϋι ΒΒΙϋ nn m_i— VV m · ϋ1 ϋϋ ϋϋ — ^ ϋ · * (Please read the back first (Please fill in this page again) -134-

580491 Printed A7 B7 by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention () Add 10% palladium on carbon (1 g) and ammonium formate (6.7 g) to N-third in ethanol (21 ml) Butoxy-2- [4- (4-phenoxybenzenesulfonyl) -N_CBZ-hexahydropyridin-4-yl] -acetamidamine (1.2 g, 2.1 mol) The mixture was refluxed for 1 hour. The mixture was filtered through celite, and the filter cake was rinsed with ethanol (150 ¾ liters) followed by methanol (150 ml) in digas. The solvent was removed from the filtrate under reduced pressure, and the residue was dissolved in hot ethyl acetate. The filtrate was filtered and concentrated, followed by chromatography on silica gel and elution with 10% methanol / dichloromethane to give N-third-butoxy-2- [4- (4-phenoxybenzene) as a colorless oil. Sulfofluorenyl) hexahydropyridin-4-yl] -ethylamine. 14B · Preparation of Formula 1 (where n is 2 and changing R1, R2 bis Jg ^ 4: Similarly, following the procedure of Example 1 4 A above, but replacing N with other N-CBZ protected formula I compounds -Third-butoxy_2 · [4- (4-phenoxyphenylfluorenyl) -N-CBZ-hexahydroeodo-4-yl] -acetamidine, where η is 2 and Y is Third · BuONH • Other compounds of formula I. Example 15 5 Preparation of a compound of formula Id where Y is HONH- 15A.1 where η is 2, R1 and R2 are hydrogen, and R3 ^ _4g_ is connected together with carbon atoms to represent Hexahydropyridine and r5 is 4-phenoxyphenyl of the formula Id will be N-third-butoxy-2_ [4- (4-phenoxybenzenesulfonyl) in dichloroethane (2 ml) ) -Hexahydropyridin-4-yl] -acetamidamine (27 mg, 0.05 mmol) was cooled to -20 ° C and saturated with hydrogen acid gas for 30 minutes. The reaction was then The container was sealed, and the solution was stirred for 2 days at 25 ° C. The solvent was removed from the reaction mixture under reduced pressure, and the residue was dissolved -135- This paper size applies Chinese National Standard (CNS) A4 Specifications (210X297 mm)---m--1 m-_ · _r i 4 Γϋ = 1! —--Ί I I (Please read the notes on the back before filling this page)

1T ip 580491 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 V. Description of the invention (133) in 500 / methanol in dichloromethane. In addition to hexane, N-hydroxy- 2- [4- (4-phenoxybenzenesulfonyl) -hexahydropyridin-4 · yl] -acetamidine was precipitated, m / e = 391 (MH +, FAB ) 0 1 5 B. Prepare the formula Id where η is 2 and change R1, R2, R3, R4, and R5. Similarly, follow the procedure of Example 1 5 A above, but with Y as the third _ BuONH-other Compound of formula Ic instead of N-tertiary-butoxy · 2 · [4- (4 · phenoxybenzenesulfonyl) _hexahydropyridin-4-yl] -acetamidine, where η is 2 and Υ A compound of the formula I d which is ΗΟΝΗ-; N-hydroxy-2-2- [4- (4-phenoxybenzenesulfonyl) -N-CBZ-hexahydropyridine-4-ylbuethamine, m / e = 525 (MH +); N · hydroxy_2- [4_ (4_methoxybenzenesulfonyl) -N-CBZ · hexahydropyridin-4-yl] -acetamidamine, m / e = 463 (MH +, FAB); 2- {4 · [4 · (4 · (Gasoxyphenoxy) benzene continued brewing group] chloropyridine 4-yl} ·] ^] Hydroxyacetamide, melting point 196-197 ° C; 2 · {4 · [4 · (4 · chlorophenoxy) benzenesulfonyl] -hexahydropyridine-4-S} -N-hydroxyacetamidine, melting point 200-20TC; 2- {4- [4_ (4-chlorobenzene (Oxy) benzenesulfonyl] -tetrahydropiperan- 4-S} -N_ hydroxyacetamidine, melting point 135.7-136.1 ° C; iH NMR (CDC13) β 1.60 (mC5 2Η), 1.83 (mc, 2Η), 3.00 (s, 2Η), 3.66 (mc, 2Η), 3.88 (mc, 2H), 7.06 (d, J 8.8 Hz, 2H), 7 · 09 (d, J = 8.8 Hz, 2H), 7.42 (d, J = 8.9 Hz, 1H), 7.79 (d, J = 8.9 Hz, 2H), 7.25 (s, 1H), 9.49 (s, 1H); FABHMS calculation for C19H2oNS06C1 (M + + H) 値: 426.0778, experimental 値: 426.0775. Analysis and calculation of C19H20NSO6Cl 値: C, 53.39; H, 4.73; N, 3.29, experiment 値: C, ____ 136-_ This paper size is applicable to China National Standard (CNS) A4 (2l0X297mm) (please first Read the notes on the back and fill in this page) Order 580491 A7 B7 V. Description of the invention (134) 53.30; H, 4.67 ·, N, 3.35 〇2- [4- (4-$ Four wind p-Chenan-4 -yl] -N · # is acetoacetamide, melting point 7 7-7 8 Ό; N_hydroxy-2_ [4 · (4-fluorenylbenzenesulfonyl)-hexahydropyridine -4-yl] • Acetylamine, m / e = 329 (MH +); N -Hydroxy-2- 2- [4_ (4 -phenoxybenzenesulfonyl) -hexahydropyridin-4-yl] • Acetylamine , M / e = 391 (MH +); 2 fluorenyl-N-sulfonyl-3-(4 methoxybenzyl) -propyl 8¾amine 'm / e = 350.2 (MH +); 3-benzyl- N-Hydroxy-3- (4-methoxybenzenesulfonyl) -propanamide, m / e = 350 · 2 (ΜΗ +); 3-benzyl_N-hydroxy_3_ (4. Fluorenyl) propanilamine, m / e = 350 · 2 (ΜΗ +); 3-benzyl-N-hydroxy_3-[(4-phenylthiophenyl) sulfonylbupropionamine, m / e = 427 (ΜΗ +); '3-benzyl-N-hydroxy-3- (benzenesulfonyl) -propanilamine, m / e = 320 (MH +); 3 -Yeki-N · Byki- 3- (4-phenoxybenzene continued 8¾-yl) · Propanamine, m / e = 412.2 (MH +); Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs ( Please read the notes on the back before filling in this page) 3-Benzyl-N · hydroxy-3-[(4-diphenyl) sulfonamido) -propanilamine, m / e di395 (MH "); 3-benzyl-N-hydroxy-3- (2-fluorenylsulfonyl) -propanilamine, m / e di 370.1 (MH +); 3 -fluorenyl-N-hydroxy_3-[(4-methoxy Styrenylbenzenesulfonyl] -propanyl _-137- _ This paper size applies to China National Standard (CNS) A4 (210X 297 mm) 580491 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 5. DESCRIPTION OF THE INVENTION (135) Amine, m / e = 452 · 2 (ΜΗ +); 3-(simianpentylmethyl) -N-Cyclo-3-(4-methoxybenzyl) -propyl S & amine ' m / e = 342 (MH +); 3 · (cyclopentylmethyl) -N -hydroxy-2-isopropyl_3- (4 · methoxybenzenesulfonyl) -propanilamide; 3 -ethyl- N-Hydroxy-2-methyl-3- (4-methoxyphenylsulfonyl) -propanilamine, m / e di301 (MH +); 3,3-dimethyl-3- (4-methoxy Benzenesulfonyl) -N-hydroxy-propanamidine, Elemental analysis: CiHiN; N · mesogen-2- [4 · (4-methoxy Continued donkey group) -line pentyl-1 -yl] -ethyl amine 'm / e = 313 (ΜΗ +); Ν · OH- 2- [4 · (4-methoxymethoxysulfonyl) -4 -methyl Cyclohex-1-yl] -acetamidamine, m / e di341 (MH +); N -hydroxy- 2- [4- (4-phenoxybenzenesulfonyl) -cyclohex_1_yl] • Ethylamine, m / e di389 (MH +); N · # was radical_2- [4- (4 -Ethyloxybenzidine · vinyl group) -tetrahydrofuran · 4-yl] -ethylethylamine, melting point 88.5-90 ° C, m / e = 391 (MH +); 2- {4 · [4 · (4-chlorophenoxy) benzoic acid] tetrachlorosulfan-4 -yl} _N-hydroxyacetamidine Amine; 2- {4- [4- (4- (Phenylphenoxy) phenythracene] -tetrachlorosulfan-4yl} _ N hydroxyacetamide, melting point 9 1 9 5 ° C; N- Hair group-2- [4- (4-phenylphenyl phenyl benzoic acid group) -tetrachlorop-thioxan-1,1-dioxide · 4 · yl] -acetamidine, m / e = 440.1 (MH + ); N-Hydroxy-trans-2- (4-methoxybenzenesulfonyl) -cyclopentanecarboxamide, 138- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)

Li--r ------ ^^ install ------ order ------ (Please read the notes on the back before filling this page) 580491 Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 _______B7 V. Description of the invention (136) ~~~~ m / e = 313 (MH +); N-hydroxy-trans- (2-methoxybenzenesulfonyl) _cyclohexanecarboxamide, m / e = 327 (MH +); and 2-benzyl-N-hydroxy-trans-2- (4-methoxybenzenesulfonyl) -cyclopentane-carboxamide, m / e = 390 (MH +) 〇1 5 C · Preparation of formula Id in which η is 2 and changed to fR1, R2, R3, R4 and R5 Similarly, according to the procedure of Example 1 5 A above, but with other formula ic in which γ is the third -BuONH- Instead of N-tertiary-butoxy-2- [4- (4-phenoxybenzenesulfonyl) _hexahydropyridine_4 • ylpyridamidine, a method in which η is 2 and Y is HONH- Other compounds of the formula Id, for example; 2_ {4- [4_ (4-fluorophenoxy) benzenesulfonylsulfonyl n-CBZ_hexahydropyridine_4-yl} -N-hydroxyacetamidamine; 2- {1 -Methyl-4- [4- (4 · chlorophenoxy) benzenesulfonyl] -hexahydropyridine_4_yl}-Ν-hydroxyacetamidinyl; N- # yl · 2- {1-methyl -4- [4- (4 • fluorophenoxy) benzenesulfonylpyridiniumpyridine · 4- ketylacetamide; And 2- {4_ [4_ (4 - bromophenoxy) Ji Bu · benzene Sulfonic tetrahydropyran-4 - acetyl Jibu Ν- hydroxyl amine. 1 5 D · Where η is 2, R 1 and R 2 are argon, R 3 and R 4 1 are connected together with carbon atoms to represent hexanone, and R 5 is 4-phenoxyphenyl. The procedure outlined in Example 5 A of this article was used to prepare N-hydroxy-2- [4- (4-phenoxybenzenesulfonyl) _cyclohexanone_4 from the corresponding n third · butoxy precursor. -Yl] -acetamidinyl ketal (400 mg). The above product was dissolved in a 1.1 mixture (40 ml) of acetone and 1M hydrochloric acid, and the solution was prepared at room temperature. Paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling out this page) ▼ Packing · ,,?! 580491 A 7 B7 V. Description of the invention (137) Mixing 1 8 Hours. The reaction was concentrated under reduced pressure and extracted with ethyl acetate. Silica gel chromatography using 10% methanol / digasmethane gave 2- [4- (4-phenoxybenzophene) as a white solid. (Methenyl) cyclohexanone-4-yl] ylacetamidinium, melting point 106C (cracking), m / e = 404 (MH +, FABMS). 1 5 E · Let η be 2, R3 and R4 are hydrogen, and The carbon atom connects R 1 and R 21 together to replace hexamidine, and R 5 Free Test of 4 · (4 · Gaphenoxy) phenyl Formula Ld Containing -3 (TC at 1,2 · Dichloroethane (35 ml) Ν_third-butoxy_ 2_ {4_ [4_ (4_phenoxy) benzenesulfonylmethylbuhexamine-4-ylbucarboxamide (780 mg, 1.62 millimoles) in a sealed test tube 'to make gaseous hydrogen acid Bubbling until the saturation point is reached. The reaction vessel is then sealed and the solution is stirred for two days. The vessel is cooled again to -30 ° C and then opened again to allow the vapor of nitrogen to bubble through the solution and return it Warm to room temperature. Concentrate the mixture to give 2 _ {4 _ [4 _ (4 _ chlorophenoxy) benzenesulfonylmethyl] -hexahydropyridine_4-yl} _ ^^-hydroxycarboxamide (747 mg, 100%). Melting point 166.7-176.2 ° C; 4 NMR (CD3OD) β 2.39 (mc, 2Η), 3.12 (mc, 2Η), 3.36 (mc, 2Η), 3.63 (s, 2Η), 7.12 (d, J = 8.9 Hz, 2Η), 7.15 (d, J = 8.9 Hz, 2Η), 7.44 (d, J = 9.0 Hz, 2H), 7.89 (d, J = 8.9 Hz, 2H) ; FABMS (M + + H): 425.0; Analysis and calculation of c19H21N2S05C1 · HC1 · 1.5H20 値: C5 46.73; H, 4.33; N, 5.74, Experiment 値: C, 46.83; H, 4.66; N, 5.71. 1 5 F · Preparation where n is 2, change the formula Id of R1, R2, R3, R4 and R5 Similarly, according to the procedure of Example 15E above, but with Y as the -140- This paper size applies Chinese national standards (CNS) A4 specification (21 × 297 mm) l_lv mi aBBUi mmmMammmt eMWMMtm 0 (Please read the precautions on the back before filling out this page)-^ Equipment · Central Standards Bureau of the Ministry of Economic Affairs and Consumer Cooperatives Printed by the Central Standards Bureau of the Ministry of Economic Affairs Printed by the employee consumer cooperative 580491 A7 _____B7 V. Description of the invention (138) III. BuONH-other compounds of formula Ic instead of n_third-butoxy-2 · {4- [4- (4-chlorophenoxy ) Benzenesulfonylmethylbuxahydropyridin-4-yl} • carboxamide, to prepare other compounds of formula Id where η is 2 and y is 110 ^^ 11-, for example; 2- {4- [4- (4-chlorophenoxy) benzenesulfonylmethyl] _1_ (cyclopropylmethyl) -hexahydropyridine-4-*}-N · hydroxycarboxamide hydrochloride (1.30 g, 84%). Melting point 120.5-124.0 ° C; IR (KBr) 3429 (br), 1582 cm1; 4 NMR (CD3〇D) β 0.40-0.50 (m, 2H), 0.73-0.81 (m, 2H), 1.1 · 12 (mc, 1H), 2.1S (mc, 2H), 2.41 (d, J = 14.8 Hz, 2H), 2.63 (d, BU 14.3 Hz, 2H), 3.03 (mc, 2H), 3.10 (mc, 2H) , 3.60 (mc, 2H), 7.13 (mC5 4H), 7.43 (d, J = 8.7 Hz, 2H), 7.89 (d, J = 8.8 Hz, 2H), 7.93 (d, J = 8.8 Hz, 2H); FABMS (M + + H): 479 · 10; Analysis and calculation of C23H27N2S05C1 · HC1 · H20 値: C, 51.77; H, 5.09; N, 5.25, Experiment 値: C, 51.90; H, 5.53; 5.26 0 / 2_ {4_ [4_ (4-Gaphenoxy) benzenesulfonylmethyl] -N_hydroxy · nicotinylmethylmethylhexahydropyridine-4 _ylcarbamidine hydrochloride ( 590 mg, 89%). Melting point 160.5 ° C (bubble); IR (KBr) 3426 (br), 1638 cm_ ^ 'H NMR (CD3OD) d 1.97 (mC5 2H), 2.25 (mc? 2H), 3.55 (mc, 4H), 3.64 (s, 2H), 7.10 (d, J = 8.9 Hz, 2H), 7.13 (d, J = 8.7 Hz, 2H), 7.43 (d, J = 8.6 Hz, 2H), 8.12 (mC5 1H), 8.61 ( d, J = 7.9 Hz, 2H), 8.92 (d, J = 5.5 Hz, 2H), 8.98 (br s, 1H); FABMS (M + + H): 530.0; Analysis of C25H29N3S06C1 · HC1 · 0 · 5Η20 Calculation 値: c, 51.38; H, 4 · 14; N, 7.19, experiment_ -141-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) (Please read the precautions on the back before reading (Fill in this page)

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 580491 A7 B7 V. Description of Invention (139) 値: C, 51.80; H, 4.46; Ν, 7.25. 2- {4- [4- (4- (chlorophenoxy) benzenesulfonylmethyl]]-N-hydroxy_1_methanesulfonyl 7T hydrogen ρ Biyodo · 4-yl} -fermenting amine hydrogen Compound (682 mg, 69%). 107.3-112.3 ° C NMR (CD3C1) δ 1.95 (mc? 2Η), 2.40 (mc, 2Η), 2.79 (mc, 3Η), 3.12 (mc, 2Η), 3.42 (s, 2Η) ), 3.51 (mc, 2H), 7.01 (d, J = 8.9 Hz, 2H), 7.07 (d, J = 8.9 Hz, 2H), 7.39 (d, J = 8.9 Hz, 2H), 7.83 (d, J = 8.9 Hz, 2H); FABMS (M + + H): 503.2; Analysis and calculation of C22H23N2S207C1 値: C, 47.76; H, 4.61; N, 5.57, Experiment 値: C, 47.32; H, 4.56; N, 5.52 . 4- [4- (4 · Pyridyloxy) benzenesulfonylmethylbutytrahydropiperan_4- (N · hydroxycarboxamide) hydrochloride; melting point 188_197 ° C; IR (KBr) 3431,1638 Cm "; 1H NMR (DMSO-d6) d 1.73 (mc, 2H), 2.01 (dm, J = 14.7 Hz, 2H), 3.43 (mc, 2H), 3.65 (mc, 2H), 3.78 (s , 2H), 7.56 (mC5 4H), 8.02 (d, J = 8.7 Hz, 2H), 8.82 (d, J = 6.6 Hz, 2H), 10.64 (s, 1H); 13C NMR (DMSO-d6) S 33.01 (t), 39.78 (t), 61.13 (s), 63.26 (t), 114.48 (d), 121.81 (d), 130.87 (d), 138.41 (s), 144.92 (d), 156.14 (s) , 168.4 (s), 168.8 (s); Analysis and calculation of Ci8H21N2S06C1 · HC1 · 0.66H20: 49.17; H, 5.09; N, 6.37, Experiment 値: C, 49.16; H, 5.03; N, 6.27 〇4 -[4- (5 -Chloro-2-p-pyridyloxy) benzoic acid methyl] -tetrahydroouran-4- (N-hydroxycarboxamide); melting point 14i.9-142.7 ° C; IR (KBr) 3432, 1636 cm 1; 4 NMR (DMSO-d6) d 1.73 (mc, 2H), 2.01 (dm, ___ -142 -__ This paper size is suitable for financial rewards county (CNS) A4 size (210X297 cm) Li) 'I--L ----- II (Please read the notes on the back before filling this page) -Order printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 580491 A7 ______ ___B7 ______ ___ V. Description of the invention (140) J = 14.7 Hz, 2H), 3.33 (s, 2H), 3.46 (mC5 2H), 3.64 (mc , 2H), 7.23 (dd, J = 8.7, 0.4 Hz, 2H), 7.40 (d, J = 8.8 Hz, 2H), 7.92 (d, J = 8.8 Hz, 2Η), 8.03 ( d, J = 8.7, 2.7 Hz, 2H), 8.26 (dd, J = 2.7, 0.4 Hz, 2H) 5 8.69 (s, 1H), 10.62 (s, 1H); 13C NMR (DMSOd6) d 32.89 (t) 5 41.81 (s), 60.96 (t), 63.26 (t), 113.88 (d), 121.32 (d), 126.3 l (s), 129.58 (d), 136.93 (s), 140.33 (s), 145.74 (d) ), 157.82 (s), 160.69 (s), 169.02 (s); FABHRMS calculation of C18H19N2S06C1 (M + + H) 値: 427.0731, experimental 値: 427.0726. Analytical calculations for C18H19N2S Ο 6 Cl · 0 · 5Η20, 値: C, 49.49; H, 4.61; N, 6.41, experimental 値: C, 49.54; Η, 4.35; Ν, 6.47. 3- [4- (5-Gas-2-pyridyloxy) benzenesulfonyl] -2,2-dimethyl-N-hydroxypropylamidine; melting point 115.8-116.6 ° C; IR (KBr) 3412 ( br), 1644 cm1; iH NMR (CD3OD) θ 1.38 (s, 6H), 3.58 (s, 2H), 7.13 (d, J = 8.7 Hz, 1H), 7.34 (d, J = 8.8 Hz, 2H), 7.89 (dd, J = 8.7, 2.7 Hz, 2H), 7.95 (d, J = 8.8 Hz, 1H), 8.15 (d, J = 2.5 Hz, 1H); 13C NMR (CD3OD) d 25.55 (q), 41.76 (s), 65.06 (t), 114.91 (d), 122.35 (d), 128.40 (s), 130.98 (d), 138.21 (s) 5 141.44 (d), 146.88 (d), 159.89 (s), 162.32 (s), 174.51 (s); FABHRMS calculation of C16H18N2S05C1 (M + + H) 値 · 385.0625, Experiment 値: 383.0625. Analysis and calculation of C16H17N2S05C1 C · C, 49.94; H, 4.48; N, 7.28, Experiment 値: C, 49.58; H, 4.42; N, 7.30 0 1 5 G. Preparation where η is 2, R3 and R4 are hydrogen ， R1 and R21 with carbon atoms ___- 143- This paper size is applicable to Chinese National Standard (CNS) Α4 specification (210'〆297 mm) (Please read the precautions on the back before filling this page)

、 1T 580491 A7 ______B7 V. Description of the invention (141) Find out that li -pyridylmethylhexahydropyridine is substituted, and r 5 κ 4 -chlorozyl) phenyl is of formula Id in trifluoroacetic acid (5 ml) Contains N-tertiary · butoxy-2_ {4- [4- (4-chlorofluorenyloxy) benzenedioxanylmethylbudden methylhexahydroedian_4 • yl} • lepinamine (324 mg, 0.566 mmol), heated to 30-5 hours, cooled to room temperature, and concentrated in the air. The residue was dissolved in ethyl acetate (100 ml), washed with saturated sodium bicarbonate (2 x 30 ml), dried over magnesium sulfate, and concentrated in the air. Chromatography on silica gel, eluting with 6% methanol / dichloromethane, gave 2_ {4_ [4_ (4_chlorophenoxy) benzylfluorenylmethyl] _1_pyridylmethylhexahydropyridine-4 -Hydroxycarbamidine hydrochloride; melting point 222.5 · 223.9Ό; IR (KB〇3436〇) r), 1645 cm1; iHNMMDMSO-dJ d2.15 (mc, 3H), 2.40 (mc, 2H) , 3.32 (mc, 2H), 3.57 (mc, 2H), 3.97 (mc, 2H), 4.44 (mc, 2H), 4.51 (mc, 2H), 7.19 (mc, 4H), 7.50 (d, J = 8.8 Hz, 2H), 7.87 (mc, 3H), 8.49 (mc, 3H), 8.85 (mc, 1H), 8.99 (br s, 1H); FABMS (M + + H): 516.1. Analysis and calculation of c29H34N3S05Cn · 2HC1 · 0.5H2O 値: c, 50.22; Η, 4.89; N, 7.03, experiment 値: C, 50.17; H, 4.65; N, 7.00. Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page). Example 1 6 Preparation of the compound of formula Ih 16 VIII. | _ Preparation where the rule 1 2 ^ 2 and & 3 are argon, And 114 is a benzyl group of formula 16 In a solution of 3 -fluorenyl-3-(4-bromophenylthio) -propionic acid in methanol (50), which has been cooled, is added to water (50 ml) In a solution of οχοΝΕ (8 g). Stir the reaction mixture at room temperature for 2 hours, and then distribute it at __- 144- __ This paper size applies the Zhongguanjia Standard (CNS) A4 specification (21GX297 mm) 580491 A7 B7 Employees of the Central Standards Bureau of the Ministry of Economic Affairs Cooperative printed 5. Description of the invention (142) Monochloromethane and water. The solvent was removed from the organic layer under reduced pressure to obtain 3-benzyl · 3_ (4-bromobenzenesulfonylpropanoic acid) as a crystalline solid. 1 6 B 1, R 2 and R 3 are hydrogen, and R4 is benzyl group τf 1 · 3 · (4 -bromophenyl) sulfonyl-4-benzylpropanoic acid (200 mg, 0%) in a 1 ·· 1 mixture of ethanol and benzene (5 ml). 52 millimoles), phenylboronic acid (127 mg '1.04 millimoles), and tetravalent (triphenylphosphine) palladium (〇) (24 mg, 021 millimoles) were heated to reflux temperature and added Stir. 2 M sodium carbonate solution (1 ml) was added to the reaction mixture, and stirring was continued for about 2 hours under reflux. Cool to the mixture, then distribute between ethyl acetate and water. Rinse the solvent with brine The layer was dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure. The residue was chromatographed and eluted with 7% methanol / chloroform to give 3- (4-diphenyl) sulfonyl _4. Phenylpropionic acid. Η NMR (CDC13): 7.75 ppm (m, 14H); 3.42 ppm (dd9 1H); 2.82 ppm (dd, 1H); 2.77ppm (dd, 1H); 2.51ppm (dd, 1H) ). 16c * R2 and R3 Argon and r4 is a fluorenyl group of the formula ih. 3_ (4-Diphenyl) sulfofluorenyl-4-benzylpropanoic acid was prepared as shown above and then converted to 3_ (4_Di Phenyl) sulfonyl-4benzylhydroxypropionamine, melting point 6yC (shrinkage cracking). 1 6 D · where the next atom R 1 and R 2 are attached together to represent tetrahydropiperidine 4 [hydrogen, R5 is 4 -(Pyrimidin-2-yl) benzylhydrogen Iff 1 · 4_ [4- (4 (4) [4 (4 (4)), cooled to 15 ° C in 20% tetrahydrofuran / methanol (135 ml), and mechanically stirred -Bromophenoxy) phenylthiomethyl] · Tetrahydrophonic · 4 · Carboxylic acid (5.50 g, 13.0 mmol), dropwise added 145- This paper size applies to Chinese National Standard (CNS ) Α4 size (21〇 > < 297mm) (Please read the precautions on the back before filling this page)

, 1T Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 580491 A7 __B7 V. Description of Invention (143) OXONE (13.0 g, 21.2 mmol) solution in water (86 ml), maintaining 1 5-2 0 C's internal temperature. The mixture was stirred for 12 hours and dissolved in 40% ethyl acetate / water (1200 ml). The layers were separated and the aqueous layer was back-extracted with ethyl acetate (2 X 300 mL). The mixed ethyl acetate was dehydrated (MgS04), concentrated, and the residue was crystallized from a small amount of dichloromethane / hexane to give 4- [4- (4-bromophenoxy) benzene as a white powder. Sulfomethyl] -tetrahydropiperan-4-carboxyl, which was used directly without further purification (5.00 g, 84%). 2 · Add tetravalent (triphenylphosphine) · Palladium (0) (108 mg), 2-Phenylboronic acid (857 mg, 6.70 to 4 in 1 ^ 3-dimethylformamide (15 ml) -[4- (4-Bromophenoxy) benzenesulfonyl-methyl] tetrahydropiperan-4-carboxylic acid (1.10 g, 2.42 mmol), followed by 2 M aqueous sodium carbonate (2.7 mL, 5.4 mmol). The reaction was heated to reflux for 10 hours, cooled to room temperature, and the mixture was distributed between dichloromethane (100 mL) to 1 N aqueous hydrogen acid (20 mL). ). The layers were back-extracted with dichloromethane (100 mL), and the combined organic layers were dehydrated (MgS04), and the residue was chromatographed on 100 g of silica gel (dichloromethane to 10% Methanol / dichloromethane), and the resulting foam was crystallized from a small amount of dichloromethane / hexane to give 4- [4 · (4_fluoren-2-yl) phenoxybenzenesulfonylfluorenyl ] -Tetrahydropiperan-4-carboxylic acid (1.04 g, 94%). Melting point 181.2-193.3X:; IR (KBr) 3432 (br), 1718.9 cm 1; iH NMR (DMSO-d6) d 1.67 (ddd , J = 13.8, 9.4, 4.0 Hz, 2H), 1.95 (dm, J = 13.8 Hz, 2H) 3.47 (mc, 2H), 3.67 (mc, 2H), 3.68 (s, 2H), 7.14 (dd, J 4.9, 3.6 Hz, 1H), 7.20 (d, J = 8.8 Hz, 2H), 7.22 (d , J 2 8.9 Hz, 2H), 7.50 (dd, ___- 146 -__ This paper size applies to China National Standard (CNS) A4 size (210 X 297 mm) (Please read the precautions on the back before filling in this page)

580491 A7 ____B7 V. Description of the invention (144) • 1.2 3.6, 1.2 Hz, 111), 7.54 ((1 (1,) = 4.9, 1.2 Hz, 111), 7.74 ((1, J 2 8.8 Hz, 2H) , 7.87 (d, J = 8.8 Hz, 2H), 12.80 (s, 1H); 13C NMR (DMSO-d6) ^ 32.92 (t), 42.25 (s)? 61.73 (t), 63.26 (t), 117.82 ( d), 123.75 (d), 125.66 (d), 127.39 (d), 128.50 (d), 130.08 (d), 130.74 (s), 134.90 (s), 142.42 (s), 154.13 (s), 161.33 ( s) 5 174.39 (s); FABHRMS Calculation of C23H24S206 (M + + H) 45 459.0936, Experiment 45 459.0936. Analysis and calculation of C23H23S206 6: c, 60.24; H, 4.83, Experiment 値: C, 60.57; H, 4.90. 16E. Preparation where R1 and R2 are attached together with carbon atoms to represent tetrahydropiperan-4-yl, R3 and R4 are argon, and R5 is 4- (pyrimidine_3_yl ) Phenoxyphenyl · Type Ifb Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (Please read the precautions on the back before filling this page)

Similarly, according to the above procedure, other compounds of the formula Ifb are prepared, for example, 3-pyridineboronic acid is used in place of 2-phenolylboronic acid to prepare 4-[4-(4 · pyrimin-3-yl) phenoxybenzene Ethoxymethyl] -tetrahydron-di-an-4-lectic acid. Melting point 206.6 412.4 ° C; IR (KBr) 3430 (br), 1719 & * _ 1; 1HNMR (DMSO-d6) d 1.67 (mc, 2H), 1.95 (mc, 2H), 3.47 (mc, 2H) , 3.66 (mc, 2H), 3.67 (s, 2H), 7.20 (mc, 4H), 7.56 (dd, J = 5.0, 1.4 Hz, 1H), 7.64 (d, J = 5.0, 2.9 Hz, 2H), 7.81 (d, J = 8.7 Hz, 2H), 7.87 (mc, 2H), 7.96 (s, 1H), 12.77 (s5 1H); 13 C NMR (DMSO_d6) d 32.92 (t), 40.38 (s) , 61.19 (t), 63.26 (t), 117.66 (d), 120.54 (d), 120.87 (d), 126.04 (d), 127.07 (d), 127.96 (d), 130.02 (d), 132.00 (s) , 134.66 (s), 140.45 (s), 160.80 (s), 174.32 (s); FABHRMS Calculation of C23H23S206 (M + + H) 値: ___- 147-_ This paper standard applies Chinese National Standard (CNS) A4 Specifications (210X297 mm) " 580491 A7 __________B7 V. Description of the invention (145) I '-459.0936, Experiment 値: 459.0934. About the analysis and calculation of C23H22S2〇6 · 0.5H20 (please read the precautions on the back before filling this page): C, 59 08; H, 4 96, Experiment: c, 58 82; H, 4.69. 1 6 F · 4-[4 · (4-(bromophenoxy) phenyl dioxanylmethyl 1 -tetrahydrotofuran-4 _ catalyzed reduction of carboxylic acids Printed by the Consumer Cooperative of the China Standards Bureau of the Ministry of Economic Affairs At atmospheric pressure, using palladium-carbon catalyst, 660 mg (1.45 mmol) of 4- [4 · (4-bromophenoxy) benzene benzidine in 80% ethanol / tetrahydrotripan (40 ml) The solution of methyl methyl tetrahydroxan-4 -chitoic acid was hydrogenated for 14 hours, filtered on a pad of celite, washed with dichloromethane, and concentrated in the air to obtain 4- [4-Phenoxybenzenesulfonylmethyl] -tetrahydropiperan-4 · carboxylic acid (546 mg, 100%), which was directly included in the next reaction without further purification; melting point 162.5-165.3 ° C; IR (KBr) 3431 (br), 1727 cm 1; NMR (DMSO-d6) d 1.67 (ddd, J = 14.1, 10.0, 4.0 Hz, 2H), 1.95 (dm, J = 14.1 Hz, 2H), 3.47 (mc, 2H), 3.65 (mc, 2H), 3.66 (s, 2H), 7.15 (d, J = 8.8 Hz, 2H), 7.27 (t, Hz, 1H), 7.45 (t, J = 7.5 Hz , 2H), 7.86 (d, J = 7.9 Hz, 2H), 12.74 (s, 1H); 13C NMR (DMSO-d6) J 32.88 (t), 42.26 (s), 61.75 (t), 63.26 (t), 117.64 (d), 120.11 (d), 125.03 (d), 130.04 (d), 130.39 (s), 134.69 (s), 154.69 (s), 161.53 (s), 174.39 (s); FABHRMS calculation for C19H21S06 (M + + H) 値: 377.1059, experiment 値: 378.1010. Analysis and calculation of C19H2〇S06 · 〇_75H20 値: C, 58.52; H, 5.56, experiment 値: C, 58.54; Η, 5.19 〇 Example 1 7 -148- This paper standard is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 580491 A7 B7 V. Description of the invention (146)-A compound of formula Π R2 * R3 is hydrogen and R4 is benzyl. Formula benzene sulfide (80 mg) and ν Potassium hydride (40 φ g) in N-dimethylformamide (1 ml) was mixed together for 4 5 minutes to produce a homogeneous solution of potassium thiophenolate. To this mixture was added 3-benzyl-3- (4-bromobenzenesulfonyl) -propionic acid (100 mg) dissolved in N, N dimethylformamide (1 ml) at room temperature. After stirring at 7 5 C for 16 hours, the mixture was distributed between aqueous citric acid and water to prepare a product obtained by TLC purification, to obtain 3 _ unyl-3 · (4-phenylthiobenzenesulfonate Group) -propionic acid (30 mg). 17Β · | _ where Ri 2 and 3 are hydrogen, and R 4 is benzyl of the formula π 3 -fluorenyl-3 · (4-phenylthiophenylphenyl) -propionic acid is prepared as above, and then As described in Example 10A, this was converted to 3-benzyl-3- (4-phenylthiophenylphenylfluorenyl) -N- # fluorenylpropanilamine. Example 1 8 Preparation of compound Ik of formula 1 «A · 1 where R1, R2, and R3 are hydrogen and R4 is fluorenyl. Formula Ik perturbs 3 -methyl- 3- (4-bromophenylene) at 80 C g Shengji) _propionic acid (250 mg), p-methoxystyrene (0.1 ml), diisopropylethylamine (0,25 l), palladium acetate (5 mg), and tris (m-xylene) A mixture of sulfonyl) phosphine (16 mg) overnight. The reaction mixture was dissolved in dichloromethane and washed with aqueous citric acid. The solvent was removed from the dichloromethane solution, and the residue was chromatographed on silica gel (preparation of TLC, eluted with 10% methanol / digas methane) to 3 · fluorenyl_3_ (4_phenylethyl cotton Benzylbenzene and S & yl) propionic acid (21 g). 18B.1, where R1, R2 and r3 are hydrogen, and r4 is benzyl. Ik -149- This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) —1 --- L --- -^^ 衣-(Please read the precautions on the back before filling out this page) Order printed by the Central Consumers ’Cooperative Bureau of the Ministry of Economic Affairs, printed by the Consumer Cooperative 580491 Printed by the Central Consumers’ Bureau of the Ministry of Economic Affairs, printed by the Consumer Cooperative of A7 _______ B7 _ V. Invention Explanation (147) 3-benzyl-3- (4-styrylbenzenesulfonyl) -propionic acid was prepared as described above and then converted to 3_benzyl_3-(as described in Example 10A) 4-styrene 7-phenylphenoxy acid group) _N-kilmylpropanamine, lSIMS m / e = 452.2 (M + H) + 〇 Example 1 9 Preparation of the compound of formula II ΜΛΛ ± η is 2, R1 is represented by carbon atom And r2 are attached together to represent hexahydrobenzyl 3_4 is hydrogen, and R5 is 4 · (4-chlorophenoxy) benzyl of formula II. Add trifluoroacetic acid (4 ml) to dissolve in N-Second · Butoxy · 2- [4- (4-phenoxybenzoic acid fluorenyl) _n-BOC-Hexahydropyridine · 4-Based Carboxyl in Dichloromethane (4 ml) Amidamine (2 g, 3.64 mmol). The reaction mixture was stirred for 1.3 hours and concentrated in the air. The crude hydrochloric acid residue was dissolved in ethyl acetate (150 ml), rinsed with saturated aqueous sodium bicarbonate (2 X 50 ml), dried over magnesium sulfate, and concentrated in the air to obtain the free base, N _Third-butoxy- 2- [4 · (4-phenoxybenzenesulfonylmethyl) -hexahydroeridine-4 · yl] · Junamine (1.57 g, 90%). ^ NMRCCDCU) β 1.28 (s, 9H), 2.23 (me, 2H), 2.56 (me, 2H), 3.30 (me, 2H), 3.44 (mc, 2H), 3.53 (mc, 2H), 7.00 (d, J = 8.9 Hz, 2H), 7.05 (d, J = 8.8 Hz, 2H), 7.38 (d, J = 8.8 Hz, 2H), 7.82 (d, J = 8.8 Hz, 2H ), 8.25 (br s, 1H), 8.48 (br s, 1H). Example 2 0 Preparative formula Im 2 ^ 2 A. where η is 2, R is ethoxymethyl, pi and r2 are hydrogen, and M5 is 4-phenoxyphenyl. Im 150- This paper applies to China National Standard (CNS) A4 Specification (210X297 mm) C Please read the notes on the back before filling in this page j-Order- 580491 Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (148) Ethyl acetate (0.2 ml) and potassium carbonate (600 g) were treated with N-N-dimethylformamide (10 ml) N-tert-butoxy-2_ [4_ ( 4_ lactobenzoic acid group) · ττ rat p ratio-4 -yl]-ethyl amine (750 mg) solution. The mixture was stirred at room temperature overnight and then distributed between ethyl acetate and water. After dehydration, the solvent was removed from the organic layer under reduced pressure to obtain N-third-butoxy · 2-[4 _ (4 -phenoxybenzenesulfonyl) i _ (ethoxycarbonylmethyl ) Hexahydropyridin-4-yl] · acetamidine, which was used directly in the next step without further purification. 2 0 B · Preparation where η is 2, R is isopropyl, R1 and R2 are hydrogen, and r 5 is 4 · phenoxyphenyl of the formula Im Add 10% und (100 mg) to N-third-butoxy_2_ [4 · (4 · phenoxybenzene) in acetone (20 ml)醯）) hexahydro ρ than 唆 _ 4 · yl]-acetamide (500 mg), and the mixture was stirred for three days under hydrogen. Filter the filter and adjust the pressure from the filtrate under reduced pressure. The solvent was removed in chloroform. The residue was chromatographed on chopped gum and eluted with 10% methanol / dichloromethane to obtain N_second-butoxy · 2- [4- (4 · phenoxybenzene). Group) _1_ (isopropyl) hexahydrobambodin-4-yl] · acetamidamine (300 mg). 20C · Preparation where η is 2 and changing the formula of R im Similarly, according to Example 20A above Procedure, but using 3-pyridylmethyl chloride instead of ethyl bromide to prepare N_ Tri-butoxy_2_ [4_ (4 • phenoxyphenylammonyl) _1 · (3 · outer b-methyl) hexahydrop-pyridine_4-yl] acetamidamine. Similarly, according to the above Example 2 Procedure for OA, but with N-third-butoxy- 2- {4- [4- (4- (fluorophenoxy) benzenesulfonylpyridine-6-pyridylpyridinamine) Instead of N_third-butoxy_2_ [4air-capped phenoxybenzenesulfonyl) _hexa-151-exhaust, scale, and scale scales are applicable to China National Standard (CNS) A4 (210 X 297 mm) ) (Please read the notes on the back before filling in this page) -Order __ 580491 Α7 Β7 V. Description of the invention (149) ^ ^ -—- Hydropyridine-4 -yl] -ethyl amine, and ring Methyl methyl, i methyl, odor instead of ethyl bromoacetate's purpose 'preparation of N-tertiary butoxy-2_ {4- [4- (4-fr 公 # #, ^ (fluoroepoxy) benzyl ~ Alkyl] _1 · (3-cyclopropylmethyl) -hexahydropyridine_4_yl} • Ethylamine. Similarly, N-tertiary-butoxy-2_ [4_ (4_benzene ™ oxybenzene continued) Acyl) (Ethylaminocarbonylmethyl) hexahydropyridin-4-yl] -ethanamine. 2 0 D. Preparation where η is 2, changing the formula of R & Similarly, according to Example 20 A above Program but visual To replace N-third-butoxy_2_ [4- (4_phenoxyphenyl ^ fluorenyl ^ hexahydropyridin-4-yl] -acetamidine with other formula ly, other A compound of formula rx instead of ethyl bromoacetate, where R is lower alkyl, cycloalkyl ^, fluorenyl, alkoxycarbonylalkyl, methylpyridine, -SO2Ra, where Ra is lower alkyl or -NRbRe, in which Rb and fluorene or lower alkyl and their analogs, respectively, and X is chlorine, bromine, or hydrogen, to prepare other compounds of formula 丨 m: N -Second-butoxy- 2- [l -Ethyl · 4- (4 · phenoxybenzenesulfonyl) _hexahydropyridine-4 -yl] -acetamidine; Ν · third-butoxy-2 · [1_methyl-4 -(4-phenoxybenzenesulfonyl) · hexahydropyridin-4-yl] -acetamidine, melting point 152-155. (:; N-Third-butoxy · 2- [1- (2_methylpropyl) -4- (4_phenoxybenzenesulfonyl) · hexahydro late lake-4_yl] • Acetyl Amine; N. tertiary-butoxy-2- [1-cyclopropylmethyl-4- (4-phenoxybenzenesulfonyl)-hexamidine 1 ^ bidian-4-yl] ethylamine; N -Third-butoxy- 2- [1 · Cyclopropylmethyl-4- [4 · (4 -chlorophenoxy) benzene oxonyl] -Hexahydroxanthen-4 -yl] • Ethylamine ; And -152- This paper size applies to Chinese National Standard (CNS) Α4 specification (210X297 male shame) J · --- L · ----- ^^ clothing-(Please read the precautions on the back before filling in this Page), 1T Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 80491 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 ______B7 V. Description of the invention (150) ~~~ Ν · third-butoxy_2- [b Acetyl_4- [4- (4-fluorophenoxy) phenyl transverse fluorenyl] -hexahydrochrysanthemum I: Yodo-4-ketoacetamide. 2 0E. Preparation of which is 1, R3 and R4 is new. R1 and R2 are attached together with a Swiss atom to represent 1-1 propylmethylhexahydropyridine, and R5 is a 4- (4-chlorophenoxy) phenyl group. The formula T c is dissolved in N, N. -Free inspection in dimethylamine formate (17ml) N -Third-butoxy- 2- [4- (4-phenoxybenzenesulfonylmethyl) -hexahydropyridine-4 · yl] Carboxamide (1.28 g, 2.66 mmol ) Solution, cyclopropylmethyl bromide (0.26 ml, 2.66 mmoles) was added, followed by potassium acid breaking acid (1.84 g, 13.3 mmoles). After stirring the reaction mixture for 20 hours, water (100 Ml), and the aqueous solution was extracted with ethyl acetate (3 x 100 ml). The combined organic extracts were washed with brine (2 x 50 ml), dried over magnesium sulfate, and concentrated in the air. On silica gel Chromatographed and eluted with 25% ethyl acetate / hexane to give N_tertiary · butoxy-2- [4- (4-phenoxybenzenesulfonylmethyl) _ 1-(cyclo (Propyl) hexahydropyridin-4-yl] -carboxamide (1.30 g, 92%). 4 NMR (CDC13) d 0 · 10 (ddd, J 5.6, 4.7, 4.6 Hz, 2H), 0.53 (ddd , J = 8.7, 4.7, 4.5 Hz, 2H), 0.85 (mc, 1H), 1.31 (s, 3H), 1.64 (mc, 2H), 2.06 (mc, 2H), 2.24 (mc, 2H), 2.28 ( d, J = 6.5 Hz, 2H), 2.67 (mc, 4H), 3.50 (me, 2H), 7.10 (d, J = 8.8 Hz, 2H), 7.04 (d, J = 8.8 Hz , 2H), 7.37 (d ,. JU Hz, 2H), 7.85 (d, 8.8 Hz, 2H), 8.33 (br s, 2H); FABMS (M + + H): 535.2. 2 〇F · Preparation in which n is 2, R3 and R4 are fluorene, R1 and R2 are joined together with carbon atoms to substitute 1-(3-pyridylmethyl) hexahydropyridine, and R5 is 4- (4 • Chlorine ___ 153 -____ This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page) 580491 A7 B7,151 V. Description of the invention phenoxy group) The formula Tc for benzyl is the same as in the procedure of Example 20 E above, but using 1.25 equivalents of 3-pyridylmethylhydroide instead of cyclopropylmethyl bromide to prepare n-third-butoxy-2- [4 · (4-phenoxybenzenesulfonylmethyl) -1_ (pyridylmethyl) hexahydropyridin-4-yl] -carboxamide; melting point 83.3-93.8. (:; 111 (〖61 *) 3436,1661 cm-1; h NMR (CDC13) β 1.31 (s, 9Η), 2.00 (me, 2Η), 2.24 (mC5 2H), 2.55 (mc, 4H), 3 48 (s, 2H), 3.53 (s, 2H), 7.01 (d, J = 8.9 Hz, 2H), 7.04 (d, J = 8.9 Hz, 2H), 7.25 (dd, J = 7.6, 4.6 Hz, 2H), 7.38 (d, J = 8.8 Hz, 2H), 7.64 (brd, .b 7.8 Hz, 2 only), 7.85 ((1,2, 8.9 Hz, 211), 8.36 〇8, 111 ), 8.52 (m, 2H); FABMS (M + + H): 572.0. About the calculation of C29H34N3S05C1 · 0.5H2O 値: C, 59.03; H, 5.81; N, 7.12, Experiment 値: 59.37; H, 6.15; N, 7.98. 2 0 G · Tomb preparation where n is 2, R3 and R4 are hydrogen, R1 and R2 are connected together with carbon atoms to represent 1- (nicotinyl) hexahydropyridine, and R5 is 4- (4-Gasphenoxy) benzyl of formula Ic Free base N-Third-butoxy-2 · [4- (4-Benzene) in dichloromethane (2 ml) cooled to 0 ° C Oxybenzenesulfonylmethyl) _hexahydropyridin-4-yl] • carboxamide (491 mg, 1.02 mmol) and ν, N · diisopropylethylamine (444 mg '2.55 耄Mol) solution, added in batches Test for chlorohydrochloride (219 mg, 1.27 mmol). After stirring the reaction mixture for 3 hours, add water (30 ml) and extract the aqueous solution with ethyl acetate (2 × 60 ml). Brine (2 X 50ml) Rinse the mixed organic extract, cover it with magnesium sulfate, dehydrate it, and concentrate it in the air. Layer 154 on the silicon gel. The paper size is applicable to the Chinese National Standard (CNS). M specification (training-public meal) J ·- --U ------- (Please read the precautions on the back before filling out this page), 1T Printed by the Employee Consumer Cooperative of the Central Standards Bureau of the Ministry of Economy 180491 Printed by the Employee Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 Description of the invention (152) analysis and elution with 6% methanol / dichloromethane to obtain N-third-butoxy-2- [4- (4-phenoxybenzenesulfonylmethyl) -1_ (fumes Base fluorenyl) hexahydropyridin-4-yl] -carboxamide (233 mg, 39%). 4 NMR (CDC13) d 1.33 (s, 9H), 1.95 (mc, 2H), 2.35 (mc, 2H), 3.45 (mC5 2H), 3.49 (s, 2H), 3.55 (mc, 4H), 7.01 (d, J = 8.8 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 7.39 (d , J = 8.8 Hz, 2H), 7.41 (mc 2H), 7 · 79 (mc, 2H), 7.83 (d, · J two 8.8 Hz, 2H), 8.69 (br s, 1H), 8.52 (mc, 2H). 20H. Preparation where n is 2, R3 and R4 are hydrogen, and R1 and R2 are attached together with a carbon atom to represent 1_ (methylfe transverse brewing group) hole chlorine? Biyodo 'and free base N_third- of formula Ic of which R5 is 4- (4-chlorophenoxy) phenyl group cooled to -78 ° C in 67% dichloromethane / pyridine (16.5 ml) To a solution of butoxy_2- [4_ (4-phenoxybenzenesulfonylmethyl) -hexahydropyridin-4-yl] -carboxamide (1.57 g, 3.26 mmol) was added Methanesulfonium (0.51 ml, 6.53 mmol) in methane (2 ml). After the reaction mixture was stirred for 4 hours, 3N aqueous hydrochloric acid (• 25 ml) was added, and the aqueous solution was extracted with ethyl acetate (2 × 60 ml). The combined organic extracts were rinsed with brine (2 x 50 ml), dried over magnesium sulfate, and concentrated in the air. Chromatography on silica gel and elution with 45% ethyl acetate / hexane gave N-tert-butoxy-2- [4- (4-phenoxybenzenesulfonylmethyl) -1 -(Methanesulfonyl) hexahydropyridin-4-yl] -carboxamide (1.16 mg, 64%). iH NMR (CDC13) d 1.33 (s, 9H), 2.05 (mc, 2H), 2.37 (mc, 2H), 2.79 (s, 3H), 3.23 (mc, 2H), 3.43 (s, 2H), 3.47 ( mc, 2H), 7.01 (d, J = 8.9 Hz, 2H), 7.06 (d, J = 8.9 Hz, 2H), 7.39 (d, J = 8.9 Hz, 2H), 7.85 (d, J = 8.9 Hz, 2H); -155- (Please read the precautions on the back before filling this page) This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 580491 A7 ______B7 V. Description of the invention (153) FABMS (M + + H): 559.1. Example 2 1 Preparation of compound 2 1 A of formula In · Preparation where η is 2, R is ethoxycarbonyl, R1 and R2 are hydrogen, and JLR5 is 4-phenoxyphenyl. Formula In will be obtained from Example 2A. Product, N-Third-butoxy_2_ [4_ (4_phenoxyphenylfluorenyl) -1 · (ethoxycarbonylmethyl) hexahydrop-pyridine_4 · yl] -ethylamine In digas methane (10 ml), cool to 0 ° C and saturate with hydrochloric acid gas. The reaction vessel was then sealed and the solution was stirred at 25 ° C for two days. The solvent was removed from the reaction mixture under reduced pressure, and the residue was purified by preparative TLC, eluting with 100/0 methanol / dichloromethane to give N-hydroxy-2- [4- (4 · Phenoxybenzenesulfonyl) -1 · (ethoxycarbonylmethyl) hexahydropyridin-4-yl] -acetamidamine (420 mg), m / e = 477.1 (MH +, FABMS). 2 1 B. Where η is 2, R is isopropyl, R1 and R2 are hydrogen, and R5 i is a phenoxyphenyl group of the formula I n Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Hydrochloric acid gas was used to treat the product obtained from Example 2OB, N-Third-butoxy-2- [4- (4-phenoxybenzenesulfonylisopropyl) hexahydrop-Hydro-4_ []] Acetylamine to give N_superyl-2-[4-(4 · phenoxyphenylfluorenyl) -1- (isopropyl) hexahydropyridin-4 · yl] Mg), melting point 128 ° C, m / e = 432 (MH +, EIMS) 〇2 1 c · Preparation where η is 2, change the formula of R In Similarly, according to the procedure of Example 2 1 A above, but with 3 _Pyridylmethyl instead of ethyl bromide to prepare N-hydroxy-2- [4_ (4-phenoxybenzenesulfonate-156-) This paper is sized to the Chinese National Standard (CNS) M specifications (210 X m mm) A '580491 A7

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 醯 Base) -1- (3-pyridylmethyl) hexahydropyridin-4-yl] -acetamidine, melting point i85 • 192 ° C (cracked). Similarly, according to the procedure of Example 19A above, but the third_butoxy-2- {4- [4- (4- (fluorophenoxy) phenyIhydratino] hexahydropyridine_4_yl] _ ethyl Ammonium amine instead of N-tert-butoxy-2- [4 · (4-phenoxybenzenesulfonyl ^ hexahydro ρ biden_ 4yl] -acetic acid amine, and cyclopropylmethyl instead of bromine Acetic acid ethyl acetate to prepare N-hydroxy-2- {4- [4- (4-fluorophenoxy) _benzenesulfonyl] cyclopropylmethylhexahydropyridin-4-yl] · acetamidine, Melting point: 104-105. In the same manner, N-hydroxy-2- [4 · (4-phenoxybenzenesulfonyl) -κ-acetamidoacetamidomethylhexahydroethan-4-yl] -ethyl 21D. Preparation where η is 2 and changing the formula of R In the same manner as in the procedure of Example 2 1 A above, but using other compounds of formula Iy instead of N-tert-butoxy-2- [ 4- (4-phenoxybenzenesulfonyl) _hexahydroca: pyridin-4_yl] -acetamidine, and other compounds of formula RX may be used in place of ethyl bromoacetate if necessary, where R is low carbon Alkyl, cycloalkylalkyl, fluorenyl, alkoxycarbonylalkyl, methylpyridine, -S02Ra, where Ra is lower alkyl or _NRbR., Where Rb and Re are hydrogen or Carboalkyl and its analogs, and X is chlorine, bromine or iodine, to prepare other compounds of formula In: 2- [1-ethyl-4- (4-phenoxybenzenesulfonyl) · hexahydropyridine_ 4-yl: 1-N-hydroxyacetamidine, melting point 182-183 ° C; N-hydroxy · 2- [1 · methyl-4 (4 · phenoxybenzenesulfonyl) -hexahydropyridine-4-yl ] -Acetylamine, melting point 152-155X :; Ν-protecting group · 2 · [1 · (2-methylpropyl) _4- (4 -phenoxybenzenesulfonyl) · hexahydro said -157- paper Standards are applicable to China National Standard (CNS) A4 specifications (210 × 297 mm) ^ ----- clothing-(Please read the precautions on the back before filling in this page j, τ 580491 Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 ___________ _B7 V. Description of the invention (155) Pyridin-4 _yl] _acetamide, melting point 226 -227 ° C; 2- [l-cyclopropylmethyl-4- (4-phenoxybenzenesulfonyl) _Hydrohydropyridine_4-Bibecide, melting point 210-211 ° C; 2- [l-Cyclopropylmethyl · 4- [4- (4-chlorophenoxy) phenylcontinyl] -hexa Hydrogen p ratio lake 4-yl] -N-hyperacetylacetamide, melting point ii〇_ii2 ° C; and 2- [1_ethynyl-4- [4- (4-fluorophenoxy) benzene Acid group] -hexahydro υ than bite-4-yl] -N-hydroxyacetamidamine m / e di 450 (MH +). Example 22 Preparation of a compound of formula lab. Formula iab where R5 is 4-phenoxybenzyl. 4-phenoxythiophenol (4.8 g) was mixed with N, N_dihydrazone. Potassium hydride (0.98 g) in methylformamide (100 ml) was stirred together for 45 minutes, resulting in a homogeneous solution of potassium 4-phenoxyphenthiolate. Then, at room temperature, lactone, (s) -3-fluorenyloxycarbonyl-amino · 2-spiro [4 · 4] dioxol dissolved in N, N-dimethylformamide (50 ml) was added. Hexane (5.3 grams) (Arnold, LD et al.). Human 111.0 ^ 111 · Soc · '107, 7105 (1985)). After stirring for 30 minutes, the mixture was poured into water and extracted with ethyl acetate. The mixed extract was dehydrated with sulfuric acid, and the solvent was removed under reduced pressure to obtain (R) _2_ (benzyloxycarbonylamino) -3- (4-phenoxyphenylthio) · propionic acid (9.2 G). You can use it directly in the next step. Example 2 3 Preparation of a compound of formula 10 where R5 is 4 · phenoxyphenyl Formula 10 Formulation of (R) _2- (benzyloxycarbonylamino) -3- (4-phenoxyphenylsulfide) prepared above -158- This paper size is applicable to China National Standard (CNS) 8-4 specification (21〇 < 297mm) L ---, ----- clothing-- (Please read the precautions on the back before filling This page) Order 580491 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (156) based) _ Propionic acid is dissolved in dichloromethane (175 ml), cooled to 0X :, and 0- ( Tert-butyl) hydroxylamine hydrochloride (7.7 g), 4-methylmorpholine (9.4 ml), 1 · hydroxybenzotriazole (2.8 g), and N-ethyl-N,-(3-di Methyl-aminopropyl) -carbodiimide (7.9 g). The mixture was allowed to warm to room temperature 'and stirred for 1.5 hours, then allowed to distribute between methylene chloride and water. The solvent was removed from the organic phase under reduced pressure, and the residue was purified by flash chromatography on silica gel, eluting with 0 to 50% ethyl acetate / hexane to give (R ) -2- (benzyloxycarbonylamino) -N-tert-butoxy · 3- (4 · oxyoxythio) -propionic acid amine (74 g). Example 2 4 Preparation of a compound of formula Ip wherein η is 2 and R5 is 4 · benzyloxyphenyl Formula Ip (&) ^ _ third-butoxy-2- (benzyloxycarbonylamino) -3 -(4-phenoxyphenylthio) · propanamide (1.5 mmol) was dissolved in methanol (140 ml), and a solution of 0 × 〇ne (15 g) in water (50 ml) was added and vigorously Stir gently. This oxidation is usually completed within 2 hours. The mixture was then distributed between dichloromethane and water. The solvent was removed from the dehydrated organic phase under reduced pressure, and (R) -2_ (benzyloxycarbonylamino third-butoxy-3_ (4 · phenoxyphenylthio) · was obtained in pure quantitative yield. Promethazine (8.3 g). Example 2 5 In the compound of formula I q, η is 2, R1 is hydrogen, R2 is · Ν16Κ7, where R6 is hydrogen nonylcarbonyl, and L nonoxycarbonylamino group, and R5 is 4-phenoxyphenyl formula Iq will be obtained in (16 ml) of dichloromethane (5 ml) from (R) -2- (fluorenyloxycarbonyl-159-) This paper is in accordance with Chinese National Standard (CNS) 8-4 Specifications (21〇χ297mm) I .-- ^ ------- (Please read the precautions on the back before filling out this page) Order 580491 Printed by the Consumers' Cooperative of the China Prospective Bureau of the Ministry of Economic Affairs A7 ___ B7 V. Description of the invention (157) A ~ 1-s-based amino group) -N-second _ butoxy-3- (4-phenoxyphenyl fluorenyl) _ propyl amine (I: grams) solution , Diluted with trifluoroacetic acid (30 ml). The solution was allowed to stand overnight 'and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel, eluting with 10% methanol in dioxane. To give (R) _2_ (henoxycarbonylamino -N-hydroxy-3- (4-phenoxybenzenesulfonyl) -propanamide (400 g), melting point 195-202 ° C. Example 2 6 Preparation of a compound of formula Ir where η is 2, R5 is 4 · phenoxybenzyl of formula lr will be obtained from (R) -2- (benzyloxyphenylamino) -N-tertiary-butoxy-3- (4-phenoxyphenylphenone) of Example 17 Amidino)-Propylamine (6.0 g) was dissolved in ethanol (100 liters) and subjected to a hydrogenation reaction at 1 atmosphere in the presence of 10% carbon-free (6 g) for 18 hours. The catalyst was filtered off And, under a reduced pressure, the solvent was removed from the filtrate to obtain glassy (R) -2-amino-tertiary-butoxy-3- (4-phenoxyphenylfluorenylpropionamidine). 2 7 Preparation of a compound of formula Is where η is 2, R1 is hydrogen, R2% -NR6R7, where R6 and R7 are good hydrogen, and R5 is 4-phenoxyphenyl. Formula Is is similar to Example 25, (R) -2-amino-N-tertiary-butoxy-3- (4-phenoxybenzenesulfonyl) -propanamide (6.0 g) was dissolved in 1,2-dichloromethane (5 ）), And cooled to -20 Ό, and bubbled with hydrochloric acid gas in a pressure tube for 20 minutes. Then the flask was sealed and stirred The mixture was left overnight. The test tube was cooled, degassed, and allowed to warm up. Rinse the solvent with methanol -160- This paper size applies to Chinese national standards (CNS> A4 specification (21〇 '乂 297mm) III ·- -Engine 丨. C Please read the precautions on the back before filling in this page. J-Order. H. 580491 Printed by the Consumer Cooperatives of the Central Standards Bureau, Ministry of Economic Affairs, A7 ________ ^ B7_ V. Description of the Invention (158) ^ One solution, The solvent was removed from the filtrate under reduced pressure and triturated with 1: 1 hexane / ethyl acetate (4 mL). The residue was filtered and dehydrated to give (R) -2-amino-N-hydroxy-3 (4-phenoxybenzenesulfonyl) -propanamidin hydrochloride, melting point 178180 ° C (cracked ). Example 2 8 Preparation of a compound of formula It wherein η is 2, R1 is hydrogen, R2 is -NR6 R7, where R6% R_7 is CBZ_ (S) _valamine group, and R5 is 4 · phenoxyphenyl group Formula It combines CBZ- (S) -valinic acid (1.6 g), 1-light phenyl hydrazone saponin (09 g), triethylamine (1 ml), and N '· ethyl-N,-(3 -Dimethylaminopropyl) _carbodiimide (1.3 g), added to (R) _2-amino-N-tertiary-butoxy-3- in dichloromethane (30 ml) (4 · phenoxybenzenesulfonyl) · Propanamide (19 g). After stirring at room temperature overnight, the solution was distributed between dichloromethane and water, and after the organic layer was dehydrated with magnesium sulfate, the solvent was removed under reduced pressure to obtain (R) -N-th Tri · butoxy_2- (CBZ-valine amine) · 3 · (• 4-phenoxybenzenesulfonyl) -propanilamine can be used directly without further purification. Example 2 9 Preparation of a compound of formula Iu wherein η is 2, R1 is hydrogen, R2 is -NR6 gj, where R6 is hydrogen and is (S) · valamine group, and R5 is 4-phenoxybenzene In particular, at 1 atmosphere, (R) -N-tertiary-butoxy-2- (CBZ-valinamine) in methanol (300 ml) and ethanol (100 ml) will be 3- A solution of (4-phenoxybenzenesulfonyl) -propanamide (prepared above) was stirred with a palladium-carbon catalyst (10% Pd, 4 g) for 3 hours. Filter the mixture, and under reduced pressure -161-This paper size applies the Chinese National Standard (CNS) A4 size (210X 297 mm) L .--- "----- clothing-(Please read the back first Note for refilling this page) Order 580491 A7 ____ B7 V. Description of the invention (159) The filtrate is evaporated. The residue is chromatographed on chopped gum, eluting with 0.3% methanol in dichloromethane. (R) -N-Third-butoxy-2 · Valamineamido) -3- (4-phenoxybenzodiamidino) -propylamidoamine (ι · 6 g) was obtained. Example 30 Preparation A compound of formula Iv is prepared in which η is 2, R1 is hydrogen, R2 ^ -NR6R7, where R6 is hydrogen and is (S) -j-amidinoamino group, and R5 is 4-phenoxyphenyl. (R) -N-Third-butoxy-2-valinamidoamino- 3- (4-phenoxyphenylfluorenyl) -propane in 1,2-dichloroethane (50 ml) Donkey amine (1.6 g) solution, cooled to -20 ° C, and bubbled with hydrochloric acid gas in a pressure tube for 15-20 minutes. Then the flask was sealed and the mixture was stirred for 2 4 hours. Carefully make The cooled test tube is deflated and its contents are evaporated to obtain a gum. Triturated with ethyl acetate to give the crude product as a white powder. The product was stirred with 10% methanol / dichloromethane (20 mL) overnight and filtered to remove impurities. Repeated three times to give hydroxyl · 2_ Valaminamine-3- (4-phenoxybenzenesulfonyl) _propanamide hydrochloride (760 mg), melting point 214-217 ° C ○ Example 3 1 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs L. Clothing-(Read the precautions on the reverse side and then fill out this page) Prepare compound Iw of Formula 1 where η is 2, Y is hydroxyl or lower alkyl, and carbon atoms are connected together to represent tetrahydro Piperan-4-yl, r3 is hydrogen and r4 is benzyl, and & 5M- (4-Gaphenoxy) benzyl group Tw 1. will be 〇〇ΝΕ in water (8 ml) 1.53 g, 2.49 mmol) solution, added dropwise to 4 _ [4-_____ -162- scale standard suitable for financial countries (CNS) in 20% tetrahydrofuran · methanol (9.5 ml) Α4 specifications (21Gx297 public holiday) " 580491 Α7 Β7 V. Description of the invention (16G) (4-Gaphenoxy) phenylthio fluorenyl] -tetrahydrofuran _4 -chitoic acid formaldehyde solution, with The internal temperature was maintained at 15-20 ° C. The mixture was stirred for 2 hours, and the mixture was dissolved in 40% ethyl acetate / water (200 ml). The layers were separated and the ethyl acetate was used (2X50 liters) back extract the aqueous layer. The mixed organic layer was dehydrated with magnesium sulfate, concentrated, and the residue was purified by preparing TLC (20 X 40_1000 micron plate) with 50% vinegar & Ethyl ester X was eluted with hexane 'to give 4- [4- (4-phenyloxy) phenylpentanylmethyl] tetrahydropiperan-4.carboxylic acid methyl ester (460 mg, 71%). NMR (CDC13) β 1.71-1.82 (m, 2H), 2.23 (dm5 J = 13.6 Hz 2H), 3.47 (s, 2H), 3.58-3.67 (m, 2H), 3.59 (s5 3H), 3.73- 3.81 (m, 2H), 6.97-7.10 (m, 4H), 7.39 (d, J = 8.7 Hz, 2H), 7.84 (d, J = 8.7 Hz, 2H). Printed by the Employees' Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) 2. By 〇. (Next, add 2.5M N-butyl lithium (610 μl '1.53¾ mole) in hexanes to diisopropylamine (200 μl, 1.53 in tetrahydrofuran (3 ml)) MM) solution, and allowed to fall for 20 minutes to prepare an isopropylated amination bell. Then at -78 ° C, 4_ [4- ( 4-Gaphenoxy) phenylbenzylidenemethyl] · tetrahydrolanan-4 · carboxylic acid methyl ester (540 mg, 1.27 mmol) was added to the solution of diisopropylamine And stir for an additional 60 minutes. Add benzyl bromide (181 μl, 1.53 moles) to the mixture, stir for 50 minutes, warm to room temperature within 30 minutes, and stir for additional 3 hours. The mixture was then diluted with 0.1 M aqueous hydrochloric acid (25 mL) and extracted with methane (2 x 50 mL). The mixed organic layer was dehydrated with magnesium sulfate, concentrated in the air, and Chromatography on silica gel, eluting with 20% ethyl acetate / hexane, to obtain 3--163- This paper size applies Chinese National Standards (CNS) μ specifications (21〇X 297 mm) A7 V. Description of the invention ( 161) benzyl_4Ή · (4-chlorophenoxy) benzenesulfonylmethyl]] tetrahydropiperan_4-carboxylic acid formaldehyde (40 shoulder; force 1 (please read the note on the back first) Please fill in this page again, υυ Pico, 67%). IR (KBr) 1736 cm 1; 4 NMR (CDC13) Γ " 1. ό 178 (dm, J = 13.5 Hz, 1Η), 2.02_2 · 17 (m, 2Η), Bu (dm, J = 13.5 Hz, 1H), 3.19-3.23 (m, 2H), 3.37-3.45 (td, 119, 2.4 Hz, 2H), 3.77_3.85 (m, 1H) , 3.84 (s, 3H), 3.88-3.98 λ,, 2H), 4.07-4.17 (m, 2H), 6.83-6.90 (m, 4H), 6.94 (d,)-8.7 Hz, will it work, 2H), 7.08-7.15 (m, 3H), 7.37 (d5 J = 8.7 Hz, 2H), 7.62 (d, J = 8.7 Hz, 2H); FABMS (M + + H): 515. Example 3 2 Preparation of a compound of formula lx: Y is a hydroxyl group, and R 1 and R 2 are attached together by a carbon atom

R3 is hydrogen and R4 is benzyl, and IA & A) phenyl is represented by formula IX. The Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs prints and adds yuan and chemical compounds (1.06 g, 7.96 mmol) to 3_benzyl · 4_ [4-Ga4_Gaphenoxy] benzenesulfonylmethyl] _ in tetrahydropiran_4_carboxylic acid in Ν, Ν-dimethylfluorene (4¾ liters) To a solution of methyl ester (410 mg, 080 mmol) was added sodium cyanide (78 mg, 159 mmol). The mixture was heated to 120Ό8 hours, cooled to room temperature, and the N, N-dimethylformamide solvent was removed by heating under reduced pressure, and the residue was distributed between ethyl acetate (150¾ liters) and Saturated between aqueous sodium bisulfite (50 ml). The ethyl acetate layer was dehydrated with magnesium sulfate, concentrated in the air, and purified by a preparative layer method (20 × 40-1000 μm plate), and eluted with 8% methanol / dichloromethane to obtain 317 mg (80%) of 3-benzyl_4_ [4_ (4-chlorophenoxy) benzenesulfonylmethyl] • tetrahydropiperan_4_carboxylic acid. iH NMR (N, N_: methyl methyl-164- This paper size applies to Chinese National Standard (CNS) A4 specification (210x ^ 97 mm) ----- 580491 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention 162 :) Ammonium contamination, CDC13) d 1.74 (dm, J = 13.5 Hz, 1Η), 2.05_2.18 (m, 2H), 2.42 (dm, J = 13.5 Hz, 111), 3.22 -3.26 (111,211), 3.48-3.58 (m, 2H), 3.78-4.18 (m, 5H), 6.83-6.88 (m, 4H), 6.93 (d, J = 8.5 Hz, 2H), 7.08-7.13 (m, 3H), 7.36 (d, J = 8.7 Hz, 2H) 7.62 (d, J = 8.7 Hz, 2H); CIMS (NH3, M + + NH4 +): 518. Example 3 3 Preparation of a compound of formula I where n is 2, R2 is -NR0BJ, where R6 and R7 are both methyl di ^ S-5 is 4-phenoxyphenyl of formula I '~ ^ potassium carbonate (0.5 G) and methyl iodide (550 μl) were added to (R) _2-amino-N-tertiary-butoxy_3_ (4) in N, N_dimethylformamide (5 ml) _ Phenoxybenzyl)-a solution of amine propionate (1.6 g). After stirring for 2.5 hours, the mixture was distributed between ethyl acetate and water, and after the organic layer was dehydrated with tritium sulfate, the solvent was removed under reduced pressure, and the residue was layered on chopping gum. Analysis, eluting with 50% ethyl acetate / hexane, to obtain (R) -N-third · butoxy_2 · dimethylamino-3_ (4-phenoxybenzoic acid group) _propanamide (0.6 g). This compound, that is, (R) -N-tert-butoxy-2-dimethylamino_3_ (4-phenoxyphenylfluorenyl) _propanilamine was dissolved in 1,2-digasethane (50 ml), cooled to -30 ° C, and bubbled with hydrochloric acid gas in a pressure tube for 5_2 minutes. The flask was sealed and the mixture was stirred overnight. After the cooled test tube was deflated carefully, the contents were evaporated to obtain a gum, which was ground together with 2: 1 hexane / ethyl acetate to obtain a white powder, (r) _2-dimethylamino-N -Protective base- 3- (4 -phenoxybenzothenyl) -propanilamine hydrochloride_ -165- This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) ''-j. -------- Clothing-{Please read the notes on the back before filling this page} -Order_ 580491 Printed by A7 B7, Consumer Cooperatives of the Central Procurement Bureau of the Ministry of Economic Affairs 5. Description of Invention (163) (0.43 G), melting point 65 -70 ° C. Example 3 4 Preparation of a compound of formula I

Ya Bei where η is 2, R2 is -NR6gJ, where R6 is hydrogen and R7 is dimethylaminosulfonyl, and R5 is 4-phenoxyphenyl. Formula I Dimethylsulfonium (1 ml) (R) -2-Amino-N-tertiary-butoxy-3- (4-phenoxybenzenesulfonyl) in dichloromethane (20 ml) and pyridine (1.2 ml)- A solution of propylamine (1.5 g), and the mixture was stirred at room temperature overnight. The mixture was distributed between dichloromethane and water, and after the organic layer was dehydrated with magnesium sulfate, the solvent was removed under reduced pressure. The residue was chromatographed on a second gel, eluting with 0-45% ethyl acetate / hexane, to give (R) -N-tert-butoxy-2-methylaminosulfonamido -3- (4.Benzene, Benzene, Benzene) -propionic acid amine (1.6 g). This compound, (R) -N_third_butoxy-2 · dimethylaminosulfonamido-3 · (4-phenoxybenzenesulfonyl) -propanilamine was dissolved in trifluoroacetic acid (30 ml), and the mixture was stirred at room temperature overnight, difluoroacetic acid was removed under reduced pressure, and the residue was chromatographed on a chop gel with 10% methanol / dichloromethane Elution gave (R) _2-dimethylaminosulfoamido · 3- (4-phenoxyphenoxyfluorenyl) -N- # propylpropylamidohydrochloride (550 mg). iHNMR (d6-DMSO) 7.90 (d5 2H), 7.47 (d, 2H), 7.25 (t, 1H), 7.13 (m, 4H), 3.95 (m, 1H), 3.55 (m, 2H), 2.6 (s , 6H). Example 3 5 Examples of large-scale preparation of compounds of formula I Star where η is 2 ′ Attach R1 and R2 together with carbon atoms ’represents four (Please read the precautions on the back before filling this page)

-166- 580491 Description of the invention (164) Hydrogen, and R5 is a formula of 4_ (4_ exhaust, a certain hydrogen) phenyl! 1 · of the compound, in N, N 'dimethylformamide (56 kg) and diethyl malonate (22 kg), _, add 21% ethanol steel (45 kg) in ethanol Then, pour in 2-chloroethyl ether (19 kg). The mixture was heated to 8 5 t, which caused the acetamidine to distill out. The temperature was raised to 120 ° C until all the ethanol forms were removed (3 hours), and then the mixture was allowed to cool down to 25 ° C. The mixture was then warmed to 120 ° C and again at a rate sufficient to cause distillation of the ethanol form, 4 5 kg of ethanol = 2 1% sodium ethoxide solution were added. Upon completion of the distillation, the mixture was cooled # to 100 C 'and cooled to 25 after deciding that the reaction had been completed. . . The mixture was distributed between toluene (80 kg) and water (216 kg), and the solvent was removed from the organic layer by evaporation. This product was used directly in the next step without further purification. Attached to — 耜, Fu Xi uses a murmur (8a, printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, J, --K ----- Lu Yi II (Please read the precautions on the back before filling in this Page)-Order to cool tetrahydro-4H_piperan_4,4_dicarboxylic acid diethylamine in toluene (104 kg), that is, the compound of formula (7a) (12 kg) is cooled to _ 3 0 ° C To 3 5 ec, and add diisobutylaluminum hydride (69 kg) at a rate sufficient to maintain the reaction temperature at _ 2 5 ° C. After the addition is complete, increase the temperature within 3 hours. To 15 C and stir the reaction until all starting material is consumed. The mixture is then cooled again to -15. 0 and allowed to stand overnight. The product is distributed between ethyl acetate (54 kg), ethanol (48 kg) and a saturated sodium sulfate solution (60 liters), and stirred at 25. (: stirring the mixture overnight. -167 · 580491 Printed by A7 B7, Consumer Cooperative of the Central Standards Bureau, Ministry of Economic Affairs 165) " " — " a ~ " — filter the precipitated salt, rinse with tetrahydrofuran, and rinse with brine The organic layer was separated by dehydration. The organic layer was dehydrated with magnesium sulfate, and the reducing agent was removed under reduced pressure and passed on to 4-4-methyltetrachloropropan-4 _chitoate (3 § kg). , That is, the compound of formula (8 a). 3 · Re-fishing-in which the end is thick .. R and fi are connected together to represent tetrahydrofuran ritsu 9 a) compound 4-hydroxymethyl tetrahydropipe Ethane-4-carboxylic acid ethyl ester (8.0 kg) was added to a solution of lithium hydroxide monohydrate (446 kg) in methanol (44 liters) and water (11 kg). The mixture was refluxed for 3 times. Minutes, then the solvent was removed under reduced pressure. The mixture was cooled to 20 t, tertiary-butyl acid (14.8 kg) was added, stirred for 10 minutes, and allowed to precipitate. The upper organic layer was separated. Again This was repeated twice, and the remaining mixture was cooled to _0 ° C. A 31% solution of hydrochloric acid in water (3 kg) (3 kg) was added and the temperature was maintained below 5 ° C. The mixture was extracted several times with tetrahydrofuran, and the mixed organic layer was dried over magnesium sulfate. Approximately 90% of tetrahydrofuran 'was removed and the remaining solution was added to a mixture of hexane (645 kg) and methyl tert-butyl ether (23.7 kg) and stirred. The precipitated solid material was filtered off and dehydrated at 60 ° C under reduced pressure to obtain 4-hydroxymethyltetrahydropiperan-4-carboxylic acid (3.7 kg), which is a compound of formula (9a). 4. Star ^ _ is attached together with carbon atoms to replace the compound of formula I a. Diethylamine (4.88 kg) is added to the methylol tetrahydrogen in digas methane (32 liters). A mixture of piperan-4-carboxylic acid (3.84 kg) and dimethylaminopyridine (0.6 kg). Cool the mixture to _2 (rc, and within a 35 minute period ------—_____- 168-this paper is of the right size (please read the precautions on the back before filling out this page)

Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 580491 V. Description of the invention (166) The benzoic acid gas (466) added to methylene chloride (5 liters) keeps the temperature below _1G ° C. The mixture was stirred for 30 minutes under a stage, and then 3N hydrogen acid (10 liters) and water (10 liters) were added while stirring, and then the layers were allowed to separate. The organic layer was separated and washed with methane (16 ml). The liquid layer was washed with a 5% aqueous solution of sodium bicarbonate, and the mixed organic layer was then washed with water (12 ml). The solvent was removed under reduced pressure to obtain 2,7-bispirel [3 · 5]. Alkanone is a compound of formula (10a). A solution of 4- (4-gasphenoxy) thiophenol (437 kg) in tetrahydrofuran (15 liters) was added to 60/0 sodium hydride (0.4 kg) in tetrahydrofuran (26 kg) at Ot. · 92 kg) of the mixture, and the temperature was maintained below 〇π. The mixture was allowed to warm to room temperature for 3 () minutes and then cooled to 0 ° C. Then slowly add the concentrated solution of 2,7 · bispyrospiro [3 5] nonanone obtained above to the mixture, and maintain the temperature below 1 (rc. Allow the mixture to warm to room temperature And stirred for 30 minutes. The mixture was then treated with 3 N hydrochloric acid (16 liters) and dichloromethane (30 liters). The organic layer was separated and the liquid layer was extracted with dichloromethane (20 liters) Twice. Rinse the mixed organic layer with water (20 liters), filter, and remove 100 liters of solvent at atmospheric pressure. Add acetonitrile (60 liters) to the remaining reaction product and re-distill by distillation. After removing 60 liters of solvent, acetonitrile (40 liters) was added and the total volume of the residue was reduced to 30 liters by distillation. The mixture was then heated to a gentle reflux (80 ° C) and then again Cool slowly to 0 ° C. The product was filtered, rinsed with hexane, and dehydrated at 60 ° C under reduced pressure to give 4_ [4- (4-chlorophenoxy) · phenylthiomethyl] -169 This paper size applies to China National Standard (CNS) A4 (210X297 mm) L-^ --------- --- (Please read the precautions on the back before filling out this page) 1-il Hi-" 580491 A7 B7 Invention Description (167 Printed Tetrahydropiran-4-carboxylic acid by the Consumer Cooperatives of the Central Standards Bureau, Ministry of Economic Affairs ( 5.61 kg). 5. The compound of the formula I ba will be 4- [4- (4-chlorophenoxy) _phenylthiomethyl] tetrahydropipe in dichloromethane (27.5 liters). A solution of ran-4-carboxylic acid (5.5 kg) and N, N-dimethylmethanine (27 liters) was cooled to 5.0 and slowly added to the grasshopper air bucket liters) while stirring. After the addition is complete, the mixture is allowed to warm to room temperature and stirred for 2 hours, so a compound of formula (2) is formed. Then the solution is cooled again to 10 乇 and slowly added 50% A mixture of aqueous hydroxylamine (5.4 liters), tertiary butanol (M ·! Liters) and tetrahydrofuran (305 liters) was maintained at a temperature below 2: rC. The mixture was then allowed to warm to room temperature until reaction Done. Evaporate the solvent under reduced pressure until 90% has been removed, at which point add acetonitrile (42.5 liters) And the residual dichloromethane was removed under reduced pressure by distillation. The remaining solution was heated under reflux, and water (126 kg) was added at a rate capable of maintaining reflux. Then the solution was cooled to 51 2 hours, And the solid thus obtained was filtered. The product was washed with water and dehydrated under a 50-t emptiness to give 4- [4- (4-gasphenoxy) phenylthiomethyl] tetrahydropiperan-4 -(N · hydroxycarboxamide) (5.06 kg), which is a compound of formula Iba. 6 · A compound of formula Id in which R1 and R2 are attached together with a carbon atom to represent a tetra I sulfan will be in water (72 A solution of OXONE (14.23 kg) in liters was added to 4 · [4- (4-chlorophenoxy) in tetrahydrofuran (28 liters) and methanol (112 liters) at 15 ° C. Phenylthiomethyl] tetrahydrobranyl skinny donkey-170- This paper is subject to the Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page} Clothing--Order -• I-1- 1 580491 A7 B7 V. Explanation of the invention (168 amine) (5.06 kg), stir it and make sure Degree not exceeding 1 6 ° C. After the addition was complete, the temperature was raised to 20 π, and the mixture was stirred for 3 hours, then poured into an ice-cold mixture of toluene (60 liters) and ethyl acetate (98 liters) (5 ° C) ) While stirring. The organic layer and liquid layer thus obtained were separated through the obtained mixture, and the liquid layer was washed with a mixture of ethyl acetate (25 liters) and toluene (10 liters). Repeat this rinse step twice more. The mixed extract and organic layer were rinsed twice with water (25 liters) and the solvent was removed with reduced reputation to a volume of 30 liters. The solution was cooled to 5 ° C, and the solid was filtered, washed with ethyl acetate / water, and dehydrated under a vacuum at 50 ° C to obtain 4-[4-(4-chlorophenoxy) benzenesulfonyl Methyl] tetrahydropiperan-4. (N-hydroxycarboxamide) (4.3 kg). 7. Other compounds of formula I can be prepared in the same manner. Example 3 6 This example illustrates the preparation of a representative oral pharmaceutical composition containing a compound of formula I or a pharmaceutically acceptable salt thereof, such as N-hydroxy_ 2 _ [4- (4.phenoxybenzen Yenyl) _Hexahydro P Biyodo · 4 · yl] Ethylamine: 1 * --- U ----- Clothing-- (Please read the precautions on the back before filling out this page}-11 Ministry of Economy Printed by the Consumer Standards Cooperative of the Central Bureau of Standards A. Ingredients Formula I Compound Lactose Magnesium Stearate% w / w 20.0% 79.5% 0.5% The above ingredients are mixed and distributed into 100-mg hard-shell gelatin capsules, one The capsule will be close to the total dosage. -171- This paper size applies to the Chinese National Standard (CNS) A4 specification (210 × 297 mm) 580491 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 5. Description of the invention (169) Β Ingredients % Weight / weight compound of formula I 20.0% magnesium stearate 0.9% starch 8.6% lactose 79.6% P V P (polyvinyl pyrrolidine) 0.9% The above ingredients are mixed in addition to magnesium stearate and used as a granulating liquid Water to granulate it. The formulation is then dehydrated and mixed with magnesium stearate C. Ingredients Formula I 0.1 g of propylene glycol 20.0 g of polyethylene glycol 400 20.0 g of polysorbate 8 0 1.0 g of water to 100 ml of compound of formula I Dissolved in propylene glycol, polyethylene glycol 400, and polysorbate 80. Then add a sufficient amount of water and mix with sandalwood to provide a 100 ml solution, which is filtered and bottled. D. Ingredient% Weight / Book compound of formula I 20.0% Peanut oil 78.0% Sorbitol 6 0 2.0% Melt the above ingredients, mix and fill in soft and elastic capsules. _ · ___ ^ _____ 乙 _ ϋ ^ · ϋ ^ — Ϋϋ «I HI HI eKmmmmmt .Hi ·· ϋ_ϋ · ϋ (Please read the notes on the back before filling out this page), 1T • 172 · This paper size applies to China National Standard (CNS) A4 specification (210: 297) (%) 580491 A7 B7 V. Description of the invention (17Q) Example 3 7 This example illustrates the preparation of a representative pharmaceutical composition for parenteral administration, which contains a compound of formula I or a pharmaceutically acceptable salt thereof, For example N_hydroxy-2- [4 (4-phenoxybenzenesulfonyl) hexa Pyridine_4 • Glycolamide: Ingredients Compound of formula I Propylene glycol polyethylene glycol 4 00 Polysorbate 8 0 0.9% physiological saline solution 0.02 g 20.0 g 20.0 g 1.0 g appropriate amount to 100 ml Compound I decomposes in propylene glycol, polyethylene glycol 400, and polysorbate 80. Then, a sufficient amount of a 09% physiological saline solution was added and stirred to provide 100 liters of an intravenously injected solution, which was filtered through a 0.211 filter membrane, and packaged in a sterile state. Example 38 This example illustrates the preparation of a representative pharmaceutical composition in the form of a bolus containing a compound of formula I or a pharmaceutically acceptable salt thereof, such as N-hydroxy-2- [4 (4-benzene Oxybenzenesulfonyl) hexaargyridine_4_yl] • acetamidamine: 1- ',-1 I ii jI- I--—--I (Please read the precautions on the back before filling this page) Order _ Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, a compound of formula I, polyethylene glycol 1000, polyethylene glycol 4000. These ingredients are fused together. The model contains 2.5 grams of total weight,% weight / 1.0% of weight 74.5 % 24.5% and mixed in a steam bath, and then poured into 173- This paper size applies Chinese National Standard (CNS) A4 specifications (21〇 > < 297 mm) 580491 A7 B7 V. Description of the invention (171 Example 3 9 This example illustrates the preparation of a representative pharmaceutical composition for use in aeration, the composition containing a compound of formula I or a pharmaceutically acceptable salt thereof, such as N-hydroxy_2_ [4 (4_phenoxybenzene Sulfonyl) hexahydropyridyl f ethylglycosamine: 乂 Weight / reintroduction of micronized compound of formula I 1% of micronized milk 910% These ingredients are ground, mixed, and packaged into an inflator equipped with a dose pump. Example 40 This example illustrates the preparation of a representative pharmaceutical composition in inhaled form, which contains a compound of formula I or a Pharmaceutically acceptable salts, such as N-hydroxy-2- [4 (4_phenoxybenzenesulfonyl) hexahydropyridine_4_ylbuethamine: Ingredients of the compound of formula I water «L ... ....- I I-I—I: ....... I II---...... C Please read and read the notes on the back and fill in this page), ιτ Central Standard of the Ministry of Economic Affairs Bureau staff consumer cooperatives printed% weight / Cao Dawei 0.005% 89.995% 10.000% and mixed with water. This ethanol blend was then dissolved in ethanol to package the compound of formula I into an inhaler with a dose pump. Example 4 1 This example illustrates the preparation of a representative pharmaceutical composition in the form of a spray, the composition containing a compound of formula I or Its pharmaceutically acceptable salts, for example, female N-fatyl-2 · [4 (4-phenoxybenzenesulfonyl) hexahydropyridin-4-yl] -acetamidine: formulate this-174- The paper size applies the Chinese National Standard (CMS) A4 specification (210 × 297 mm) 580491 A7 B7 172 V. Description of the invention (% weight / weight 0.10% 98.90% 1.00%) Then the obtained mixed ingredients (please read the precautions on the back first) (Fill in this page) Propellant of Formula I 1/1 2 Oleic acid disperses the compound of Formula I in oleic acid and propellant and pours into a spray container equipped with a metering valve. Example 4 2 Analysis in vitro 4 2A MMPs were isolated for analysis using the catalytic functional site of human collagenase-1 and expressed in E. Coli as a fusion protein with ubiquitin Gehring, ER et al., J. Biol. Chem ., 270, 22507, (1995)). After the fusion protein was purified, the catalytic functional site of fibroblast collagenase-1 was released by treating with ImM aminophenylmercury acetate (APMA) for 1 hour at 37 ° C, and the zinc chelate layer Analytical method to purify. Isolation of active forms of human collagenase-2 and gelatinase B from buffy coats (Mookhtiar, K.A. et al., Biochemistry, 29, 10620 (1990)) 〇 Consumption by employees of the Central Bureau of Standards, Ministry of Economic Affairs The cooperative prints the propeptide and catalytic functional site of human collagenase-3, which is expressed in E. coli as a fusion protein with ubiquitin. After purification, this functional site was obtained by treatment with 1 mM APMA at 37 ° C for 1 hour, and it was purified by chelation chromatography. Rat collagenase-3 was purified from the culture medium of uterine smooth muscle cells in an active form (Roswit, WT et al., Arch. Biochem. Biophys., -175. This paper is in accordance with Chinese National Standard (CNS) A4 (210X297) (Mm) 580491 A7 B7 173 V. Description of the invention (225, 285-295 (1983)) 〇 Catalytic activity of human gelatinase (progelatinase) A and the fibrin-like protein moiety 'in E. coli with ubiquitin The expression of the fusion protein together. The analysis was completed on the material activated by autolysis. From the culture medium of keratinocytes stimulated by interleukin-1, rat gelatinase A was purified. Treatment with 1 mM APMA at 7 ° C for 1 hour to activate it, followed by dialysis to remove excess APMA. Human affinity was purified from synovial fibroblasts by affinity chromatography using fixed monoclonal antibodies Prolysin (prOstromolysin) · 1. The enzyme was activated by treatment with trypsin (L5 µg / ml) at 23 ° C for 1 hour to obtain a mixture of 45 and 28kD species. Behave like The pro-stromal lysin was converted into human stromal lysin to prepare the human stromal lysin and treated with 1 mM APMA for 1 hour at 37 ° C, followed by dialysis to activate it. In Chinese hamster ovary cells Rat mesenchymolysin-1 was expressed and purified from the medium. It was activated by treatment with i mM AMPA for 1 hour at 37 ° C, followed by dialysis to activate it. It was expressed in Chinese hamster ovary cells and Purified human matrix lysin (Promatrilysin) (Barnett, j, et al., Prot Εχρι ^, p Hong, $, 27 Printed by the Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs (1994)). At 37 ° c It was then treated with 1 mM APMA for 1 hour to activate it and purified by zinc chelation chromatography. When tested in this analysis, compounds of formula [shown] the ability to inhibit these collagenases. 4 2 B Procedures for in vitro analysis: The analysis is carried out at 25% with enzymes and inhibitors diluted 176- 174 580491 A7 B7 V. Description of the invention (Analysis buffer solution of formazan (DMSO) (50) mM lactoflavone pH 7.5, 200 mM sodium chloride, 10 mM calcium chloride, 0.005% B rij-35). The mother liquor of the inhibitor was prepared in 100% DMSO. The enzyme-containing mother liquor with a concentration of 2 mM was prepared in 100% DMSO. The analysis method was based on MCA-Pro-Leu-Gly_Leu_DPA_AU_Arg-NH2 ( Bachem, Inc.) is based on hydrolysis at 37 ° C (Knight, CG. Et al., FEBS, 296, 263-266 (1992)). A Perkin-Elmer LS-50B fluorometer was used to monitor changes in fluorescence using an excitation wavelength of 328 nm and an emission wavelength of 3 93 μm. The substrate concentration used in this analysis was 10 micromolar. In this analysis, dilution inhibition was started from the dropping of 100% dms0, while the control group replaced an equal volume of dms0 to achieve the final DMSO concentration in the inhibitor and enzyme-diluted fraction in all analyses. It was 2.5%. Inhibition results are expressed as inhibitory concentrations (%.) That produce a 5G% inhibitory effect on the activity in the control (un.inhibited) response. tjH 4 3. The external compound & rn Formula 1 inhibits collagen derived from osteo-implants = ¾ (determined by the release of spermic acid hydroxyproline) and proteoglycan (by S-standard: To judge the release of glucosamine polysaccharides) Second sacrifice: preparation of small cheekbones in the knee joint: hold straight) s. The 4 '5s labeled glucosamine polysaccharide (GAG, S) protects and makes the gum: protein fragments are released into the culture medium in response to its induction of chondrocyte matrix metalloproteinase (MMP, S). Financial Standards (CNS) A4 Specification —-r— IIII -— I —— I —. Ding I: (Please read the precautions on the back before filling out this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 177- 580491 A7

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, including interstitial lysin and collagenase. The lack of automatic release was used to correct the percentage inhibition of hydroxyproline and GAG, s release. When the compounds of formula I were tested in this analysis, the ability to inhibit the release of both collagen fragments and 35s_GAG, S from cartilage colonies was shown. Yuexi Example 4 4 Fenyan Cartilage Plugs Transplantation Analysis in vivo to measure the destruction of cartilage matrix of cartilage plugs transplanted into rats (Bishop, J. et al., J. Pharm. Tox MethQds, 30, 19 (1993)). A previously frozen bovine nasal cartilage plug weighing about 10 mg was buried in a polyethylene sponge infused with Mycobacterium tuberculosis and subcutaneously transplanted into female Lewis rats. Dosing was started 9 days after transplantation, and the plug was harvested after about one week. The stopper was weighed, hydrolyzed, and the hydroxyproline content was measured. The effectiveness was determined by comparing the compound-treated group with the vehicle-treated control group. • The compounds of formula I show the ability to inhibit the degradation of cartilage plugs in this analysis. Example 4 5 Procedure for in vivo analysis 4 5 A • Decision to generate T N F following L PS stimulation. Female Balb / rats (Jackson Labs or Harlan) at 6 to 8 weeks of age were used. Six to eight mice were used for each treatment group. After treatment with the compound of formula I, each mouse was injected intraperitoneally with LPS (Sigma, 13129, 10-20 micrograms per mouse). 30-60 minutes before the LPS challenge, the compound or vehicle of formula I is administered subcutaneously (sc ·) once. Animals in the control group only accepted CMC or 178- This paper size applies Chinese National Standard (CNS) Α4 size (210X297 mm) ϋ—J m —i J-—ϋ n ϋϋ —ϋ ϋϋ ϋ (Please read the notes on the back first (Fill in this page again)-Ordered by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs to print 580491 A7 _________ B7 V. Invention Description (176) ~ CMC + 2-5% DMSO. 1.5 hours after LPS injection, the animals were bled from the posterior orbital plexus using a Pasteur pipette under anesthesia with metofane. Blood was collected into a microtainer's serum separation tube (Becton Dickinson # 5960). Serum is isolated and tested the next day, or stored under _ 2 0 until ready to test TNF-pan 4 5 B · Mouse TNF Han ELIS A analysis endogenous (EM _ TNFA tool set) small Mouse tumor necrosis factor (mTNF ") tool kit for quantitative measurement of mouse TNF-pan in vitro enzyme-linked immunosorbent assay (order code: EM-TNFA; Endogen, 30 Commerce Way, Woburn, Μ01 01801- 1059, USA). To each well of a pre-coated anti-mTNF-α culture plate, add two standards (freeze-dried recombinant E. coli · derived mouse TNF-T) and serum samples (each 50 microliters). Add biotinylated antibody (50 microliters) and incubate the plate at room temperature for 2-3 hours. Rinse each well five times with wash buffer solution and add to each well 100 microliters of diluted streptavidin HRP and then incubate at room temperature for 30 minutes. After washing (5x), add 100 microliters of premixed TBM enzyme solution to each well 'Let the plate develop in the dark at room temperature for 30 minutes The reaction was stopped by adding 100 μl of stop solution. The absorbance at 450-575 nm was measured on a plate reader (ThermoMax, Molecular, Devices). Using Immunofit Beckman software, by comparison with a standard curve, Calculate the results in picograms per milliliter of TNF · α. Take the average picograms per milliliter of TNF-from, and with the control group (inject only lps of _______ -179-) This paper scale applies Chinese national standard i— ( CNS) Α4 specification (21GX297 mm) ~ --- 丄! J ------- (Please read the precautions on the back before filling this page), 1T 580491

V. Description of the invention (expressed in comparison with the percentage of inhibition printed by employees of the Central Standards Bureau of the Ministry of Economic Affairs, Consumer Cooperatives). The control group is considered to produce 100% TNF-Han. When tested in this analysis, Compound I showed the ability to inhibit TNF_ ^ production. Example 4 Conjugated immunoassay of 6 Γ_ΝF Human Monoc 6 cells were cultured at 37 C in a RPMI 1640 medium supplemented with 10% fetal bovine serum to a density of 1 X 105 cells / ml. All subsequent cultures were completed at 37. 230 microliters of these cells were placed in each well in a 96-well tissue culture plate, and the cells were cultured for 15 minutes. 10 microliters of the compound of formula I in the desired concentration in the medium mentioned above is added to the appropriate wells and incubated for an additional 5 minutes. 10 microliters of the LPS / PMA mixture was added to each well, which brought the final concentration of LPS to 10 nanograms / ml and the final concentration of PMA to 30 nanograms / ml. The cells were then cultured for 2 hours, after which the culture plate was centrifuged to remove the medium and analyzed for TNF content. The R & D system TNF Quantikine immunoassay was followed by the manufacturer's draft (r & d system, 614 Mckinley Place N.E., Minneapolis, MN 55413, USA; Catalog No. DTA50) to complete the analysis. 1C50 was calculated from the percent inhibition of TNF released into the culture medium. When tested in this analysis, compounds of formula I show the ability to inhibit the production of τ N F. Example 47 Immune analysis of TNFR emissions 180- This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) ^ ----- Dining clothing — (Please read the precautions on the back before filling this page)

1T 580491 A7 ----------- B7 V. Description of the invention (178) Human Monoc 6 cells were cultured at 37 ° C in RPMI 1640 medium supplemented with 10% fetal bovine serum To a density of i X 106 cells / ml. All subsequent cultures were completed at 37 ° C. 230 microliters of these cells were placed in each well of a 96-well tissue culture plate, and the cells were cultured for 15 minutes. 10 microliters of the compound of formula I in the desired concentration in the medium mentioned above is added to the appropriate wells and incubated for an additional 5 minutes. Add 10 µl of PMA to each well to a final concentration of 30 ng / ml. The cells were then cultured for 16 hours, after which the plate was centrifuged, the culture medium was removed and the content of the TNF receptor was analyzed. The R & D system TNF receptor Quantikine immunoassay was followed by the manufacturer's draft to complete the analysis. Measurements of each TNF receptor (Receptor I and Receptor π) were performed in this manner. IC50 was calculated from the percentage inhibition of TNF released into the medium. When tested in this analysis, the compounds of formula VII show the ability to selectively inhibit T N F production. At the same time, the present invention has been described in terms of its specific embodiments. Those skilled in the art will understand that various changes can be made and equivalents can be substituted without departing from the scope of this invention. It is intended that all such modifications fall within the patentable scope of the appendix here. 1 ^-^ ------- (Please read the notes on the back before filling this page)

, 1T Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs _-181-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) --------

Claims (1)

580491 Patent Application No. 086102686 g Chinese Patent Application Scope Replacement (1993) 丨 C8 Α8 Β8 C8 D8 1. An aryl-S (0) n-substituted hydroxamate of the formula: R1 R2 S (〇) nR5 OR3 B4 where n is 2; Υ is χΟΝΗ-, where χ is hydrogen; R1 is hydrogen or Ck-fluorenyl; R2 is hydrogen, Ck-alkyl, phenyl-Cw alkyl, valamine Amine group or -nr6r7, where: R is murine or Ci_6-alkyl; R7 is hydrogen or -S02NR8R9; where R8 and R9 are Cn alkyl; or R1 and R2 and the carbon atom to which they are attached together represent the C38_ ring Alkyl, R13-hexahydro? Pyridyl or tetrahydrocarbyl; where R13 is hydrogen, Ci-6-alkyl, C3-8-cycloalkyl-Ci.6-alkyl, pyridyl · carbonyl, Pyridyl- ¢: ^ 6-alkyl or Cn-alkyl-continuous group; R3 is hydrogen, Cw alkyl, C3.8-cycloalkyl-Ci-6-alkyl, phenyl-Cu-alkyl ; R4 is hydrogen, Cn alkyl or C3-8-cycloalkyl-Cy alkyl; or R2 and R3 and the carbon atom attached to them represent C3_8-cycloalkyl; or the Chinese standard (CNS) applies to this paper A4 specification (210 x 297 mm) 2. 3 · 4 · 5 · 6. 8. R t and its attachment , Tetrahydropiperanyl or tetrahydrosulfide: ran-s, s-dioxo-group, wherein R10 is hydrogen, 'alkyl, ~ -cyclofluorenyl-Cw alkyl, or Ci | alkyl_c 〇; and t is fluorenyl or R " phenyl, where Rll is hydrogen, k-alkoxy, CM Woxy, chloroethoxy "than dianoxy or u group _r12, where is the cadaver bond , _S or _CH = CH-, and R12 is hydrogen, Cw alkoxy, fluorine, chlorine, bromine or thiophenyl; or a pharmaceutically acceptable salt or ester thereof. According to the application # 1 patent scope 苐 1 item The compound of which R2 is · Nr6r7. According to the compound of the scope of the patent application, the compound of the first item, wherein R2 is hydrogen and R3 is a phenylalkyl group, and R4 is the hydrogen. The compound of the scope of the patent application item, wherein R 3 The compound is according to item 4 of the scope of patent application, wherein R5 is phenyl, 4-methoxyphenyl, 1- (renmethoxymethoxyphenyl) -2-phenylphenylethyl, phenylthiophenyl, phenoxy Phenyl or diphenyl. The compound according to item 5 of the scope of patent application, wherein R 5 is 4-phenylthiophenyl, 4-phenoxyphenyl, or 4-diphenyl. According to item 1 of scope of patent application Compounds in which R 3 and R 4 together with the carbon atoms attached to them form a c3_8-cycloalkyl or Cl_6-alkyl < 3_8-cycloalkyl. Compound according to item 7 of the scope of patent application, wherein R 5 is 4 _methyl Phenyl or 4-phenyl milk phenyl, c3_8-cycloalkyl is cyclopentyl or cyclohexyl and c1 < > 6-, pit-C3-8-cycloalkyl is 4-methylcyclohexyl. According to the application The compound of item 1 of the patent scope, in which R 3 and R 4 are attached with 9. The carbon atoms attached to the scope of the patent application collectively represent Rig_hexahydropyridyl, tetrahydrothiopyranyl or tetrahydrothiopiperan_S, s -Dioxo-group, in which R10 is hydrogen, Cl_6.alkyl, C3-8-cyclofluorenyl-Cn,]: a charge group or Cnfluorenyl-C0. 10. The compound according to item 9 of the scope of patent application, wherein R3 & R4 and its adjacent carbon atom are hexahydropyridin-4-yl, and R5 is 4-phenoxyphenyl, 4- (4-bromophenoxy) Phenyl, 4- (4-chlorophenoxy) phenyl or 4- (4-fluorophenoxy) phenyl. Π. The compound according to item 9 of the scope of patent application, wherein R3 and Chi 4 and adjacent carbon atoms are 1-methylhexahydropyridin-4-yl, and R5 is 4-phenoxyphenyl, 4- (4- Bromophenoxy) phenyl, 4- (4-chlorophenoxy) phenyl or 4- (4-fluorophenoxy) phenyl. 12. The compound according to item 9 of the scope of patent application, wherein R3 and R4 and their adjacent carbon atoms are 1- (cyclopropylmethyl) hexahydropyridin-4-yl, and R5 is 4-phenoxyphenyl, 4- (4-bromophenoxy) phenyl, 4- (4-chlorophenoxy) phenyl, or 4- (4-fluorophenoxy) phenyl. 13. The compound according to item 9 of the scope of patent application, wherein R3 and Chi 4 and their adjacent carbon atoms are tetrahydropiperan-4-yl, and R5 is 4-phenoxyphenyl, 4- (4-bromophenoxy) Group) phenyl, 4- (4-chlorophenoxy) phenyl or 4- (4-fluorophenoxy) phenyl. 14. The compound according to item 1 of the scope of patent application, in which R2 and trans 3 are adjacent to each other. The carbon atom is cyclopentyl or cyclohexyl, R4 is hydrogen and R5 is 4-methoxyphenyl. 15. The compound according to item i in the scope of the patent application, wherein r2 is -NR6r7 and R1, R3 and R4 are hydrogen. ___ -3- This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) C8 D8 Patent Application Scope • According to the 15th patent application scope of the compound, where R5 is 4-phenoxyphenyl, 4- (4-chlorophenoxy) phenyl or 4fluorophenoxy) phenyl. • The compound according to item 1 of the scope of patent application, in which R 1 and R 2 and the carbon atom to which they are attached together represent R 13 -hexahydro? Bidyl or tetrahydropyranyl; where R is fluorenyl, phenyl, C3-8-cyclopit-Ci_6-carbyl, p-pyridyl, p-yl, p-pyridyl, or Cw alkyl-sulfo醯 基. 18. The compound according to item 17 of the scope of patent application, in which R2 and R3 and their neighboring anti-atoms are hexahydropyridin-4-yl, and R5 is 4-phenoxyphenyl, 4- (4-phenylphenoxy) ) Phenyl, 4- (4-chlorophenoxy) phenyl or 4- (4-fluorophenoxy) phenyl. θ 'The compound according to item 7 of the scope of the patent application, in which R2 and R3 are tetrahydropiperan-4-yl and R5 is 4-phenoxyphenyl and 4- (4- / odorous benzene) Oxy) phenyl, 4- (4-chlorophenoxy) phenyl, 4- (4-fluorophenoxy) phenyl, 4- (thiophen-2-yl) phenoxyphenyl, 4- (thiophene) 3-yl) phenoxyphenyl, 4- (2-pyridyloxy) .phenyl, 4- (5-chloro-2-pyridyloxy) phenyl. 20. The compound according to item 1 of the scope of the patent application, wherein R1 and R2 are both Cw alkyl groups, feet 3 and 4 are hydrogen, and R5 is 4-phenoxyphenyl, 4- (4-bromofungoxy) ) Fungyl, 4- (4-chlorophenoxy) phenyl or 4- (4-fluorophenoxy) phenyl. 21. The compound according to item 1 of the scope of application for a patent, which is selected from any of the following N-methyl- 2- [4- (4- (Phenyloxybenzoic acid) tetrazinean- 4-yl]- Acetylamine; -4- This paper size applies to China National Standard (CNS) A4 specifications (210X 297 mm) 580491 2_M- [4- (4-chlorophenoxy) _benzenesulfonyl] tetrahydropiperan-4-yl} -N-#empty ethyl amine; 2_ {4- [4- (4-fluorobenzene Oxy) benzenesulfonyl] tetrahydropiperan_4_ylb-N-perethylethylamine; N- # yl-2- [4- (4-phenoxybenzenesulfonyl) hexahydropyridine_ 4-yl] -acetamidamine; {4 [4- (4--aspartyloxy) pyrene]] anaerobic bipyridine_4-yl} -1 ^ -rotylacetamide; 2 · {4- [4_ (4-fluorophenoxy) benzenesulfonyl] hexahydropyridine-4 -yl}-Ν-Rosinylethylamine; Ν-Μ 基 -2- [1-methyl-ren (4 -Phenoxybenzenesulfonyl) hexahydropyridin-4-yl] -ethylamine; 2 [1% propylmethyl-4- (4-phenoxyphenylfluorenyl) hexahydroρ ] _ N-Hydroxyacetamide; 2- {1_Cyclopropylmethyl-4- [4- (4-chlorophenoxy) benzenesulfonyl] hexahydropyran-4-ylb-hydroxyacetamidine ; 2-U-Cyclopropylmethyl-4- [4- (4-fluorophenoxy) benzenesulfonyl] hexahydropyridine-4-ylb-N-hydroxyacetamidine; Pentyl) -2- ( 〇32-Valaminoamido)-~ hydroxy-3- (4-phenoxyphenyl_continamido) -propylamidoamine; (R) -N-hydroxy_2-valamineamido-3_ ( 4_phenoxybenzenesulfonyl) _propanamide; (R) -2-dimethylamino-N_hydroxy-3- (4_phenoxybenzene Acyl) _ j ____5_ I propan Amides Applicable paper China National Standard Scale (CNS) A4 size (210X 297 mm) a '--- 580491 A8 (R) -2-Dimethylaminosulfonamido-N-hydroxy_3_ (4-phenoxybenzenesulfonyl) -propanamide; 4 · [4- (4-chlorophenoxy) benzenesulfonate Fluorenylmethyl] tetrahydropiperan_4_ (n_hydroxycarboxamide); & 4- [4- (4-thien-2-yl) phenoxybenzenesulfonylmethyl] tetrahydropiperan ( N-hydroxycarboxamidine); 3-[4- (4-chlorophenoxy) benzenesulfonyl] -2,2 • dimethyl-N-hydroxypropanamide; 4- [4- (4- Pyrimiphen_3_yl) phenoxybenzenesulfonylmethyl] tetrahydropiperan (N-hydroxycarboxamide); and pharmaceutically acceptable salts thereof. 22. —A method for preparing a compound as described in item 1 of the scope of patent application, the method comprising contacting a compound of the formula with an oxidant: R1 R2 WR5 OR3 R4 wherein γ, Rl, R2, R3, R4 and r5 are as patented Range η is defined. 23. A pharmaceutical composition for inhibiting matrix metalloproteinases, comprising a pharmaceutically acceptable non-toxic excipient, and a therapeutically effective amount of a compound according to any one of claims 1 to 21 of the scope of patent application. 24. The pharmaceutical composition according to item 23 of the scope of patent application, which is used to treat a disease state that has been reduced by treatment with a matrix metalloproteinase inhibitor ', especially wherein the disease state is rheumatoid arthritis, bone Joint-6- This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 public directors) 580491 8 8 8 8 AB CD 6. Application for patent scope inflammation, osteoporosis, periodontal membrane disease, labyrinthic blood vessels Formation, multiple sclerosis, tumor metastasis, or corneal ulcer. 25. The pharmaceutical composition according to item 23 of the scope of patent application, which is used to treat a disease state regulated by tumor necrosis factor, especially wherein the disease state is inflammation, bleeding, transplantation response to the host, or autoimmune disease . 26. The pharmaceutical composition according to item 23 of the scope of patent application, which is used for treating chronic obstructive pulmonary disease. This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)