TW415941B - Nitric oxide synthase inhibitors derived from cyclic amidines - Google Patents

Abstract

The current invention discloses useful amidino derivative compounds, pharmaceutical compositions containing these novel compounds, and to their use as nitric oxide synthase inhibitors.

Description

V. Description of the Invention (A7 B7 This case was printed by the Consumer Cooperatives of the Central Procurement Bureau of the Ministry of Economic Affairs as part of a continuation of US Patent Application 08 / 438,321 filed on May 10, 1995, the contents of which are incorporated herein by reference. Invention FIELD OF THE INVENTION The present invention relates to fluorenyl derivative compounds, pharmaceutical compositions containing these novel compounds, and their medical uses, particularly as inhibitors of nitric oxide synthase. BACKGROUND OF THE INVENTION Acetylpyridine has been known since the early 1980s. Choline-induced vascular relaxation depends on the presence of endothelium. This activity is attributed to unstable humoral factors, called endothelial-derived relaxation factor (EDRF). Nitric oxide (NO) as a vasodilator is known for its activity For more than 100 years, N 0 is the active ingredient of amyl nitrite, glyceryl trinitrate and other nitro vasodilators. Recently, EDRF was confirmed as NO, and it was found that NO was synthesized by amino acid L-arginine by NO synthetase. The biochemical pathways are consistent. Ν Ο is an endogenous stimulator of soluble ornithine cyclase, involving many biological effects, in addition to the relaxing effects of endothelial dependence, including the cytotoxicity of phagocytes Sexual and central nervous system (see Moncada et al., Biochemical Pharmacology, 38, 1709-1715 (1989) and Moncada et al., Pharmacoloical Reviews, 43, 109-142 (1991)) a The production of excess NO may involve many conditions, especially those involving systemic hypotension, such as toxic shock, and treatment with certain cytokinins. NO is synthesized from L-arginine and can be an L-arginine analogue LN- Methyl · arginine (L-NMMA) inhibition, L-NMMA has been proposed for the medical use of toxic shock and other types of systemic hypotension (WO 91/04024 and GB-A-2240041) -4- This paper is applicable China National Standard (CNS) A4 specification (210X297 mm) Please-read it first-the above is a cautionary note written by the Central Consumers Bureau of the Ministry of Economic Affairs Employee Cooperatives Seal 415941 A7 B7 ----------- -------------------- V. Description of the invention (2). Certain non-L-NMMA other N ◦ synthetic inhibitors for medical purposes for the same purpose are disclosed in W0 91/04024 and EP-A-0446699. At least three NO synthetases are known recently, as follows: (i) Structural Ca ++ / Caimodulin depends on enzymes and is located in the endothelium, which releases NO in response to receptors or physical stimuli. (Ii) Structural Ca ++ / Dhomodulin-dependent enzymes in the brain, which are released in response to receptors or physical stimuli. NO. (iii) Ca ++ is enzyme-independent and is proliferated after vascular smooth muscle, macrophages, endothelial cells, and many other cells are activated with endotoxins and cytokines. Once expressed, this inducible NO synthetase can synthesize NO for a long time. NO released by structural enzymes serves as a transduction mechanism for several physiological responses. The no produced by the inducing enzyme is tumor cells and cytotoxic molecules that invade microorganisms. It has also been shown that the adverse effects of excessive NO production, especially pathological vasodilation and tissue destruction, are mostly caused by the effect of NO synthesized by the exaggerated NO synthetase. There is also more evidence that NO may be involved in the degradation of cartilage, which occurs in certain symptoms ' such as arthritis, and it is also known that the synthesis of NO is increased in rheumatoid arthritis. Therefore, other symptoms beneficial in inhibiting the production of NO by L-arginine include autoimmune and / or inflammatory symptoms that affect joints, such as arthritis, inflammatory bowel disease, cardiac tube hemorrhage, diabetes, hyperalgesia (aUodynia) ), Cerebral hemorrhage (local hemorrhage 'thrombotic stroke and globaal hemorrhage, followed by cardiac arrest, and other NO-mediated CNS diseases, including patients who need long-term opioid analgesics Opal tolerance (tolerance), benzodiazepine tolerance of patients with stupid diazepines, and other addictive behaviors _ · 5- This paper is applicable to China National Standards (CNS) Α4 regulations 2丨 ------- ----- Packing— (Please read the precautions on the private side first. This page, -fl line 415941 A 7 ~ ______ B7_ 5. Description of the invention (3), such as nicotine and diet violations Other conditions beneficial for inhibiting NO from L-arginine include systemic hypotension associated with septic and / or toxic shock induced by multiple agents; cytokines such as TNF, IL-1 and IL-2 ) Treatment; and adjuvant for short-term immunosuppression in transplantation treatment. Inhibition of N 0 by L- Other symptoms that are beneficial for amino acid production include autoimmune diseases and / or inflammatory conditions such as those affecting the joints, such as arthritis or ARDS 'or inflammatory bowel disease, or asthma, cardiovascular hemorrhage, congestive heart failure, myocarditis , Arteriosclerosis, migraine, reflux esophagitis, chin, irritable bowel syndrome, gallbladder fibrosis, emphysema, and diabetes. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read ^- Precautions ^^^ Write this page) Some NO synthetase inhibitors currently proposed for medical use, especially L-NMMA, are non-selective and can inhibit structural and inducible NO synthase. Non The use of selective NO synthetase inhibitors requires great care to avoid the potentially severe consequences of excessive inhibition of structural NO synthetases, including hypertension 'possible thrombus and tissue destruction. Especially in L_NMMA for the treatment of toxic shock For medical use, patients have been advised to perform continuous blood pressure monitoring during treatment. Therefore 'although non-selective NO synthetase inhibitors are used with appropriate alert Medical use, but selective NO synthetase inhibitors inhibit the inducible N 0 synthetase much more than the structurally isomeric form of the N 0 synthetase, which will have greater medical benefits and easier use. Wo 94/12165, WO 94 / 14780, WO 93/13055, EP 0446699A1 and U.S. Patent 5,132,453 disclose compounds that inhibit nitric oxide synthesis, preferentially inhibiting the inducible isomeric forms of nitric oxide synthetase ^ This disclosure is incorporated herein by reference in its entirety. _ -6- This paper is scaled by Zhongguan Jiaxian (CNS) A4 · _Xinle Gongshou)-415941 A7 • B7 V. Description of the invention (4) Abstract of the invention Provides novel fluorenyl derivatives β based on uninvented novelty Inhibitor compounds are represented by the following formula (I): R5

(I) ---------- install --- (fill in this matter of the first reading of the first reading of ii) Accepted by the East Central Standards Bureau of the Ministry of Economic Affairs, Consumers Cooperative, Yindong and its salt and medicine are acceptable Esters and prodrugs, where: R1 is selected from hydrogen 'hydroxyl, lower alkyl, lower alkenyl, lower alkynyl, alkoxy, thioalkoxy, cycloalkyl,' heterocyclyl, and aromatic Can be selected from lower alkyl, lower alkyl, lower alkyl, cyclocyclyl, heterocyclyl, aryl, meridian, low, pitoxy, aryl + oxy, thiol, low Solventoxy, halogen, cyano, nitro, amine, alkylamino, dialkylamino, aminealkyl, dialkylaminealkyl, arylamine, aminearyl, aminearyl, amine Base, base, CGNR10RU * S (O) R10 > S (0) 2R10 ^ SO2NRI0Rn »Po (〇R10) (ORn), pompano, guanidyl; all the substituents are optionally substituted with one Or more of the following groups substituted: haloyl, lower alkyl, amine, alkylamino, dialkylamino, amidane i, amidino, carboxyl, cai (bo) alkoxy, carbonylaryloxy , Carbonylalkaryloxy, hydroxyl, lower alkoxy, S (0) R10, S (〇) 2R1C), fluorenyl, guanidine Basis; this paper size applies Chinese National Standard (CNS) A4 specifications (21 × 297 mm) 415941 A7 B7_ V. Description of the invention (5) X = NR2, 0, S, SO, S02, (CH2) p, CH = CH; p = 0 to 6; A = NR3, 0, S, SO, S02, (CH2) q, CH = CH; q = 0 to 6; B = NR4, 0, S, SO, S02, ( CH2) V, CH = CH; v = 0 to 6; R2 = hydrogen, lower group, aryl, heterocyclic group; r3 = hydrogen 'lower alkyl, aryl, heterocyclic group; r4 = hydrogen, lower alkyl R5, R6, R7 are each selected from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, heterocyclyl, hydroxy 'lower alkoxy, mercapto, lower thioalkoxy, S (〇) r9, s (〇) 2r9, halogen, nitro, amino'alkylamino, dialkylamino, amine alkyl, dialkylamine alkyl, arylamine, amine aryl, amine aromatic Stilbene amine, carboxyl, carbonylpooxy ', carbonylaryloxy, carbonylaralkyloxy, cyano, aminecarbonylalkoxy, aminecarbonylamino'aminocarbonylalkyl, haloalkyl'S. 2NR10Rn, in which all substituents can be optionally substituted with one or more of the following: lower alkyl, halogen, amine, domain amine, di Amine group, amine alkyl group, amine alkyl group, carboxyl group, carbonylalkoxy group, carbonylaryloxy group, carbonylalkaryl group, hydroxyl group, low alkoxy group; R5 and R6 can optionally form alicyclic hydrocarbons and heterocyclic rings together Or aromatic hydrocarbon, the selectively formed ring can be optionally substituted with one or more of the following groups: low-burning group 'low alkenyl' low-block group, optionally with carboxyl, carbonylalkoxy, aryloxy, carboxyl Alkaryloxy and lower alkoxy substitution: R8 = Hydroxy ', OH-alkyl; R9 = Hydroxy, hydroxy, O-alkyl; * 8-Paper Size Laizhong (CNS) A4 Specification (2IGx297 male thin ) --- Du Yi ------- 1T ------ ^ (^ Notes for reading the endorsement first ^^% Write this page) ί Du Yin, Central Ministry of Economy Preparation A7 415941 _ _ V. Description of the invention (6) R1 D = hydrogen, low-carbon, aryl, aryl;

Ru = Hydrogen, lower alkyl, alkaryl, and aryl: —— (read the notes on f-face first < fill out this page) R〗 G and R11—can be subalkyl groups to produce N-containing hetero Ring; with the proviso that when R1 is low alkyl, low alkenyl or lower alkyl, it cannot be optionally substituted with cyclopalyl, heterocyclyl and aryl, unless A or B is NR 2, 0, S, SO , So2; with the condition that when A and B are (CHdp or CH = CH and R1 is a low dry group, a low alkenyl group or a low alkynyl group, R1 is not substituted with a cycloalkyl group, a heterocyclic group or an aryl group, and R5 And R6 is not Η; with the condition that only one of X, A, and B can be selected from NR2, NR3, NR4, or 0, s, SO, so2; the other condition is when X = (CH2) p; A = (CH2) q, B = (CH2) V, p + q When v = 3, then no more than one of R1, R5, R6 and R7 may be alkyl, alkoxy, cycloalkyl or cycloalkoxy The base is at the 5th position: Another condition is that when X = (CH2) p; A = (CH2) q 'B = (CH2) V and line P + q + v = 3, then R1, R5, R6 and One of R7 is alkyl, cycloalkyl or aryl at the 5th position, then the remaining R1, R5, R6 and R7 cannot be cyano, substituted amine, alkoxy or sulfur Oxygen is in the 5th position; the consumption co-operation of the Central Government Bureau of the Ministry of Economic Affairs of the People's Republic of China is printed with another condition: when X = CH = CH; A = (CH2) q, B = (CH2) V, and q + v When = 2, then R1, R5 ', R6 and R7 cannot be carboxyl groups at the 6th position; another condition is when X = NH: A = (CH2) q, B = (CH2) V, and q + v = 4 When Ri, R5, r6 & r7 cannot be a carboxyl group at position 7. In another broad aspect, the present invention relates to inhibition-the synthesis of nitrogen oxides in an individual in need of such inhibition or treatment, by administering an oxidation to the individual Nitrogen synthesis — _____ · 9-Chinese National Standard (CNS) A4 size of this paper (2! Ox29]-Printed by Shellfish Consumer Cooperatives, Ministry of Economic Affairs, Bureau of Standardization, 415941 A7 ------- B7 _ V. Description of the invention (7) An inhibitory amount of a compound of formula (I) which inhibits the inducible isomeric form of nitric oxide synthase is superior to the structural isomeric form of nitric oxide synthase. The present invention also relates to a compound containing formula ( I) Pharmaceutical compositions of compounds The above compounds and compositions are useful as inhibitors of nitric oxide synthase. These compounds also selectively inhibit inducible forms. Inhibition of NO L-arginine is produced from nitric oxide-mediated diseases. Favorable conditions include systemic hypotension associated with multiple agents-induced septic and / or toxic shock; cytokines such as TNF, IL-1, and IL- 2) Treatment; and adjuvant for short-term immunosuppression in transplantation. Inhibition of NO by L-spermonic acid. Other symptoms beneficial include autoimmune diseases and / or inflammation symptoms such as those affecting the joints, such as arthritis, or inflammatory bowel disease, cardiovascular hemorrhage, diabetes, and congestive heart failure. , Myocarditis, arteriosclerosis, migraine, reflux esophagitis, chancre, irritable bowel syndrome, gallbladder fibrosis, emphysema 'hyperodynia (allodynia), cerebral hemorrhage (local sclerosis, thrombotic stroke, and ball Hemorrhage, secondary to cardiac arrest, and other NO-mediated CNS diseases, including opiate temporality in patients requiring long-term opioid analgesics, benzodiazepine tolerance in patients taking benzodiazepine, and others The formation of niobium, such as nicotine and dietary disorders. The present invention includes salt forms of compounds of formula (I), especially acid addition salts. Suitable salts include those formed by organic and inorganic acids. Acid addition salts are generally medically acceptable However, non-pharmaceutically acceptable salts can be used to prepare and purify the compound. Therefore, preferred salts include hydrochloric acid, hydrobromic acid 'sulfuric acid, citric acid, tartaric acid, phosphoric acid, milk , Acetic acid, succinic acid, fumaric acid, maleic acid, formic acid, ethylene acid, p-methyl benzoic acid, benzoic acid, etc. -10- This paper size applies China National Standard (CNS) Α4 specification (210X297 mm) ^ ------------- ^ {Please read the notes on the back to write this page) ί 415941 A 7 B7 V. Description of the invention (8) (See, for example, SM, Berge et al., Pharmaceutical Salts, J. Pham.

Sci ,, 1977, 66, 1-19). Salts of a compound of formula (I) can be prepared by reacting a free base form of a suitable compound with a suitable acid. Although the compound of formula (I) can be administered as a raw chemical, it is preferably administered as a pharmaceutical formulation. According to another aspect, the present invention provides a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. And one or more of its pharmaceutically acceptable carriers, and optionally one or more of the other medical ingredient beta carriers must be "acceptable" meaning compatible with the other ingredients of the formulation and not harmful to the recipient. Formulations include suitable for oral, inhalation, parenteral (including subcutaneous, intradermal, intramuscular 'transvenous' and intraarticular), rectal, and topical (including intradermal 'intracheal' sublingual and ears (Internal) application, but the most suitable route depends on the recipient's symptoms and disease. The formulations can be conveniently provided in unit dosage forms and can be prepared by methods well known in the art of medicine. All methods include the step of combining a compound of formula or a pharmaceutically acceptable salt or solvate ("active ingredient J") with a carrier (constituting one or more supplementary ingredients) β-generally, the formulation is composed of uniform and close combination of active ingredients And liquid carrier or finely divided solid carrier or both, and then (if necessary) the product is formed into the desired formulation. Formulations of the invention suitable for oral administration may be in separate units such as capsules, cachets ) Or lozenges, each containing a predetermined amount of active ingredient; powder or granules; solution or suspension in aqueous or non-aqueous liquid; or oil-in-water liquid emulsion or water-in-oil liquid emulsion. The active ingredient can also be a pellet Bolus, tincture or paste. Lozenges can be compressed or molded by selective and one or more supplementary ingredients. -11-This paper applies + National Standard (CNS) A4 (210 XD7) Public t ~ '--------- I -------. 1T ------ ^ (#-First 51 notes on reading t-faces to write books) (. Ministry of Economic Affairs Central Labor Bureau Consumers ’Cooperative, India A7 415941 _______B7 V. Description of Invention (9) Spindown can be prepared by freely mixing the active ingredient (such as powder or granules) with a mixture of a suitable admixture, lubricant, inert diluent, surfactant or dispersant, and compressing it in a suitable machine. Molded ingots can be inert from powder compounds The liquid-wet diluent moistened mixture is molded in a suitable machine, and the beta bond can be selectively coated or scored, and can be formulated to provide a slow or controlled release of the active ingredient. Parenteral administration Formulations include aqueous and non-aqueous sterilization injection solutions, which may contain antioxidants, buffers, bacteriostatic agents and solutes that make the formulation isotonic with the recipient's blood; and aqueous and non-aqueous sterilization suspensions, which may include suspending agents And thickeners. The formulations can be provided in single or multi-dose containers, such as sealed ampoules and vials, which can be stored under freeze-dried (lyophilized) conditions, and only need to be added with a sterile liquid carrier, such as saline, immediately before use, Water for injection. Temporary injection solutions and suspensions can be prepared from sterilized powders, granules and lozenges of the kind described above. Formulations for rectal administration Provided as a suppository in general carriers (such as coconut oil or polyethylene glycol). Topical formulations (such as menstrual tendons or sublingual) for topical application to the mouth include lozenges containing active ingredients in flavoring bases (such as sucrose and gold) Albizia gum or tragacanth gum), and pastilles contain active ingredients in a matrix (such as gelatin and glycerin or sucrose and acacia gum). The active ingredients in the formulation for inhalation are smoked or used with an inert carrier. It is applied to the lungs. The preferred single-dose formulations are those containing the following active doses or appropriate parts of the active ingredients. -12- This paper size applies to the Chinese National Standard (CNS) A4 (210X 297 mm) '{ The rabbit first reads the crying matter of the face 55 and fills this education)

___T Central Standards of the Ministry of Economic Affairs. Printed by the Cooperative Bureau of the quasi-bureau. Cooperative cooperatives printed 415 ^ 41 A7 B7. Printed by the Central Laboratories of the Ministry of Economic Affairs. The formulation may include other agents known in the art to the type of formulation used, for example, those suitable for oral administration may include flavoring agents. The compounds of the present invention can be administered orally or by injection at a daily dose of from 0.001 to 2500 mg / kg. The dosage range for adults is generally from 0.05 mg to 10 g / day. Lozenges or other dosage forms are provided in individual units in an amount which can conveniently contain the compound of the present invention in an effective amount in the agent or multiple doses, for example, containing 5 mg to 500 mg, generally about 10 mg to 200 mg. The compound of formula (I) is preferably administered orally or by injection (intravenously or subcutaneously). The exact amount of compound administered to the patient is determined by the physician. However, the dosage used depends on many factors, including the age and sex of the patient, the disease being treated and its severity. The route of administration can also depend on the symptoms and severity. The term "low alkyl" as used herein, alone or in combination, means an acyclic courtyard, containing 1 to about 0 carbon atoms, preferably 1 Up to about 8 carbon atoms, more preferably about 1 to about 6 carbon atoms. Examples of the group include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, second butyl, third butyl, fluorenyl, isopentyl, hexyl, octyl and the like. The term "low dilute group J means that the unsaturated acyclic hydrocarbon contains at least one double bond. This group contains from about 2 to about 10 carbon atoms, preferably from 2 to about 8 carbon atoms, more preferably from 2 to about 6 Carbon atom. Examples of suitable fluorenyl groups include propionyl, butenyl q · yl'isobutenyl'penten-1-yl, 2-2-methylbutan-1-yl, and 3-methylbutynyl -1-yl, hexen-1-yl, heptene_1-yl, and octyl_1-yl, etc. The term "low alkynyl" means that an unsaturated acyclic hydrocarbon contains one or more triple bonds. The base contains about 2 to about 10 carbon atoms, preferably 2 to about 8 carbon atoms, more -13 private paper size applicable to China National Standard (CNS) A4 specifications (2 丨 0X 297) Packing --- (Be sure to read the precautions on t side first! Quoting this page!) — Printed by Shenyang Bureau of Standards, Ministry of Economic Affairs, Shellfish Consumer Cooperative Co., Ltd. 415941 A 7 B7 V. Description of Invention (! 1) Better 2 to about 6 carbon atom. Examples of suitable alkynyl groups include ethynyl, propidyl, butyn-1-yl'butyr-2-yl, pentyl-1-yl, pentynyl-2-yl, and 3 • methylbutynyl-1- The group 'hexyn-1-yl' hexyn-2-yl, hexadecyl-3, 3 3-dimethylbutyne-butyl and the like. The term "alicyclic hydrocarbon" or "cycloalkyl" means that the ring of an aliphatic group has 3 to about 10 carbon atoms, preferably 3 to about 6 carbon atoms. Examples of suitable alicyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl and the like. The term "arene" means that the aryl group has 4 to about 16 carbon atoms, preferably 6 to about 12 carbon atoms, and more preferably 6 to about 10 carbon atoms. Examples of suitable aromatic hydrocarbon groups include phenyl, phenyl and the like. The term "aryl" means that 5- and 6-membered monoaryl groups may include 0 to 14 heteroatoms. Representative aryl groups include phenyl, 11 cephenyl, amyranyl, p-pyridyl, (iso) fluorenyl and the like. DCM means dichloromethane. DEAD means diethyl azodicarboxylate. DIB AL-H means diisobutylaluminum hydride. DMAP means dimethylaminopyridine. DMSO stands for Dimethyl Ammonium. EDC means 1- (3-dimethylaminopropyl) -3 · ethylcarbodiimide hydrochloride. The term "heterocyclyl" means a saturated or unsaturated cyclic hydrocarbon group, including aromatic systems, having from 4 to about 10 carbon atoms, preferably from about 5 to about 6 carbon atoms: of which from 1 to about 4 carbons Atoms are replaced by nitrogen, oxygen, sulfur, or carbonyl. A "heterocyclyl" can be combined with arsonyl copper. Suitable examples include Rocky, Bite, and Blow -14-This paper size applies to China National Standard (CNS) A4 specifications (210X297 male thin) a 'nn ---- i I--Hi m Hi I___ I ding- -------. I 1-5 ° each (t first ^ read ^ the above notes ^ fill in this 1) (415941 Member of the Central Standards Bureau of the Ministry of Economic Affairs X Consumer Cooperatives printed A7 ____B7 _V. Description of the invention (12 ) Oxazolyl, triazolyl, pyrimidinyl, dacrotyl, henazolyl, isoxazolyl, pyrenyl, imidyl, 11-yl, '«sedenyl, succinyl, tetrabenzyl , 2-p-pyrrole " Lingyl, 3-pyrrolidinyl, pyrrolidinyl, 1,3-dioxolyl, 2-imidazolinyl, tetrahydroimidyl, 2-pibitulinyl , P ratio, bite group, isotope, linyl 'isop, thiazolyl', oxadiazolyl, triazolyl, oxadiazolyl, 2H -ouranyl '4 Pyridyl, 1,4-dioxolanyl, molyl, 1,4 · di-porphyllyl 'thiomathyl 11 linyl' P ratio 11 well base, six gas JT ratio P well base, 5 plug ( I well-based '1,3,5-three-distant dry-based' phenylhydrazone (b) thiophenyl, benzimidyl, p-quelinyl, etc. HOBT 意N-Hydroxybenzotriazole. The term "low alkoxy", alone or in combination, means an alkyl ether group, wherein the pit group is as defined above, preferably containing from 1 to about 4 carbon atoms. Examples of suitable alkyl acid groups include Methoxy'ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, second butoxy, third butoxy, etc. The term "low sulfur pitoxy", Separately or in combination, it means an alkyl thioether group, in which the alkyl group is as defined above, and preferably contains 1 to about 4 carbon atoms. Examples of suitable alkyl thioether groups include thiocarboxide, thioethoxy, and thiopropyl Oxy, thioisopropoxy, thio-n-butoxy, thioisobutoxy, thio-butoxy, thio-butoxy, etc. As used herein, the term "carbooxyalkyl" means the above The alkoxy group has several radicals (〇〇) connected. The term "halogen" means fluorine, gas, bromine or kiln. MCPBA means m-gas perbenzoic acid. NMM means N-methylmorpholine. -15- This paper size applies to China National Standard (CNS) A4 specification (210X 297 mm) '-< Cheng Xian ¾ read t side ;! Matters' Bp 'fill in this page) • Binding, binding line 415941 A7' ___B71 'Explanation of the invention (13) NMMO means 4-methylmorpholine N-oxide. The term "prodrug" means to form a more active compound in vivo. The term "sulfenylJ" means SO. The term "sulfofluorenyl j means so2. TEA means triethylamine. Tmsn3 means azidotrimethylsilane. As used herein," treating "a patient is intended to include the prevention of all references cited in this case. , Patents, or applications (US or foreign) are incorporated herein by reference, as contained herein. The compounds of the invention may exist in geometric or stereoisomeric forms. The invention includes all such compounds, including cis and trans geometric isomers, E- and Z- geometric isomers, R- and S-enantiomers, diastereomers, d-isomers, 1- Isomers, racemic mixtures, and other mixtures are within the scope of the invention. It is also disclosed that 11 general synthetic methods can be used to prepare the compounds of the present invention. --------- Equipment ------- ΐτ ------ ^ (^ -First read ^ -Precautions ^ Fill in this page) {Shiyang Standard Bureau of the Ministry of Economic Affairs Printed by the Industrial and Consumer Cooperatives -16- This paper iron scale is applicable to the Chinese National Standard (CNS) A4 specification (210 × 297 mm) 415941 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

This paper size applies the Chinese national standard i CNS) A4 specification (210X297 mm) (# * Read the t-face precautions ^^ Fill in this page),-° 415941 A 7 s a -_ ^ ____ i, invention Explanation (15) a) Mg >THF; b) CuI, -301C.; T) -3 (TC to 0 ° C or room temperature; d) DMSO, grass base gas, CH2Cl2_, -70 ° C; e ) Et; N, -70 ° C to 0 ° C; f) NH2OH, NaOAc, EtOH: g) PhS02Cn, NaOH, H20, acetone; h) Me30 + BF4-; i) NH4C1; j) K2C031NaH, DMF; k ) NaCN, DMSO, H20, heat: 1) DMF, L-R1 (where L'-R1 is CH2 = CHCO-R1); m) IN LiOH, MeOH. Buckle clothes-(Beam first ^ read ^ face notes ^ ^ copy 1)

* 1T Printed by Shellfish Consumer Cooperatives, Central Bureau of Standards, Ministry of Economic Affairs

figure 2 :

I · Bu 1 18-The size of the paper method is applicable to China National Standard (CNS) A4 (210X 297 mm)

415941 A7 BT V. Description of the invention (16) (Y = CN, COO alkyl, N02, S02 alkyl), S02NH2, SC ^ NR10! ^ 11, heteroaryl Rm = H, alkyl, cycloalkyl, aromatic Heterocyclic, Rn = H, fluorenyl, aryl, heterocyclic Rin and rii can form a ring together_ a) Solvent (benzene); b) NH2OH, NaOAc, EtOH; c) PhS02Cl, NaOH, H20, propyl_ d) Me30 + BIV, CH2C12: e) NH4Cn, MeOH.

a) Test, Rkl ^ NC ^ b) H2 / RaNi, 55 ° C c) Me30 + BF4., CH2C12; d) NH4a, MeOH. Figure 4: --------- Installation --- (if you read the first note ^, < fill in this page) '-° line printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs o

e M o This paper size is in accordance with Chinese National Standard (CNS) A4 specification (2) 0X 297 mm 415941 A7 B7 V. Description of the invention (17) a) R5COR6 inspection: b) inspection, R7CH2C〇2Me c) I ^ / RaNi, 55 C d) Me30 + BF4-, CH2C12; e) ΝΗ4α, MeOH. Figure 5: Ο R7

NH r5 (CH2) p °

R5 (CH

iT ^ rc〇2M OCH2Ph 0 (Ph = phenyl) --- coupons

C02Me ^ rS

Ah 0 OCH2Ph HN, C02Me '

Ah O OCH2Ph

OCH2Ph

Y

C02Me Printed by the staff of the Central Bureau of Standards, Ministry of Economic Affairs, F. Cooperatives. A) DBU, Z-a-trimethylglycinate; b) H2 / [Rh [(C0D) (R, R_ DIPAMP)] + BF4 '( Enantiomeric catalysts can be used): c) Me3O + BFV'CH2C12; d) NH4a, MeOH; e) H2, Pd / C. -20- This paper size applies Chinese National Standard (CN ’S) A4 pit (210 X 297 mm) 415941 Μ B7 'V. Description of the invention (π Figure 6: 0

R1 a

c

d

f --------- install —----- ^ ------ line {Please read the notice on the reverse side and fill in this page first) Printed a) (Third butyl 0C0) 20, DMAP, THF; b) LiHMDS, HMPA, THF, (lSH +)-(10-Camphorsulfonyl "propane or (1R) _ (_) _ (10_ Camphor stilbene) e-aziridine; c) third butyldimethylsilyl gas, imidazole, DMF; d) Mg (C104) 2 (20%), CH3CN; e) Me30 + BF4 ·, CH2C12; f) NH4a 'MeOH ·-g) (butyl) 4N + F-, MeOH. -21-This paper size is applicable to China National Standard (CNS) A4 (210 x 297 cm) 415941 A7 B7 V. Description of the invention (19) Figure 7:

-22- --------- install ------- order ---- *-line (please read the precautions of f-face first and write this page) {This paper size is applicable to China National Standards (CNS) A4 specifications (210X297 mm) 415941 A7 B7 V. Description of the invention (20) a) NaH / THF: b) BrCH2CN / THF; c) ethylene glycol / p-toluene acid / toluene; d ) LiAlH4 / Et20; e) carbonylbenzyloxy chloride / third butanol / water / NaOH; f) p-toluenesulfonyl gas / CH2C12 / pyridine; g) KCN / acetonitrile: h) KOH / ethylene glycol I) MeI / DMF / NaHC03; j) H2 / Pd / MOH; k) B2H6 / THF; m) HC1 / Ac0H / H20; n) NH2OH: p) benzenesulfonyl group gas / H20 / acetone NaOH; q) Trimethoxytetrafluoroborate salt; r) NH4Cl / MeOH; (t first read ^-& notes ^ fill in printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs -23 This paper applies Chinese national standards ( CNS) A4 specification (2I0X 297mm) 415941 A7 B7 V. Description of invention (21) 囷 8: Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

-24- This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) (if you need to read the 5th side of the paper, please fill in this one hundred;

1T line 415941 A7 B7 V. Description of the invention (22) a) (Third butyl 0C0) 20, DMAP, THF; b) LiHMDS, HMPA, THF, (1S)-(+)-(l0-camphorsulfonate Fluorenyl) aziridine or (lR)-(-)-(l0-camphoryl) aziridine; c) third butyldimethylsilyl chloride, imidazole 'DMF; d) Mg (C104 ) 2 (20%), CH3CN; e) Me30 + BF4-, CH2C12; f) NH4C1, MeOH; g) (butyl) 4N + F., MeOH: h) H2, Pd / C. --------- f ^ r-- (Mu Xianwen read the note on f. noodles page)-Printed by the Consumer Cooperative of the Central Government Bureau of the Ministry of Economy China National Standard (CNS) A4 specification (210X297 mm) 415941 A7 B7 V. Description of invention (23 Figure 9:

0 X

B C02Et a, b

0 / NH2

e ° v r " NHZ f 0 \ / 〇 广 1 ^ 21 for E = CH2

X

B

X

A- B 〇Ts a

OH R7 R7

--------- Approve clothes -------- IT ------ ^ (+ Please read the notes on r face first, fill in this purchase) ί Consumer Cooperatives, Central Standards Bureau, Ministry of Economic Affairs For e = ch2 or e = ch2ch2

X

B ΈΤ.

NZ m 0

n

NOH

26- The guilt scale of this paper applies to the National Park Standard (CNS) A4 specification (210X297 mm) 415941 V. Description of the invention (24) Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

Figure s NH .HC1 X eight NH

^ One £ NH.HC1 9 (continued)

NH.HC1 dry into iJH a) NaH / THF; above) BrCH2CN / THF: c) ethylene glycol / p-toluenesulfonic acid / toluene d) LiAlH4 / Et20; e) carbonylbenzyloxy gas / third butanol / Water / NaOH; f) p-toluenesulfonyl gas / CH2C12 / pyridine; g) KCN / acetonitrile; h) KOH / ethylene glycol; i) MeI / DMF / NaHC03; j) H2 / i &d; d / MeOH ; k) B2H6 / THF; m) HC1 / Ac0H / H20; n) NH2oh; p) benzenesulfonium gas / HaO / NaOH; q) tris (fluorenyl) tetrafluoroborate trioxoyl salt r) NH4Cl / MeOH; s ) H2, Pd / C. -27 This paper size applies to China National Standards (QVS) A4 specifications (210X297 mm) --------- installation ------- order ------ line (read first r Notes on the face ^ Fill in this page) 415941 A7 B7 V. Description of the invention (25) Figure 1 0

, Me

R

NZ

Install --- (t Xian Min read the notes on the back of the page to fill in this page) Printed aM third butyl 0C0) 20, DMAP, THF by the Central Consumer Bureau of the Ministry of Economics and the Ministry of Economic Affairs; b) LiHMDS 'HMPA' THF (1S)-(+)-(l0-Camphorsulfonyl acryl) or (lR)-(-)-(10_camphorsulfonyl) acryl 11: c) third butyl dimethyl Silicon pit base gas' imidazole 'DMF; d) Mg (C104) 2 (20%), CH3CN: e) Me30 + BF4-, CH2C12; f) NH4a, MeOH; g) (butyl) 4N + F ·' MeOH: h) H2 'Pd / C. -28 The size of this paper applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 415941 Μ B7 V. Description of the invention (26) Figure 11:

a

R5NH

R7

B

R = alkyl, cycloalkyl, aryl, heterocyclic 'CH2CH (NH2) C02H Rm = H, alkyl, cycloalkyl ,, aryl, heterocyclic Rn = H, alkyl, cycloalkyl, aryl , Heterocyclic ring and ^^ can form a ring together z = leaving group η = 1-4 m = 1-4 m NH 2

Central Bureau of Standards of the Ministry of Economic Affairs®: Printed by Industrial and Consumer Cooperatives

a) Catalytic argonization; b) RCHO; c) reduction; d) CH2 = C (NHZ) C02] e) reduction lf) hydrolysis 0 No further explanation is necessary. Those skilled in the art can use the present invention to make use of the above description. Most complete. Therefore, the following more specific specific examples are illustrative, rather than limiting the rest of the present disclosure.6 All examples are performed under dry nitrogen or argon. All solvents and reagents are not available. -29 --------- Kun Yi ------- IT ------ ^ (¾Precautions for reading the meeting first, write this page) {. The dimensions of this paper are in accordance with Chinese National Standards and Standards (CNS) A4 (210X297 male thin) 415941 Α7 87 5. Description of the invention (2?) Purified and used unless otherwise stated. The general processing of the reaction involves adding the reaction mixture to a neutral 'or acidic, or a mixture of an aqueous test solution and an organic solvent. The aqueous layer was extracted n times (X) with the organic solvent shown. The combined organic extracts were washed n times (X) with the aqueous solution shown, dried over anhydrous Na2S04, filtered, concentrated in the air, and purified as shown. Separation by column chromatography was achieved under the conditions described by Still (Still, WC ,; r Kahn, M .; Mitra, A. Rapid f Chromatograhic Technique for Preparative Separation with Moderate Resolution. J. 〇rg. Chem., 1978, 43, 2923-2925) »Hydrochloride is made from · IN HQ, HC1 in ethanol (EtOH), 2N in MeOH, or 6NHC 丨 in dioxolane. Thin-layer chromatography was performed on a 0.25 mm EM precoat of silicone 60F254. High Performance Liquid Chromatograms (HPLC) were obtained on C · 8 or C-18 reverse phase columns! (Obtained from several vendors). Analytical samples were dried in an Abderhalden apparatus at 56 ° C or 78eC. The lH NMR spectrum was obtained using a General Electric QE-300 or Varian VXR 40 MHz spectrometer with tetramethylsilane as the internal standard. NMR was obtained from an a-Varian spectrometer at 125.8 MHz using tetramethyl 'fragmentane as an internal standard. 3 Example 1 2,2,6-Trismidinocyclohexanone, monthly loss --------- I ------- 1τ ------ ^ (please read > 7 notes of ^^^ fill in the wooden page) The Central Bureau of Procurement, Ministry of Economic Affairs

Sample of 2,2,6-trimethylcyclohexanone (Aldrich, 4.9 g, 39.0 mmol) combined with hydroxylamine hydrochloride (NH2OH. HC1, 3.6 g, 52.4 mmol) and vinegar-30 -1:. · This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 male f) 415941 A7 B7 V. Description of the invention (Sodium 28 (NaOAc '5.2 g, 62.9 mmol) ears in ethanol (EtOH, 3 5 ml) • 'I and water (25 ml) mixture. This mixture was refluxed under a nitrogen atmosphere for 5 hours. After the reaction mixture was cooled to room temperature and stirred for 5 days, all solvents were removed and removed under reduced pressure. The residue was partitioned between ethyl acetate (EtOAc) and water. The organic phase was washed with 1 X 75 ml of saturated NaCl (brine), dried over Na 2 SO 4, and all solvents were stripped under reduced pressure. 5.0 g (91%) ) The title compound is a white solid. The substance is a 0.25 mm X 25M methyl, 5% phenyl silicone column, and helium is used as the carrier gas. The temperature program starts at 5 5 ° C and increases by 10 ° per minute. 200ac, Shimadzd GC-14A gas chromatogram (GC) shows that the retention time is 9.6 centimeters latitude (100% purity, with peak area product ). NMR and IR spectrum. The spectrum is also consistent with the structure shown. Elemental analysis: C9Hi7NO · 0.1 H20 (MW = 157.04) C Η 68.83 11.04 69.00 11.00 Example 2: Hexahydro-3,3,7-trisino-211 -Azapyridin-2-one: hexahydro-3,7,7-trimethyl, yl-2Η-azepine-2 · one

Calculation 値 · Measured 値: Isomer A Isomer B N 8.92 8.85

I equipment-(Notes for the first reading of the h side! ^ 100 copies of this C-= 0 line printed by the staff consumer cooperatives of the Central Bureau of the Ministry of Economic Affairs

Isomers-B -31-This paper is in accordance with the general Chinese National Standard (CNS) A4 specification (2MXM7 mm) 415941 A7 __B7_ 5. Description of the invention (29) 4.9 g (34.3 mmol) of the title substance of Example 1 The sample was added to a dropping funnel containing 6 ml of 80% H2S04. After using stirred hazel to obtain a turbid solution, 5 ml of 80% H2S04 was added dropwise (10 minutes) as a mixture, magnetically stirred and kept in an external oil bath at 120 ° C. An exotherm occurred within 5 minutes of the start of the addition, and the reaction temperature rose to 160 ° C and then cooled to 120 ° C. After 10 minutes, the flask was removed from the oil bath and cooled to room temperature. The product mixture was diluted with water (20 ml) 'to a pH of 6 with concentrated NH40. This solution was diluted with 75 ml of water 'and extracted with 3 x 75 ml of CH2C12. The combined organic phases were washed with 50 ml of brine, dried (Na2SO4), filtered, and all solvents were stripped under reduced pressure. An oily residue (2.9 g, 56%) was separated by HPLC on a crushed product to obtain the title product. Example 3 3,4,5,6-Tetrazol-7-methoxy-2,6,6-trifluorenyl-2H_aza leather I — (^ -closed reading ^ cloud precautions ^^ write Order CH ^

Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Online Economics on Tetramethyloxonium (oxonium) salt (Lancaster, 0.30 g, 2.0 mmol) and 3 A molecular sieve (2 g), CH2C12 ( 15 ml) of the magnetically stirred slurry under argon (Ar) was added the product of the isomer of Example 2 (0.31 g '1.5 mmol). The mixture was stirred at room temperature for 3 days, then diluted with 10 mL of CH2C12, and partitioned between 40 $ L of saturated KHC03 and 50 mL of EtOAc. The organic phase was separated, dried with $ Naj04, filtered, and stripped under reduced pressure. -32-Εϊ used Chinese National Standard (CNS) A4 specifications (_2Ι〇Χ297 公 ^ '-415941 AT' ----- B7 ___.__ V. Description of the invention (30) (Notes on the back of this article first read this page) Solvent 'produces crude title product' is pale yellow oil. This substance is in the upper layer of short path Merck rapid silica tubing It was isolated with Et0Ac / n-hexane (1: 1). The titled light yellow liquid product (308 · mg, 93%) had a GC retention time of 5.5 minutes under the conditions of Example 1 (10%). 〇 / 0), the NMR and IR spectra are consistent with the products shown. Example 4 3,4,5,6-Tetrahydro-7-methoxy-2,2,6-trimethyl-2Η-azapyridine

The product of the isomer B of Example 2 was reacted with trimethyloxyphosphonium tetrafluoroborate in the same manner as in Example 3 to produce the title material. Γ Example 5 Hexahydro-3,3,7-trimethyl-2Η-aza leather -2-imine, monohydrochloride CH ^

The title product of Example 3 (0.3.0 g, 1.4 mmol) and 0.06 g (1.1 mmol) of ammonium gasified (NH4C1) in 13 ml of methanol ( MeOH) under reflux under nitrogen for 19 hours. After the reactants have cooled to room temperature, they are filtered and stripped under reduced pressure. • -33.- This paper scale is applicable to the Chinese National Standard (CNS) A4 specification (2 丨 0X29? Mm) 415941 A7 B7 V. Invention Note (31) There is a solvent, partitioned between 15 ml and 7 millimeters, and ch2c] 2, the organic phase and the aqueous phase are separated. The aqueous phase is washed with 2.5 ml of EtOAc, and then dried on ice to obtain 0.24 g ( 92%) of the title material as a white solid. Example 6 Hexahydro-3,7,7 · trisino- · 2Η-doza 萆 -2_imine, monohydrochloride

The product of Example 4 was reacted with ammonium gasification in MeOH in the same manner as in Example 5 to give the title material. .Example 7 3,3,5,5'-tetramethylcyclohexanone, monthly loss of one OH A- --------- pack-< free first 5? Read the meaning of ii on the back (Fill in this page) Sample of 3,3,5,5-tetramethylcyclohexanone printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (Aldrich, 6.2 g, 40.0 millimoles) Take Example 1 This method uses 5.6 grams (80.0 millimoles) of hydroxylamine hydrochloride and 6.7 grams (82.0 millimoles) of NaOAc in 60 ml of EtOH and 60 ml of water to convert to the title compound. This procedure produced 7.5 g (100%) of the title material as a white solid. 34- This paper size applies Chinese National Standard (CNS) A4 specification (2 〖〇297297mm） A7 B7 V. Description of the invention (32) Example 8 Hexa-4-4,4,6,6-tetramethyl-2H- Azepine-2-one

A sample of the product of Example 7 (7.5 g, 44.4 mmol) was converted to the title compound in the method of Example 2 using 11 ml of 80% H2SO4. This procedure produced 5.6 g (75%) of the title material as a pale yellow viscous solid * Example 9 3,4,5,6-Tetrahydro-7-fluorenyl-3,3_, 5,5-trimethyl-211 -Aza leather (please read the precautions on the back first)

ΟΜθ The title product of Example 8 (845 mg, 5.0 mmol) was reacted with trimethyloxyphosphonium tetrafluoroborate (962 mg, 5.0 mmol) in the same manner as in Example 3 to yield 815 mg (100%) of the title substance. Example 1 0 Hexahydro-4,4,6,6-tetramethyl-2Η · aza leather imine, monohydrochloride

The paper scale is applicable to China National Standards (CNS) Α4 specifications (210 · 〆297 mm).

Printed by 415941 A7 of the Central Bureau of Quasi-Bureau of the Ministry of Economic Affairs A_ — B7__ V. Description of the invention (33) The product of Example 9 (110 mg., 0.6 mmol) was dissolved in 3.5 ml of MeOH with ammonium vaporized ( (32 mg '0.6 mmol) was reacted in the same manner as in Example 5 to produce 90 mg (67%) of the title material. Calculated RMSm / e 168.163 for HRMS (El) C10H20N2, measured 値 m / e 168.162. ! H NMR (CD3OD): ci 3.21 (s, 2H) * 2.62 (s, 2H) > 1.54 (s, 2H) '1.1 (s, 6H), 1.01 (s, 6H). Elemental analysis: C10H20N2. HC1. 0.3 H20 · 0.25 NH4C1 (MW = 223.52) C Η Ν C1 Calculated 値: 53.74: 10.19 14.10. 19.83 Found 値: 53.71 9.66. 13.99 19.59 Example 1 1 • Tetrahydro-4 Η-piran -4-ketone, oxime / 5Η Ν tetraargon-4H · weinan-4-one (5.0 g, 0.05 mole), polyamine hydrochloride (5.2 g '0.075 mole) and sodium acetate (13.6 g' 〇 .1 mole) refluxed in ethanol (30 ml) / H20 (20 ml) overnight. The contents were cooled and concentrated in the air to remove the ethanol. The remaining water was extracted with CHaCi2, dried (Mg $ 〇4), and concentrated in the air to obtain the title material as a white solid (54 g). WNMRCCDCl;): d9.15 (br, lH); 3.85-3.70 (m, 4H); -36- The standard of this paper is applicable to Chinese national standards (CNS M4 specification (2 丨 0X29? Mm) (will read first (Notes on the r side fill in this page)

Printed on line -1T, printed by Shelley Consumer Cooperative of Central Bureau of Standards, Ministry of Economic Affairs 415941 A7 ____B7 V. Description of Invention (34) 2.72-2.60 (m, 2H); 2.40-2,35 (m, 2H). 'Example 1 2 Tetrahydro-1 oxazepin-5 (2H) -one 0-s.α. Η To the title substance C5.4 g, 0.047 mol) of Example 11 in acetone (30 ml) was added 1N sodium argon oxide at 0 ° C. Benzenesulfonium gas (6 ml, 0.047 mole) was added dropwise in acetone (1 ml), and the β contents were magnetically stirred for 72 hours' and concentrated in 眞 S to remove acetone. The aqueous solution was extracted with CH2C12 (2 X 150 ml), dried (MgS04), and concentrated in the air to obtain an amber-colored oil / solid (2'2 g). The residue was solidified from hexane to obtain the title substance as a white solid (1.37 g) /! H NMR (CDCI3): ά 6 90 (br >1H); 3.82-3.70 (m, 4H): 3.38-3.30 (m , 2H); 2.75-2.65 (m, 2H). Example 1 3 Tetrahydro-1,4-pyrazine-5 (2H) -imine, trifluoroacetate

• The title substance of TFA Example 12 (960 mg, 0.008 moles) and trimethyloxyphosphonium tetraargonate (1.5 g, 0_〇1 mole) were mixed in CH2C12 (50 ml). Bang-37 ---------- t .------- ΐτ ------ Line (¾Notes on reading the Emperor's Noodles before writing this page) < · This paper is made in China Standard (CNS) A4 now (210X297 mm) " A7 415941 _______B7 V. Description of the invention (35) Mix for 72 hours "The content is concentrated in the air, and the residue is dissolved in methanol (50 ml). Anhydrous ammonia was bubbled through for 15 minutes. The contents were stoppered 'and stirred overnight. After concentrating in the air, the residue was partitioned between CI ^ Cl2 and water. The aqueous layer was purified by c_18 reverse phase chromatography and dissolved with 100%% β (0'05% TFA) to obtain the title substance as a white solid (73 mg). NMR (D20): 3.78-3.72 (m, 2H); 3.68-3.63 (m, 2H): 3.49-3.44 (m, 2H); 2,85-2.80 (m, 2H). Example 1 4 1- (5,6-—argon-2H-weiran-4-yl) τ »Bilo bite --------- load ---- (I first Miilr * face of; (Italy Matters' ^^ Writing this tile)

Tetrahydro · 4Η-piran-4 · one (5.0 £, 〇, 05 mole) and pyrrolidine (4.6 ml '0.055 mole) in benzene (50 ml) with Dean Stark trap (trap) Reflux to collect water for 2 hours. The contents were concentrated under vacuum to obtain a thick amber oil (7.6 g) 'which was distilled on a Kugelrohr apparatus at 40 ° C (0.1 mm) to obtain the title substance' as a transparent colorless oil (5.9 g). 1E NMR (CDC13): 4.28-4.20 (m, 2H); 4.20-4.13 (m, 1H); 3.88-3.78 (m, 2H); 3.07-2.95 (m, 4H); 2.35-2.22 (m, 2H) ; 1.90-1.80 (m, 4H). -38.- This paper size applies to the Chinese National Standard (CNS) A4 (210X 297 mm) line. The policy of the Consumers' Cooperatives Cooperative Standards Bureau of the Ministry of Economic Affairs 415941 A7 B7.

V. Description of the invention (36) r Example 1 5 (2 · butenyl) tetrahydro-4H-anan-4-one 0

The title material of Example 14 (23 g, 0.15 mole) and crotyl bromide (15.4 ml, 0.15 mole) were mixed in benzene (200 ml) and stirred for 72 hours = water (50 ml) was added and stirred for 2 hours. The benzene layer was removed and the aqueous layer was extracted with EtOAc (150 mL). The organic extracts were combined, dried (MgS04), and concentrated under vacuum to obtain an oil (20.8 g). The oil was chromatographed on Miao Gum and dissolved with 5% EtOAc / hexane. The title material was found as a colorless oil (2.3 g). NMR (CDC13): (ί 5.52-5.25 (m, 2H); 4-.20-4.07 (m, 2H); 3.82-3.70 (m, 1H); 3.50-3.40 (m, 1H); 2.68-2.40 ( m, 4H); 2.03-l'90 (m, 1H); 1_65 (d, J = 6 Hz, 3H). Example 1 6 3- (2-Butenyl) tetrazol-4H-A Copper, monthly loss HO, the title substance in Example 15 (13.0 g, 0.084 mole) and the amine hydrochloride 39- K degree of this paper applies the Chinese National Standard (CNS) A4 specification (2 lOX: 297 mm> --------- ^ -------, 玎 ------ ^ (Notes on the t * side of Mu Xianwen • This page) · {A7 ----- * ________B7 V. Description of the invention (37) (6.5 g '0.093 mol) in methanol (100 liters) was added dropwise with methanol containing anhydropyridine (^ .1 ml' G'l mol) (5 ( ) Ml). The contents were stirred overnight. The internal substance was concentrated under agitation and the residue was partitioned between Che] and water. The CHjCl2 layer was dried (MgS04) and concentrated under agitation to obtain the title substance as an oil. Shape (19.5 g). IH NMR (CDCl3) 1 [9 0 '8 85 Gal 1H)] of cis-trans-trans-mixture, [5.80-5.25, 5.20-4.85 (m, 2H)]; 4.20-2.90 (m , 5H); 2.80-2.00 (m, 4H); [1 > 63 (d J = 6. Hz), 12〇-9〇 (m) (3H)]. Example 1 7 3- (2-butenyl) tetrahydro-1 >4-Hazepine; 5 (211) _ Ketone equipment-(please read vr-before you know the meaning of ^^ fill out this page)

D Printed by the Central Bureau of Standards of the Ministry of Economy—Industrial and Consumer Cooperatives. To the title substance of Example 16 (5.0 g, 0.03 mol) in acetone (30 ml) was added 1N sodium argon oxide (30 ml). Benzenesulfonium (3.8 ml, 0.03 moles) was added dropwise to propane (10 ml), and the reaction was stirred overnight after it reached room temperature. The contents were concentrated in the air to remove acetone, and the remaining water solution was extracted with CH2C12 (2 × 150 ml). The CH2C12 extracts were combined, dried (MgS04), and concentrated in the air to obtain an oil. Hexane was added to the oil, and the resulting white solid was filtered and recrystallized from .EtOAc / hexane to give the title material as a white solid (812 mg). Separate other titled substances and its isomers (regeoisomer) 6- (2-butane) tetrahydro-pyrene, 4-θ aza leather--40- from this mother liquor. The paper standard is applicable to China National Standard (CNS). M specification (2! 0 × 29? Mm) 415941 at B7 ____________ —----- ------—- _______, description of the invention (38) 5 (2 Η) -ketones, separated by chromatography 6! H NMR (CDC13): ^ 5 75 1H); 5.70-5.50 (m, 1H); 5.40-5.23 (m, 1H); 400-3.8-80 (m, 2H); 3.72-3.52 (m, 2H); 3.40- 3.30 (m, 1H); 2,95 · 2 8〇 (m, ih); 2.60-2.55 (m, 1H); 2.30-2.15 (m, lH); 2.10-1.95 (m, 1H ); 17〇 (d, J = 6Hz3H) 0 Example 1 8 3- (2-butenyl) tetrahydro. I, 4, gas aza i_5 (2H) _imine, trifluoroacetate (previous VT Read! TVg's Note: Write this page]

, π To the title substance of Example I7 (60 mg, 3.6 mmol) was added CH2Cl2 (25 ml) trimethyloxytetrafluoroborate salt (54 mg, 36 mmol). The contents were stirred overnight. 'After concentration in the air, the residue was dissolved in methanol (25 ml). Anhydrous ammonia bubbled through the solution. The contents were stoppered and stirred for 72 hours. The contents were concentrated in the air, and the residue was purified by C-18 reverse phase chromatography and dissolved in a CH3CN / H2o concentration gradient (0.05% TFA) to obtain the title. Substance as a white solid (404 mg) ° C9H16N20 Mass spectrum analysis: M + H = 169 NMR (CDCI3): < y 9.7 (br, 2H); 8.9 (br, 1H); 5.70-5.54 (m, 1H) ; 5.40-5.25 (m, 1H); 4.03-3.92 (m, 1H); 3.90-3.80 -41-This paper size applies to China National Standard (CNS) A4 (210_X297 mm): ~ Central Bureau of Standards, Ministry of Line Economy Printed by the employee consumer cooperative 41594 ^ 1594 ^ A7 B7 V. Description of the invention (39) (m, 1H); 3.76-3.58 (m, 2H); 3.46-3.32 (m, 1H); (m, 2H); 2.42- 2.18 (m, 2H); 1.67 (d, J = 6 Hz, 3H) Example 19 9 Methyl-4-hexahydropyridin-4-one, M, monohydrochloride ί.04-2.76

MCI please * first% back " Si's note to fill in% too 1 printed by 丨 _ methyl-4-pyridone (10 ml, 0.08 mole) and hydroxylamine hydrochloride (6.1 g, 0.088 mole) in a slurry of methanol (100 ml) was added dropwise methanol (50 ml) containing anhydrous pyridine (7.8 ml, 0.097 mole). The contents were stirred overnight 'and the title material was filtered as a white solid (9.2 g). More title material was recovered from the methanol filtrate (7.7 g). ^ NMR (D20): 3.70-2.90 (m, 5Η); 2.80 (s, 3H); 2.60- 2.45 (m, 2H); 2.40-2.10 (m, 1H) »Example. 20 Hexahydro-1-methyl -5H-1,4-diazapine- · 5-one

-42 The standard of this paper is applicable to Chinese National Standard (CNS) Α4 specification (210 × 297 mm). Economic and Trade Standards, Standard and Consumer Printing Cooperatives ¾ 415941 λ7 Β7 — — * '1 · — 1 — 1 5. Description of the invention (40) To the title material of Example 19 (9.2 g '0.056 mole) was added dropwise 1N sodium hydroxide in acetone (50 ml) at 0 ° C. After stirring for 5 minutes, benzenesulfonium (7.1 ml) was added dropwise in acetone (5 ml). The contents were stirred for 72 hours to room temperature. The contents were in vacuo and concentrated to remove acetone. The aqueous solution was made alkaline with 1 N sodium hydroxide and freeze-dried to obtain a solid substance. The solid matter was passed through CH2C1 # _. The CH2C12 dish shrank in tears to obtain the title substance as a solid (4.9 g). ^ NMR (CDC13): δ 6.85 (br, 1H); 3.30-3.20 (m, 2H); 2.65-2.40 (m, 6H); 2.35 (s, 3H)? Example 2 1 Hexahydro-1-methyl- 5H-1,4 -diazapyrene:: 5-imine, trifluoroacetate

The 5-oxy_2,3,4,5,6,7-hexahydro-1,4_diaza leather product of Example 20 was treated with Mep BF4 in CH2C12N and stirred overnight. After concentrating in the air, the residue was dissolved in methanol and anhydrous ammonia. The contents of the β were bubbled and stirred overnight to concentrate in the air. The residue was purified by .C-18 reverse phase chromatography to obtain the title product. r Mass spectrometry analysis of C6Pl3N3: Μ + Η = 12έ. Area rule (DMSO-d6): 9.80-9.40 (s, 1Η); 9.40 (s, 1Η); 9.10 (s, 1Η); 8.60 (s, 1H); 3.70-2.85 (m, 8H); 2.80 (s , 3H) ___ -43 * This paper size 剌 Zhongguanji rapes --------- ΐτ ------ ^ (I read the precautions for f · face first 5 ^ Write this page) {, 415941 A 7 B7 V. Description of the invention (41) 'Example 2 2 Tetrahydro · 3_ (2-methoxyethyl) -4H -piperan-4-one

Me The title compound of Example 14 was reacted with bromoethyl methyl ether in the manner of Example 1.5 to give the title compound. Example 2 3 Tetrahydro-3- (2-methoxyethyl) -4H-pyran-4-one, M

{Please read the note on the back first to write this page) Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. The title compound of Example 2 and hydroxylamine were reacted in the same manner as in Example 16 to produce the title compound. 1 Example 2 4 Isomer A: Tetrahydro-3- (2-methoxyoxyethyl) -1,4-henzazepine 5 (2H) -one isomer B: Tetrahydro-6- (2 -Methoxyethyl) -1,4-Hazepine-5 (2H) -Ketone-44- The paper scale is applicable to the Chinese National Standard (CMS) A4 specification (2 m X 297 mm) A7 B7 0

0, Isomer-B 415941 V. Description of the invention (42

0,

Isomer-A The title compound of Example 23 was reacted with benzylsulfonium chloride in the same manner as in Example 17 to give the title compound "Isomers were separated by column chromatography. Example 2 5 --------- 装 — (# * 先 Kitf * Precautions & fill in this page) 2,3,6J-tetrahydro-3 (2 · methoxyethyl)- 5 -Methoxy-1,4-Hazepine MeO,

The isomer A of Example 24 was reacted with trimethyloxyphosphonium tetrafluoroborate in dichloromethane in the same manner as in Example 3 to give the title compound. 26Example 26 2,3,6,7-tetrahydro-6- (2-methoxyethyl) -5-methoxy-1,4-pyridine azabenzene line Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Poly OMe

0. The product of the isomer B of Example 24 and trimethyloxyphosphonium tetrafluoroborate in digas-45-This paper size applies to Chinese national standards (CNS > A4 specifications (2) 0'X297 mm) 415941 A7 — _ B7____ V. Explanation of the invention (43) The methane was reacted in the same manner as in Example 3 to give the title compound. Example 2 7 Tetrahydro-3- (2-methoxyethyl) · 1,4 · Purinazepine_ 5 (2H) · imine'-hydrochloride · HC1

The product of Example 25 was reacted with gasified ammonium in MeOH in the manner of Example 4 'to give the title compound. Example 28 Tetrahydro-6- (2-methoxyethyl) -1,4-humazazepine-5 (2H) -imine, monohydrochloride

The product of Example 26 was reacted with ammonium chloride in MeOH in the manner of Example 4 to give the title compound. Example: 9 4,4, dimethyl-pentylpyridine-2-imine, monohydrochloride-46- This paper size applies the Chinese National Standard (CNS) M specification (2 丨 〇 > < 297 public variable ) --------- Refer to ------- 1T ------ ^ # * '* (Ten first read the notes on the back and fill out this page) {Central Standards Bureau of the Ministry of Economic Affairs Industrial and consumer cooperatives printed by the Central Standards Bureau of the Ministry of Economic Affairs, printed by the consumer and industrial cooperatives 415941 A7, B7 V. Description of the invention (44) HC1 Η ΗΝ Ν

Example 29A) Ethyl 3,3-dimethacrylate (4.9 g, 38 mmol) with nitrohexane (5.0 g, 38 mmol), 1M tetrabutylammonium fluoride (in THF, 38 Ml) mixed and heated at 40 ° C for 24 hours. The reaction mixture was diluted with diethylsulfonium and purified by chromatography on silica gel with brine and then washed with water to give the product methyl 3,3-dimethyl-4-nitrononanoate (6.6 g, 67%). Example 29)) The product of Example 29 (5. chocolate grams of '24 millimoles) was hydrogenated with RaNi at 55 ° C and 60 psi in absolute 1 ^ 011. The reaction product was purified by column chromatography to give 4,4-difyl-5-pentylpyrrolidin-2-one (2.63 g, 60%) »Example 29C) The product of Example 29B. (2.63 g, 14, 3 millimoles) was treated with trifluorenyloxyphosphonium tetrafluoroborate (2.56 g '17.4 millimoles) in DC.M (20 ml) according to the method of Example 3 to produce' 3,4-dihydro -5-methoxy: 3,3-dimethyl-2-pentyl-2H4 (2.0 g, 71%). Example 29) A solution of the title product of Example 29C (2.0 g, 10 mmol) in MeOH (30 mL) was reacted with ammonium gasification (529 mg, 9.9 mmol) in the same manner as in Example 5, and the "reverse phase HPLC chromatography. Example 3 0 5 -pentyl-4,4-bis (trifluoromethyl) p-pyrrolidine-2-imine, monohydrochloride-47- This paper is suitable for Chinese National Standard (CNS) A4 (210X) 297 mm) Gutter (Notes for reading rvg first, fill out this page) {415941 A7 __ B7 V. Description of the invention (45) HC1 Η Η

Printed by the Central Standards Bureau, Ministry of Economic Affairs, Consumer Cooperative, Example 30A) Ethyl 4,4,4-trifluoro-3- (trifluoromethyl) crotonate (9.0 g, 38 mmol) and nitrohexane ( A mixed mixture of 5.0 g '38 mmol), potassium carbonate (5.0 g, 38 mmol) and Aliquat 336 (20 drops) was sonicated at room temperature. When the reaction was complete by gas chromatography, the mixture was acidified with HCI (1N) and the aqueous phase was extracted with ether. Purification by chromatography on silica gel gave the product 4-nitro-3,3-bis (trifluoromethyl) nonanoate (3 g, 21%). Example 30B) The product of Example 30 A was hydrogenated in absolute MeOH with RaNi at 55 ° C and 60 psi for 24 hours. The reaction product was purified by column chromatography to give 5-pentyl-4,4-bis (trifluoromethyl) p-biloxo-2 -fluorene. Example 30C) The product of Example 30B was treated with trifluorooxotetrafluoroborate in DCM (20 mL) and treated as described in Example 3 to produce 3,4-dihydro-5-methoxy-2-pentane. -3,3-bis (trifluoromethyl) -2H-pyrrole. Example 30) A solution of the title product of OC: in MeOH (30 ml) was reacted with ammonium vaporized in the same manner as in Example 5 '. Then the title material was produced by i-phase HPLC chromatography. Example 3 1 2-Imino-4-methyl-5 · pentylpyrrolidin-3-hexanoic acid 'monophosphate-48-This paper size is in accordance with China National Standard i (cNS) M specification (210x297) Slim can --------- ^ ------- 1T ------ ^ (½ read M · note on the back 125 ^ fill out this page) ί 415941 A7 _____B7 V. Invention Instructions (46)

Example of printing by the Ministry of Economic Affairs and the Consumer Cooperatives of the Central Government Bureau 31A) Diethyl ethylene malonate (6.4 g, 33 mmol), nitrohexane (5 g '38 mmol), potassium carbonate (2 g) and Aliquat 336 (10 drops). The mixture was sonicated at room temperature. When the reaction was complete by gas chromatography, the 'mixture was acidified with HC1 (1N) and the aqueous phase was extracted with ether. Purification by chromatography on silica gel yielded the product 2- (1-methyl-2-nitroheptyl) propane-1,3-diacid diethyl ester. Example 31B) Example 3 The product of 1A was treated with RaNi in absolute EtOH. Argonize at 55 ° C and 60 psi for 24 hours. The reaction product was purified by column chromatography to give 4-methyl-2_oxy-5-pentyl. ≪ »Biloxibenzine. Example 31C) The product of Example 3 1 B was treated with trimethyltetrafluoroborate. The oxyphosphonium salt was treated in DCM in the same manner as in Example 3 to produce 3,4-dihydro-5-methoxy-2-pentyl- 2 Ethyl-pyrrole-3 dicarboxylic acid ethyl ester. Example 3 1) Example 3 A solution of the title product of 1 C in MeOH was reacted with ammonium vaporization in the same manner as in Example 5 and then subjected to reverse-phase HPLC chromatography to give the title substance β Example 3 2 2 -imino- 4-methyl-5-pentyl erlotan-3-chinoic acid, Deng-49-hydrochloride- This paper uses Chinese National Standard (CNS) A4 (210X297 mm) for this paper size ------- --- Yi ------ ίτ ------ ^ ί Α Read the t-face precautions and write this page] (415941 A7 B7 V. Description of the invention (47) .HC1 Η

Employees' cooperation of the Central Bureau of Quasi-Ministry of Economic Affairs. Social seal Example 32A) f Example 3! The title product of β was mixed in Me_N 仏 with M, af ’and then iced; dried in the east. The resulting solid was dissolved in water: EOAci benzyl hangar. The conjugate is shaken in a separation funnel. The organic solution was separated ', dried and evaporated. The residue was purified by column chromatography to give phenylmethyl 2-methoxy-5-pentylpyrrolidinate carboxylate. Example 32B) Example 3 The product of 2 A was treated with trifluorooxotrimethyloxy salt in DCM and treated in the same manner as in Example 3, yielding 3, rendiargon_5_methoxy_3-methyl_ 2 -Pentyl-2H-pyrrole-4-carboxylic acid benzyl ester. β Example j 2C) A solution of the title product of Example 2 2 B in MeOH and gasification was reacted as in Example 5 and then subjected to reverse phase hplc chromatography to give 2-imino-4.methyl-5 -Pentyl-3-metanoic acid benzyl cleavage. Example 32) Example 3 A solution of the product of 2 C in absolute MeOH was hydrogenated at pd / C. The reaction product was purified by reverse-phase HPLC chromatography to give the title material. • Example 3 3 «τ-Amino-4-hydroxy-5-imino-3- (trifluoromethyl) pyrrolidine-2-butanoic acid, monohydrochloride .HC1

OH .HC1 First " Reading the general meaning of ^^^ and big two shells). Packing ---. The size of the paper is in accordance with China National Standard (CNS) A4 (210 X 297 mm) Central Ministry of Economic Affairs Standards Bureau Shellfish Consumer Cooperative Co., Ltd. printed oxygen 415941 A7 '______—____ B7 V. Description of the invention (48) Example 33A) 4,4,4-trifluoromethylcrotonate (10 mmol) and 2 _ ( 2-Nitroethyl) -1,3-dioxolane (12 mmol) and potassium carbonate (5 mmol) and Aliquate 336 (3 drops) were reacted in the same manner as in Example 14. Purification by chromatography on silica gel gave ethyl nitro (trifluoromethyl) -1,3-dioxolane-2-valerate. Example 33B) The product of Example S3 A in MeOH with RaNi at 55. (: And 60 psi hydrogenation for 6 hours. The reaction product was purified by column chromatography to yield 5-[(1,3-dioxolane-2-yl) methyl] -4- (trifluoromethyl p-bilo Diastereomers of bite-2-one

Mixture D Example 33C) Example 3 The product of 3B was treated with di-tertiary butyric acid and DMAP in THF and refluxed for 2 hours. The solvent was removed and the product was purified by column chromatography to give 2-[(1,3-dioxolane-2-yl) methyl] -5-oxy-3- (trifluoromethyl) pyrrolidine- 1-carboxylic acid-1,1-difluorenylethyl ester. Example 33D) The product of Example 33C and HMPA (1 equivalent) in THF at -70 ° 0: treated with lithium hexamethyldisilazide (12 equivalents, 1M in THF). The solution was heated to -4 ° C, and then cooled to -7 °. (:, A solution of camphor sulfopyridine aziridine in THF was added. The solution was at -40. (: Stirred for 2 hours, and then quenched with saturated NH4C1. The solution was then extracted with EtOAc. The organic phases were combined. The solvents were removed and the product was purified by column chromatography to give 2-[(1,3-dioxolane-2-yl) methyl] -4-hydroxy-5- Oxy-3- (trifluoromethyl) pyrrolidin-1-carboxylic acid, 1,1-dimethylethyl ester. Example 33E) The product of Example 3 D was treated with NaH and benzyl bromide in THF. The product was purified by column chromatography to give 2-[(1,3-dioxolane-2-yl) methyl] -5-oxy-4- (benzyloxy) -3- (trifluoromethyl) Group) pyrrolidine-1-carboxylic acid __ -51-This standard iiiil towel §! National | 1 standard (CNS 210X297 male thin) " --------- ^ ------- II ------ ^ ($ first 5? Notes on reading ^ * ^^ %% copy \ 00 (A7 B7 415941 V. Description of the invention (49) 1,1-Dimethyl ethyl ester. Example 33F) The product of Example 33E was treated with HC1 (1N) in MeOH to give 5-oxo-4- (benzylmethoxy) -3- (trifluorofluorenyl) p-bilolide-2-ethyl chain, which was used directly In the next step. 33G) DBU was added to the product of Example 33F and a solution of Z-π-phosphonoglycinol trimethyl ester in CH2C12. The solution was stirred for 2 hours. 3 The solvent was removed. The product was purified by column chromatography to give 4- [5 -oxy- 4- (benzyloxy) -3- (trifluoromethyl) pyrrolidin-2-yl] -2-[[(benzyloxy) carbonyl] amino] -2 -butane Ethyl enoate. Example 33H) The product of Example 33G was [Rh (COD) (R, R-DIPAMP)] + BF4-argonated. The solvent was removed and the product was purified by column chromatography to give 5-oxy- £ y-[[(benzyloxy) carbonyl] amino] -4 · (benzyloxy) -3 · (trifluoromethyl Methyl) pyrrolidine-2-carboxylic acid methyl ester. Example 331) The product of Example 33H was treated with trimethyloxyphosphonium tetrafluoroborate in DCM and treated as described in Example 3 to produce 3,4-dihydro-5-methoxy-α-[[(benzyloxy ) Carbonyl] amino] -4- (phenylfluorenyloxy) -3- (trifluoromethyl) -2） -pyrrole-2 -butenoic acid methyl ester. Example 33J) A solution of the title product of Example 3 3 I in MeOH was reacted with ammonium vaporized in the same manner as in Example 5 and then subjected to reverse phase HPLC chromatography to give 5-imino-«-[[(benzyloxy ) Carbonyl] amino] -4- (benzyloxy) -3- (trifluoromethyl) pyrrolidine-2-butenoic acid methyl ester, monohydrochloride. Example 3 3) The product of Example 3 3 J was argonized with Pd / C in absolute MeOH for 24 hours. The reaction product was purified by reverse phase HPLC chromatography to give 3 3. -52- This paper is in the standard Chinese National Standard Soap (CNS) A4 (210X 297mm). — — ·· Please read the notes on the tit * side before filling in this page. Printed by Pui Gong Consumer Cooperative Co., Ltd. 415941 Α7 ________ Β7 V. Description of the invention (50) Example 34 Hexahydro-2-imino-4-methyl-7- (2-propene: yl) _ih_aza leather_3_ alcohol

Me

The Central Bureau of Standards of the Ministry of Economic Affairs and Consumer Cooperation; -t Example 34 A) Hexahydro-4 -methyl-7- (2-propenyl) · 2 · -azapyridin-2-one in THF solution Tertiary butyl vinegar and dimethylamino dm AP, 1 equivalent) treatment 'yields BO (protected mesaminol, hexahydro_4-methyl_2-oxy-7- (2-propenyl) -1Η- Azapyridine_i.acid.i, dimethyl ethyl ester Example 34B) The product of the above Example 34A was dissolved. Τ η F and cooled to a low temperature. Hexamethylphosphonamine (HMP A, 1 equivalent) was added. ), And then add hexamethyldisilazide lithium azide (LHMDS, 1.1 equivalents). Add 12 equivalents of this, (lS)-(+)-(Camphor contininyl) -indacryl or (1R) _ (_) _ (camphorsulfonyl'yl) -indacryl 'can be separated by chromatography Diastereomer isomer A hexahydro-3R-Cyclo-4-fluorenyl-2-oxy-7- (2-palkenyl) -lH-azafluoren-1-acid 1,1 -Dimethyl ethyl acetate 'or isomer 3 hexahydro_3S- ^ yl-4-methyl- 2-oxy-7- (2-propenyl) -1 Ι · dimethyl ethyl ester mixture 9 Example 34C) The product or product mixture of the above Example 3 4 B was dissolved in d μF and treated with imidazole (2 equivalents) and tertiary butyl-dimethylsilyl gas to produce 3_ [(1,1 · Dimethylethyl) dimethylsilyloxy] hexahydro-4 -methyl_2_oxy_7 · (2_propenyl) -1Η-aza leather-1-tan Acid 1, dimethyl dimethyl ethyl ester. -53- < degree applies to Chinese National Standard (CNS) A4 specification (2! 〇 × 297mm) equipment— (1 read the precautions on the back first! ^ Write this page) Order 415941 A7 B7 V. Description of the invention (51) Examples 34D) In the product or product mixture of Example 3 4 C described above, dissolved in acetonitrile and heated to about 50SC, magnesium peroxy acid [Mg (CI04) 2, 0.2 equivalent] 'was added to produce 3-[(1,1-difluorenyl Ethyl) dimethylsilyloxy] hexahydro-4-methyl-2-oxy-7- (2-propenyl) -2H-azaderma-2-one. Example 34E) The product or product mixture of the above-mentioned Example 3 4 D was treated with trimethyloxyphosphonium tetrahydroborate in CH2C12 and treated according to the method of Example 3 to produce 6-r [(1,1-dimethylethyl) Dimethylsilyloxy 3,4,5,6-tetrahydro-7-methoxy-5-methyl-2H-azafluorene. Example 34F) Example 3 A solution of the title product or product mixture of 4E in MeOH was reacted with the gasified ammonium by the method of Example 5 to produce 3-[(1,1-dimethylethyl) dimethylsilyloxy] Hexahydro-4. Formamidine-7- (2-propenyl) -2H-aza leather · 2-imine, monohydrochloride. This material was treated with a fluoride ion source and the crude product was subjected to reverse phase HPLC chromatography to give the title material. Example 3 5 6-Butyl-3-hydroxy-4-methylhexahydropyridine-2-imine, monohydrochloride Mθ

Printed by the Consumer Cooperatives of the Central Procurement Bureau of the Ministry of Economic Affairs -------- ^-(t first read the precautions on the back & fill in the tile) line example 35A) 6-butyl-4 -fluorene The THF. Solution of hexahydropyridin-2-one was treated with di · third butyl dicarbonate and dimethylaminopyridine (DMAP, 1 eq.) To produce β0 (protected lactamamine, 2-butyl-4- Methyl-6-oxyhexahydro, than dian · 1-carboxylic acid 1,1-dimethyl ethyl ester. -54- This paper size is applicable to the national standard (CNS) A4 specification (210 × 297 mm) ~ ~ ~ ~~-Duozhuo 4j5941 A7 · __ B7 V5. Invention description (52) Example 35B) In the above example 3 5 A the product was dissolved in T HF and cooled to At low temperature, hexafluorenylphosphoramidene (HMP A, 1 equivalent) was added, and then hexamethyldisilazide lithium azide (LHMDS, 1.1 equivalent) was added. 1.2 equivalents of (lS)-(+)-(camphorsulfonyl) · azazepine or (camphorsulfonyl) -humazine were added to give a chromatographically separable diastereoisomer A6- Butyl-3R-hydroxy-4-methyl-2-oxyhexahydropyridine-1-carboxylic acid 1,1-dimethylethyl ester, or isomer B6 -butyl-3S -hydroxy-4-methyl A mixture of stilbyl-2-oxyhexapyridine-dicarboxylic acid 1,1-dimethylethyl ester. Example 35C) The product or product mixture of the above Example 35B was dissolved in DMF and treated with imidazole (2 equivalents) and a third butyldimethylsilyl gas to produce 6-butyl-3-[(l, l-difluorenyl Ethyl) dimethylsilyloxy] -4-methyl-2-oxyhexahydropyridine-1 -carboxylic acid 1,:!-Dimethylethyl ester. Example 35D) The product or product mixture of the above Example 3 5 C was dissolved in acetonitrile and heated to about 50 ° C. Magnesium peroxy acid [Mg (C104) 2, 0.2 equivalent] was added to give 6-butyl-3- [ (l, l-dimethylethyl) dimethylsilyloxy] -4-methylhexaargon p ratio bite -2 -fluorene. Example 35E) The product or product mixture of the above Example 3 5 D was treated with trimethyl borate tetrahydroborate in CH2C12 and treated in the same manner as in Example 3 to give 2-butyl-5-[(1,1-difluorenyl Ethyl) dimethylsiloxy] -6-ethoxy-2,3,4,5-tetrahydro-4 -methyl f ratio bite. Example 35F) Example 3 A solution of the title product or product mixture of 5E in MeOH was reacted with ammonium gasification in the same manner as in Example 5 to produce 6-butyl-3-[(1,1-dimethylethyl) dimethylsilane Oxy] -4 -methylhexahydropyridine-2-imine. This substance was treated with a fluoride ion source, and the crude product was chromatographed by reversed-phase HPLC to produce the standard -55- Wei Zhile scale applicable to the Chinese National Standard (CN'S) A4 specification (2.0 × 297 mm) ~ ------ --- β ------ IT ------ ^ (Xianxianwen #Notes on the side: buy a copy) {V. Description of Invention (53) A7 * B7 Substance. Example 3 6 6 -imino-2,4-dimethylhexapyridine-3-methylamine, hydrochloride CH,

6-Amino-2,4-diamidinopyridine-3-carbonitrile (1.5 g) and platinum oxide (500 mg) in ethanol (30 ml) and concentrated HC1 (1 ml) on a Parr hydrogenation unit at 55 psi Argon was shaken at 5 5 aC for 4 8 hours. The contents were filtered and the filtrate was concentrated in the air to obtain a waxy solid. It was triturated with ethanol to obtain the title substance as a white solid (191 mg). Mass spectrum analysis of C8H17N3: M + H = 156. 1HNMR (D20): iy 3.63-3.40 (m, 2H); 3.20-3.07 (m, 1H): 2.72-2.60 (m, 1H); 2.40-2.25 (m, 1H); 2.05-1.90 (m, 2H) ; 1.25 (d, J = 6 Hz, 3H); 1.00 (d, J = 6 Hz, 3H). Example 3 7 '4,6,' 6-Trimethylhexahydropyridine-2-imine, trifluoroacetate ----------------- (# * 先 闰 读 背 * 的Note ^% write this page) to set the economy. Then the Central Bureau of Standards Consumer Cooperatives India policy CH ,,

56. This paper size is in accordance with Chinese National Standard (QVS) A4 specification (2 丨 0 X 29.7 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 415941 A7 ______B7 V. Description of the invention (54) Example 37A) 2,2, A solution of 4-trimethylcyclopentanone (5.5 g, 44 mmol) in 35 ml of EtOAc / 25 ml of water was treated with hydroxylamine hydrochloride (46 g, 66 mmol) and sodium acetate trihydrate (1.0%). 8 grams, 79 millimoles) under reflux for 4 hours under nitrogen. After the solvent was removed by evaporation, the residue was redissolved in 1000 ml of Eto-Ac, washed with a saturated aqueous solution of sodium vaporization, and dried over magnesium sulfate. All solvents were stripped to obtain 5.6 g of a white powder, 2, 2 , 4-Trimethylcyclopentanone. 1: 8 8/1 ^: (MH +) = 142. Example 3 7B) The product of Example 37 A was dissolved in 50 ml of acetone and 50 ml of 1 N sodium hydroxide at 0X. Toluenesulfonium (7.8 g, 44 mmol) was added in 5 minutes. The reaction mixture is warmed and stirred for 18 hours until it is complete. It is determined by HPLC retention time shift (Vydac C-18, linear concentration gradient 5 to 75% acetone / 0.05% D? Eight in water / 0_05% D Eight, in 20 minutes). The solvent was removed by evaporation, and the residue was redissolved in 100 ml of EtO Ac, dried with saturated aqueous sodium vaporization solution and dried over magnesium sulfate to strip all the solvent by evaporation. The crude semi-solid material was purified on Waters Deltapak C-18 using a linear concentration gradient of 10% to 15% acetonitrile (0.05% TFA) in water (0.05% TFA) for 20 minutes. The freeze-dried product 4,6,6-trimethylhexapyridin-2-one was a yellow-brown semi-solid, 0.47 g, FAB / MS: (MH +) = 142. Example 37C) To the product of Example 37B (3.3 mmol) was added trimethyloxyphosphonium tetrafluoroborate (0.6 g, 4.0 mmol) in 10 ml of CH2C12. After stirring for 18 hours, the reaction mixture was diluted with 10 ml of CHjCl2, washed with a saturated aqueous potassium carbonate solution, dried over magnesium sulfate, and all solvents were stripped to yield 2,3,4,5_tetrahydro-6-methoxy-2. , 2,4 · trimethylpyridine. -57- The standard of this paper is applicable to the Chinese National Standard (CNS). Λ4 is now (2 丨 0X297mm). -------------------- II _ * / t * ^ (Please read the back first (Please fill in this page again) 4U941

Al '______B7_ V. Description of the invention (55) Example 37) Example 37 The product of 7 C · Dissolved in 25 ml of methanol and refluxed with ammonium gas for 3 hours. The solvent was removed by evaporation, the residual oil was dissolved in 25 mL of EtOAc, washed with water, and all solvents were stripped under reduced pressure to give a crude product. This material was purified on Waters Deltapak C-18 using a linear concentration gradient of 5% to 70% acetonitrile (0.05% TFA) in water (0.05% TFA) for 30 minutes and freeze-dried to obtain 0.075 g of the title material as a white dry powder. FAB / MS: (MH +) = 141. ^ NMR (CDC13): ά 10 4 (bs, 1Η); 9.7 (bs, 1H); 7.5 (bs, 1H); 2.6 (q, 1H); 2.0 (q, 2H); 1.8 (d, 2H); 1.4 (s, 3H); 1.3 (s, 3H); 1.1 (d, 3H) »Example 3 8 4,4,6-Trimethylhexahydropyridine-2-subcutaneous, trifluoroacetate pack-( (Ten first X reading ^ Face: 1 Italian matter ¥ fill in Tai Xuan)

.CF3e〇2H Printed by the Central Bureau of Standards, Ministry of Economic Affairs, Shellfish Consumer Cooperative, Example 38A) Solution of 2,4,4-trimethylcyclopentanone (5.5 g, 44 mmol) in 35 ml of EtOAc / 25 ml of water Hydroxylamine hydrochloride (4.6 g, 66 mmol) and sodium acetate trihydrate (10.8 g, 79 mmol) were refluxed under nitrogen for 4 hours. The solvent was removed by evaporation, and redissolved in 100 mmol (L of EtOAc, washed with a saturated aqueous sodium vapor solution, dried over magnesium sulfate, and the solvent was transferred to obtain 6.2 g of a white powder, 2,4,4-trimethyl ether. Cyclopentanone oxime b faB / MS: (MH +) = 142. Example 3δB) Example 3 The product of 8 A was dissolved in 50 ml of acetone and 50 ml of 1 N argon '-58-. Standard (〇 \ 5 to 4 specifications (2) 0 > < 297 public meetings) '~~ 419941 A7 ____B7 V. Description of the invention (56) Sodium oxide in 0 ° C. Benzenesulfonium gas (7.8 g, 44 milligrams) Mol) was added within 5 minutes. The reaction mixture was warmed and turned off for 18 hours until complete, measured by HPLC retention time shift (VydacC-18, linear concentration gradient 50/0 to 75% acetonitrile / 0.05% TFA in water / 0.05% TFA in 20 minutes). The solvent was removed by evaporation, and the residue was redissolved in 100 ml of EtO Ac, washed with a saturated aqueous sodium vaporized solution, slowly dried with sulfuric acid, and evaporated to strip all solvents. Semi-solid material was purified on Waters Deltapak C-18 using a linear concentration gradient of 10% to 15% acetonitrile (0.05% TFA) in water (0.05% TFA) for 20 minutes The freeze-dried product 6,6,4-trimethylhexahydropyridin-2-one was a yellow-brown semi-solid, 0.75 g, FAB / MS: (MH +) = 142. Example 38C) The product of Example 8B (5.3 Millimoles) To 15 ml of CH2C12 was added trifluorenyl tetrafluoroborate salt (0.9 g, 6.0 millimoles). After stirring for 18 hours, the reaction mixture was diluted with 15 ml of CH2C12, washed with saturated aqueous potassium carbonate solution, dried over magnesium sulfate, and all solvents were stripped to yield 0.69 g of 2,3,4,5-tetrahydro-6-formaldehyde Oxy-2,4,4-trimethyl p is more oily than fluorene. Printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs, Example 3 8) Example 3 The product of 8 C was dissolved in 25 ml of methanol and refluxed with gasified ammonium (0,25 g, 4.6 mmol) for 3 hours. The solvent was removed by evaporation, the residual oil was dissolved in 25 ml of EtO Ac, washed with water, and all solvents were stripped. The residue was linearly concentrated on a Waters Deltapak C-18 using 5% to 70% acetonitrile (0.05% TFA). It was purified in water (0.05% TFA) for 30 minutes and freeze-dried to obtain 0.66 g of the title material as a white powder. : FAB / MS: (MH +) = 141 α 1K NMR (CDC13): 10.4 (bs, 1H); 9.5 (bs, 1H); 8.1 (bs, 1H); 3.8 (m, 1H); 2.3 (q, 2H) ) J 1.75 (d, 2H); 1.3 (d, 3H); -59- This paper is A degree applicable to Chinese National Standard (CNS) A4 specification (21 OX W7 mm) mm A7, B7 V. Description of the invention (耵) 1 · 1 (s, 3H); 1.0 (s, 3H). Example 3 9 3- (2-Butenyl) hexahydro-5_imine-azepine-6-ol, trifluoromalate

Isomers-A Printed by the Consumers' Cooperative of the China Standards and Quarantine Bureau, Ministry of Economic Affairs, Example 39A) Example 3- (2-buten-1-yl) -5-oxy · 2,3,4,5,6, Sample of 7-Hydrogen-1,4 · »azepine product (6.6 g, 39 mmol) 'Di-tertiary butyl diacid (17.5 g, 80 mmol) and 4-dimethylamine Pyridine (200 mg) was refluxed in anhydrous THF (80 ml) overnight. The contents were cooled, diluted with EtOAc ', washed with 5% NaHC03 aqueous solution, dried over MgS04, and concentrated in the air to obtain an oil (2,9 g). The oil was chromatographed on silica gel and dissolved at 100 / 〇 £ 108 / hexane to obtain 4- > [-180 (:-3- (2-buten-1-yl) -5_oxy -2,3,4,5,6,7-Hexahydro-1,4-Azapine 'was a colorless oil (37 g). Example 39B) 4-NB in Example 39A -Butyl · 1_yl) · 5 · oxy-2,3,4,5,6,7-hexaargine_1,4_pyridazine product (31 g, 12 mmol) in water THf (60 ml) was added dropwise at -7 § § Lithium bis (trimethylsilyl) amide (1 M in THF, U ml), and the temperature was kept below -7 τ. The contents are warmed to -4 0 C and then cooled to _ 7 8. (〖§) _ (+) _ (i 〇 一 -60- This paper size is applicable; National Standards (CNS) A4 specifications. (210x ^ 97 male ginger " 7 Ministry of Economic Affairs Central Standards Bureau Off-duty Consumer Cooperative) Print A7 ______ Β7 V. Description of the invention (58) A solution of camphor sulfonyl) pyridine acridine (3.0 g, 13 mmol) in THF (30 ml) was added. The contents were heated to _ 2 5 ec, stirred 3 Hours, then poured into saturated NH4C1 'extracted with EtOAc. The EtOAc layer was dried over MgS04 and concentrated in the air to obtain 4-NBOC-3- (2-buten-1-yl) -6-hydroxy-5- Oxy-2,3,4,5,6,7-hexahydro-1,4-pyridazine, as a waxy solid. Example 39C) 4-NBOC-3- (2-Butane of Example 39B) Ene-1 -yl) -6-hydroxy-5-oxy-2,3,4,5,6,7 · hexaargine-1,4-pyridazine (600 mg), tert-butyldimethyl Stiff base gas (2.0 g), Mijun (1.6 g) and anhydrous THF (50 ml) were stirred overnight. The contents were partitioned between EtOAc and water * The EtOAc layer was dried over MgS04 and concentrated in vacuo to produce an oil. This oil is on silicone at 25% £ 108. / Hexane separation chromatography to obtain 4-] ^-; 80 (:-3- (2-buten-1-yl) -6- (third butyldimethylsilyloxy) -5-oxy- 2,3,4,5,6,7-Hexahydro-I, 4-Hentaza leather, oily (400 mg). Example 39D) 4-N-BOC-3- (2 · D) of Example 39C Fluoren-1-yl) -6- (tertiary butyldimethylsilyloxy) -5-oxy-2,3,4,5,6,7-hexaargon-1,4-indazine ( 400 mg, 1 mmol) and magnesium peroxyacid (45 mg) were heated at 50 ° C in CH3CN (25 ml) for 3 hours. The contents were cooled and partitioned between EtOAc and water. The EtOAc layer was dried over MgS04, and concentrated in the air to obtain 3- (2-buten-1-yl) -6- (second butyldimethylformamide milkyl) -5 -oxy · 2,3,4, 5,6,7-Hexahydro-1,4-Hazaza leather, oily (300 mg). Example 39) 3- (2-butene-butyl) -6- (third butyldisilyloxy) -5-oxy-2,3,4,5,6,7-hexade of Example 39D The hydrogen-1,4-arsenazine product (300 mg, 1 mmol) and Me3O + BF4- (150 mg'1 mmol) were stirred in CH2C12 overnight. The contents are concentrated in the air, and the residue is dissolved in A-61.-This paper has a Chinese standard. (CNS) A4 size (210X297 mm) --------- ^ ----- ---. 11 ------ line (please read the notes on the back to write this page) {415941 A7 -B7. V. Description of the invention (.59) In alcohol, anhydrous ammonia bubbling into the solution . The reaction mixture was stoppered and stirred overnight. The contents were concentrated in the air to obtain a yellow oil (366 mg). The oil was purified by C-18 reverse phase chromatography with (: 113 €) ^ 1120 to obtain the title product of Example 39 (Isomer A, 16 mg) and the title product of Example 40 (Isomer B, 1). 1. mg.), Mass spectrum analysis of β C9H16N202 as oil: M + Η = 185 »^ NMR (D20): ά 5.60-5.42 (m, 1H); 5.35-5.20 (m, 1H); 4.75-4.60 ( m, 1H); 3.95-3.50 (m, 5H); 2.35-2.20 (m, 2H); 1.60-1.45 (m, 3H). "Example 4 0 3- (2-butenyl) hexahydro-5- Imine-1,4-Hazaza-6-ol'trifluoroacetate

Printed by the Employees' Cooperatives of the Central Government Bureau of the Ministry of Economic Affairs

Isomer B The crude product of Example 39 was purified by C-18 reverse phase chromatography with CH3CN / H20 to obtain the title product of Example 39 and the title. Product of Example 40 (Isomer B, 11 mg). Mass spectral analysis of C9H16N202: M + Μ = 1β5. f lK NMR (D20): ά 5.65-5.45 (m, 1H): 5.35r5.20 (m, 1H); 4.90-4.75 (m, 1H); 3.90-3.45 (m, 4H); 3.35-3.20 (m ， .LH): -62- This paper size is applicable to China National Standard (CN'S) A4 (210X297mm) Printed by the Consumers' Cooperatives of the Central Standards Bureau of the Ministry of Economy ¾ 41 ^ ft. A7. ------. 87____ V. Description of the invention (60) 2.25-2.05 (m, 2H); 1.60-1.45 (m, 3H). Example 4 1 Butyl) Hexargon · 1,4-Hazepine-5-imine, three Fluoroacetate

The title substance% was prepared according to the procedure of Example 18 using the 6- (2-butenyl) tetrahydro-1,4-oxinazapine-5 (2fluorene) -one isolated in Example 17. C9Hl6N20tf spectrum analysis: μ + Η = 169. ^ NMR (D2 °): ί 5.65-5.50 (m, iH); 5.40-5.20 (m, 1H): 3.95-3.25 (m, 6H) '2.80-2.6.0 (m, lH); 2.50-2.30 ( m, 2H); 1.60-1.50 (m, 3H). Example 4 2 3 -Butylhexahydro-1,4-azapyridine-5-imine, trifluoroacetate

The product of Example 18 (1.3 g, (6 mmol), 5% germanium / carbon (400 mg), ethanol (30 ml), and glacial acetic acid (30 ml) on a Parr argonizer at 55 p si hydrogen < Shake overnight. The contents of the reaction are filtered, and the filtrate is concentrated in the air to obtain an oil ----------------- ($ first κ read f-vg; i meaning ^% write this f) Order Line • 63- 4ii $ 4i A7 'B7 V. Description of the invention (61) (1.1 g). The oil was purified by C-18 reverse phase chromatography with ch3cn / h2o and the title product was obtained as an oil (701 mg, 54 % Yield). Mass spectral analysis of C9H1SN20: M + H = 171. LH NMR (CDC13): ^ 8.90 (s, 1H); 9.50 (s, 1H); 8.90 (s, 1H); 4.00-3.40 (m, 6H); 3.00-2.70 (m, 2H); 1.80-1.20 (m? 6H) 1.00-0.80 (m, 3H). Example 4 3 Hexahydro-5-imino-l, 4-® _3_ Ethylamine, bis (trifluoroacetic acid) salt ------------ Install I (^ • Read the notice on the back first ^ ΓFill in this page

-ο Printed by the Shellfish Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 54 Example 43A) Add 2-nitroethanol (Aldrich, 50 ml, 0.7 mol) in CH2C12 (50 ml) dropwise with ethyl alcohol-containing base gas (53.3 ml) , 0.75 moles) of CH2C12 (50 ml). The contents were stirred overnight, washed with water, dried over MgS04, and condensed in the air to obtain ethyl 2-nitroethanol as a pale yellow oil (86 g). Example 43B) A sample of tetrahydropiperan-4-one (Aldrich, 30 g, 0.3 mole) and morpholine (Aldrich, 3 0.5 ml, 0.35 cold ear) were refluxed in bulk (500 ml) for 3 hours. Collect water by Dean Stark. The contents are cooled and concentrated in the air. The residue was dissolved in acetonitrile (250 ml), and the solution of the acetamidine-2 · nitroacetic acid product (46.6 g, 0.35 mole) in acetonitrile (250 ml) of Example 43 A was added dropwise to- 20 ° C. The reaction contents were stirred overnight and rose to room-64- This paper size is applicable to China National Standard (CNS) A4 size (2I0X297 mm) '" Printed by A7' 67 '"; 丨, II-I 丨 丨 'am 5. Description of the invention (62) Wen' concentrates in the air. The residue was partitioned between Et20 and water = ether layer was dried over MgS04 and concentrated in the air to obtain an oil. The oil was distilled on a Kugelrohr apparatus at 100 ° C (0.1 mm) to obtain 2-nitroethyltetrahydropiperan · 4-one, which was 'oily' and partially cured (20.9 g). Example 43 C) Example 4 The 2-nitroethyltetrahydrotripan-4-one product of 3B was refluxed with amine-o-sulfonic acid and formic acid (98%) for 0.5 hour. The contents were cooled and concentrated in the air. The residue was partitioned between CH2C12 and water. (: 112 (: 12 layers were dried over MgS04 and concentrated in the air. The residue was purified by C-18 reverse phase chromatography to obtain 3- (2-nitroethyl) -5-oxy-2,3,4, 5,6,7-Hexahydro-1,4-fluorenazazepine. Example 43D) In Example 4 3 3-(2-nitroethyl) -5 -oxy- 2.3.4.5.6.7- hexa The product of hydrogen-1,4-hemazine leather was added to (: 112 <: 12 (25 ml) Me30 + BF, and the contents were stirred overnight. After concentration in the air, the residue was dissolved in methanol (25 ml) Anhydrous ammonia was bubbled into the solution. The contents were stoppered and stirred for 72 hours. The contents were concentrated in the air and the residue was subjected to C-18 reverse phase chromatography with a CH3CN / H20 concentration gradient (0.05% TFA). Isolation and purification 'to obtain 3- (2-nitroethyl) -5-imino-2,3,4,5,6,7-hexahydro-i, 4-pyridazine. Example 4 3) Example Sample of 4 3 D 3-(2-nitroethyl) -5 -imino- 2.3.4.5.6.7- Hexahydro-1,4-Hazepine product and palladium black in ethanol at 55 psi Hydrogen was shaken overnight on a parr aerator device. The contents were filtered and the filtrate was concentrated in the air. The residue was purified by C-18 reverse phase chromatography to obtain the title compound. Zhang scale is applicable to China National Standard (CNS) A4 specification (210X 297 mm) (^. Please read the notes on the back to write this page. _ V. Description of the invention (63) Example 44 (±) 3β-methoxy · 4α-methyl-5β-pentylhexahydro. 11 pyridine-2-imine monohydrochloride

Example 44 was prepared from Example 45e, methyl iodide, and sodium argon. The synthesis of Example 44 was performed in the manner described in Example 45. Example 45 (±) 2-imino-4α-methyl-5α · pentyl-3α-pyrrolidinol, monohydrochloride

Example 45A) DBU (2_39 ml, 16.0 mmol) was added to a stirred solution of crotonic acid (3.28 g, 3 2.8 mmol) and nitropyrene (1.08 g '16 .0 mmol) in 20 ml of CH3CN. . After 72 hours, the reaction mixture was concentrated under reduced pressure. The residue was taken up in EtOAc. The EtOAc solution was washed with 0.5N HC1 and brine, dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain 3.05 g. -66-This paper size is applicable to China National Standard (CNS) A4 specification (210X 297mm) ~~. ΜII (+ Precautions for reading on this page) ----- 1-i--i I -I- t-: Hi 11--1 -----. A7 4ί9 $ 4 \ _______B7 V. Description of the invention (64) Example 45B, C) Example 45A (34 g, 0.15 mole) under catalytic argonization conditions Reduction using Raney Ni in MeOH. After the reaction mixture was heated at 55t for 16 hours, the solvent was removed under vacuum. Crude lactam was separated into cis (45B) and trans (45C) lactam by column chromatography. Example 45) Example 453 (20 g, 0.12 mol), (30 (: 0) 20 (38.7 g, 0.18 mol) 'DMAP (14-4 g, 0.12 mol) was infused in 500 ml of THF The solution was heated at reflux for 3 hours. After the reaction mixture was concentrated under vacuum, the residue was taken up in EtOAc, washed with KHS04 and brine. The organic layer was dried over hot Na2S04, stripped, stripped. The crude product was purified by column Analytical purification yielded 31 g. Example 45E) In Example 45D (2.7 g, 9.9 mmol) and UMPA (1.8 g, 1.0 mmol) were cooled to -7 (TC in 15 ml) To the stirred solution was added 7 g of lithium hexamethyldisilazide (10.0 mmol). After 20 minutes, the reaction mixture was heated to -40 ° C and then cooled to -70 ° C. To the stirred solution was added (R)-(-)-(camphorsulfonyl) azepine (2.4 g, 10.4 mmol) in 7 ml of THF. After stirring at -7 0 ° C for 30 minutes, the reaction mixture was heated to 30 ° C and stirred for 2.5 hours. To the reaction mixture was added a saturated NH4C1 solution and then EtOAc. The organic layer was washed with brine, dried over anhydrous Na2S04, filtered, and stripped. The crude product was purified by column chromatography to obtain 1.3 g of 3-hydroxylactam. Example 4SF) To a solution of Example 45E (1.3 g) in CH2C12 was added T F A (6 ml). After 2 hours, the reaction mixture was concentrated under vacuum to obtain 0,85 g of product. Example 45G) In Example 45F (0.S5 g, 4.6 millimolar) and imidazole (0.35 g, -67-this paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm 1 ...... — (read first) Read the note on the back ^ This page]-Install · Printed by the 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 A7 B7. V. Invention Description (65)-4.6 millimoles) To a stirred solution in 15 ml was added tert-butyldimethylsilyl base gas (0.70 g, 4.6 mmol). After 18 hours, the reaction mixture was concentrated under high vacuum. To the residue was added EtOAc. Organic layer KHC03 solution 'washed with water and brine' was dried over anhydrous Na2S04, filtered, and stripped to obtain 1.1 g of product. Example 45H) Example 45 G (1.1 g, 3.7 mmol) and trimethyloxyphosphonium tetrafluoroborate ( A solution of 0.6 g, 4.7 mmol) in 30 ml was stirred at ambient temperature for 72 hours. After the solvent was removed in air, the residue was dissolved in EtO Ac. The organic layer was washed with KHC03 solution and brine, and dried with water. Na2S04 was dried, dried, stripped, and produced 1 g of product. Example 4 51) Example 45H (1 g) in MeOH with NH4C1 (0.3 g) at 12

Processed under Kbar pressure. The reaction mixture was concentrated under vacuum. The residue was taken up in CH2C12 *, filtered and stripped to obtain 0.8 g of product. Example 45) To a solution of Example 451 (0.8 g) in 40 ml of MeOH was added 10 ml of IN HC1. After 1.5 hours, the reaction mixture was concentrated under vacuum. The residue was partitioned between 0.5 NHC1 and CH2C12, and the aqueous layer was stripped. The residue was purified by chromatography on a reverse-phase C-18 column to obtain two alcohols. The first eluate is Example 4 6 and the second eluate is Example 4 5. Elemental analysis: C10H20N2O · 1 HC1 · 〇 · 2 H20 (MW = 224,35) C Ν Ν C1 Calculated 値: 53.80 9.61 12.49 15.80 Measured 値: 53.80 9.47 12.14 15.46 Example 4 6 (±) 2-imino-4 -Methyl-5 £? -Pentyl- -3 points -ρ biha 'bitanol,--68- _ _ _ --------------------- ------ --1 '" ** The size of this paper is suitable for households (CNS) A4 specification (210X297 male thin) --------- ^ ------- ir ----- " — 线. * {If closing the t-face precautions ^ (Fill in this X) (Printed by the Central Laboratories Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperative, 415941 A7 " B7 .... ............------------ 5. Description of the invention (66)

The synthesis and isolation of Example 46 are described in Example 45 »Elemental analysis: C10H20N2O · 1 HC 0.2 H2〇 (MW = 224.35) C .Η Ν C1 Calculated 値: 53.80 9.61 12.49 15.80 Found 値: 53.78 9.37 Example 4 7 12.14 15.78 ( ±) 2-imino-5α-pentyl-4 /?-(Trifluoromethyl) · 3α monohydrochloride-pyrrolidine,

Example 47A) Ethyl 4,4,4-trifluorocrotonate (10.0 g, 59 mM), 1-Nitrogen (7.86 g, 60 mM), K2C03 (4.1 g), and Aliquot 336 ( 6 drops) sonicated for 5 hours. Et20 (200 ml) was added to the reaction mixture. The reaction mixture was filtered and extracted with brine, dried over Na2SO4 (anhydrous), filtered, and concentrated under reduced pressure to obtain a yellow liquid. The product was purified by column chromatography to obtain 13.8 g (77%). . -69- The standard of this paper is applicable to Chinese National Standard (CNS) A4 (210X297 male) ~ --- Seed clothing ------ iT ------ line- * (Please read the Note ΓΓFill in this page) 415941 Α7 Β7 V. Description of the invention (67) Example 47B, C) Example 47A (13_〇g) in MeOH solution under catalytic & chemical conditions (60 psi, 55 ° C) Reduction 3 After the reduction of nitrate, the reaction mixture

I Heated for 8 hours for cyclization. After the reaction mixture was concentrated under reduced pressure, the residue was purified by column chromatography to obtain 9.0 g of a pale yellow liquid. The second column was used to separate cis' (47B) and trans-lactam (47C). Example 47D) Example 4 7 C was treated as Example 4 5 D to prepare Example 4 7 Elemental analysis: c10h17n2f3-〇 · 1] HC1_ (MW: = 274.71) C .Η Ν Cl Calculated 値: _ 43.72 6.60 10.20 12.91 Found Tritium: 43.62 6.44 10.15 12.73 'Example 4 8 Hexahydro-5-imino · cold · phenyl-1,4-henazapyridine_3 · Ethylamine, bis (trifluoroacetic acid) salt-d Ministry of Economic Affairs印 Standards Bureau Shellfish Consumer Cooperation Du Yince

NH .2TFA

The title product is based on Example 43-Ethyl I-nitroethanol, and the sequence is shown in the following example, and phenylphenylene is replaced by ^-(3,4-diargon-211- | »Bilo-Example 4 9) Hexahydrogen -5 · imino group q 4 -Gas-aza-70- This paper rule is applicable to China National Standard (CNS) A4 specification ΠΤο ^ Τ ^ Γ " 415941 A7 B7 V. Description of the Invention (Book) Leather-3-Ethylamine , Bis (trifluoroacetic acid) salt

NH Example 43 was reacted with .2-methoxypyrroline to obtain the title product ... Example 5 0 3 _ [[2- (hexahydro-5-acidylene-1,4 -57 aza leather-3-yl) ethyl] amino] alanine, tris (trifluoroacetic acid) salt Please · Read the back, the notes, fill in 'Write this page

H02C

Printed by Shelley Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs, Example 50A) Example 4 3 was reacted with N-C B Z -desarginine methyl ester to obtain the protected title product. Example 50) The CBZ protecting group was removed from Example 50A by hydrogenation and then acid hydrolysis to obtain the title product. Example · 5 1 Hexahydroimino-1,4-Hazepin-3-yl) -2-phenethyl] amino] alanine, tris (trifluoroacetate) salt-71-Applicable for paper size China National Standard (CNS) Α4 Specification (2 丨 0X297 mm―) 415941 A7 B7 V. Description of Invention (69

NH Example 51A) Example 48 was reacted with n-Cbz-dehydroalanine methyl ester to obtain the protected title product. Example 5 1) The CBZ protecting group was removed from Example 5 1 A by hydrogenation and then acid hydrolysis to obtain the title product. Example 5 2 2- (Hexahydro-5 · imino group, 4-hexazepine) cyclohexylamine, bis (trifluoroacetic acid) salt

NH Please read it first. Please fill in the pages on the back of the book to order the title printed by the Consumers Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. Based ethanol. Prepared. Example 5 3 /? Cyclopropylhexahydro-5-imino-1,4-azaaza leather-3-ethylamine, bis (trifluoroacetic acid) salt 72- This paper size is applicable to China National Standards (CNS ) A4 specifications (2 丨 〇χ 29? Mm) 415941 A7 B7 V. Description of the invention (70)

^ NH.2TFA Example 53 A) 2-Nitro-2-cyclopropylethanol was prepared from cyclopropylcarboxyl via Henry reaction. Example 53) The title product was prepared by the method of Example 43 using the 2-nitro-2-cyclopropylethyl product of Example 5 3 A in place of the 2-nitroethanol. • Example 54 α-hexylhexahydro-5-imino · wan-methyl _ aza leather · 3_ethylamine, bis (trifluoroacetic acid) salt

Ν ΝΗ Π Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs

.2 The TFA title product was prepared by the method of Example 4 3 'using 3 -nitro-4 -hydroxypentane in place of 2 -ethanol. Β 5 5 2- (hexahydro-5-imino. Pyridazine-3-yl) cyclohexylamine, bis (trifluoroacetic acid) salt-73- This paper rule money standard ^ Τ ^ (210χ 297mm 415941 A7 * ___ — _B7______ V. Description of the invention (71)

NH η

2TFA Example 55A) Tetrahydropiperan · 4-one was reacted with o-nitrobenzyl bromide under basic conditions' to obtain 2- (o-nitrobenzyl) tetrahydropiperan-4-one. Example 55B) Example 5 5 a 2-(-o-nitrobenzyl) tetrahydropiperan-4-one product was performed as in Example 4 3 C-D to obtain 3-(o-nitrobenzyl ) -5 -imino-2,3,4,5,6,7 "hexahydro-1,4-gashybrid leather. Example 55) Example 55 3- (o-nitrobenzyl) -5-Iminide-2,3,4,5 7-hexaargon ·, 4-henaza leather product was reduced under hydrogen pressure using a platinum oxide catalyst to obtain the title product. Example 5 6 Hexahydro- 5-Iminino-fluorene- (2-thienyl) -1,4-indazine-3-ethylamine, bis (trifluoroacetic acid) salt H2N

(11 notes on the back of Mu Xianmin read this page ¾ page) Binding and printing The title substance printed by the Central Standards Bureau of the Ministry of Economic Affairs and Consumer Cooperatives printed the title substance according to the procedure of Example 48 using 1-nitro-2- (2-thiobenzene Based) ethylene production. Example 5 7 < ^-Amino group 7 ^ Aza-5-imino group-/?-(2- > 1 sphenenyl) -1,4- (No. 1 azazol-3-- -74- This paper size applies to China National Standard (CNS) A4 specification (210X 297 male #) 415941 A7 B7 V. Description of the invention (72) Propionic acid, bis (main fluoroacetic acid) salt

Please read it first and note the matter. 'Example 5 8 (Aminomethyl) hexahydro-5-imino-1,4-Hazepine-3-methanol, bis (trifluoroacetic acid) salt I Hold

.2TFA- Example 5 9 -imino-3,7-diazaspiro [5.6] dodec-9-ol, dihydrochloride

7- (spiro-4-hexahydropyridyl-N-Z) caprolactam was treated as described in Example 34 to obtain the title compound. -75- This paper size applies Chinese National Standard (CNS) Α4 size (210 X 297 mm) Printed by the Central Standards Bureau of the Ministry of Economic Affairs Printed by the Shellfish Consumer Cooperative, Printed by the Central Standards Bureau of the Ministry of Economic Affairs Printed Example 60A) Example 4 3 The product of C was reacted as in Example 39 to obtain 3- (2-nitroethyl) hexahydro-5-imino-1,4-, azapine-6-ol. Example 60) 3-(2-Nitroethyl) hexagon-5 -imino-1,4-henzapine-6-ol was reduced as in Example 4 3 to obtain the title compound. Example 6 1 Hexahydro-5-imino-3- [2-[(2-pyrrolidinyl) amino] ethyl] -1,4-azepine-6-ol, bis (trifluoro Acetic acid salt) The product of Example 60 was reacted as in Example 49 to obtain the title compound. Example 62. 3- (2-Amino-1-phenethyl) hexahydro-5-imino-1,4-pyridazine-6-ol, bis (trifluoroacetic acid) salt-76 -415941 A 7 'B7 V. Description of the invention (73) Example 6 0 3- (2-aminoethyl) hexahydro-5-imino-1,4-p-azaaza-6-ol, bis (Trifluoroacetic acid) salt

This paper size applies to China National Standard (CNS) A4 specification (210X297 mm). Buttoning. * Thread * (Notes on the first side of this page) (415941 A7 B7 V. Description of the invention (74)

Example 62A) 3 · (2-Citylbenzylethyl) -5-oxy · 2,3,4,5,6,7-hexakis''heterodermic system is used as in Example 4 3 Ethyl Substitute] -Ethyl-2-Aryl ethanol. Example 62B) 3- (2-Nitro, # _ 肖 暴 -1-% 基 ethyl) -5 -oxy-2,3,4,5,6,7-hexahydro_1,4 · hum nitrogen The heterofluorene system was reacted as in Example 39 to obtain 3- (2-nitro-1-benzylethyl) -6-¾yl · 5 · imino- ^ hexylhexahydro- ^ azepine 6 2) 3-(2 -nitro, i _phenylethyl) _ 6 _hydroxy_ 5 _imino_ 2,3'4,5,6,7-hexahydro-1,4-henyl nitrogen Miscellaneous leather was reduced as in Example 43 to obtain the title compound. · Example 6_3 (±) 2-Imine 4 4α- (trifluoromethyl) -fluorenyl pyrrolidinol --------- ^ -------- 1τ ----- -0 " (Please read the note on the back "^^; script 苋) (printed by the Central Ministry of Economic Affairs and Consumer Cooperatives)

Example 63 was synthesized and separated from Example 4 7-77- This paper size is in accordance with Chinese National Standard (CNS) A4 specification (21 ° dog 297 mm) 415941 • Α7 — ___________ Β7 V. Description of the invention (75) Example 6 4 (土) 2-imino ~ 4々- (trifluoromethyl) -5y5 · fluorenyl pyrrolidine-3α-ol

Example 6 4 was prepared from Example 4 7 B in the manner of Example 47. Example 6 5 (±) 2-imino · 4 α (trifluoromethyl) -5 α-pentylpyrrolidine < ^ alcohol H〇, CF3

NH

HCI Central Standards Bureau Employees' Cooperative Printing Bags Example 6 5 was prepared from Example 4 7 B in the manner of Example 47. Example 6 6 (±) 2 -imino-4 / 5 -methyl-5 彳 -pentylpyrrolidin_3 α -alcohol

Example 6 6 was prepared from Example 4 5 C in the manner described in Example 45. -78- This paper size applies to China National Standard (CNS) A4 specification (210X297 public celebration)

41594J A7B7 V. Description of the invention (76) Example 6 7 (±) 2 -imino-4λ-fluorenylpentyl pyrrolidine_3α_ol

Example 6 7 was prepared in the manner described in Example 4 5 C #Example 4 5. • Example 6 8 (±) 5 «-(3-Aminopropyl) -2-imino_4but_methylpyrrolidine_3 ubiquinol

NHg Economy. Xing Yinyang Standard Bureau Employee Consumer Cooperative Cooperative Example 6 9 (Shi). 5 β-(3-aminobutyl) -2 -imino-4 α -methyl! R bilo bite-3 α- alcohol

-79 The paper size is applicable to Chinese National Standard (CNS) Α4 specification (210X297 mm) V. Description of invention (77 A7 B7

Example 7 1 (Earth) -Amino-4 tv-Kidyl-5-imino-3 -methyl eicosine bite 2 β-Butyric acid methyl ester, dihydrochloride

7 Example 7 2 (±) 2-imino-4α-methyl-5β-amidinopyrrolidin-3α-amine, dihydrochloride --------- I-- (Please read first " * Notes on this page)

Line -1T Printed by the Central Standard of the Ministry of Economy

Η Example 72 was prepared from Example 45E and Boc2NH under Mitsunobu reaction conditions. The synthesis of Example 72 was completed in the manner described in Example 45. -80-This paper size applies to China National Standard (CNS) Α4 size (210X 297mm)

Η 415941 A7 B7 V. Description of the invention (T8) Example 7 3 (±) 5-imino-4α-fluorenyl-2β-pentylpyrrolidine-3α-alcohol dihydrochloride NHc Example 7 5 (±) 2_imino-4α-fluorenyl-5, -pentylpyrrolidine3α-carboxylic acid hydrochloride (Please read ^ Notes on each side ^^ Also write this page) t Printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs

-81-This paper size is in accordance with Chinese National Standard (CNS) A4 (21 OX 297 mm) 415941 A7 B7 V. Description of the invention (79) Example 7 6 (Earth) 2-Imino-4α-methyl -5α · pentylpyrrolidine-3α -methanol, monohydrochloride

Η Example 7 7 (Earth) 5 α-[3- (4,5 · diazine-1Η-Weitu-2 -yl) two groups] · 2-Imine-4 Methyl-Methylpyridine · 3α · Alcohol's dihydrochloride

Pyridine α-alcohol, dihydrochloride — * Pack one i (" No reading r side:; i Italian matter < fill in too many pages) D-'1 · line Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

82- This paper size is in accordance with Chinese National Standard (CNS) A4 (210X 297 mm). Printed by the Bayer Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 415941 A7 _B7_____ V. Description of the invention (80) Example 7 9 (±) 5α- [3-Amino-3- (1'-imidazol-2-yl) propyl] -2-imino-4α-methylpyrrolidine-3α-alcohol, trihydrochloride Γ

Example 80 (±) 2 · imino-4β-methyl [(phenylfluorenyl) amino] propyl] -bilolide- 3π-alcohol, dihydrochloride

Example 80A) cis and trans-5: [(1,3-dioxolane-2-yl) fluorenyl] · 4- (fluorenyl) pilolide-2 -one ketone.0111 ' 16111, '\ ^. 8 £; 11 \ ^ 1 >, 11, £ 111 ^ 1 ",' 7. Jager, Synthesis 1986, 535-538 in the manner described in ι, ι · dioxo-3 -Nitropropane and crotonic acid methyl esters are prepared initially. Example 80B, C) Example 80A. Reduction in MeOH using a ruler under catalytic hydrogenation conditions. The reaction mixture was heated at 55 ° C for 1.6 hours, and the solvent was removed under vacuum. Crude lactam was separated into cis (80B) and trans (80C) lactam by column chromatography. -83- This paper size applies to Chinese national standards (CNS > Α4 size (210X297 mm) ~ '-------- i ^ -------- IT ------ ^ < Write this page as the first notice ¾ Note on the back) {Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 415941 A7 '—______ B7_ V. Description of the invention (81) Example 80D) Example 80B, (BocO) 20, DMAP The stirred solution in THF was heated at reflux for 3 hours. After the reaction mixture was concentrated under vacuum, the residue was taken up in EtOAc and washed with KHS04 and brine. The organic layer was dried over anhydrous Na2S04, filtered, and stripped. The crude product was purified by column chromatography. Example 80 E) To a stirred solution of Example 80 D and HMP A cooled in THF to -70 ° C was added lithium hexamethyldisilazide. After 20 minutes, the reaction mixture was heated to -40eC, and then Cool to -70 ° C. To the stirred solution was added (R)-(-)-(camphorsulfonyl) indacryl in THF. After stirring at -70 ° C for 30 minutes, the reaction mixture was heated to -305 ° C and stirred for 2.5 hours. To the reaction mixture was added a saturated NH4C1 solution and then EtOAc. The organic layer was washed with brine, dried over anhydrous Na2S04, filtered, and stripped. The crude product was purified by column chromatography to obtain 1.3 g of 3-hydroxylactam. Example SOF) To a stirred solution of Example 80E in CHC13 was added H20 and TFA. After stirring for 2 hours, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc. The organic layer was washed with a minimum of saturated NaHC03, dried over MgS04, filtered, and concentrated under reduced pressure to recover the crude aldehyde. Example 80G) To a stirred solution of Example 80F in MeOH was added NaBH3CN. The reaction mixture was maintained at pH 4 by the addition of HOAc. After stirring for 3 days, the reaction mixture was concentrated under vacuum. To the residue were added 1N HC1 and EtOAc. After the layers were separated, the aqueous phase was neutralized with NaHC03 and extracted with EtOAc. After the organic phase was concentrated, the residue was treated with IN HC1 and lyophilized. The resulting solid was purified by reverse-phase column chromatography on a C-18 column. Example 80H) As described in Example 45, the product of Example 80 G was treated with trimethyloxyphosphonium tetrafluoroborate in CH2C12. -84- This paper size is suitable for financial affairs (C \ s) A4 Lai (21GX29? Public director) — n ------ H--------- Ding ------- ----- Good, read it first :: i Italian matter $ write this page) {printed by Shellfish Consumer Cooperative, Central Standards Bureau, Ministry of Economic Affairs 415941 A7 'B7 V. Description of Invention (82) Example 80) Example A solution of the 80H product in MeOH was reacted with the gasified ammonium according to the method of Example 5, and then subjected to reverse phase HPLC chromatography to give the title material. Example 8 1 4ύτ-fluorenyl-5α-pentyl-3a-L-sulfenyl) 11 Bisha.-2-imine, monohydrochloride

Biological data The activity of the above compounds as N 0 synthetase inhibitors was determined by the following analysis. The citrulline analysis of nitric oxide synthase-Nitric oxide synthase (NOS) activity was detected by detecting [3H] -arginine To [3H] -citrulline (Bredt and Synder, Proc. Natl. Acad. Sci. USA, 87, 682-685, 1990, and Misko et al., Eur. J. Pharm., 233, 1 19 -125, 1993). Human inducible NOS (hiNOS), human endothelial structure NOS (hecNOS), and human neuronal structure (NOC) (hncNOS) are each cloned from winter tissue extracted from human tissues. Human inducible NOS (hiNOS) cDNA is isolated from a lambda cDNA library made from RN A extracted from colonic samples of ulcerative colon and inflammatory patients. Human endothelial structure NOS (hecNOS) cDNA is isolated from AcDNA library made from RNA extracted from human navel vein endothelial cells (HUVEC). Human neuronal structure NOS (hncNOS) -85- This paper scale is applicable to Chinese National Standard (CNS) A4 Specifications (210 X 297 mm) --------- installation -------, 1T ------- line (also read ^ on the first: ^ Italian matter write this page) < Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs, Consumer Cooperative Seal 415941 A7 B7 V. Description of the invention (83) cDNA is a cDNA library made from RNA extracted from human cerebellum obtained from dead corpses. Recombinant enzymes are isolated from S f 9 insect cells Expression using baculovirus vectors (Rodi et al., The Biology of Nitric Oxide, pt. 4: EnzvmoloRy, Biochemistry and Immunology; Moncada, S., Feelisch, M. Busse, R., Higgs, E ., Eds .; Portland Press Ltd .: London, 1995; pp 447-450) »Enzyme activity is separated from soluble cell extracts to separate and purify. To measure NO activity, 10 microliters of enzyme was added to 40 microliters of 50 mM Tris (pH 7.6) in the presence or absence of the test compound. The reaction consisted of 50 microliters of reaction mixture containing 50 mM Tris (pH 7.6). ), 2.0 mg / ml bovine serum albumin, 2.0 mM DTT, 4.0 mM CaCl2, 20 juM FAD, 100 AM tetrahydrobiopterin, 0.4-2.0 mM NADPH and 60 " M L-Arginine L- [2,3-3H] -arginine by 0.9 y Ci. The final concentration of L-arginine in the analysis was 30 aM. For hecNOS and hncNOS, calmodulin is added ' to a final concentration of 40-100 nM. After 15 minutes of incubation at 37 C, the reaction was stopped by adding 300 microliters of cold stop buffer containing 10 mM EGTA, 100 mM HEPES (pH 5.5) and 1 mM citrulamic acid. [3H] -citrulline was chromatographed on Dowex 50W X-8 cation exchange resin, and the radioactivity was measured by a liquid scintillation counter. The results are reported as 1 to 50% of the compounds for hiNOS 'hecNOS and hncNOS in Table I. The compounds have less than 50% inhibition at 100 μM, and the system is reported to have IC50 +> ι〇〇 # Μ, The compound has a greater than 50% inhibitory effect at 100 # 1 ^, which is reported to have a 1C 50 値 < 100. The following examples have been analyzed and have the following results. -86- Home Standard (CN.S) Α4 Specifications (210X297 mm) ----- ^ -------- 1T ------ ^ (I first read the precautions on the back to write this page) ί 5. Description of the invention ( 84 415941 A7 B7 Table I ........................................ --ic5〇 [ ^ M] Example hiNOS hecNOS hncNOS 10 > 100 13 < 100 < 100 < 100 18 < 100 > 100 > 100 21 > 100 > 100 > 100 36 > 100 37 < 100 < 100 < 100 38 > 100 < 100 < 100 39 < 100 > 100 < 100 40 < 100 > 100 < 100 41 > 100 > 100 > 100 42 < 100 > 100 < 100 44 > 100 > 100 > 100 45 < 100 > 100 < 100 46 < 100 > 100 < 100 47 < 100 > 100 < 100 packs, --- ----- 1T -------- Cheng (t read '(Notes on this page to write this page)) Central Bureau of Standards, Ministry of Economic Affairs, Shellfish Consumer Cooperation, printed hiNOS table, humans can induce NOS, hecNOS table Human endothelial structure NOS hncNOS represents human neuronal structure NOS From the above description, those skilled in the art can easily ascertain the symptoms, and without departing from the spirit and scope, can modify the invention to suit various uses and situations. Various changes and -87- This paper music scale is applicable to China National Standard (CMS) Ad specifications (2! 〇 × 297 mm)

Claims (1)

Month 148 49 9 < 8 Xiangben Qinzheng 4 Xiuliwei Specialty " Shou 38 Specialty 95 Please 10 Application 85 Article No. Aess 1 Application Specialist Village Fan Zhou-1 i ..... A compound of the formula R5 And its salts and pharmaceutically acceptable esters, among them. R 1 is selected from hydrogen, mesityl, C [-(: 6 alkane, ^ glyceryl ^ C2-C6 alkenyl, amine Cr (alkyl And cyano C ^ Cg alkyl: X represents CC2 or (CΗ2) 2; B represents CH2 or (CH2) 2; A = NR3, 0, CH2; R3 = hydrogen, C!-C4 R5, R6, R7 are each hydrogen, or one of them is Ci-Ce pit base, 匚 2_ (alkenyl; R8 and R9 = hydrogen; Ministry of Economic Affairs, Central Ministry of Vehicles, Japan, Consumer and Industrial Cooperation, Du printed equipment Mt »Note on the back (fill in this) 苋) The restriction is: when x and a # b are both · CH2, r1, r5, R6 and R7 must not have more than one Ci 6 which represents the fifth position on the ring The compound according to item 1 of the scope of patent application, wherein the compound is a group consisting of the following: The paper's standard scale uses tB country rate (CNS > A4 specification (2 丨 0X297)) month 148 49 9 &8; Xiangben Qinzheng 4 Xiuliwei Special Model " Shou 38 Specialty 95 Please 10 Application 85 Article No. Aess 1 Application Specialist Village Fan Zhou-1 i ..... Compound supplement R5 And its salts and pharmaceutically acceptable esters, among them. R 1 is selected from hydrogen, mesityl, C [-(: 6 alkane, ^ glyceryl ^ C2-C6 alkenyl, amine Cr (alkyl And cyano C ^ Cg alkyl: X represents CC2 or (CΗ2) 2; B represents CH2 or (CH2) 2; A = NR3, 0, CH2; R3 = hydrogen, C!-C4 R5, R6, R7 are each hydrogen, or one of them is Ci-Ce pit base, 匚 2_ (alkenyl; R8 and R9 = hydrogen; Ministry of Economic Affairs, Central Ministry of Vehicles, Japan, Consumer and Industrial Cooperation, Du printed equipment (please first Mt »Note on the back (fill in this) 苋) The restriction is: when x and a # b are both · CH2, r1, r5, R6 and R7 must not have more than one Ci 6 which represents the fifth position on the ring The compound according to item 1 of the scope of patent application, wherein the compound is a group consisting of the following: The paper's t-scale country tB country rate (CNS > A4 specification (2 丨 0X297)) 415941 USC8D8 &, Patent application scope printed by the Central Laboratories Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperative «. Sifeng-1,4-pyridazine-5 (2H) _imine, trifluoroacetate; 3- (2-butene Group) Tetrahydroazepine ^ _5 (2Η) · imine, trifluoroacetic acid ; Hexahydro-1-methyl-5'-1,4-diazepine-5_imine, trifluoroacetate; 3- (2-butenyl) hexahydro-5-imine-fluorene, 4 -Azazapyridine-6-alcohol, trifluoroacetate; 6- (2-butenyl) hexaargine-1pyridine-azaazepine_5_imine, trifluoroacetate: 3-butylhexadecane Hydrogen-1,4-pyridazine-5-imine, trifluoroacetate; N- (3,4-diargon-2Hpyrrole-5yl) -ethanolamine, bis (trifluoroacetate) salt. 3- -A pharmaceutical composition for use in an individual in need of such inhibition to inhibit the synthesis of nitric oxide, comprising a therapeutically effective amount of a compound according to item 1 or 2 of the scope of patent application " In inhibited individuals, to selectively inhibit the synthesis of nitric oxide produced by inducible nitric oxide synthase is superior to the production of nitric oxide produced by nitric oxide synthase in the endothelium A synthetic pharmaceutical composition comprising a therapeutically effective amount of a compound according to item 1 or 2 of the scope of patent application. 5. A pharmaceutical composition for use in an individual in need to reduce the amount of nitrogen oxides, comprising A therapeutically effective amount of a compound according to item 1 or 2 of the scope of patent application ^ -2 ^ This paper is scaled for use in China National Standards (CNS) A4 grid (2 〖〇X297mm） (Please read the notes on the back first (Fill in this page again)