TW517057B - Substituted biphenyl isoxazole sulfonamides - Google Patents

Abstract

Compounds of formula (I) inhibit the activity of endothelin. The symbols are defined as follows: R1, R2, R3 and R4 are each directly bonded to a ring carbon and are each independently (a) hydrogen; (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aryloxy, aralkyl or aralkoxy, any of which may be substituted with Z1, Z2 and Z3; (c) halo; (d) hydroxyl; (e) cyano; (f) nitro; (g) -C(O)H or -C(O)R5; (h) -CO2H or -CO2R5; (i) -Z4-NR6R7; (j) -Z4-N(R10)-Z5-NR8R9; or (k) R3 and R4 together may also be alkylene or alkenylene, either of which may be substituted with Z1, Z2 and Z3, completing a 4- to 8-membered saturated, unsaturated or aromatic ring together with the carbon atoms to which they are attached; and the remaining symbols are as defined in the specification.

Description

517057 A7 ___ _B7__ 5. Description of the invention (1) The present invention relates to endothelin antagonists useful for, inter alia, the treatment of hypertension. Compound of formula

(Please read the notes on the back before filling out this page) Its enantiomers and diastereomers, and their pharmaceutically acceptable salts are useful as endothelin receptors for (especially) antihypertensive agents Body antagonist. In this patent specification, the definitions of the symbols shown above are as follows. One of X and Y is N and the other is 0; R1, R2, R3, and R4 are each directly bonded to the ring carbon and each is (a) hydrogen; printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs ( b) Alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aryloxy, aralkyl or aralkyloxy Any one of them can be substituted by Zι, z 2 and Z 3; (c) Halo; (d) Hydroxyl; (e) Cyano; This paper size applies to Chinese National Standard (CNS) A4 (210 X 297) (Centi) 4 517057, description of the invention (2 (f) nitro; (g) — C (〇) Η or a C (〇) R5; (h) — C〇2H or a co2r5; (i) a Z4 -NR6R7; (j) — Z4-N (R1 °)-Z5 to NR8R9; or (R3 and R4 Φ can be _ or olefin, both of which can be replaced by Z, Z2 and so, so Connected from 4 to 8-saturated, saturated carbon atoms printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs to complete 4 and or aromatic rings; R5 is alkyl, alkenyl, alkynyl, cycloalkyl, ring Alkylalkylalkenyl, cycloalkenylalkyl, aryl or aralkyl, either Both can be substituted by 2 ζ 2 and Z 3; R6, R7, R8, R9 and R1. Each is (a) hydrogen; or (b) alkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl Or Fang Yuanji, either one can be replaced by Z2 and Z6; or R6 and 7 can be used as courtyard support or green support, and either can be replaced by 2; ι, Z 2 and Z3, and Wait for the nitrogen atoms to be bonded together to complete a 3 to 8-section saturated or unsaturated ring; or R8, R9, and feet 2. Any one of them can be a courtyard support or a suspicion, either can be used, Z2 And Z3 are substituted, thus forming 3_ to 8-section saturated or unsaturated rings together with the atoms to which they are bonded; R 11, R12, R13 and their respective rings are aromatic ^^ I order (please read the precautions on the back first) (Fill in this page again) The paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) 5-517057 A7 B7 5. Description of the invention (3) (a) hydrogen; (b) alkyl, alkenyl, alkyne Group, alkoxy group, cycloalkyl group, cycloalkylalkyl group, cycloalkenyl group, cycloalkenylalkyl group, aryl group, aryloxy group, aralkyl group, or aralkyloxy group, any of which may be Z1, Z2 and Z 3 are replaced; (c ) Heterocyclic ring, substituted heterocyclic ring or heterocyclic oxy; (d) dentyl, (e) hydroxyl; (f) cyano; (g) nitro; (h) -C (0) H or -C ( 0) R5; (i)-(: 〇21 * 1 or one (: 〇2115; (j) -SH, -S (〇) nR5, -S (〇) m-〇H, -S (〇) m _〇R5, 〇S (〇) m-0 R 5, 〇_3 (〇) 111〇 "[or 〇S (〇) m-〇R 5; (k)-Z4-NR6R7; Or printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) (j?)-Z 4- N (R 1 °)-Z5-NR8R9; z 1, Z 2 and Z 3 each is (a) hydrogen; (b) tooth group, (c) hydroxyl group; (d) alkyl group; this paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) -6-517057 A7 B7 five Description of the invention (4) (e) Alkenyl; (f) Aryl; (g) Aralkyl; (h) Alkoxy; (i) Aryloxy; (j) Aralkyloxy; (k) Heterocyclic ring, substituted heterocyclic ring or heterocyclic oxy group; (ii) -SH, -S (0) nZ6, -S (〇) m-〇H, _S (〇) m-〇Z6, 010 S (〇) m- Z 6, 010 S (〇) mOH or 010 S (〇) m-〇Z 6; (m) Hexyloxy; (η) nitro; (ο) amino; (p) — C (〇) H or one C (〇) Z6; (q) — C02H or one C02Z6; employee consumption of the Central Standards Bureau of the Ministry of Economic Affairs Printed by the cooperative (please read the notes on the back before filling this page) (r) — Z4— NR7R8; (s) -Z4-N (Z11) -Z5-H; (t)-Z 4- N (Z 1 1) — Z5 — Z6; or (u)-Z4-N (Z11)-Z5-NZ7Z8; Z 4 and Z 5 are each (a) single bond; (b)-Z 9- S (〇) n-Z 10-; This paper size applies to Chinese National Standard (CNS) A4 (210X 297 mm) 1-7-Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 517057 A7 ---____ V. Description of the Invention (5) (C ) A Z9— C (Ο)-Z 10-; (d) a Z9— C (S)-Z 10-; (e) — Z 9—10—ζ ι〇-; (f)-Z9-S- Z10-; (g) a Z9 —〇a c (ο)-ζ10 —; or (h) a Z9 — c (ο) — ο-ζ 1〇-; Z 6 is an alkyl group; one to three by halogen Alkyl, aryl, aryloxy, and alkoxy substituted alkyl groups; alkenyl; alkynyl; cycloalkyl; one to three by alkyl, aryl, alkenyl, and alkoxyaryl base Cycloalkyl substituted with selected group; Cycloalkyl with benzene ring fused, aryloxy substituted with one or two halogens; Cycloalkylalkyl; Cycloalkenyl; Cycloalkenylalkyl; Aromatic By methyldioxy or by one to four by alkyl, dialkylamino, cyano, halogen, trihaloalkyl, alkoxy, trihaloalkoxy, dialkylaminocarbonyl, alkylcarbonylamino , Arylalkoxy, aryloxyalkyl, alkaryloxyalkyl and heterocyclic rings substituted with selected groups; or heterocyclic rings or substituted heterocyclic rings. Z7 and Z8 are each hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl or aralkyl, or Z7 and Z8 are both alkylene or alkenylene, and therefore they The joined nitrogen atoms together complete a 3-to 8 -section saturated or unsaturated ring; Z9 and Z1. Each is a single bond, alkylene, alkenylene, or alkynylene; Z " is (a) hydrogen; or (b) alkyl, which is one, two or three halogens, cycloalkyl, cycloalkyl This paper is applicable to China National Standard (CNS) Α4 Specification (21〇χ297mm) --------- ^ Installation ------ Order ------ (Please read the precautions on the back before filling this page ) ~ 8-517057 A7 —____ B7__ 5. Explanation of the invention (6) Alkyl, cycloalkenylalkyl, aryl or arylalkyl substituted radical 9 or Z7, Z8 and Z11 are both alkylene or Ethylene, thus completing 3-to 8-saturated or $ saturated rings with the atoms to which they are bonded; J is 0, S, N or NR15; K and L are N or C, but at least one of K or L Which is C; R15 is hydrogen, alkyl, hydroxyethoxymethyl or methoxyethoxy_methyl; each in is 1 or 2, each η is 0, 1, or 2; and ρ is 0 or an integer from 1 to 2. For compound I, at least one of the substituents, or the majority, preferably all the substituents are as follows: R1 and R2 are each hydrogen, alkyl, alkoxy, aryl, hydroxyalkane, -C02R5 or -Z4-NR6R7; R3 and R4 are each alkyl; and R11 ,: Ri2, Ri3 and R14 are each hydrogen, hydroxyl, amine, heterocyclyl, alkenyl, alkoxy, formamidine Amine or substituted lower alkyl, the most ideal compound is at least one, or most of them, all the substituents are as follows: R1 and R2 are each lower alkyl or hydrogen; R3 and R4 are each lower alkyl , Especially methyl; and this paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) (Please read the note 1 on the back before filling in this page; printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs -9-517057 A7 —__ B7 V. Description of the invention (7) R12, R13 and R14 are hydrogen and Rii is hydrogen, hydroxyl, amine, heterocyclic, alkenyl, alkoxy, formamidine or substituted lower alkane The compounds in question include, inter alia, applications to (i) to (iv) One of: (i) at least one of R11, R12, R13 or Ru (preferably R11) is a heterocyclic ring, a substituted heterocyclic ring or a heterocyclic oxy group; (ii) one of Z1, Z2 or Z3 At least one is aryl, heterocyclic, substituted heterocyclic or heterocyclic oxy; (iii) Z6 is substituted with one to three selected from halogen, aryl, aryloxy and alkoxy. Alkyl, at least one of which is not aryl; alkyl substituted with two or three aryl groups; one to three selected from alkyl, aryl, alkenyl, and alkoxyaryl Cycloalkyl substituted with a group; Cycloalkyl fused with a benzene ring; Aryloxy substituted with one or two halogens; Aryl substituted with methyldioxy; One to four alkyl and dioxane Amine, cyano, halogen, trihaloalkyl, alkoxy, trialkoxy, dialkylaminecarbonyl, alkaminocarbonyl, aralkyloxy, aryloxyalkyl, alkaryloxyalkyl and hetero An aryl group substituted with a selected group in the ring; or a heterocyclic ring or a substituted heterocyclic ring; or (iv) Z11 is an alkyl group substituted with one, two, or three halogens, and the compound in question is particularly in the Ministry of Economic Affairs Printed by the Consumer Standards Cooperative of the Central Bureau of Standards (please read the notes on the back before filling out this page) who uses (i), or at least one of the groups cited in (ii) to (iv) (Z1 , Z2, Z3, Z6, or Z11) compounds that form part of the R11 group (that is, form or form part of a substituent in a substituted alkyl group (which is part of R11)). Particularly desirable compounds include this patent specification The following are the definitions of the special terms used in the patent specification. Unless otherwise specified, these definitions can be used individually or as one of another group. This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 (Mm) " 1 10-517057 A7 ___B7_ 5. The description of the invention (8) applies to the terminology used throughout this patent specification. The so-called ★ alkylfluorene or 1k- — means a straight or branched chain hydrocarbon group having 1 to 10 carbon atoms, preferably 1 to 7 carbon atoms. ≫ Lower alkylfluorene means an alkyl group having 1 to 4 carbon atoms. The so-called ~ alkoxyfluorene means alkyl 10-. The so-called arylfluorene or r-fluorene means phenyl, a certain group and biphenyl. The so-called "alkenyl" means a straight or branched hydrocarbon group having 2 to 10 carbon atoms having at least one double bond. It is preferable to use a group having two to four carbon atoms. The so-called " alkynyl " means a straight or branched chain group having 2 to 10 carbon atoms having at least one triple bond, and preferably a group having 2 to 4 carbon atoms. The so-called a-alkylene " means a straight-chain bridge with 1 to 5 carbon atoms (such as one (CH2) x_, where X is 1 to 5) connected by a single bond, which can be reduced by 1 to 3 Alkyl group substitution. Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) The so-called " eneylene " refers to a device with one or two double bonds connected by a single bond. A straight chain bridge of 5 carbon atoms, which can be substituted by 1 to 3 lower alkyl groups. Examples of olefinic groups are-CH = CH — CH = CH-,-CH2 = CH = CH-,-CH 2 —CH = CH — c Η 2-, —c (CH3) 2CH = CH-and —CH ( C2H5)-CH = CH-. The so-called "alkynylene" refers to a straight-chain bridge with 2 to 5 carbon atoms connected by a single bond with a triple bond within it, which can be used by 1 to 3 lower alkyl papers. Applicable to Chinese countries. Standard (CNS) A4 specification (210X297 mm)-11-517057 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 Description of the invention (9) Examples of m substituted for alkynyl groups are-C three C-, -C Η 2-CC — One C Η (C Η 3) — -C 丨 Three: C One and —c = C--C Η (C 2H 5) C Η 2 One-C \ C (〇) courtyard group: the group 0 the so-called cyclic group and cycloalkenyl π means a cyclic hydrocarbon group having 3 to 8 carbon atoms; the so-called hydroxy group ff means to include one or more hydroxyl groups : An alkyl group of a group such as -C Η 2 C Η 2 〇Η — C Η 2 C Η 2 ο η C Η 2 0 Η, 〇 Η (C Η 2〇Η) 2 etc. so-called halogen > r and Halo A means fluorine, chlorine, bromine and iodine. The so-called heterocyclic heterocyclic ring and "heterocyclic group" means any substituted fully saturated or unsaturated aromatic or non-aromatic cyclic group, such as > It is a 4 to 7 section monocyclic ring 7 to 1 1 A bicyclic ring, or a 10 to 15 tricyclic ring system with at least one heteroatom in at least one carbon atom-containing ring. A heteroatom-containing heterocyclic group may have 1, 2, 3, or Nitrogen and sulfur heteroatoms can be oxidized and nitrogen atoms can be quaternized. Heterocyclic groups can be used for any of the 4 heteroatoms selected from nitrogen atom oxygen atom or sulfur atom. Examples of monocyclic heterocyclic groups bonded at the atom include pyrrolidinyl, pyrrolyl, pyrazolyloxanylpyrazolyl > imidazolyl, imidazolinyl, imidazole B amidyl, oxazolyl oxazole B Isoxazolyl, isoxazolyl, oxazolyl, thiadiazolyl > oxazolyl D oxyl, isoxazolyl isoxazolyl , Furyl, tetrahydrofuryl, 0-sedenyloxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxooxypiperidinyl, 2-oxooxypyrrolidinyl Please read the notes on the back before filling out this page) This paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm)-12-Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 517057 A7 B7 V. Invention Description ( 10), 2-Hydroxyazepine, azathio, 4-piperidone, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, sulfur Heteromorpholinyl, thiamorpholino, thiamorpholinium fluorene, 1,3-dioxocane, tetrahydro-1,1-dioxofluorethenyl, blinddiazolyl, dihydro Thiazolyl, tetrazolyl and triazolyl. Examples of bicyclic heterocyclic groups include vermicarbyl, benzoxazolyl, benzoxazolyl, benzoxynyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinoline , Benzimidazolyl, benzopyranyl, indazinolyl, benzofuranyl, chromone, coumarinyl, benzopyranyl, fluorinyl, oxazolyl, oxazolyl, Pyrrolopyridyl, furanopyridyl (such as furano [2,3-c] pyridyl, furano [3,2-b] pyridyl] or furano [2,3-b] pyranyl), Dihydroisoearminyl, dihydroquinazolinyl, (such as 3,4-dihydro-4,1-oxo-blazolinyl), tetrahydroquinolinyl, pyrazolopyridyl, dihydro Benzoxazolyl, benzotriazolyl, triazolopyridyl, pyridoxazinyl and azabenzimidazolyl. Examples of the tricyclic heterocyclic group include oxazolyl, benzoyl, phenanthroline, acridinyl, phenanthryl, glutaryl and the like. The so-called "substituted heterocyclic ring" means a heterocyclic ring substituted by 1, 2 or 3 of the following: (a) alkyl, especially lower alkyl, or alkyl (including substitution by one or more halogens) Alkyl group) (b) hydroxyl group (or protected hydroxyl group); (c) halo group; this paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) (Please read the notes on the back before filling This page), item refill -13-517057 Printed A7 B7 Invention Description (11) (d) Hexy (ie = 0), (e) Amine, Alkylamino or dialkylamino; (f) alkoxy; (g) carbocyclyl, such as cycloalkyl; (h) carboxyl; k nx m η ο

ρ Q

Alkyl group: Oxycarbonylamino ... anylamine epoxy group ester 5_heteroalkylamines nitrocyananesulfonyl R _ methoxyalkylamine lower alkyl or lower Methyl groups such as amines, alkylalkyldiylamines, sulfonates or alkylalkylamines, sulfo

N 丨 R (r) R5-S02-N-;

(Please read the notes on the back before filling out this page) (s) aryl group; (t) courtyard oxy group; (U) aryl feroxy group; (V) arylthio group; (W) aryloxy group; ( X) Sulfur group; (y) Formazan; This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm)-14-517057 A7 B7 5. Description of the invention (12) (z) aralkyl; (a ') an aryl group substituted with at least one alkyl, cycloalkyl, alkoxy, hydroxy, amine, alkylamino, dialkylamino, -yl, or trihaloalkyl group; (b') as used herein Other heterocycles or substituted heterocycles as defined, in particular bonded to the above heterocycles by a single bond; (c ') alkylcarbonyl; or (d,) = S. The so-called " heterocyclooxy " Refers to a heterocyclic group bonded via an oxygen bridge. Throughout the application specification, groups and their substituents are selected to provide stable moieties and compounds. Compounds of formula I can form salts, which are also within the scope of the invention. Although other salts are also effective in isolating or purifying the compounds of the present invention, pharmaceutically acceptable (i.e. non-toxic, physiologically acceptable) salts are preferred. Compounds of formula I can form alkali metals such as sodium, potassium, and lithium, alkaline earth metals such as calcium and magnesium, organic bases such as dicyclohexylamine, butylamine, star, N-methyl-D-glucose Amidoamine and hypamine, etc., and salts containing amino acids such as arginine, lysine, etc. These salts can be obtained by reacting the compound I with the desired ion in a medium capable of precipitating the salt or in an aqueous medium, followed by lyophilization. When to the ruler 4 or to! ^ 4 The substituent contains a basic part, and the paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page) Printed by the Consumer Cooperatives -15-517057 A7 __B7 V. Description of the Invention (13) Compounds such as amine groups or substituted amine groups can form salts with various organic and inorganic acids. The salts include hydrochloric acid, hydrogen bromide, methanesulfonic acid, sulfuric acid, acetic acid, maleic acid, benzenesulfonate, tosylate and various other sulfonates, nitrates, phosphates, borate, Formed by acetate, tartrate, maleate, succinate, citrate, benzoate, ascorbate, salicylate, etc. The salts can be obtained by reacting Compound I with an equivalent amount of acid in a medium capable of precipitating the salt or in an aqueous medium, and then lyophilizing. In addition, when the R1 to R4 or R11 to R14 substituents contain a basic moiety such as an amine group, the zwitterion (a internal salt may be formed. Some of the R1 to R4 and R11 to R14 substituents in the compound may contain non- Symmetric carbon atoms. Therefore, this compound of formula I can exist in enantiomeric and diastereomeric forms and in the form of racemic mixtures. All are within the scope of the present invention. In addition, compound I When present, they can also exist in enantiomeric forms. All such enantiomers are within the scope of the present invention. Compounds of formula I are antagonists of ET_1, ET-2 and / or ET-3, and are useful for treating ET values. Increases related conditions (such as dialysis, trauma, and surgery) and all endothelin-dependent disorders. They are therefore useful as antihypertensive agents. By administering a composition that has (or binds) a compound of the invention, Reduce blood pressure in hypertensive mammals (eg, humans). They are also used in pregnancy-induced hypertension and coma (early daughters and daughters), acute portal hypertension, and subsequent treatment of red blood cells. Blood pressure. This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm)-16-(Please read the notes on the back _, and then fill in,: Write this page} Staff Consumer Cooperatives, Central Bureau of Standards, Ministry of Economic Affairs Printed 517057 A7 B7 V. Description of the invention (14) The compounds of the present invention are also useful in the treatment of conditions related to the function of kidneys, glomeruli and mesangial cells, including acute and chronic renal failure, glomerular injury, Renal damage recurring or related to dialysis, nephrosclerosis (especially hypertensive nephrosclerosis), nephrotoxicity (including nephrotoxicity related to imaging agents and contrast agents and cyclosporine), renal deficiency Blood, primary bladder and ureteral reflux, glomerulosclerosis, etc. The compounds of the present invention are also useful for treating disorders related to paracrine and endocrine functions. The compounds of the present invention are also useful for treating endotoxemia or endotoxin shock and bleeding Shock. The compounds of the invention are also useful in hypoxic and ischemic diseases, and as anti-ischemic agents for the treatment of, for example, heart, kidney and cerebral ischemia and reperfusion (such as in the heart). Occurred after bypass surgery), coronary artery and cerebral spasm, etc. 0 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) In addition, the compounds of the present invention are useful as anti-arrhythmia Agents; anti-pharyngitis agents; anti-tremor agents, anti-asthmatic agents; anti-atherosclerotic and anti-atherosclerotic agents; additives for cardioplegia solutions for cardiopulmonary bypass; adjuvants for thrombolytic therapy; The compounds of the present invention can be useful for the treatment of myocardial infarction; for the treatment of peripheral vascular diseases (such as Raynaud's disease and High's disease); for treatment of cardiac hypertrophy (such as hypertrophic cardiomyopathy); Blood pressure (eg, plexiform, embolic) and pulmonary hypertension due to heart failure, radiation and chemotherapy damage, or other trauma; treatment of vascular disorders of the central nervous system, such as stroke, migraine and subarachnoid hemorrhage; Treatment of central nervous system behavior disorders; treatment of gastrointestinal diseases such as ulcerative colitis, Crohn's disease, gastric mucosal damage, ulcers This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) 17-517057 A7 B7 V. Description of Invention (15) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the notes on the back before filling in) This page) Ischemic bowel disease; treatment of diseases such as cholangitis based on the gallbladder or biliary tract; Restenosis; treatment of congestive heart failure including inhibition of fibrosis; inhibition of left ventricular dilatation, remodeling and dysfunction; and treatment of liver poisoning and sudden death. The compounds of the present invention are useful in the treatment of sickle cell disease, including the onset and / or progression of a painful dangerous period of the disease; the harmful consequences of treating ET-producing tumors such as hypertension due to hemangiopericytoma; the treatment of early and progressive liver disease and Injuries include concomitant complications (such as liver poisoning, fibrosis, and cirrhosis); treatment of spastic diseases of the urethra and / or bladder; treatment of hepatorenal syndrome; treatment of immunological diseases involving vasculitis such as lupus, systemic sclerosis, mixed Cryoglobulinemia; and treatment of fibrosis associated with renal dysfunction and liver toxicity. The compounds of the present invention are useful in the treatment of metabolic and neurological disorders; cancer; insulin-dependent and non-insulin-dependent diabetes mellitus; neuropathy; retinopathy; maternal neonatal respiratory distress syndrome, dysmenorrhea; epilepsy; hemorrhagic and ischemic stroke Bone remodeling; psoriasis; and chronic inflammations such as rheumatoid arthritis, osteoarthritis, sarcoidosis, and eczema dermatitis (all types of dermatitis). The compounds of the present invention may also interact with endothelin converting enzyme (ECE) inhibitors such as phosphamine and the like; thromboxane receptor antagonists; potassium channel openers; thrombin inhibitors such as hirudin; and growth factor inhibitors such as PDGF Activity modulators; platelet activating factor (pa F) antagonists; angiotensin II (AII) receptor antagonists; renin inhibitors; angiotensin converting enzyme (ACE) inhibitors such as captopril (present The paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) _ 18-517057 printed by the central quasi-% employee consumer cooperative. System A7 V. Invention Description (16) captopril), Zofenopril, Eph Fosinopril, ceranapril, aracepril, enalapril 'delapril, pentopril, queen Quinapril, ramipril, lisinopril, and salts of these compounds; neutral peptide endonuclease (NEP) inhibitors; double NE P — ACE inhibitors; Η MGC ο Α reductase inhibitors such as pravastatin and mevacor; horny synthase inhibitors; bile acid sequestering agents such as quizun (Duestran), etc .; calcium channel blockers; potassium channel activators; / 5-adrenaline stimulants; antiarrhythmic agents; Hydrofluoromethazine, benzyl fluoride P plug, meclozine, trichloromethyl P thiazide, poly P thiazide or benzopyrazine and diuretic acid, tricolanafen, chloracetone, Furosemide, musolimine, papamidine, amphetamine, pyriprazine and spironolactone and mixtures of these compounds; cardiac glycosides such as Digoxin, etc., or other suitable for the treatment of congestive heart failure Preparations; and thrombolytic agents such as tissue plasminogen activator (tPA), combined with tPA, streptokinase, urokinase, prourokinase, and fennelized plasminogen plasminogen activator complex (AP SAC) combined with deployment. If formulated in a fixed dose, the combination product preferably uses the compounds of the present invention within the following dosage ranges and other pharmaceutically active agents within their approved dosage ranges. The compound of the present invention can also be used with antifungal agents and immunosuppressive agents such as amphotericin B, cyclosporine, etc. This paper size applies Chinese National Standard (CNS) A4 specifications (210X297 mm) (Please read the precautions on the back before (Fill in this page) -19-517057 A7 ____B7 V. Description of the Invention (17) Formulated or used simultaneously to combat glomerular contraction and subsequent renal toxicity caused by the compound. The compounds of the invention can also be used simultaneously with hemodialysis. The compounds of the present invention can be administered to various mammals, such as humans, known to suffer from the disease, in an effective amount in any suitable manner, such as orally or parenterally, and the effective amount is from about 0.1 to about 100 mg. / Kg, preferably about 0.2 to about 50 mg / kg, especially about 0.5 to about 25 mg / kg (or from about 1 to about 250 mg, preferably from about 5 to about 20 mg (0 mg) is administered in a single dose or in divided daily doses divided into two to four times. The effective substance may be in the form of a composition such as tablets, capsules, solutions or suspensions containing, for example, about 5 to about 500 mg of a compound of the formula I or a mixture of compounds per unit dose, or a topical site for wound healing Use in a form (such as from 0.01 to 5% by weight of Formula I, treated 1 to 5 times a day). They are conventionally used with physiologically acceptable vehicles or carriers, excipients, binding agents, preservatives, stabilizers, perfumes, etc., or topical carriers such as Plastibase (mineralized gelatinized polyethylene ) Combine as required by acceptable pharmaceutical practice. Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back and fill in this page) The compound of the present invention can also be administered topically for the treatment of peripheral vascular diseases and it can be formulated in the form of cream or ointment. The compounds of formula I can also be formulated into compositions such as sterile solutions or suspensions for parenteral administration. For example, about 0.1 to 500 milligrams of a compound of formula I and a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, etc. may be manipulated by acceptable pharmaceutical practice as required. The method is combined in unit dosage form. The amount of effective substances in these compositions or preparations The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) '-20-517057 A7 B7 V. Description of the invention (18) It is best to be within the specified range The appropriate dose. The present invention therefore provides a novel method for using a pharmaceutical composition comprising a compound of formula I and a salt thereof. The present invention particularly contemplates a method of treating a mammalian endothelin-related disorder, comprising administering to a mammal a compound of formula I or a pharmaceutically acceptable salt thereof in an amount effective to treat the endothelin-related disorder. In particular, the present invention also contemplates a pharmaceutical composition for treating an endothelin-related disorder, which contains an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof and a physiologically acceptable vehicle or carrier. The compound of the present invention or a salt thereof may, for example, alone, or in combination with one or more other compounds of formula I or a salt thereof and / or with at least one other effective agent such as an angiotensin π (AII) receptor antagonist, kidney Inhibitors, Angiotensin-Converting Enzymes (ACE) Inhibitors, Double Neutral Endopeptidases (NEP)-ACE Inhibitors, Diuretics or Cardiac Glycosides, or other effective agents listed above are used in combination with this method Or pharmaceutical composition. Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the notes on the back before filling this page) / In this method, this other effective preparation can be taken before, at the same time, or after the administration of the compound of formula I or its salt Conquer. In the pharmaceutical composition, other effective preparations may be co-formulated with the compound of formula I or a salt thereof, or may be administered separately according to the method described above for use in this method. This method and composition is particularly ideal for the treatment of hypertension, especially low renin hypertension (such as published by JE Bird on January 30, 1997, entitled 'Method for Preventing or Treating Low Renin Hypertension by Administering an Endothelian Antagenist 〃 (Catalogue for Attorney Proceedings Case No. HA 7 0 0 *) of the US Patent Application Series No. _ This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) -21-517057 A7 _____B7 V. Description of the invention (19), which is incorporated herein by reference in its entirety) or pulmonary hypertension ', especially primary pulmonary hypertension; benign prostatic hypertrophy; migraine; kidney, renal small Glomerular or mesangial cell disorders; endotoxemia; ischemia; atherosclerosis; restenosis; subarachnoid hemorrhage; and congestive heart failure. The compounds of the present invention can be prepared as follows. (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

S N C

4 A

Centimeter 7 9 2 X 517057 A7 B7 V. Description of the invention (20) Reaction diagram R1 (CH2) P J R11 —

_R. Halo 12 H〇 \ / 〇H B R13

S02I Prot R_ 2 (where ‘Prot’

X—Y R3 R4 14 is a protecting group) Palladium (〇), alkali, solvent Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economy (where ha 1 〇 is Br or I)

Removal of Protecting Groups As described in Reaction Figure 1, the title compound 1 can be obtained by appropriately protecting the phenylsulfonamide-2 π boronic acid intermediate t and the 4-heterocyclic aryl halide- Water-based potassium carbonate, etc., and solvents such as toluene and ethanol. The size of this paper is applicable to the Chinese National Standard (CNS) A4 specification (210X 297 mm) (Please read the precautions on the back before filling this page) -23-517057 A7 _________B7_ V. Description of the invention (21) It is prepared by performing palladium (0) catalytic coupling in the presence of a liquid mixture. Boric acid intermediates can be prepared from 2-bromophenylsulfonamide K as described in European Patent Gazette No. 0,569,193 (1993). Lithification by appropriate alkyllithium (such as n-butyllithium) , Followed by treatment with a trialkyl borate (such as triisopropyl borate), and finally adding an aqueous acid such as aqueous hydrochloric acid (Reaction Diagram II): trans diagram Π (please read the precautions on the back before (Fill in this page)

light

• Φ 'printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs r 〇t 〃 is an appropriate protecting group for the functional group of sulfonamide. It is also described in European Patent Gazette 0, 5 6 9, 1 9 3 (1 9 9 3) No. 0 This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 24-517057 A7 _____B7 __ V. Description of the invention (22) The title compound can also be synthesized by other paths shown below (Response mouse m): Response map m

(Please read the notes on the back before filling out this page) Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

As mentioned above, 4, _heterocyclic aryl halides also refer to compound 1) can be converted into a boric acid intermediate via the following sequence: L, this compound: can be provided by palladium (0) catalytic coupling with a compound Double aryl is similar to this paper standard applicable to China National Standard (CNS) M specification (210X297 mm) " ---- 517057 A7 __B7_ V. Description of Invention (23) Object 1, which can be obtained after deprotection Compound 1. In some cases, heteroatoms: [and K or L may need to be protected to prepare boric acid 1 and / or promote the coupling reaction to prepare compound 1_. (For example, when: [and K or L is N, a group can be protected by a suitable protecting group such as tert-butoxycarbonyl, etc.). In addition, under certain conditions, boric acid can be replaced by tins and / or halogen groups can be replaced by a 0 S 02C F3 moiety for palladium-catalyzed coupling reactions. General strategy for the synthesis of bisaryl groups, see: Bringmann et a 1 ·, Angew. Chem. Inst., Ed. Engl. 2 9 (1990) 977-991 ° The specific R11 — R14 group is shown in the reaction diagram above Preselected to be compatible with the reaction conditions shown. In addition, specific R11 to R14 groups can be converted into other R 1 1 to R 1 4 groups before or after coupling of compound 1 and compound 2 or before or after coupling of compound 5 and compound 7 using methods known in the art. Synthesis of compounds 1 and 6 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) Compounds 丄 _ and i can be prepared by the following reaction diagrams. 2-Aryloxazole is prepared by the method described in Reaction Diagram IV, Method A-；; 4-Aryloxazole is prepared by the method described in Reaction Diagram V, Method A-B; 5-Aryloxazole Prepared by the method described in Reaction Diagram VI, Method A-B; Thiazole is prepared by the method described in Reaction Diagram VI I, Method A-B; Imidazole is prepared by the method described in Reaction Diagram VI II; 2-Benzene Alkyloxazole is prepared by the method described in Reaction Diagram IX and Method AB; pyrazole is prepared by the method described in Reaction Diagram X; 3-arylisoxazole is prepared by the method described in Reaction Diagram XI; 5 This paper size applies the Chinese National Standard (CNS) ^ 4 specification (210〆297 mm) ~ '-26-517057 A7 B7 V. Description of the invention (24) An aryl isoxazole is based on the method described in reaction chart XII And N-arylimidazole was prepared by the method described in Reaction Scheme XIII. In these reaction diagrams, R11 and R12 are also selected to be compatible with the reaction conditions shown. A. Aryloxazole

Reaction Diagram I · Method A coci

0 f R + R1 — C—CH_NH2

R1 R2 〇 NH

R 12 cyclization (for example: sulfuric acid)

R. 12 (Please read the notes on the back before filling out this page) The 醯 amido compound printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs is prepared according to the above method and can be cyclized to oxazole using various dehydrating agents 10. For a review of this and other methods of oxazole synthesis, see: Lankan et a 1., A-dv. Het. Chem., 1 7 (1 9 7 4), 9 9 ° This paper is also applicable to Chinese national standards ( CNS) A4 specification (210X29? Mm) -27-517057 A7 B7 V. Description of invention (25)

Reaction Diagram I · Method B conh2

〇 II R12 + R2-C -CH2X 12 X = Cl, Br, heating

R R2

12

R 13 Br (Please read the precautions on the back before filling this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, as shown, heating the mixture of benzamide 11 and α-halocarbonyl compound 12 together to obtain Related oxazole 13, this method has been widely used to provide 2,4-disubstituted oxazole, for review please see: L-akhan eta 1., Adv. Het. Chem · 1 7 '(1 9 7 9) 9 9 — 211. This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) -28-517057 A7 B7 V. Description of invention (26)

Reaction Diagram I · Method C

COOH

^ CO ^ H-R2 OH Esterification Ammonium acetate / acetic acid (Please read the notes on the back before filling this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Ester R1 R2

R 16 12 _ can be prepared by reacting α_halo ketone with benzoic acid 14 in the presence of a base such as triethylamine, or by esterification with an appropriate α-hydroxy ketone. After treating compound 15 with acetic acid solution of ammonium acetate, oxazole 16 will be obtained. The paper size applies the Chinese National Standard (CNS) A4 specification (210 × 297 mm) -29-517057

c ^ c--C

2 R R1 +

2 R1 Hot add 2 R 3 Η R1 Σν. 19IR12 (Please read the notes on the back before filling out this page) The Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs prints some acetylenic methanol such as compound 17 which can directly interact with aryl eyes 18 React to obtain 5-methyloxazole, 19, (see, for example, 'Y. Yura, Japanese Patent 29849 (1964).) This paper size applies the Chinese National Standard (CNS) A4 specification (210X 297 mm) -30-

R 12

R

Br 517057 A7 B7 V. Description of the invention (28

Reaction Diagram I · Method E CH C0C1

III

C

2SL

CH

22 12 Heating (Please read the precautions on the back before filling this page)

The acetylene fluorene 2 printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 2 2 is cyclized to oxazole derivatives after heating 2 3 This paper size applies to China National Standard (CNS) A4 (210X 297 mm) -31- 517057 A7 B7 V. Description of the invention (29

Reaction Diagram I V · Method F

12) 25. Heating

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

R 11.

R · 12 Br 26 4,5-Unsubstituted oxazole 26, can be condensed by 4 -bromobenzimidamine 11 and vinylene carbonate 25 at high temperature in the presence of preparations such as polyphosphoric acid And made. (See, for example, Ferrini et al., Angew. Ch em. Internat. Ed., Vo 5.2.2, 1963, printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, 9 9 °) This paper standard applies to Chinese national standards (CNS ) A4 specifications (210X 297 mm) -32-517057 A7 B7 V. Description of the invention (30)

Reaction Diagram IV · Method G R11- Br 27

(Please read the notes on the back before filling this page) C1

I HC \ cr ch2 α,, νη The cyclization of N- (2 '2-dichloroethyl) amidine derivative 27 in the presence of a suitable base such as sodium ethoxide, can also provide oxazole derivatives物 26。 26. (See, for example, U.S. Patent No. 3,953,465). . Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economics This paper is in accordance with the Chinese National Standard (CNS) A4 (210X 297 mm) -33-517057 A7 B7 V. Description of the Invention (31) Reaction Diagram I V · Method Η COC1

heating

R 12 (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs, aryl chloro 21 and oxime 29 in which R 1 and R 2 are alkyl (produced by methods known in the art The mixture is obtained by heating together to obtain the oxazole derivative 10 (for example, see Bhatt, M.V. and Reddy, A.S., Tet. Lett., 21, 2359 (1980)) ° This paper is applicable to China National Standard (CNS) A4 Specification (210X297 mm) -34-517057 Α7 Β7 V. Description of Invention (32)

Reaction Diagram I · Method I COC1

• N

Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs, a mixture of arsenyl chloride 21 and triazole 25 '(where R is a method known in the art) in which R is trimethylsilyl, together in an appropriate solvent such as toluene Heating, to obtain the oxazole derivative 2 6 (for example, see Williams, EL, Tet. Lett.. 3 3, 10 3-1036 (1992)). The oxazole derivative 26 can also be prepared by treating arsenyl chloride 2-1 with triazole (where R is hydrogen) in the presence of a suitable base such as potassium carbonate, and then heating the mixture to the optimal temperature. Β. 4 aryloxazole This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) Order (Please read the precautions on the back before filling this page} ~ 35-517057 A7 B7 V. Description of the invention ( 33)

Reaction Diagram V · Method A R2

R 12 R1CONH〇 Heating

31 R 12 (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs The α-bromoacetophenone derivative 3 0 is heated at a high temperature (usually 13 0_1 50 ° C), and 4-aryloxazole 31 is obtained. This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) -36-517057 A7 B7 V. Description of invention (34)

Reaction Diagram V · Method B

(Please read the notes on the back before filling this page) Make some α-metallized hetero eyes 3 2 (made by methods known in the art) react with fluorenyl halide, imidazole or other active fluorene groups, That is, 2-unsubstituted oxazole 3 3 in which R 2 is an alkyl group or an aryl group. C ·. 5 -Aryloxazole Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs This paper size applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) -37-517057 A7 B7 V. Description of the invention (35

Reaction diagram V

Method A

R ^ OCl 34

〇, NH

R 15 12 R1 sulfuric acid

(Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs α-Aminoacetophenone is fluorinated with fluorenyl chloride to obtain compound 35. After cyclizing compound 35 with an appropriate dehydrating agent such as sulfuric acid, oxazole 36 is obtained. (This method is similar to that described in Reaction Diagram I V, Method A.) This paper size applies to the Chinese National Standard (CNS) A4 (210X 297 mm) -38-517057 A7 B7 V. Description of the invention (36)

Reaction diagram V

Method B

CHO

R- 12 + TsCH2N = C 38 potassium carbonate methanol (Ts = tosylate)

R

39 R. 12 (Please read the notes on the back before filling this page) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 4—Halobenzaldehyde 3 7 Tosylsulfonium methyl isocyanate 3 8 To alkalis such as carbonic acid In the presence of potassium, treatment in an appropriate solvent such as methanol yields a 5-aryl oxazole derivative 39. (See, for example, People. ^ *. ¥ & 111 ^ 113-en, eta 1 ·, Te t. Lett., 2369 (1972).) DP Hanazole This paper size applies the Chinese National Standard (CNS) A4 specification ( 210X 297 mm) -39-517057 A7 B7 V. Description of the invention (37)

Reaction Diagram W · Method A

H〇 \ / 〇H B

R1 R2 .R12 Palladium (〇) R11—r-T >

Br

Alkali / solvent

12 R 4H (Please read the notes on the back before filling out this page) The 4-Bromophenylboronic acid 41 printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs can be substituted with the 2-Bromopyrazine 4 2 appropriately substituted in Palladium (0) Coupling in the presence of a catalyst, a suitable base (such as aqueous potassium carbonate), and a solvent to obtain thiazole 40. This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) -40-517057 Α7 Β7 V. Description of invention (38)

Reaction Diagram W · Method B

CN

〇 Q-T-R12 + HS-CH2-C-Ri R2

12 (Please read the precautions on the reverse side before filling out this page) R- 44. Condensing para-bromobenzyl 18 and α-thione directly to obtain orazolazole derivative 44. Ε · imidazole Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs This paper size applies to the Chinese National Standard (CNS) A4 (210 × 297 mm) -41-517057 A7 B7 V. Description of the invention (39) Reaction diagram Μ

CHO

R 12 37 CHOCHO + ΝΗ3 heating 45 R 11.

R12 Br (Please read the notes on the back before filling this page)

Br Printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs

Rli / base ‘R1 R11 —r () ~-R12 The benzaldehyde derivative 37 is condensed with glyoxal and ammonia to obtain a 2-arylimidazole derivative 45. (See, for example, U.S. Patent No. 3,682,949). This compound can be further substituted by reacting with a halogen compound in the presence of a suitable base to obtain, for example, the N-alkyl derivative 46. To review the synthesis method of mili, please refer to: Ad v. He t. Chem., 27, (1980), 241-323. This paper size applies to Chinese National Standard (CNS) A4 (210 X 297 mm) -42-517057 A7 B7 V. Description of the invention (1 2 30) F · 2 -phenylalkyloxazole

Reaction Diagram I X · Method A

47

V 〇 25 ° β 〇 Heating polyphosphoric acid

R. 12 (Please read the notes on the back before filling out this page) This paper size applies to China National Standard (CNS) Α3 size (210 X 297 mm) Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs-43-1 — Phenyl oxazole 48 (where ρ is 1 or 2 and unsubstituted at 4 and 25 positions) can be obtained by combining benzamidine 4 7 and vinylene carbonate 3 2 5 in preparations such as polyphosphoric acid. It is prepared by co-heating in the presence. 517057 Α7 Β7 V. Description of the invention (41)

Reaction Diagram I X · Method B

R 11. (CH2) P-CN (^ LR12 + H〇-CH2 «-Rl

Br

49. / 〇〜1 (CH2) P — < 0 η CH2-R1

51 (Please read the notes on the back before filling out this page) / 2 —Aralkyl—4 —Substituted—oxazole 51 (where R 1 is a courtyard and η is 1 or 2) can start from the above indication 4 9 And made (see, for example, U.S. Patent No. 4,168,379). Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs G · Sozole This paper size applies to the Chinese National Standard (CNS) A4 (210X297 mm) One 44 One 517057 A7 B7 V. Description of the Invention (42

^ HCl R 12 +

Reaction Diagram X Ethylamine Ethanol

N N

R 12 (Please read the notes on the back before filling this page) The pyrazole derivative 5 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs can be obtained by combining the aryl trap 5 3 with epichlorohydrin in an appropriate base such as triethylamine It is prepared by co-heating in the presence of such. Η. 3 —Aryl isoxazole This paper size is applicable to Chinese National Standard (CNS) A4 specification (210 × 297 mm) -45-517057 A7 ._ 一 _B7 V. Description of the invention (43)

Reaction Diagram X I

Br 55 (Please read the precautions on the back before filling out this page) 1 Hydrochloric acid / O 2 Triethylamine. 3 = \ OAc 4 Hydrochloric acid / Ethanol Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. 4_ (Prepared by methods known in the art) treatment with hydrochloric acid / hum, followed by treatment with a base such as triethylamine to obtain oxidized aromatic eyes. The oxidized aromatic nitrile is usually not isolated but reacts with vinyl acetate. The mixture is then heated in an acid (e.g., hydrochloric acid) in a suitable solvent such as ethanol to obtain a 3-arylisoazole derivative. 1.5 —Famous isoxazole This paper size is in accordance with Chinese National Standard (CNS) A4 (210X 297mm)-46-517057 A7 B7 5. Description of the invention (44) Reaction chart X _5_

2 iodine / potassium iodide 〇 1 hydroxylamine

) 12 (Please read the notes on the back before filling this page) The Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs prints α, yS-unsaturated ketones and i (made by a method known in the art) treated with hydroxylamine to The relevant oxime derivatives are obtained. This material is then cyclized in the presence of iodine and potassium iodide to obtain a 5-arylisospiroline derivative 'R1 in this reaction scheme is an alkyl group or an aryl group. (See, for example, J. Het · c 'hem ·, 30, 467 (1993).) N-Fang a certain imidazole paper size applies the Chinese National Standard (CNS) A4 specification (210X 297 mm) -47-517057 A7 B7 5 Description of the invention (45) Reaction diagram X ΠΙ

Potassium carbonate R11-R12 T Br

59 (Please read the precautions on the back before filling this page) N-arylimidazole analogs printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 5 9 You can borrow 1,4_dibromobendan 8 and imidazole in copper salts In the presence of CuBr, etc., it is produced by the coupling of Ullmann known in the art. The ideal preparation method of the compound of the present invention is also included in the US Patent Application Series No. _ (Attorney's Proceedings List, No. HA 6 8 9 a), the title is ^ " Methods for the Preparation of Biphenyl Isoxazo1e Sulfonamides, Published on January 21, 1997 by Polniaszek et al. 'It is incorporated herein by reference in its entirety. For example, the compound of the present invention can be prepared by a method containing the following steps: (a) A pinacol ester or a salt thereof of the following formula: This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm)-48- 517057 A7 B7 V. Description of the invention (46

Or the boric acid or its salt of the formula = 3 R1

NIP / 1

4 -R 3 R (Please read the notes on the back before filling this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs and '4 Heterocyclic Aryl Halide J_ (its structure is shown in Reaction Diagram I) Or a salt thereof in the presence of a palladium (0) catalyst and a base to form a nitrogen-protected compound K whose structure is also shown in Reaction Scheme I) or a salt thereof; and (b) the above-mentioned compound 1 or Salt nitrogen is deprotected. Preferably, the palladium (0) catalyst is a palladium (Π) salt (especially palladium acetate) and triphenylphosphine; the base is aqueous potassium carbonate or sodium carbonate; > PrOt is methoxyethoxymethyl; And the halogen group in the 4-heterocyclic aryl halide is an iodo group. The initial pinacol ester or its salt can be prepared by methods including the following steps: The paper size applies the Chinese National Standard (CNS) A4 specification (210 X297 mm) -49-517057 A7 B7 V. Description of the invention (47 ) (a) the compound of the formula or its salt: R- 13 halo

V 〇 leaving group

R. 14 wherein the halogen group is preferably a bromo group, and the leaving group is preferably a halogen group (especially a chloro group), and an amine or a salt thereof of the formula:

(Please read the precautions on the back before filling out this page} Printed by the Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs, halo

R1 is bonded in the presence of an organic base and an organic solvent to form a compound of the formula or a salt thereof: 〇

(b) Protect the nitrogen of the compound formed in step (a) to form a compound of the following formula or its salt: This paper size applies the Chinese National Standard (CNS) A4 specification (210X 297 mm)-50-1517057 A7 B7 V. Description of the invention (48

(c) Lithinating the compound formed in step (b) with an alkyl or aryl lithium compound, and then joining the formed lithiated product with a trialkyl borate, followed by hydrolysis to form boric acid of the following formula or Salt: (Please read the notes on the back before filling this page) (h〇) 2b

R1

And printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (d) joining the compound formed in step (c) with pinacol and removing water at the same time. Preferably, > Prot " is methoxyethoxymethyl; the organic base in step (a) is an amine (especially pyridine or trialkylamine); the organic solvent is a haloalkane, or the organic base also has Functions of organic solvents; alkyl or aryl lithium compounds are n-butyllithium or phenyllithium; lithiation and / or bonding with the above trialkyl borate is at about -4 0 ° C to about -1 0 It is carried out at a temperature of 5 ° C; the trialkyl borate is triisopropyl borate or trimethyl borate; the removal of water is carried out by adding a desiccant, or by azeotropic removal of water by heating with a solvent. This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) -51-517057 A7 B7 V. Description of the invention (49) The compound of the present invention can also be prepared by a method containing the following steps: (a) 4- Heterocyclic aryl halide _! _ (Its structure is shown in Reaction Scheme I) or its salt is lithiated with an alkyl lithium or aryl lithium compound in the presence of a trialkyl borate, and then hydrolyzed to form the following formula Boric acid or its salt:

(b) The boric acid or its salt formed in step (a) and the compound or its salt of the following formula: (Please read the precautions on the back before filling this page)

The Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs printed on a palladium (0) catalyst and reacted in the presence of a base to form a nitrogen-protected compound i_ (the structure of which is shown in Reaction Scheme I) or a salt thereof; and (c) deprotecting the nitrogen of the compound formed in step (b). The oxazole phenyl of the following formula or its salt: This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm)-52-517057 A7 B7 V. Description of the invention (5〇

R 12 can be prepared by a method comprising the following steps: (a) the phenyl fluorenyl halide of the following formula or a salt thereof

With the acetal or its salt of the formula: Order (Please read the precautions on the back before filling this page) R2 h2n

O-alkyl 0 ~ alkyl Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. Joined in the presence of alkali and solvent to form amidoacetal or its salt of the formula

halo This paper size applies the Chinese national standard ('·-53-517057 A7 B7 V. Description of the invention (51); and (b) the step (a) household kg% $ & M 月 安 _ MK 盐 方 含 _ & lt Cyclization in the presence of a dagger. Preferably, the halogen group of the fluorenyl moiety in the phenylfluorenyl halide is a chloro group, and the dentate group that is in the opposite position to the fluorenyl tooth moiety is an iodo group; Part of the hospital group is methyl; step (a) + household weight: B gastric carbon; and the cyclizing agent is Eton's reagent (formic acid expansion solution of phosphorus pentoxide). The present invention will now The following current examples further illustrate 'these examples are specific embodiments of the present invention. These examples are for illustration and not limitation. Example 1 N — (3, 4 dimethyl a 5 — iso 11 oxalyl) A 4, — (2 —B stilbyl) ί 1, 1, 1 biphenyl] a 2_ disamin r = \

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) A? — (4-bromobenzene) oxazole will be 4-bromobenzamide (4 g, 20 mmol) Ears), carbonic acid sub-Asian paper size applies Chinese National Standard (CNS) A4 specifications (210X297 mm) -54-517057 A7 B7 V. Description of the invention (52) vinyl ester (1.72 g '20 millimoles) and A mixture of 10 g of polyphosphoric acid was heated at 170 ° C for 3 hours. After cooling, the mixture was partitioned between 200 ml of water and 200 ml of ethyl acetate. The aqueous layer was extracted with 2 × 150 ml of ethyl acetate. The combined organic liquid was then washed with 100 ml of water and 50 ml of brine, dried and concentrated. The residue was separated on a silica gel using 10: 1 hexane / ethyl acetate for color separation to obtain a white solid compound A (2.49 g, 56%). N— (3,4—dimethyl—5—isoxazole) —N ′ — (methoxyethylargon—methyl) benzylsulfonamide_ At-7 8 ° C Cyclohexane solution at a concentration of 2 moles, 8 1 1 ml, 16 2 3 mmoles) was added to 2-bromo-N- (3,4-dimethyl-5-isoxazone) in 10 minutes. Azolyl) — Ν '-(methoxyethoxymethyl) besylate (5.667 g, 13.52 millimoles, according to European Patent No. 569,193 (consumption by employees of the Central Bureau of Standards, Ministry of Economic Affairs) Printed by the cooperative (please read the precautions on the back before filling in this page) 1 9 9 3) in 70 ml of tetrahydrofuran solution, and then stir the resulting solution at 78 ° C for 15 minutes Then, add triisopropyl borate (1-52 g, 8.06 mmol). The mixture was then warmed to room temperature and stirred for 2 hours. The mixture was cooled to 0 ° C, 10% aqueous hydrochloric acid (120 ml) was added, and the solution was stirred for 10 minutes. The mixture was then concentrated to 120 ml and extracted with 4 × 60 ml of ethyl acetate. The combined organic extract was washed once with 100 ml of brine, and dried (magnesium sulfate) and concentrated to obtain compound B (4.25 g, 82%) as a pale yellow gel. This paper size applies the Zhongguanjia Standard (CNS) A4 specification (21GX297 mm) — ~ -55-517057 A7 B7 V. Description of the invention (53) C. N — (3, 4 dimethyl 1 — 5 — evil Oxazolyl) -N-[(2-methoxyethoxy) methyl] -4 '-(2-oxazolyl) [1,1'-biphenyl] -2-fluoramine ___ in Under argon, tris (triphenylphosphine) palladium (0) (95 mg, 0.082 mmol) was added, followed by 4.5 ml of 2 molar aqueous sodium carbonate to compound B (315 mg, 0.5 82 mmol), compound A (456 mg, 2.05 mmol) in 7.5 ml of toluene and 6 ml of a 9 5% ethanol solution. The reaction mixture was heated at 75 ° C for 4 hours, cooled and diluted with 50 ml of ethyl acetate. The organic liquid was then separated and washed with 10 ml and 10 ml of brine, dried and concentrated. Then the residue was separated on a silica gel using 2: 1 hexane / ethyl acetate to obtain a colorless gel-like compound C (279 ml, 70%). D · N — (3,4 dimethyl-5 —isoxazolyl) — 4, 1, (2 —oxazolyl) ί 1,1 'monobiphenyl] — 2 —sulfonamide Printed by the Consumer Bureau of Standards Bureau (please read the precautions on the back before filling this page). Add 10 ml of 6 equivalent aqueous hydrochloric acid to 10 ml of compound C (276 mg, 0.57 mmol). % Ethanol solution, reflux for 1 hour and 10 minutes. The reaction mixture was then concentrated and the pH of the solution was adjusted to 8 using sodium bicarbonate solution. It was then acidified to pH 5 with glacial acetic acid, and the mixture was extracted with 3 x 40 ml of ethyl acetate. The organic liquid was then washed with 10 ml of water and 10 ml of brine, dried and concentrated. The residue was separated on silica gel using 100: 1 dichloromethane / methanol for color separation to obtain the title compound as a white solid (this paper size is in accordance with Chinese National Standard (CNS) A4 specification (210X 297 mm) -'" -56-517057 A7 B7 5. Description of the invention (54) 117 mg, 52%). Melting point 90-98 ° C (amorphous). Calculation and analysis of C2QH17N3〇4S: Calculated value: C, 6 〇_ 7 5; Η, 4. 33; N, 10. 6 3; S, 8. 1 1; Found: C, 6 〇_ 8 0; Η, 4 _ 15; N, 10.38; S, 8 12. ---------— (Please read the precautions on the back before filling out this page) Example 2 N — (2, 4-Dimethyl-F5 _ isoxazolyl 1 1

Ordered by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs to print A (4-bromophenyl) indazole under argon, will (palladium) (triphenylphosphine) palladium (〇) (] _ 〇4 g, 0 9 mmol) 'Next, add 72 ml of 2 Molar aqueous sodium carbonate to 4-bromophenylboronic acid (3.01 g, 15 mmol), 2-bromothiazole (9.44 g, 60 mmol) 120 ml of toluene and 96 ml of a 9 5% ethanol solution. React the reaction mixture at 7-5. <: Heating for 1 hour and 15 minutes, cooling and diluting the paper with 300 ml of ethyl acetate. Applicable to China National Standard (CNS) A4 (210X297 mm) '-57-517057 A7 B7 V. Invention Explanation (55). The organic liquid was then separated and washed with 100 ml of water and 100 ml of brine, then dried and concentrated. Then, the residue was separated on a silica gel using 30: 1 hexane / ethyl acetate for color separation to obtain the title compound (2.0 g, 56%) as a white solid. B. N— (3,4_dimethyl-5—isoxazolyl) —N — [(2-methoxyethoxy) methyl] —4 '— (2—fluorenyl) ί 1, 1—biphenyl] —2 —basic amine _ —_ Under argon, will (triphenylphosphine) palladium (0) (96 mg, 0.083 mmol), and then 4. 5 ml 2 Molar concentration aqueous sodium carbonate was added to compound B (320 mg, 0.83 mmol) and compound A (400 mg, 1.67 mmol) in Example 1 in 7.5 ml toluene and 6 ml 95% ethanol In solution. The reaction mixture was heated at 75 ° C for 3 hours, cooled and diluted with 50 ml of ethyl acetate. The organic liquid was then separated, washed with 10 ml of water and 10 ml of brine, dried and concentrated. The residue is then separated on silica gel using 25: 1 hexane / ethyl acetate for color separation. The colorless gel is printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling in this Page) Compound B (291 mg, 70%). C. N— (3,4—dimethyl-5—isoxazolyl) —4, 1 (2-cryptazolyl) [1,1 ′ —biphenyl] —2-amine will be 1 0 6 ml of aqueous hydrochloric acid at a concentration of 6 equivalents was added to 10 ml of a 95% ethanol solution of Compound B (290 mg, 0.58 mmol) and refluxed for an additional hour. Then the reaction mixture was concentrated, and then the carbon paper was applied to the Chinese National Standard (CNS) A4 specification (210X297 mm). 58-517057. 5. Description of the invention (56) A7 B7 sodium hydrogen acid solution to adjust the P of the solution. To 80, then acidified to PΗ5 with glacial acetic acid, and the mixture was extracted with 3 × 40 ml of ethyl acetate. Then the organic liquid was washed with 10 ml of water and 10 ml of brine, dried and concentrated. The residue was separated on silica gel using 1 0 1 dichloromethane / methanol for color separation > The title compound was obtained as an off-white solid (180 mg 75%). Mp 8 7 — 9 7 ° C (> & □: Pick shape) 〇C 2 0 Η 1 7 Ν 3 〇3 S 2 ·. (). 3 4 Η 2 〇 Calculated analysis calculation value: C > 5 7 5 2; Η 9 4 2 7 9 Ν 1 0 0 6; S 1 1 5 3 5 9 Found: C > 5 7 6 8; Η 9 4 0 8; Ν 9 9 0; S, 1 5.0. 6 ° Example 3 N — (3,4-dimethyl-1-5-isoxazolyl) _4 '-(4, 5-dimethyl-1,2-oxazolyl) [1,1'-biphenyl] -2-sulfamethoxamine I ------- ^ Install ------ Order ------ (Please read the precautions on the back before filling out this page) Printed on the paper by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economy China National Standard (CNS) A4 specification (21〇 × 297 mm) -59-517057 A7 _____B7 V. Description of the invention (57)

---------— (Please read the notes on the back before filling out this page) A. 4— _Bromobenzoic acid, 2 —One of argon monomethylpropyl is set at 0 ° C Next, 5 ml of pyridine was added dropwise to 15 of 3-hydroxy-2-butanone (1.32 g, 15 mmol) and 4-bromobenzyl chloride (3.29 g, 15 mmol) Ml of dichloromethane. Printed by J. Consumer Cooperatives, Central Bureau of Standards, Ministry of Economic Affairs, stir the reaction at room temperature for 5 hours, then add 150 ml of ethyl acetate and filter. The solution was then washed with 2 x 50 ml of 10% hydrochloric acid, 30 ml of water and 30 ml of brine, dried and concentrated. The residue was separated on a silica gel using 10: 1 hexane / ethyl acetate for color separation to obtain a white solid Compound A (3.4 g, 84%). B 2 — (4-Bromophenyl) -4,5-dimethyloxazole compound A (3.4 g, 12.54 mmol), ammonium acetate (9.67 g, 12 5. 4 mmol) Mol) and a mixture of 10 ml of acetic acid were heated at 100 ° C for 4 hours. After cooling, the mixture was delimited between 150 ml of water and 200 ml of ethyl acetate. The paper size of the organic liquid is then applied to the Chinese National Standard (CNS) A4 (210X297 mm) -60-517057 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, printed A7 B7 V. Description of the invention (58) with 50 ml of water and It was washed with 50 ml of brine, dried and concentrated. The residue was separated on a silica gel using 25: 1 hexane / ethyl acetate for color separation to obtain a white solid compound B (1.52 g, 48%). 〇C. Ν— (3, 4_ 2 Methyl- 5 -isoxazolyl) -4,5- (4,5-dimethyl-2-oxazolyl) -N-[(2-methoxyethoxy) methyl] [1,1 'One biphenyl]-2-expandase m___ Under argon, will (triphenylphosphine) palladium (0) (96 mg, 0.083 millimolar), and then 4.5 ml 2 Molar concentration aqueous Sodium carbonate was added to 7.5 ml of toluene and 6 ml of 95% ethanol solution of the compound B (320 mg, 0.83 mmol) obtained in Example 1 and the compound B (420 mg, 1.67 mmol) shown above. . The reaction mixture was heated at 75 ° C for 4 hours, cooled and diluted with 50 ml of ethyl acetate. The organic liquid was then separated, washed with 10 ml of water and 10 ml of brine 'and dried and concentrated. The residue was separated on a silica gel using 1: 1 hexane / ethyl acetate to obtain a colorless gel-like compound C (300 mg, 70%). D. N— (3,4-Dimethyl-5—isoxazolyl) —4,1 (4,5-dimethyl-2—oxazolyl) [1,1, —biphenyl 1— 2 —Sulfonamide_ Add 10 ml of 6 equivalent concentrations of aqueous hydrochloric acid to Compound C (This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm)-61--------- -— (Please read the precautions on the back before filling in this page) Order 517057 A7 B7 V. Description of the invention (59) 3 0 0 mg 0 5 9 mmol) 10 ml of 95% ethanol solution, and then reflux After 1 hour, the reaction mixture was concentrated, and then sodium bicarbonate solution was used to adjust the pH of the solution to Η to 〇, followed by acidification with glacial acetic acid to Η Η 5. The mixture was then extracted with 3 × 40 ml of ethyl acetate. The solution was washed with 10 ml of water and 10 ml of brine, dried and concentrated. The residue was separated on silica gel using 1: 1 hexane / ethyl acetate to separate the color layers to obtain the title compound as a white solid. (178 mg 7 2%) 〇 Melting point 9 6 — 1 2 ° C (^ πτΤ.m shape) 〇C 2 2 Η 2 1 Ν 3〇4 S See 0 2 4 Η 2 0 Value: C 6 1 7 6 • 'Η 9 5 0 6 9 N 9 8 2 > S 7 4 9 9 Found: C 6 1 6 7; Η 9 4 7 6 9 N y 9 9 1 9 S 7 5 9 〇 Example 4 N — (3 J 4-1 Jia Di-5-Dixie Bieji) — 4 > — (! 5-— (Please read the precautions on the back before filling out this page) Central Bureau of Standards, Ministry of Economic Affairs Employee Consumer Cooperative Co., Ltd. prints the base) 卩 1,1, a joint 茏 碏 醯 — 碏 醯 amine r = N This paper size applies to Chinese national standards (

517057 A7 B7 V. Description of the invention (60) A · 5- (4-bromophenyl) oxazole 4.74 g (25.6 mmol) para-bromobenzaldehyde, 5.0 g (25 6 millimoles) tosylate methyl isocyanide and 4.25 g (30.7 millimoles) of anhydrous potassium carbonate in 150 ml of methanol were refluxed for 3 hours. Then the solvent was evaporated, and 150 ml of water was added to the remaining solids. The yellow-brown-white solid was filtered, washed with water several times, and then dried to obtain compound A (3. 65 g, 64%) 〇 ·· B— (3,4-dimethyl-1, 5-isoxazolyl) -N — [(2-methoxyethoxy) methyl] —4 ′ — ( 5 —oxazolyl] [1,1 'a biphenyl]-2-hydrazine _ Under argon, 15 ml of 2 molar aqueous sodium carbonate, and then 0.70 g (3. 12 mmol) Moore) 15 ml of 95% ethanol solution of compound A was added to 0.8 g (2.0 mmol) of compound B obtained in Example 1 and 0.12 g (0.1 mmol) of triphenylphosphine ) Palladium (printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page)) 2) in 25 ml toluene solution The mixture was refluxed for another 3 hours, diluted with 100 ml of water and extracted with 3 x 7 5 ml of ethyl acetate. The combined organic extracts were washed once with 1000 ml of brine, dried and evaporated. Then, the residue was separated on 50 g of silica gel using hexane / ethyl acetate 1: 1 to obtain 0.49 g (49%) of compound B as a colorless gel. C. N— (3,4 dimethyl-5—isoxazolyl) —4, 1 (this paper size applies to China National Standard (CNS) A4 specification (210X297 mm) " " ONE 63-517057 A7 _____ _ B7 V. Description of the invention (61) and an oxazolyl group [1,1 '-biphenyl] -2-sulfonamide Add 10 ml of 6 equivalent concentration aqueous hydrochloric acid to 0.4 9 g (101 mmol) Compound B in 10 ml of a 9 5% ethanol solution was refluxed for an additional hour. The mixture was then concentrated and diluted with 50 ml of water. The solution was neutralized to pH 7 with saturated aqueous sodium bicarbonate and then acidified to pH 4 with glacial acetic acid. The resulting white solid was filtered and dried (0.37 g). Then, it was crystallized from methylene chloride / ethyl acetate / hexane to obtain 0.23 g (58%) of the title compound as a white solid. Melting point 189-191. (： --------- 衣 — (Please read the notes on the back before filling this page) C 2 0 Η ιγΝ 3 〇4 S, .0 • 2 8 Η 2 0 Calculated value: C , 6 0. 0 0; Η, 4.4 2 Ν, 1 0. 4 9; S, 8. 0 1 found: C, 6 0. 1 0; Η, 4. 1 7 Ν, 1 0. 3 9; S, 8.0 4

Order J0 517057 A7 B7 V. Description of the invention (62) A · 4 — (4-Mobenzol) n mile will be 5 — 0 grams (18.0 millimolar) α, ρ_dibromoacetophenone and 4 05 grams (89. 9 millimoles) of the metformamide mixture in oil (please read the precautions on the back before filling this page) in the bath, and stir at 130 ° C for 3 hours. The mixture was then poured into 150 ml of ice / water and the solution was extracted with 3 x 1000 ml of ether. The combined ether extract was washed once with water, dried and evaporated. Then, the residue was separated on 200 ml of silica gel using hexane / ethyl acetate 1: 1 to obtain 1.3 g (32%) of compound A as a light brown solid. B. N — (3,4 —dimethyl-5 —isoxazolyl) —N — [(2 —methoxyethoxy) methyl] — 4, _ (4 —oxazolyl) __ 〔 1,1,1 biphenyl]]? Monosulfonamide_ Under argon, 15 ml of 2 mol aqueous sodium carbonate was added, and then 0.52 g (2.32 mmol) of compound A in 15 ml of 95% ethanol was added to 0.668 Example (1_74 millimoles) Example 1 Printed by a Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs and Compound 104 and 0.014 grams (0.09 millimoles) of palladium (triphenylphosphine) 2 in 5 ml of toluene solution. The mixture was refluxed for another 3 hours, diluted with 100 mmol of water and extracted with 3 × 7 5 ml of ethyl acetate. The combined organic extracts were washed once with 1000 ml of brine, dried and evaporated. Then, the residue was separated on 50 g of silica gel using hexane / ethyl acetate 2: 1 to obtain chromatographic separation, to obtain 43 g (51%) of Compound B as a colorless gel. This paper size applies the Chinese National Standard (CNS) A4 specification (21〇 > < 297 mm) -65-517057 V. Description of the invention (63) Printed by A7 B7 C Ν— 3 9 4 — dimethyl — 5 monoisoxazolyl) — 4, mono- \ (4 —oxazolyl) C 1 1 f _ -biphenyl]-2-_ extended amine at 0 V 9 Add dimethylsilyl chloride (201 grams) and sodium chloride (27.3 grams) to 0.85 grams (1.55 millimoles) of compound B under M The mixture was stirred at room temperature for 1 hour in ml of acetonitrile solution, and then the mixture was diluted with 10 ml of water and extracted with 100 ml of ethyl acetate. Then the organic layer was washed with 10 ml of saturated aqueous sodium thiosulfate and Pre-dried and evaporated. This material was then borrowed on a 30 X 500 mm 〇DSS 1 .C) column for reverse-phase preparation of high-performance liquid chromatographic separation and the use of 68% solvent A (90% methanol 10% water »0 1 % Trifluoroacetic acid) and 32% solvent B (10% methanol 90 0 *% water washes 0 1% trifluoroacetic acid) were purified by elution. Then the appropriate fraction y was collected and neutralized with aqueous sodium bicarbonate. To pH 7 and then concentrated to 10 ml. Then the solution was acidified to PΗ4 with glacial acetic acid, and then the white solid was filtered and dried to obtain 0.33 g (54%) of the title compound. Melting point 8 5 — 9 3 ° c (/ πτ m shape) 0 C 2 0 Η 1 7 Ν 3 〇4 S • 0 2 1 Η 2 0 Calculated and calculated value C y 6 0 1 8 Η 4. 4 0 9 Ν 1 1 0 5 3 S 8. 0 3 9 Measured value: C y 6 0 2 7 9 Η 4 4. 0 5 9 Ν > 1 0 4 4 JS 7. 8 8 0 (Please read the precautions on the back before filling in this Page) Example 6 This paper size applies to China Standard (CNS) A4 (210 × 297 mm) -66-517057 5

N A7 B7 、 Explanation of the Invention M amine

n

CH, --------- ^^ 衣-(Please read the notes on the back before filling this page)

, 1T printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs, A. ^-(4-bromophenyl) -2-methyl will be 2 '4-monobromoacetophenone (2.78 g, 10 mmol) Ear) and acetamide (1-448 g, 25 mmol) were heated at 130 ° C for 3 hours. The mixture was poured onto 30 g of ice, and then 150 ml of ethyl acetate was added. Then, the organic layer was separated, washed with 30 ml of 1 equivalent sodium hydroxide, 30 ml of equivalent hydrochloric acid and 30 ml of brine ', dried and concentrated. The residue was separated on a silica gel using 15: 1 hexane / ethyl acetate for color separation to obtain a white solid Compound A (1.29 g, 54%). B. N — (3,4-Dimethyl-5—isoxazolyl) —N _ [(2-methoxyethoxy) methyl] -4,1- (2-methyl-4) Paper size Applicable to Chinese National Standard (CNS) A4 specification (21 × 297 mm) ~ 67-517057 A7 B7 V. Description of the invention (65) " " Dioxazolyl) [1, 1 '—biphenyl] ? Monoamine under argon, will be (triphenylphosphine) palladium (0) (78 mg, 0_ 068 millimolar), and then 3.9 ml 2 Molar aqueous sodium carbonate to Compound A (402 Mg, 1.7 mmol) and compound B (259 mg, 0.68 mmol) obtained in Example 1 in 6.5 ml of toluene and 5.2 ml of a 95% ethanol solution. The reaction mixture was heated at 75 ° C for 3.5 hours, cooled and diluted with 40 ml of ethyl acetate. The organic liquid was then separated, washed with 10 ml of water and 10 ml of brine, dried and concentrated. The residue was separated on a sand gel using 1: 1 hexane / ethyl acetate for color separation to obtain compound B (183 mg, 54%) as a colorless gum. C_N— (3,4-Dimethyl-5—isoxazolyl) —4,1- (2-methyl—4-oxazolyl) [1,1,1-biphenyl] —2—sulfonamidine Amine ___ Add 6 ml of 6 equivalent concentrations of aqueous hydrochloric acid to 6 ml of 95% ethanol solution of compound B (180 mg, 0.36 mmol) printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the back first) Note: Please fill in this page again) and return the binding solution for 5 5 minutes. The reaction mixture was then concentrated, and the pH of the solution was adjusted to 8 using sodium bicarbonate solution. It was then acidified to ρ Η 5 with glacial acetic acid. The mixture was extracted with 3 × 30 ml of ethyl acetate. The organic liquid was then washed with 10 ml of brine, dried and concentrated. The residue was separated on a silica gel using 100: 1 dichloromethane / methanol for color separation to obtain the title compound (56 mg, 38%) as a pale yellow solid. 〇 This paper standard applies Chinese National Standards (CNS ) Α4 specifications (2! 〇χ297 mm) -68-517057 V. Description of the invention (66) A7 B7 Melting point 9 0-1 0 0 ° C (/ rrp m shape) ο C 2 1 Η ι9Ν 3 〇4 S Calculation and analysis: Calculated value ·· C 6 1 6 0 Η, 4. 6 8; Ν 1 0 2 6 S, 7.8 3; Measured value: C 6 1 5 6 Η, 4. 3 3; Ν, 9. 8 9 S 1 7 9 4 〇 Example 7 N- (3,4-dimethyl- 5 -isoxazolyl)-4 '-(4-

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) A. 2 — (4-Bromophenyl) -4_methyloxazole at -15 ° C, the 4 —Bromobenzyl (9.1 g, 50 mmol) and propargyl alcohol (2.8 g, 50 mmol) were added to 12.5 ml of concentrated sulfuric acid in portions. The reaction was stirred at 0 ° C for 3 hours. The paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm) -69-517057 A7 B7 V. Description of the invention (67) Slowly warm to room temperature, then Stir overnight. The mixture was then poured into 2000 ml of ice water, neutralized with sodium bicarbonate and extracted with 3 × 20 esters. The combined organic liquid was then washed with 50 ml of brine, dried, and concentrated. The residue was separated on a silica gel using 30: ιB | end / ethyl acetate for color separation to obtain a white solid compound A (144 g, 12%). B. N- (3,4-dimethyl-2-5-isoxazolyl) -N-[(• 2-methoxyethoxy) methyl]-4 '-(4-methyl-2— π-Evilyl) [1,1, -biphenyl]-2-mineral beer_ Under argon, will be (triphenylphosphine) palladium (〇) (96 mg, 0.083 mmol), and then 4.5 ml of 2 mole aqueous sodium carbonate was added to compound B (320 mg, 0.83 mmol) obtained in Example 1 and 7. 5 ml of toluene of compound A (397 mg, 1.67 mmol). And 6 ml of 95% ethanol solution. Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Reaction and Mixing (please read the precautions on the back before filling this page). The mixture was heated at 75 ° C for 4 hours, cooled and diluted with 50 ml of ethyl acetate. The organic liquid was then separated, washed with 10 ml of water and 10 ml of saline, dried and concentrated. The residue was separated on a silica gel using 1: 1 hexane / ethyl acetate to obtain a colorless gel-like compound B (300 mg, 72%). C. N— (3,4-dimethyl-5—isopyridyl) —4 ′ — (4-methyl-2-oxazolyl) [1,1′—biphenyl] —2—expansion Fermented amines_ This paper size applies to Chinese National Standard (CNS) A4 specifications (210X297 mm) -70-517057 Employees' cooperation cooperation with the Central Standards Bureau of the Ministry of Economy Du printed A7 B7 Γ ------ V. Description of the invention < 68) 10 ml of 6 equivalent strength aqueous hydrochloric acid was added to 10 ml of a 95% ethanol solution of compound B (300 mg 0 60 mmol), and the mixture was refluxed for 1 hour, and then the reaction mixture was concentrated. The sodium bicarbonate solution was used to adjust the P Η of the solution to 8 and then acidified to P Η 5 with glacial acetic acid. The mixture was then extracted with 3 × 40 ml of ethyl acetate, and the organic liquid was washed with 10 ml of water and 10 ml. Washed with brine, dried and concentrated. Then the residue was separated on silica gel using 100 • 1 dichloromethane / methanol to separate the layers to obtain a white solid standard. The title compound (2 1 30 mg 81%) 〇 Melting point 8 5 — 9 5 ° C (selective shape) 〇C 2〇Η 1 9 Ν 3 〇 4 S See 0 2 5 Η 2 0 calculation analysis calculated value C > 6 0 9 2 > Η 4 7 5 9 Ν, 1 0 1 5 9 S > 7 7 4 9 found: C 6 1 1 5; Η 9 4 6 0; Ν, 9 _ 8 9 y S 7 6 2 〇 Example 8 N _ (3, 4 monomethyl _ 5 _ isoxazolyl)-4,--(5-—methyl 2 oxanyl) 1 9 1 9 _ -biphenyl]) . 2 monosulfon'njyfsr amine (please read the precautions on the back before filling this page) This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) -71-517057 A 7 B7 V. Description of the invention ( 69) ch3

----------- (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs A. 2 — (4-bromobenzene) -5—methyl At 0 ° C, propargylamine (1.10 g, 20 mmol) was added, followed by triethylamine (4.05 g, 40 mmol) to 4-bromophenylphosphonium chloride (4 39 g, 20 mmol) in 40 ml of dichloromethane. The mixture was stirred at room temperature for another 40 minutes. Then 150 ml of ethyl acetate was added and filtered. The filtrate was then washed with 2 × 40 ml of water and 40 ml of brine, dried and concentrated to give 4-bromo-N- (2-propynyl) benzidine. 4-Bromo-N- (2-propynyl) benzidine was added to 47 ml of concentrated sulfuric acid which had been cooled with ice. The reaction was stirred at 5-10 ° C for 3 hours and at room temperature overnight. The mixture was then poured into 500 ml of ice water, neutralized with sodium carbonate to pH Η 8, and extracted with 3 x 250 ml of ethyl acetate. Then, the combined organic extract was washed with 200 ml of water and 100 ml of brine, and dried and concentrated to obtain Compound A (4.5 g, 95%) as a pale yellow solid. This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) -72-517057 A7 B7 V. Description of the invention (70) B · N— (3,4-dimethyl_5—isoxazolyl group ) -N-[(2-methoxyethoxy) methyl] -4 '-(5-methyl-2 2-otriazole) [1,1'-biphenyl] -2 -sulfamethoxamine Under argon, tris (triphenylphosphine) palladium (〇) (96 mg '0.083 mmol) was added to 4.5 ml of 2 molar aqueous sodium carbonate to compound B obtained in Example 1 (3 2 0 Mg '0.83 mmol) and compound A (397 mg, 1.67 mmol) in 75 ml of toluene and 6 ml of 95% ethanol solution. The reaction mixture was heated at 75 ° C for 3 hours, cooled and diluted with 50 ml of ethyl acetate. The organic liquid was then separated, washed with 10 ml of water and 10 ml of saline, dried, and concentrated. The residue was separated on a silica gel using 1: 1 hexane / ethyl acetate for color separation to obtain the compound B (298 mg, 72%) as a colorless gel. C_ N — (3,4 dimethyl-5—isoxazolyl) —4 ′ — (5-methyl-2—oxazolyl) [1,1′_biphenyl] —2—sulfonamidine Amine _ Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) Add 10 ml of 6 equivalent aqueous hydrochloric acid to Compound B (298 mg, 0.60 mmol ) In 10 ml of 95% ethanol solution and reflux for 1 hour. The reaction mixture was then concentrated, and the pH of the solution was adjusted to 8 using sodium bicarbonate solution, then acidified to pH 5 with glacial acetic acid, and the mixture was extracted with 3 x 40 ml of ethyl acetate. The organic liquid was then washed with 10 ml of water and 10 ml of brine, dried and concentrated. The residue is then used on silicon gel with 100: 1 dichloromethane / A paper size applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) -73-517057 A7 B7 V. Description of the invention (71) Central Ministry of Economic Affairs Standard Bureau employee consumer cooperative printed alcohol to separate the color layer to obtain the title of gray-white solid mg 60%) 〇 Melting point 9 0 — 1 0 0 ° c (amorphous) ο C 2 1 Η 19 Ν 3 (S calculation Analytical calculation C, 6 1 6 0 Η > 4. 6 8 Ν 1 0 2 6 S 7. 8 3 Measured value; C 6 1 3 9 ϊ. 4. 1 1 • Ν 1 0 0 3 S 7. 6 1 N — (Example 14 7, 4 —Dimethyl-5_ isoxazolyl) — 4′_ (1H pyrazol-1 —yl) [1,1 ′ —biphenyl] — 2 —sulfonamide

Mono (4-bromophenyl) 1 _ _pyrazole Triethylamine (8.75 g, 12.05 mmol) was added dropwise to epichlorohydrin (4 g, 4 3.3 mmol) And 4 monobromophenylhydrazone hydrochloride (19.32 g, 86.46 mmol) in 20 ml of 60% ethanol. The mixture is then slowly warmed, and then refluxed for 1 hour. The paper size applies the Chinese National Standard (CNS) Α4 specification (210 × 297 mm) (Please read the precautions on the back before filling this page) 74-517057 Α7 Β7 V. Description of the invention (72). The solvent was then evaporated and the residue was heated at 170 ° C for 30 minutes and at 2000 ° C for another 10 minutes. Then 150 ml of water was added to the '' and the mixture was extracted with 3 x 2000 ml of ethyl acetate. Then the combined organic liquid was washed with 50 ml of brine, dried and concentrated, and the residue was separated on a silica gel using 40: 1 hexane / ethyl acetate for color separation to obtain compound A (2.92 G, 30%), which was crystallized from hexane to give a yellow needle. Melting point 7 2 — 7 4 ° C. B_ N — (3,4—dimethyl-5—isoxazolyl) —N — [(2-methoxyethoxy) methyl] —4 '— (1H—pyrazole—1-yl) [1,1 'a biphenyl sulphate] _2 -sulfamethoxamine_ Under argon, will be (triphenylphosphine) palladium (◦) (96 mg, 0.083 mmol), and then 4.5 ml 2 Molar concentration of aqueous sodium carbonate was added to compound B (320 mg, 0.83 mmol) and compound A (372 mg, 1.67 mmol) obtained in Example 1 in 7.5 ml toluene and 6 ml 95% ethanol In solution. Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Reaction and Mixed Economy (please read the precautions on the back before filling in this page). The mixture was heated at 75 ° C for 2.5 hours, cooled and 50 ml of ethyl acetate. dilution. The organic liquid was then separated, washed with 10 ml of water and 10 ml of brine, dried and concentrated. The residue was separated on a silica gel using 2.5: 1 hexane / ethyl acetate for color separation to obtain the compound B (280 mg, 70%) as a colorless gel. C. N— (3,4 dimethyl-5—isoxazolyl) —4, — (This Zhang scale applies to China National Standard (CNS) A4 specification (210X297 mm)-75-517057 A7 ____B7 _ V. Description of the invention (73) 1H-pyrazole-l-yl) [1,1, -biphenyl]-2-sulfamethoxamine 10 ml of 6 equivalent hydrochloric acid is added to compound B (2 8 (0 mg '0 58 mmol) in 10 ml of a 95% ethanol solution. The reaction mixture was concentrated and the pH of the solution was adjusted to 8 using sodium bicarbonate solution. It was then acidified to pH 5 with glacial acetic acid. The mixture was extracted with 3 × 40 ml of ethyl acetate. The organic liquid was then washed with 10 ml of water and 10 ml of brine, dried and concentrated. The residue was then separated on silica gel using 100: 0.8 dichloromethane / methanol to separate the color layers to obtain the title compound (161 mg, 70%) as an off-white solid. Mp 88 — 98 ° C (amorphous) . C20Hi8N403S * 〇. 12H2〇 calculation and analysis: Calculated value: C, 60. 56; H, 4. 64; N, 14. 12; S, 8. 08; Found: C, 6 1. 2 6; Η, 4. 52; N, 13. 96; S, 8.06 ° Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) Example 1 0 N— (3, 4, 12 Methyl_5 —Isoxazole, a) 4 ′-[1 — [((2 —Acetoethoxy) methyl] —1H —imidazol-2-yl] [1,1 ′ —biphenyl]] 1 2-The standard of this paper is Chinese National Standard (CNS) A4 (210X297 mm) -76-Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 517057 A7 ____ B7 V. Description of Invention (74)

A. 1- (4-bromophenyl) -1H-imidazole was added dropwise 60 ml of 30% aqueous ammonium hydroxide to 4-bromobenzaldehyde (9.25 g, 50 mmol) and ethylenediol. Aldehyde (40% by weight aqueous solution, 11.6 ml, 80 mmol) in 20 ml of methanol was added and the mixture was stirred at room temperature overnight. The solvent was then evaporated under vacuum. Aqueous sodium hydroxide was added to make the residue slightly alkaline, followed by extraction with 3 × 300 ml of ethyl acetate. The combined organic extracts are dried and concentrated. The residue was dissolved in 100 ml of methanol and filtered. Then, the filtrate was concentrated, and the residue was triturated with 20 ml of ether to obtain Compound A (1.8 g, 16%) as a brown solid. B. 2 — (4-Bromophenyl) —1 — [(2-methoxyethoxy) methyl] —1H—Miridine ___ Sodium hydride (60% mineral oil, 86 mg, 2 15 mmol) was added to 18 ml of tetrahydrofuran solution of compound A (400 mg, 1.79 mmol). The mixture was stirred at room temperature for another 10 minutes. Then methoxyethoxymethyl chloride (335 mg, 2.59 mmol) was added dropwise. The reaction was then stirred at room temperature for 2 hours and then concentrated. Then 100 ml of ethyl acetate was added, and the organic liquid was washed with 20 ml and 10 ml of brine, dried and concentrated. Then apply the remaining paper size to Chinese National Standard (CNS) A4 specification (210 × 297 mm) ----------- (Please read the precautions on the back before filling this page),? Τ -77- 517057 A7 B7 V. Description of the invention (75) The retentate was separated on silica gel using 1 00: 4 0 0: 1 hexane / ethyl acetate / triethylamine for color separation to obtain compound B (390 mg, 70%) . C. N — (3,4-dimethyl-1, 5-isoxazolyl) — N — [(2-methoxyethoxy) methyl] — 4 '— [1 — [(2 — methoxy Ethoxy) methyl] -1H-imidazol-2-yl] [1 :: L'-biphenyl]] sulfonamide_ Under argon, (triphenylphosphine) palladium (0) (145 Mg, 0.125 millimolar), and then 6.75 ml of 2 mole aqueous sodium carbonate was added to the compound obtained in Example 1 (722 mg, 1.88 millimolar) and Compound B (390 mg shown above) (1, 25 mmol) in 11.25 ml of toluene and 9 ml of a 9 5% ethanol solution. The reverse mixture was heated at 75 ° C for 3 hours, cooled and diluted with 75 ml of ethyl acetate. The organic liquid was then separated, washed with 15 ml of water and 15 ml of brine, dried and concentrated. The residue was then separated on silica gel using 100: 0. 2 ethyl acetate / triethylamine for color separation, which was printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page ) Compound C (400 mg, 56%) as a colorless gel. D_N — (3,4 —dimethyl-5 —isoBoxanyl) — 4 ′ — [1 — [(2-methoxyethoxy) methyl] —1H—imidazole—2-yl] il, 1'-biphenyl]-2-amidine_ 12 ml of 6 equivalent aqueous hydrochloric acid was added to 12 ml of 95% ethanol solution of compound C (400 mg, 0.70 mmol) Paper size applies Chinese National Standard (CNS) A4 specification (210 × 297 mm) -78-517057 A7 B7 V. Description of the invention (76) Reflow in liquid for 1 hour. The reaction mixture was then concentrated, and the pH of the solution was adjusted to 8 ° using sodium bicarbonate solution, and then acidified to pH 5 with glacial acetic acid. Another 200 liters of ethyl acetate was added to 'the organic liquid was washed with 20 ml and 20 ml of brine', filtered, dried and concentrated. The residue was separated on silica gel using 100: 4: 0. 2 dichloromethane / methanol / ammonium hydroxide for color separation to obtain the title compound (2 10 mg, 62%). Crystallization from ethyl acetate / hexane gave white crystals. Melting point 8 1 — 8 4 ° C. C24H26N405S · 0.2 4H20 calculation analysis: Calculated value: C, 59. 20; H, 5. 48; Ν, 11. 51; S, 6. 58; Found: C, 5 9. 2 5;;, 5. 42; N, ll. 46; S, 6.39. Example 1 1 N- (3,4 Dimethyl-5 -isoxazole) -4, _ [1 — [(2-hydroxyl ethoxy) methyl]-1H-mili 2 ^ Ministry of Economic Affairs Printed by the Consumer Standards Cooperative of the Central Bureau of Standards (please read the precautions on the back before filling this page) _2 One and One Base] [1,1 '—Biphenyl] -2 —Phenamine

This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 79-517057 A7 B7 V. Description of the invention (77) A. N — (3, 4 — dimethyl — 5 — isoxazolyl) One 4, one [1 one [(2-Ethylethoxy) methyl] one 1H —imidazine 2 —some] [1,1 ′ —biphenyl] one? Monoamidine_ Boron tribromide (1 mole of dichloromethane, 0.37 ml, 0.37 mmol) was added dropwise to the title compound of Example 10 (120 mg, 0 at 0 ° C) 25 millimoles) in 2.5 ml of dichloromethane. The reaction mixture was stirred at 0-3 ° C for 4 5 minutes. Then add 5 ml of saturated aqueous sodium bicarbonate and stir for another 10 minutes. It was then acidified to pH 5 with glacial acetic acid and extracted with 3 x 40 ml of 100: 5 dichloromethane / methanol. The combined organic extracts are then dried and concentrated. The residue was then borrowed on a 30 X 500 mm ◦ DSS 100 column for preparative high performance liquid chromatography and using 62% solvent A (10% methanol, 90% water, 0.1% three Fluoroacetic acid) and 38% solvent B (90% methanol, 10% water, 0.1% tetrahydrofuran) were eluted and purified to obtain the title compound (80 mg, 69%) as a white solid. Melting point 93 — 103 ° C. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the notes on the back before filling this page) C23H24N405S · 0.7 5H20 Calculation and analysis: Calculated values: C, 57. 31; H, 5. 33; N, 11.62; S, 6.65; Found: C, 5 7 6 1; Η, 5.0 4; N, ll. 3 3; S, 6. 55. This paper size applies to Chinese National Standard (CNS) A4 (210X 297 mm) -80-Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 517057 A7 _____ B7 V. Description of the Invention (78) Example 1 i 1L— (3, 4-dimethyl-1, 5-isoxazolyl) -4,1- (1-methyl-1H-imidazol-2-yl) [1,1'-biphenyl] -2-sulfamethoxamine, lithium salt

A. 2- (4-bromobenzene)-1-methyl-1H-imidazole Sodium hydride (60% mineral oil, 151 mg, 3. 77 mmol) was added to compound A obtained in Example 10 (700 Mg, 3.14 mmol) in 7.8 ml of tetrahydrofuran and 7.8 ml of dimethylformamide solution. The mixture was stirred at room temperature for another 10 minutes. Then methyl iodide (891 mg, 6.28 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour and concentrated. Then 100 ml of ethyl acetate was added, and the organic liquid was washed with 20 ml of water and 20 ml of brine, dried and concentrated. The residue was separated on silica gel using 100: 1: 1: 0.1 dichloromethane / methanol / ammonium hydroxide for color separation to obtain compound A (500 mg, 67%). Β · N — (3,4 dimethyl-5 —isoamyl) —N — [(2 -methoxyethoxy) methyl] -4, 1 (1 -methyl-one paper size Applicable to China National Standard (CNS) A4 specification (210X297mm) --------------- Order ------ 9 (Please read the precautions on the back before filling this page) -81-517057 A7 ____ B7 V. Description of the invention (79) 1H —imidazol-2-yl) [1,1, —biphenyl] 2-sulfamidazine _________ Under argon, triphenylphosphine (triphenylphosphine) ) Palladium (0) (96 mg, 0.083 mmol), and then 4-5 ml of 2 molar aqueous sodium carbonate was added to Compound B obtained in Example 1 (320 mg, 0.83 mmol) And compound A (395 mg, 1.67 mmol) in 7.5 ml toluene and 6 ml 95% ethanol solution. The reaction mixture was heated at 75 ° C for 3 hours, cooled and diluted with 50 ml of ethyl acetate. The organic liquid was then separated, washed with 10 ml of water and 10 ml of saline, dried and concentrated. The residue was then separated on a silica gel using 100: 1. 5: 0_ 1 dichloromethane / methanol / ammonium bicarbonate for color separation, to obtain a colorless gel-like compound A (254 mg, 61%). N— (3,4—dimethyl—5—isooxazolyl) —4, — (1—methyl—1H—imidazole—2—yl) [1,1, biphenyl] —2—sulfo Phenamine, lithium salt _ Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) Add 9 ml of 6 equivalent aqueous hydrochloric acid to Compound B (250 mg, 〇. 50 mmol) in 9 ml of 95% ethanol solution and refluxed for 1 hour. The reaction mixture was concentrated, and the pH of the solution was adjusted to 8 using a sodium bicarbonate solution. It was then acidified to pH 5 with glacial acetic acid. The mixture was extracted with 200 ml of ethyl acetate, and the organic layer was washed with 20 ml of water and 20 ml of brine, dried and concentrated. Then use the residue on the silicone 100: 6: 0. 3 dichloromethane / This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) -82-517057 A7 B7 V. Description of the invention (SO) Printed with methanol / bicarbonate Afr by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. Strict chromatographic separation to obtain Ν-(3,4 —dimethyl — 5 — isoxazolyl) — 4 f — (1 monomethyl — 1 Η —imidazole — 2 —yl) [1 1 9 mono-biphenyl]-2--sulfamethoxamine (189 mg 92 2%), dissolved in 1 equivalent of lithium hydroxide, and added to Η On a P-20 column > eluting with water and then 10: 3 water / methanol to obtain the title compound as a white solid. Melting point > 2 0 0 ° c decomposition 0C 2 1 Η 19 Ν 4 0 3 SL i • 2 7 5 Η 2 0 calculation analysis: Calculated value: C 9 5 4 3 7 9 Η 1 5. 3 2; Ν 9 1 2 0 8, S 9 6. 9 1; Measured value C 1 5 4 5 8; Η 1 5. 0 5; Ν 9 1 1 8 7; S 1 6. 8 0 ° 3 1 Example (please read the notes on the back before filling This page) Ν

3 / IV 5-Methylmethylazolium isofluorene 1 ± yl- 2-azole imidium salt rrrll lithium amine sulfonyl-2ylbenzene

Benzyl bromide I 4 / VI 2 Zolimi I Η 1 ± The size of the acid carboxyl paper is applicable to the Chinese National Standard (CNS) A4 (210X297 mm) -83-517057 A7 ___B7 V. Description of the invention (si) 1 —Dimethyl Ethyl acetate_: Ditert-butyl dicarbonate (524 mg, 2.4 mmol) and 4-dimethylaminopyridine (24.4 mg, 0.2 mmol) are added to (please read first Note on the reverse side, please fill in this page again) In the compound A (446 mg, 2 mmol) obtained in Example 10 in 20 ml of acetonitrile solution. The reaction mixture was stirred at room temperature overnight and concentrated. Then, the residue was separated on a silica gel using 6: 1 hexane / ethyl acetate for color separation to obtain Compound A (500 mg, 7 7%) as a pale yellow oil. B_4, [[1-[(1,1-Dimethylethoxy) carbonyl] _1H—Milim-2-yl] -N— (3,4-Dimethyl-5—isoD-oxa Group) -N — [(2-methoxyethoxy) methyl] [1, 1, —biphenyl] _2_sulfonamide_ Under argon, the (triphenylphosphine) palladium (0) (149 mg, 0: 129 millimoles), and then 6.75 milliliters of 2 moles sodium bicarbonate sodium carbonate was added to compound B (496 mg, 1.29 millimoles) and compound A obtained in Example 1. (500 milligrams, 1.55 milligrams printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, printed in Moore) 11. 2 5 ml toluene and 9 ml 9 5% ethanol solution. The reaction mixture was heated at 75 ° C for 3 hours, cooled and diluted with 75 ml of ethyl acetate. The organic liquid was then separated, washed with 15 ml of water and 15 ml of brine, dried and concentrated. The residue was separated on a silica gel using 40: 60: 0.2 hexane / ethyl acetate / triethylamine to separate the chromatographic layers to obtain compound B (380 mg, 51%) as a colorless gel. ^ The paper size applies the Chinese National Standard (CNS) A4 specification (210X: 297 mm) " I-84-517057 A7 —_B7__ V. Description of the invention (82) c. N— (3, 4 — Dimethyl-5 —Isoxazolyl) -1,1 (1H-imidazol-2-yl) [1,1'-biphenyl] -2-sulfonamide, lithium salt __ 12 ml of 6 equivalent concentration aqueous hydrogen Chloric acid was added to 12 ml of a 95% ethanol solution of compound B (38 mg, 0.65 mmol) and refluxed for an additional 1 hour 4 5 minutes. The reaction mixture was then concentrated, and the pH of the solution was adjusted to 8 using sodium bicarbonate solution. It was then acidified to pH 5 with glacial acetic acid and extracted with 3 x 80 ml of 100: 5 dichloromethane / methanol. The organic extract was dried and concentrated. The residue was dissolved in a working equivalent concentration of lithium hydroxide, and then water was applied on a HP-20 column, followed by elution with 10: 2 water / methanol to separate the color layers to obtain the title compound as a white solid ( 180 mg, 69%). Melting point> 2 2 0 ° C Decomposes. Calculation and analysis of C20Hi7N4〇3SLi, 2.006H2〇: Calculated value: C, 54. 91; H, 4. 87; N, 12. 81; S, 7. 33; Found: C, 5 4. 9 9; Η, 4. 7 8; printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) N, 12. 73; S, 6. 95 ° Example 1 4 N— (3, 4-dimethyl-1, 5-isoxazolyl), 4, _ (5-methyl-4, 4-oxazolyl) [1,1'-biphenyl, one], 2-diamine, paper scale applicable to China National Standard (CNS) A4 Specification (210X297 mm) -85-517057 A7 B7 V. Description of Invention (83)

A 4 — (4-Bromophenyl) -5methyloxazole Bromine (2.40 g, 15 mmol) was added dropwise to 4 ′ monobromo at 50 ° C over 10 minutes Propofaben (3.52 g, 16.5 mmol) and formamidine (10. 81 g, 240 mmol). The reaction mixture was heated from 50 ° C to 130 ° C over a period of 20 minutes, and then heated at 130 ° C for 4 hours. After cooling, 150 ml of ethyl acetate was added, and the liquid was washed with 2 × 20 ml of water and 20 ml of brine, dried and concentrated. The residue was separated on a silica gel using 40: 1 hexane / ethyl acetate for color separation to obtain compound A (1.59 g, 45%). (Please read the notes on the back before filling out this page) Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

3 I N B based Iso

N 4 group 1 benzene 3 biyl methyloxy d ethyl / yl, oxymetazole-oxal 2 yl methyl-5 amine sulfonium I 2 11 1 、, the ear 1 A, no argon under the examples Up to 1 plus. Sodium} ο Acid phosphine will benzylbenzene followed by palladium 5 carbon, 6 grams of water and 1 concentration of 1 ear 1 mo (2) liter ο milli (4

Mo Shenghao ο 9 1 X] /, ear grams Mohao 4 7 8 3 1 Γν, Β grams of matter are 8 ο ο get 4 C This paper size applies the Chinese National Standard (CNS) A4 specification (210X 297 mm) -86-517057 A7 B7 V. Description of the invention (84) Toluene and 7.2 ml of 95% ethanol. The reaction mixture was heated at 7 ° C for 3 hours, cooled and diluted with 60 ml of ethyl acetate. The organic liquid was then separated, washed with 15 ml of water and 15 ml of brine, dried and concentrated. The residue was separated on a silica gel using 2 · 5: 1 hexane / ethyl acetate for color separation to obtain the compound B (317 mg, 64%) as a colorless gel. C · N— (3,4-dimethyl-5—isooxazolyl) -4, 1 (5-methyl-4—oxazolyl) [1,1′-biphenyl] —2—sulfonic acid Phenamine _ Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) Add 10 ml of 6 equivalent concentration aqueous hydrochloric acid to Compound B (300 mg, 0.60 mmol Mol) in 10 ml of 95% ethanol solution and refluxed for another 1 hour. The reaction mixture was then concentrated and the pH of the solution was adjusted to 8 using a sodium bicarbonate solution. It was then acidified to pH 5 with glacial acetic acid. The mixture was extracted with 3 x 40 ml of ethyl acetate, and the organic extract was washed with 10 ml of water and 10 ml of brine, dried and concentrated. The residue was then borrowed on a 30 X 500 mm 〇DSS 10 column for preparative high-performance liquid chromatography and 30% solvent A (10% methanol, 90% water, 0.1% three Fluoroacetic acid) and 70% solvent B (90% methanol, 10% water, 0.1% tetrahydrofuran) were eluted and purified to obtain the title compound (150 mg, 61%) as a white solid. Melting point 86 — 96 ° C (amorphous). C2iH19N3〇4S · 〇. 16 1 ^ 2〇 calculation and analysis: This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm)-87-517057 A7 B7 V. Description of the invention (85) Calculated value: C, 61. 17; H, 4. 72; N, 10.19; S, 7. 77; Found: C, 6 1. 1.2; H, 4. 35; N, 10.16; S, 7 58 ° Example 1 5 ϋ— (3,4—Di Shenmou-5—Isoxazolyl) —4, 1 (1 η-imidazol-1-ylmethyl) [1,1'-biphenylm] 2-sulfonamide

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page)-Temsulfonium _____ 1.32 grams (11.74 mmol) A 5-isoxazolamide was added to a solution of 3.0 g (11.74 mmol) of 2-bromobenzenesulfonyl chloride in 10 ml of pyridine. The mixture was stirred at room temperature under argon overnight, added to 150 ml of ice water, and then filtered. Then, the filtrate was acidified to P Η 2 with 6 equivalent concentrations of aqueous hydrochloric acid. The paper size applies the Chinese National Standard (CNS) A4 specification (21〇 > < 297 mm) -88-517057 A7 ____B7 5. Description of the invention (86) The gray solid is filtered and dried. Then the solid was crystallized from methanol / water to obtain 4.0 g (> 100%) of yellow-brown crystalline needle-like compound (melting point 125-126 ° C; Rf = 0.5 1 (10% Methanol / dichloromethane)). Β · 2-Bromo-N- (3,4-dimethyl-1-5-isoxazolyl) -N '-(methoxyethoxymethyl) benzenesulfonamide_ at room temperature, at Under argon, 0.19 g (4.8 mmol) of sodium hydride (60% mineral oil suspension) was added portionwise to 1.1 g (3.3 mmol) of compound A in 15 ml of tetrahydrofuran. In the solution, the solution was stirred at room temperature for 10 minutes. Then methoxyethoxymethyl chloride (0.55 g, 4.4 mmol) was added and the solution was stirred overnight. The mixture was then concentrated, diluted with 30 ml of water, and extracted with 40 ml of ethyl acetate. The combined organic extract was washed with 50 ml of brine, dried and evaporated to obtain 1.2 g (87%) of compound B as a brown gum. ---------— (Please read the notes on the back before filling this page)

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

N 1 ± IN—fi) methyl benzyl 15, iso 4-I LO / — ^-methyl methyl amine I A} diphenyl sulfide I-oxygen 4 ethyl 21, radical 3 oxygen, C methyl II benzene N2 C Phosphine 1 Benzene will be three (following .1, will be), Mo argon under the ear is less than 1 palladium acid, carbon gram 3 water 4 degrees • Concentrated 2 ear (Mo) 2 ο C millimole 5 liquid 3 Soluble, alcohol g 6% 7 5 9 4 liters (milli acid ο boron benzene 2 benzene and toluene I methyl 4 liters, milli Β ο compound 5 in 2 to} Garnamo This paper size applies to Chinese national standards (CNS) A4 specification (210 '乂 297 mm)-89 — 517057 A7 B7 V. Description of the invention (87). The reaction mixture was heated at 80 ° C for 2.5 hours, cooled and cooled to 3.00 Dilute with ml of ethyl acetate. Separate the organic liquid, wash with 2000 ml of water and 200 ml of brine, dry and concentrate. Then use 5: 1 hexane / ethyl acetate on the residue on silica gel. The ester was subjected to chromatographic separation to obtain compound C (9.0 g, 60%) as a colorless gel.

Rf = 0.74, silicone, 1: 1 hexane / ethyl acetate. D. 4, mono (bromomethyl) -N — (3, 4-dimethyl-5 — isoxazolyl) — N — [(2-methoxyethoxy) methyl] [1, 1 'One biphenyl]-2-amine__ η-bromosuccinimide (4. 14 g, 23. 25 millimoles) and phenylhydrazine (385 mg, 1. 59 milli Mol) was added to 180 ml of carbon tetrachloride solution of Compound C (7.7 g, 17.89 mmol). The reaction was refluxed for another 1.5 hours. After cooling down, printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) The reaction mixture was diluted with 200 ml of dichloromethane, 2 X 200 ml of water and 1 70 ml of brine was washed, dried and concentrated. The residue was separated on a silica gel using 4: 1 hexane / ethyl acetate for color separation to obtain the compound D (3-464 g, 40%) as a colorless gum.

Rf = 0.38 silicone, 2: 1 hexane / ethyl acetate. Ε · N— (3,4—dimethyl-5—isoBoxalyl) —4 ′ — (1 Η—miwa_1—ylmethyl) —N— [(2-methoxyethargon (Very) methyl] [1,1'-biphenyl]-2-sulfamidamide will be potassium carbonate (K2C03) (326 mg, 2. 36 millimoles scale applicable to Chinese National Standard (CNS) A4 specifications (210x297 (Mm) '90-517057 A7 B7 V. Description of the invention (88) ears) was added to compound D (400 mg '0.79 mmol) and imidazole (133 mg, 1.95 mmol). The reaction was stirred for another 10 hours at room temperature and then for 1 hour at 50 ° C. The mixture was then diluted with 50 ml of ethyl acetate, washed with 10 ml of water and 10 ml of brine, dried and concentrated. Then, the residue was separated on silica gel using 100: 1.5 methylene chloride / methanol for color layer separation 'to obtain compound E (220 mg, 56%) as a colorless gel.

Rf = 0. 52, Silicone, 10: 1 Trichloromethane / methanol F. N — (3,4 dimethyl-5 —isoxazolyl) — 4 '— (1H —imidazole—1-ylmethyl) ) [1,1, -biphenyl]-2-diamine ____ 6 ml of 6 equivalents of aqueous hydrochloric acid was added to 6 ml of compound E (220 mg, 0.44 mmol) 95% In ethanol solution. The reaction was refluxed for another 2 hours, cooled and concentrated. The reaction mixture was then neutralized with saturated aqueous sodium bicarbonate (N a HC03), and then acidified with acetic acid to PH <5, and the mixture was filtered to obtain a white solid (printed by the Consumer Cooperative of the Central Government Bureau of the Ministry of Economic Affairs). (Please read the precautions on the back before filling this page) 9 1 mg, 50%) 'Dissolve it in 1 equivalent concentration of hydrochloric acid, and then concentrate under vacuum to obtain the title compound as a white solid. Acid salt (melting point 150 ° C decomposition) ° R f = 0.27, silicone, 10: 1 dichloromethane / methanol. C 21 H 2〇N 40 3 S · 1. 1 Η 20 · 〇 8HC meaning calculation analysis: Calculated value: C, 55 · 〇2; Η, 5 · 28; This paper size applies Chinese National Standard (CNS) A4 specifications (210 X mm)-91-517057 A7 B7 V. Description of the invention (89) N, 12.22; S, 6. 99; C, 6-19; Found: C, 5 4 · 6 7; Η, 4 8 8; N, ll. 97; S, 6. 93; C j ?, 6 3 0 ° Example 1 6 N- (3, 4 dimethyl-5_ oxazolyl) one 4, one (3 — Razozolyl) [1,1'-biphenyl]-2 -Pyridamine ----------- (Please read the precautions on the back before filling in this page)

Order A · 4 Monobromo-N-Hydroxybenzyl imide and bromine. Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. Add 8.5 grams (4.2 millimolar) of 4-monobromobenzaldehyde oxime 0.5 mol of hydrochloric acid in dimethylformamide solution and cooled to 5 ° C, and then add 13 grams of humor in portions. The mixture was then slowly warmed to room temperature and stirred for 8 hours, then the reaction mixture was poured into 300 ml of cold water and extracted with 2 × 150 ml of ether. The combined organic extract was washed once with 150 ml 0.5 equivalent aqueous hydrochloric acid and brine (150 ml), and dried and evaporated to obtain 7.9 g. This paper size is applicable to Chinese national standards ( CNS) A4 specification (210 × 297 mm) — 92-517057 A7 ----------- B7 V. Description of the invention (90) (79%) Compound a. B 5— (ethoxyl) —3— (4-bromophenyl) —4,5— (Please read the precautions on the back before filling out this page) ________ Will be 4.0 grams (17.06mmol) ) Compound A, 7 34 g (85. 3 mmol) of vinyl acetate and 1.9 g (18.76 mmol) of triethylamine in 50 ml of toluene were stirred at 75 ° C for 2 hours, The mixture was cooled and then added to 150 ml of water. The organic layer was separated, the aqueous layer was extracted with 2 × 50 ml of ethyl acetate, and the combined organic extract was washed once with 100 ml of brine. , And dried and evaporated. Residue from hexane / ethyl acetate

Crystallized in the ester, that is, 3.6 grams (74%) of a white solid compound B 〇c ——-bromobenzene a) oxazole will be added 5 milliliter 6 equivalent concentration aqueous hydrochloric acid to 3.0 grams ( 10. 56 millimoles) 100 ml of absolute ethanol solution of compound B in printing by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 'reflux the solution for another 3 hours, and then concentrate the mixture to about 10 ml' before using aqueous carbonic acid The sodium hydroxide neutralizes the solution. The resulting mixture was then extracted with 2 × 50 ml of ether. The combined organic extract was washed once with 100 ml of brine, dried and evaporated, and then the residue was separated on 100 g of silica gel using hexane / ethyl acetate 9: 1 for color separation. 1.6 g (68%) of Compound C was obtained as a white solid. This paper size applies to Chinese National Standard (CNS) A4 specifications (210X297 mm) -93-Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 517057 A7 B7 V. Description of the invention (91) D_ N— (3, 4—2) 5 —Isoxazolyl) —N — [(2-methoxyethoxy) methyl] —4, — (3-Isoxazolyl) _1, 1′—biphenyl] —2 — 45g （1 12ml 2 mol aqueous sodium carbonate with a concentration of 2 mol, and then 315 g (1.4 mmol) of compound C in 95% ethanol was added to 0.45 g (1 17 millimoles) of compound B obtained in Example 1 and 0058 g (0.05 millimoles) of (triphenylphosphine) palladium (0) in 20 ml of a toluene solution, and the mixture was refluxed for 2 hours to 1 It was diluted with 00 ml of water and extracted with 3 × 50 ml of ethyl acetate. The combined organic extracts were then washed once with 100 ml of brine, dried and evaporated. The residue was separated on 50 g of silica gel using hexane / ethyl acetate 2: 1 to separate chromatographic layers to obtain 0.27 g (56%) of compound D as a colorless gum. Ε · N— (3,4—dimethyl—5—isoamyl) —4, — (3-isooxazolyl) [1,1′-biphenyl] —2-sulfamethoxine 10 6 ml of aqueous hydrochloric acid at a concentration of 6 equivalents was added to a solution of 0.26 g (0.554 mmol) of compound D in 10 ml of 95% ethanol, and the mixture was refluxed for 1 hour. The mixture was then concentrated, diluted with 50 ml of water and extracted with 3 x 2 5 ml of ethyl acetate. The combined organic extract was washed once with water, dried and evaporated (0.21 g). Again

This material was subjected to reverse-phase preparative high-performance liquid chromatography on a 30X50 0 mm ODS S10 column and used 67% solvent B (90% methanol, 10% water, 0.1% trifluoroacetic acid) and 33% solvent A. This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) ---------------, 1T ------ (Please read the precautions on the back before filling (This page) -94-A7 B7 (10% methanol 90% water 0 1% trifluoroethane). Extract with pure water and collect the appropriate fractions. »Neutralize to P Η with aqueous sodium bicarbonate. 7 1 was reconcentrated] L 0 ml 0 m and the solution was acidified to P 使用 with glacial acetic acid 4 The white solid was filtered and dried to obtain 0 1 3 g (6 1%) of the title compound 0 C 2 0 Η 1 7 Ν 3〇4 S, .0 2 6 Η 2 0 calculation and analysis; calculated value C, 6 0. 0 4 Η &gt; 4 4 1 &gt; Ν 1 0. 5 0 S 8 0 1 9 actual measured value C, 6 0. 0 4 Η ϊ 4 3 0 9 Ν 1 0. 5 0 S ϊ 8 1 5 0 517057 V. Description of the invention (92) (Please Read the precautions on the back before filling this page) Example 1 7 N— (3,4-Dimethyl-5—isoxazolyl) —4 ’— (2 —

The Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs printed A · 4-monobromophenethylamine under argon, and added 14 ml of a 2 mol solution of chloramphenicol in dichloromethane to 6 g (27.9 mmol). ) 4-Bromophenylacetic acid 200 This paper size applies to Chinese National Standard (CNS) A4 specifications (210X 297 mm) -95-517057 A7 B7 V. Description of the invention (93) in dichloromethane solution, and then four Dimethylformamide was added dropwise, and the mixture was stirred at room temperature for 1 hour. The solution was then evaporated and dried in vacuo. The residue was dissolved in 150 ml of methanol, and 30 ml of 28% aqueous ammonium hydroxide was added to the mixture. The solution was then stirred at room temperature overnight and then diluted with 150 ml of water. Then, the obtained white solid was filtered, washed with water and dried to obtain 5.1 g (85%) of compound A. B. 2-[(4-bromophenyl) methyl] oxazole compound A (2 g, 9.34 mmol) and vinylene carbonate (0.9 g, 10.45 mmol) 6 grams of the polyphosphoric acid mixture was heated at 170 ° C for 3 hours. The residue was added to 100 ml of water and extracted with 2 × 100 ml of ethyl acetate. The combined organic extracts were then washed once with water, dried and evaporated. Then, the residue was subjected to chromatographic separation on 200 ml of silica gel using hexane / ethyl acetate 2: 1 to obtain 1.12 g (50%) of Compound C as a white solid. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) C. N — (3,4 —dimethyl — 5 — isoxazolyl) — N — [(2 — Methoxyethoxy) methyl] -4,1- (2-oxazolylmethyl) [1,1, -dioxo-pyridine — 2 -sulfamethoxamine ____ Under argon, add 15 ml 2 Molar concentration of aqueous sodium carbonate ', then 0.45 g (1.87 mmol) of 15 ml of 95% ethanol solution of the compound B shown above was added to 0.6 g (1.56 mmol) of the compound obtained in Example 1 B and 〇. 092 (0.08 millimoles) (Triphenylphosphine paper size applies Chinese National Standard (CNS) A4 specifications (210X297 mm) -96-A7 B7 ____ V. Description of the invention (94)) Palladium (0) of 30 ml of toluene solution, the mixture was refluxed for another 2 hours, diluted with 100 ml of water and extracted with 3 × 50 ml of ethyl acetate. The combined organic extracts were then washed once with 100 ml of brine 'and dried and evaporated. The residue was separated on 200 ml of silica gel using hexane / ethyl acetate 2: 1 for color separation to obtain 0.72 g (93%) of compound C as a colorless gel. D · N— (3,4—dimethyl—5—isoxazolyl) —4, 1 (2-oxazolylmethyl) [1,1′-biphenyl] —2—sulfofluorene m___ will 15 ml of 6 equivalent concentrations of aqueous hydrochloric acid was added to 0.7 g (1.41 mmol) of compound C in 15 ml of 95% ethanol, and refluxed for an additional hour. The mixture was then concentrated, diluted with 250 ml of water, and extracted with 3 × 50 ml of ethyl acetate. The combined organic extract was washed once with water, dried and evaporated to obtain 0.41 g of colorless rubber printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page). Thing. The residue was borrowed on a 30X500 mm 〇DS S 1 0 column for reverse-phase preparative high-performance liquid chromatography and used 67% solvent B (90% methanol, 10% water, 0.1% trifluoroacetic acid ) And 23% solvent A (10% methanol, 90% water, 0.01% trifluoroacetic acid) and purified. The appropriate fractions were then collected, neutralized to PΗ7 with aqueous sodium bicarbonate, and concentrated to 10 ml. The solution was then acidified to pH 4 with dilute hydrochloric acid, and the resulting white solid was filtered and dried to obtain 0.098 g (17%) of the title compound. Melting point 6 5 — 70 ° C. This paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 517057 A7 B7 V. Description of the invention (95) 1 Η NMR (CDC 1 3): 51. 80 (s, 3H) '2. ll (s, 3H), 4.16 (s, 2H), 7.04 (s, 1H), 7.27 — 8. 02 (m, 1 0 H). 13 C NMR (CD Cj? 3) 'δ 6.99, 11. 20, 3 4 .6 7, 10 8] L 0, 1 2 7 5 4 1 2 8. 3 2, 1 2 8. 9 2 ， 1 2 9 .4 7, 1 3 0. 8 2, 1 3 3. 1 5, 1 3 3. 4 4, 1 3 5. 9 5, 1 3 7. 9 1, 1 3 8 5 1, 1 3 9. 3 7, 1 4 1. 2 5, 1 5 4 6 9, 16 2. 2 7, 16 3. 4 2. Example 1 8 N— (3,4-dimethyl-1-5-isoxazolyl) —4 ′ _ (5 — • isoxazolyl) [1,1’-biphenyl] -2—sulfonamide

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) A. 1- (4-bromophenyl) -3-(dimethylamino) _2 -propylene-1 -one _ Will be 7.0 grams (35.2 millimoles) 4 monobromoacetophenone 7 This paper size applies the Chinese National Standard (CNS) A4 specifications (210X297 mm) -98-517057 A7 B7 V. Description of the invention (96) ml of N, N-dimethylformamide diacetal solution was refluxed for 20 hours. Then, the solution was diluted with 1000 ml of diethyl ether, and then cooled to 0 ° C. Then, the yellow crystalline solid was filtered and dried to obtain Compound A (6.85 g, 77%). B and a (4-bromophenyl) isoxazole at 0 ° C, 3_ 31 g (29_ 27 millimoles) hydroxylamine-0-sulfonic acid in 20 ml of methanol solution was added to 6.2 in 3 minutes G (24.4 mmol) of compound A in 70 ml of a methanol solution, and after stirring at room temperature for 1 hour, the reaction mixture was poured into a cold saturated sodium bicarbonate solution (200 ml) and ice water (2 0 0 ml). The resulting mixture was deposited as 5.1 g of a pale yellow solid. This material was recrystallized from hexane / ethyl acetate to obtain 3.12 g (57%) of Compound B as an off-white solid. C. N — (3,4 —dimethyl_5 —isoxazolyl) —N — [(2 —methoxyethoxy) methyl] — 4 ′ — (5 —isoxazolyl) Printed by the Central Bureau of Standards Consumer Cooperatives (please read the precautions on the back before filling this page)) _ [1, 1 '—biphenyl] — 2 — amine_ Under argon, place 15 ml 2 Molar concentration of aqueous sodium carbonate, and then 0.59 g (2.18 mmol) of compound B in 15 ml of 95% ethanol solution was added to 0.56 g (1.46 mmol) of compound 1 obtained in Example 1 and 0.081 g (0.007 millimolar) of (triphenylphosphine) palladium (0) in 25 ml of toluene solution. The mixture was refluxed for another 2 hours, diluted with 100 ml of water and extracted with 3 x 50 ml of ethyl acetate. The paper is sized to the Chinese National Standard (CNS) A4 (210X 297 mm) -99-517057 A7 B7 5 Description of the invention (97). Then, the combined organic extract was washed once with 100 ml of brine, and dried and evaporated. Then, the residue was separated on 50 g of silica gel using hexane / ethyl acetate 2: 1 to obtain chromatographic layer separation, so as to obtain 0-26 g (37%) of compound C as a colorless gel. D. N— (3,4—dimethyl—5—isoxazolyl) —4, — (5-isoxazolyl) f 1, 1′—biphenyl] —2—fluorenamine will be 10 6 ml of aqueous hydrochloric acid with a concentration of 6 equivalents was added to 0.25 g (0.52 mmol) of compound C in 10 ml of a 95% ethanol solution, and the mixture was refluxed for 1 hour. The mixture was then concentrated, diluted with 100 ml of water, and extracted with 3 × 50 ml of ethyl acetate. The combined organic extract was washed once with water, dried and evaporated (0.21 g). This material was then separated on a 30x500 mm ODS S10 column for reverse-phase preparative high-performance liquid chromatography and used 69% solvent B (90% methanol, 10% water, 0.1% trifluoroacetic acid) and 31% solvent A (10% methanol, 90% water, 0.1% trifluoroacetic acid) was purified and printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) and purify it. The appropriate fractions were collected, neutralized to pH 7 with aqueous sodium bicarbonate, and concentrated to 10 ml. The solution was acidified to pH 4 with glacial acetic acid, and the white solid was filtered and dried to obtain 0.11 g (53%) of the title compound. Melting point 8 5-9 0 ° C. C20H17N3〇4S · 〇. 2 7H2〇 calculation analysis: Calculated value: C, 60. 02; H, 4. 42; N, 10.50; S, 8. 01; This paper size applies to Chinese national standards (CNS ) A4 specification (210X297 mm) -100-517057 A7 B7 V. Description of the invention (98) Measured value: C, 6 〇

N 0 1 6; Η, 4 · 2 4 3 6; S, 8. 179 cases

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

Oxazoxyl I 5 I methyl methyl I hydroxy V3 / oxazolyl monophenylenediamine sulfonate tolyl hydroxy I 3 I based bromide printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 8 g 5 liters ( Br ο 5 sides of C, OC under liquid agitated with B) 5 ears 1 is less than 6 sides 3 slow, the time between milliseconds is small

T—I 9 (Before and after warm acid chamber B &gt; Shi Er Xiao Mo 6 another 3 Stir • Stir ο Down '. C grams 5 ο 1 5 in (OH solution of benzene solution in methyl alcohol &gt; hydroxyl I Milli 3 5 to 4 plus .1 small (4 acid dry and dried and pre-filtration. Over package A matter filter-like solid solidified gas} into the empty% shape ο Draw 3 will borrow ^, then grams Washed after 5 o'clock. Xiaorun 3 7) 2 1 liters should be stirred and stirred ο, the next 2 o'clock this paper size applies Chinese National Standard (CNS) A4 specifications (210X297 mm) -101-517057 Central Bureau of Standards, Ministry of Economic Affairs Printed by employee consumer cooperative A7 B7 V. Description of the invention (99) B · 4-bromo-_3-hydroxybenzoic acid, methyl ester Sulfuric acid (concentrated, 9.4 ml) was added to compound A (23.5 g, 0.11 mole) in methanol (350 ml) solution. After refluxing for 19 hours, the reaction was allowed to cool to room temperature, and then saturated sodium bicarbonate was used to bring PΗ to about 4. After methanol was evaporated, the remaining The solution was transferred to a separatory funnel. Extracted with diethyl ether (2 x 2000 ml), and the combined organic layers were washed with brine (50 ml) and applied over magnesium sulfate. After drying, the solvent was evaporated to obtain 25 g of crude product. After recrystallization from ether / hexane, 13.3 g (53%) of compound B was obtained. C. 4-bromo-3-methylarginylbenzene Formic acid, methyl ester. Dimethyl sulfate (6.4 ml, 67 mmol) and potassium carbonate (10 g) were added to a solution of compound B (13.3 g, 57 mmol) in acetone (86 ml). After 19 hours at reflux, the reaction was cooled, the precipitate was filtered off and the filtrate was evaporated in vacuo to give 14.7 g of crude product. A flash layer separation was performed (silicone, 50 mm diameter, 10% ethyl acetate Ester / hexane), to obtain 13.9 g of compound c (100%) 〇 D. 4 monobromo 3-methoxybenzoic acid potassium hydroxide (2 equivalent concentration, 120 ml, 240 milligrams Mol) was added to a solution of compound C (19 g, 79 mmol) in methanol (670 ml). After stirring at room temperature for 5.5 hours, water (100 ml) was added, and then methanol was added to Remove in vacuum. Then apply the remaining paper size to Chinese National Standard (CMS) A4 specification (21.0X297 mm) (Please read the precautions on the back before filling this page) Order i # -102-517057 A7 B7 V. Description of the invention (100) The remaining solution is extracted with dichloromethane, then acidified with 6 equivalents of hydrochloric acid ^ to PHI · 5, and then with dichloromethane (1x500 ml and 2x 200 ml) After extraction and evaporation of the solvent, 17 g (93%) of compound D was obtained. E. _4 Monobromo_3-Methylbenzidine. Compound D (17 g, 73 mmol) and dimethylformamide (0.3 ml) of thionyl chloride (18 ml, 3 ml) 5 mol) solution was heated at 60 ° C for 2 hours. After the reaction was evaporated in vacuo and azeotroped with toluene (twice), the residue was dissolved in tetrahydrofuran (30 ml) and then slowly added to a vigorously stirred concentrated ammonium hydroxide solution (95 ml). The precipitate was then filtered, washed with water and dried in a vacuum drier overnight to obtain 17 g (100%) of compound E. F: _2_ — (4-bromo-1, 3-methoxyphenyl) oxazole adds polyphosphoric acid (18 g) to compound E (8.5 g, 37 printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please First read the notes on the back and then fill in this page) (Moore), then heat and stir the mixture until it is homogeneous. Then add vinylene carbonate (2-3 grams, 2.4 milliliters, 37 millimoles), and stir the reaction mixture at 160 ° C for 2 hours, during which time the reaction mixture evolves gas and turns into Black gelatinous. After cooling, water and ether were added, mixed and decanted (three times). Then the decanted layer was filtered through Celite® and the filtrate was transferred to a separating funnel. The organic layer was washed with water (10 ml) and 1 equivalent of sodium hydroxide (30 ml). Dry on magnesium sulfate, and then evaporate the solvent to obtain the crude product. The paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) -103-517057 A7 B7 V. Description of the invention (101). Rinse any solids left in the reaction flask and wash Celite® with dichloromethane (3 X 10 ml), and wash with 1 equivalent of sodium hydroxide (30 ml) And dried over magnesium sulfate. 6 克。 The crude product of these two parts was 3.6 grams. After performing a flash chromatography (silica gel, 50 mm diameter, 30% ethyl acetate / hexane), 2.3 g (24%) of compound F was obtained. Melting point 68.5 — 70.5 ° C. G_ N— (3,4-dimethyl-1—5-oxazolyl) —2, monomethoxy—N— (2-methoxyethoxymethyl) —4, — (2-oxazole Group) [1,1, -biphenyl] -2-sulfanilamide Compound B (2.3 g, 2.9 mmol) obtained in Example 1 in ethanol (sprayed with argon for 20 minutes, 16 Ml) solution was added to a solution of compound F (1.1 g, 4.4 mmol) in toluene (sprayed with argon for 20 minutes, 32 ml), and then sodium carbonate (1.0 g) in water (to Spray with argon for 20 minutes, 16 ml) solution, and then add (triphenylphosphine) palladium (0) (0.28 g '0.24 mmol) to this solution. Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. (Please read the notes on the back before filling out this page). After refluxing under argon for 2 hours, the solution was cooled and poured into brine (40 mL). It was then extracted with ethyl acetate (2 x 150 ml), the combined organic layers were dried over magnesium sulfate, and the solvent was evaporated to give 41 g of crude product. After rapid color separation (sand glue, 50 mm diameter, 40% ethyl acetate / hexane), 0.50 g (34%) of compound G was obtained. This scale is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) '~~ -104-517057 A7 B7 V. Description of the invention (102) H_N-(3, 4-dimethyl-5 —Isonyl) -2, _methoxy-4 '— (2_oxazolyl) [1,1, biphenyl] -2 -amidoamine _________ compound G (0.45 g , 0.88 mmol) of ethanol (13-4 ml) and 6 equivalents of hydrochloric acid (13.4 ml) were stirred at 90 ° C. 3. After 5 hours, evaporate the ethanol in vacuo and transfer the residue and dichloromethane / water to a separatory funnel. Then, it was extracted with dichloromethane (2 × 50 ml), dried over magnesium sulfate, and the solvent was evaporated to obtain 0.37 g (100%) of compound η. I · Ν— (3,4-dimethyl-1,5-isoB-oxazyl) -2, —Cyclo-4, — (2-oxazolyl) [1,1, biphenyl] -2 Monosulfonamide ___ While stirring at-7 8 ° C, boron tribromide (1 mole of dichloromethane, 6.2 ml, 6.2 mmol) was added to the compound η ( (033 g, 0.77 mmol) in dichloromethane. After stirring at -78 ° C for 30 minutes, the cold bath was removed. Stirred a total of 2.5 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page). After an hour, transfer the reaction mixture and dichloromethane / water to a separatory funnel. 5。 Then use saturated sodium bicarbonate to bring the pH to 3.5. It was then extracted with dichloromethane (2 x 70 ml), dried over magnesium sulfate and the solvent was evaporated 'to obtain 0.68 g of crude product. After two flash chromatography separations (silica gel, 25 mm diameter, 6% methanol / dichloromethane and silica gel, 15 mm diameter, 50% ethyl acetate / dichloromethane), 60 mg (19%) of the title compound was obtained. . This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) ~ ~ -105-517057 A7 B7 V. Description of the invention (103)

Melting point 1 1 1 0-11 0 ° C

Base] Extending] 1,2,1'-biphenyl] -4 mono]] 4-oxazole monomethylamine A. 2-(4-bromobenzene)-4_ oxazole carboxaldehyde central Standard Bureau employee consumer cooperative printed a mixture of Compound A (810 mg, 3.40 mmol) obtained in Example 7, selenium dioxide (1.89 g, 17 mmol) and 6.8 ml of dioxane Reflux for 24 hours. After cooling, the mixture was filtered and the filtrate was concentrated. Then the residue was separated on silica gel using 60: 1 dichloromethane / ethyl acetate for color layer separation to obtain a pale yellow solid compound. The size of the paper is applicable to China National Standard (CNS) A4 (210X297 mm)- 106-517057 A7 B7 V. Description of the invention (104) Compound A (406 mg, 47%). B. N— (3,4_dimethyl-5—isoamyl) —4 ′ — (4-monocarboxylic acid—2—oxazolyl) —N — [(2-methoxyethoxy), a— 1 ί 1,1'-biphenyl]-2-sulfamidazine under argon, will be (triphenylphosphine) palladium (〇) (116 mg, 0.1 mmol) and then 9 ml of 2 Mol Concentration aqueous sodium carbonate was added to compound B (772 mg, 2.0 mmol) obtained in Example 1, 15 ml of toluene and 12 ml of 9 5% ethanol of compound A (390 mg, 1.55 mmol). In solution. The reaction mixture was heated at 75 ° C for 1 hour, cooled and diluted with 80 ml of ethyl acetate. The organic liquid was then separated, washed with 15 ml of water and 15 ml of brine, dried and concentrated. Then the residue was separated on a silica gel using 3: 2 hexane / ethyl acetate to obtain a colorless gel-like compound B (290 mg, 37%). Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) C. 2 — [2, — [[(3, 4 — dimethyl-5 —isoxazolyl)] [ (2-methoxyethoxy) methyl] amino] sulfofluorene] [1 ,: L 'monobiphenyl]] 4- 4-yl] -4-oxazolemethoxamine

At 0 ° C, 5.6 ml of an aqueous solution of sodium chlorite (101 mg, 1.11 mmol) that had been cooled with ice was added to the above-mentioned compound B (285 mg, 0.56 mmol) ) And aminosulfonic acid (108 mg, 1.11 mmol) in 5.6 ml of tetrahydrofuran solution, and the mixture was stirred at 0 ° C. for 3 minutes. Then, 50 ml of dichloromethane was added to the mouth-107-517057 A7 B7. 5. Description of the invention (105) The organic liquid was washed with 10 ml of brine, and dried and concentrated to obtain 2-[2 '— [[(3,4 dimethyl-5'-isoDoxafluorenyl) [(2-methoxyethoxy) methyl] amino] sulfofluorene] [1, 1' biphenyl 〕 -4 a base] a 4 a d oxalic acid. Chlorochloride (dichloromethane solution at 2 moles, 0.05 ml, 1.11 mmol) was added to 2- [2, a [[(3,4-dimethyl-5 —isoxa Oxazolyl] [(2-methoxyethoxy) methyl] amino] sulfofluorene] [1,1, biphenyl] -4-yl] -4-oxazolecarboxylic acid and 0.014 ml di In 5.6 ml of methylformamide, dichloromethane was stirred for 0.5 hours and concentrated, and then 10 ml of tetrahydrofuran and 2 ml of concentrated ammonium hydroxide were added. The reaction mixture was stirred at room temperature for 50 minutes and concentrated. The organic liquid was then washed with 15 ml of water and 15 ml of brine, dried and evaporated. The residue was separated on silica gel using 1 ·· 4 hexane / ethyl acetate for color separation to obtain compound C (245 mg, 84% in three steps) as a colorless gum. D_ 2 — [2, 1 [[(3,4 —dimethyl-5 —isoxazolyl is printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (Please read the precautions on the back before filling out this page)) 〕 Sulfofluorene] [1,1'-biphenyl] -4 monoyl] -4 monooxazomethoxamine_ Trimethylsilyl chloride (297 mg, 2.74 mmol) at 0 ° C Then, sodium iodide (410 mg, 2.74 mmol) was added to 4.6 ml of acetonitrile solution of compound C (240 mg, 0.46 mmol). The mixture was stirred at room temperature for another hour. Then 5 ml of water was added and extracted with 50 ml of ethyl acetate. Then apply the organic paper size to the Chinese National Standard (CNS) A4 (210X297 mm) -108-517057 A7 ___ B7 V. Description of the invention (10) The solution is 5ml saturated aqueous sodium thiosulfate and 5ml brine Wash and print to the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs for printing and drying. Then borrow the residue on a 30 X 5 0 mm 0 DSS 1 0 column for preparative high-performance liquid riiz. Color layer separation and Eluted with 37% solvent A (10% methanol 90% water> 0.01% trifluoroacetic acid) and 63% solvent B (90% methanol 9 110% water> 0.01% tetrahydrofuran). Purify to obtain the title compound as a white solid (122 mg &gt; 61%). Analytical calculation value: C 5 7 0 0; Η 4 2 0 Ν 1 2 • 6 6 S '7 2 4 Found: C &gt; 5 7 0 1 f Η 4 1 0 Ν 1 2 6 5; S 7 1 8 〇

(Please read the precautions on the back before filling this page) The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) -109-517057 A7 ______B7 V. Description of the invention (107) A. 4 Monobromo Under a certain amount of 3-methylamine, under argon, 30 ml of a dichloromethane solution of 2 moles of chloracetin in dichloromethane was added to 10 g (46.5 mmol) of 4-bromo-3-methyl Benzene (please read the precautions on the back before filling this page) in 200 ml of formic acid in dichloromethane solution. Four drops of dimethylformamide were then added, and the mixture was stirred at room temperature for 1 hour. The solution was then evaporated and dried in vacuo. The residue was dissolved in 100 ml of methanol, 25 ml of 28% aqueous ammonium hydroxide was added to the mixture, and the solution was stirred at room temperature for 3 hours, and then diluted with 500 ml of water. Then, the obtained white solid was filtered, washed with water, and dried to obtain 8.9 g (89%) of Compound A. B _ 2— (4-, 3-methyl-tolyl) B oxazine compound A (12 g, 56 mmol) and vinylene carbonate (6.5 g, 75.5 mmol) 25 grams of polyphosphoric acid mixture printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, heated at 170 ° C for 3 hours, then the residue was added to 700 ml of water and 3 x 250 ml of ethyl acetate extraction. The combined organic extract was then washed once with water, dried and evaporated. The residue was separated on 200 g of silica gel using dichloromethane to separate chromatographic layers to obtain 6.7 g (50%) of compound B as a white solid. C 2-[4-Bromo-3-(bromomethyl) -phenyl] n oxidizes compound B (6.5 g, 27.3 mmol), N-bromosuccinimide (9 72 grams, 54.6 millimoles) and benzene peroxide (250 milligrams) of 250 milliliters of carbon tetrachloride reflux 8 This paper is sized to the Chinese National Standard (CNS) A4 (210X297 mm) ） ~ 110-517057 A7 ____B7 V. Description of the invention (108) hours, while using fluorescent lamps to illuminate the solution. The mixture was then cooled and filtered. The filtrate was concentrated to give 10 g of a pale yellow solid, which was used in the next step without any further purification. D. 2-Bromo-5- (2-oxazolyl) benzaldehyde under argon, 5.5 g of anhydrous triethylamine N-oxide (according to 80-derquist et al. Tet. Letters., 27 '3961 (prepared by the method described in 1 9 8 6)) was added to 15 ml of anhydrous dimethylarsin solution of 7 g of crude compound C, and the mixture was stirred at 55 ° C for 6 hours. The mixture was then cooled, added to 150 ml of ice / water and extracted with 3 × 100 ml of ethyl acetate. The combined organic extracts were then washed once with 100 ml of brine, dried and evaporated. The residue was separated on 300 ml of silica gel using hexane / ethyl acetate 8: 1 to obtain 2.2 g (46% in two steps) of compound D as a white solid. Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the notes on the back before filling this page) N — [(2-methoxyethoxy) methyl] -4 ′-(2-oxazolyl) 1,1′-biphenyl] -2-sulfonamide under argon. 2 milliliters of aqueous sodium carbonate, followed by 1.0 g (6.28 mmol) of compound D in 20 mL of 95% ethanol was added to 2.3 g (6 mmol) of compound B obtained in Example 1 and 0.3 g (0.26 mmol) of palladium (triphenylphosphine) in 40 ml of toluene solution. Reflux the mixture for another 2 hours, and apply the Chinese National Standard (CNS) A4 specification (210 × 297 mm) at the size of 100 paper. Fill in this page again and dilute with ml of water and extract with 3 x 50 ml of ethyl acetate. The combined organic extracts were then washed once with 1000 ml of brine, dried and evaporated. The residue was separated on 200 ml of silica gel using hexane / ethyl acetate 1: 1 for color separation to obtain 1.69 g (55%) of compound E as a colorless gum. F. N— (3,4-Dimethyl-5—isoxazolyl) -2, _formamidine-4 (2-oxazolyl) [1,1, —biphenyl] -2 —sulfofluorene Amine_ Add 30 ml of a 6-equivalent concentration aqueous hydrochloric acid to 1.6.8 g (e.28 mmol) of compound E in 30 ml of a 9 5% ethanol solution and reflux for 1 hour. The mixture was then concentrated, diluted with 250 ml of water and extracted with 3 x 150 ml of ethyl acetate. The combined organic extract was washed once with water, dried and evaporated to obtain 1.46 g (90%) of compound F as a colorless gel.

G 2 methylamine

N Iso I 5 I Dimethyl di I 4 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, oxazolyl oxazolyl anilide sulfonium I 2 g 8 2 ο to sieve A 3 g 1 ± and ammonium Ethyl 5 will be dissolved in C liquid sodium to dissolve the alcohol, boron, methyl, methyl, and hydrazine 5 毫 2 and the other three will be combined. } When the ears are small, mix 1 millimeter, mix 6 times, and stir 6 times. Warm, mix another 5 millimeters, mix 2 things, mix and mix them again, 1 ± into the expansion and contraction> thick ears, Mo filter over 8 fluids 9 dissolve _ will 1 after, and grams. 2 minutes 4 minutes 5 ο 4 This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) -112-517057 A7 ____ B7 _ V. Description of the invention (110) Dilute with water and add 3 X 2 5 ml of ethyl acetate Ester extraction. The combined organic extracts were then washed once with water, dried and evaporated. Then, the residue was separated on 15 g of silica gel using 5% methanol in dichloromethane to obtain 0.1 g (3 6%) of compound G as a white solid. Η. N — (3,4—dimethyl—5—isooxazolyl) —2, — [(formamido) methyl] —4, — (2-oxazolyl) [1, 1 ,, , Biphenyl] -2 —Extended amine __ At 0 ° C, 0.02 g of acetic acid formic anhydride and 0.02 g of triethylamine were added to 0.06 g (0.14 mmol) of the compound. G of 10 mM in dichloromethane solution. The mixture was slowly warmed to room temperature and then stirred for 1 hour. The mixture was further diluted with 10 ml of dichloromethane, washed with 20 ml of 0.1 equivalent aqueous hydrochloric acid and then washed with 20 ml of water. The organic layer was then dried and evaporated. The residue was borrowed on a 30 X 5.0 mm 0 DSS 1 0 column for reverse-phase preparative high-performance liquid chromatography and separated using 5 6% solvent B (90% methanol, 10% water '. _ 1% trifluoroacetic acid) and 44% solvent A (10% methanol, printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) 90% water, 0.1% trifluoro Acetic acid) was eluted and purified. The appropriate fractions were then collected, neutralized to pH Η 7 with aqueous sodium bicarbonate, and concentrated to 10 ml. The solution was acidified to pH 4 using dilute hydrochloric acid, and the white solid was filtered and dried to obtain 0.013 g (21%) of the title compound. Melting point 105 — 109 ° C. ^ -NMR (CDC 13): δ 1. 8 7 (s, 3H), this paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) '-113-517057 A7 B7 V. Description of the invention (111) 2. 12 (s, 3H), 3 · 8 9 (AB q

This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) -114-517057 A7 _____ Β7_ V. Description of the invention (112) Α · N_ (3, 4 dimethyl one 5 — isoxazolyl) one 2, [[((methoxycarbonyl) amino] methyl] methyl]-4 '-(2-oxazolyl) [1,1 _' one biphenyl]]-2 -sulfonylamine_ triethylamine ( 35 mg, 0.35 mmol), then methyl chloroformate (17 mg, 0.18 mmol) was added to 3.5 of compound G (75 mg, 0.18 mmol) obtained in Example 21 In tetrahydrofuran. The reaction was stirred at room temperature for an additional hour. Triethylamine (18 mg, 0-18 mmol) and methyl chloroformate

(17 mg, 0-18 mmol), and the reaction was stirred at 40 ° C for another 1.5 hours. The reaction mixture was then concentrated, and the residue was borrowed on a 30X500 mm ODS S10 column for preparative high-performance liquid chromatography and used 4 2% solvent A (10% methanol, 90% water, 0.1% Trifluoroacetic acid) and 58% solvent B (90% methanol, 10% water, 0-1% trifluoroacetic acid) were purified by elution to obtain the title compound (30 mg, 35%) as a white solid. Melting point 110 — 120 ° C (amorphous). C 23H 22N 4〇eS · 0.4 1 H2C) g ten-ten analysis · Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) Calculated value: C, 56. 39 ; H, 4. 69; N, ll. 44; S, 6. 54; Found: C, 5 6. 1 1; Η, 4. 4 8; N, 11.19; S, 6. 49. * Example 2 3 N — [[2 '-[[3,4-dimethyl-1-5-yloxazolyl) amine This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) -115-517057 A7 B7 V. Description of the invention (ll3) Group] Distillation] —4— (2-π axyl group) [1,1 biphenyl] — 2 —yl] methylamidine — Ν ′ —methyl urea CH,

〇 II S- Ν 6 Η 〇, Ν

CH3 CH, A. N — [) aminobiphenyl [2 'one [[3,4-dimethyl-1 5-isoxazolyl] sulfofluorene] -4 4- (2-oxazolyl) [1 ， 1 '—] ～ 2 —based] Jiamou Ί — N' monomethylurea _ Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

7.1 ml of the isocyanate obtained in Example 21 was then concentrated. Elution with solvent A (154% solvent acid) on the S 10 column and mg, 4 5 melting point> 1 5 C 2 3 Η 2 3 Ν Calculated analysis = calculated value: methyl C acid ester (71 mg, 1. 24 mmol) to tetrahydrofuran solution of compound G (75 mg, 0.18 mmol). The reaction was stirred at room temperature overnight, and the residue was borrowed by 30 × 500 mm 〇DS for preparative high-performance liquid color separation and 46% 0% methanol, 90% water, 0.1% Trifluoroacetic acid) and B (90% methanol, 10% water, 0.1% trifluoroethyl) were purified to obtain the title compound (38%) as a white solid, which was decomposed at 0 ° C. 5 0 5 s · 0 4 5 Η 2 0 0. 2 (: 112 (: Article 2 of 5 0 0; Η 4 8 3; Order (please read the precautions on the back before filling this page)) This paper size applies to Chinese National Standard (CNS) A4 specifications (210X297 mm) — 116 — 517057 A7 B7 V. Description of the invention (114) N, 13. 82; S, 6. 33; Found: C, 5 4 _ 5 7; Η, 4. 58;

Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs, mesylate (57 mg, 0.5 mmol) was added to 7. of Compound G (75 mg, 0.8 mmol) obtained in Example 21. 1 ml of tetrahydrofuran solution. The reaction was stirred at 4 5 ° C for 2 hours, and then the reaction mixture was concentrated. Then, the pH of the solution was adjusted to 8 using sodium bicarbonate solution. It was then acidified to pH 5 using ice. Acetic acid. The mixture was extracted with dichloromethane. Then the organic liquid was concentrated, and the remaining material was borrowed on a 300 × 500 mm ODS S 10 column for preparative high-performance liquid. The paper size applies the Chinese National Standard (CNS) A4 specification (210 × 297 mm) -117 -517057 A7 B7 V. Description of the invention (115) The chromatographic layer is separated and uses 47% solvent A (10% methanol, 90% water, 0.1% trifluoroacetic acid) and 53% solvent B (90% methanol, 10% water , 0.1% trifluoroacetic acid) was eluted and purified to obtain the title compound (27 mg, 30%) in the form of a white solid (please read the precautions on the back before filling this page). Melting point 110-120 ° C (amorphous). C22H22N4〇6S * 0. 14CH3CO0H calculation analysis calculated value: C, 52. 37; H, 4_45; N, 10.96; S, 12. 56; Found: C, 5 2 4 3; Η , 4. 37; N, 10.76; S, 12. 11 ° Example 2 5 N — [[2 '_ [[(3,4-Dimethyl-5_isoxazolyl) amino] sulfonyl] ] 4-(2-oxazolyl) [1,1'_biphenyl] -2 -yl] methyl] amine

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

0 pH ^ hr 〇h3 ch3 A. N — [[2 '— [[3,4-dimethyl-5 —isoxazolyl) amino] sulfofluorene] -4 4- (2-oxazolyl) [ 1,1 '— biphenyl]-2 -yl] methyl] acetamidinium _ This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) -118-517057 A7 B7 V. Description of the invention (116 ) At 0 ° c, 0. 019 grams (0_19 millimoles) of acetic anhydride and 0.019 grams of triethylamine were added to 0 075 grams (0,177 millimoles) to 0.075 grams ( 0. 177 millimoles) Example 21 1 in a solution of 10 ml of dichloromethane. The mixture was then slowly warmed to room temperature and stirred for an additional hour. The mixture was then diluted with 10 ml of dichloromethane, washed with 20 ml of 0.01 equivalent aqueous hydrochloric acid and then washed with 20 ml of water. The organic layer was dried and evaporated. Then the residue was subjected to reverse-phase preparative high-performance liquid on a 30x500 mm ODS S10 column for chromatographic separation and 58% solvent B (90% methanol, 10% water, 0.1% trifluoroacetic acid) and 42% Solvent A (10% methanol, 90% water, 0.1% trifluoroacetic acid) was eluted and purified. The appropriate fractions were collected, neutralized to pH 7 with aqueous sodium bicarbonate, and concentrated to 10 ml. It was then acidified to pH 4 with dilute hydrochloric acid, and the white solid was filtered and dried to obtain 0.041 g (.50%) of the title compound. Melting point 1 〇5_1 〇7 ° C (amorphous) ° C 23 Η 22 N 4 0 5 S · 0.4 2 Η20 Calculation and analysis: Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back first) (Fill in this page) Calculated value: C, 5 8. 27; Η, 4. 86; N, ll. 82; S, 6. 76; Measured value: C, 5 8. 3 8; Η, 4 _ 7 1; N, 1 1. 71; S, 6. 93 ° Example 2 6 N-[[2, 1, [[3,4 -dimethyl-1,5 -isoxazolyl) amine) The paper dimensions are subject to the Chinese National Standard (CNS ) A4 specification (210 X297 mm) -119-517057 A7 B7 V. Description of the invention (117) group] sulfofluorene] -4— (2_oxazolyl) [1,1'-biphenyl]-2 — Yl] methyl] -N'-phenyl gland

(Please read the precautions on the back before filling this page) A. Ν — [[2 '_ [[3,4-Dimethyl-5_isoxazolyl) amino] sulfonyl] -4 — (2- Oxazolyl) [1,1'-biphenyl] -2-yl] methyl]]-N'-phenyl face_ Add phenyl isocyanate (56 mg, 0.47 mmol) to the example The compound G (25 mg, 0.059 mmol) obtained in 21 was printed in 3 ml of tetrahydrofuran by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. The reaction was stirred at room temperature overnight and concentrated. The residue was then separated on a 30x500 mm ODS S10 column for preparative high performance liquid chromatography using 33% solvent A (10% methanol, 90% water, 0.1% trifluoroacetic acid) and 67% solvent B ( 90% methanol, 10% water, 0.1% trifluoroacetic acid) was eluted and purified to obtain the title compound (18 mg, 5 6%) ° 1 Η NMR (CDC 1 a): 1. 82 (s, 3H),

2. 16 (s, 3H), 3. 99 — 4. 38 (m, 2H), 6. 06 (s, br, lH), 6. 91 — 8. 03 This paper size applies to the Chinese National Standard (CNS) A4 specifications (210X 297 mm) -120-517057 A7 B7 V. Description of the invention (IIS) (m, 1 5 Η). 13 CNMR (CDC 1 6 0 8 δ Ί 4 2 6 5, 1 0 9 _ ί, 1 1 9. 9 2, 1 2 3. 2 9, 1 2 4. 1 3, 1 2 7. 1 0, 1 2 8. 2 6, 1 2 9. 6 1, 1 3 0. 6 8, 1 3 0. 7 9, 1 3 2. 9 6, 1 3 4. 8 0, 1 3 7. 7 2, 1 3 9. 5 6, 1 4 0. 0 0, 1 4 0. 2 5, 1 4 0. 4 3, 1 5 5. 6 3, 1 5 6. 5 8 〇 (Please read the notes on the back before filling (This page) Printed by the Staff Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs

〇 II S— Ν 丨 丨 Η 0, Ν

CH3 Example 2 7 N — [[2 '-[[3,4-Dimethyl-5 —isoxazolyl) -amino group Γ —sulfofluorene] -4— (2 —oxazolyl) [1, 1 'Monobiphenyl]-2-yl] methyl] N' -propylurea ch3 N_ [[2 '-[[3,4 -dimethyl-1 -isoxazolyl) -amino] monosulfonate醯] -4_ (2-oxazolyl) [1, 1'-biphenyl] -2-yl] methyl] N'-propylurea_ Propyl isocyanate (36 mg, 0.424 mmol Moore) is added to this paper standard applicable to China National Standard (CNS) A4 specifications (210 × 29? Mm) -121-517057 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (119) A7 B7 Example 2 1 Compound G (20 mg 0 0 4 7 mmol; mole) in 3 ml of tetrahydrofuran solution. The reaction mixture was then stirred at room temperature: overnight, and concentrated. Then the residue was used on silica gel. Chromatographic separation of 4 5 Dichloromethane / methanol yields the title compound as a pale yellow solid (1 6 mmol 6 7%) 0 1 Μ N MR (CD 3〇D) 0! 8 丨 9 丨: 1 t, I = = 7 Hz 3 Η), 1 4 6 (m &gt; 2 Η) 1 7 0 (S , 3 Η) 2 1 0 (S 3 Η) y 3 0 6 (t J = 7 Η ζ »2 Η), 4 0 8 (s 2 Η) 7 1 0 — 8 .12 (my 9 Η) 〇13 CNMR 丨: c D 3 〇D) δ 6 5 7 1 0 5 8 ， 1 1 6 2 2 4 3 7 ， 4 2 9 1 1 2 4 8 3 ， 1 2 5 0 6 1 2 7 9 7 y 1 2 9 1 0 1 2 9 6 2 1 3 0 3 4 1 3 1 6 7 1 3 3 1 1, 1 3 3 7 4 1 3 9 8 3 &gt; 1 4 0 4 4 1 4 0 8 7 &gt; 1 4 1 2 4, 1 4 1 9 6 1 6 0 9 1 1 6 2 9 9 1 6 3 4 2 〇 Example 2 8 Ν [C 2 9 _ [C (3,4 mono-dimethyl-mono) 5- -Yloxazolyl) amine sulfamidine] 4 (2 —oxazolyl) C 1, 1 y _ biphenylberry _ 2 monomethyl] _ N — methylacetamide (please read the note on the back first) Please fill in this page again for this matter) This paper size is applicable to China National Standard (CNS) A4 size (210x297 mm) -122-517057 A7 B7 V. Description of the invention (12〇) CH,

CX. N 11 Η

ch3 (please read the precautions on the back before filling in this page) ch3 4 dimethyl-1 5 -isoDoxanyl)-amine] 醯] 4-(2-n oxanyl) [1, 1, _biphenyl] -2-yl] methyl-1, N-methylacetamidine methylamine (33% anhydrous ethanol solution, 0.13 ml, 106 mmol), glacial acetic acid ( 0.12 g, 2 mmol) and 1 g of 3A molecular sieve were added to 0.15 g (0.35 mmol) of 15 ml of the compound F obtained in Example 2 1 in a solution of 15 ml of dichloromethane. The mixture was stirred at room temperature for another hour. Subsequently, sodium triethoxyalkoxyborohydride (0.22 g, 1.06 mmol) was added, and the mixture was stirred overnight. Then the solution was filtered, washed once with water, dried and evaporated, the resulting residue was dissolved in 10 ml of dichloromethane, and then 0.072 printed by the Consumer Cooperative of the Central Standard Bureau of the Ministry of Economic Affairs (70.70) Millimolar) acetic anhydride and 0.071 g (0.70

Mol) triethylamine was added. The mixture was then stirred at room temperature for 16 hours and pre-evaporated. The residue was borrowed on a 3 × 500 mm 〇DS S10 column for reverse-phase preparative high-performance liquid chromatography and used 58% solvent B (90% methanol, 10% water, 0.1% three Fluoroacetic acid) and 42% solvent A (10% methanol, 90% water, 0.01% trifluoroacetic acid) were purified by elution. Then collect the appropriate dissolving fraction, and apply the Chinese National Standard (CNS) A4 specification (210X297 mm) to the paper size of water based paper -123-517057 A7 __B7 V. Description of the invention (121) neutralize sodium bicarbonate to P Η 7, and then Concentrated to 10 ml. Then the solution was acidified to pH 4 with glacial acetic acid, and the white solid was filtered and dried to obtain 0.069 g (41%) of the title compound as a pale yellow solid. Melting point 1 0 5-1 1 5 ° C . Example 2 9 N — [[2 '-[[(3,4-Dimethyl-5 —rioxazolyl] amino]]]] — 4 — (2-oxazolyl) [1,1' — Biphenyl] One 2 —One] A certain 1 benzamidine (Please read the precautions on the back before filling this page)

A. N — [[2,1 [[(3,4-dimethyl-1,5-isoxazolyl) amino] sulfonyl]]-4 4- (2-oxazolyl) [1 '1' Ministry of Economic Affairs Printed by the Consumer Standards Cooperative of the Central Bureau of Standards on a Biphenyl]-2 -yl] methyl] phenylhydrazine _ Triethylamine (37 mg, 0.36 mmol) was added to the compound G obtained in Example 21 (70 3 milligrams, 0.17 millimoles) and phenylhydrazine (23 milligrams, 0.17 millimoles) in 3.3 milliliters of dichloromethane solution. The reaction was stirred at room temperature for 1.5 hours and concentrated. Then the residue was borrowed on a 30x500 mm ODS S10 column for preparative high-performance liquid color layer separation using 33% solvent A (10%) This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) -124-517057 A7 B7 V. Description of the invention (I22) methanol, 90% water, 0.1% trifluoroacetic acid) and 67% solvent B (90% methanol, 10% water, 0.1% trifluoroacetic acid) washing It is given in% 4 3 grams. Ο 3 / {V The color of the title of the object is fixed and white, and it is purely melted. Η 2 Η 2 m 6 7 ο 4 Η I 4) 6 1 shape, 1 set: _m no 4C C3), 3 ° cl} 1 5 c H 3 D 3 8 1C, I-(S3 8 R (1 2 M 8 1 N 1 7 points 9

S (Please read the notes on the back before filling out this page) o 3 Examples of N 2 3 4 oxazosino-5 I-methylmethylamino] sulfonyl] -4 — (2 —oxazolyl) [1, 1'-biphenyl] -2-yl] methyl]]-2,2-dimethylpropanamide ch3 h3c h3c

ο / ^ \

Ον

CHa Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A. ch3 N — [[2'a [[(3,4_dimethyl-5 —isoxazolyl) amino] sulfonyl]] 4 — (2- Oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -2,2-dimethylpropanyl m_ Add triethylamine (55 mg, 0.54 mmol) to Examples The paper size applies to the Chinese National Standard (CNS) A4 (210X297 mm) —125-A7 ____B7 2 1 The compound G (105 mg 1 .2 5 mmol) obtained and trimethylacetamidine ( 30 mg, 0 2 5 mmol) in 4 ml of dichloromethane. The reaction was stirred at room temperature overnight and concentrated [condensed, then the residue was borrowed by 30 x 50 mm. 〇DSS] L (): Preparative high-performance liquid πϋ chromatographic separation and use of Σ i 3% solvent A (10% methanol 990% water '0 1 difluoroacetic acid) and 67%; solvent B (90% methanol, 10% water'0 1% tritrifluoroacetic acid) was purified without extraction. j The title compound of the title BΈ5 (52 mg 34%) was obtained as a white solid. 熔点 Melting point 1 2 2 — 1 2 8 ° c 〇 1 Η N MR (CDC 1 3): 5] L.] L 8 ( ^, 9 Η) 1 9 3 (S 3 Η) redundant 2 1 8 (S, 3 Η) &gt; 3 9 6 — 4 4 6 (m 2 Η) 9 7. 2 4 — 8 0 5 (m 9 Η ) 〇517057 V. Description of the invention (l23) (Please read the precautions on the back before filling this page) Example 3 1 2 'one [[3,4 -Dimethyl-5 -isoxazolyl) amino]- Printed by the Consumer Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

2 / IV based oxazoxyl 1 based phenylenedicarboxylic acid carboxylic acid I 2 This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) ~ 126-517057 A7 _____B7 V. Description of the invention (I24)

(Please read the precautions on the back before filling in this page) A. 2 '— [[3,4 —Dimethyl-5 —isoxazolyl) monoamino] monosulfonyl] -4 (2 —oxa Oxazolyl) [1,1'-biphenyl J-2 —carboxylic acid — 52 ° C sodium chlorite (9.40 mg, 10.39 mmol) at 0 ° C Ml of an aqueous solution was added to 52 ml of a tetrahydrofuran solution of compound F (2.20 g, 5.20 mmol) obtained in Example 21 and aminosulfonic acid (01_01 g, 10.39 mmol). The mixture was stirred at 0 ° C for 2 minutes and then diluted with 150 ml of dichloromethane. The organic liquid was then separated, washed with brine, dried and concentrated. The residue is then prepared on an ODS S 10 column. Preparative high-performance liquid chromatographic separation and the use of 4% solvent A (10% A) Central Laboratories of the Ministry of Economic Affairs employee consumer cooperative printed alcohol, 90% water , 0.1% trifluoroacetic acid) and 57% solvent B (90% methanol, 10% water, 0.1% trifluoroacetic acid) were eluted and purified to obtain a white solid compound A (50% 3 mg, 2 2%) 〇B. 2, [[((3,4-Dimethyl-5-isoxazolyl) monoamino] sulfofluorene] -4— (2-oxazolyl) [1 1, 1, the size of the biphenyl paper is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) -127-517057 A7 —__ B7 V. Description of the invention (l25) radical] a 2-carboxylic acid methyl ester __ 于At 0 ° C, 1,1'-carbonyldiimidazole (209 mg, 1.29 mmol) was added to 5.9 ml of tetrahydrofuran solution of compound A (258 mg, 0.59 mmol). After stirring at room temperature for 1 hour, 1 ml of methanol was added, and the reaction mixture was stirred at room temperature overnight. Then another 3 ml of methanol was added, and the mixture was heated at 50 ° C for another hour. After cooling to room temperature, 10 ml of 0.5 eq.

Add aqueous hydrochloric acid and stir for 10 minutes. Then, 60 ml of ethyl acetate was added, and the organic liquid was separated, washed with brine, dried and concentrated. The residue was then borrowed on a 3 x 5 0 mm 0 DS 5 1 0 column for preparative high performance liquid chromatography and used 3 4% solvent A (10% methanol, 90% water, 0.1% trifluoro Acetic acid) and 66% solvent B (90% methanol, 10% water, 01% trifluoroacetic acid) were purified by elution, and the compound (98 mg, 37%) was obtained. Melting point 106 — 112 ° C (amorphous), Rf = 0.54, silicone, 20: 1 dichloromethane / methanol. Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) 1 Η NMR (CDC 1 3): 51. 84 (s, 3H), 2. 17 (s, 3H), 3. 73 (s, 3H), 7_ 2 7 — 8.62 (m, 10H). Example 3 2 N— (3,4—dimethyl—5—isoxazolyl) —2 (1—hydroxy—1— Methyl ethyl) 4, 1, (2-oxazolyl) This paper size applies to China National Standard (CNS) A4 (210X297 mm 1 128-517057 A7 B7

Α · N— (3,4—dimethyl—5—isoxazolyl) —2, — ((1—hydroxy—1-methylethyl) —4, — (2—oxazolyl) [1, 1 ′ —biphenyl] —2—sulfamidamide __ At 0 ° C, methylmagnesium bromide (1.4 molar mole of toluene / tetrahydrofuran 75: 25 liquid, 0.43 ml, 0. 60 mmol) was added to Example 3 1 of the title compound (87 mg, 0.19 mmol) in 1.9 ml of tetrahydrofuran solution, and the reaction was stirred at 0 ° C for 10 minutes and at room temperature for 3 minutes. hour. Then add another methylmagnesium bromide (toluene / tetrahydrofuran 75:25 at 1.4 moles, 0.069 ml, 0.096 mmol), and stir the other Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Printing (please read the precautions on the back and fill in this page) for 10 minutes, then use ice water and acetic acid (45 mg, 0.777 mol) to stop the reaction, and stir for 10 minutes. The mixture was then extracted with ethyl acetate, and the organic extract was washed with brine, dried and concentrated. The residue was then subjected to preparative high performance liquid chromatography on an ODS S 10 column using 3 7% solvent A (10% methanol, 90% water, 0.01% trifluoroacetic acid) and 63% solvent. B (90% A

Alcohol, 10% water, 0.1% trifluoroacetic acid) and purified by elution, good P The paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) -129-517057 A7 B7 V. Description of the invention I27) to give the title compound (40 mg, 46%) as a white solid. Melting point 112 — 118 ° C (amorphous) ° Rf = 0.27, silicone, 20: 1 dichloromethane / methanol. 1 Η NMR (CDC 1 3): ^ 1. 46 (s, 3H), 1. 76 (s, 3H), 1. 91 (s, 3H), 2. 19 (s, 3H), 7. 11- 8. 08 (m, 1 0 H). Example 3 3 N — [[2 '1 [[[3,4-dimethyl-5 —isoxazolyl) amine]] sulfonyl] 4 — (2 -oxazolyl) [1,1' —bi Phenyl]-2 -yl] methyl]-2-methylpropanamide (Please read the precautions on the back before filling this page)

Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs A. N — [[2 '-[[(3,4-dimethyl_5_isoxazolyl) amino] sulfonyl]] — 4 — (2 -oxazole Group) [1,1'-biphenyl] -2-yl] methyl] -2 methylpropanamine Triethylamine (37 mg, 0.36 mmol) was added to compound G obtained in Example 21 (70 mg, 0.17 mmol) and isobutyridine chloride (18 mg, 0.17 mmol) of dichloromethane. This paper applies Chinese National Standard (CNS) A4 specifications (210X 297). (Mm) -130-517057 A7 B7 V. Description of the Invention (l28) (Please read the precautions on the back before filling this page) in alkane solution. The reaction was stirred at room temperature for 2 hours and concentrated. The remnants were then borrowed on a 30x500 mm ODS S10 column for preparative high performance liquid chromatography using 38% solvent A (10% methanol, 90% water, 0.1% trifluoroacetic acid) and 62% Solvent B (90% methanol, 10% water, 0.1% trifluoroacetic acid) was eluted and purified to obtain the title compound (36 mg, 44%) as a white solid. Melting point 1 1.2 — 120 (amorphous) , Rf = 0.31, silicone, 20: 1 dichloromethane / methanol. 1 Η N M R (C D C 1 3): 51. 13 (m, 6H), 1. 93 (s, 3H), 2. 19 (s, 3H),

2. 42 (m, lH), 4. 0 4-4. 43 (m, 2H), 6. 56 — 8. 40 (m, 11H) 〇 Example 3 4 N — [[2 '一 [[(3 , 4 dimethyl-5 (isoxazolyl) sulfanyl / ~ \ amine

Oxazoxan I 2 / {V 1 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 2 2 1 i— \ 甲 甲 i— \ 基-2 2 Amine ethane ethyl fluoride Three paper standards apply Chinese national standards ( CNS) A4 specification (210X 297 mm) -131-517057 A7 B7 V. Description of the invention (I29) γο

F3C

A. N_ [[2 '-[[(3,4-Dimethyl-5-isoxazolyl) amino] sulfofluorene] -4 4- (2-oxazolyl) [1,1'-biphenyl Base]-2 -yl] methyl] _2,2,2-trifluoroacetamidine_ will be triethylamine (19 mg, 0.19 mmol), and then trifluoroacetic anhydride (20 mg, 0.1 094 mmol) was added to 1.9 ml of dichloromethane in compound G (40 mg, 0.094 mmol) obtained in Example 21. The reaction was further stirred at room temperature for 2 hours and concentrated. The residue was then borrowed on a 30x500 mm ODS S10 column for preparative high performance liquid chromatography and 37% solvent A (10% methanol, 90% water, 0.1% trifluoroacetic acid) and 63% economic Printed by the Ministry of Standards and Staff's Consumer Cooperatives (Please read the precautions on the back before filling this page)

H3 C

H3 CH solvent B (90% methanol, 10% water, 0.1% trifluoroacetic acid) was extracted and purified to obtain the title compound as a white solid. Melting point 1 1 2 —120 ° C (amorphous) ° Rf = 0.31, silicone, 20: 1 dichloromethane / methanol. 1 Η N M R (C D C 1 3): (51. 94 (s, 3H),

2.19 (s, 3H), 4.03-4.56 (m, 2H), 7.06-8.06 (m, 10H). This paper is again applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) -132-517057 A7 _ B7 V. Description of the invention (13〇) Example 3 5 N — (3, 4 — 2A, 1 5 — different An oxazole) -2 '-[(methylamino) amino] -4'-(2-ozozolyl) [1,1, -biphenyl] -2-碏 醯 ^

A. N— (3,4 dimethyl-5—isoxazolyl) —2, — [(methylamino) carbonyl] —4 '— (2-oxazolyl) [1, 1, 1 unit Benzene]-2 _sulfamethoxamine__ At 0 ° C, 1,1'-carbonyldiimidazole (101 mg, 0.62 mmol) was added to compound A obtained in Example 31 (1 2 4 Mg, 0.28 mmol) in 2.8 ml of tetrahydrofuran solution, printed at the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page). After stirring for 2 hours, 1 ml of methylamine (40% aqueous solution) was added, and the reaction was stirred at room temperature for 3 hours. Then, 10 ml of 1 equivalent strength hydrochloric acid was added and stirred for 3 minutes. The mixture was then extracted with 50 mL of ethyl acetate, and the organic extract was washed with water and brine, dried, and concentrated. The residue was dissolved in 3 ml of a saturated aqueous sodium hydrogen carbonate solution and filtered. Then, the filtrate was acidified to pH <5 with sulfuric acid sodium bisulfate, and then filtered to obtain the title compound (80 mg, 63%) as a white solid. This paper is in accordance with China National Standard (CNS) A4 (210X297) %) _ 133-517057 A7 B7 V. Description of the invention (131) Melting point 1 2 2 — 1 3 1 ° C.

Rf = 0.1 1, silicone, 20: 1 dichloromethane / methanol. 1 Η NMR (CDC 1 a): δ 1.89 (s, 3H), 2. 20 (s, 3H), 3. 73 (s, 3H), 2. 76 (d, J = 3. 5Hz, 3H ), 6. 5 3- 8 · 16 (m, 1 1 H). Example 3 6 N— (3,4-Dimethyl-5—isoxazolyl) —2 ′, 4′—bis (2-oxazole) [1,1′—biphenyl] -2— 碏Amidine

ch3 Α · 2 'I [[(3,4-dimethyl-1,5-isoxazolyl) [(Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) 2 —Methylethoxy) methyl] amino] sulfonyl]] 4- (2—Pentazolyl), 1′-biphenyl, 1] -2-carboxylic acid at 0 ° C, will be ice-cold Sodium chlorite (186 mg, 2.0 mmol) in 14.7 ml of water was added to Compound E (525 mg, 1.03 mmol) obtained in Example 21 and aminosulfonic acid ( 199 mg, 2.05 mmol) in 14.7 ml of tetrahydrofuran solution. Stir the mixture at 0 ° C for 2 minutes, and then apply the Chinese National Standard (CNS) A4 specification (210X297 mm) at 100 paper size &quot; '-134-517057 A7 B7 V. Description of the invention (l32) Dilute with ml of dichloromethane. The organic liquid was then separated, washed with brine, dried and concentrated to give a gelatinous compound A, which was used without further purification. B. 2 '-[[(3'4-dimethyl-1,5-isoBoxal) [(2-methylethoxy) methyl] amino] sulfofluorene] -4- (2-η Oxazolyl) [1,1'-biphenyl] -2-carbonyl chloride_ Add chlorchloride (dichloromethane solution of 2 mole concentration, 1.3 ml, 2. 6 mmol) to the compound A and 0.026 ml of dimethylformamide in dichloromethane. The reaction was stirred at room temperature for 1 hour and concentrated to obtain compound B. C _ N — (3,4-dimethyl-2-isoxazolyl) -N — [2-methylethoxy] methyl] -2 ', 4'-bis (2-oxazolyl • ) [1,1'-biphenyl] -2-amidine_ Compound B, 1H-1,2,3-triazole (71 mg, 1.03 mmol) and potassium carbonate (936 mg, 6.8 millimoles printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page)) 4.1 ml of acetophenane mixture heated at 140 ° C for 3 hours . The mixture was diluted with 100 ml of ethyl acetate, washed with water and brine, dried and concentrated. The residue was separated on a silica gel using 50 70: 0.1 hexane / ethyl acetate / triethylamine for color separation to obtain the compound C. D. N — (3,4 dimethyl-5—isoxazolyl) —2, 4, 4, This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) -135-517057 A7 _____B7 5 2. Description of the invention (l33) A bis (2-oxazolyl) [1,1'-biphenyl] -2-sulfamethoxamine ____ Add 10 ml of 6 equivalent concentration hydrochloric acid to Compound C-10 Ml of 95% ethanol. The mixture was refluxed for an additional hour and concentrated. The residue was then neutralized to about Η with sodium bicarbonate and extracted with ethyl acetate. The organic extract was then washed with brine, dried and concentrated. The residue was then separated on an ODS S 10 column for preparative high-performance liquid chromatography and 35% solvent A (10% methanol, 90% water '0.1% trifluoroacetic acid) and 65% were used. Solvent B (90% methanol '10% water, 0.1% trifluoroacetic acid) was eluted and purified to obtain the title compound (56 mg, 12% in four steps) as a white solid. Melting point 108 — 113 ° C (amorphous) 30, silicone, 20: 1 dichloromethane / methanol. 1 Η N M R (C D C 1 3): 51. 90 (s, 3H), 2: 19 (s, 3H), 7. 0 2-9. 6l (m, 1 2 H). Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the notes on the back before filling this page) Example 3 7 and Example 3 8 (Z) — N — (3, 4 — Dimethyl 1 5 — Isoxazole Base) — raw hydrazone (2 —oxazolyl) — 2, 2, (2-phenylethylene — [1 '1- ·· biphenyl] — 2 —sulfonamide CNS) A4 size (210X297 mm) -136-

〇 II S— N o H 0,

ch3 517057 A7 B7 V. Description of the invention (134) and E) — N — (3,4 —dimethyl-5 —isoxazolyl) — 4 * (2 -oxazolyl) — 2 '— (2 — Phenylvinyl) [1 ,: biphenyl]-2-sulfamethoxamine (Please read the precautions on the back before filling this page)

N

〇 II S— N 0 H 0,

ch3 ch3 (Z) — N — (3,4 dimethyl-5_isoxazolyl)-printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

And BN — [(2-methylethoxy) methyl] _4 ′-(2-oxazolyl) _2 ′-(2-phenylvinyl) [1,1′-biphenyl] —2— Sulfonamide ____ (E) — N — (3 '4 —Dimethyl-5 —isochowyl) —N — [(2-methylethoxy) methyl] — 4' — (2 — (Oxazolyl) —2 '— (2-phenylvinyl) [1,1' —biphenyl paper size applicable to Chinese National Standard (CNS) A4 specification (210 X 297 mm) -137-517057 A7 ______B7 5 Description of the invention (135) group]-2-basic amine ___ At 7.8 ° C, the n-butyllithium (pentane solution of 2 molar concentration, 0.39 ml, 0.88 mmol ) Was added to 7.7 ml of tetrahydrofuran solution of fluorenyl triphenyl scaled chlorine (300 mg, 077 mmol). The cold bath was removed, and the mixture was stirred at room temperature for 4 5 minutes, after which it was cooled again to 178 ° C. The compound E (304 mg, 0.59 mmol) obtained in Example 21 was added at -78 ° C, and then the reaction was stirred at room temperature for 2.5 hours. Then, 10 ml of water and 40 ml of ethyl acetate were added, and the organic liquid was separated, washed with saturated aqueous ammonium chloride and brine, dried, and concentrated. The residue was separated on a silica gel using 2: 1 hexane / ethyl acetate for color separation to obtain a mixture of compounds A and B. C. (Z) — N — (3,4 —dimethyl-5 —isoxazolyl) — 4 '— (2_oxazolyl) — 2, 1, (2-phenylvinyl) [丄, 1 'a biphenyl]-2-Sulfonamide_ and printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) D. (E) — N — (3, 4-dimethyl-1, 5-isoxazolyl) 4 '-(2-oxazolyl) _2'-(2-phenylvinyl) [1,1'-biphenyl]-2 -sulfofluorene Amine ____ Add 6 ml of 6 equivalent aqueous hydrochloric acid to 6 ml of a 9 5% ethanol solution of compounds A and B, and reflux for 1 hour. The reaction mixture was then concentrated and 80 ml of ethyl acetate was added. The organic liquid was then separated, washed with brine, dried and concentrated. The remaining material is borrowed from this paper to the Chinese National Standard (CNS) A4 (210X297 mm) -138-517057 A7 _____B7_ V. Description of the invention (I36) 〇 Preparative high-performance liquid color layer on DSS 10 column Isolate and elute with 22% solvent A (10% methanol, 90% water, 0.1% trifluoroacetic acid) and 78% solvent B (90% methanol, 10% water, 0.1% trifluoroacetic acid) Purification gave compound C as the title compound of Example 37 as a white solid (73 mg, 19% in two steps). Melting point 102 — 109 ° C (amorphous), Rf = 0.32 (silica gel, 20: 1 dichloromethane / methanol). The high-performance liquid chromatography separation column was further eluted with the same solvent to obtain a mixture, which was then separated on a silica gel using 100 0 ·· 2 dichloromethane / methanol to obtain a compound D, which was obtained as a pale yellow solid. Example 38 The title compound (27 mg, 7% in two steps). Melting point 10 9-116 ° C (amorphous), Rf = 0.32 (silica gel, 20: 1 dichloromethane / methanol). Example 37 NMR (CDC 1 3) of the title compound: δ 1.86 (s, 3H), 2. 16 (s, 3H), 6. 3 8-6. 51 (m, J = 12. 3 Hz, 2H ), Printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs (please read the precautions on the back before filling this page) 6. 60 — 7. 98 (m, 15H) 〇 Example 38 iH NMR of the title compound (CDC 1 3) :, 5 1. 74 (s, 3H), 2. 01 (s, 3H), 6. 7 2-7. 10 (m, J = 16. 4Hz, 2H), 7. 17 — 7. 9 8 ( m, 15H). This paper size applies to China National Standard (CNS) A4 (210X297 mm) -139-517057 A7 B7 V. Description of the invention (137) Example 3 9 4-氱 A certain N — 〔ί 2, 一 [[(3, 4 —Dimethyl-5 sulfonium / — \ aminoaminooxazolyloxazolyl-2-ylphenylbenzidine 醯 ethylbenzene i— \ methylmethyl i — \ group I 2 cl

o = ο

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs of the People's Republic of China. 4 mono (2-oxazolyl)-[1,1'-biphenyl] -2-yl] -methyl] phenylacetamidamine_ • 0. 082 g (0.47 mmol) —Chlorophenylphosphonium chloride and 0.104 g (1.03 mmol) of triethylamine were added to 0.20 g (0.47 mmol) of 15 ml of a solution of compound G obtained in Example 2 1 . The mixture was then stirred at room temperature for 16 hours and evaporated. The residue was borrowed on a 30 X 500 mm 〇DS S10 column for reverse-phase preparative high-performance liquid chromatography and 79% solvent B (90% methanol, 10% water, 0 1% trifluoro) was used for separation. Acetic acid) and 21% solvent A (10% methanol, 90% water, 0.1% trifluoroacetic acid) were purified by elution. The appropriate fractions were collected and neutralized to pH 7 with aqueous sodium bicarbonate and concentrated to 10 ml. Then make the Tsukasa paper size applicable to the Chinese National Standard (CNS) A4 specification (210X297mm) --------------- IT ------ Aw (Please read the precautions on the back first (Fill in this page again) -140-517057 A7 __B7 V. Description of the invention (1) The solution was acidified to pH 4 with glacial acetic acid, and the white solid was filtered and dried to obtain 0_ 033 grams (12. 5%) of the title compound as a white solid. 130-134 ° C. Example 4 Π N — [[2,1 [[(3,4-dimethyl-5 —isoxazolyl) amino] sulfofluorene] -4 — (2-oxazolyl) [fluorene, 1,1 Biphenyl]-2 -yl] methyl] -N, 2,2-Mitapronamine (Please read the notes on the back before filling this page) Γ = \

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs Oxazolyl) [1,1, biphenyl]-2-yl] monomethyl] -N, 2,2-trimethylpropylamine ___ 0 078 grams (0.65 millimolar ) Tvalprom chloride and 0131 g (1.30 mmol) of triethylamine were added to the compound formed in the preparation of Example 28 Compound A. 0.25 g (0.59 mmol) of 10 ml of intermediate In dichloromethane. The mixture was then stirred at room temperature for 16 hours and pre-evaporated. The leftovers were borrowed on 30 X 5 0 0 This paper is in accordance with China National Standard (CNS) A4 (210X297 mm) -141-517057 A7 ____B7 V. Description of the invention (l39) mm ODS S 10 column Reverse-phase preparative high-performance liquid chromatographic separation and use of 75% solvent B (90% methanol, 10% water, 0.1% trifluoroacetic acid) and 25% solvent A (10% methanol, 90% water, 0.1 % Trifluoroacetic acid), and purified. The appropriate fractions were then collected, neutralized to PΗ7 with aqueous sodium bicarbonate, and concentrated to 10 ml. Then, the solution was acidified to pH 4 with aqueous sodium hydrogen sulfate, and the white solid was filtered and dried to obtain 0.036 g (12%) of the title compound as a white solid. Melting point 125-130 ΐ. Example 4 1 (Please read the precautions on the back before filling out this page), one [[(3,4—two-shenji one 5--base oxanyl)

This paper size applies the Chinese National Standard (CNS) A4 specification (210x297 mm) -142-517057 A7 ____B7 V. Description of the invention (14) Gram (1.3 mmol) Triethylamine is added to Example 28 Compound A In a solution of 0.25 g (0_59 mmol) of the intermediate formed in the preparation in 10 ml of dichloromethane. The mixture was then stirred at room temperature for 16 hours and pre-evaporated. The residue was borrowed on a 30 X 500 mm 0 DS S10 column for reverse-phase preparative high-performance liquid chromatography and 68% solvent B (90% methanol, 10% water, 0.1% trifluoro) was used for separation. Acetic acid) and 32% solvent A (10% methanol, 90% water, 0.1% trifluoroacetic acid for purification. Then collect the appropriate fractions, neutralize with aqueous sodium bicarbonate to pH 7, and concentrate to 10 Ml. Then the solution was acidified to p Η 4 with aqueous sodium hydrogen sulfate, and the white solid was filtered and dried to obtain 0.075 g (23%) of the title compound as a white solid. Melting point 1 3 2-1 4 0 ° C. ---------— (Please read the notes on the back before filling this page)

, 1T Printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs Example 4 2 1 1 (3,4-dimethyl-1,5-isoxazolyl) -1, 2, oxazole

This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) -143-517057 A7 ___ B7__ V. Description of the invention (HI) A. N — (3, 4 dimethyl-5 — isoxazolyl ) -N — (2 -methoxyethoxy) methyl] —2, —oxazolyl — 5 —yl — 4, —oxazole — 2 —yl — [1,1, biphenyl] — 2 —Sulfonamide _____ Compound E (300 mg, 0.57 mmol) obtained from Example 21 (Toluenesulfonyl methyl isocyanide (112 mg, 0.57 mmol)) and potassium carbonate (95 mg , 0.69 mmoles) of 4 ml of methanol solution was refluxed for two hours. After cooling to room temperature, the reaction mixture was pre-absorbed onto Celite®, and the resulting powder was loaded on a 2.5x20 cm silica gel column. Stepwise gradient elution was performed with 200 ml of ethyl acetate: hexane, 50:50 to ethyl acetate at 10% intervals. The pure soluble fraction was concentrated to obtain 96 mg (30%) of Compound A as a pale yellow oil. Β · _ N — (3,4 dimethyl-5 —isoxazolyl) -2, 1 -oxanyl -5 -yl-4 '-chewing 2 -yl-[1,1'- Phenyl] -2 -sulfamethoxamine _ Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) Compound A (90 mg, 0.16 mmol), 6 equivalents A mixture of concentrated hydrochloric acid (1.6 ml) and ethanol (1.6 ml) was refluxed for 2.5 hours. After cooling to room temperature, the solvent was removed in vacuo, and the residue was delimited between ethyl acetate (75 ml) and saturated ammonium chloride solution (50 ml). The organic layer was washed with water (50 ml) and brine (50 ml). It was dried (magnesium sulfate) and concentrated to give a pink solid. To make this solid dissolved in a saturated sodium bicarbonate solution, the paper size shall be in accordance with Chinese National Standard (CNS) A4 (210X297 mm) &quot; -144-A7 B7 The intention was unsuccessful, the resulting suspension was filtered and Wash thoroughly with water, and then dry under local vacuum to obtain 30 mg (41%) of the title compound as a pale pink solid. Melting point 2 1 2 — 2 1 8 ° C (decomposed) 1 Ν Ν Μ R ( D Μ S 0 — d 6): ά 1 5 丨 6 (s,》 Η) 2 0 6 (S, 3 Η) &gt; 5 8 2 (S 1 Η) 7 2 1 (d &gt; J = 8 Η zj 1 Η) 9 7 3 6 (m &gt; 1 Η) 7 4 7 (S y 1 Η) y 7 7 9 (m 2 Η) 7 9 2 (d J = 8 Η ZE 1 Η) 9 8 1 3 (m, 1 Η) 8 3 2 (S 2 Η) 8 3 4 (S, 1 Η) 517057 V. Description of the invention (142) (Please read the notes on the back before filling this page) Others covered by the present invention The compounds include the following compounds: 1. · N — [[2, 1 [[(3,4 —dimethyl-5 —isoxazolyl) monoamino] sulfonium] 4 — (2-oxazolyl) [1, printed by the Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs, 1 ′ —biphenyl] -2 —yl] methyl] —N —methylcyclopropanamide (see Example 5 3); 2. N — [[2 '-[[(3,4-dimethyl-1,5-isoxazolyl) -amino] sulfofluorene] _4- (2-oxazolyl) [1, 1 'Monobiphenyl] _2-yl] methyl] -2,2-dimethyl-N — (1-methylethyl) propanamide (see Example 43); The paper size applies to the Chinese National Standard (CNS ) A4 specification (210 X 297 mm) -145-517057 A7 B7 V. Description of the invention (l43) 3. N -cyclopropyl-N-[[2 '-[[(3, 4-dimethyl-1 5 -Isoxazolyl) amino] sulfofluorene] -4- (2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -2,2-dimethylpropionamidine Amine 4. N — [[2 '-[[(3,4-Dimethyl-5-isoxazolyl) -amino] sulfonyl]] 4- 4 (2-oxazolyl) [1, 1, 1, "Biphenyl] -2-yl] methyl] -2,2-dimethyl-N- (2,2,2-trifluoroethyl) Amidoamine (see Example 4 6); 5. N_ (3,4-dimethyl-1-5-isoxazolyl)-2 '_ [2-(1-methylethyl) -5-oxazolyl] -4 '-(2-oxazolyl) [1,1'-biphenyl] -2-sulfanilamide; 6. N- (3,4-dimethyl-1,5-isoxazolyl) -2 '一 (4 _oxazolyl) —4' — (2-oxazolyl) [1,1 'Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economics (Please read the notes on the back before filling in this P) 2-Sulfamethoxamine; 7. N— (3,4—dimethyl—5—isooxazolyl) —2 ′ — [2- (1-methylethyl) —4-oxazolyl ] 4 ′-(2-oxazolyl) [1,1'-biphenyl] -2-sulfonamide; 8. N— (3,4-dimethyl-1—5-isooxazolyl) — 4 '一 (This paper size applies Chinese National Standard (CNS) A4 specifications (210X297 mm) -146-517057 A7 B7 V. Description of the invention (144) 2 —oxazolyl) — 2' — (2 —oxazolyl (Methyl) [1,1'-biphenyl] -2-sulfanilamide (see Example 47); 9. N- (3,4-dimethyl-1 5-Isoxazolyl)-4 '-(2 -oxazolyl)-2'-[[5- (1-methylethyl) -2-oxazolyl] methyl] [1, 1 '- Biphenyl]-2 -sulfamethoxamine; 10. N— (3,4-dimethyl-1—5-spirospirino) —4 ′ — (2-oxazolyl—2 ′ — [4— (1 monomethylethyl) -2-oxazolyl] methyl] [1,1'-biphenyl] -2-sulfonamide; 11. (E) —N — (3,4 —dimethyl -5-isoxazolyl) -2,-(4-monomethyl-2-pentenyl) _4'_ (2-oxazolyl) [1,1'-biphenyl]-2 -sulfofluorene Amine; printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) 12. (Z) — N — (3,4 —dimethyl-5 —isoxazolyl) — 2 '-(4-methyl-2-pentenyl) -4'-(2-oxazolyl) [1,1'-biphenyl]-2 -sulfonamide; 1 3. N — (3 , 4-dimethyl-1, 5-isoxazolyl) -2, '1- (4-methylpentyl) -4'_ (2-oxazolyl) [1,1' -biphenyl] -2 -Sulfonamide; 14. trans N — (3, 4 — dimethyl — 5 — isoxazolyl) A paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) -147-517057 A7 B7 V. Description of the invention (145) 2 'A [[2- (1-methylethyl) cyclopropyl] methyl] -1 4'-(2-oxazolyl) [1,1'-biphenyl] -2-sulfonamide; 1 5. Cis-N— (3,4-dimethyl-1—5-oxazolyl) — 2 ′-[[2- (1-methylethyl) cyclopropyl] methyl- 4 ′-( 2_oxazolyl) _ [1,1'-biphenyl] -2-sulfanilamide; 16. N— (3,4-dimethyl-1—5-isoamyl) —4 ′ — (2 — Oxazolyl) [1,1, 2, 2, ln_bitriphenyl] -2 monosulfonamide; 17. N — (3, 4 —dimethyl — 5 — isoxazolyl) — 3 π — (1-methylethyl)-4 ′-(2-oxazolyl) [1,1 ': 2', 1 ”—bitriphenyl] -2 —sulfonamide; 18. Ν— ( 3,4-dimethyl-1,5-isoxazolyl)-4 "-printed by (1-methylethyl) -1,4- (2-methylethyl) (Oxazolyl) [1,1 ': 2', 1 "triphenylphenyl]-2 -sulfamethoxamine; 1 9. N-(3,4_dimethyl-5 -isoxazolyl) _2. ' Mono-[(2-methylpropoxy) methyl]-4 '-(2-oxazolyl) [1, 1'-biphenyl]-2 -sulfonamide (see Example 56); 20. Ν — (3,4 —Dimethyl-5 —isoxazolyl) — 2 'One paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) One 148-(Please read the precautions on the back before (Fill in this page) 517057 A7 B7 V. Description of the invention (l46) [2- (1-methylethoxy) ethyl]-4 '-(2-oxazolyl) [1,1'_biphenyl] —2_sulfamethoxamine; and 21. N — (3,4—dimethyl-5—isoxazolyl) —2 ′ — [(1-methylethyl) sulfonyl] ethyl] —4 ′ — ( 2-oxazolyl) [1,1'-biphenyl] -2-sulfamethoxamine. The compounds shown above are equivalent (in order of numbers) to the following structure: (Please read the notes on the back before filling out this page) Printed on the paper by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. The paper size applies to the Chinese National Standard (CNS) A4 (210X297 mm) -149-517057 A7 B7 V. Description of Invention (147) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

(Please read the notes on the back before filling out this page) This paper size applies to Chinese National Standard (CNS) A4 (210 X 297 mm) -150-517057 A7 B7 V. Description of Invention 〇48) Employees of the Central Bureau of Standards, Ministry of Economic Affairs Printed by Consumer Cooperatives

MeMeMe (Please read the notes on the back before filling this page) This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) -151-517057 A7 B7 V. Description of the invention (l49)

Me

s: NH

Me

Me

Me 1 1 (Please read the notes on the back before filling out this page)

2 ii This paper size applies the Chinese National Standard (CNS) A4 specification (210X29? Mm) -152-517057 A7 B7 5. Description of the invention (l50) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

(Please read the precautions on the back before filling this page) This paper size applies Chinese National Standard (CNS) A4 (210X297mm) -153-517057 A7 B7 V. Description of the invention (151) Staff consumption of the Central Standards Bureau of the Ministry of Economic Affairs Printed by a cooperative

(Please read the precautions on the back before filling this page) This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) -154-r = \

517057 A7 B7 V. Description of the invention (l52) Example 4 3 1 ^-[[2 '-[[(3,4-Dimethyl-5 5-isoxazolyl) amino] sulfonyl]] 4-(2 —Oxazolyl) [1,1 ′ —biphenyl] -2 —yl] methyl] —N — (1 (Please read the precautions on the back before filling this page)

This paper size applies to China National Standard (CNS) A4 (210X 297 mm) -155-517057 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A 7 B7 V. Description of the invention (153) Millimolar) 'Acetic acid (〇 12 ml; 2 millimoles) and 3A molecular sieves (1 g) of 3.5 ml of dichloromethane compound were stirred at room temperature for 1 hour, and then the sodium triacetoxyborohydride (2 2 5 Mg; 1.06 mmol). After stirring at room temperature for 18 hours, the reaction mixture was filtered through Celite, and the filtrate was diluted with 25 ml of dichloromethane and washed with water (25 ml) and then brine (25 ml). It was dried (magnesium sulfate) and concentrated to give 159 mg (96%) of the title compound in this step as a yellow-brown solid. (The title compound contains about 30 mole% acetic acid). 1 Η N M R (C D C 1 3) · δ 0. 92 (d, J = 6.5 Hz, 3H), l_〇〇 (d, J = 6. 5 H z

, 3H), 1_86 (s, 3H), 2.10 (s, 3H), 3.12 (m, lH), 3.89 (d, J = 13 Hz'ih), 4.04 (d, J = 13Hz, 1H), 7.10 (d, J = 7.5 Hz, 1H), 7. 2 1 (s, 1H), 7.39 (m, 1H), 7. 4 7 (m »2 H) , 7.67 (s, lH), 7.98 (dd, J = 1.5, 8Hz, lH), 8.08 (d, J = 7.5

Hz, 1H), 8.11 (d, J = 15Hz, 1H) 〇B. N — [[2 '-[[(3,4-Dimethyl-5 —isoamidine) amino] sulfonium ] 4_ (2-oxazolyl) [1,1 'monobiphenyl]-2 -yl] methyl] -N-(1-methylethyl) This paper applies Chinese National Standard (CNS) A4 specifications ( 210X297 mm) Clothing --- I--Order ------ (Please read the precautions on the back before filling this page) -156-517057 A7 _______B7 V. Description of the Invention (I54) 1—2, 2— Dimethypramine ____ To 0 (C, 022 ml, 0.18 millimoles) to the title compound (75 mg; 016 millimoles) at 0 ° C. ) And triethylamine (0.050 ml; 0.36 mmol) in 2 ml of dichloromethane melt solution. After warming to room temperature and stirring for 18 hours, another amount of TPA (0. 022 ml; 0.15 mmol; and triethylamine (0.050 ml; 0.36 mmol). Add. Then stir the reaction mixture for 1 hour and concentrate to dryness. Then the crude oil Dissolved in 2 ml of methanol and 1 ml of 0.5 molar potassium carbonate The mixture was stirred for 18 hours, and the mixture was delimited between dichloromethane (25 ml) and a saturated potassium bicarbonate solution (25 ml). The aqueous layer was then dichloromethane (2 X 15 ml). Extract and dry the combined organic layer (magnesium sulfate) and concentrate. Then, the residue was separated on a 2.5 × 1 5 cm silica gel column for color separation, and the elution was as follows: 1 liter of 5% methanol / ethyl acetate; 1 liter of 10% methanol / ethyl acetate; 0.5 liters of 15% methanol / ethyl acetate and 0.5 liters of 20% methanol / printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before Fill out this page) Ethyl acetate. Concentrate the pure and less polar eluate into a solid residue and recrystallize from ethyl acetate / hexane to obtain 35 mg (40%) colorless. The title compound of this example is a crystalline solid. Melting point 205-207 ° C. Example 4 4 N — [1,2,1Γ [(3,4-dimethyl-1-5-isooxazolyl) amino] 碏 醯] A 4 — (2 —oxazolyl) [1, this paper size applies to China National Standard (CNS) A4 specifications (210X297 mm) 517057 A7 B7 V. Description of the invention (155) 1 ′ —biphenyl] -2-yl] methyl] ~ N — (1 monomethylethyl) propanamide f = \

The more polar fractions obtained in the separation of the color layer of Example 43 were concentrated to give the title compound of this example as a white powder. Melting point 1 4 5 — 1 5 5 ° C (decomposed). Example 4 5 N — (3 '4 dimethyl-5 —isoxoxanyl) — 4' — (2 ~ • oxazolyl) — 2 '— [[(2,2,2 —trifluoroethyl Amine) Amine] Methyl] [1,1 '—biphenyl] -2 —sulfamethoxamine (Please read the notes on the back before filling out this page) Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs ί = \ f3c

And N dimethyl-5_isoxazolyl) _4'a (2 paper sizes are applicable to China National Standard (CNS) A4 specifications (210 × 297 mm) -158-Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 517057 A7 ___B7 V. Description of the invention (l56) Lingazolyl) -2, [[((2,2,2-trifluoroethyl) amine L-Li-yl]] [1,1'-biphenyl] -2— 碏Lamine, monohydrochloride / = \

Example 21 Step 1 (F) The title compound (150 mg; 0.35 mmol), 2,2,2-trifluoroethylamine (0.085 ml, 1.06 mmol), acetic acid ( 0.12 ml; 2 millimoles) and 3.5 ml of a dichloromethane mixture of 3A molecular sieves (1 g) were stirred at room temperature for 1 hour, and then the sodium triacetoxyborohydride (2 2 5 Mg; 1.06 mmol). After stirring at room temperature for 18 hours, the reaction mixture was passed through the Celite desalinite and the furnace solution was diluted with 25 ml of dichloromethane, then with water (25 ml) and then brine (2 5 Ml). It was then dried (magnesium sulfate) and concentrated to give a pale yellow residue. The residue was delimited between ether (30 ml) and water (30 ml). The organic layer was washed with water (30 ml) and brine (30 ml). It was dried (magnesium sulfate) and concentrated to give 170 mg (9 6%) of the free base title compound of this example as a pale yellow oil. The free base was dissolved in ether and about 2 ml of etheric hydrochloric acid was added. Then, the obtained precipitate was filtered and dried to obtain 160 mg (83%). The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) &quot; -159-Binding (please read the note on the back first) Please fill in this page for matters) 517057 A7 ____B7 V. Description of the Invention (I57) White powder. A 45 mg portion of this powder was quickly stirred in ether. 18 hours. After filtering and drying, 28 mg of the title compound of the monohydrochloride of this example was obtained as a white powder. Example 4 6 N — [[2 '-[[(3,4 dimethyl-1, 5-yloxazolyl) amine]] sulfonium]-4-(2 -oxan) [1, 1'- Biphenyl] -2-1-methyl] -N- (2,2,2-trifluoromethyl) -2,2-dimethylamphetamine (Please read the precautions on the back before filling in this page)

At 0 ° C, TPA (0.035 ml; 0.25 milligrams printed by the Employees' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs) was added to Example 4 5 Monohydrochloride Title Compound (100 mg .20 mmol) and triethylamine (0.105 ml; 0.75 mmol) in 2 ml of dichloromethane. After warming to room temperature and stirring for 18 hours, the reaction mixture was partitioned between ethyl acetate (30 ml) and a saturated potassium hydrogen sulfate solution (30 ml). The organic layer was washed with a saturated potassium hydrogen sulfate solution (30 ml) and then brine (30 ml). It was then dried (magnesium sulfate) and concentrated to obtain a crude residue. It was used on a 2.5 x 1 8 cm silica gel column with 40% ethyl acetate / hexane. (Mm) -160-517057 A7 B7 V. Description of the Invention (l58) The chromatographic separation was performed as a mobile phase. The pure fractions were then concentrated to a white solid and recrystallized from ethyl acetate / hexane to give 76 mg (6 6%) of the title compound as a colorless crystalline solid. Melting point 146 — 147 ° C. c28h29f3n4o5s calculation and analysis value: C »5 6. 94; H, 4. 95; N, 9_ 49 found: C, 5 6. 8 8; Η 4 (Please read the precautions on the back before filling this page) Ν -(Example 4 7 Dimethyl-5-isooxazolyl)-4 '-(2oxazolyl)-2'-(2-oxazolylmethyl) [1'-biphenyl] -2- Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

Ο 0-N S-νΑΛ ** H r ^ CH3 CH3 〇 A 2 —Bromo-5 — (2-oxazolyl) —Phenylacetonitrile Potassium cyanide (1.04 g, 16 mmol) 2 5 ml of water was added to the normal boiling 2- [4-bromo-3— (bromomethyl) phenyl] oxazole (3. 17 g, 10 mmoles) via a reflux condenser, this paper size Applicable to China National Standard (CNS) A4 specification (210X297 mm) -161-517057 A7 B7 V. Description of the invention (l59) Prepared according to the method described in step 2 (C) of Example 2) 10 ml 9 5%. Ethanol In solution. The mixture was refluxed for another 45 minutes and concentrated. Then 100 ml of ethyl acetate was added to the mixture, and the mixture was washed with water and brine, dried and concentrated. The residue was separated on silica gel using 3: 1 hexane / ethyl acetate for chromatographic separation to obtain the title compound (2.11 g, 80%) of this step as a white solid. B 2 -bromo-5- (2-oxazolyl) phenylacetic acid. The title compound (500 mg, 1.9 mmol) from step (A) was added to 10 ml of 2 g of potassium hydroxide. 9 5% In ethanol solution. The reaction was refluxed for another 1.5 hours. After cooling, the mixture was acidified with aqueous sodium bisulfate to pH &lt; 4 and extracted with ethyl acetate. The combined organic extracts were then washed with brine, dried and concentrated to give the title compound as a white solid in this step. C. 2 —Bromo-5 — (2_oxazolyl) phenethylhydrazone will be chloramphenicol (2 moles of dichloromethane solution, 2.38 ml printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs ( Please read the precautions on the back before filling in this page), 4.7.5 mmol) to the title compound in step (B) and 19 ml dichloromethane of 0.448 ml of dimethylformamide. The reaction was stirred at room temperature for 1 hour and concentrated to give the title compound as a gel in this step. D · One 2-[4 -bromo- 3-(2-oxazole, one, one, benzene, one, benzene, one, one, oxa) This paper size is applicable to Chinese National Standard (CNS) A4 specifications (210X297 mm) one 'one 162-517057 A7 B7 V. Description of the Invention (ΐβ〇) The title compound of step (C), 1Η-1,2,3-triazole (144 mg, 2.1 mmol) and potassium carbonate (1.3 g, 9. 5 Millimoles) of 3.8 ml of benzophenane mixture was heated at 140 ° C for 3 hours. After cooling, 30 ml of water was added, and the mixture was extracted with 1: 1 ethyl acetate / hexane. The combined organic extracts were then washed with water and brine, dried and concentrated. The residue was separated on silica gel using 1: 1 hexane / ethyl acetate for chromatographic separation to obtain the title compound of this step (256 mg, 44% in three steps). EN — (3,4 dimethyl-5 —isoxazolyl) —N — [(2-methoxyethoxy) methyl] — 4 '— (2 —oxazolyl) — 2' one (2-oxazolylmethyl) [1,1'-biphenyl-1, 2-sulfonamide under argon, will be (triphenylphosphine) palladium (0) (95 mg, 0.082 mmol) ), And then print 4.8 ml 2 Molar concentration of the Ministry of Economics, Central Standards Bureau employee consumer cooperative printed (please read the precautions on the back before filling this page) Sodium carbonate is added to 2-dihydroxyboryl-N— ( 3,4-Dimethyl-5-isoxazolyl) -N-[(2-methoxyethoxy) methyl] benzenesulfonamide (472 mg, 1.3 mmol, according to the example 1) (prepared by the method described in step (B)), step (D) of this example in the title compound (250 mg, 0.82 mmol) in 8 ml of toluene and 6.4 ml of a 9 5% ethanol solution. The reaction mixture was heated at 75 ° C for 4 hours, cooled and diluted with 50 ml of ethyl acetate. The organic liquid was separated, washed with 10 ml of water and 10 ml of brine, dried and concentrated. Then the residue was made on silicone using 1: 2 hexane / ethyl acetate for the paper. The size of the paper is applicable to Chinese National Standard (CNS) A4 (210X297 mm) ~ -163-517057 A7 B7 V. Description of the invention (161) The chromatographic layer was separated to obtain the title compound (47 mg. 10%) in this step as a colorless gum, Rf = 0.17, silica gel, 1: 2 hexane / ethyl acetate. F n_ (3 '4 -dimethyl-5 -isoPoxazolyl)-4'-(2 -oxazolyl-2 '-oxazolylmethyl) [1,1' -biphenyl]- 2-Basalamide Add 3 ml of 6 equivalent strength aqueous hydrochloric acid to 3 ml of 95% ethanol solution of the title compound (46 mg, 0.081 mmol) in step (E), and reflux for 1 hour. The reaction mixture was then concentrated and the pH of the solution was adjusted to 8 using an aqueous sodium bicarbonate solution. It was then acidified to pH 5 with sodium hydrogen sulfate, extracted with ethyl acetate, and the combined organic extracts were washed with water and brine, dried and concentrated. The residue was then subjected to preparative high-performance liquid chromatography on an ODS S 10 column using 36% solvent A (10% methanol, 90% water, 0.1% trifluoroacetic acid) and 64% solvent B ( 90% methanol, 10% water, 0.1% trifluoroacetic acid), and purified, which is printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economics and White Solid (please read the precautions on the back before filling this page). The title compound of this example (18 mg, 47%), melting point 88-95 ° C (amorphous). Example 4 8 2 'Mono (cyanomethyl) -N — (3,4-Dimethyl certain Fi-diisoxyl group) — 4' — (2-oxazolyl) [1,1 '—biphenyl 〕 —2 — Sulfuramine This paper is sized to the Chinese National Standard (CNS) A4 (210X297 mm) &quot; &quot; '— &quot; —--164-517057 A7 B7 V. Description of the Invention (162)

0

〇 ~ KI

ο Η ί CH, CH3

2 'mono (cyanomethyl) _N methyl mono-iso-4' mono (2-oxazolyl) [fluorenylamine under argon methyl] methyl] -biphenyl]]-2- (Triphenylphosphine) (0.1105 millimolar), and then sodium was added to 2-dihydroxyboryl-N_ (oxazolyl) -N-[printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (5 2 2 millimoles) The method described above (in the method described in 275 milliseconds. Then 50 ml of ethyl liter water and 10 were put on the silicon gel to make it colorless gel. R f = 0 · grams, 1 preparation), grams, 1 preparation ) Should be mixed with 4 ml of ethyl acetate salt: this step is 4 3 ^ (〇) (1 2 1 mg, 6 ml 2 mol concentration aqueous carbonic acid 3, 4-dimethyl-5-isoxamine 2-methoxy Diethylethoxy) methyl] -benzene_36 pen odor, according to the procedure of Example 1 ((2-oxazolyl) 2_bromo group ~ 5. 0 5 mmol 10 ml of formazan diluted at 7 5 ° C Then washed with water and 5 hexanes / B of the title compound silicone, 2 ears according to Example 4 7 steps and 8 ml 95% 5% heating for 4 hours, cooled to separate the organic liquid, dried and concentrated. Ethyl acetate is then colored Isolated material (2 3 5 mg, 4: 5 hexane / ethyl acetate sulfonamide B), acetoin (A) alcohol solution and 10 millimeters of residue, that is 3%) (Please read the back first Note: Please fill in this page again)-Order d This paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) -165-517057 Printed by A7 B7, Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economy ) B. 2, 1 (cyanomethyl) -N — (3, 4 dimethyl 1, 5 —isoxazolyl) — 4, 1, (2 — oxazolyl) ΐ, 1, 1 unit, etc.] —2 —Sulfonamide at 0 ° C, trimethylsilyl chloride (287 mg, 2.64 mmol), and then sodium iodide (396 mg, 2.64 mmol) It was added to 4.4 ml of acetonitrile solution of the title compound (230 mg, 0.44 mmol) in step (A). The reaction was stirred at room temperature for 2.5 hours. Then 5 ml of water and 50 ml of ethyl acetate were added. The organic layer was washed with 5 ml of saturated sodium thiosulfate and 5 ml of brine, dried and concentrated. The residue was borrowed on a 0 DSS 10 column for preparative high performance liquid chromatography and 39% solvent A (10% methanol, 90% water, 0.1% trifluoroacetic acid) and 61% solvent were used. B (90% methanol, 10% water, 0.1% trifluoroacetic acid) was eluted and purified to obtain the title compound (58 mg, 43%) of this example as a white solid, m.p. 103-110 ° C ( Amorphous) ° Example 4 9 1, 1 -Dimethylethyl)-2 '-[[(3, 4-di I a 5-isoxazolyl) amine] sulfo]] 4 4 (2 One bite of evil) [1 '1' one biphenyl] one 2 —basic amine This paper size is applicable to China National Standard (CNS) A4 specification (21〇 × 297 mm) I --------- -(Please read the notes on the back before filling out this page) Order • 4 -166-517057 A7 B7 V. Description of the Invention (I64)

Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs—2 _Expansion of amine at -78 ° C, lithium diisopropylamide (LDA) / tetrahydrofuran (1.5 mol of cyclohexane solution, 73 ml, 4.09 mmol) was added to (methoxymethyl) triphenylphosphine chloride (1.22 g, 3.56 mmol) in 18 ml of tetrahydrofuran solution. The mixture was warmed to 0 ° C and stirred for 20 minutes. Then it was cooled to -78 ° C, and then N-(3,4-dimethyl-5-isoxazolyl)-2 '-formamidine-N-[(2-methoxyethoxy) Methyl] -4,2- (oxazolyl) [1,1, -biphenyl] -2-sulfamethoxamine (910 mg, 1.78 mmol, as described in Example 21, step (E) 5 ml of tetrahydrofuran solution was added dropwise. The cold bath was removed and the reaction was stirred at room temperature for 1 hour and 15 minutes. Then, 30 ml of saturated ammonium chloride was added, and the mixture was extracted with 3 × 50 ml of ethyl acetate. The combined organic extracts were then washed with water and brine, dried and concentrated. Residues were then applied to silicone using a scale of 5: 7. The Chinese National Standard (CNS) A4 specification (210X297 mm) -167-A7 __B7 / ethyl acetate was used for color layer separation &gt; to get &gt; priceτΓ The title compound of this step for color picking glue (8 7 3 mg &gt; 9 1%) 〇BN (3 4 monomethyl 5 isoxanyl) 2 (formamylmethyl) NC (2 methoxyoxy ) Methyl 4, _ 1 (2--Crylyl) 1 [] L ',] L, biphenyl] 2 Sulfonamide Add 5 ml of para-toluene acid m Tmr. To the step ( A) The title compound (870 mg, 161 mmol) in 20 ml of dioxin solution. The reaction mixture was refluxed for 4 hours. After cooling, 100 ml of ethyl acetate was added and the organic layer was added. Wash with water and 豳 ΤΓΠΤ. Water, pre-dried and concentrated. The residue was then applied to silicone using 1: 1 5 hexane / ethyl acetate. Chromatographic separation &gt; get &gt; fnrf. M color gel-like title compound in this step (5 35 5 mg 63%) ο 517057 5. Description of the invention (I65) (Please read the notes on the back before filling in This page) c. 2 '1 [[(3,4-dimethyl-5 —isoxazolyl printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 2 -methoxymethoxyethoxy) methyl] amine]碏 醯] a 4-mono (2-oxazolyl) [1,1, biphenyl] -2-acetic acid at 0 ° C 'will be ice-cooled sodium chlorite (103 mg, 1 · 14 millimoles) of 11.4 ml of aqueous solution was added to step (B) of the title compound (300 mg, 0.57 millimoles) and aminosulfonic acid (111 mg, 1.14 millimoles). 4 ml of tetrahydrofuran solution. The mixture was stirred for 2 minutes at 0 ° C. Then 60 ml of dichloromethane was added. Then, the organic layer was separated, and the paper was washed with water and brine. The paper was scaled to Chinese National Standard (CNS) A4 (210X297 mm) -168-517057 Α7 B7. 5. Description of the invention (166), and dried and concentrated, The title compound was obtained in this step, which was relatively pure and was used in the next step without further purification. D. N — (1,1 dimethylethyl) -2,1 ί (3,4 _dimethyl-1 5-isoxazolyl) ί (2-methylaminoethoxy) a methyl group ] Amine] sulfofluorene] 4- (2-oxazolyl) [1,1, -biphenyl] -2-acetamidinium chloride (2 moles of dichloromethane, 20 ml, 0.40 mol) was added to step (C) of the title compound (85 mg, 0.16 mol) and 0.004 ml of dimethylformamide in 1.6 ml of dichloromethane . The mixture was stirred at room temperature for 0.5 hours and concentrated. Then 2 ml of dichloromethane and tert-butylamine (69 mg, 0.94 mmol) were added to the residue. The reaction was stirred at room temperature overnight, diluted with ethyl acetate, washed with water and brine, dried, and concentrated. The residue was then chromatographed on silica gel using 2: 1 hexane / ethyl acetate to give the title compound (45 mg, 48%) as a colorless gum in this step. Printed by the Consumers 'Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) E. N— (1,1 dimethylethyl) —2' — [[(3,4 12 A certain 5_ isoxazole an amine group] -sulfofluorene]-4-(2 -oxazole an) [1,1 'monobiphenyl]-2-acetamidine trimethylsilyl Chlorine (41 mg, 0.38 mmol) and then sodium iodide (57 mg, 0.38 mmol) was added to step (D) of the title compound (45 mg, 0.075 mmol) This paper size applies to the Chinese National Standard (CNS) A4 specification (210 × 297 mm) -169-517057 A7 B7 5. Description of the invention (167) in acetonitrile solution. The mixture was stirred at room temperature for 1.5 hours. Then, after 30 minutes and 1 hour of stirring, another trimethylsilyl chloride (32 mg, 0.3 mmol) and sodium iodide were added. (46 mg, 0.3 mmol) was added in two portions, and 3 ml of water and 30 ml of ethyl acetate were added. The organic layer was then washed with saturated sodium thiosulfate and brine, dried and concentrated. The residue was then subjected to preparative high-performance liquid chromatography on an ODS S10 column using 33% solvent A (10% methanol, 90% water, 0.1% trifluoroacetic acid) and 67% solvent B (90% Methanol, 10% water, 0.1% trifluoroacetic acid) was eluted and purified to obtain the title compound (23 mg, 60%) of this example as a white solid, melting at 117-123 ° C (amorphous). Example 5 0

3,4 dimethyl-1 5_isoxazolyl) amino] sulfofluorene-N (Please read the precautions on the back before filling this page)

This paper size is applicable to Chinese National Standard (CNS) A4 specification (210 × 297 mm) -170-517057 Printed by A7 B7 of the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economy Methyl] amino] basic enzyme] -N, N —di-methyl-4dione (2-oxazolyl) [1,1, monobiphenyl] — 2-acetamidine — chloramphenyl chloride (2 moles of dichloromethane solution, 021 ml '0.42 millimoles) was added to 2, one [[(3,4 dimethyl-5-isoxazolyl) one [(2- Methoxyethoxy) methyl] amino] sulfofluorene] -4 4- (2-oxazolyl) [1,1, -biphenyl] -2 monoacetic acid (90 mg, 017 millimoles, Prepared according to the method described in step (C) of Example 49) and 008 ml of dimethylformamide in 3.3 ml of dichloromethane, and the mixture was stirred at room temperature for 0.5 hours, and then concentrate. Then 3.3 ml of tetrahydrofuran and 1 mmol of 40% aqueous dimethylamine were added to the residue. The reaction was stirred at room temperature for 2 hours and concentrated. Then, 30 ml of ethyl acetate was added, and the organic liquid was washed with water and brine, dried and concentrated, and then the residue was separated on silica gel to separate the ethyl acetate color layer to obtain a colorless gel. Step title compound (77 mg, 82%). B · —2 '— [[(3,4-Dimethyl-5—Lioxazolyl) fluorenyl] sulfonyl 1—N, N—Dimethyl-1 4 1 (2—oxazole only) [_1 , 1'-biphenyl] -2-acetamide will be trimethylsilyl chloride (74 mg, 7.68 mmol), followed by sodium iodide (101 mg, 0.68 mmol) Add to step (A) the title compound (77 mg, 0.135 mmol) in 4.5 ml of acetonitrile solution, and then stir the mixture at room temperature. 0.5 This paper size applies Chinese National Standard (CNS) A4 specifications (210X297 mm) --------- ^^ clothing-(Please read the precautions on the back before filling out this page) Order -171-517057 A7 B7 5. Description of the invention (169) hours. Then add the other trimethylsilyl chloride (60 mg, 0.54 mmol) and sodium iodide (82 mg, 0.54 mmol) (please read the precautions on the back before filling this page) ) Was added in two portions, and the mixture was stirred for another 1.5 hours. The mixture was then added to 5 ml of water and 50 ml of ethyl acetate. The organic layer was washed with saturated sodium thiosulfate, brine, and dried. And thick The residue was then separated on an ODS S 10 column for preparative high performance liquid chromatography using 43% solvent A (10% methanol, 90% water, 0.1% trifluoroacetic acid) and 57% solvent B ( 90% methanol, 10% water, 0.1% trifluoroacetic acid) and purified by purification to obtain the title compound (40 mg, 62%) of this example as a white solid, melting point 89 -9 6 ° C ( Amorphous) Example 5 1 N —Cyclopropyl-N — [[2, 1 [ί (3,4 dimethyl_ 5-- • -isoxazolyl) amino] sulfonyl] —4 one ( ) 〔1,1 '—Biphenyl 1-2-yl-2—methylpropylamine ί = \

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs A, 2, [[(Cyclopropylamino) methyl] —N — (One or two papers are applicable to the Chinese National Standard (CNS) A4 specification (210X 297 mm)- 172-517057 A7 _ B7 V. Description of the invention (no) group -5 -isoxazolyl) -4, ((2-oxazolyl) il, 1 '-biphenyl)-2-sulfonamide will be N- (3,4-Dimethyl-5-isoxazolyl) -2,1-methylammonium-4,1- (2-oxazolyl) [1,1,1-biphenyl]-2-sulfamethoxamine (300 Mg; 0.71 mmole, prepared in Example 21 step (F)), cyclopropylamine (0.15 ml; 2.12 mmol), acetic acid (0 24 ml; 4 mmol) and 3Α After a mixture of 7 ml of dichloromethane of a molecular sieve (2 g) was thoroughly stirred at room temperature for 1 hour, sodium triethoxylate borohydride (45 mg; 2.12 mmol) was added. After stirring at room temperature for 18 hours, the reaction mixture was filtered through Celite, and the filtrate was diluted with 25 ml of dichloromethane and washed with water (25 ml). It was then dried (magnesium sulfate / sodium sulfate) and concentrated to obtain the residue, and then used on a 2.5 x 15 cm silica gel column with 1000 ml of 2.5% methanol / dichloromethane and 500 ml of 5% methanol / dichloromethane as flow. The phases undergo chromatographic separation. The pure soluble fraction was then concentrated to obtain 83 mg (2 5%) of the title compound as a white powder in this step. Printed by the Consumers 'Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) Β · Ν — Cyclopropyl — Ν_ 〔〔2' 一 ί [(3,4 dimethyl-1 5- Isoxazolyl) amino] sulfofluorene] -4 mono (2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -2-methylpropanilamide at room temperature Next, isobutylammonium chloride (0.022 ml; 0.21 mmol) was added to step (A) of the title compound (78 mg; this paper size applies the Chinese National Standard (CNS) A4 specification (210 × 297 mm) -173-517057 A7 ___B7 V. Description of the invention (171) 0.17 mmol) and triethylamine (0.060 ml; 0 42 mmol) in 1.5 ml of dichloromethane solution. After 1 hour, the reaction mixture was delimited between ethyl acetate (25 ml) and water (25 ml). The organic layer was washed with saturated potassium bisulfate (2x25 ml), brine (25 ml), dried (magnesium sulfate) and concentrated. The 1Η NMR of the crude residue indicated the existence of the "double-halided substance" obtained from the sulfonamide hydration reaction, "a double-halogenated substance" was decomposed into the desired product after being treated with silicone. Most The residue was loaded on a 2.5 x 10 cm silica gel column wrapped in ethyl acetate: hexane 6: 4. After 1 hour, the column was packed with 1000 ml of ethyl acetate: hexane 6: 4,500 ml of ethyl acetate Ester: Hexane 8: 2 and 500 ml of ethyl acetate. The pure fractions were concentrated to a yellow oil, and then milled with hexane to give 28 mg (31%) of the title as a white powder. Compound. Melting point 1 1 0 -12 0. Example 5 2 N — (3,4 dimethyl-5 —isoxazolyl) 2 2 — 1 [[(---------- ----- IT ------ 0 (Please read the notes on the back before filling out this page) Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm) -174-517057 Α7 Β7 V. Description of the invention (Π2) 7.1 mg Ν— (3,4_dimethyl-1 5-isoxazole Group). —N — [(2-methoxyethoxy) methyl] -2 ′-[[(1-methylethyl) amino] methyl] -4 ′-(2-oxazolyl ) [1,1′-biphenyl] -2-sulfamethoxamine (as prepared in Example 4 3 step (A)) was heated to reflux in about 3 ml of ethyl acetate. Methanol was added dropwise until the solvent was complete. Hexane was then added to the hot mixture for the purpose of slightly turbidity. After cooling to room temperature and allowing to stand for several hours, the crystals were filtered and dried to obtain 39 mg (55%) of the title compound of this example as a colorless crystal solid. Melting point 225-228 ° C (darkened at 200 ° C). Example 5 3 N — [[2 '— [[(3 ′ 4-dimethyl-5—iso-n-oxazolamine) amine] sulfonyl]] 4— (2 —oxazole) • —biphenyl ] 2 -yl] methyl] -N -methyl-methanemethylamine = = \ Π Μ

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) At room temperature, add ciprofloxacin (0.025 ml; 0.263 mmol) to Ν — (3,4-dimethyl-1,5-isolated paper standards are applicable to Chinese National Standards (CNS) A4 specifications (210 × 297 mm) -175-517057 A7 B7 V. Description of the invention (l73) oxazolyl) one 2, one [ (Methylamino) methyl] -4,1- (2-oxafluorenyl) [1,1'-biphenyl] 2-sulfamethoxamine, monohydrochloride (

100 mg; 0.21 mmol, as prepared in Example 28, step (A)) and triethylamine (0.090 ml; 0.63 mmol) in 1 ml of dichloromethane. After 1 hour, the reaction mixture was delimited between ethyl acetate (20 ml) and water (20 ml). The organic layer was washed with saturated potassium hydrogen sulfate (20 ml), water (20 ml), brine (20 ml), dried (magnesium sulfate) and concentrated. The residue was separated on a 2.5 x 12 cm silica gel column using ethyl acetate: hexane 4: 1 as a mobile phase. The pure soluble fractions were then concentrated to obtain 88 mg of the oily dihybridized material (as seen in Example 51). This oil was dissolved in methanol (2 ml), and 0.5 mol sodium carbonate was added. After stirring at room temperature for 1 hour, the reaction mixture was acidified with a saturated potassium hydrogen sulfate solution and extracted with ethyl acetate (20 ml). The organic layer was then dried (magnesium sulfate) and concentrated, and the residue was printed on a 2.5 x 10 cm silica gel column using ethyl acetate as a mobile phase for printing by the Employees' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the notes on the back first Fill out this page again) Color separation. The pure soluble fraction was then concentrated to obtain 33 mg (31%) of the title compound of this example as a white powder. Melting point 92 — 102 (Note: This compound exists as a 3: 1 rotator mixture in CD C solution at room temperature). Example 5 4 N— (3,4—Dimethyl-1—Isoxazolyl) —2, —Γ rmethyl (2,2,2-—trifluoroethyl) amino] methyl— —Paper Applicable to China National Standard (CNS) A4 specification (210X297 mm) &quot; One '-176-517057

r = \ F ^ C

0 ',-' A7 B7 i, Description of the invention (174) 4 '— (2-oxazolyl) [1 2 —sulfonamide, trifluoroacetate (

• CF3COOH

At room temperature, sodium cyanoborohydride (51 mg; 0-76 millimoles) was added to N— (3,4—dimethyl—5—isooxamyl) —4— (2— Oxazolyl) one 2, one [[(2,2,2 — trifluoroethyl ---------— (please read the precautions on the back before filling this page)) Consumer co-operative printed monobiphenyl] -2-sulfonamido) amine monohydrochloride Example 4 5 2: 5 to strong 25 micro mixture (30 taken. And dried (silica gel column separation. Substance-based) formic acid Salt (4 millimoles produced in China and exothermic acetic acid boundary in milliliter) will be used on magnesium sulfate and then added. The base] [13 8 preparation) and ear) are added to the gas, ethyl acetate, and The most pure) and concentrated ethyl acetate are at 2.1, 1 mg; 37% 1.2 are released and then the reverse ester (3 shrinks the aqueous organic layer. Re-ester: has been dissolved 5x1 0.2 Formaldehyde is dissolved in ml of B. The reaction is mixed with a layer of 0 ml of B brine (The remaining hospital 3: concentrated with 0 cm 5 4 mmol solution (0 2 eye solution. Should be cooled back to the room and stirred 2 Small) and saturated ethyl carbonate (115 ml) on 2.51 as a flow of 8.8 mg of silica gel column, as in the actual 1 ml; at this time you can observe the temperature, let the time. Let the reaction acid hydrogen Sodium solution (5 ml), extracted and washed, and the color layer was subjected to X 1 5 cm phase. Partial purification was performed using ethyl acetate. # This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) -177-517057 A7 B7 V. Description of the invention (1) Ester: hexane 1: 1 as mobile phase, and color separation was carried out again to obtain a little purification effect. The purest soluble fraction was concentrated, and the residue was subjected to preparative high-performance liquid color. Layer separation (flow rate = 35 ml / min; 30X500 mm S — 10 〇DS — 120A column, using 69% methanol / water + 0.1% trifluoroacetic acid to 8 5% methanol / water + 0.1% trifluoro A gradual gradient of acetic acid, which increases by 2% every 5 minutes). The pure soluble fractions are concentrated and lyophilized to obtain 41 mg (2 5%) of the title compound as a white powder. Melting point 4 9-6 0 ° C. Example 5 5 N — [[2, 1 [[(3,4-Dimethyl-5 isoxazolyl) amino] sulfonate醯] -4 — (2 —oxazolyl) [1 '-1′-biphenyl] -2 —some] methyl]] 3' 3 —, 3-trifluoro-N-methylpropanamide ί = \

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page). At 0 ° C, place 1-ethyl-3— [3— (dimethylamino) propyl] — Carbodiimide hydrochloride (EDC, 50 mg; 0.26 mmol) was added to N- (3,4-dimethyl-5-isoxazolyl) -2, [[methylamine ) Methyl]-4 '-(2-the basic paper size of chewing tincture applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) -178-517057 A7 _____B7_ V. Description of the invention (l76)) [1, 1' a Biphenyl] 2- 2-Hexamine, monohydrochloride (

100 mg; 0 21 mmol, as prepared in Example 28, step (A)), N-methylmorpholine (0.80 ml; 0.73 mmol), 3,3,3-trifluoro Propionic acid (33 mg; 0.26 mmol) and hydroxybenzotriazole (40 mg; 0.26 mmol) in dimethylformamide solution. After 18 hours at room temperature, the reaction mixture was partitioned between ethyl acetate (30 ml) and water (30 ml). The organic layer was washed with saturated potassium hydrogen sulfate (2x30 ml), water (30 ml), brine (30 ml), dried (magnesium sulfate) and concentrated. The residue was then separated on a 2.5 x 12 cm silica gel column using 1,000 ml of ethyl acetate: hexane 3: 1 and 500 ml of ethyl acetate as mobile phases for chromatography. The pure soluble fraction was concentrated to obtain 49 mg (43%) of the title compound of this example as a white powder. Melting point 8 5 — 100 ° C (Note: This compound exists in a COCj? 3 solution as a 2: 1 mixture at room temperature) 〇 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs ( Please read the precautions on the back before filling this page) Example 5 6 ϋ One (3,4-dimethyl-5 -isoxazolyl)-2 '-[A methyl argon a methyl]-4' One (2-oxazolyl) [1,1, one biphenyl] One 2-base amine This paper is sized to the Chinese National Standard (CNS) A4 specification (210X 297 mm) -179-517057 A7 ___ B7 5 Description of the invention (m)

(Please read the precautions on the back before filling this page) A. N — (3,4 dimethyl-5 —isoxazolyl) —N — [(2 —methoxyethoxy) methyl] — ?. '一 ί (2-methylpropoxy) methyl] -4'-(2-oxazolyl) [1,1'-biphenyl] -2-Expanded amine_ in the argon layer Next, at room temperature, 2.5 equivalents of 60% sodium hydride (27.5 mg '1. 375 millimoles) was added to 5 equivalents of 2-methyl-1 propanol (102 mg' 0. 275 milligrams). Mol) in 2 ml of anhydrous dimethylformamide solution. The reaction mixture was stirred for another 0.5 hours, and then 2 '-(bromomethyl) -N — (3,4-dimethyl-5 —isoxazolyl) —N — [(2-methoxyethyl (Oxy) monomethyl] _4, mono (2-oxazolyl) [1,1, _biphenyl] -2-printed amine (160 mg, 0.275 In millimoles, 0.5 ml of a solution of dimethylformamide was added as in Example 57 (B). Tetrabutylammonium iodide (3.7 mg, 0.1 mmol) was added, followed by stirring at room temperature overnight. The reaction was then diluted with 8 ml of water and extracted with ethyl acetate (3 x 10 ml). The ethyl acetate extract was washed with 5% lithium chloride (2 x 20 ml), brine, and dried over sodium sulfate. Then apply the crude material on Merck silica gel column at 40% ethyl acetate / paper &amp; degree to the Chinese National Standard (CNS) A4 specification (210'〆297 mm) 1 -180-5Π057 A7 B7 V. Description of the invention (I78) Extraction and purification with hexane to give 24 mg (15%) of a colorless oil. The title compound of this step was repeated for 100 mg of 2 '-(bromomethyl). _N — (3,4 dimethyl-5 —isoxazolyl) —N — [(2-methoxyethoxy) methyl] -4 '-(2-oxazolyl) [1,1 'One biphenyl]-2-sulfamidamide was performed to obtain 18 mg (18%) of the title compound of this step. B · N — (3,4-dimethyl-5 -isoxayl) -2,-[(2-methylpropoxy) methyl] -4 '-(2-oxazolyl) 〔 1，1 '—biphenyl] —2-sulfamethoxamine Step (A) of the title compound (42 mg, 0.074 mmol) in 0.4 ml of ethanol solution and 0.4 ml of 6 equivalents of hydrogen chloride The acid was heated under reflux (bath at 100 ° C) for 2.5 hours. Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Anti-Economics (please read the precautions on the back before filling this page). It should be concentrated to dryness, dissolved in ethyl acetate, washed with sodium bicarbonate, water, brine After drying on sodium sulfate, the crude product was purified on a Merck silica gel column with ethyl acetate to obtain 12 mg of the product as a colorless oil. This oily residue was lyophilized from dioxane under reduced pressure to obtain 10 mg (30%) of the title compound of this example as a colorless solid, m.p. 8.6 to 9800 ° C. Example 5 7 N— (3,4 dimethyl-5_isoxazolyl)-2 '-[[(2-methyl-propionyl) sulfonyl]] methyl] _4'_ (2-oxazole-methyl) [1,1'_ Biphenyl] _2 —fluorine This paper is sized for China National Standards (CNS) A4 (210X 297 mm) -181-517057 A7 B7 V. Description of the invention (I79) [= \

A. N — (3,4 dimethyl-5—isoxazolyl) —2 ′ — (hydroxymethyl) —N — [(2-methylaminoethoxy) methyl] —4, — (2-oxazidinyl) [1 '1, -biphenyl]-2-mineamine at 0 ° C under an argon layer, 1.1 equivalents of sodium borohydride (19 mg, 0 5 mmol) to the aldehyde N — (3,4 dimethyl-5.isoxazolyl) -2, _formamidine N — [(2-methoxyethoxy) methyl ] 4 '-(2-oxazolyl) [1,1'-biphenyl]-2-sulfamethoxamine (204 mg, 0.4 millimolar, as printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economy (Please read the precautions on the back before filling this page) 2 in 8 ml of methanol solution prepared in step (E). The reaction was stirred at 0 ° C for 2.5 hours, and then 2 ml of a saturated sodium bisulfate solution was added. After stirring for 20 minutes, 1 equivalent of sodium hydroxide (20 ml) was added, and the mixture was extracted with ethyl acetate (3 × 20 ml). The ethyl acetate extract was washed with water, brine and dried over sodium sulfate. The solvent was evaporated to obtain 195 mg (95%) of the title compound as a pure alcohol in this step as a colorless oil. The size of this paper applies the Chinese National Standard (CNS) A4 specification (210X297 mm) — -182-517057 A7 ___B7 V. Description of the invention (iso) B. 2, 1 (bromomethyl) — N — (3, 4 — 2) Methyl-5 —isoxazolyl) -N — [(2-methylargon ethoxy) methyl] -4, — (2-oxazolyl) [1,1, —biphenyl] -2 —Sulfonamide at 0 ° C, under an argon layer, 1.5 equivalents of carbon tetrabromide (182 mg, 0.548 mmol) and then triphenylphosphine (144 mg, 0 548) was added Go to step (A) in a solution of the title compound (190 mg, 0.37 mmol) in 4 ml of anhydrous dimethylformamide. The reaction was stirred at 0 ° C for 2.5 hours, diluted with 20 mL of saturated sodium bicarbonate and extracted with ethyl acetate (2 x 25 mL). Then, the ethyl acetate extract was washed with 5% lithium chloride (2 × 20 ml), brine, and then dried over anhydrous sodium sulfate. The crude product was separated by column chromatography on silica gel and ethyl acetate was used. : Hexane (1 ·· 1) was eluted and purified to obtain 165 mg (78%) of the title compound as a colorless oil in this step, which will solidify after standing. Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) C. N — (3, 4 — dimethyl — 5 — isoxazolyl) — N _ [(2 —A Oxy-ethoxy) methyl] -2 '-[[(2-methylpropyl) thio] methyl] -4'-(2-oxazolyl) [1, 1'-biphenyl] 2-Sulfamethoxamine under argon, at room temperature, add 2.5 equivalents of 60% sodium hydride to 5 equivalents of 2-methyl-1, 1-propanesulfide (125 mg, 1. 3 9 MM) in 1 ml of anhydrous dimethylformamide solution. The reaction mixture was stirred for 0.5 hours, and then step (B) was titled. The paper size was adapted to Chinese National Standard (CNS) A4 specifications (210X 297 mm). One -183-517057 Α7 B7. 5. Description of the invention (1S1) Compound (160 mg, 0.278 mmol) was added to 1 ml of dimethylformamide solution. The reaction was stirred for an additional hour, diluted with 15 ml of water and extracted with ethyl acetate (3 x 20 ml). The ethyl acetate extract was washed with 5% lithium chloride (2 x 30 ml), brine, and dried over sodium sulfate. The crude material was purified on a Merck silica gel column with 40% ethyl acetate / hexane to obtain 118 mg (68%) of the title compound as a colorless oil in this step. D. N — (3,4-dimethyl-1, 5-oxazolyl) -N — [(2-methoxyethoxy) methyl] 2 ′-[[(2-methylpropyl ) Sulfonyl] methyl] -4 '-(2-oxazolyl) [1,1, biphenyl]-2-benzidineamine at 0 ° C, will hum (347 mg, 0.564 mmol) Moore) aqueous slurry was added to step (C) of the title compound (110 mg, printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs) in 10 minutes with the temperature kept below 10 ° C. 1 ml of methanol solution. The reaction was stirred at room temperature for 2 hours, diluted with 5 ml of water and extracted with ethyl acetate (3 x 8 ml). The ethyl acetate extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give 112 mg (98%) of the title compound as a colorless oil in this step. E. N— (3,4-dimethyl-1,5-isoBoxafluorenyl) —2 ′ — [[(2-methylpropyl) sulfonyl] methyl] —4 ′ — (2-πoxazolyl ) [1,1'-biphenyl]-2-Sulfonamide This paper is sized according to Chinese National Standard (CNS) A4 (210 × 297 mm)-184-(Please read the precautions on the back before filling this page) 517057 A7 B7 V. Description of the invention (l82) 1.75 ml of ethanol solution and 1.75 ml of 6 equivalent concentration hydrochloric acid in step (D) of the title compound (110 mg, 0.18 mmol) were refluxed ( The bath was heated at 100 ° C for 2.5 hours. The reaction was concentrated to dryness, dissolved in ethyl acetate, washed with sodium bicarbonate, water, brine, and dried over sodium sulfate. The product was then purified by purification on Merck silica gel with ethyl acetate to give 40 mg of a colorless oily product. This oily residue was lyophilized from dioxane under reduced pressure to obtain 36 mg (38%) of the title compound as a colorless solid, melting point 8 2 to 95 ° C. Example 5 8 N — [〔2 '一 ί ί (3,4_dimethyl_5 —Moxazole) amine group] 碏 醯] -4 ((2-oxazolyl) [1, 1 ′ —biphenyl] — 2-yl] methyl] -4 —fluoro-N-methylbenzidine

Ο Ρ ^ Ν ^ Η I Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) Triethylamine (43 mg, 0.42 mmol) and 1-hydroxyl 7-Azabenzotriazole (31.6 mg, 0.23 mmol) added to 2 '-[(methylamino) methyl] -N- (3,4-dimethyl) This paper is applicable to China National Standard (CNS) A4 specification (210X297 mm) -185-517057 A7 _____B7 _ _ 5. Explanation of the invention (183)-5-isoxazolyl)-4, one (2-oxazolyl) [1, 1 , A pair. Phenyl] -2-sulfamethoxamine, monohydrochloride (100 mg, 0.21 mmol, prepared according to the method described in Example 2 8 step (A)) and 4 a Fluorobenzoic acid (29.5 mg 21 mmol) in 0.3 ml of dichloromethane, and then 1,3-diisopropylcarbodiimide (29.3 mg, 0.23 mmol) Ear), the reaction was stirred at room temperature for 3 hours and concentrated. The residue was then borrowed on a 0 DSS 10 column for preparative high performance liquid chromatography and 31% solvent A (10% methanol, 90% water '0.1% trifluoroacetic acid) and 69% solvent B ( 90% methanol ', 10% water, 0.1% trifluoroacetic acid), and purified to obtain the title compound (60 mg, 51%) of this example as a white solid. Melting point 125-135 ° C (amorphous) . Example 5 9 2, — [[(3,4 —dimethyl-5 —isoxazolyl) I --------------, order ------ (please first (Read the notes on the back and fill out this page)

This paper size applies the Chinese National Standard (CNS) M specification (210x297 mm) _ 186 _ 517057 A7 ______B7 V. Description of the invention (l84) 0037 g (0. 348 millimolar) of isobutyric chloride and 0.065 Grams (0 638 millimoles) of triethylamine to 0.12 grams (0.29 millimoles) of 2 '-[(methylamino) methyl] -N- (3,4-dimethyl-5 —Isoxazolyl) -5,5- (2—oxazolyl) [1,1′-biphenyl] -5-basic amine (prepared according to the method described in Example 21, step (A)) 5 Ml of dichloromethane solution. The mixture was then stirred at room temperature for 12 hours and evaporated. The residue was borrowed on a 30x500 mm ODS S10 column for reverse-phase preparative high-performance liquid chromatography and separated using 68% solvent B (90% Methanol, 10% water, 0.1% trifluoroacetic acid) and 32% solvent A (10% methanol, 90% water, 0.1% trifluoroacetic acid) were eluted and purified, and the appropriate fractions were collected, and then water-based Sodium bicarbonate was neutralized to P Η 7, and concentrated to 10 ml. Then, the solution was acidified to pH 4 with aqueous sodium hydrogen sulfate, and the white solid was filtered and dried to obtain 0.052 g (35%) of the title compound as a white solid, melting point 105-115 ° C. Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) Example 6 0 ΚΓ-"" 2, _ 〔[(3,4 — two-shenyl-5 —isoxazolyl ) Tick] sulfonyl] -4- (2-oxazolyl) [1 丄 _ 1, one biphenyl]-2-some 1 syl]-2-I group-N-methylbenzidine Paper size applies to China National Standard (CNS) A4 (210x297 mm) -187-517057 A7 B7 V. Description of the invention (185)

(Please read the precautions on the back before filling this page) Ο Ο- Μ 0 H r &quot; cH3 ch3 Triethylamine (13. 3 mg '0. 13 mmol), and then 2-fluorophenylphenyl chloride (8.3 mg, 0.053 mol) plus 2 '-[(methylamino) methyl] -N- (3,4-dimethyl-5 —Isoxazolyl) _4, mono (2-oxazolyl) [1,1, monobiphenyl] _2-sulfonamide, monohydrochloride (25 mg, 0.053 mmol, according to the example 28) in the method described in step (A)). The reaction was stirred at room temperature overnight and concentrated. The residue was then subjected to preparative high-performance liquid chromatography on an ODS S10 column using 29% solvent A (10% methanol'90% water, 0.1% trifluoroacetic acid) and 71% solvent B (90 % Methanol ', 10% water, 0.1% trifluoroacetic acid), and purified' to obtain the title compound of this example (20 mg '68%) 'Melting point 127-137 ° C (amorphous ). Example 6 1 N One "ί? ·, One 〔[3,4—diyl group-5—moxazolyl group] 碏 醯] -4 4 (2-Axazolyl group) [1, 1, one combination Phenyl] -2-yl] methyl] -3 -fluoro-N-_ some phenylamidine 188-This paper size applies to the Chinese National Standard (CNS) A4 (210x297 mm) 517057 A7 B7 Central Printed by the Bureau of Consumers Cooperatives of the Bureau of Standards V. Invention Description (186)

Ο s-νΛΛ ·· HY ^ CH3 ch3 〇 Triethylamine (13. 3 mg, 0.13 mol) and then 3-fluorophenylhydrazine chloride (8.3 mg, 0.053 mM) ) Added to 2,-[(methylamino) methyl] -N- (3,4-dimethyl-5-isoxazolyl) -4,1- (2-oxazolyl) [1,1, Monobiphenyl] -2-sulfamethoxamine, monohydrochloride (25 mg, 0.053 mmol, prepared by the method described in Example 28, step (A)). The reaction was stirred at room temperature overnight and concentrated. The residue was then borrowed on a 0DSS 10 column for preparative high performance liquid chromatography and 29% solvent A (10% methanol, 90% water, 0.1% trifluoroacetic acid) and 71% solvent B ( 90% methanol, 10% water, 0.1% trifluoroacetic acid) and purified by purification to obtain the title compound (18 mg, 61%) of this example as a white solid, melting point 125-135 ° C (amorphous ). Example 6 2 N — (3,4 —dimethyl-1,5 —isoxazole) —? ·, [[[Methyl (2-methylpropylamino) amino] methylmonoyl] -4 '-(? · —Midyl) [1,1'-biphenyl] -2-sulfonamide (Please read the notes on the back before filling this page)

This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) 1 189-517057 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (187) / = λ A7 B7

Add N— (3,4-dimethyl-5—isoxazolyl) -2, 1-methylamidine-4, 1 (2-oxazolyl) [1,1, biphenyl] -2—sulfone Amidine (100 mg; 0-24 millimoles, as prepared in step 21 (F) of Example 21), isobutyl methylamine (0.087 milliliters; 0.71 millimoles), acetic acid (0.08 milliliters; 1. 3 4 mmol) and 3 A molecular sieve (670 mg) in 2 ml of dichloromethane mixture was stirred at room temperature for 1 hour, and then sodium triethoxyhoxyborohydride (150 mg; 71 millimoles). After stirring at room temperature for 18 hours, the reaction mixture was filtered through Celite, and the filtrate was separated between ethyl acetate (40 mL) and saturated sodium bicarbonate solution (20 mL). The organic layer was then washed with water (20 ml) followed by brine (20 ml). It was dried (sodium sulfate) and concentrated to obtain the residue. 'It was used on a 2-5x12 cm silica gel column with a stepwise gradient of 300% @ dichloromethane to 5% methanol / dichloromethane. The chromatographic separation was performed, and then the pure soluble fraction was concentrated to obtain 88 mg of the title compound of this example as a white powder, melting at 90 ° to 100 ° C (foaming at 60 ° C). Example 6 3 4 —Chlorine N — [〔2 '— if (3,4 One Two One One 5 — (Please read the notes on the back before filling this page) ) A4 specification (21 × 297 mm) -190-517057 A7 B7 V. Description of the invention (188) Isoxazole an amine group] sulfonium] -4- (2-J1 a warm group) [

(Please read the notes on the back before filling out this page) The Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs printed 4 dimethylaminopyridine (6.7 mg, 0.055 mmol), and then 1, 3 -Diisopropylcarbodiimide (6.9 mg, 0.05 mg) added to 2 '-[(methylamino) methyl] -N— (3,4-dimethyl-1 5-Iso-fluorenyl) -4 '-(2-oxazolyl) [1,1'-biphenyl] -2-sulfamidamide (24.1 mg, 0.055 mmol, according to Example 28 5mL of methylene chloride solution prepared in the method described in step (A)) and 4-chlorobenzoic acid (7.8 mg, 0.05 mmol). The reaction was stirred at room temperature for 18 hours and concentrated. The residue was then dissolved in methanol, neutralized with aqueous sodium bicarbonate to pH &gt; 8, and filtered. The filtrate was then acidified to PΗ &lt; 5 with sodium hydrogen sulfate, and then filtered to obtain the title compound (18 mg, 62%) of this example as a white solid, melting point 122-13 2 ° C (amorphous). . Example 6 4 The paper ^ dimensions are in accordance with Chinese national standards ([there are] 8 4 specifications (210 father 297 mm) ~ '191 1 517057 A7 __B7 ___ V. Description of the invention (l89) N-(3, 4-dimethyl One 5-isoxazolyl) one 2, [[ethyl (2,2,2-trifluoroethyl) amino] _methyl] -4 'one (2-oxazolyl) [1,1 'One biphenyl] di-2-disulfonaminium Γ = \ η κι

At room temperature, sodium cyanoborohydride (13 mg, 0.20 mmol) was added to N— (3,4—dimethyl—5—isooxazolyl) —4, — (2— Oxazolyl) -2,-[[(2,2,2-trifluoroethyl) amino] methyl] [1,1'-biphenyl] -2-sulfamethoxamine, monohydrochloride (55 mg, 0.10 mmol, as prepared in Example 4/5), 100 mg 3A molecular sieve and acetaldehyde (0.1 ml; 1.80 mmol) in 1 ml of methanol mixture Printed by the Consumer Standards Cooperative of the Central Bureau of Standards (please read the notes on the back before filling this page). After stirring at room temperature for 18 hours, the reaction mixture was filtered through a nylon syringe filter. The filtrate was concentrated and the residue was delimited between ethyl acetate (20 ml) and saturated sodium bicarbonate solution (20 ml). The aqueous layer was extracted with ethyl acetate (20 ml). The combined organic layers were washed with brine (25 ml), dried (magnesium sulfate) and concentrated. The residue was then separated on a 2.tx6 cm silica gel column using ethyl acetate: hexane 1: 1 as a mobile phase for chromatographic separation. The pure soluble fraction was concentrated to an oil, which was dissolved in about 0.2 ml of methanol. And then the water (the size of the mound paper is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) ~ &quot; a 192-

517057 A7 B7 V. Description of the invention (19) 3 ml) was added, and then the turbid mixture was frozen. After further lyophilization, 24 mg of the title compound of this example was obtained as a white solid. Melting point 5 5-65 ° C. Example 6 5 2 -Chloro-N-[[2 '— [[(3' 4 -Dimethyl-5 -isoxazole) amino] sulfonyl]] 4 4- (2-oxazolyl) [ 1, 1'-biphenyl]-2 -yl] methyl]-N-methyl benzene brewing Yuean f? 0 H r ^ CH3 ch3 0 061 g (0.3348 mmol) 2-chloro group Phenylhydrazone and 0.065 g (0.638 mmol) of triethylamine were added to 0 12 g (0.29 mmol) of 2 '-[(methylamino) methyl] -N— (3, 4-dimethyl-1,5-isoDoxoxanyl) -4,1- (2-oxazolyl) [1,1, -biphenyl] -2-sulfonamide (as in Example 2 in step 8) 5 ml of dichloromethane solution). The mixture was then stirred at room temperature for 12 hours and evaporated. The remaining material was borrowed on a 30x500 mm ODS S10 column for further degradation: reversed-phase preparative high-performance liquid chromatographic separation and the use of 72% solvent B (This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) ) One --- One 193-Binding (Please read the notes on the back before filling out this page) Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 517057 A7 B7 V. Invention Description (191) 90% methanol, 10% water, 0.1% trifluoroacetic acid) and 28% solvent A (10% methanol, 90% water, 0.1% trifluoroacetic acid) were eluted and purified. Then collect the appropriate fractions, neutralize to pH 7 with aqueous sodium bicarbonate, and concentrate to 10 ml, then acidify the solution to pH 4 with aqueous sodium bisulfate, and filter and dry the white solid to obtain 0. 043 g (26%) of the title compound of this example as a white solid. Melting point 125 — 135 ° C. Example 6 6 N — [[2 '_ [[(3,4 dimethyl-5 —iso-n-oxazolyl) amino] sulfonyl]] 4-4 (2-oxazolyl) [1,1' Monobiphenyl]-2-yl] methyl] -N-methylphenethylamine (Please read the precautions on the back before filling this page)

Order

0 〇 ~ N s-n-AXH Y ^ CH3 ch3 〇

I The Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs has added 1,3-diisopropylcarbodiimide (8.6 mg '0068 mmol) to N_ (3'4-dimethyl-5— Isoxazolyl) -2 '-[(methylamino) methyl] -4'-(2-spiroyl) [1,1, -biphenyl]-2-sulfamethoxamine (30 μg 〇. 068 mmol 'according to the method described in Example 28, step (A). The paper size applies the Chinese National Standard (CNS) A4 specification (210x297 mm) -194-517057 A7 B7. 5. Description of the invention (l92) (Prepared) and phenylacetic acid (8.5 mg, 0.02 mmol) in 0.6 ml of dichloromethane solution. Then the reaction was stirred at room temperature for 5.5 (Please read the precautions on the back before filling (On this page) hours and concentrated. Then the residue was borrowed on an ODS S 10 column for preparative high performance liquid chromatography using 25% solvent A (10% methanol, 90% water, 0.1% trifluoro Acetic acid) and 75% solvent B (90% methanol, 10% water, 0.1% trifluoroacetic acid) were purified by elution to obtain the title compound (21 ml, 61%) of this example as a white solid, Melting point 114 — 122 ° C (amorphous). Example 6 7 2,4 Dichloro-N- [[2'-ί [(3,4-Dimethyl-5-isoxazolyl) amino] sulfonyl] —4 mono (2-oxazole) ί 1,1'-biphenyl] -2-yl] methyl] -N —methyl-benzidine

S-N I I ί ·

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs, adding 1,3-diisopropylcarbodiimide (9.5 mg, 0.075 mmol) to N- (3,4-dimethyl-5 -Isoxazolyl)-2 '-[(methylamino) methyl]-4'-(2-oxazolyl) [1,1'-biphenyl]-2-sulfamethoxamine (30 mg, This paper size applies the Chinese National Standard (CNS) A4 specification (210 × 297 mm) -195-517057 Α7 B7 V. Description of the invention (193) 0.068 mil, prepared according to the method described in Example 28 step (A) ) 和 2,4-dichlorobenzoic acid (13.1 mg, 0068 mmol) in 0.68 ml of dichloromethane. Then (please read the notes on the back before filling in this page) and stir the reaction at room temperature overnight and concentrate it. The residue was then separated on a 〇DS S10 column for preparative high-performance liquid chromatography using 20% solvent A (10% methanol, 0.00% water, 0.1% trifluoroacetic acid) and 80% solvent B. (90% methanol, 10% water, 0.1% trifluoroacetic acid) and purified by elution to obtain the title compound (20 mg, 48%) of this example as a white solid, m.p. 134-142 ° C (none Shape). Example 6 8 N- (3,4-Dimethyl-5-isoxazolyl) -2'-ί (tolylamino) methyl] -4 '-(2-oxazolyl) [1,1 '—Biphenyl'yl] ~ 2 -sulfofluorenyl, trifluoroacetate (1: 1)

The Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs printed the title compound of Example 21, Step (F) (42 mg, 0.1 Gmole), N-methylaniline (0 033 ml; this paper size is applicable to China Standard (CNS) A4 specification (210 × 297 mm) -196-517057 A7 B7 V. Description of the invention (194) 0 30 millimoles), acetic acid (0.04 milliliter, 0.68 millimoles) and 3A molecular sieve ( 350 mg) of 1 ml of a dichloromethane mixture was thoroughly stirred at room temperature for 1 hour, and then sodium triethoxyloxyborohydride (65 mg; 0.30 mmol) was added. Stir at room temperature for 18 hours

After that, the reaction mixture was filtered through a nylon filter, and the filtrate was diluted with dichloromethane (20 ml) and washed with water (20 ml). The aqueous layer was then back-extracted with dichloromethane (10 ml), and the combined organic layer was dried (magnesium sulfate) and concentrated. The residue was then separated on a 2.5 x 12 cm silica gel column using 1 liter of ethyl acetate: hexane 1: 1 and 1 liter of ethyl acetate · Kewon 3: 1 as a mobile phase for chromatographic separation. The pure soluble fraction was concentrated and the free base was converted to the hydrochloride to obtain a substance of insufficient purity. This material was subjected to preparative high-performance liquid chromatography (flow rate = 35 ml / min; 30 x 500 mm S — 100 DS — 120 A column using an equivalent system of 78% methanol / water + 0.1% trifluoroacetic acid). Then, the pure soluble fraction was concentrated and lyophilized to obtain 27 mg (43%) of the title compound of this example as a white powder. Melted black accounted for 8 5-900 ° C. _ Binding (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

N 2 sulfonium i--

2 / IV-based oxazolyl phenyl N I-based fluorodi I 4 醯 ethyl phenyl 1Q7 This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 517057 Α7 Β7 V. Description of the invention (195)

Ο Ρ'Ν S ~ N- 〇 Η

CHa CH 3 (Please read the notes on the back before filling this page) Add 1,3-diisopropylcarbodiimide (9.5 mg, 0.075 mmol) to N — (3, 4 Monodimethyl- 5 -isoxazolyl) -2,1-[(methylamino) methyl]-4 '-(2-oxafluorenyl) [1,1'-biphenyl] -2-sulfo Amidine] (30 mg, 0.08 mmol, prepared according to the method described in step (A) of Example 28) and 3,4-difluorobenzoic acid (10.8 mg, 0.068 mmol) Ear) 0.68 ml of dichloromethane and 0.1 milliliter printed in the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs in the methyl zirconium solution. The reaction was stirred at room temperature for another 5 hours and concentrated. The residue was then subjected to preparative high performance liquid chromatography on an ODS S 10 column using 19% solvent A (10% methanol, 90% water, 0.1% trifluoroacetic acid) and 81% solvent B ( 90% methanol, 10% water, 0.1% trifluoroacetic acid) and purified by purification to obtain the title compound (22 mg '5 6%) of this example as a white solid, melting point 122-128 ° C ( Amorphous). Example 7 0 Ν-〔[2, 一 ΓΓ (3,4-dimethyl-1 5 _ isoxazolyl group 1) This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm) -198 a 517057 A7 B7 V. Description of the invention (196) Amine] 碏 醯] 1-2] yl] methyl] -N, α, α-trimethylphenethylamine

Ο P'N S — N- Ο Η

CH, CH 3 Add liters, 0 1 6. Hours of chloramine 1 chlorammonium chloride (2 mol concentration of dichloromethane, 0.125 mmol • 25 mmol) to ", 〇:-dimethyl Phenylacetic acid (printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 4 mg, 0.01 mmol) and 0.03 ml of dimethylformamide in 1 ml of dichloromethane. The mixture was stirred at room temperature for 15 minutes and concentrated. A mixture containing α, α-dimethylphenethylsulfonium chloride was dissolved in 1 ml of dichloromethane, cooled to 0 ° C, and then N- (3,4-dimethyl-5-isoxazolyl ) One 2, one [(methylamino] methyl] one 4, one (2-oxazolyl) [1,1, one biphenyl] one 2-sulfamethoxamine (33 mg, 0.075 mmol) Ear, prepared according to the method described in step (A) of Example 28) and triethylamine (23 mg, 0.225 mmol) were added, and the reaction was stirred at room temperature for 40 minutes and concentrated. The residue was then subjected to preparative high-performance liquid chromatography on an ODS S 10 column using 18% solvent A (10% methanol, 90% water, 0.1% trifluoroacetic acid) and 82% solvent. B (90% methanol, 10% water, 0.1% trifluoroacetic acid) was eluted and --------- ^ pack ------ order ------ (Please Please read the notes on the back before filling this page) This paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) -199-517057 Printed by A7 B7, Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs ) Purification to obtain the title of this example as a white solid Compound (20 mg, 4 6%), melting point 130-138 ° C (amorphous). Example 7 1 N— (3,4-Dimethyl-5-isospirofluorenyl) —4, 1 (2 — Blueazolyl) -2 ′ — [[(benzyl) (2,? ·, 2-digas. 7.yl) amino] methyl] [1,1′-biphenyl 1— 2-碏 醯 ticker = \

/ At room temperature, sodium cyanoborohydride (13 mg; 0.20 mmol) was added to Example 45 title compound Z (55 mg; 0.10 mmol), 100 mg of 3A molecular sieve and benzene Formaldehyde (0.05 ml; 0.5 mmol) in a 1 ml methanol mixture. After stirring for 18 hours, additional benzaldehyde (0 25 ml; 2.5 mmol), sodium cyanoborohydride (95 mg; 1-25 mmol) and acetic acid (0.05 ml) were added. After 60 hours, the reaction mixture was filtered through Celite and the filtrate was diluted with dichloromethane (50 ml). The resulting solution was then washed with a saturated sodium bicarbonate solution: water 1: 1 (50 ml). The water-based layer is then dichloromethane (2 X 2 0 millimeter paper size applicable to Chinese National Standard (CNS) A4 specifications (210X297 mm)) 200 — binding (please read the precautions on the back before filling this page) A7 ________B7_ 5. Description of the invention (l98) liters) Extraction ', and then the combined organic layer was washed with brine (50 ml). It was dried (magnesium sulfate) and concentrated to obtain a yellow oil. It was separated on a 2 • 5x10 cm silica gel column using ethyl acetate: hexane 1: 1 as a mobile phase, and the pure fractions were concentrated. An oil was formed, which was then dissolved in about 0.2 ml of methanol. Water (3 ml) was then added and the turbid mixture was frozen. It was then lyophilized to give 34 mg (57%) of the title compound as a white solid. Melting point 50—600 ° C. Example 7 2 --------- ^ 批 衣 — (Please read the precautions on the back before filling in this page) N — (3, 4 —dimethyl-5 —isoxazolyl) —2, One 1

^ The paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) -201-517057 A7 B7 V. Description of the invention (1 &quot;) in sodium hydride (50% mineral oil suspension, 0.03 3g 0.69 mmol) was added to a solution of isopropyl alcohol (0.14 g, 1.73 mmol) in 2 ml of dimethylformamide, and the mixture was stirred at room temperature under argon. 10 minutes. Then, 1 ml of a solution of the title compound (0.2 g, 0.346 mmol) in dimethylformamide was added in step 5 (b) of Example 5 and the mixture was stirred overnight. The mixture was then added to 50 ml of water and the solution was extracted with 3 x 2 5 ml of ethyl acetate. The combined organic extracts are then washed with water, dried and evaporated. The obtained residue was then subjected to chromatographic separation on 20 g of silica gel using 1: 1 hexane / ethyl acetate to obtain 0.019 g (10%) of the title compound as a colorless gum in this step. B _ N — (3,4 dimethyl-5—isoxazolyl) —2′—ί (1 monomethylethoxy) methyl] —4 ′ — (2-oxazole. Some) il , L'-biphenyl]-2-sulfamethoxamine 2.5 ml 6 equivalents aqueous hydrochloric acid was added to step (A) of the title compound (0.018 g, 0.032 mmol) 2. Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) • 10 5 ml of 9 5% ethanol solution, and then reflux for 1 hour. The mixture was then concentrated and diluted with 15 ml of water and extracted with 3 × 15 ml of ethyl acetate. The combined organic extract was washed once with water, dried and evaporated to obtain 0.015 g of colorless gum. The residue was subjected to reverse-phase preparative high-performance liquid chromatography on a 30 × 500 mm 3 S 10 column using 75% solvent B (90% methanol '10% 7jc, 0.1% three Fluoroacetic acid) and 25% solvent A (10% methanol, ^ Paper size applies Chinese National Standard (CNS) A4 specifications (210X297 mm)-202-517057 A7 ___B7 V. Description of the invention (200) 90% water, 0 1% trifluoroacetic acid) was purified by elution, and the appropriate fractions were collected, and then neutralized to pH 7 with aqueous sodium bicarbonate, then concentrated to 10 ml, and the solution was acidified with aqueous sodium hydrogen sulfate to普 4, and then the white solid was filtered and dried to obtain 0.006 g (40%) of the title compound of this example. 1 H NMR (CDCj? 3): (51. 01 (d, 3H), 1. 04 (d, 3H), 1. 89 (s, 3H), 2. 17 (s, 3H), 3. 58 ( m, lH),

4.38 (ABq, J = 16. 8, 11.2Hz, 2H), 7. 2 5-8. 17 (m, 9H) 〇 Example 7 3 (Please read the precautions on the back before filling this page) N — Γ Γ2 '-[[(3,4-Dimethyl-5—isoxazolyl) amino] 碏 醯] -4— (2-oxazolyl) [1,1, -biphenyl

The size of this paper is applicable to Chinese National Standard (CNS) A4 specification (2ΐ〇χ297mm) -203-517057 A7 ______B7 V. Description of the invention (2101) Moxa group) 2 '-[(methylamino) methyl Base] -1,4,2- (2-oxafluorenyl.) [1,1'-biphenyl] -2-benzidine (30 mg, (Please read the precautions on the back before filling out this page) 〇. 068 millimoles, prepared in accordance with the method described in step 28 (A) of Example 28) and 68-68 milliliters of dichloromethane in hydrocinnamic acid (10. 3 mg, 0.068 millimoles). The reaction was stirred at room temperature overnight and concentrated. The residue was then subjected to preparative high-performance liquid chromatography on an ODS S 10 column using 20% solvent A (10% methanol, 90% water, 0.1% trifluoroacetic acid) and 80% Solvent B (90% methanol, 10% water, 0.1% trifluoroacetic acid) was eluted and purified to obtain the title compound (18 mg, 4 6%) of this example as a white solid, m.p. 110-117 ° C (amorphous). Example 7 4 N — (3,4-dimethyl-1, 5-isoxazole, etc.) — 2 ′ — [(3,3 —dimethyl — 2 —oxyl — 1 — slightly steep radical) A Base] _z_ 4, — (2-oxazolyl) [1,1, —biphenyl] —2—Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

N Η OZIS-: ο

CH This paper size is in accordance with Chinese National Standard (CNS) A4 specification (21 × 297 mm) -204-517057 A7 _B7_ V. Description of the invention (202) A · 3,3-Dimethyl-2 2-pyrrolidone will be 1 An equivalent concentration of hydrochloric acid in diethyl ether (15 ml) was added to a solution containing 3,3-dimethyl-1, 2-oxyl-1, pyrrolidinecarboxylic acid, 1,1,2-dimethylethyl ester, and hydrochloric acid. In a flask (0.5 g, 2.34 millimoles, prepared according to the method described in J. Chem. Res. (Synopsis). J 414-415 (1 9 9 3)), the mixture was stirred overnight . The solution was then evaporated and the residue was dried in vacuo to obtain 0.26 g (98%) of the title compound as a pale yellow gum in this step, which would solidify upon standing. B. N— (3,4-dimethyl-1—5-oxazolyl) —2, one [(3,3-dimethyl-1—2-oxyl—1-pyrrolidine) Tian]] N — [(2-methylaminoethoxy) methyl] -4 '-(2-oxazolyl) [1,1'_biphenyl] -2-sulfonamide / Sodium hydride (50% Mineral oil suspension, 0.015 g, 0.31 mol) was added to 2 ml of dimethylformamide in step (A) of the title compound (0.035 g, 0.31 mol) Printed by the Consumer Standards Cooperative of the Ministry of Standards and Standards (please read the precautions on the back before filling this page), and then stir the mixture at room temperature under argon for 30 minutes. Then, 2 ml of dimethylformamide solution of the title compound (0.121 g, 0.21 mmol) of the step (B) of Example 57 was added, and the mixture was stirred overnight. The mixture was then added to 50 ml of water and the solution was extracted with 3 x 2 5 ml of ethyl acetate. The combined organic extracts are then washed with water, dried and evaporated. Then the obtained residue was separated on 20 g of silica gel using 1: 1 hexane / ethyl acetate for color separation, and the paper was obtained. The size of the paper was applicable to China National Standard (CNS) A4 (21GX297 mm). -205-517057 A7 V. Description of the Invention (203) 0 · 072 g (56%) of the title compound as a colorless gel

C (Please read the precautions on the back before filling this page) [― (3,4Di ^ methyl-5-isoxazole) —2, — [^ ~~: ~~ One shame two: 2 — Aiki — -1 — with attached cryptopyridine — methyl] — 4, — (—2 ^^ oxazolyl) [1,1, a combination of its two sulfonylamines and chlorotrimethylsilane (〇 1 gram, 〇_92 millimoles) and sodium iodide (0.138 grams, 0.92 millimoles) were added to step (B) of the title compound (0_072 grams, 〇_118 millimoles) 2 In ml of acetonitrile solution, the mixture was stirred at room temperature for 2 hours. Then add another portion of chlorotrimethylsilane (〇_ 〇1 grams, 0 029 millimoles) and sodium iodide (0.014 grams, 0.02 millimoles), the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Print and stir the mixture for another 1 hour. The mixture was then diluted with 15 ml of water and extracted with 3 x 15 ml of ethyl acetate. The combined organic extracts were washed once with water, dried and evaporated. The residue was then borrowed on a 300 × 500 mm OD SS 100 column for reverse-phase preparative high-performance liquid chromatography and separated using 7 1% solvent B (90% methanol, 10% water, 0 · 1% trifluoroacetic acid) and 29% solvent A (190% methanol, 90% water, 0.1% trifluoroacetic acid) were purified by elution. The appropriate fractions were collected, neutralized to pH 7 with aqueous sodium bicarbonate, and concentrated to 10 ml. The solution was then acidified to pH 4 with aqueous sodium bisulfate, and the white solid was filtered and dried to obtain 0.019 g (51%) of the title compound of this example as a white solid. Melting point &gt; 2 0 ° C (decomposed). This paper size applies the Chinese National Standard (CNS) A4 specification (210 &gt; &lt; 297 mm) -206-517057 Α7 Β7 V. Description of the invention (204) Example 7 5 Ν-(3,4-dimethyl-1 5 — Isoxazolyl) one 2, one [(4

The title compound of Example 21, Step (F) (42 mg, 0.10 mmol), N-methyl-para-anisidine (42 mg; 0.30 mmol), acetic acid (0 04 ml; 0.68 mmol) and 1 ml of a dichloromethane mixture of 3A molecular sieves were stirred at room temperature for 1 hour, and then sodium triethylhexyloxyborohydride (65 mg; Central Standard of the Ministry of Economic Affairs) Bureau employee consumer cooperatives printed 0.30 millimoles) to join. After stirring at room temperature for 18 hours, the reaction mixture was filtered through Celite, and the filtrate was diluted with dichloromethane (20 ml) and washed with water (20 ml). The organic layer was then dried (magnesium sulfate) and concentrated. The residue was separated on a 2.5 x 10 cm silica gel column using 1 liter of ethyl acetate: hexane 1: 1 and 1 liter of ethyl acetate: hexane 3: 1 as a mobile phase. The purest fractions are then concentrated to obtain substances of insufficient purity. Make this material accept the preparative high-grade paper. The λ degree of the paper is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) -207-517057 A7 B7 V. Description of the invention (205) Effective liquid color separation Ml / min; 30 x 500 mm, S — 10 ODS — 120A column, using a stepwise gradient of 60% methanol / water + 0.1% trifluoroacetic acid to 68% methanol / water + 0.1% trifluoroacetic acid, every 5 minutes increase 2%), the pure soluble fraction was concentrated, dissolved in about 1 ml of methanol, and then 1 equivalent of hydrochloric acid (0.5 ml) was added and then 2 ml was added. The mixture was then frozen and lyophilized to give 38 mg (6 6%) of the title compound as a white powder. Melting point 1 2 5-1 3 5 ° C. Example 7 6

2, [[(3,3-difluoro-1,1-pyrrolidinyl) methyl] -N- (3,4-dimethyl-5-isoxazolyl) -4 '— (2 —oxazole Group) "1,1, a biphenyl group] —2 -sulfamethoxamine, monofluoric acid 1 ί = \

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) Bo c —anhydride (Boc = terbutoxycarbonyl) (5.31 g; 24.33 mmol) was added to 3-pyrrolidol (2.12 g; 24.33 mmol) and triethylamine ( 4_ 3ml This paper size is applicable to the Chinese National Standard (CNS) A4 (210X297mm) -208-517057 A7 B7 V. Description of the invention (206); 31 millimoles in 100 ml of methanol solution. A slight exothermic reaction was observed at this time. After stirring at room temperature for 18 hours, the solvent was removed in the air, and the residue was delimited between ethyl acetate (1000 ml) and a saturated potassium hydrogen sulfate solution (100 ml). The organic layer was washed with a saturated potassium hydrogen sulfate solution (100 ml) and brine (100 ml), and then dried (magnesium sulfate) and concentrated to obtain 4.45 g (98%) of a light yellow oily substance. The title compound for this step. B. 3-Hydroxy-1-_1-bipyridinecarboxylic acid, 1,1,2-dimethylethyl ester at -60 ° C. Dimethoate (1.56 ml; 22 mmol) was Add to a solution of chloramphenicol (0.97 ml; 11 mmol) in dichloromethane (20 ml) over a period of 15 minutes. After stirring at 60 ° C for 15 minutes, the title compound of step (A) (1.87 g; 10 mmol) was dissolved in dichloromethane (20 ml) over 15 minutes. Add dropwise as a solution. After stirring at 60 ° C for 15 minutes, diisopropylethylamine (8.75 ml; 50 mmol) was printed on the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back first) Fill out this page again) Join in 5 minutes. After stirring at -60 ° C for 15 minutes, the reaction mixture was allowed to warm to room temperature and stirred for 30 minutes. The reaction mixture was then diluted with dichloromethane (100 ml) and washed with a saturated potassium bisulfate solution (2 x 100 ml), a saturated sodium bicarbonate solution (100 ml) and saline (100 ml). After drying (magnesium sulfate) and concentrating, good taste yielded 1.87 g (99%) of the title compound (99%) in this step as a pale yellow oil. 〇 This paper applies Chinese National Standard (CNS) A4. Specifications (210X297 mm) -209-517057 A7 B7 V. Description of the invention (207) 1 H NMR (CDCj ^ s): δ 1.49 (s, 9H), 2.59 (t, J = 8Hz, 2H), 3.75 (m, 4 Η) 〇c. _3, 3-difluoro-1-pyrrolidinecarboxylic acid, 1, 1,2-dimethyl ethyl at 0 ° C, step (B) A 1 ml toluene solution of the title compound (0.74 g; 4 mmol) was added to a 1 ml toluene solution of diethylaminotrifluorosulfide (0.53 ml; 4 mmol). After stirring for 1 hour at 0 ° C and 20 hours at room temperature, the reaction mixture was carefully poured onto ice. After the ice melted, the aqueous mixture was extracted with ethyl acetate (50 ml). The organic layer was washed with a saturated sodium bicarbonate solution (50 ml) and brine (50 ml), dried (magnesium sulfate) and concentrated. The residue was separated on a 5 × 10 cm silicone gel using hexane: ethyl acetate 9: 1 as a mobile phase for chromatographic separation. The pure fractions were then concentrated to give 0.47 g (58%) of the title compound as a pale yellow liquid in this step. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) 1 H NMR (CDCj ^ s): 51. 47 (s, 9H) '2 · 30 (m, 2H), 3. 55 (m, 2H), 3. 6 8 (m, 2 Η). D-_3,3-difluoropyrrolidine, hydrochloride at 0 ° C, the title compound of step (C) (0.42 g; this paper size applies Chinese National Standard (CNS) A4 specifications (210X297) (Centre) -210-517057 A7 B7 5. Description of the invention (208) 2 millimolar) 5 ml of ethyl acetate solution was added to a saturated hydrogen chloride (g). Ethyl acetate (15 ml) solution. After stirring at 0 ° C for 2 hours, the reaction mixture was purged with nitrogen. The volatiles were removed in vacuo to give 301 mg (99% +; solvent in the presence of residue) of the title compound as an off-white solid in this step. 1 Η NMR (CD a 〇D): 52. 57 (m, 2H) 3. 6 1 (t, J = 7.5 Hz, 2H), 3. 71 (, J = 14 Hz, 2H) 〇 13 CNMR (CD a 〇D): (534. 1 (t, Jc —F2

25Hz, 45 · 2, 51_ 7 (t, J C_F2 = 3 5 H), 128 · 8 (t, J C_F = 2 4 8 H z) 〇E. 2 '[(3,3-difluoro-1 —Pyrrolidinyl) methyl] — N — (3,4-dimethyl-1,5-isoBoxanyl) -4, 1 (2-oxazolyl) [1,1 'biphenyl]] 2-Sulfonamide, printed by the Consumer Cooperative of the Central Standards Bureau, Ministry of Economics, Monohydrochloride (please read the precautions on the back before filling this page). Example 2 Step 1 (F) of the title compound (55 mg; 0.13 mmol), the title compound of this example step (C) (57 mg; 0.40 mmol), acetic acid (0.054 ml) and 3A molecular sieve (500 mg) 1.2 ml of dichloride After the methane mixture was sufficiently stirred at room temperature for 1 hour, sodium triethenyloxyborohydride (87 mg; 0.40 mmol) was added. After stirring at room temperature for 4 hours, the reaction mixture was filtered through Celite, and the filtrate was applied to the Chinese National Standard (CNS) A4 (210 X297 mm) -211-517057 A7 B7 at this paper size. 5. Description of the invention (209) Dichloromethane (25 ml) is diluted and washed with water (20 ml). The organic layer was then dried (magnesium sulfate) and concentrated. Put the residue on 2.5 (please read the precautions on the back before filling this page). Use 1 liter of ethyl acetate: hexane 1: 1 and 1 liter of ethyl acetate: hexane 3 on X10 cm silica gel column: 1 Color separation was performed as a mobile phase. The purest fractions are then concentrated to obtain substances of insufficient purity. This material was subjected to preparative high-performance liquid chromatography (flow rate = 35 ml / min; 30x500 mm S — 10 〇 DS — 120A column, using 44% methanol / water + 0_1% trifluoroacetic acid to 56% methanol / water + 0% stepwise gradient of trifluoroacetic acid, increasing by 2% every 5 minutes). The pure soluble fraction was concentrated and dissolved in about 0.5 ml of methanol, and then 1 equivalent of hydrochloric acid (0.5 ml) was added followed by 5 ml of water. The mixture was further frozen and lyophilized to obtain 48 mg (66%) of the title compound of this example as a white powder. Melting point 1 0 5-1 2 0 ° C. Examples 77 to 139 Example 7 The compounds of 7 to 139 have the structure shown below, in which, for each compound, R * is the part shown in Table I below. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Γ = \

This paper size applies the Chinese National Standard (CNS) A4 specification (210X 297 mm) -212-517057 A7 __B7 V. Description of the invention (21〇) These compounds are prepared by mechanization as follows. 2,1 [(methylamine.) Methyl) -N— (3,4-dimethyl-1—isooxazolyl) —4 ′ — (2-oxazolyl) [1,1′—biphenyl] _2—sulfamethoxamine, according to Example 28 (32.9 mg, 0.075 mmol) was prepared by the method described in step (A) of 0.34 ml of dichloromethane and 0.99 ml of dimethylformamide solution, and then 1, 3-diisopropylcarbodiimide in dichloromethane (0-28 equivalents, 0.320 ml, 0.09 mmol) was added to the acid containing R * -COOH (0.075 mmol) ) In the vial. The reaction mixture was vortexed for another 3 minutes and allowed to stand at room temperature for 24 hours. Then the mixture was loaded on 1.5 g of strong anion exchange (, SAX〃, quaternary amine) resin and washed with 20 ml of dichloromethane and then 10 ml of 3% trifluoroacetic acid in dichloromethane. Desired compound. (Please read the notes on the back before filling in this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, one standard, one country, China-one piece of paper, one centimeter, 517057 A7 B7 V. Description of the invention (211)

Table I Example number printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs r Compound name High-performance liquid chromatography separation time (minutes) △ 77% N- [[2 '-[[(3,4-dimethyl- 5-Isoxazolyl) amino] sulfofluorenyl] -4- (2-oxazolyl) [1, Γ-biphenyl] -2-yl] methyl] -N-methylcyclopentanemethane Amine 7.6 78 α, N- [[2 '-[[(3, 4-Dimethyl-5-isoxamidino) amino] sulfofluorene] -4- (2-oxazolyl) [1,1 '-Biphenyl] -2-yl] methyl] -N-methylpyrazinemethanamine 6.4 79 a, N- [[2'-[[(3, 4-Dimethyl-5-isoxamine (Oxazolyl) amino] sulfofluorenyl] -4- (2-oxazolyl) [1, Γ-biphenyl] -2-yl] methyl] -N-methylcyclohexanecarboxamide 7.8 80 Me ί N- [[2 '-[[(3,4-Dimethyl-5-isoxamidino) amino] sulfofluorene] -4- (2-oxazyl) [1, Γ-biphenyl ] -2-yl] methyl] _N, 3- ~~ • methyl-2-benzophenethylbenzidine 7.4 81 CN 3-cyano-N- [[2 '-[[(3, 4- Dimethyl-5-isooxazolyl) amino] sulfofluorene] -4- (2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -N-methyl Aniline 6.8 210X297 mm) (Please read the precautions on the back before filling out this page) Applicable in I-214-517057 A7 B7 V. Description of the invention (2 丨 2) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 82 ζχ / OMe N- [[2 '-[[(3, 4-dimethyl -5-Isoxazolyl) amino] sulfofluorenyl] -4- (2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -2-methoxy-N -Methylbenzylamine 7.3 83 N- [[2 '-[[(3, 4-Dimethyl-5-isoxazolyl) amino] sulfofluorene] -4- (2-oxamyl) [ 1,1'-biphenyl] -2-yl] methyl] -2-fluoro-N-methylacetophenamine 7.5 84 N- [[2 '-[[(3,4-dimethyl -5-Isoxazolyl) amino] sulfofluorenyl] -4- (2-oxafluorenyl) [1,1'-biphenyl] -2-yl] methyl] -N-methylcyclohexane Promethazine 8.6 85 N- [[2 '-[[(3, 4-Dimethyl-5-isoxamidino) amino] sulfofluorene] -4- (2-oxazolyl) [1,1 '-Biphenyl] -2-yl] methyl] -N-methyl-1,3-benzodiHomolocene-5 -methylformamide 7.2 86 OMe (R) -N- [[2'- [[(3,4-Dimethyl-5-isooxazolyl) amino] amidine] -4- (2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl Group] -α-methoxy-N-methylphenethylamine 7.3 87 cr ^ 5 N- [[2 '-[[(3, 4-Dimethyl-5-isoxanthino) amino] Sulfonyl] -4- (2-oxanyl) [ 1,1'-biphenyl] -2-yl] methyl] -2-methyl-N-methyl-2-benzophene-butyramine 7.9 This paper size applies to China National Standard (CNS) A4 specifications ( 210X297 mm) Clothing ------ 1T ------ 0, (Please read the precautions on the back before filling this page) -215-517057 A7 B7 V. Description of Invention (213) Central Standard of the Ministry of Economic Affairs Bureau employee consumer cooperative prints 88% of N- [[2 '-[[(3, 4-Dimethyl-5-isoxanyl) amino] sulfonyl] -4- (2-oxanyl) [ 1,1'-biphenyl] -2-yl] methyl] -3,4,5-diamino-N-methylbenzidineamine 7.7 89 F N- [[2 '-[[(3, 4 -Dimethyl-5-isooxazolyl) amino] sulfofluorene] -4- (2-oxazolyl) [1, Γ-biphenyl] -2-yl] methyl] -2,4, 6-Diamino-N-methylbenzylamidine 7.5 90 N-[[2 '-[[(3, 4-dimethyl-5-isoxazolyl) amine.yl] sulfofluorene] -4- ( 2-oxazolyl) [1, Γ-biphenyl] -2-yl] methyl] -4-methoxy-N-methamphetamine 7.7 91 M4e 4- (1,1- — * (Methylethyl) -N- [[2 '-[[(3, 4- 9.0 Dimethyl-5-isoxanyl) amino] mine}]-4- (2-oxazolyl) [1 , Γ-biphenyl] -2-yl] methyl] -N-methylcyclohexylmethanamine 92 N- [[2 '- [[(3,4-Dimethyl-5-isooxazolyl) amino] sulfofluorene] -4- (2-oxazolyl) [1, Γ-biphenyl] -2-yl] methyl ] -N-methyl-1-acetamidine 8.0 93 CF3Ok, N-[[2 '-[[(3,4-dimethyl-5-isooxazolyl) amino] sulfonyl] -4 -(2-oxazolyl) [1, Γ-biphenyl] -2-yl] methyl] -N-methyl-4- (trifluoromethyl) -phenylhydrazine 7.8 This paper is applicable to China Standard (CNS) A4 specification (210 X297 mm) • Clothing ------ 1T ------ 0 (Please read the precautions on the back before filling this page) -216-517057

AB 5. Description of the invention (2i4) 94 CF3〇XX, N- [[2 '-[[(3, 4-dimethyl-5-isooxazolyl)) amino ] Sulfofluorene] -4- (2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -N-methyl-4_ (trifluoromethoxy) benzamidine 8.0 95 N- [[2 '-[[(3, 4-dimethyl-5-isooxazolyl) amino] sulfofluorene] -4- (2-oxazolyl) [1, Γ-biphenyl ]-2-yl] methyl] -N-methylcyclopropaneacetamidamine 7.0 96 α, N- [[2 '-[[(3, 4-dimethyl-5-isooxazolyl) amine ] 基 醯] -4- (2-oxazolyl) [1, Γ-biphenyl] -2-yl] methyl] tetrahydro-N-methyl-2-furancarboxamide 6. 6 97 N- [[2 '-[[(3, 4-Dimethyl-5-isooxazolyl) amino] sulfofluorene] -4- (2-oxafluorenyl) [1,1'-biphenyl ] -2-yl] methyl] -N, 3, 3-trimethylbutyramine 7.5 98 α, N-[[2 '-[[(3, 4-dimethyl-5-isoxazolyl ) Amine] sulfofluorene] -4- (2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -N-methyl-4-pyridinecarboxamide 5.6 99 N -[[2 '-[[(3, 4-dimethyl-5-isooxazolyl) amino] sulfofluorene] -4- (2-oxazolyl) [1,1'-biphenyl]] -2_yl] methyl] -N-methyl-3Q 5.8 Paper scales applicable Chinese National Standard (CNS) A4 size (210 X 297 mm) (Please read the back of the precautions to fill out this page) and then fill out the term wood-mounted - set -217--517057

B V. Description of the invention (2i5) 100 A N-[[[2 '-[[(3, 4-Dimethyl-5-isoxanyl) amino) sulfonyl] printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs ] -4- (2-oxazolyl) [1, Γ-biphenyl] -2-yl] methyl] -N-methyl-3-D than pyridoxamine 6.3 101 Ν-[[2 ' -[[(3, 4-Dimethyl-5-isooxazolyl) amino] sulfofluorene] -4- (2-oxazolyl) [1, Γ-biphenyl] -2-yl] form Group] -N-methyl-1,2,3-triazol-4-methylamidine 6.5 102 Me 'nn Me-V ^ N- [[2'-[[(3, 4-dimethyl- 5-Isoxamidinyl) amino] sulfofluorenyl] -4- (2-oxazyl) [1,1'-biphenyl] -2-yl] methyl] -N, 1, 5-trimethyl -1H-pyrazole-3-carboxamide 6.4 103 Me Me ^ N- [[2 '-[[(3, 4-Dimethyl-5-isoxazolyl) amino] sulfofluorene] -4 -(2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -N, 3, 5-trimethyl-4-isooxazolecarboxamide 6.5 104 &lt; X ^ (R) -N- [[2 '-[[(3, 4-Dimethyl-5-isooxazolyl) amino] pyridine] -4- (2-oxazolyl) [1, Γ -Biphenyl] -2-yl] methyl] -N-methylcyclopentanepropanamine 8.0 105 N- [[2 '-[[(3, 4-Dimethyl-5-isoxanthene ) Amino] sulfofluorenyl] -4- (2-oxafluorenyl) [1,1'-biphenyl]- 2-yl] methyl] -N-methylcyclohexaneacetamidine 7.9 This paper size applies to China National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling this page) · Please fill in the wooden order Φ -218-517057

AB V. Description of the invention (216) 106 N-[[[2 '-[[(3,4-dimethyl-5-isooxazolyl) amino]] expanded by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs ] -4- (2-fluoroxanyl) [1 '1'-biphenyl]-2- 7.4 group] methyl] -N-methylbicyclo [4. 2. 0] octane-1, 3 , 5-triene-7-formamidine 107 MeO N- [[2 '-[[(3,4-Dimethyl-5-isoxamidino) amino] amidine] -4- (2- Spirofluorenyl) [1,1'-biphenyl] -2-yl] fluorenyl] -3-methoxy-N-methylbenzidine amine 7.1 108 N- [[2 '-[[(3, 4-dimethyl-5-isoxanthene) amino] mine]] [4- (2-xanthene) [1,1'-bibenyl] -2 7.0 -yl] methyl]- 2, 5-difluoro-N-methylbenzylamine 109 Λ N- [[2 '-[[(3,4-Dimethyl-5-isooxanyl) amino] sulfofluorene] -4 -(2-oxazolyl) [1,1'-biphenyl] -2- 7.2yl] methyl] -3, 5-difluoro-N-methylbenzidine 110 ^ [[2'- [[(3,4-Dimethyl-5-isooxazyl) amino] sulfofluorene] -4- (2-oxazolyl) [1, Γ-biphenyl] -2-yl] methyl ] -N-methyl-1-phenylcyclopropanecarboxamide 7.5 111 Me2N 3- (dimethylamino) -N- [[2 '-[[(3, 4-dimethyl-5-isoxan Azolyl) amino] sulfofluorenyl] -4- (2-oxafluorenyl) [1 , Γ -biphenyl] -2-yl] methyl] -N-methylbenzidine 6.0 112 Me, Me X, N- [[2 '-[[(3, 4-dimethyl-5- Isoxazolyl) amino] sulfofluorene] -4- (2-oxazolyl) [1,1'-biphenyl] -2- 8.1 Λ ^ Me Me group] methyl] -N, 2, 2 -Trimethyl-3- (2-methyl-1-propenyl) cyclopropanecarboxamide (Please read the notes on the back before filling this page) This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm) -219-517057 A7 B7 V. Description of the invention (2Π) Printed by the Consumers 'Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 113 N- [[2'-[[(3, 4-dimethyl-5-isoxan Oxazolyl) amino] sulfofluorenyl] -4- (2-oxazolyl) [1, Γ-biphenyl] -2-yl] methyl] -N-methyl-1-methaneamine 7.6 114 0 ^ N- [[2 '-[[(3, 4-Dimethyl-5-isoxamidino) amino] sulfofluorene] -4- (2-oxazolyl) [1, Γ-biphenyl Methyl] -2 -yl] methyl] -N-methyl-2-pyridineacetamide, trifluoroacetate (1: 1) 5.4 115 N-[[2 '-[[(3, 4-dimethyl Methyl-5-isooxazolyl) amino] sulfofluorene] -4- (2-oxazolyl) [1, Γ-biphenyl] -2-yl] methyl] -N-methyl-4- D-pyridamidine, trifluoroacetate (1: 1) 5.3 116 N-[[2 '-[[(3, 4- Methyl-5-isoxanthene) amine] mine]] [4- (2-xanthene) [1 '1'-bibenyl] -2-yl] methyl] methyl-3- Aziridine acetamidinium, trifluoroacetate (1: 1) 5.4 117 Οχ Me ^ N-[[2 '-[[(3, 4-dimethyl-5-isoxazolyl) amino] mine Brewing] -4- (2-fluoroxanyl) [1,1'-bibenyl] -2-yl] methyl] -N, Ι-dimethyl-1H-sakizol-2-carboxamide 7.7 118 ft F N- [[2 '-[[(3, 4-Dimethyl-5-isooxazolyl) amino] amidine] -4- (2-oxazolyl) [1,1' -Biphenyl] -2-yl] methyl] -2, 3, 6-trifluoro-N-methylbenzidine 7.2 119 N-[[2 '-[[(3, 4-dimethyl -5-isochelyl) amino] sulfofluorenyl] -4- (2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -1, 2, 3, 4 -Tetrakisylmethyl-2-nemethanamine 7.9 (Please read the notes on the back before filling this page) This paper size applies to China National Standard (CNS) Α4 (210 X 297 mm) -220-517057

AB 5. Description of the invention (218) 120 Me J005 Me N-[[2 '-[[(3,4-dimethyl-5-isooxazolyl) amino group] printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs] Spread] 4- (2-Chrylyl) [1 'Γ-biphenyl] -2-yl] methyl] -N, 2,4, 6-tetramethylphenethylamine 8.0 121 Ν- [[2 '-[[(3,4-Dimethyl-5-isoxamidino) amino] sulfofluorene] -4- (2-oxazolyl) [1, Γ-biphenyl] -2 -Yl] methyl] -N-methyl-1,3-benzodioxo-5-acetamidamine 7.1 122 N-[[2 '-[[(3,4-dimethyl-5-iso Ethyl) amino] sulfofluorenyl] -4- (2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -N-methyl-4_ (1-methyl Ethyl) benzylamine 7.6 123 OMe N-[[2 '-[[(3, 4-Dimethyl-5-isooxazolyl) amino] sulfofluorene] -4- (2-oxafluorenyl ) [1,1'-Biphenyl] -2-yl] methyl] -2,3-dimethoxy-N-methylbenzidineamine 7.0 124 Me Me '1- (1,1 one-one · (Methyl) -N- [[2 '-[[(3, 4-monomethyl-5-isooxazolyl) amino] pyridine] -4- (2-oxazolyl) [1' 1 '-Bibenyl] -2-yl] methyl] -N, 3- — ^ * methyl-1H-pyrazole-5-carboxamide 7.2 125 cf3 N- [[2'-[[(3, 4-dimethyl-5-isoxazolyl) amino] sulfofluorene] -4- ( 2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -N-methyl-3- (trifluoromethyl) benzidine 7.5 (Please read the precautions on the back first (Fill in this page again) This paper size applies Chinese National Standard (CNS) A4 (21 OX297 mm) -221-517057 V. Description of Invention (2i9) Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 126 N-[[2 '-[[(3,4-Dimethyl-5-isoxanyl) amino group 7.7] Hydroxy] -4- (2-oxyl) [1, Γ-biphenyl] -2-yl ] Methyl] -4-fluoro-N-methyl-1-methaneamine 127 C! Human 3, 5-dichloro-N- [[2 '-[[(3, 4-dimethyl -5-iso7.9oxazolyl) amino] pyridine] -4- (2-oxazolyl) [1, Γ -biphenyl] -2-yl] methyl] -N-methylbenzidine 128 Cl 3, 4-dichloro-N- [[2 '-[[(3, 4-Dimethyl-5-iso7.8 XX, oxazolyl) amino] sulfofluorene] -4- (2- Oxazolyl) [1, Γ y biphenyl] -2-yl] methyl] -N-methylbenzidine 129 MeO 丄 N-[[2 '-[[(3,4-dimethyl -5-Isooxalyl) amino group 7.5] mineralase] -4- (2-fluoroxanyl) [1 '1'-bibenyl]-2-X group] methyl] -bu (4 -Methoxyphenyl) -N-methylcyclopropaneformamide 130 F N- [[2 '-[[(3, 4-Dimethyl-5-isoxamidino) amino7.3 F] sulfofluorene] -4- (2-oxazolyl) [1,1' -Biphenyl] -2-yl] methyl] -2, 3, 5, 6-tetrafluoro-N-methylbenzidine 131 N- [[2 '-[[(3,4-Dimethyl Methyl-5-isoxanthene) amino 7.7] mine enzyme] -4- (2-fluorenyloxazyl) [1,1'-bibenyl] -2-yl] methyl] -N-methyl- 4- (trifluoromethyl) phenethylamine (Please read the precautions on the back before filling this page) This paper size applies to China National Standard (CNS) A4 (210X297 mm) -222-517057

7 7 AB V. Description of invention (220) 132 CI 2, 6-dichloro-N-[[[2 '-[[(3,4-dimethyl-5- Iso7.7 όο oxazolyl) amino] phenyl] -4- (2-oxazolyl) [1,1 'monobiphenyl] -2-yl] methyl] -N-methylphenethylamine 133 N- [[2 '-[[(3, 4-Dimethyl-5-isooxazolyl) amino 7.6 V] sulfofluorene] -4- (2-oxafluorenyl) [1, Γ-linked Phenyl] -2 cf3 -yl] methyl] -3-amino-N-methyl-5- (difluoromethyl) benzamidine 134 cf3 N- [[2 '-[[(3,4- Dimethyl-5-isoxazolyl) amino 7.5] sulfofluorene] -4- (2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -4-fluoro -N-methyl-2- (trifluoromethyl) benzamidine 135 Q N- [[2 '-[[(3, 4-Dimethyl-5-isoxazolyl) amino 7.9] sulfonic acid醯] -4- (2-oxazolyl) [1, Γ-biphenyl] -2-Cr ^ yl] methyl] -N-methyl-α-phenylphenethylamine 136 Cl ^ 2- (2-Chlorooxy) -N- [[2 '-[[(3,4-A ^ methyl-5-isoxanthene) amino] pan]]-4- (2-oxazolyl ) [1,1'-Biphenyl] -2-yl] methyl] -N, 2-dimethylpropanamide 8.3 137 Me0v ^ 2-chloro-N-[[2 '-[[(3 , 4- Dimethyl-5-isoxazole 7. 1 1yl) amino] sulfofluorene] -4- (2-oxazolyl) [1, Γ -biphenylClyl] -2-yl] methyl] -3 , 4-Dimethoxy-N-methylbenzidine --------- 0 ^ ------ 1T ------ Φ. (Please read the precautions on the back first (Fill in this page) This paper size applies Chinese National Standard (CNS) A4 (210X297 mm) -223-517057 A7 B7 V. Description of the invention (221) Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 138 1 CI 2- ( 2,4-dichlorophenoxy) -N-[[2 '-[[(3, 4-dimethyl-5-isoxazolyl) amino] sulfofluorene] -4- (2-oxo Oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -N-methylacetamide 8.0 139 cf3 human 2-chloro-N- [[2 '-[[(3, 4-dimethyl-5-isoxazole 7.7.7) amino] sulfofluorene] -4- (2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -N -Methyl-5- (trifluoromethyl) benzidine (please read the precautions on the back before filling this page) This paper size applies to China National Standard (CNS) A4 (210X297 mm) -224-517057 A7 V. Description of the invention (222) △ High-performance liquid chromatographic separation status: Column: YMC S3 0 DS 4. 6x50 For 0 to m during 8 min --100% gradient elution of B, and held at 100 ° CB 3 minutes. Flow rate: 2.5 ml / min A: 10% methanol—90% water — 0.2% phosphoric acid B: 90% methanol—10% water—0.2% phosphoric acid Verification wavelength: 254 nm Example 1 4 0 N— (3,4-dimethyl-5-isoxazolyl)-2 '-[hydroxy (5-phenyl-2-oxazolyl) methyl] -4'-(2-oxazolyl) [1, 1 '—biphenyl] —2—sulfamethoxamine (Please read the precautions on the back before filling this page)

This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -225-517057 A7 B7 5. Description of the invention (223) Concentration. Then 250 ml of ethyl acetate was added, and the mixture was washed with water, brine, dried, and concentrated. The residue was then separated on silica gel using 15: 1 hexane / ethyl acetate for chromatographic separation and chromatographic separation to obtain the title compound (2.5 g, 57% B.N) as a white solid in this step. — (3,4—dimethyl—5—isoxazolyl) —2 ′ — [[Thryl (5-phenyl-2-oxazolyl) methyl] —N—ί (2 —methylargon Ethoxy) methyl] -4 '(2_oxazolyl) ί 1,1'-biphenyl]-2-sulfamidamide at -78 ° C, the n-butyl lithium (2 Molar concentration Pentane solution, 1 23 ml, 2.46 mmoles) was added to step (A) of the title compound (324 mg, 2.23 mmoles) in 9 ml of tetrahydrofuran and 4.5 ml of ether. In — After stirring at 78 ° C for 30 minutes, 3 ml of a tetrahydrofuran solution of the title compound (760 mg, 1.49 mmol) of step 21 in Example 21 was added dropwise. The staff of the Central Bureau of Standards of the Ministry of Economic Affairs was also added dropwise. Printed by a consumer cooperative (please read the precautions on the back before filling out this page) Reaction Stirred at -78 ° C for 30 minutes, then warmed to room temperature and stirred for 2 hours. Then the reaction was stopped with saturated ammonium chloride , It was extracted with ethyl acetate. The organic extract was washed with water, brine, dried and concentrated. Then the residue was separated on silica gel using 1: 1.5 hexane / ethyl acetate to separate the color layers to obtain the gel. The title compound in this step (540 mg, 55%). C. N — (3,4 —dimethyl-5 —isopropyl oxo) — 2 ,, [This paper size applies to China Standard (CNS) A4 specification (210X 297 mm) -226-517057 A7 __B7 V. Description of the invention (224) Hydroxyl (5-phenyl-2-oxazolyl) methyl] -4, 1 -oxazolyl) [1,1'-biphenyl] 2-methyl-trimethylsilyl chloride (199 mg, 1.83 mmol), followed by sodium iodide (274 mg, 1.83 mmol) Ear) was added to 10.2 ml of acetonitrile solution in step (B) of the title compound (200 mg, 0.305 mmol). The mixture was stirred at room temperature for another hour. Then add the other trimethylsilyl chloride (199 mg, 1.83 mmol) and sodium iodide (274 mg, 1.83 mmol) in three portions, and stir the reaction for another 5 . 5 hours. The mixture was then added to 5 ml of water and 50 ml of ethyl acetate. The organic layer was washed with saturated sodium thiosulfate and brine, dried, and concentrated. The residue was then separated on an ODS S 10 column for preparative high-performance liquid chromatography and 27% solvent A (10% Methanol, 90% water, 0.1% trifluoroacetic acid) and 73% solvent B (90% methanol, 10% water, 0.1% trifluoroacetic acid) were eluted and purified to obtain a white solid. Example title compound (65 mg, 37%), melting point 125-135 ° C (amorphous). Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) Example 1 4 1 N— (3, 4—dimethyl-1—5-oxazolyl) —4 ′ — ( 2 — oxazolyn) —2 ′ — [(5-茏 a certain 2-oxazolyl) A]] [1, Γ '—lian 茏 a] —2 -sulfamethoxamine This paper applies Chinese national standards ( CNS) A4 specification (210X297 mm) -227-517057 A7 B7 V. Description of invention (225) Ο Μ

Ο ρ- Ν S ~ N- * · \ ° H CHs

ch3 N— (3,4-dimethyl-1—5-oxazolyl) —N— “2-methoxyethoxy] methyl] -diphenyl ^ ((2-oxazolyl) —2 ' 1 [(Benzyl argon thio) oxy J _ (_... 5 —Pingyl-2-oxazolyl) methyl] Γ1, 1-linked group] 2 2 Basic employees of the Central Standards Bureau of the Ministry of Economic Affairs The Consumer Cooperative printed phenyl chlorothiothioate (169 mg '0.098 mmol), followed by 4-dimethylaminopyridine (137 mg, 1-12 mmol) to Example 1 40 steps ( B) 1.4 ml of acetonitrile solution of the title compound (9.2 mg, 0.14 mmol). The mixture was stirred at room temperature overnight, and then 20 ml of ethyl acetate was added. It was washed with water, brine, dried and concentrated. Then the residue was separated on a silica gel using 1: 1. 5 hexane / ethyl acetate for color separation to obtain the title compound in this step as a gel.

B

N

(3,4 one and two 5 -yloxazolyl) -N 2 ± _ -methoxyethoxy) methyl]-4 'one (2-p-oxazolyl)-2' one [( 5 —Stupid 2 -B oxalyl) methyl] [1, 1 '-biphenyl]-2-amidine. All the substances obtained as the title compound in step (A). Three paper sizes apply. China National Standard (CNS) A4 specification (21〇'297 mm) I -------- Cloth ------ II ------ (Please read the precautions on the back before filling (This page) -228-517057 A7 ____B7 _ _ V. Description of the invention (226) Butyl tin hydride (1 14 mg, 0.39 mmol) and 2, 2'_ azobis (2-methylpropane) (8 mg) of 3 ml of toluene was refluxed for 3 hours. The mixture was separated on a silica gel using a 1: 1.5 hexane / ethyl acetate for color separation to obtain the title compound (26 mg, 29% in two steps) as a gel. CN— (3,4-dimethyl-5—yloxazolyl) —4 ′ — (2-oxazolyl) _2 ′ — [(5-benzene—2—oxazolyl) — [1, 1 '—Biphenyl] -2 —sulfamidamide will be trimethylsilyl chloride (26.5 mg, 0.244 mmol), and then sodium iodide (35 mg, 0.244 mmol) Add to 2 ml of acetonitrile solution of the title compound (26 mg, 0.041 mmol) in step (B). The mixture was stirred at room temperature for another 20 minutes. Then another trimethylsilyl chloride (26. 5 mg, 0.244 mmol) and sodium iodide (35 mg, 0.244 mmol) were added in three portions, and the reaction was stirred for another 1. 5 hours. Then print the mixture printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page). Add the mixture to 2 ml of water and 25 ml of ethyl acetate. The organic layer was washed with saturated sodium thiosulfate and brine, dried and concentrated. The residue was borrowed on a 0 DSS 10 column for preparative high performance liquid chromatography and 21% solvent A (10% methanol, 90% water '0.1% trifluoroacetic acid) and 79% solvent B were used. (90% methanol, 10% water, 0.1% trifluoroacetic acid) and purified by elution to obtain the title compound (13 mg, 58%) of this example as a white solid. 'Melting point 120-128 ° C (Amorphous). This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) -229-517057 A7 B7 V. Description of the invention (227) Example 1 4 2 2 (Amino) amino] methyl] -N — (3,4-dimethyl-1-5-yloxazolyl) —4, — (2-oxazolyl) [1,1, biphenyl] -2 _Sulfonamide, monohydrochloride / = \

7. 12 grams; 40 millimolars) and diethylamino trisulfide (5.9 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economy (please read the precautions on the back before filling this page) ml; 4 4 milliliter Mol) was stirred at room temperature for 18 hours. After the reaction mixture was carefully poured onto ice and the ice was melted, the resulting mixture was extracted with ether (200 ml). The organic layer was then washed with a saturated sodium bicarbonate solution (2 x 75 ml), brine (50 ml), dried (magnesium sulfate) and concentrated to give a yellow liquid. Distill at 75-80 ° C; 3-4 mmHg to obtain 6.04 g (75%) of the title compound as a colorless liquid in this step. 1 Η N M R (C D C 1 a) · δ 1.29 (t, J = 7. 5Hz, 3H), 4. 2 8 (q 5 J = 7. 5 H z

, 2H), 7.46 (m, 3H), 7.61 (m, 2H) The paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) -230-517057 A7 B7 V. Description of the invention (228) ) ° 13 CNMR (CDC 1 3): (513. 5, 62.8, (Please read the notes on the back before filling in this page) 113. 1 (t, J C_F = 251Hz), 125 · 1, 12 8 3, 130. 7, 132.6 (t, J c —F2 = 25. 5 H z) »163. 9 (t, J c — F2 = 3 5 H z) 0 B · α, α —difluoro 50% ethanol solution of the title compound (6.0 g; 30 mmol) in step (A) was saturated with anhydrous ammonia. An exothermic reaction was observed at this time. The reaction mixture was stirred at room temperature After 60 hours, the volatiles were removed in vacuum, and the solid residue was placed in a minimum amount of hot ethyl acetate. Then a small amount of insoluble matter was filtered off, and hexane was added to the filtrate Until slightly cloudy. After cooling to room temperature and standing for several hours, the crystals were filtered and dried to obtain 4.68 g (91%) of the title compound as a colorless crystal in this step. 1 Η NMR (CDC 1 ο) ·· δ Ί. 49 (m, 3H) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs d / V 1 ± 6 7 χ) κ H 2 z H 5 7 1 ± 5 1 ± 1M- xu \) y 3 I-*-c D c RMN c 3 F- cz H 2 5 2 3 3 3 1 ± 5 7 6 1 o 9 2 rH 8 5 2 1 ±

z H 5 5 2-2 F I c J

c J z H 5 2 3 1 ± Amine ethylphenyl fluorodi I θ * θ- c This paper size applies to China National Standard (CNS) A4 specification (210X 297 mm) -231-517057 A7 B7 V. Description of the invention ( 229) 'Morbofluorene-dimethylsulfide (1.5 ml; 15 · 4 mmol) was added dropwise to step (B) of the title compound (1 g; 5 at 30 minutes) at room temperature. 84 millimoles) in 6 ml of tetrahydrofuran solution. After stirring at room temperature for 18 hours and under reflux for 2 hours, the reaction mixture was cooled to 0 ° C, and then 3 ml of methanol was carefully added over 15 minutes. The solution was then saturated with hydrochloric acid (g), and the cloud-like mixture was stirred at room temperature for 6 hours, stirred at reflux for 30 minutes, and stirred at room temperature for 60 hours. After removing the volatiles in vacuo, the residue was delimited between ether (50 ml) and 1 equivalent of hydrochloric acid (30 ml). The ether layer was extracted with 1 equivalent of hydrochloric acid (10 mL), and the combined aqueous phases were back-extracted with ether (50 mL). After adjusting p Η to 8 using solid sodium bicarbonate, 1 equivalent of sodium hydroxide (1 ml) was added, and the aqueous layer was extracted with ether (50 ml). After washing with a saturated sodium bicarbonate solution (25 ml), water (25 ml) and brine (25 ml), the ether layer was dried (magnesium sulfate) and concentrated to obtain 3 3 5 mg (39%). The title compound as a colorless liquid in this step. Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) 1 Η NMR (CDC 1 3): 53. 17 (t, J = 14.5 Hz, 2H), 7. 47 (m, 5H). 13 C NMR (CDC 1 3) · "9. 4 (t, JC_F2 = 30.8 Hz), 121.6 (t, J c —F = 2 4 2. 1 Hz,), 125.2, 128.5 ， 130. 0 ， 1 3 5. 5 (t ， J C_F2 = 2 6. 4 H z) 〇 This paper size applies to China National Standard (CNS) A4 specification (210X 297 mm) -232-517057 A7 B7 V. Description of the invention (23〇) D. 2 '一 ί (2,2-Diargonyl-2-phenylethyl] amino group]. Methyl] —N — (3, dimethyl-5 —isoxazole A) 4 '-(2-oxazolyl) "1,1'-biphenyl] -2-sulfanilamide, monohydrochloride Example 2 1 The title compound of step (F) (50 mg 〇. 12mmol), this example step (C) of the title compound (80 mg; 0.550 mmol), acetic acid (0.067 ml) and 3 A molecular sieve (500 mg) After the methyl chloride mixture was sufficiently stirred at room temperature for 1 hour, sodium triethoxylate borohydride (109 mg; 0.50 mmol) was added. After stirring at room temperature for 18 hours, the reaction mixture was allowed to stir. Filter through Celite, then filter the filtrate with dichloromethane (2.5 ml) Dilute and wash with water (20 ml) and brine (10 ml). The organic layer is then dried (magnesium sulfate) and concentrated. The residue is then borrowed onto 2.5 x 10 cm silicone gel using 500 ml of ethyl acetate: hexane. 1: 1 and 500 ml of ethyl acetate: hexane 3: 1 are printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) for color separation of mobile phase. The pure eluate was concentrated to obtain a substance of insufficient purity. This material was subjected to preparative high-performance liquid chromatography (flow rate = 35 ml / min; 30 x 500 mm S-10 〇DS — 120A column, using 40% methanol / water + 25% MeOH。 gradual gradient of 1% trifluoroacetic acid to 68% methanol / water + 01% trifluoroacetic acid, increasing by 2% every 5 minutes). Then the pure soluble fraction was concentrated to make it soluble in about 0.25 ml methanol Medium. Then add 1 equivalent of hydrochloric acid (0.25 ml), and then add 2-5 ml of water. Then cool and lyophilize the mixture to obtain 43 mg (60%) of light yellow solid paper. Standards are applicable to China National Standard (CNS) A4 specifications (210X297 mm) -233- 517057 Α7 Β7 V. Description of the Invention (231)

The title compound of this example. 12 2 _ 1 3 5 ° C

Oxazolyl) -N — [(2-methoxyethoxy) methyl 1 1 _ (Please read the notes on the back before filling out this page} Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 4 '1 ( 2 —oxazolyl) il, 1 ′ —biphenyl 1 — 2 hydrazine adds imidazole (106 mg, 1.56 mmol) to potassium carbonate (215 mg, 1.56 mmol) to Example 5 Step 7 (B) of the title compound (150 mg, 0.26 mmol) in 0.6 5 ml of dimethylformamide solution. The mixture was stirred at 40. (: stirring for 3 hours, 1 Diluted with 0 ml of water and extracted with 3 × 20 ml of ethyl acetate. Then the combined organic extracts were washed with water and brine, and the paper size was applied to the Chinese National Standard (CNS) A4 (210X297 mm) 234 -Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 517057 A7 B7 V. Description of the invention (232) Dry and concentrate to obtain the title compound in this step in the form of a gel. BN— (3,4—dimethyl-5—iso An oxazolyl)-2 '-[(1H —imidazole-1 1-ylmethyl)-4' — (2-oxazolyl) il, 1 '—Biphenyl] -2-sulfamethoxamine, monohydrochloride will be trimethylsilyl chloride (169 mg, 1. 56 mmol), and then sodium iodide (231 mg, 1. 56 MM) was added to 5.2 ml of the acetonitrile solution of the title compound in step (A). The mixture was stirred at room temperature for 30 minutes. Then another trimethylsilyl chloride (169 mg, 1 56 millimoles) and sodium iodide (231 mg, 1.56 millimoles) were added in three portions, and the reaction was stirred for another 1.5 hours. Then the reaction mixture was added to 3 ml of water and 25 ml of ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium thiosulfate, brine, dried and concentrated. Then the residue was separated on an ODS S100 column for preparative high performance liquid chromatography and used. 50% solvent A (10% methanol, 90% water, 0.1% trifluoroacetic acid) and 50% solvent B (90% methanol, 10% water, 0.1% trifluoroacetic acid) were purified by elution. The product was obtained, which was treated with 1.0 ml of aqueous 0.5 equivalent hydrochloric acid and concentrated to give the title compound of this example as a white solid (90 mg 68% in two steps), melting point 135 — 145 ° C (amorphous). Example 1 4 4 N — (3, 4 — Dimethyl, 5_ isoxazolyl) — 4,, (2 — paper size Applicable to China National Standard (CNS) A4 specification (210X297 mm) --------- ^^ clothing-(Please read the precautions on the back before filling this page) Order -235-517057 Α7 Β7 V. DESCRIPTION OF THE INVENTION (233) oxazolyl) -2'-phenoxymethyl] "1,1 -biphenyl] -2 -amidoamine

A. N— (3,4 dimethyl-5—yl η-zolizolium) —N (2-methoxyethoxy) methyl] -4, — (2-oxazolyl) -2, Mono (phenoxymethyl) [1,1, biphenyl] -2-sulfosulfonium Sodium hydride (60% mineral oil, 8.3 mg, 0.21 mmol) was added to Example 5 Step 7 (B) of the title compound (100 mg, 0.17 mmol) in 0.27 ml of dimethylformamide solution was stirred at room temperature for 20 minutes. Then add phenol (18 mg, 0-19 mmol) to the mixture, and then stir the reaction at room temperature for printing by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page ) 3 hours. Subsequently, 10 ml of water was added, and the mixture was extracted with 3 × 20 ml of ethyl acetate. Then the combined organic extracts were washed with water, brine, dried and concentrated to obtain the title compound in this step. Β · Ν— (3 '4—dimethyl ~~ 5 ~ • isothiazine Wowyl) — 4 '— (2 —oxazolyl) 2' — (phenoxymethyl) [1,1 '-biphenyl paper size applicable to Chinese National Standard (CNS) A4 specification (210X297 mm)- 236-517057 A7 B7 V. Description of the invention (234) group]-2-Amine Add 6 ml of 6 equivalent hydrochloric acid to 6 ml of 95% ethanol solution of the title compound in step (A). The reaction was refluxed for another 1.5 hours and concentrated. The residue was then neutralized with sodium bicarbonate to a pH of about 5, and extracted with 3 × 20 mL of ethyl acetate. The organic extract was washed with brine, dried and concentrated. The residue was then separated on silica gel using 100: 2 dichloromethane / methanol to separate the chromatographic layers to obtain the title compound of this example (48 mg, 55% in two steps), m.p. 91-97 ° C (amorphous). Example 1 4 5 N— (3,4-Dimethyl-5—isoxazolyl) -4, — (2 -oxazolyl) 2 ′-[(4-phenylphenyl-1piperidyl) methyl ] A [1,1'-biphenyl] one? , Sulfamethoxamine --------- ^^ 衣 ------ Order (Please read the notes on the back before filling this page)

I Printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs r = \

0 Example 2 1 Step (F) The title compound (42 mg; 10 millimolar), 1-phenylpiperazine (46 μl; 0-30) This paper size applies Chinese National Standard (CNS) A4 specifications (210X 297 mm) -237-517057 A7 B7 V. Description of the invention (235 mol), acetic acid (0_04 ml; 0_ 068 mol) and · (Please read the precautions on the back before filling this page) After stirring the 1 ml dichloromethane mixture of 3A molecular sieve (350 mg) at room temperature for 1 hour, add sodium triethoxylate borohydride (β 5 mg; 0-30 mmol). After stirring at room temperature for 20 hours, the reaction mixture was filtered through Celite, and the filtrate was diluted with dichloromethane (20 ml) and washed with water (20 ml). The organic layer was then dried (magnesium sulfate) and concentrated. The residue was then separated on a 2.5 x 10 cm silica gel column using a stepwise gradient of 200 ml of dichloromethane to 4% methanol / dichloromethane (increase by 1%). Then, the pure soluble fraction was concentrated and dissolved in about 0.5 ml of methanol. Water (2.5 ml) was added, followed by mixing, such as freezing and lyophilizing, to give 44 mg (79%) of the title compound as a white powder. Melting point 123-131 ° C. Example 1 4 6 N-(3,4 -Dimethyl-5 -isoxazole)-4,-(2-

This paper size is in accordance with Chinese National Standard (CNS) A4 (210x297 mm)-238-517057 A7 _______B7_ V. Description of the invention (236) Boron tribromide (1.0 mol concentration at -8 ° C) Dichloromethane solution, 2.45 ml) was added to the title (step F) of Example 19 (please read the precautions on the back before filling in this page). Compound (0.52 g, 2.5 mmol) In 15 ml of dichloromethane solution, the mixture was slowly warmed to room temperature, and then stirred at room temperature for 36 hours. Then another portion of boron tribromide (1.23 ml) was added, and the mixture was stirred at room temperature for another 24 hours. The mixture was then added to 25 ml of water and the solution was extracted with 3 x 2 5 ml of ethyl acetate. The combined organic extracts are then washed with water, dried and evaporated. 48 g (98%) of the title compound in this step was obtained as a colorless gum by color separation of the obtained residue on 2 '5 g of silica gel using 3: 1 hexane / ethyl acetate. B · 2-[4-Bromo- 3-(3-phenylpropoxy) phenyl] acetone at 50 ° C, anhydrous potassium carbonate (0.29 g, 2.09 mmol) and 1 Monobromo-3-phenylpropane (0.52 g, 2.63 mmol) was added to step (A) of the title compound (0.42 g, printed by the Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs, 1. 75 millimoles) in 5 ml of dimethylformamide solution, and stirred for 15 hours. The mixture was then added to 25 ml of water and the solution was extracted with 3 x 2 5 ml of ethyl acetate. The combined organic extracts were then washed with water, dried and evaporated. The remaining residue was separated on 25 g of silica gel using 3: 1 hexane / ethyl acetate to obtain 0.32 g (51%) of the title compound in this step as a pale yellow oil. This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) -239-517057 A7 B7 _ V. Description of the invention (237) C. ) -N—. 2-methylaminoethylargonyl) methyl] —4,1- (2-oxazolyl) —2, — (3-phenylpropoxy) fl, 1, _biphenyl] — 2-Ammonium (triphenylphosphine) palladium (0) (0.047 g, 0.04 mmol), followed by 7 ml of 2 mole sodium carbonate and 7 ml of 95% ethanol. N-alcohol ester N — [(2-methoxyethoxy) methyl] —N — (3,4 —dimethyl-5 —isoBoxafluorenyl) — 2 — (4 ′ 4,5,5 — Tetramethyl-1,3,2-dioxaborazene-1-2-yl) sulfenazamide (0 377 g, 0.81 mmol) (according to January 21, 1997 〇111 丨 &amp; 3261 ^ and others published the title of Methods for Preparation of Biphenyl I soxazo1e Sulfon amides &quot; (Attorney's Proceedings List No. HA6 8 9 a) The method described in the US Patent Series No. _, which is incorporated herein by reference in its entirety, and the preparation of a pinacol ester as shown below (15) prepared in the method described in the above paragraph) and step (B) of the title compound (0.29 g, 0.81 mmol) in 15 ml of toluene. Printed by the Employees' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page), then reflux the mixture under argon for 2 hours, then dilute with 100 ml of water and 3 x 50 ml of ethyl acetate Ester extraction. The combined organic extracts were washed once with 100 ml of brine, dried and evaporated. The residue was separated on 50 ml of silica gel using hexane / ethyl acetate 1: 1 to obtain 0.41 g (82%) of the title compound as a colorless gum in this step. This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm)-240-517057 A7 B7 V. Description of the invention (238) Preparation of pinacol esters 3 Η

3 in

3 Η (Please read the precautions on the back before filling out this page) Ν I bromo 5 -yl ¥ oxazoxisoisosulfenamide

Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs in a 2-liter three-necked flask equipped with a mechanical stirrer overhead, 250 ml addition funnel and argon line, 2-bromobenzenesulfonyl chloride (150 g '587 mmol, commercial) and anhydrous pyridine (150 ml). The resulting pale yellow solution was cooled to -18 ° C (internal temperature) with an ice / salt bath. Then, while stirring, a solution of 5-amino-3,4-dimethylisoxazole (69.1 g, 616 mmol, commercial) in anhydrous pyridine (195 ml) was added dropwise over an hour via an addition funnel. Join. During the addition, the internal reaction temperature does not exceed-6 ° C. After the addition, remove the ice / salt bath. The paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) -241-517057 A7 B7 V. Invention Explanation (239), then the reaction mixture was warmed to room temperature, stirred for 1 hour, and then stirred at 40 ° C for 21 hours. The reaction mixture was cooled to room temperature, and then poured into a mixture of ice water (3 liters) and celite (37.5 g). After stirring for 20 minutes, it was filtered and rinsed with water (250 ml X 3). Charcoal (45 g) was added to the filtrate. The mixture was then stirred at room temperature for 40 minutes and filtered through a Celite pad. Rinse the Celite pad with water (500 ml x 3). Then, the filtrate was acidified by adding dropwise cold hydrochloric acid (6 equivalents, 750 ml) over 2 hours while vigorously stirring. The product was precipitated, and after adding hydrochloric acid, the mixture was stirred for another hour. The mixture was filtered, and the solid matter was rinsed with cold water (750 ml × 4), and then dried under suction for 3 days. That is, the title compound of this step i was obtained as a yellow-white solid in 88% yield (high-performance liquid chromatographic layer separation area percentage = 97.4%). Thin-layer chromatographic separation (TLC): R f = 0.47 (from Waterman's silica gel; ethyl acetate: hexane / 1: 1, visualized CAM or UV light). Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page). Another method for making the title compound in this step: Under an argon layer, put 2 -Bromobenzenesulfonyl chloride (50 g, 196 mmol) and anhydrous 1,2-dichloroethane (125 ml). The resulting colorless solution was cooled to 0 ° C, then anhydrous Dttn (40 ml, 396 mmol), and then 5-amino-3,4-dimethylisoxazole (24.1 g, 196 Millimoles) Added in solid form. After the addition, remove the ice bath, and then apply the paper size of the reaction mixture I to the Chinese National Standard (CNS) A4 specification (210X297 mm) &quot; &quot; ~ -242-517057 A7 B7 V. Description of the invention (240) 55 ° C 2 for 1 hour to obtain a crude reaction mixture containing the title compound of this step i. 1 1 · .2 —Bromo-1—N — (3,4 Dimethyl—5 —Isocracy —) — One N. — [(2-methoxyethoxy) shenyl] benzene Under argon, potassium carbonate (130.5 g, 944 mmol) and anhydrous dimethylformamide (268 ml) were placed in a 1-liter three-necked flask equipped with a mechanical stirrer. in. This heterogeneous mixture was stirred for another 15 minutes at room temperature. The title compound of step i (125 g, 378 mmol) was then added as a solid. The mixture was then stirred at room temperature for another 15 minutes. Then methoxyethoxymethyl chloride (47.5 ml, 415.8 mmol) was added dropwise via an addition funnel over 40 minutes. After the addition, the reaction mixture was stirred for 40 minutes. The reaction was then monitored by high-efficiency liquid chromatography. The reaction mixture was diluted with ethyl acetate (400 mL), stirred for 5 minutes and filtered. The solid was then washed with ethyl acetate (200 ml X 2) and hexane (250 ml X 2). The filtrate was treated with charcoal (25 g), stirred at room temperature for 1 hour, and passed through a Celite pad. The Celite pad was rinsed with ethyl acetate (50 ml X 3). The ethyl acetate layers were then combined and washed with sodium carbonate (χ mol concentration, 500 ml). Precipitation occurs in the aqueous layer. It is suppressed by adding water. The aqueous layer was then separated and discarded. The organic layer was washed with water (750 ml), brine (500 ml X 2), dried over sodium sulfate, filtered and concentrated to obtain a slightly yellow color. The paper is sized to the Chinese National Standard (CNS) A4 (21 °). X297 mm) (Please read the precautions and items on the back before filling in this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs -243-517057 A7 ____B7 V. Description of the Invention 3 grams, 9 9% of the material balance value.) (Please read the precautions on the back before filling out this page) Dissolve the residue in ethanol (125 ml) and put it in the freezer (0 ° C) 20 hours. Crystallization occurred at this time. The solid was filtered and suction-dried. The title compound of this step ii (75.65% yield 'high-performance liquid chromatographic separation area' was obtained as a yellowish white solid. Percent = 98.2%). Thin layer color separation: Rf = 〇55 (silicone from Waterman; ethyl acetate: hexane / i: 1; visualization: CA Μ or UV light). This step ii Another method for making the title compound: will be obtained by another method for making the title compound in step i The reaction mixture was cooled to room temperature, and then concentrated on a rotary evaporator under reduced pressure at 40 ° C to obtain a dark thick oil (102 g). This dark oil (98 g, 188 mmol) Mol) was dissolved in anhydrous dichloromethane (240 ml). Diisopropylethylamine (97 ml, 4 equivalents) was added, and then methoxyethoxymethyl chloride (25.7 ml, 225 6 millimoles) was added dropwise. Then the reaction mixture was stirred at room temperature for 4 hours. Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, the reaction mixture was concentrated under reduced pressure to a thick oil on a rotary evaporator. Material, dissolved in ethyl acetate (400 ml), and then added charcoal (10 g). Then the charcoal mixture was stirred at room temperature for 30 minutes, and passed through celite. Filter in a pad. Rinse the Celite pad with ethyl acetate (100 ml X 3) and hexane (200 ml X 2). Then transfer the filtrate to a separatory funnel, and then use water ( 100 ml X2), hydrochloric acid (0.5 equivalent concentration, 100 ml χ2) This paper size applies to Chinese national standards CNS) A4 specifications (210 × 297 mm) -244-517057 A7 B7 V. Description of the invention (242) (Please read the notes on the back before filling this page) 'Water (100 ml X2) and saline (100 ml X2) Wash. Dry over sodium sulfate and filter and concentrate to obtain a thick oil (64 · 9 g, 83% material balance). Dissolve the thick oil in ethanol (65 ml) Use an ice bath to cool to 0 ° C to seed the product and stir at 0 ° c for 6 hours. Crystallization occurred at this time. The solid was filtered and suction dried. The title compound in this step i i was obtained as a yellowish solid (62% total yield, high-performance liquid chromatographic separation volume percentage = 98.2%). Thin-layer chromatographic separation: Rf = 0.55 (silicone from Waterman; ethyl acetate: hexane / 1: 1, visualization: CAM or UV light). iii 2 ^ &gt; After a certain N — (3,4 — — ^ &gt; methyl-5 —isoxazolyl) -N — [(2-methoxyethoxy) methyl] benzenesulfonium The amine was charged with the title compound of step ii (40.0 grams; 95.4 milligrams printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs) on a head-mounted mechanical stirrer, gas adaptor, thermocouple, and partition It was dried in a 3-necked 1 liter round bottom flask, then thoroughly degassed, and then placed under an argon layer. Tetrahydrofuran (185 ml) was then added via a syringe, and the mixture was cooled to about -100 ° C (internal temperature). Then n-butyllithium (42.5 ml, 101 millimoles, 2.38 moles of hexane) was added dropwise during 16 minutes, while keeping the internal temperature at -97 ° C to -1 0 1 ° C. Stir the pale yellow-orange solution at about 98 ° C to -10 ° C for another 16 minutes. Trimethyl borate (16.0 ml, 14 · 9 mmol) This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) -245-517057 A7 B7 V. Description of the invention (243) tetrahydrofuran (24 ml) was added dropwise during 14.5 minutes, while keeping the internal temperature between -96 ° C and -99 ° C. The mixture is then stirred at about -9 ° C to -110 ° C for about 44 minutes, and then at about -9 ° C to -72 ° C for another 39 minutes. Then add hydrochloric acid (3.0 equivalents, 120 ml, 360 mmol) to the reaction (the solution exotherms to about -7 ° C), and stir for another 20 minutes (-7 ° C to + 6 ° C) Then, the two layers were separated in a separating funnel, and the aqueous phase was washed with toluene (3 × 1 20 ml) and tert-butyl methyl ether (3 × 100 ml). The combined organic layer was washed with brine (4 x 100 ml), dried over sodium sulfate, and concentrated on a rotary evaporator to an amount of about 100 ml, which contained the title compound of this step iii (high efficiency Percentage of liquid chromatographic layer separation area = 97.7%). In another method for preparing the title compound in step iii, place the title compound in step ii (20-0 g, 47.7 mmol) into a 500 ml 3-necked flask equipped with a stir bar, and purify it with argon. 5 hours. Then print it with anhydrous tetrahydrofuran (200 ml) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) Add via syringe and cool the flask in an acetone / dry ice bath -78 ° C. Then phenyllithium (37.1 ml, 48.2 millimoles '1. 3 moles of cyclopropane-ether solution, according to j. 〇rgan_ omet. Chem., 18-6' 1 5 5 (1 9 8 0) was titrated and found to be a concentration of 1-3 Molar) was added via an addition funnel over a period of 25 minutes. The rate of addition of phenyllithium was such that the internal temperature of the reaction mixture was kept below _ 5 ° (:. The resulting solution was stirred at 78 ° C for 15 minutes, and then trimethyl borate (10.8 Tetrahydrofuran ^ Zhang's scale of ml '95 .4 millimoles) is applicable to China National Standard (CNS) A4 specification (210X297 mm) &quot;-246-517057 A7 B7 V. Description of the invention (244) (5 ml) The solution was added dropwise to the reaction mixture via a cannula during 15 minutes. The trimethyl borate / tetrahydrofuran solution was then cooled in an ice water bath before addition. The addition rate was maintained so that the internal temperature of the reaction mixture did not exceed -73 ° C. The reaction mixture was stirred at -78 ° C for 0.5 hours, and then the solution was stopped by adding a solution of acetic acid (15 ml) in tetrahydrofuran (10 ml). The acidified solution was then stopped. Stir at-7 8 ° C for 10 minutes, and then warm the solution to 0 ° C. Then, 1 equivalent concentration of hydrochloric acid (25 ml) (1 equivalent concentration of hydrochloric acid will be used by 4 2 ml 1 2 equivalent concentration of hydrochloric acid diluted to 500 ml of water) was added dropwise. A large amount of acid was added to ensure that the reaction was completely stopped. Before the addition, the hydrochloric acid solution was pre-chilled in an ice / water bath. Then the reaction mixture was warmed to room temperature, and t-butyl methyl ether (4 X 250 millimolar liters). The organic layers were combined and extracted with 0.5 equivalents of aqueous sodium hydroxide (4 X 25 ml). The aqueous layers were then combined with tert-butyl methyl ether (1 X 1 0 ml) back extraction. Then the aqueous extract was cooled to 0 ° C, and 6 equivalents of hydrochloric acid was added dropwise with rapid stirring to adjust p Η to 2.0 (ρ Η meter). Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) The solution was extracted with butyl methyl ether (4 x 250 ml), and the organic layer was collected and then dried in water. Dry over magnesium sulfate. Then filter the suspension and concentrate the solution to obtain the title compound of boric acid in step iii as a light brown oil (17.1 g, 93%, high-performance liquid chromatographic separation area percentage = 8 8 %). High-performance liquid chromatographic separation: column one Y MC ODS — A, 6 X 250 mm; surveillance at 233 nm; flow rate 1.5 mm Paper size applies to Chinese National Standard (CNS) A4 specifications (210X297 mm) 1 247-517057 Staff consumption of the Central Standards Bureau of the Ministry of Economic Affairs Cooperative printed A7 B7 V. Description of the invention (245) l / min; solvent A (%): water / methanol / phosphoric acid 90: 10: 0.2; solvent B (%) water / methanol / phosphoric acid 10: 90: 0.2; Gradient: 40% B to 100% B, showing a linear gradient during 10 minutes, 100% B for 5 minutes, 40% B for 4 minutes; the residence time of the title compound in this step iii = 8.3 minutes. i v. Pinacol ester The mixture obtained in step i i i was diluted with toluene (170 ml) so that the total amount was about 270 ml, and then the flask was equipped with a Ding-Stark trap and a magnetic stir bar. Then, pinacol (11.6 g, 98.2 mmol) was added, and the resulting mixture was heated to reflux for about 1.25 hours. The water was then drained from the Ding-Stark trap to obtain the title pinacol ester in step iv of the solution. (98% conversion effect, high-performance liquid chromatographic layer separation area percentage = 93.6%). Reverse phase high-performance liquid chromatography column: YMC-Pack〇DS — A; 150x6 mm; S-5 nm, 120A and monitoring at 233 nm; Solvent: A = 90% water, 10% methanol and 〇 2% phosphoric acid; B = 10% water, 90% methanol and 0.1% phosphoric acid; flow rate = 100 ml / min; gradient; from 40% B to 100% B in 10 minutes. Holding time: 5 minutes at 100% B, gradually reduced to 40% B and held for 5 minutes. The dwell time of the title compound in this step = 11.5 minutes. Another method of preparing the title compound in this step iv: Let the boric acid obtained in another method of preparing the title compound in step iii (this paper size applies the Chinese National Standard (CNS) A4 specification (210 X297 mm) -24f------- --------- IT ------ ^ (Please read the notes on the back before filling out this page) 517057 A7 _ B7 V. Description of the invention (246) 17. 1 g, 44.5 milli Mol) is dissolved in a solution of anhydrous toluene (425 ml) and pinacol (5.51 g, 46.7 mmol). Place the flask in an oil bath, and then heat to 120 ° C for 2 hours (note: the reaction is complete within the first 40 minutes), and then borrow a Stark trap (the flask and the trap are covered in foil; the mixture is mixed) Quickly boil in about 0.5 hours) and the condenser continuously removes water. An entire portion was analyzed by high-performance liquid chromatography (by repeating azeotropy with CDCj? 3). The results indicated that the boric acid starting material was completely converted to the title compound in this step. The reaction mixture was cooled to room temperature and concentrated to obtain the title compound of this step iv in the form of a toluene solution. The area percentage of high-performance liquid chromatography = 86%. The yield of boric acid converted to pinacol ester was determined as 100%. The dwell time of the title compound in this step iv = 12.4 points (using the high-performance liquid chromatographic separation state described in the raw material for boric acid) 〇 D. N — (3, 4 — dimethyl — 5 — isoxazolyl) — 4'_ (2-oxazolyl printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs) —2 ′-(3-phenylpropoxy) [1,1, —biphenyl] -2 12 ml of a 6-equivalent aqueous hydrochloric acid was added to a 95% ethanol solution of the title compound (0.36 g, 0.58 mmol) in step (C), and refluxed for an additional hour. The mixture was then diluted with 100 ml of water and extracted with 3 × 50 ml of ethyl acetate. The combined organic extract was washed once with water, dried and evaporated to obtain 0.36 g of colorless gum. Then borrow the leftovers at 30x500 millimeter paper size to apply Chinese National Standard (CNS) 8 4 specifications (210X297 public director) (Please read the precautions on the back before filling this page)-2〆 /-517057 A7 B7 V. Description of the invention (247) reverse phase preparative high performance liquid chromatography on ODS S 10 column using 89% solvent B (90% methanol, 10% water, 0.1% trifluoroacetic acid) and 11% solvent A (10% methanol, 90% water, 0.1% trifluoroacetic acid) was eluted and purified. The appropriate fractions were then collected and neutralized to PΗ7 with aqueous sodium bicarbonate and concentrated to 10 ml. Then, the solution was acidified to pH 4 with aqueous sodium hydrogen sulfate, and then the white solid was filtered and dried to obtain 0.181 g (59%) of the title compound of this example, with a melting point of 8 0 -9. ° C. Example 1 4 7 2 '-[(2,3-Dioxo_1H —Indole-1 1-yl) methyl] -N — (· ?, 4—dimethyl-5—isoxazole) One 4 'one Γ2 —oxazolyl) [1,1, _biphenyl] -2 -sulfamethoxamine, monohydrochloride / = \

Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page). Example 2 1 Step (F) The title compound (42 mg; 0.1 mmol) was filled with earthworms (34 Μl; 0.30 mol) Acetic acid (〇_ 04 ml; 0.68 mol) and 3A molecular sieve

(350 mg) of 1 ml of dichloromethane mixture was stirred at room temperature. The paper size is applicable to Chinese standards. A4 size (21 × 297 mm) J 517057 A7 B7 V. Description of invention (249)

0 〇 ~ N

s-nAA Ο H CH3 ch3 A · One, one [("1,1'-biphenyl]-4 -yloxy some) A certain] -N — (3, 4 dimethyl — 5 —iso Oxazolyl) -N-fluorene (2-ethenylethoxy) methyl] ~ 4,1- (2-oxazole _ [_ L, 1'-biphenyl] -2-mineral amine will be sodium hydride (60% mineral oil, 5 mg, 0.13 mmol) was added to Example 5 7 step (B) of the title compound (60 mg, 0.1 mmol) 0.2 ml of dimethyl In the formamide solution, it was stirred at room temperature for 20 minutes. Then 4-phenylphenol (20 mg, 0.1 mmol) was added to the mixture, and the reaction mixture was stirred at room temperature for 4 minutes. Hours. Then 10 ml of water was added, and the mixture was extracted with 3 × 20 ml of ethyl acetate. Then the combined organic extracts were washed with water'brine, dried and concentrated to obtain a gelatin. 1 This step The title compound: Β 2, -πι, 1-biphenyl]] 4 -yloxy) methyl 1 1 2 N — (· \ _, 4-dimethyl-5-isoxazolyl)-4, 1-2 -oxo) [1,1, a biphenyl one J — 2 —Sulfonamide This paper is sized to the Chinese National Standard (CNS) a4 (210X 297 mm) -252 I ---------------- II ----- -· (Please read the precautions on the back before filling out this page) Printed by the Employees' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 517057 A7 B7 V. Description of the invention (250) Add 3 ml 6 equivalent concentration hydrochloric acid to step (A) 3 ml of the title compound in a 9 5% ethanol solution. The reaction was refluxed for 1 hour and 10 minutes and concentrated. The residue was then neutralized to P Η &gt; 8 using sodium bicarbonate, and then aqueous sodium bisulfate was used. Acidified to ρΗ5, and extracted with 3 × 20 ml of ethyl acetate. Then the organic extract was washed with brine, dried and concentrated. The residue was then used on silica gel 70:30: 0. 25 hexane / acetic acid Ethyl acetate / acetic acid was subjected to chromatographic separation 'to obtain the title compound of this example (45 mg, 75% in two steps), melting point 95-105 ° C (amorphous). Example 1 4 9 N — [[2 'One ί (3,4 One dimethyl one 5 —Isoxazole) amine one] Basic brewing] — 4 One (2-πoxanyl) [1' 1, one pair Yl] -2 - yl] methyl Ί - Ν - 1__ [methyl, 1 'a biphenyl] - 4 - methyl Amides

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page). Add triethylamine (10_ 6 mg, 0.1 mmol) to Example 2 at 0 ° C. Step (A) The title compound (23 mg, this paper size applies Chinese National Standard (CNS) A4 specifications (210X297 mm)-254-517057 A7 B7 V. Description of the invention (251) 0.053 millimoles) and 4 53mL of dichloromethane in biphenylcarbonyl chloride (11.4 mg, 0.053 mmol). The reaction was stirred at room temperature overnight and concentrated. The residue was then separated on a 0DSS 10 column for preparative high performance liquid chromatography and 20% solvent A (10% methanol, 90% water, 0.1% trifluoroacetic acid) and 80% solvent B ( 90% methanol, 10% water, 0.1% trifluoroacetic acid) and purified by elution to obtain the title compound (19 mg, 58%) of this example as a white solid, m.p. 137-146 ° C (amorphous ). Example 1 5 0 N— (3,4 dimethyl-5—rixazole) -1,4 (2—oxazole-1) _2, — [(2—benzene-1H—imidazole-1—yl ) Methyl] il, 1, _biphenyl]-2-M amine, monochlorate-(Please read the notes on the back before filling this page) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

This paper size applies the Chinese National Standard (CNS) A4 specification (210 × 297 mm)-25th evening-517057 A7 __B7 V. Description of the invention (252) 2 —Shenyl ethoxy group) A]] 4 'one (2 —oxazole one ) 1 2 '1 [(2-Phenyl-1H —imidazole 1 1 1) A 1 1 [1,1' 1 biphenyl] 2 2-sulfonylamine 2-phenylimidazole (28.8 mg 0.5 millimoles of anhydrous tetrahydrofuran solution was cooled to 0 ° C under an argon layer, and then 60% sodium hydride (8 mg, 0.18 millimoles) was added. Then, a solution of the title compound (58 mg, 0.1 mmol) in step 57 of Example 57 (0.25 ml) in tetrahydrofuran was added, and the mixture was stirred at 0 ° C. for 1 hour and then subjected to thin layer chromatography (silica gel) , Ethyl acetate: hexane 1: 1) inspection showed that only raw materials were present. The reaction was warmed to room temperature and stirred for 1 hour (only raw materials were present). Then, dimethylformamide (about 2 drops) was added, and the reaction was stirred at room temperature overnight. Thin layer Separation of color layers shows no raw material is present. The reaction was diluted with water and extracted with ethyl acetate (3 × 10 ml). The combined extract was washed with brine, dried over anhydrous sodium sulfate, and evaporated to obtain a crude product as a colorless oil. After purification on a Merck silica gel column with ethyl acetate, 56 mg (8 6%) of the title compound was obtained as a colorless solid. Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the notes on the back before filling out this page) B. N— (3, 4 — Dimethyl 1 5 — Isoxazolyl) 1 4 '1 (2- Oxazolyl) -2 '-"(2-phenyl-1H-imidazol-1-yl) methyl] [1,1 _'- biphenyll- 2 -amidamine, monohydroxamate will Step (A) The title compound (90 mg, 0.14 mmol) is 1.5 ml of 6 equivalent hydrochloric acid and 1-5 ml of ethanol. The paper is sized to the Chinese National Standard (CNS) A4 (210X297 mm). ) 517057 A7 B7 V. Description of the invention (253) (Please read the precautions on the back before filling this page) The liquid is heated at 90 ° C for 3 hours. Then the reaction is evaporated to dryness, and then the residue is delimited at Saturated sodium bicarbonate solution and ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate and pre-evaporated to obtain a crude mixture as a colorless oil. The crude material was used on a Merck silica gel column for 5 minutes. % Methanol / dichloromethane was eluted and the colored layer was separated to obtain a mixture having three components. A 30x50 mm S-10 ODS_120 column was purified by preparative high-performance liquid chromatography at a flow rate of 35 ml / min. The eluent was a methanol / water + 42 stepwise gradient of 42 to 52%. 1% trifluoroacetic acid solvent system, with an increase of 2% every 5 minutes. The fractions containing the pure product are combined and evaporated to dryness to give 22 g of pure product trifluoroacetate (24%). Let this trifluoro Acetic acid salt was dissolved in 0.5 ml of methanol, 1 ml of 1 equivalent strength hydrochloric acid was added, and the mixture was evaporated to dryness to obtain a colorless solid hydrochloride. The material was then reduced from dioxane / water Freeze-drying yields 14 mg (17%) of the title compound of this example as a white solid, melting point 1 60-16.8 ° C 〇 Example printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Example 1 5 1 2 '一 [(1,3 -Dioxin-1,3-Dihalium certain 2H —Iso-Pin-2 2 -yl) methyl] -N- (3,4 -Dimethyl-5 -Iso B-oxanyl) —4 '— (2—πoxanyl) ί 1, 1' —biphenyl] —2—sulfonamide The paper dimensions apply to Chinese National Standard (CNS) A4 specifications ( 210X297 mm) -25 Q ~ 517057 A7 B7 V. Description of the invention (254) Ο κι

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

〇—N CH, CH3 2, — [(1,3-Dioxo—1,3 — — >> Hydroxy-2H—isoindole—2—some) Formamidine—N—C3, 4— Dimethyl its —5 —isoxazolyl) -N — Γ (2-methoxy-ethoxy), methyl — —4 '— (2-oxazolyl) [1,1'-biphenyl Ί '2-basic amines Potassium phthalimide imide (0.031 g, 0.166 mmol) was added to the title compound of step 57 (B) in Example 57 (0.8 g, consumed by employees of the Central Bureau of Standards, Ministry of Economy Cooperative printed 0.14 millimolar) in 1 ml of dimethylformamide solution, and the mixture was stirred at room temperature for 12 hours. The mixture was then added to 25 ml of water and the solution was extracted with 2 x 2 5 ml of ethyl acetate. The combined organic extracts were then washed with water, dried and evaporated. The obtained residue was further subjected to chromatographic separation on 20 g of silica gel using 2: 1 hexane / ethyl acetate to obtain 0.051 g (57%) of the title compound as a colorless gum in this step. B. 2 '— ί (1,3 —dihydro-1, 3 —dioxo — 2Η —isoindone late one ?, one, one) methyl] one N — (3,4, one dimethyl paper The scale is applicable to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) -25; 517057 A7 ____ £ 7 ____ V. Description of the invention (255) —5 —Isoxazolyl) — 4 '-_oxazolyl] [1 ， 1, —biphenyl] -2- basic amines (please read the precautions on the back before filling this page) chlorotrimethylsilane (0.019 g, 0.17 mmol) and iodinated Sodium (0_026 g, 0.01 mmol) was added to a solution of the title compound (0.05 g, 0.087 mmol) in 10 ml of dichloromethane in step (A), and the mixture was allowed to stand at room temperature. Stir for 2 hours. Then additional portions of chlorotrimethylsilane (0.019 g, 0.17 mmol) and sodium iodide (0.026 g, 0.17 mmol) were added, and the mixture was stirred for another 1 hour . The mixture was then diluted with 15 ml of water and extracted with 3 X 1 5 ml of dichloromethane. Knot

The combined organic extracts were washed once with water, dried and evaporated. The residue was then subjected to reverse-phase preparative high-performance liquid chromatography on a 30X500 mm ODS S10 column using 7 5% solvent B (90% methanol, 10% water, 0.1% trifluoroacetic acid) and 25% solvent A (10% methanol, 90% water, 0.1% trifluoroacetic acid) was eluted and printed to the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs for purification. The appropriate fractions were collected, neutralized to pH 7 with aqueous sodium bicarbonate, and concentrated to 19 ml. Then the solution was acidified to pH 4 with aqueous sodium hydrogen sulfate, and the white solid was filtered and dried to obtain 0.026 g (54%) of the title compound of this example as a white solid. ° C. Example 1 5 2 N — (3,4 Dimethyl—5—yloxazolyl) —4 ′ — (2—oxazolyl) —2 ′ — [(_ 1, 2, 3, 4-tetrahydro A certain paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm)-25 in-517057 A7 B7 V. Description of the invention (256) Di 1-quinolinyl) methyl] 1,2,1 Even j a 2-amine r = \

(Please read the notes on the back before filling this page) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Example 2 1 Step (F) The title compound (4.3 mg; 0.1 mmol), tetrahydroquinoline (38 μl; 0.30 mmol), 1 mL of a dichloromethane mixture of acetic acid (0.04 mL; 0.68 mmol) and 3A molecular sieve (400 mg) were stirred at room temperature for 1 minute Hours later, sodium triacetoxyborohydride (64 mg; 0.30 mmol) was added, and after stirring at room temperature for 18 hours, the reaction mixture was filtered through Celite, and then The filtrate was diluted with dichloromethane (20 ml) and washed with water (20 ml). The organic layer was then dried (magnesium sulfate) and concentrated. The residue was separated on a 2.5 × 1 2 cm silica gel column using 1000 ml of ethyl acetate: hexane 1: 1 and 500 ml of ethyl acetate as mobile phases for color separation. The purest fractions were then concentrated to give 48 mg (89%) of the title compound as a white solid. Melting point 9 8 — 108 ° C. Example 1 5 3 This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 517057

V. Description of the invention (257) N '4 — I; 5 5 radical oxazolyl) 2 2 ′ 1 Γ ethyl fluorene ”~~ U, 2,2-trifluoroethyl) amine Ί】 — 4. · '2 —An oxazole) [1, 1, —] —? Monoamidine / = \

Α, _, 2 ... ditriyl-N- (1-methylethyl) acetyl (please read the precautions on the back before filling this page)

MlM mm Acetone (1.1 ml; 15 mmol), 2,2,2 difluoroethylamine hydrochloride (1 g; 4 mmol), acetic acid (2 ml) and 3A molecular sieve (5 After 30 milliliters of the dichloromethane mixture was stirred at room temperature for 2 hours, sodium triacetoxyborohydride (3-20 g; 15 mmol) was added. After stirring at room temperature for 18 hours, printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs ’ΊΓ3 reaction mixture passed through the Celite diatomite, and 5 ml of acidic hydrochloric acid was added. After removing the volatiles in vacuo, the residue was delimited between ether (100 ml) and 1 equivalent of sodium hydroxide (1000 ml). The organic layer was washed with brine (50 ml), dried (magnesium sulfate) and filtered. Then add etheric hydrochloric acid (5ml) and remove the volatiles in vacuum to obtain 855g (65%) of the title compound as a white powder in this step, melting point = 8 0-9 0 ° C . This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) ~ 517057 A7 B7 V. Description of the invention (258) B · N-(3, 4-dimethyl a-5-base chewing base)-2 , — [丄 (methylethyl) (2,? ·, 2-trifluoroethyl) amino] methyl] -4, — ((2-oxazole)) 1—, 1, —biphenyl] 2-Sulfamethoxamine Step (A) of the title compound (53 mg; 0.30 mmol), Example 21 Step (F) of the title compound (43 mg; 0.1 mmol), acetic acid (0.04 Ml; 0.68 millimoles) and 1 ml of a dichloromethane mixture of 3A molecular sieves (400 mg) was stirred at room temperature for 1 hour, and then sodium triacetoxyborohydride (64 mg; 0 30 millimoles) added. After stirring at room temperature for 18 hours, the reaction mixture was filtered through Celite, and the filtrate was diluted with dichloromethane (20 ml) and washed with water (20 ml). The organic layer was then dried (magnesium sulfate) and concentrated. The residue was separated on a 2.5 x 15 cm silica gel column using ethyl acetate: hexane 1: 1 as the mobile phase. The purest fraction was then concentrated to obtain a gum, which was dissolved in 0.5 ml of methanol. Then add water (2.5 ml printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page)), and then freeze and lyophilize the mixture to obtain 20 mg (37 %) The title compound of this example as a white solid, mp 80-90 ° C. Example 1 5 4 N — (3, 4 — Dimethyl, 5 — isoxazolyl) — 2, 1, (2 — 2 — mesityl — 4 —phenethyl) — 4 '— (2 — oroxazyl ) [1,1'-biphenyl]-2 -sulfamethoxamine, isomer A The paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) f 517057 A7 B7 V. Description of the invention ( 259)

〇 p-u U II \ 〇 H

CH. CH 3 isomer A_ contains 7.7% isomer BA. (+, A) -N — (3, 4_ dimethyl-isoxazolyl) -2, — (2-hydroxyl 4 1-Phentermine) -N — [(2-Methoxyethoxy) Methyl] —4 ′-(2-oxazolyl) [1,1, —biphenylhydrazone—2-sulfamethoxamine (Please read the precautions on the back before filling out this page) The Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs printed a catalytic amount of iodine to magnesium (267 mg, 10 ml of ether. Then add about 1/5 The amount of (1. 85 grams, 10 millimoles) of 5 ml of Ethyldan was gradually added at the rate of slow reflux of the remaining bromide in diethyl ether. The reaction was then refluxed to room temperature. ° C, 0. 37 ml of Gree Example 4 9 step (B) of the title compound (13 31 mmol) in 2.5 ml of tetrahydrofuran solution. Then to room temperature, and then stirred at room temperature 0. The reaction was stopped with an aqueous solution of sodium chloride for 5 hours, and the solution was added with a solution of ethyl bromoethyl) phenyl ether in ethyl acetate (11 mmol). One solution was kept to slowly return for another 1 hour * and then cooled. The reagent was added dropwise to mg. 0.25 The reaction was slowly warmed and then extracted with ice and saturated water. The paper size of the extracted paper shall be in accordance with Chinese National Standard (CNS) A4 (210X297 mm) 262-517057 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 V. Description of the invention (260) The solution was washed with brine and dried and concentrate. Then, the residue was separated on a silica gel using 1: 1 · 3 hexane / ethyl acetate for color separation to obtain the title compound in the form of a gel. B. N— (3,4-dimethyl-1—5-oxazolyl) —2, 1—

2-Hydroxy-4Phenylbutyl) -4,1- (2-oxazole) 1,1,1'-biphenyl] -2-amidamine, isomer A trimethylsilyl chloride (163 mg, 1.50 mmol) and then sodium iodide (225 mg, 1.50 mmol) was added to a solution of the title compound in step (A) in 5 ml of acetonitrile. The mixture was stirred at room temperature for 30 minutes. Then additional trimethylsilyl chloride (81 mg, 0.75 mmol) and sodium iodide (112 mg, 0.75 mmol) were added, and the reaction was stirred for another 1.5 hours, followed by The reaction mixture was added to 3 ml of water and 30 ml of ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium thiosulfate, brine, dried, and concentrated. The residue was separated on an ODS S 10 column for preparative high-performance liquid chromatography using 34% solvent A (10% methanol, 90% water, 0.1% trifluoroacetic acid) and 66% solvent B. (90% methanol, 10% water, 0.1% trifluoroacetic acid) was eluted and purified to obtain a mixture of two isomers, which was used on silica gel with 70: 30: 0. 5 hexane / acetic acid Ethyl acetate / acetic acid was subjected to chromatographic separation to obtain the title compound isomer A (23 mg) of this example as a white solid, m.p. 9 2-102 ° C (amorphous). This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) -26 Today------- IT ------ Aw (Please read the precautions on the back before filling this page) 517057 r \

CH, CH3 A7 B7 V. Description of the invention (261) Example 1 5 5 N — (3,4 —dimethyl-5 —isoxoxanyl) — 2 — (2 hydroxy-4 monophenylbutyl) -4 'One (2-oxazolyl) [

1,1'-biphenyl] -2-fluorenamine, isomer B

Ο 0-N Μ \ Ο Η

Isomer B, containing 22.0% Isomer A (please read the precautions on the back before filling this page) State ο Solid 9 The color point was melted in white, and was obtained. Separate layer B to form a color gel. Combined Forms 4 Cases of C with LO No. 1 ° c Real 9 9 of 9 | Printed by the Staff Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs

N 6 5 1 ± Example

N sulfonyl i- ^ aminoamino 1 phenylbenzazoxiso I 5 -methylmethyloxazolyl ethyl t- ^ yl I 2

Amine 醯 Ethyl Benzene I N This paper size applies to Chinese National Standard (CNS) A4 size (210X 297 mm) -26〆- 517057 A7 B7 V. Description of the invention (262)

(Please read the precautions on the back before filling out this page) A · N— (3, 4 — Dimethyl 1 5 — Rizozolyl) — N_ [(2 — Methoxyl, Argon, A), Membrane 1 1 ? · '-[(2- (methylamino) ethyl] -1] -4'-(2--Crazy) [1,1'_biphenyl]-2-Amine at 0 ° C Amine (8.03 Molar ethanol solution, 0.045 ml, 0.37 mmol), and then cyanoborohydride

Sodium (23 mg, 0.37 mmol) was added to the title compound (96 mg, 0.18 mmol) and the 3A molecular sieve in 2.5 ml of methanol in Example 49 (B). The mixture was stirred at room temperature for 2 hours. When printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs, it was diluted with 2.5 ml of ethyl acetate, washed with water and brine, dried and concentrated. The residue was separated on a silica gel using 100: 4: 0 · 5 dichloromethane / methanol / ammonium hydroxide for chromatographic separation to obtain a gelatinous compound Isomer A (29 mg, 12 · 5%). B · N — [2 — [2, 1ί [N — (3,4 dimethyl-5 5isoxazole)] [(2 —methylargon ethoxy) methyl] amino] sulfonium ] —4— (2-oxazole) ί 1,1'-biphenyl] This paper size applies to China National Standard (CNS) A4 specifications (210X297 mm) Guang-26th-517057 A7 B7 V. Description of the invention ( 263) One 2 —One] E1 1 N —Methylphenethylamine Acetochlor (2 mol concentration of dichloromethane solution, 0.073 ml, 0.15 mmol) was added to phenylacetic acid (7.9 mg '0.058 mmol) and 0.03 ml of dimethylformamide in 1 ml of dichloromethane. The mixture was stirred at room temperature for 1.5 hours, and concentrated. Then, the residue was dissolved in 0.5 ml of dichloromethane, and then cooled to 0 ° C, and then 0.5 ml of the title compound of step (A) (29 mg, 0.553 mmol) was used. Chloromethane solution, followed by triethylamine (16 mg, 0.16 mmol). The reaction was further stirred at room temperature for 2 hours and concentrated to obtain the title compound of this step, OC. N-[[2 '-[[(3,4 -dimethyl-5 -isoxyl) amine []] Sulfonyl 1-4 (2-oxazolyl) [1,1 '-biphenyl] -2-some] ethyl] -N -methylphenylethyl fluorenamine trimethylsilyl chloride (34 mg, 0.32 mol), and then add sodium iodide (48 mg, 0.32 mol) to the step printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back first) (Fill in this page) (B) 1.5 ml of acetonitrile solution of the title compound. The mixture was stirred at room temperature for 0.5 hours. Then additional trimethylsilyl chloride (46 mg, 0.42 mmol) and sodium iodide (63 mg, 0.42 mmol) were added in three portions, and the reaction mixture was stirred for an additional hour 4 5 minutes. The mixture was then added to 2 ml of water and 20 ml of ethyl acetate. The organic layer was washed with 1 ml of saturated sodium thiosulfate and brine, dried and concentrated. Then the residue is applied to the ODS S-1 〇I paper scale to apply the Chinese National Standard (CNS) A4 specification (210X297 mm) ~ -266-517057 A7 ____ _B7 V. Description of the invention (264) Preparative high performance on the column The liquid chromatographic layer was separated and 30% of solvent A (10% methanol, 90% water, 0.1% trifluoroacetic acid) and 70% of solvent B (90% methanol, 10% water, 0.1% trifluoroacetic acid) were used. Eluted and purified 'to give the title compound of this example as a white solid (7 mg, 23% in two steps), melting point 98-106 ° C (amorphous) ° Example 1 5 7 K- (3, 4— Dimethyl-5-isoxazolyl) -2 '-[(aniline) methyl] -1,4- (2_oxazolyl) [bis, 1'-biphenyl]]-2-sulfamethoxamine. f = \

Printed by the Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs Example 2 1 Step (F) The title compound (42 mg; 0.1 mmol), aniline (0.027 ml; 0.30 mmol

Moore), acetic acid (0.04 ml; 0.68 mmol) and 1 ml of dichloromethane mixture of 3A molecular sieve (400 mg) were stirred at room temperature for 1 hour. Sodium borohydride (65 mg; 0.30 mmol) was added. After stirring at room temperature for 18 hours, the reaction mixture was filtered through Celite, and the filtrate was applied to the standard of China National Standard (CNS) A4 (210X 297 mm) according to the paper size of dichloromethane. (Please Read the precautions on the back before filling this page) -26?-517057 A7 ______B7__ 5. Description of the invention (265) (20 ml) diluted and washed with water (20 ml). The organic layer was then dried (magnesium sulfate) and concentrated. The residue was separated on a 2.5 x 1 5 cm silica gel column using 1 liter of ethyl acetate: hexane 1: 1 and 500 ml of ethyl acetate: hexane 3: 1 as a mobile phase for chromatographic separation. The pure soluble fractions were then concentrated to obtain 35 mg (70%) of the title compound of this example as a white powder. Melting point 9 5-97 ° C; Rf = 0.32, ethyl acetate. Example 1 5 8 N — (3,4 dimethyl—5—yloxazolyl) —4, — (2—πoxazolyl) —2 ′ — [(1— (trifluoromethyl) —ethyl] ] Amine] methyl] _ [1, 1,1 biphenyl]-2 -sulfonamide [= \

Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) 1: 1 diastereoisomeric mixture A. N — (2, 2, 2 — difluoro-1 — 1 Monomethyl ethyl) benzylamine will be 1,1,1-trifluoroacetone (10 ml; 11.2 mmol), benzylamine (1.1 ml; 10 mmol), acetic acid (2 ml) And 3A molecular sieve (5 g) with 30 ml of dichloromethane mixture is applied to Chinese paper standard (CNS) A4 (210X297 mm) &quot; -26 ί-517057 A7 B7 in the paper size of the paper V. Description of the invention (266) After stirring at room temperature for 2 hours, sodium triacetoxyborohydride (4.25 g; 20 mmol) was added. After stirring at room temperature for 48 hours, the reaction mixture was filtered through celite. After removing the volatiles in vacuo, the residue was delimited between ether (100 ml) and 1 equivalent of sodium hydroxide (100 ml). The organic layer was washed with brine (50 ml), dried (magnesium sulfate) and filtered through a 5 x 5 cm silicone pad. The pad was then rinsed with ether, and the filtrate was concentrated to obtain 2.0 g (99%) of the title compound in this step as a colorless liquid.

1 Η N M R (C D C 1 a) · δ 1. 25 (d, J = 7H

z, 3H), 3. 18 (m, lH), 3. 8 8 (d »J = 13. 5 Hz, lH), 3. 94 (d, J = 13. 5

Hz, 1H), 7.27 (m, 1H), 7.33 (m, 4H) 〇13 CNMR (CDC 1a): (516. 0, 55.3 (printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs) QJJ c-F3 = 2 9. 3 H z), 67_ 1, 128.3 (Q, J c — F = 283.2 2 H z), 128. 5, 12 9. 3, 129.8, 140. 9. B. 2, 2, 2, 2-trifluoro-1-methylethylamine will be the title compound of step (A) (2 g; 9.84 mmol) and 6 equivalents of hydrochloric acid (3.3 ml ) 9 5 ml of methanol mixture at 1 atm and room temperature, 400 mg 20% palladium hydroxide / carbon This paper is sized for China National Standard (CNS) A4 (210X297 mm) (Please read the back Note: Please fill in this page again) -26f- 517057 A7 B7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (267) Hydrogenated for 20 hours 〇 Allow the reaction mixture to pass 0 4 5 μm rr; r Nylon 1 6 6 After filtering in the filter, the furnace liquid was concentrated and co-evaporated several times from methanol. Then it was milled with ether to obtain 8 8 5 mg (60%) of white powder. The title compound of the step 〇 1 Η NM MR (CD 3〇D), δ] L · L, (d = 6 5 Η Zn, 3 Η), 4 2 2 (m 1 Η) 〇C Ν (3 &gt; 4 monomethyl 5 isoxazolyl) 4 9 mono (2 oxazolyl) 2 9 — -1 [1 [[] L-(tristrifluoromethyl) ethyl) amino) methyl C 1, 1 9 mono-biphenyl]-2--sulfonamide. Step (B) of the title compound (45 mg; 0 3 0 mmol), Example 4 9 Step (F) of the title compound (38 mg) 1 0 ml of dichloromethane mixture of 9 0 9 mmol) acetic acid (0.4 ml 0 6 8 mmol) and 3 A molecular sieves (400 mg) was stirred at room temperature for 1 hour. Sodium hydroxide borohydride (64 mg ·, 0.30 mmol) was added. After stirring at room temperature for 18 hours, the reaction mixture was filtered through Celite and the filtrate was filtered with dichloromethane. Koin (20 ml) diluted with (20 ml) cleaning. The organic layer was then dried (magnesium sulfate) and concentrated. The residue was then applied on a 2 x 15 cm silica gel column with 1000 ml of ethyl acetate: house: 1; 1 and 500 ml of ethyl acetate The ester is used as a mobile phase for chromatographic separation. Then the purest fractions are concentrated to obtain a gum which is dissolved in 0.5 ml of methanol. Then water (25 ml) is added, and the mixture is frozen and reduced. Freeze-drying> 37 mg (79%) white solid paper size applicable to China National Standard (CNS) A4 specifications (210X 297 mm) 270-(Please read the precautions on the back before filling this page) 517057 A7 ___B7 5. The title compound of this example in the form of description (268). Melting point 6 0-70 ° C; Rf = 0.24, ethyl acetate (as a 1: 1 mixture of diastereomers

2 —methoxy, ethoxy, and methyl)] 4 '-(2-oxazolyl) 2'_ ί (3 -benzene-1H—pyrazole-1-yl) methyl]] Central Bureau of Standards, Ministry of Economic Affairs Printed by the Employee Consumer Cooperative [1,1'-biphenyl]-2-Pyridamine and 3-Phenylpyrazole (38.2 mg, 0 265 mmol) • See Takahashi et al., Synthesis, 6 9 0 — 6 9 1 (1985), 5 ml of tetrahydrofuran solution was cooled to 0 ° C under an argon layer, and then 60% sodium hydride (10.6 mg, 0.26 5) This paper is in accordance with Chinese National Standards (CNS ) M specifications (Dan Yan Dong) _ lying _ 517057 A7 B7 V. Description of the invention (269) mol)) added. After stirring at 0 ° C for 0.5 hours, the title compound (153 mg, millimoles) of Example 5 7 step (B) was added, and then 0.5 ml of anhydrous dimethylformamide was added. The reaction was warmed to room temperature and stirred overnight. The reaction was then diluted with water and extracted with ethyl acetate. The ethyl acetate extract was washed with brine and dried over anhydrous sodium sulfate. Then the crude product was purified by column chromatography on silica gel and purified by ethyl acetate / hexane to obtain 115 mg (68%) of methoxyethyl in this step as a colorless solid. Oxymethyl protected intermediate title compound. BN — (3 '4 —dimethyl — 5 -isoxanyl) — 4' — (2 —Poxanyl) — 2, _ [(3 -phenyl-1H —she beer — 1 —yl ) Methyl] [1,1'-biphenyl] -2-basic alcohol. In step (A), the title compound (110 mg, 0.172 mmol) is 0.4 ml of ethanol and 0.4 ml of 6 equivalents. Concentrated hydrochloric acid solution is heated at reflux at 90 ° C for 2 _ 5 hours. The reaction was then concentrated and printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page), dry it, and dissolve it in ethyl acetate. Dry over sodium sulfate. The crude product was purified by elution on a Merck silica gel column with methanol / dichloromethane to obtain 50 mg of the product as a colorless oil. The oily residue was lyophilized from dioxane to obtain 48 mg (51%) of the title compound as a colorless solid, m.p. 164-168 ° C. Example 1 60 This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210X297 mm) '--27i-517057 A7 __B7__ V. Description of the invention (270) N — (3' 4 —dimethyl — 5 -iso n)) 4 '-(2-oxazolyl) -2'-(1 Η -pyrazol- 1 -ylmethyl) [1,1'-biphenyl fluorene-2 -sulfonylamine Γ = \

〇

(Please read the precautions on the reverse side before filling out this page) A. N — (3,4-Dimethyl-Ft —Iso-oxaxanyl) —N — [(2-methoxyethoxy) methyl A] -4, 1 (2-oxazolyl)-2, 1 (1H-D than fluorenyl-1-methyl) [1, 1,-biphenyl]-2-amine (22.3 mg, 0.34 mmol) 2.5 ml of a tetrahydrofuran solution was cooled to 0 ° C under an argon layer, and 60% sodium hydride (12 mg, 0.34 mmol) was added . At 0. (: After stirring for 0.5 hours, the title compound of Step 57 (B) in Example 57 (130 mg, 0.225 mmol) printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs, and then 0-5 ml of anhydrous dimethyl ether Methylformamide was added. The reaction was warmed to room temperature and stirred overnight. The reaction was then diluted with water and extracted with ethyl acetate. The ethyl acetate extract was washed with brine and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography on silica gel and eluted with methanol / dichloromethane to obtain 118 mg (92%) of methoxyethoxylate in this step as a colorless solid. The title compound of the intermediate protected by methyl methyl group. ^ The paper size applies the Chinese National Standard (〇 呢) 8 4 specifications (210, / 297 mm) Γ &quot; -27)-517057 A7 _____ _B7 V. Description of the invention (271) B. N— (3,4—dimethyl-1, 5-isoxazole, etc.) — 4, — (2-oxazolyl) —2, — (1H—pyrazole—1—some methyl) — [1, 1 '—biphenyl] —2-amidine (Please read the precautions on the back before filling this page) Title the step (A) Compound (110 mg, 0.172 mmol) of 1.5 ml of ethanol and 1.5 ml of a 6-equivalent hydrochloric acid solution were heated at reflux at 90 ° C for 2.5 hours. The reaction was concentrated to dryness, dissolved in ethyl acetate, washed with sodium bicarbonate, water, brine and dried over sodium sulfate. The crude product was then purified by elution with methanol / dichloromethane on a Merck silica gel column to obtain 40 mg of the product as a colorless oil. This oily residue was lyophilized from dioxane under reduced pressure to obtain 38 mg (5 6%) of the title compound as a colorless solid, m.p. 140 — 146〇Co Example 1 6 1 2 f- ((1,3 —Dihydrol—1—Hoxy— 2 Η —Isopropanol

This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210 X 297 mm) t -27 /-517057 A7 __B7__ V. Description of the invention (272) A. 2, 1 [(1, 3-dihydro, a certain 1-Hydroxy—2H—Isobutyl bow [口 朵 一 2 —yl) a certain Ί-N — (3, 4 dimethyl-5 — isoxazolyl) — N — Γ Γ ?. — A Ethoxyethoxy) methyl] 4 '— (2-π oxidant · yl) [1' monobiphenyl]-2-hydrazine will be sodium hydride (60% mineral oil, 1. 0.4 mg, 0.26 mmol) to 2,3-dihydro-1H-isoearmide — 1-one (32 mg, 〇24 mmol, according to J. Chem. Soc · Perkin Trans · I. 2251 (1989)) in 0.4 ml of dimethylformamide solution, and stirred at room temperature for 20 minutes. Then, the title compound (115 mg, 0.2 mmol) of step (B) of Example 57 was added, and the mixture was stirred at room temperature overnight. Then 10 ml of water was added to the mixture and filtered. The residue was dissolved in 2.5 ml of ethyl acetate, washed with water, brine, dried, and concentrated to give the title compound as a gel in this step. B _ 2 ， — [(1,3 —Dioxyl—1 Yiheyi—i Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) 口 弓 [口 朵—2 -yl) methyl] —N — (3,4 dimethoyl — isoxazolyl) — 4 ′ — (2 —oxazolyl) [1, 1, ~ i phenyl] 2- Sulfonamide added trimethylsilyl chloride (174 mg, 1.6 mmol), followed by sodium iodide (240 mg, 1.6 mmol) to step 4 of the title compound Ml of acetonitrile solution. Stir the mixture at ^ temperature for 20 minutes. Then add another trimethyl methsalyl chloride (i paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) &quot; ---— -275- Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 517057 Α7 ____ Β7 V. Description of the Invention (273) 74 mg, 1.6 mmoles and sodium iodide (240 mg, 1.6 mmoles) (Ear) was added in four portions, and the reaction was stirred for an hour and 10 minutes. Then the reaction mixture was added to 3 ml of water and 30 ml of ethyl acetate. The organic layer was separated Wash with 1 ml of saturated aqueous sodium thiosulfate, brine ', and dry and concentrate. The residue was borrowed on a 0DSS 10 column for preparative high performance liquid chromatography and 30% solvent A (10 % Methanol, 90% water, 0.1% trifluoroacetic acid) and 70% solvent B (90% methanol, 10% water, 0.1% trifluoroacetic acid) were eluted and purified to obtain a white solid. The title compound of the example (43 mg, 40% in two steps), melting point 135-142 (amorphous). Example 1 6 2 [Γ Γ 3,4-Dimethyz-5—rimidazole) amino group

Phenyl chloroformate (29 mg, 0.18 mmol), and then --------- will ------ 1T ------ #. (Please read the note on the back first Please fill in this page for matters) -276-517057 A7 B7_ ___ V. Description of Invention (274) (Please read the notes on the back before filling this page) Add triethylamine (37 mg, 0.36 mmol) to 2 '-[(methylamino) methyl] _N — (3,4-dimethyl-1, 5-isoxamidino) amino] —4, 1 (2-oxazolyl) [1, 1, 1 Biphenyl] -2-sulfamethoxamine (80 mg, 0.018 mol, prepared according to the method described in step (A) of Example 28) in 1.8 ml of dichloromethane solution. The mixture was stirred at room temperature for 1.5 hours and concentrated. The residue was then subjected to preparative high performance liquid chromatography on an ODS S 10 column using 18% solvent A (10% methanol, 90% water, 0.1% trifluoroacetic acid) and 82% solvent B ( 90% methanol, 10% water, 0.1% trifluoroacetic acid), and purified to obtain the title compound (75 mg, 74%) of this example as a white solid, melting point 1 12-120 ° C ( Amorphous). Example 1 6 3 [[(3,4-Dimethyl-5-isoxazolyl) amino] 碏 醯] _ 4 mono (2-oxaalkyl) [1 '.1' monobiphenyl] 1 2 -yl] Methylamino formic acid, printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs, CL · 0

〇 〇 ～ n ^ 人 〇H called CHa -21Ϋ- This paper size applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 517057 A7 __B7 V. Description of the invention (275) The ethyl chloroformate (31 mg, 0_ 18 millimoles), and then add triethylamine (37 mg, 0.36 millimoles) to 2, one [((Please read the precautions on the back before filling this page)

Methylamino) methyl] -N_ (3,4-dimethyl-5-isoxazolyl) -4 '-(2-oxazolyl) [1,1, biphenyl] -2 8 ml of dichloromethane solution of amidine (80 mg, 0.18 mmol, prepared according to the method described in Example 2 8 step (A)). The mixture was stirred at room temperature for 1.5 hours and concentrated. The residue was then separated on a MODS S 10 column for preparative high performance liquid chromatography using 21% solvent A (10% methanol, 90% water, 0.1% trifluoroacetic acid) and 79% solvent B (90 % Methanol, 10% water, 0.1% trifluoroacetic acid) and purified by purification to obtain the title compound (60 mg, 58%) of this example as a white solid. Example 1 6 4 N — (3,4 —dimethyl-1 5 —annoying one) — 2 ’— [(3

I 4 4 I

The paper size of Kiribati paper is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm)-27 517057 A7 B7 5. Description of the invention (276) Example 2 1 Step (F) the title compound (126 mg; 0 · 30 mmol) and 5-amino-3,4-dimethylisoxazole (102 mg; 0-90 mmol) in 3 ml of a methanol mixture were stirred at room temperature for 18 hours, Sodium cyanoborohydride (60 mg; 0.90 mmol) was added. (Note: The initial reaction is homogeneous. After 18 hours, the reaction mixture is a thick suspension). After stirring at room temperature for 4 hours, the reaction mixture was diluted with dichloromethane (6 ml), and about 1/3 of the resulting solution was loaded onto a SAX cartridge (3 ml). This cartridge was pretreated as follows: 1 Mo Ear concentration sodium acetate (2x10 ml); water (4x10 ml); methanol (2x10 ml); and dichloromethane (2x10 ml). The cartridge was then eluted with dichloromethane (2 x 10 ml), followed by dichloromethane: methanol: trifluoroacetic acid 50: 50: 3 (2 x 10 ml). The filtering effect of this cartridge is repeated for the remaining substances. The product-containing fraction was concentrated to obtain a residue, which was further separated by a preparative high-performance liquid chromatography (flow rate = 35 ml / min; 30x500 mm S—10 DS—120A column, using 5 3 % Methanol / water + 0.1% trifluoroacetic acid to 63% methanol / printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) step by step water + 0.1% trifluoroacetic acid Gradient, 2% increase every 5 minutes). 5 ‘mLMeOH 中。 The pure soluble fraction was concentrated to obtain the residue, which was then dissolved in about 0.5‘ mL methanol. Water (2.5 ml) was then added, and the mixture was frozen and lyophilized to obtain 64 mg (41%) of the title compound as a white powder in this example, melting at 9 5-11 1 ° C. Example 1 6 5 This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 517057 A7 B7 V. Description of the invention (277) N — (3, 4 — dimethyl — 5 — isoxazolyl) — 4 '-(2-oxazolyl) -2'-(2H-1,2,3-triazole-1, 2, 1, 1 and 1) [1,1'-biphenyl] -2_sulfonylamine Γ = \

π Η .S — N Ο

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

A. N 4 —Dimethyl-5_isoxazolyl) _N — [Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs—2-methoxyethoxy) methyl] _4 ′-(2—oxazolyl ) -2 'mono (2H-1,2,3-triazol-2-ylmethyl) [(1,1, -biphenyl] -2 -sulfamethoxamine and N-(3,4_dimethyl 5- (isooxazolyl) -N-[(2-methylaminoethoxy) methyl]-4 '-(2-oxazolyl) -2'-(1H-1, 2, 3— Triazole-1-ylmethyl) [1,2,1'-biphenyl]-2 -sulfamidazine 1,2,3-triazole (27 mg, 0.39 mmol) 2.5 ml The tetrahydrofuran solution was cooled to 0 ° C under an argon layer, and then 60% sodium hydride (15.6 mg, 0.39 mmol) was added. After stirring at 0 ° C for 0.5 hour, the Example 57 step (B) The title compound, and then add 0.5 ml of anhydrous dimethylformamide. Then make this paper size applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm)

28D 517057 A7 B7 V. Description of the invention (278) The reaction was warmed to room temperature and stirred overnight. The reaction was then diluted with water and extracted with ethyl acetate. The ethyl acetate extract was washed with brine and dried over sodium sulfate. The crude product was separated by column chromatography on silica gel and ethyl acetate. / Jiyuan (1: 1) 4 2 mg (2 9%) of this step eluted to give a solid color, this step is protected by methoxyethoxymethyl intermediate 2 zrazole isomer and 9 8 mg (67%) Intermediate 1 protected with methoxyethoxymethyl — ~ -azole isomer The title compound 0-BN (3 j 4 monomethyl 5 isoxazolyl) 4 $ one ( 2 oxazolyl) 2 9 1 (2 Η-1) L,, 2 '3--3 out of ft-2 methylmethyl) 1 1 9 1-biphenyl]]-2--sulfamethoxamine step ( A) methoxyethoxy-protected intermediate 2-azole isomers (42 mg y 0 0 7 5 mmol) 0 5 ml ethanol and 0 5 ml 6 equivalent hydrochloric acid The solution was heated at reflux at 90 ° C for 2 • 5 hours. The reaction was then concentrated to dryness and dissolved in ethyl acetate (please read the precautions on the back before filling this page). After washing with sodium bicarbonate, water, brine and drying over sodium sulfate. The crude product was purified by elution on Merck silica gel with methanol / dichloromethane to give 26 mg of the product as a colorless oil. This oily residue was lyophilized from dioxane at medium and low pressure to obtain 24 mg (6 7%) of the title compound of this example as a colorless solid, the melting point of 162-168 ° C. Example 1 6 6 N — (3,4—dimethyl—5—isooxazolyl) —4, — (2—oxazolyl) —2 ′ — (1H-1, 2, 3—triazole—1 — This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210X297 mm) ~ '-28 /-517057 Printed by A7 B7, Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (279) a methyl group] [1 , 1'-biphenyl]-2-amidine

1.0 mL of ethanol and 1. The methoxyethoxymethyl-protected intermediate 1 of Example 16 5 step (A) is a triazole isomer (98 mg, 0.174 mmol). 0 ml of a 6-equivalent hydrochloric acid solution was heated at reflux at 90 ° C for 2.5 hours. The reaction was concentrated to dryness, dissolved in ethyl acetate, washed with sodium bicarbonate, water, brine and dried over sodium sulfate. The crude product was purified on a Merck silica gel column with methanol / dichloromethane to obtain 50 mg of the product as a colorless oil. This oily residue was lyophilized from dioxane under reduced pressure to give 46 mg (55%) of the title compound as a colorless solid. 7 (3, 4 one-to-one application of a 5_ isoxazolyl group) -2, one "" 3-two-shenyl group -2 -oxy group 1 one eridine a) a]], 4, (2- (Oxazolyl) [1,1, —biphenyl] — 2 —basic amine This paper is sized to the Chinese National Standard (CNS) A4 (210X297 mm) -28 幺------- order- ---- (Please read the notes on the back before filling this page) 517057 A7 B7 V. Description of the invention (280)

CH? CH5 Please read the note a. 2-Hydroxy-1-piperidinecarboxylic acid, 1,1,2-dimethyl ethyl ether and triethylamine (3.6 g, 35.59 mmol) And di-tert-butyl dicarbonate (14.8 g, 67.80 mmol), then 4-dimethylaminopyridine (4. 14 g, 33. 90 mmol) was added to 5-valerolactone (3.36 g, 33.90 mmol) in 56.5 ml of dichloromethane. The mixture was stirred at room temperature overnight and concentrated. Then, the residue was separated on a silica gel using 5.5: 1 hexane / ethyl acetate for chromatographic separation to obtain the title compound (4.90 g, 73%) of this step as a pale yellow oil. B 3 '3 —Dimethyl- 2 —Hydroxy-1, 1-B-determinated acid, 1, 1-Dimethyl ethyl at 778 ° C, bis (trimethylsilyl) Lithium amine (tetrahydrofuran solution at 1 mole concentration) was added dropwise to 10.8 ml of tetrahydrofuran solution of the title compound (1.08 g, 5.42 mmol) in step (A) within 10 minutes. The mixture was stirred at ~ 78 ° C for 30 minutes, and then methyl iodide (4.62 g, 32.52) mmol was added. Then warm the reaction mixture to room temperature and apply the Chinese National Standard (CNS) A4 specification (210X297 mm) to the paper size at room temperature. Fill in this page again. F Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs-283 -517057 A7 B7 V. Description of the invention (281) Stir for two days. 30 ml of diethyl ether and 15 ml of 5% aqueous citric acid were added to the reaction mixture. The organic liquid was then separated, washed with 10 ml of 5% citric acid, water, brine, dried, and concentrated. The residue was separated on a silica gel using 19: 1 hexane / ethyl acetate for color separation to obtain the title compound (440 mg, 38% C3, 3, 3) as a pale yellow oil. —Dimethyl-2—piperidone Stir 4 ml of methanol solution of step (B) title compound (440 mg, 1.94 mmol) and 15 ml of 1 equivalent of hydrochloric acid in ether at room temperature Overnight. The solvent was evaporated and dried in vacuo to give the title compound as a pale yellow solid in this step, which is relatively pure and can be used in the next step without further purification. D · N — (3, 4 1-dimethyl- 5 -isoxazolyl)-2 '-[(3,3 -dimethyl-1, 2-oxyl- 1-eridyl) methyl] -N-[(2 -methoxy An ethoxy) methyl] -4'_ (printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) 2 —oxazolyl) il, 1 'biphenyl ] -2—Sulfamethoxamine at 0 ° C, add sodium hydride (60% mineral oil, 19.2 mg, 0.48 mmol) to step (C) of the title compound (5 1 mg, 0.40 mol) in 0.4 ml of dimethylformamide solution, and stirred at room temperature for 20 minutes. Then the Example 5 7 step (B) of the title compound (115 mg, 0 · 2 millimoles) was added to the mixture, and the reaction mixture was stirred at room temperature for 2 hours. Then the mixture was applied to Chinese paper standard (CNS) A4 (210X297 mm 1 ~ -28Zl ~ 517057) Printed by A7 __B7_ of the Consumer Standards Cooperative of the Ministry of Standards of the People's Republic of China. 5. Description of the invention (282) 30 ml of ethyl acetate is diluted, washed with water, brine, dried and concentrated. The residue is then used on silicone 1: 1. Chromatographic separation of 6 hexane / ethyl acetate gave the title compound (70 mg, 56%. E. N — (3, 4 dimethyl-5 —yl) (Oxazolyl), one, two, (3,3-dimethyl-1, 2-argon, 1_eridinyl), methane, 4 '— (2-oxazole, f), 1' Phenyl] -2-amidine will be trimethylsilyl chloride (73 mg, 067 mmol), followed by sodium iodide (100 mg, 0.67 mmol) Go to step (D) in 2.2 ml of acetonitrile solution of the title compound. Stir the mixture at room temperature for 30 minutes. Then add another trimethylsilyl chloride (98 mg, 090 mmol) And sodium iodide (135 mg, 0.90 mmol) were added in four portions, and the reaction was stirred for another 1 hour and 40 minutes. The reaction mixture was then added to 2 ml of water and 30 ml of ethyl acetate. The organic layer was separated, washed with 1 ml of saturated aqueous sodium thiosulfate, brine, dried, and concentrated. The residue was then borrowed on a 0 DSS 10 column for preparative high performance liquid chromatography and separated with 29% solvent A (10% methanol, 90% water, 0.1% trifluoroacetic acid) and 71% solvent B (90% methanol, 10% water, 0.1% trifluoroacetic acid) was eluted and purified to obtain the title compound (37 mg, 62%) of this example as a white solid, m.p.> 200 ° C, Decomposition :, Rf = 0. 5 (silicone, 10: 1 dichloromethane / methanol)-285-This paper size is applicable to Zhong Jie National Standard (CNS) A4 specification (210X 297 mm) ------- --- (Please read the notes on the back before filling this page)

1T J. 517057 A7 B7 V. Description of the invention (283) 1 Η NMR (CDC 1 a): δ 1. 〇9 (s, 3H), 1. 24 (s, 3H), 1. 75 (m, 2H ),

1. 8 5-2. 10 (M, 2H), 1. 93 (s, 3H), 2. 17 (s, 3H), 3. 48 (m, 2H), 3. 94 — 4. 52 (m , 2H), Ί. 2 5-8. 98 (m, 1 0 H). Example 1 6 8 N — [[2 '_ [[(3,4 —dimethyl_5 —isoxazolyl) amine] sulfonyl]] 4— (2 —oxazolyl) [1,1' Monobiphenyl]-2-yl] methyl] -N -methyl- 2-phenoxyacetamidine α 0-N

CH, CH, printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

0 II SN Ο Η (Please read the precautions on the back before filling out this page) Put 0.019 g (0.1114 mmol) of phenoxyacetamidine chloride and 0.014 g (0.1137 mmol) Triethylamine was added to 0.05 g (0.1114 mmol) of 2 '-[(methylamino) methyl] -N- (3,4-dimethyl-1,5-isoB-oxalyl)- 4 '-(2_oxazolyl) [1,1'-biphenyl] -2-sulfamethoxamine (applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) according to this paper size)-286-517057 A7 B7 V. Description of the invention (284) Example 2 In 8 ml of dichloromethane solution prepared in the method described in step 8 (A)). The mixture was then stirred at room temperature for 12 hours and pre-evaporated. The residue was borrowed on a 30x500 mm ODS S10 column for reverse-phase preparative high-performance liquid chromatography and used 74% solvent B (90% methanol, 10% water, 0.1% trifluoroacetic acid) and 26 % Solvent A (10% methanol, 90% water, 0.1% trifluoroacetic acid) was eluted and purified. The appropriate fractions were collected, neutralized to pH 7 with aqueous sodium bicarbonate, and concentrated to 10 ml. Then, the solution was acidified to pH 4 with aqueous sodium hydrogen sulfate, and the white solid was filtered and dried to obtain 0.038 g (58%) of the title compound of this example as a white solid, mp 105-115 ° C. Example 1 6 9 N-(3,4-Dimethyl_ 5-isoxazolyl)-2 ’-ί (4 (Please read the precautions on the back before filling this page)

This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) -28? 517057 A7 B7 V. Description of the invention (285) (4,4 dimethyl one 3 —oxygen one 2 —isoxazole (Pyridyl)) Shen Mou — Ν_ ί (2-methoxyethoxy) Shen]] 4 '— (2-oxazole Mou) 1, 1' — biphenyl motif — 2_sulfamethoxamine Anhydrous potassium carbonate (0.066 g, 0.477 mmol) was added to the title compound (0.25 g, 0.4 3 mmol) of step 57 (B) in Example 57 and 4,4-dimethyl-1 3-isoxazolidinone (0.0555 g, 0.477 mmol, prepared according to the method described in U.S. Patent No. 4,400,35,7) in 2 ml of dimethylformamide solution The mixture was stirred at 60 ° C for 2 hours under argon. The mixture was then added to 25 ml of water and the solution was extracted with 3 x 2 5 ml of ethyl acetate. The combined organic extracts were then washed with water, dried and evaporated. The obtained residue was further separated on 20 g of silica gel using 1: 1 hexane: ethyl acetate to obtain chromatographic layer separation to obtain 0.21 g (79%) of the title compound as a colorless gum in this step. Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) BN — (3,4 dimethyl-5 —isoxazolyl)-2'1 [(4,4 Monomethyl 3- 3-Azo group-2 2-isoxazolidinyl) methyl] -4 'mono (2-B-oxazyl) [1,1'-biphenyl] -2 -basic amine Chlorotrimethylsilane (0.213 g, 1.1 mmol) and sodium iodide (0.294 g, 1.965 mmol) were added to step (A) of the title compound (0.2 g (0. 327 mmol) in 4 ml of acetonitrile solution, and the mixture was stirred at room temperature for 30 minutes. And this paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 280,000-517057 A7 ______B7 V. Description of the invention (286) will be another part of chlorotrimethylsilane (0.12g, 1 84 millimoles) and sodium iodide (0.2 g, 1.33 millimoles) were added over a period of 1 hour (please read the notes on the back before filling this page), and stir the mixture for another 1 hour . The mixture was then diluted with 25 ml of water and 1 ml of saturated aqueous sodium thiosulfate was added, and the mixture was then extracted with 3 x 2 5 ml of ethyl acetate. The combined organic extracts were washed once with water, dried and evaporated. The residue was then subjected to reverse-phase preparative high-performance liquid chromatography on a 30x500 mm ODS S10 column using 68% solvent B (90% methanol, 10% water, 0.1% trifluoroacetic acid) and 32% solvent A (10% methanol, 90% water, 0-1% trifluoroacetic acid) was purified by elution. The appropriate fractions were collected, neutralized to pH 7 with aqueous sodium bicarbonate, and concentrated to 10 ml. Then, the solution was acidified to pH 4 with aqueous sodium hydrogen sulfate, and the white solid was filtered and dried to obtain the title compound of this example, which has a melting point of 95-100 ° C. Example 1 7 0 N — (3,4 dimethyl-5 —isoxazolyl)-2 '-[[2 Printed methylmethyl azomethoxazole by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs-Η 1 ± Benzylbenzazole 2-2 Sf-This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) 517057 A7 B7 V. Description of the invention (287)

/ = \

A. N — (3,4 —dimethyl-5 —isofluorenyl) —N — [(2-methylaminoethoxy) methyl] —2 ′ — [[2_ (1 — A) 1H-imidazol-1-yl] methyl] _4 '-(2-oxazolyl) il, 1'-biphenyl]-2 -sulfamethoxil == (Please read the precautions on the back first (Fill in this page again)

OMe

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs, 2.5 ml of tetrahydrofuran solution of 2-isopropylimidazole (43 mg, 0.39 mmol) was cooled to 0 ° C under an argon layer, and then 60% Sodium hydride (15.6 mg, 0 39 mmol) was added. After stirring at 0 ° C for 0.5 hours, the title compound (150 mg, 0.26 mmol) of Example 5 7 Step B was added followed by 0.5 ml of anhydrous dimethylformamide. The reaction was warmed to room temperature and stirred overnight. The scale of the paper is in accordance with Chinese National Standard (CNS) A4 (210X297 mm) -9Qf)-517057 A7 B7 V. Description of the invention (288) Then the reaction is diluted with water and extracted with ethyl acetate. The ethyl acetate extract was washed with brine and dried over anhydrous sodium sulfate. Then, the crude product was purified by column chromatography on silica gel and purified by eluting with 5% methanol / dichloromethane to obtain 136 mg (8 7%) of methoxy as a colorless oil in this step. Ethoxymethyl protected title compound. B · N- (3,4-dimethyl-1,5-isoxazolyl)-2 '-[[2 — (1-methyl-1 ethyl)-1H-imidazole-1 1-a] methyl] -4 '— (2 —oxazole) [1,1' —biphenyl]]-2-Dimethylamine will be the title compound of step A (130 mg, 0.214 mmol printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs ( Please read the notes on the back before filling out this page) Ear) 3 ml of 1 equivalent hydrochloric acid and 3 ml of ethanol solution are heated at 90 ° C for 14 hours. The reaction was then delimited between a saturated sodium bicarbonate solution (pΗ8) and ethyl acetate. The ethyl acetate was then washed with brine, dried over anhydrous sodium sulfate and pre-evaporated to give the crude product as a colorless oil. This crude material was then eluted on a Merck silica gel column with 2% methanol / dichloromethane and separated by chromatography to obtain 44 mg of the product as a colorless oil. This oily residue was lyophilized from medium in dioxane to obtain 40 mg (3 6%) of the title compound as a colorless solid. Melting point 1 8 4 — 1 8 8 ° C. Example 1 7 1 N— (3,4—dimethyl-1,5—isoxazolyl) —4 ’— (2—oxazole) —? · '一 ί (5 —Phenyl-2H —tetrazole- 2 -yl) methyl 1 [1,1'-biphenyl] — 2_ pinamine scale applicable to Chinese National Standard (CNS) Α4 specifications (210 × 297 mm) ~ &quot; -29 /-517057 Α7 Β7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs V. Invention Description (289) ί = \

The title compound of this example was prepared by a procedure similar to that of Example 170. 5-Phenyl-1,4-tetrahydrofuran (57 mg, 0.39 mmol) was used to obtain the crude product, which was separated on a silica gel for column chromatography and ethyl acetate / hexane (1: 2) Elution and purification, to obtain 94 mg (5 7%) of a methoxyethoxymethyl protected intermediate as a colorless oil. 90 mg (0.14 mmol) of methoxyethoxymethyl-protected intermediate was reacted for 6 hours to obtain a crude material, which was then eluted on a silica gel column with 3% methanol / dichloromethane Chromatographic separation was performed to obtain 44 mg milligrams. , Drying and thawing and dehydration. In the low standard, the case of alkaloids is bad. .色 CC 物 无 ο Production 6% 1 Shape 9 | Oil 4 6 Color C 5 No gram 1 2 7 1 Example (please read the precautions on the back before filling this page) Order 1. · Ν azole 5 I methylmethazole tetra I I 1 ± I methyl methylmethyl oxazolyl phenylene 2 amine sulfonium This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) 292 517057 A7 B7 V. Invention Explanation (290) r = \

(Please read the notes on the back before filling out this page) Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) -29?-517057 A7 B7 V. Description of the invention (291) Γ = \

OMe

Me Me N — (3,4 —dimethyl-R —isoB-oxalyl) —N ~~ [丨 2 —methoxy certain ethoxy) methyl] —2, one [Γ5 —shenyl — 2H —Tetrazol — 2 —yl) shenyl] —4, — (2-oxazolyl) [1,1′-biphenyl] — 2 —sulfonylamine ΛΨ II (Please read the notes on the back before filling (This page) Order Printed by the Employees' Cooperatives of the Central Government Bureau of the Ministry of Economic Affairs

OMe

The methoxyethoxymethyl protected intermediate title compound in this step was prepared by a method similar to Example 170, Step A. 5-Methyl-1H-tetrazole (33 mg, 0.39 mmol) was used to obtain the crude product, which was subjected to column chromatography on silica gel and ethyl acetate / hexane (4: 1) Eluted and purified to obtain 65 mg (43%) The paper size is applicable to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1 · 294- 517057 A7 B7____ 5. Description of the invention (292)) Colorless oily Of N-(3,4 dimethyl-5-isoxazolyl) -N-[(2-methoxyethoxy) methyl]-2 '-[methyl-1H_tetrazole-1 —Methyl] methyl] —4, — (2-oxazolyl) [1,1,1-biphenyl] —2-sulfanilamide, and further eluted with methanol / dichloromethane to obtain 8 4 Mg (5 6%) N — (3,4 dimethyl-5 —isoxazolyl) _N — [(2 -methoxyethoxy) methyl] -2, 1 [( 5-methyl-2,4-tetrazol-2-yl) methyl] -4,1- (2-oxazolyl) [1,1'-biphenyl] -2-sulfamethoxamine. B. Ν — (3,4-dimethyl-1,5-isoamyl) ~~ 2 '-[. · .. (5 -methyl-1, 1Η-tetrazole-1, 1-yl) methyl] -4 , 1 (2-oxyl) "1,1'-biphenyl_-2-pyrimidine and N- (3,4-dishenyl-5 -isospirofluorenyl)-[(5 -A Glyco-2Η —tetrahydro-2 —yl) methyl] —4, _ (2-Doxazolyl) “1, Ί, monobiphenyl] —2 — Expanded amines, Consumer Standards Cooperative of the Central Standards Bureau, Ministry of Economic Affairs Printed (Please read the notes on the back before filling this page) The title compound of this example was prepared by a procedure similar to that in Example 170, Step B. 80 mg (0.14 mmol) NR- (3,4-dimethyl-1-5-isoxazolyl) -N-[(2-methoxyethoxy) methyl] -2 '-[(5-methyl-1,1-tetrazol-1 Monomethyl) methyl] 4 '-(2-spirofluorenyl) [1,1'-biphenyl] -2-diamine amine for 6 hours to obtain a crude product, and then 2% methanol on a silica gel column / This paper size applies to China National Standard (CNS) Α4 size (210 X 297 mm) 295 Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 517057 A7 B7 V. Description of the invention (293) Dichloromethane was eluted for color separation to obtain 36 mg of a colorless oily product. After lyophilization from dioxane in low pressure, That gives 34 mg (50%) of the title compound N — (3,4 dimethyl-5 —isoxazolyl) — 2'_ [(5-methyl-1H —tetrazole-1) as a colorless solid. 1-yl) methyl] -4 '-(2-chrylyl) [1,1'-biphenyl] -2-mineamine. Melting point 168-174 ° C. Let 65 mg (0-11 mmol) Ear) N — (3,4 dimethyl-5 —isoxazolyl) — N — [(2-methoxyethoxy) methyl] 2 ′-[(5-methyl-1 2H — Tetrazol- 2-yl) methyl]-4 '-(2-oxazolyl) [1,1'-biphenyl]-2-sulfonamide was reacted for 6 hours to obtain a crude substance, which was then subjected to The silica gel column was eluted with 2% methanol / dichloromethane for color separation to obtain 42 mg of the product as a colorless oil. After lyophilization from dioxane, 40 mg (74%) of colorless was obtained. The title compound N — ( 3,4 dimethyl-5-isoxazolyl) -2,1-[(5-methyl-1 2H-tetrazol-2-yl) methyl] -4 '-(2-oxazolyl) [ 1, 1 'monobiphenyl] -2 monosulfonamide. Melting point 172-178 ° C. Example 1 7 3 N — (3,4_ Dimethyl _5_ isoxazyl) —4' — (2 — Oxazole a) 2 '_ [(5-phenyl-2H-1, 2,4-triazole-1 2 —a) a]] [1,1' a biphenyl] a 2-ammonium Paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) -29 "A ----------- (Please read the precautions on the back before filling this page) Order 517057 A7 _____B7 5 , Description of the invention (294) Γ = \

The title compound was prepared by a procedure similar to Example 170. 3-Phenyl-1,2,4-triazole (80 mg, 0.55 mmol) was used to obtain the crude product, which was then separated by column chromatography on silica gel and ethyl acetate / hexane (1: 1) was eluted and purified to obtain 198 mg (62%) of a methoxyethoxymethyl protected intermediate as a colorless solid. 190 mg (0. 29 mmol) of intermediates were reacted. 10 The crude material was printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Small Economy. The crude substance was obtained on a silica gel column with 2% methanol / dichloromethane. Isolated to give 46 mg of the product as a colorless oil. After lyophilization from dispirane, 20 mg (25%) of the title compound as a colorless solid was obtained. Melting point 1 8 6_ 19 0 ° C. Example 1 7 4 N— (3,4 dimethyl-1,5—isooxazolyl) —4 ′ — (2-oxazolyl) —2′— 〔3— (trifluoromethyl) —1Η— Pyrazole-1, 1-methyl) [1,1'-Biphenyl, Benzene, 2-2-Amine. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the note on the back first) Please fill in this page for matters) -29?-517057 A7 B7 V. Description of Invention (295) Γ = \

The title compound was prepared by a procedure similar to Example 170. Trifluoromethylpyrazole (53 mg, 0.39 mmol) was used to obtain the crude product, which was separated by column chromatography on silica gel and washed with ethyl acetate / hexane (1: 1). It was then purified to obtain 102 mg (62%) of a methoxyethoxymethyl protected intermediate as a colorless solid. 100 mg (0.158 mmol) of intermediate was reacted for 6 hours to obtain a crude material, which was then separated on a silica gel column with 1% methanol / dichloromethane for color separation to obtain 35 mg of a colorless oil. Product of the state. After lyophilization from dioxane at low pressure, 32 mg (3 7%) of the title compound as a colorless solid were obtained. Melting point 1 6 8-1 7 2 ° C. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) Example 1 7 5 (3,4-dimethyl-1,5-yloxazole, etc.) one 2, one ί 3_ Di_ ^ 3 —a certain one 2 —pyridine] one 1 Η —pyrazole one 1 one 申] Shen group]-4 '— (2 -oxazolyl) [1, 1' one biphenyl Ί — 2-Sulfonamide This paper is sized for Chinese National Standard (CNS) A4 (21 × 297 mm) -29? ~ 517057 A7 B7 V. Description of Invention (296)

The title compound was prepared by procedures similar to Example 170. 3- (3-methyl-2-pyrazine) pyrazole (84 mg, 0.53 mmol) was used to obtain the crude product, which was then separated on a silica gel by column chromatography and 2% methanol It was purified by elution with dichloromethane to obtain 168 mg (7 6%) of a methoxyethoxymethyl protected intermediate as a colorless oil. 160 mg (0.24 mmol) of the intermediate was reacted for 3 hours to obtain a crude material, which was then eluted on a silica gel column with 2% methanol / dichloromethane for color separation to obtain 44 mg of a colorless oil. Product of the state. Lyophilization from dioxane gave 76 mg (56%) of the title compound as a colorless solid. Melting point 1 9 2-1 9 6 ° C. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) Example 1 7 6 N— (3,4-dimethyl-2—isoxazolyl) —2′—1 [3 — (2 —methyl—5 —pyridine) — 1 hydrazone —pyrazol — 1 —yl] methyl] — 4 '— (2 —oxazolyl) [1, 1, monobiphenyl] — 2 —Expanded amines The paper size applies to Chinese National Standard (CNS) A4 specifications (210 × 297 mm) q 517057 Α7 Β7 5. Description of the invention (297) Γ = \

(Please read the notes on the back before filling this page) The title compound was prepared by a procedure similar to that in Example 170. 3- (2-Methyl-5pyridine) pyrazole (84 mg, 0.53 mmol) was used to obtain the crude product, which was then separated by column chromatography on silica gel with 5% methanol / Dichloromethane was eluted and purified to give 142 mg (41%) of a methoxyethoxymethyl protected intermediate as a colorless oil. A 40 mg (0.2 1 mmol) intermediate was allowed to react for 3 hours. It was printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs to obtain a crude substance, which was then washed on a silica gel column with 2% methanol / dichloromethane. The chromatographic layer was separated to obtain 44 mg of the product as a colorless oil. Lyophilization from dioxane gave 42 mg (43%) of the title compound as a colorless solid. Melting point 1 7 8-1 8 2 ° C. Example 1 7 7 2,-(1H —Benzodimile—1-Methyl) —N — (3,4-Dimethyl-5—Isoxazolyl) —4′—ηηoxazolyl) [1,1'-biphenyl]-2-amine This paper size is applicable to Chinese National Standard (CNS) A4 specification (210 × 297 mm) ~ 30 0-517057 A7 B7 V. Description of the invention (298)

Biphenyl]-2-amine

Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs, powdered sodium hydroxide (41.6 mg, 1.04 mmol), benzotriazole (31 mg, 0.26 mmol) and step 57 of Example 57 0 小时。 The title compound (150 mg, 0.26 mmol) was stirred in 0.6 ml of anhydrous dimethylformamide for 2.0 hours. The reaction mixture was diluted with 50 ml of water and a white precipitate formed. The white precipitate was collected by filtration and washed with water to obtain 106 mg of a white solid. Then, it was purified by flash chromatography (5 alkane-ethyl acetate: 1: 2) on silica gel to obtain 90 mg (52 paper sizes applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm)- 30 /-517057 A7 B7 V. Description of the invention (299)%) The title compound of this step as a white solid. (Please read the precautions on the back before filling this page) B. 2, 1 (1H —benzotriazol 1-ylmethyl) —N— (3,4 dimethyl-5 —isoxazolyl ) One, four (2-oxazolyl) [1,1, one biphenyl]-2-sulfamidamide will be the title compound of Step A (83 mg, 0.135 mmol) in 2 ml of 6 equivalents A mixture of hydrochloric acid-ethanol (1: 1) was heated at 90 ° C for 2 hours. After cooling to room temperature, water (10 ml) was added, and the mixture was extracted with ethyl acetate. The combined organic extracts were then washed with saturated sodium bicarbonate and brine, and dried over anhydrous sodium sulfate. It was then concentrated in vacuo and triturated with dichloromethane-hexane to give 47 mg (6 7%) of the title compound as a white solid. Melting point: 196 — 200 ° C (decomposed). Example 1 7 8 N — (3,4 one dimethyl one 5_ isoxazolyl _) one 4, one (2 — chelyl) one 2'_ ί (1, 2, 3, two, three, and [economic Printed by the Consumers' Cooperative of the Ministry of Standards of the People's Republic of China, 4,5 — b] pyridine] methyl] [fluorene-1,2-biphenyl]-2-amidine, isomer and b

This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) ^ 1 30 2, 517057 A7 B7 5. Description of the invention (300) and

An intermediate system protected with methoxyethoxymethyl was prepared by a procedure similar to Example -177, Step A. 1H-1,2,3-triazolo [4,5 — η] -pyridine (46 mg, 0.381) was used to obtain crude material, which was then purified by preparative high-performance liquid chromatography to 47.0 mg of methoxyethoxymethyl-protected intermediate isomer A and 35.6 mg of methoxyethoxymethyl-protected intermediate isomer B were obtained. The title compound was borrowed from Example 177, Prepared by the steps of step B. 47 mg (0.077 mmol) of methoxyethoxymethyl-protected intermediate was allowed to react for 2 hours, and the crude product was then subjected to flash chromatography on silica gel (dichloromethane-methanol: 95 : 5 to 90: 10) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) and purify to obtain 17 mg (43%) of the title as a white solid. Body A. Melting point: 116-118 ° C. 35 mg (0.077 mmol) of methoxyethoxymethyl-protected intermediate isomer B was reacted for 2 hours, and the product was separated on a silica gel for rapid color separation (dichloromethane-methanol). : 95: 5 to 90:10) and purified to obtain 12 mg of the title isomer B as a white solid. Melting point: 124-126 ° C. This paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) -303-517057 A7 B7 V. Description of the invention (301) Example 1 7 9 2 '1ί (3,4 diamino-2H_ OH ; definite union 3, 2 — b

, 4 — dioxin

The Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs printed 2H —pyrido [3,2-b] —1,4 —oxazine-3 (4H) -one (7.5 g, 50.0 mmol) and A mixture of lithium silver hydride (1.9 g, 50.0 mmol) in 20 ml of toluene and 80 ml of tetrahydrofuran was heated to reflux overnight. After cooling to 0 ° C, saturated sodium sulfate was added dropwise, followed by solid sodium sulfate, and the mixture was stirred at room temperature for 2 hours. The solid was then removed by filtration and washed with ether. The combined filtrate and cleaning solution were concentrated in a vacuum to obtain 6. 13 g (90%) of the title compound in this step as an off-white solid. The paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm) 517057 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (302) B · 2, [(3, 4-digas. Some-2 Η-pyrido [3, 2-b]-1, 4 —Evil pupil—4-based) —Methylhydrazone—N — c 3, 4 —Dimethyl-5—iso_azolyl) —methoxy

Ethoxy) A]] 4 '1 (2 — ___L biphenyl] — 2 — extended amine 1 (please read the notes on the back before filling this page) dissolve 1 hydrogen furan 5 7 steps), steps (Ear) and agitated at 40 ° C. Following drying over sodium, hexane (7 80.0 mol solution (0 B heading A heading butyl ammonium liters anhydrous overnight. And the knots, in true monoacetic acid%) earless concentration. 5 2 compounds compounds iodine (6 2 The methyl group will then be combined with concentrated ethyl ether in the air: oily double (three milliliters, (20 (94 4 mg formamidine reaction mixer extraction), and then 1: 2: this step methyl formaldehyde 0.5 mg .4 milliliter, 0 · mixture of the compound and the salt by silicon) to give the standard silane group) 2 millimoles, 0 · 3 grams, 0 · 1 7 4 milliliters, and then dilute the water and wash with water, Purify on a gel, namely the title compound sodium amidate 4) was added to the mixture of Example 4 7 mmoles (6 3 3 mmoles) in a chamber with ethyl acetate in an anhydrous sulfuric acid to obtain 170 mmol

) PN OMe C .2, 一 ί (3,4-二 氤 某 -2 Η—- pyridine # 〔3,2 This paper size applies to China National Standard (CNS) A4 specification (210X 297 mm) -305-517057 A7 _____B7_______ V. Description of the invention (303) (Please read the notes on the back before filling in this page) —b] —1, 4—Ethylamine—4—one—methyl] —N— (3? 4—two, two, one, etc.) A 5 —Isoamidine group] A 4 ———— (_ 2 — πAxyl group) [1,1, —Biphenyl 1 — 2 -sulfoUan title compound is similar to Example 1 7 7 ' Prepared by the steps of step B. 170 mg (0.269 mmol) of the title compound of Step B was reacted for 2 hours, and the crude material was separated by flash chromatography on silica gel (dichloromethane / methanol: 98: 2 to 95 ·· 5) and given. Purification gave 7 7½ g (53%) of the title compound of this example as a white solid. Melting point: 1 3 8 — 1 4 0 ° C (decomposed). Example 1 8 0 N-(3 * 4 -dimethyl-5 -isoxoxanyl)-4 '-(2-oxazole)-2'-[(imidazo [4,5 — b]- Pyridyl) methyl] — [1,1′-biphenyl] -2 —

Rhenamine, printed by the ARB of the Central Consumers Bureau of the Ministry of Economic Affairs

This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) -306-517057 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

An intermediate system protected with methoxyethoxymethyl was prepared by procedures similar to Example 179, Step B. 4 Azabenzimidazole (72 mg '0.6 mmol) was used to obtain the crude material, which was then subjected to flash chromatography on silica gel (dichloromethane: methanol: 98: 2 to 95: 5) Purified to obtain 74 mg of intermediate isomer A protected by methoxyethoxymethyl and 62 mg of intermediate isomer B protected by methoxyethoxymethyl. The title compound was prepared by a procedure similar to Example 179, Step C. 74 mg (0-12 millimoles) of intermediate isoform A protected with methoxyethoxymethyl was reacted for 2 hours. The crude material was purified by flash chromatography on silica gel (dichloromethane-methanol: 98: 2 to 90:10) to obtain 44 mg (70%) of the title isomer A as a white solid. Melting point: 171-174 ° C (decomposed). 64 mg of methoxyethoxymethyl-protected intermediate isomer B was reacted for 2 hours to obtain 20 mg (3 7%) of the title compound B as a white solid. Melting point: 175-178 ° C (decomposed). Example 1 8] N-a "3,4 one, two, one, one 5-oxazolyl) one 2 'one [[A paper size applies to the Chinese National Standard (CNS) A4 specification (210' 乂 297 mm) -307 I — III n I n — Order 1 I (Please read the notes on the back before filling this page) 517057 A7 B7 V. Description of the invention (305) Some (benzyl) amino] methyl] -4 '-One oxazolyl) [1,1'_biphenyl]-2 -Amidine / === ^

The title compound of Example 21, Step F (44 mg; 0-104 mmol), N-benzylmethylamine (0.04 ml; 0.312 mmol), acetic acid (0.4 ml), and 3A molecule (0 4 g) of 1 ml of dichloromethane mixture at room temperature. 1 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Small Economy (please read the precautions on the back before filling this page). Sodium borohydride (66 mg; 0.312 mmol) was added. After stirring at room temperature for 18 hours, the reaction mixture was filtered through a Celite pad, the filtrate was diluted with dichloromethane, washed with water, and dried over anhydrous sodium sulfate. It was then concentrated in vacuo, and then separated by flash chromatography on silica gel (dichloromethane-methanol: 98: 2 to 95: 5) to obtain 24 mg (44%) of the title compound as a white solid. Melting point: 124-126 ° C. Example 1 8 2 N — (3,4 dimethyl-1,5—isoxazolyl) —2 ′ — [(methyl ((2-phenylethyl) amino) methyl] —4] — (2 — (Oxazolyl) ί 1, 1 'monobiphenyl]-2-amine This paper size applies to Chinese National Standard (CNS) Α4 specifications (210X297 mm) _ 308-517057 A7 B7 Staff Consumption of Central Bureau of Standards, Ministry of Economic Affairs Printed by the cooperative V. Description of invention (30β)

The title compound was prepared by a procedure similar to that in Example 181. 44 mg (0.14 mmol) of N-methyl-phenylethylamine was used to obtain a crude material, which was then subjected to flash chromatography on silica gel (dichloromethane-methanol: 98 ·· 2 to 95: 5) Purification yielded 11 mg (19%) of the title compound of this example as a white solid. Melting point: 129 — 132 ° C. Example 1 8 3 2 '1ί (3,3 —difluoro-2,3 -difluorenyl — 2 —oxy 1 — 1 — — — — — — — — — — — — — — — — — ( 3, 4_dimethyl-1, 5-isoxazole, _4'-1, oxazolyl) [1,1'-biphenyl] -2, hydrazine / = \

Me A. 3,3 —difluoro-1,3 —dihydro-2H —indith — 2 This paper size applies to China National Standard (CNS) A4 (210X297 mm) -41 ^ ----- -、 Order ------ AW. (Please read the notes on the back before filling out this page) -309-517057 Α7 Β7 B. 5. Description of the invention (307)-Ketone

A mixture of diethylamino trisulfide (2.64 ml; 20 mmol) and isatin (1.47 g, 10 mmol) was stirred at room temperature for 1 hour. After carefully pouring onto ice, the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (magnesium sulfate) and concentrated to give a yellow solid. 81 g (48%) of the title compound in this step was obtained as a white solid after chromatographic separation on silica gel using ethyl acetate: hexane 1: 3 as the mobile phase. 2, — [(3,3 -difluoro-1,2,3 -digas one? · One oxygen one —1H —Indene — 1 one group) —A certain —N — —---- Order ------ (Please read the notes on the back before filling this page) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 4 1 2 A 5 5 isoxazolyl) 1 N — Γ (2 —Shen (Ethyl ethoxylate) a]] 4 'one (2 _ oxazole) [],!, — Biphenyl Ί a 2_ amine Γ = \

Me At 0 ° C, 60% by weight of sodium hydride mineral oil (1 β mg) This paper is in accordance with the Chinese National Standard (CNS) A4 specification (210X297 mm) -310-517057 A7 B7 V. Description of the invention ( 308); 0.4 mmol) was added to 1.6 ml of a solution of the title compound (54 mg; 032 mmol) in step A in tetrahydrofuran. After stirring at 0 ° C for 1 hour, the title compound of Example 5 7 Step B was added, then 0.2 ml of dimethylformamide was added, and the reaction mixture was warmed to room temperature. After stirring for 18 hours, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried (magnesium sulfate) and concentrated. After flash layer separation using ethyl acetate: hexane 1: 1 as a mobile phase on silica gel, 41 mg (19%) of the title compound as a pale yellow oil was obtained in this step. C. _2, — [(3,3-dioxo—2,3 -dioxo-2 — —oxy — 1H —methyl — 1 —yl) methyl] —N — (3, 4 -Dimethyl-1, 5-isoxazolyl) -4 '-(2-Poxazolyl) [1,1'-biphenyl] -2-methylamine at room temperature, Silyl chloride (50 μl; 0.4 mmol) was added to the second compound of step B (40 mg; 60 μmol) and sodium iodide (60 mg; 0.4 mmol) In the solution. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page). After stirring for 30 minutes, add another amount of sodium iodide (30 mg; 0.2 mmol) and Trimethylsilyl chloride (25 μl; 0.2 mmol) was added. After stirring for another 30 minutes, the reaction mixture was delimited between acetic acid 5 vinegar and water. The organic layer was then mixed with 2.5% sulfur Wash with sodium sulphate solution and brine 'and pre-dry (magnesium sulfate) and concentrate. Then use a stepwise gradient of methylene chloride to 5% methanol / dichloromethane (increase by 1%) on the silica gel for color separation, then proceed Preparative High-performance liquid color layer separation [3 〇 This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) &quot; 517057 A7 B7

N V. Description of the invention (309) X500 mm ods (s-10) column, flow rate = 35 ml / min, from 70% methanol / water + 0.1% trifluoroacetic acid to 80% methanol / water +0 Stepwise gradient of 1% trifluoroacetic acid, increasing by 2% every 5 minutes)] to obtain the residue, and then lyophilizing from methanol / water to obtain 23 mg (67%) of the title compound as a white solid. . Melting point 1 1 2 — 1 2 0 ° C. Example 1 ft 4 (3,4-dimethyl-1,5-isooxazolyl) -2 [(4-monopyrimidinylamino) methyl] -4 '_ (2-oxazolyl) [1,1,1 Biphenyl]-2-basic amine (Please read the precautions on the back before filling this page)

Printed by Sijia Swimwear Co., Ltd. by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 〇A VIII I 口 ^ ^ IJ (20 mg; 0.2 mmol), Example 21, Step F. The title compound (42 mg; 0.1 mmol) and 2 mL of a toluene mixture of magnesium sulfate (about 1 g) were heated to reflux for 10 hours. After cooling to room temperature, the reaction mixture was filtered and concentrated to about 1 ml. After cooling to 0 ° C, sodium borohydride (12 mg, 0.3 mmol) was added, followed by 0.2 ml of methanol. After stirring for 24 hours, load the reaction mixture into a SAX cartridge (3 ml). This cartridge is pre-treated such as -312-517057 A7 ___B7 __ V. Description of the invention (310) ): 1 Molar sodium acetate (2X10ml); water (4X10ml): methanol (2x10ml); and dichloromethane (2x10ml). The cartridge was eluted with dichloromethane (2x10 ml), followed by dichloromethane: methanol: trifluoroacetic acid 50: 50: 3 (2x10 ml). The product-containing fractions were concentrated to obtain the residue, and then separated by a preparative high-performance liquid chromatography (flow rate = 35 ml / min; 30 X500 mm S — 10 005 — 120 six columns, using 43 -% Methanol / water + 0.1% trifluoroacetic acid to a stepwise gradient of 53% methanol / water + 0.1% trifluoroacetic acid, increasing by 2% every 5 minutes) for further purification. Then, the pure soluble fraction was concentrated to obtain a residue, and then lyophilized from methanol / water to obtain 29 mg (54%) of the title compound of this example as a white powder. Melting point 1 5 6-1 6 7 ° C. Example 1 8 5 N-(3 &gt; 4 -dimethyl-1 5 -isoxazolyl) -2, one ί (4

This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210 × 297 mm) -313-517057 A7 B7 V. Description of the invention (311) The method described in Example 157 was prepared in the form of white solid. Melting point 9 —100 ° C. Example 1 8 6 N — (3,4-dimethyl-1-5-yloxazolyl) di '~ 1-methyl-1 1-piperidyl) methyl-1—4'di ^ 2_2oxazolyl] [1 '一 biphenyl 1 1 2-sulfonium r = \

f Please read the notes on the reverse side before filling out this page.) The title compound (38 mg; 7 6%) of this example was printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs by a method similar to that described in Example 157. Prepared as a white solid. Melting point 220-233. . . Example 1 8 7 1 One acetone 4 — ί ί 2 'One ί (3, 4 — dimethyl one Fi — isoxazole amine] amine] sulfonium 1-4 1 (2-oxazole) 〔 1,1 'monobiphenyl] -2-yl] methyl] piperone_ This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) -314-517057 A7 B7 V. Description of the invention (312 ) — F = \ rs Π ΚΙ

The title compound of this example (47 mg; 7 was prepared as a white solid by a method similar to that described in Example 15 7. Melting point 125-145 ° C. ',, (Please read the precautions on the back before Fill out this page "

517057 A7 —One ___B7 5. Description of the invention (313) ° γ ^ 3 0

I

Boc added trifluoroacetic anhydride (2.1 ml; 14.8 mmol) to N-Boc piperazine (2.5 g; 13.4 mmol), Boc at 0 ° C over 5 minutes. 〃 is tert-butoxycarbonyl) and triethylamine (2-2 ml; 16 mmol) in dichloromethane (70 ml). After stirring for 1 hour, the reaction mixture was diluted with dichloromethane, and the resulting organic layer was washed with water, 1 equivalent of hydrochloric acid, and brine. It was then dried (magnesium sulfate) and concentrated to give 3-78 g (99%) of the title compound as a colorless oil in this step. B. 丄 Di (2,2 ″ 2 —trifluoroethyl) er 腠 氤 Chloric acid (please read the precautions on the back before filling this page)

At 0 ° C, the 8 ml tetrahydrofuran solution of the title compound of Step A (2 g; 7.09 milligrams printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs) was added to 1.0 mol concentration in 15 minutes. Borane. Tetrahydrofuran (12 ml; 12 mmol) was dissolved in solution. After the addition, the mixture was refluxed for 2 hours. After re-cooling to 0 ° C, methanol (5 ml) was carefully added over a period of 30 minutes. The hydrochloric acid gas was then bubbled through the solution to saturate, and the resulting mixture was refluxed for another 2 hours. After cooling to room temperature and standing for 18 hours, the separated solid was filtered, washed with diethyl ether, and dried to obtain 1.7 g (99%). ^ The paper size applies the Chinese national standard (CNS ) 8 4 specifications (210X297 mm) &quot; -316-517057 Α7 Β7 ___ V. Description of the invention (314) The title compound of this step as a white solid. C. Ν— (3,4 dimethyl-5 —isoxazolyl)-4 '-L · 2 — Β-oxoyl)-2'-ί 〔4 一 (_2 _: _ 2_, 2 -trifluoro (B)) — ρ azinyl] methyl 1 [1, 1, '-biphenyl] _-2-amine dihydrazone chlorate The title compound was borrowed from Step B of the title compound and Example 21 Step F of the title compound It was prepared by a reaction similar to that described in Example 157. This gave 47 mg (75%) of the title compound as a white solid. Melting point 125 — 145 ° C. Example 1 8 9 Ν-ίί 2, a [[(3,4 dimethyl-5 —isoxazolyl) tick]]] 4 (2_oxazolyl) [1, 1 one two one Biphenylpyrene _2 —yl] methyl]] N-methyl-1 1 pyrene-earthworm 2-methylformamide

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page). 0. 018 grams (0 114 millimoles) of vermicompost 2-carboxylic acid and 0.021 grams (0. 142 millimoles) 1, 3-diisopropyl

This paper size applies the Chinese National Standard (CNS) A4 specification (210 × 297 male H 317-517057 A7 _ B7 _ V. Description of the invention (315) carbodiimide added to the method described in Example 2 8 Step A 0.05 gram (.114 mmol) N— (3,4 dimethyl (please read the precautions on the back before filling out this page) 1 5 — isoxazolyl) 2 ’1 [( 2-methylamino) methyl] -4 '-(2-oxazolyl) [1,1'-biphenyl] -2-sulfamidamide in 2 ml of dichloromethane and 0-1 ml of dimethylformamide In the amidine solution. The mixture was stirred at room temperature for 12 hours and evaporated. Then the residue was borrowed on a 30x500 mm DS S10 column for reverse-phase preparative high-performance liquid chromatography and used 80%. Solvent B (90% methanol, 10% water, 0.1% trifluoroacetic acid) and 20% solvent A (10% methanol, 90% water, 0.1% trifluoroacetic acid) were eluted and purified. Then collected Appropriately dissolve, neutralize to pH 7 with aqueous sodium bicarbonate, and concentrate to 10 ml. Then acidify to pH 4 with aqueous sodium hydrogen sulfate, then filter and dry the white solid That is, 0.024 g (36%) of the title compound of this example was obtained as a white solid. Melting point 1 35-1 45 ° C. Example 1 0 0 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, 1 ^, 1 ^, 1 ^, one, three, one, one, one, one, one, [[2, one, [((3,4, one, two, five, oxazolyl), amine, one]]]], one, four, one, two (2 — An oxazole) [1,1'_biphenyl]-2 —a] methyl] urea The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) -318-517057 A7 B7 V. Description of the invention (316)

This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) -319-517057 Α7 Β7 V. Description of the invention (317) [1,1, -biphenyl]-2_ expanded amine

OMe adds acetic acid (180 mg, 3 millimoles), followed by sodium triethoxylate borohydride (6 36 mg, 3 millimoles) to N-phenylethylenediamine (163 mg, 1. 2 mmol), Example 21, Step E, the title compound (511 mg, 1.0 mmol) and 3A molecular sieve in 10 ml of dichloromethane. The reaction mixture was stirred at room temperature overnight and pre-filtered. The filtrate was then washed with water and brine, dried and concentrated. The filtrate was then separated on silica gel using 10: 60: 0. 2 hexane / ethyl acetate / triethylamine for color separation to obtain the title amine (500 mg; 79%) as a gel in this step. Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) Argon 7 "Argon" methyl]-4 '-(2-oxazole)-2'-(3-phenyl-2-oxy-1-imidazolium) a certain Ί Γ1, 1_ '_Biphenyl]-2_ sulfamethoxazole This paper is sized to the Chinese National Standard (CNS) A4 (210X297 mm) -320-517057 A7 B7 V. Description of the invention (318)

Me The OMe printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs added triethylamine (1.44 mg, 1.4 1,1'-hydroxydiimidazole (104 mg) to the title compound of step A (180 mg. In 95 ml of dimethylformamide solution. Heat under 10 hours. Then 15 ml of water was filtered. Then the solid was dissolved in ethyl acetate 'and dried and concentrated. The residue was dissolved in 6 Add sodium hydride (60% mineral oil, 46 ears) to the solution. Then put the mixture in the chamber and add 10 ml of saturated sodium chloride and wash with ethyl organic extract with water and brine, And the title of this step is cyclic urea. 3 millimoles), then 064 millimoles), 0.29 millimoles), and then the mixture was added to the reaction mixture at 40 ° C, and Wash with milligrams of milliliter of anhydrous tetrahydrofuran with brine and brine, and stir for 3 hours at 1.4 mmol. Following ethyl acetate extraction. Then the residue is dried and concentrated to obtain C_N— (3,4—dimethyl-5—isoxazolyl) —4, —C 2 -oxazole —) — 2, — [(3-benzene 2-a-oxyl 1-imidazolium) methyl] [1,1, a biphenyl]] 2-monosulfonylamine trimethylsilyl chloride (186 mg, 1.71 mmol Moore's paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) -Q91 I (Please read the precautions on the back before filling this page) 517057 A7 __B7 V. Description of the invention (319) Sodium chloride (256 mg, 1.71 mmol) was added to 5-7 ml of acetonitrile solution of the title compound in step B. The mixture was stirred at room temperature for 30 minutes. Then additional trimethylsilyl chloride (248 mg, 2-28 mmol) and sodium iodide (342 mg, 2.28 mmol) were added in four portions, and the reaction mixture was stirred for another 1 hour. 45 minutes. The reaction mixture was then added to water and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium thiosulfate, brine, dried, and concentrated. The residue was then subjected to preparative high-performance liquid chromatography on an ODS S10 column and 30% solvent A (10% methanol, 90% water, 0.1% trifluoroacetic acid) and 70% solvent B ( 90% methanol, 10% water, 0.1% trifluoroacetic acid) and purified by elution to obtain the title compound (101 mg, 62%, two steps) of this example as a white solid, melting point 140-150 ° C (Amorphous). Example 1 9 2 — 〔〔2, a Γ 〔(3,4 dimethyl_ 5 —isoxazolyl) ------ 1T ------ (Please read the precautions on the back first (Fill in this page again.) Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. I ~ s-based aminooxazolyl phenylbenzyl methoxide /-based 3 base gas-based methyl carbazine. This paper is applicable to China National Standard (CNS) A4 Specification (210X297 mm) -322-517057 A7 B7 V. Description of Invention (320)

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 〇 、

Me oxazolyl)-2 '-[(1,2,3,4 -tetrahydrol -1-Aqi-2 -isodoxoline) methyl] [1,1, biphenyl]- 2-basic amine

〇 II

S-N

· »The title compound was prepared by a procedure similar to that described in Example 161. Yield ... 45% in two steps. Melting point: 127—135 ° C (amorphous). This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) -323-517057 A7 B7 V. Description of the invention (321) Example 1 9 4 2 '— (1H — benzimidazole — 1 — a methyl group) One N— (3, 4

, 4-dimethyl-1, 5-isoxazole, one), N — [(2-methoxybiphenyl, one]] Printed by a consumer co-operative of the Central Standards Bureau of the Ministry of Economic Affairs, a certain gas, a certain one, etc.] _ 4 'one (2 — Oxazolyl) [1,1'-2 _ basic amines / ^ \ 〇

CH, OMe To benzimidazole (0.017 g, 0.14 mmol) and anhydrous potassium carbonate (0.02 g, 0.14 mmol) were added to Example 57. The title compound of step B (0.068 g , 0.118 mmol) in 1 ml of dimethylformamide solution, and then the mixture is stirred at room temperature. This paper is sized for China National Standard (CNS) A4 (210X297 mm). 324-517057 A7 B7 5 Description of the invention (322) 2 4 hours. The mixture was then added to water, and the solution was extracted with ethyl acetate. The combined organic extracts were then washed with water, dried and evaporated. Then, chromatographic separation was performed on silica gel using 2: 1 hexane: ethyl acetate to obtain 0.056 g (81%) of the title compound of this step as a yellow gel. B _ 2 'mono (1H —benzimidazole—1-ylmethyl) —N — (3-—, 4-dimethyl-1, 5-isoxazolyl) —4 ′ — (2-oxazolyl) il 1'-biphenyl] -2-ammonium amine 5 ml of 6 equivalents of hydrochloric acid was added to a solution of the title compound of step A (0.056 g, 0.096 mmol) in 5 ml of ethanol, and then The mixture was refluxed for 1 hour. The mixture was then neutralized to pH 8 with aqueous sodium bicarbonate and then acidified to pH 4 with acetic acid. The mixture was then evaporated, and the residue was subjected to reverse-phase preparative high-performance liquid chromatography on a 30 X 500 mm 0 DS S10 column using 61% solvent B (90% methanol, 10% water, 0.1% trifluoroacetic acid) and 39% solvent A (10% methanol, 90% water, 0.1% printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) Fluoroacetic acid) was eluted and purified. The appropriate fractions were collected, neutralized to pH 7 with aqueous sodium bicarbonate, and concentrated to 10 ml. Then, the solution was acidified to pΗ4 with aqueous sodium hydrogen sulfate, and the white solid was filtered and dried to obtain 0.026 g (52%) of the title compound of this example as a white solid. Melting point 1 3 0 — 1 3 5 ° C. Example 1 9 5 This paper size applies the Chinese National Standard (CNS) A4 specification (210X 297 mm) -325-517057 Α7 Β7 V. Description of the invention (323) 2 '— [(2,3 -dihydro-2-2 1 Oxy-3 _benzoxamine

The title compound of this example was prepared by procedures similar to those described in Example 161. Yield: 55% in two steps. Melting point 1 3 0 — 1 3 7 ° C (amorphous). Example 1 9 6 2, — 〔(2,3 —diamino—2 —oxyl 1 Η — mouth bow 丨 late one

This paper size applies to Chinese national standards (_M specifications (should be ^ ^ 517057 A7 B7 V. Description of the invention (324) A 2, ί (2, -3-dihydro- 2-aerobic -1 Η-ind 1 mono) methyl] __ L_3_'4 monodimethyl-5 —iso-n-oxazole, 1) N— [(2-methylaminoethoxy) 1, 4 — — (2 —oxazolyl ) [1,1'-biphenyl] -2-碏 醯 r == \

Add acetic acid (135 mg, 2.3 mmol), followed by sodium triacetoxyborohydride (318 mg, 1.5 mmol) to 2- (aminophenyl) acetic acid (225 mg, 1.5 millimolar), Example 21 Step E title compound (256 mg, 0.5 millimolar) and printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economy (please read the precautions on the back before filling this page) A molecular sieve in 5 ml of dichloromethane. The reaction mixture was stirred at room temperature overnight and pre-filtered. The filtrate was then washed with water and brine, dried and concentrated. The residue was chromatographed on silica gel using 1: 3 hexane / ethyl acetate to obtain the title compound (280 mg, 89%) as a gel in this step. B. 2, — [(2,3 —dihydrol — 2 —oxyl — 1H — occluder — 1 — a) — 1 — N — (3, 4 — dimethyl — 5 — isoxic Azole a) 4'-1 (2-oxazolyl) [1,1 '-biphenyl paper size applicable Chinese National Standard (CNS) A4 specification (210X297 mm) 517057 A7 ___ _ B7__ V. Description of the invention (325 ) Some]-2-sulfamethoxamine trimethylsilyl chloride (388 mg, 3.6 mmol), followed by sodium iodide (540 mg, 3.6 mmol) to the title of step A Compound (280 mg, 0.45 mmol) in 9 ml of acetonitrile solution. The mixture was stirred at room temperature for 30 minutes. Then additional trimethylsilyl chloride (141 mg, 1.3 mmol) and sodium iodide (195 mg, 1.3 mmol) were added, and the reaction was stirred for another 2 hours. The reaction mixture was then added to water and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium thiosulfate, brine, dried, and concentrated. The residue was then borrowed on a 0DSS 10 column for preparative high performance liquid chromatography and 32% solvent A (10% methanol, 90% water, 0.1% trifluoroacetic acid) and 68% solvent were used. B (90% methanol, 10% water, 0.1% trifluoroacetic acid) was eluted and purified to obtain the title compound (162 mg, 67% in two steps) as a white solid. Melting point &gt; 185 ° C, decomposed. Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page). Example 1 9 7 N — (3, 4 -dimethyl-5 —iso Chrysyl) —4, 1 (2 —oxazolyl) — 2 ′ — [2 —oxyl —3 —methyl — 1 —imidazolidine] —methyl] il, 1 ′ —biphenyl] — 2 _Basic amine This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) -328-517057 A7 ___B7 V. Description of the invention (326)

〇, &amp; N HaC,

Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs O 0 1 g of 3A molecular sieve, 0.074 g (0.997 mmol) N-methylethylenediamine, and 0105 g (1.776 mmol) Acetic acid was added to 0-3 g (0.586 mmol) of a solution of the title compound of Example 21, Step E, 15 ml of dichloromethane, and stirred under argon for 10 minutes. Then, 372 g (1.45 mmol) of sodium triethylsulfoxyborohydride was added to the mixture, and the mixture was stirred at room temperature overnight. Then the solution was filtered through Celite diatomaceous earth, then Celite diatomaceous earth was washed with 25 ml of dichloromethane, and the combined filtrate was washed with water, and the Chinese paper standard (CNS) A4 specifications (210X297 mm) -329-517057 A7 B7 V. Description of the invention (327) The product is dried and evaporated to obtain the title compound of this step. 33 g (100%) colorless gelatinous B N — (

_4 One dimethyl one 5 —Isoxazolyl) _ N 2 ± _— .. A-Gasylethoxy) A]] 2 ′ 1 [(3 -methyldi-2- 2-Zhi-oxygen I — 1 an imidazolium] a certain] a 4 'one (_ 啜 棊 [1,1' —biennium]]-2-sulfonamide

(Please read the precautions on the back and fill in this page first) Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs Printed C · N-(to 0_33 g (.586 mmol) Step 10 of the title compound Chloromethane solution. The mixture was stirred at room temperature for 2 4 hours. Then the mixture was washed with water, dried and evaporated to obtain 0-26 g of the title compound as a colorless gel in this step. 517057 Central Ministry of Economic Affairs A7 B7 printed by the Consumer Cooperative of the Bureau of Standards ------------ V. Description of the invention (328) compound (0.26 g, 0.45 mmol) in 10 ml of 95% ethanol solution, and then The solution was refluxed for 1 hour. The mixture was then diluted with water and extracted with ethyl acetate. The combined organic extracts were then washed once with water, dried and evaporated. The residue was then borrowed to 30 × 500. Reverse phase preparative high performance liquid chromatography on a 0 mm DSS 10 column with 62% solvent B (90% methanol, 10% water, 0.1% trifluoroacetic acid) and 38% solvent A (10% methanol, 90%) % Water, 0.1% trifluoroacetic acid), and purified. Then collect the appropriate fractions, 039 克 (17%) The solution was neutralized with aqueous sodium bicarbonate to p 再 7, and then concentrated to 5 ml. Then acidified with aqueous sodium bisulfate to P ， 2, and then the white solid was filtered and dried to obtain 0.039 g (17%). The title compound of this example is a white solid. Melting point · 105-115 ° C (amorphous). — Oxazolyl) —2 ′ — ί [2 -Hydroxy-3— (1 -methylethyl)-1 -imidazolidinyl] methyl] Γ1 :: L, a biphenyl] -2 — Sulfonamide 〇II r ο

This paper size applies to China National Standard (CNS) Α4 specification (210X297 mm) --------- 41 ^ — (Please read the precautions on the back before filling this page)

1T -331-Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 517057 A7 _B7 V. Description of the Invention (329) The title compound of this example was prepared by a three-step method similar to that described in Example 197. 039 g (12% in three steps) white solid. Melting point: 105—110 ° C (amorphous). Example 1 9 9 N — Γ Γ2, one [ί (3, 4 —dimethyl-1, 5 — isoxazolyl) — amine 1 1] — 4 — (2 -oxazolyl) [1, 1 two Monobiphenyl]-2 -a certain application] -N, 3 dimethyl butanamine

The title compound of this example was prepared by using procedures similar to those in Example 28 using isoprene chloride to obtain 0.048 g (82%) of a white solid. Melting point is 114-122 ° C. Example 2 0 0 N-〔2 '-[[(4,5 —Dimethyl-1,5 —Rixazole) Amine] Spread] -4 1 (2 —Negative) (1,1 , A biphenyl] -2_yl] methyl] -N, ZL, 4-trimethylpentanamide This paper is applicable to the Chinese National Standard (CNS) A4 specification (210 × 297 mm) 41 ^^ Order (please (Please read the notes on the back before filling this page) -332-517057 A7 B7 V. Description of Invention (330)

This paper size applies to China National Standard (CNS) A4 (210X297 mm) -333-517057 A7 B7 V. Description of the invention (33〇 (2-oxazolyl) il, 1'-biphenyl)] 2 -sulfo Amidine / = \

Acetic acid (60 mg, 1.0 mmol) was added, followed by sodium triacetoxyborohydride (318 mg, 1.5 mmol) to 4-monoamino-3,3-dimethyl Ethyl butyrate (159 mg, 1.0 mmol) and the title compound (256 mg, 0.5 mmol) from Step 21 in Example 21 and 5 ml of dichloromethane in a 3A molecular sieve. The reaction mixture was stirred at room temperature overnight and pre-filtered. The filtrate was then washed with water and saline, dried and concentrated. The residue was separated on a silica gel using 1: 2.5 hexane / ethyl acetate for color separation to obtain the title compound (220 mg, 72%) in this step as a gel. Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) Β _Ν— (3, 4 dimethyl-5 — isoxazolyl)-2'_ 〔(4 , 4-dimethyl-1, 2-argon-1, 1-pyrrolidin-1) methyl] -4 '-(2-oxazolyl) [1,1'-biphenyl]-2-amidine will Trimethylsilyl chloride (315 mg, 2.9 mmol) followed by sodium iodide (435 mg, 2.9 mmol) to the title compound of Step A (218 mg, 0.36 mmol) (7 ears) of this paper standard is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm)-〇04-517057 Α7 Β7 5. Description of the invention (332) in acetonitrile solution. The mixture was stirred at room temperature for another hour. Then additional trimethylsilyl chloride (158 mg, 1.5 mmol) and sodium iodide (2 18 mg, 1.5 mmol) were added, and the reaction was stirred for another 1 hour and 15 minutes . The reaction mixture was then added to water and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium thiosulfate, brine, dried, and concentrated. The residue was then borrowed on an ODS S 10 column for preparative high-performance liquid chromatography and 35% solvent A (10% methanol, 90% water, 0.1% trifluoroacetic acid) and 65% solvent were used. B (90% methanol, 10% water, 0.1% trifluoroacetic acid) was eluted and purified to obtain the title compound of this example (80 mg, 43% in two steps), m.p. 118-125 ° C. Examples 2 0 2 to 2 7 0 The compounds 2 2 to 2 7 0 have the structures shown below, where, for each compound, R * is the portion shown in the following table II. ί = \ 汐 Ν

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the notes on the back before filling out this page) These compounds are prepared by mechanization as follows. One dimethyl-5 isoxazolyl) -4, one (2-oxazolyl) [1,1, biphenyl]-2-sulfamethoxamine, this paper size applies Chinese National Standard (CNS) Α4 Specification (210 × 297 mm) _Guild 5 517057 A7 B7 V. Description of the Invention (333) 034 ml of dichloride (32 9 mg, 0.075 mmol) was prepared according to the method described in step 28 (A) of Example 28 Methane and 009 ml of monomethylformamide solution, followed by 1,3-diisopropylcarbodiimide-chloromethane solution (0 28 equivalent concentration, 0.32 ml '0 09 millimoles) Add to a vial containing the acid r * -c00h (0_0.75 mmol). The reaction mixture was vortexed for another 3 minutes and allowed to stand at room temperature for 24 hours. The mixture was then loaded on 1.5 g of a strong anion exchange (, quaternary amine) resin and eluted with 20 ml of dichloromethane and then 10 ml of 3% trifluoroacetic acid in dichloromethane to obtain the desired compound. . (Please read the notes on the back before filling out this page) The paper size printed by the Employees' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs applies the Chinese National Standard (CNS) A4 specification (210X297 mm) ~ 000 517057 A7 B7 V. Invention Description Table Π Example number printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economy r Compound name Dwell time of high-performance liquid chromatographic separation (minutes) △ 202 N- [[2 '-[[(3,4-dimethyl-5 -Isoxazolyl) amine 6.6 V group] sulfofluorene] -4- (2-oxazolyl) [1, Γ-biphenyl] -2-yl] methyl] -N-methylcyclobutanemethyl Hydrazine- 203 h3c N-[[2 '-[[(3,4-dimethyl-5-isoxamidino) amine 6.6 group] sulfofluorene] -4- (2-oxazolyl) [1, 1'-biphenylh3c 3] -2-yl] methyl] -11,3-dimethyl-111-11 bis- 5-formamidine 204 ch3 human A N- [[2 '-[[ (3,4-Dimethyl-5-isoxylyl) amine 7.3 Cr- ^ yl] sulfonyl] -4- (2-oxyl) [1, Γ-biphenyl] -2-yl] Methyl; 1-N, 2-dimethylphenethylamine 205 H3C N- [[2 '-[[(3, 4-dimethyl-5-isoxamidino) amine 6.3 group] sulfofluorene] -4- (2-oxanyl) [1,1'-biphenylh3〇-^^]-2 -Methyl] methyl] -1-ethyl-N, 3_ — • methyl-1H-pyrazole-5-carboxamide 206 N- [[2 '-[[(3, 4-dimethyl-5 -Isoxamyl) amine 6.7 H3C'Vkc group] sulfofluorene] -4- (2-oxazolyl) [1,1'-biphenylh3c ^]-2-yl] methyl] -N, 1 ， 3, 5-tetramethyl-1H-sozoazole-4-carboxamide This paper size is applicable to Chinese National Standard (CNS) A4 (210 X 297 mm) (Please read the precautions on the back before filling this page ) 517057 A7 B7 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention (335) 207 F N- [[2 '-[[(3, 4-dimethyl-5-isooxazolyl) amino ] Sulfofluorene] -4- (2-oxafluorenyl) [1, Γ-biphenyl] -2-yl] methyl] -2, 6-difluoro-N-methylbenzidineamine 6.9 208 N -[[2 '-[[(3, 4-Dimethyl-5-isooxalidinyl) amino] sulfofluorenyl] -4- (2-oxafluorenyl) [1,1'-biphenyl]] -2_yl] methyl] -N-methylphenanthramine 7.6 209 OMe N- [[2 '-[[(3, 4-Dimethyl-5-isoxamidino) amino]] ] -4- (2-oxafluorenyl) [1,1'-biphenyl] -2-yl] methyl] -2-methoxy-N-methylphenethylamine 7.2 210 MeCkTv N -[[2 '-[[(3, 4-dimethyl-5-isoxan (Amino) amino] phenyl] -4- (2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -3-methoxy-N-methylphenethylfluorene Amine 7.0 211 N- [[2 '-[[(3, 4-Dimethyl-5-isooxazolyl) amino] fluorenyl] -4- (2-oxazyl) [1, Γ-linked Phenyl] -2-yl] methyl] -4-methoxy-N-methylphenethylamine 7.0 212 π 4-chloro-N- [[2 '-[[(3,4-dimethyl Methyl-5-isooxazolyl) amino] sulfofluorenyl] -4- (2-oxazolyl) [1, Γ -biphenyl] -2-yl] methyl] -N-methylphenethylfluorene Amine 7.5 213 Cl 2-Chloro-N- [[2 '-[[(3,4- — ~ * methyl-5-isoxazolyl) amino] sulfofluorene] -4- (2-oxo Fluorenyl) [1,1'-biphenyl] -2-yl] methyl] -N-methylphenethylamine 7.4 This paper size applies to China National Standard (CNS) A4 (210X 297 mm) ( Please read the notes on the back before filling out this page.) 338-517057 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. 5. Description of the invention (336) A7 B7 214 0C, N- [[2 '-[[(3, 4-dimethyl-5-isooxazolyl) amino] sulfofluorene] -4- (2-oxazolyl) [1, Γ-biphenyl] -2-yl] methyl] -2, 6 -· ~ ^ • Aminomethylbenzidine 7.1 215 Ν- [[2 '-[[(3, 4- Methyl-5-isooxazolyl) amino] sulfofluorenyl] -4- (2-oxazyl) [1,1'-biphenyl7.2 F] -2-yl] methyl] _3, 5- —'Aroyl-N-methylbenzidine amine 216 F N- [[2 '-[[(3, 4-Dimethyl-5-isoxamidino) amino] sulfofluorene] -4- (2 -Oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -2, 5- * amino-N-methylbenzidine 7.1 217 plus N- [[2 '-[ [(3,4-Dimethyl-5-isoxamidino) amino] orenium] -4- (2-oxazolyl) [1, Γ-biphenyl] -2-yl] methyl] -2, 4- — * Gas-N-methylbenzidineamine 7.2 218 N- [[2 '-[[(3,4-Dimethyl-5-isoxazolyl) amino] fluorene] -4- (2-oxazolyl) [1, Γ-biphenyl] -2-yl] methyl] -N-methyl-4-quinolinamidinamine 6.2 219 oa; N-[[2 ' -[[(3,4-Dimethyl-5-isooxazolyl) amino] benzyl] -4- (2-oxazolyl) [1, Γ-biphenyl] -2-yl] methyl Benzyl] -N-methyl-6-benzilbazolamide 6.5 (Please read the precautions on the reverse side before filling out this page) This paper size applies to China National Standard (CNS) A4 (210X297 mm) -339 -517057 A7

7 B V. Description of the invention (eg?) Printed by the Consumer Cooperative of the Central Bureau of Samples of the Ministry of Economic Affairs 220 h3c 3-(1,1-dimethylethyl) -N-[[2 '-[[(3,4 -Dimethyl-5-isoxyl) amino] sulfofluorene] -4- (2-oxazolyl) [1, Γ-biphenyl] -2-yl] methyl] -N, 1- Dimethyl-1H-oxazole-5-carboxamide 7.4 221 OMe 4-chloro-N- [[2 '-[[(3, 4- — * methyl-5-isoxazolyl) amine Group] sulfofluorenyl] -4- (2-oxazolyl) [1, Γ -biphenyl] -2-yl] methyl] -2-methoxy-N-methylbenzidine 7.3 222 3 -(1,1- — * methylethyl) -N- [[2 '-[[(3,4-Dimethyl-5-isoxanthene) amino] sulfofluorene] -4- (2 -Oxazolyl) [1, Γ-biphenyl] -2-yl] methyl] -N -methyl-1-phenyl-1H-1,2,3-triazole-5-carboxamide 6.6 223 ^ Π3 2, 3-dihydro-N- [[2 '-[[(3,4-Dimethyl-5-isooxazolyl) amino] sulfofluorene] -4_ (2-oxazolyl ) [1 ^ Γ-biphenyl] -2-yl] methyl] -N, 4- ^ methyl-2-thio-3-oxetazolacetamide 6.4 224 vC; f3c j N- [ [2 '-[[(3,4-Dimethyl-5-isoxawalyl) amino] sulfofluorene] -4- (2-oxafluorenyl) [1, Γ-biphenyl] -2- Yl] methyl] -N, 3-dimethyl-5- (trifluoromethyl) -4-isoxan Formamidine 7.2 225 c 3- (1,1-monomethylethyl) -N- [[2 '-[[(3, 4-Dimethyl-5-isoxazolyl) amino] sulfonic acid醯] -4- (2-oxafluorenyl) [1, Γ-biphenyl] -2-yl] methyl] -1 -ethyl-N-methyl-1H-pyrazole-5-carboxamide 7.6 This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the notes on the back before filling this page) 517057 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of Invention (338) A7 B7 226 N = N N-[[2 '-[[(3,4-dimethyl-5-isooxazolyl) amino] sulfofluorene] -4- (2-oxazolyl) [1,1 '-Biphenyl] -2-yl] methyl] -N-methyl-5- (1-pyrrolidinyl) -2H-tetrazol-2-acetamidine 6.6 227 N- [[2'-[ [(3,4-Dimethyl-5-isooxazolyl) amino] sulfofluorene] -4- (2-oxazyl) [1, Γ-biphenyl] -2-yl] methyl] -N-methyl- [1,1'-biphenyl] -2-carboxamide 7.5 228 cf3 N- [[2 '-[[(3, 4-Dimethyl-5-isoxanyl) Amine] sulfofluorenyl] -4- (2-oxafluorenyl) [1, Γ-biphenyl] -2-yl] methyl] -N-methyl-3- (difluoromethyl) benzidine Amine 7.5 229 cf3 N- [[2 '-[[(3, 4-Dimethyl-5-isooxazolyl) amino] ] -4- (2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -N-methyl_2- (trifluoromethyl) phenylacetamide 7.5 230 h3c N- [[2 '-[[(3, 4-Dimethyl-5-Isoxazolyl) amino] sulfofluorene] -4- (2-oxafluorenyl) [1, Γ-biphenyl]] -2-yl] methyl] -N, 1- — * methyl-1H-benzimidazole-2-propanilamine 5.6 231 ς cf3 N-[[2 '-[[(3,4-dimethyl Methyl-5-isooxazolyl) amino] sulfofluorene] -4- (2-oxazolyl) [1, Γ -biphenyl] -2-yl] methyl] -N, 2-dimethyl -4- (trifluoromethyl) -3-D-pyridamidine 7.1 This paper size applies to Chinese National Standard (CNS) A4 (210X 297 mm) (Please read the precautions on the back before filling this page) -341-517057 V. Description of the invention (339) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs Α7 Β7 232 \ = N N- [[2 '-[[(3, 4-dimethyl-5-isoxazole Yl) amino] pyridyl] -4- (2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -N-methyl-5- (2-pyridyl) -2-P sphenethanamine 7.0 233 s N-[[2 '-[[(3,4-dimethyl-5-isoxanthene) amino] sulfonyl] -4- (2-ox Mileyl) [1,1'-biphenyl] -2-yl] methyl] -N-methyl-4-benzyl 1, 2, 3 -5-formamidine 7.2 234 N = N N-[[2 '-[[(3,4-dimethyl-5-isooxazolyl) amino] mine hydrazone] -4- (2-oxazone ) [1,1'-biphenyl] -2-yl] methyl] -N-methyl-4- (1,2,3-P- (1-, 4-pyridyl) phenyl) amine 6.9 235 N -[[2 '-[[(3,4-dimethyl-5-isoxazolyl) amino] phenyl]]-4- (2-oxanyl) [1, Γ-biphenyl]- 2-yl] methyl] -N-methyl-2-hexyloxy-3 (2H) -benzoxazolamide 6.9 236 N-[[2 '-[[(3,4-dimethyl -5-Isoxamidinyl) amino] sulfofluorenyl] -4- (2-oxafluorenyl) [1,1'-biphenyl] -2-yl] methyl] -N, 5-dimethyl 2-Phenyl-4-oxazoleacetamidamine 7.6 237% N-[[2 '-[[(3,4-dimethyl-5_isoxazolyl) amine base brewing] -4- (2 _ 卩 oxalyl) [1,1 '_bibenyl] _2-yl] methyl] -N-methyl-1,4-dithiaspiro [4, 5] decane-8-formamidine 7.5 (Please read the precautions on the back before filling this page) This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) -〇4 ^ 517057 A7 B7 V. Description of the invention (340) Chinese Ministry of Economic Standards Printed by the Consumer Cooperative of the Bureau 238 4-Chloro-N- [[2 '-[[(3, 4-Dimethyl-5-isoxazolyl) amino] mine 醯] -4- (2- (Oxazolyl) [1, Γ-biphenyl] -2-yl] methyl] -N, 1,3-dimethyl-1fluorenyl-D than zolo [3,4-b] pyridine-5-carboxamide 7.0 239 N-[[2 '-[[(3,4-Dimethyl-5-isooxazolyl) amino] sulfofluorene] -4- (2-oxyl) [1,1'-biphenyl Yl] -2 -yl] methyl] -N-methyl-1-phenyl-5_propyl-1H-pyrazole-4-acetamidamine 7.8 240 Η N-[[2 '-[[(3 , 4-dimethyl-5-isoxazolyl) amino] sulfofluorene] -4- (2-oxazolyl) [1, Γ-biphenyl] -2-yl] methyl] -N- Methyl-3-K4-methylphenoxy) methyl] phenylhydrazine 8.1 241 FN BU [[2 '-[[(3,4-dimethyl-5-isoxanthyl) amino] mine Alcohol] -4- (2-fluoroxanyl) [1,1'-bibenyl] -2-yl] methyl] -N-methyl-5- [3- (trifluoromethyl) phenyl ] -2H-tetrazol-2-acetamidine 7.7 242 丨 Me N-[[2 '-[[(3,4-Dimethyl-5-isoxanthroyl) amine] Extender] -4- (2-Chlohexyl) [1 '1'-biphenyl] -2-yl] methyl] -N-methyl-5- [l-methyl-3- (trifluoromethyl MΗ-D ratio Azol-5-yl] -2-P-sphenformamide 7.9 243 F: Me N-[[2 '-[[(3,4-dimethyl-5-isoxanthroyl) aminogallium] -4- (2-oxanyl) [1,1'-biphenyl] -2-yl] methyl] -N, 4-dimethyl-5- [3- (trifluoromethyl) phenyl ] -5- 卩Acetazolamide 8.2 (Please read the precautions on the back before filling out this page) This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) 〇y | 〇-〇4〇517057 Α7 Β7 Central Ministry of Economic Affairs Printed by the Consumers Cooperative of the Bureau of Standards V. Description of the invention (341) 244 C f3c 1- (4-chloro) -bu [[2 '-[[(3,4-dimethyl-5-isooxazolyl) Amine] sulfofluorene] -4- (2-oxazolyl) [1, Γ monobiphenyl] -2-yl] methyl] -N-5_ (diaminomethyl) _ 1H-D 4-formamidine 7.8 245 N-[[2 '-[[(3,4-dimethyl-5-isoxanthino) amino] sulfofluorene] -4- (2-oxanyl) [1 , Γ-biphenyl] -2-yl] methyl] -N, 6-dimethyl-2-pyridinecarboxamide 7.0 246 N-[[2 '-[[(3,4-dimethyl- 5-Isoxazolyl) amino] sulfofluorenyl] -4- (2-oxazolyl) [1, Γ-biphenyl] -2-yl] methyl] -N-methyl-2-hydrazone Phenethylacetamide 7.5 247 ί 9〇N-[[2 '-[[(3,4-dimethyl-5-isoxyl) amino] sulfofluorene] -4- (2-oxazolyl) [1, Γ-biphenyl] -2-yl] methyl] -N-methyl-2- (phenylmethoxy) phenethylhydrazine 8.6 248 3- (2-chloro_6_benzyl -)-N- [[2 '-[[(3, 4- — * methyl-5-isooxazolyl) amino] sulfonyl ] -4- (2-oxazolyl) [1, Γ-biphenyl] -2-yl] methyl] -N, 5-dimethyl-4-isooxazolecarboxamide 7.8 249, N = \ Me- ^ Nns ^ v \ ^ N- [[2 '-[[(3, 4-Dimethyl-5-isoxamidino) amino] sulfofluorene] -4- (2-oxazolyl) [1, Γ -biphenyl] -2-yl] methyl] -N, 1-dimethyl-1H-pyrazole-4-carboxamide 6.7 (Please read the precautions on the back before filling this page) This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) ^ ^ -344-517057 A7 B7 V. Description of the invention (342) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 250 N-[[2 ' -[[(3,4-Dimethyl-5-isooxoyl) amino] sulfofluorene] -4- (2-oxazolyl) [1, Γ-biphenyl] -2-yl] methyl Phenyl] N, 5-dimethyl-1H-D-pyrazole-3-carboxamide 6.8 251 N-[[2 '-[[(3,4-dimethyl-5-isooxanyl) amine ] Sulfofluorene] -4- (2-oxazolyl) [1, Γ-biphenyl] -2-yl] methyl] -N-methyl-2-thienolamine 7.4 252 N-[[2 '-[[(3,4-Dimethyl-5-isooxazolyl) amino] sulfofluorene] -4- (2-oxafluorenyl) [1,1'-biphenyl] -2-yl ] Methyl] -N-methyl-3-benphenformamide 7.3 253 6-chloro-N- [[2 '-[[(3, 4- — * methyl-5-iso Fluorenyl) amino] fluorenyl] -4- (2-oxafluorenyl) [1, Γ-biphenyl] -2-yl] methyl] -N-methyl-3-pyridinecarboxamide 7.2 254 οα, N- [[2 '-[[(3,4-Dimethyl-5-isoxazolyl) amino] propanoic acid] -4- (2-fluoroxyl)] [1' 1'- Bibenyl] -2-yl] methyl] -N-methyl-1H-d3 [I ^ -5-formamidine 7.4 255 CH3 2-chloro-N- [[2 '-[[(3 , 4-dimethyl-5-isoxazolyl) amino] sulfofluorenyl] -4- (2-oxazolyl) [1,1'_biphenyl] -2-yl] fluorenyl] -N , 6-Dimethyl-4-pyridinecarboxamide 7.3 (Please read the precautions on the back before filling this page) W ^ t ^^ (CNS) A4 »(210X2 ^ ^ _ 517057 A7 B7 Central Bureau of Standards, Ministry of Economic Affairs Printed by the employee consumer cooperative V. Description of the invention (343) 256 ΓΊ N- [[2 '-[[(3, 4-Dimethyl-5-isoxanthroyl) amino 7.1] sulfofluorene] -4- ( 2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -N-methyl-4-oxolinecarboxamide 257 N- [[2 '-[[(3, 4-dimethyl-5-isoxylyl) amine 7.8] sulfofluorene] -4- (2-oxazolyl) [1, Γ-biphenyl] -2-yl] methyl] -N- Methyl-1H-methylpyridine-1-ethylamidine- 258 ΟιΤν N- [[2 '-[[(3, 4-dimethyl -5-Isoxamidinyl) amino 7.6 Η] sulfofluorene] -4- (2-oxazolyl) [1, Γ-biphenyl] -2-yl] methyl] -N-methyl-1H -Ordination late-3-acetamidine 259 2, 3-a * amino-N- [[2 '-[[(3, 4-a ^ methyl-5_iso8.4 Or oxanyl) amino] Sulfofluorene] -4- (2-oxazolyl) [1, Γ monobiphenyl] -2-yl] methyl] -N-methyl-1H-ind-2-ethylamine 260 FK N- [ [2 '-[[(3,4-Dimethyl-5-isooxazolyl) amino 8.2 〇χ] sulfofluorene] -4- (2-oxazolyl) [1,1'-biphenyl] -2- Into s5 group] methyl] -5-fluoro-N-methyl-111 "late 2-methylamidamine 261 OMe 1 N- [[2 '-[[(3, 4- 二Methyl-5-isoxamidino) amino group 7.7 ... Zhong /] mine enzyme] _4- (2-fluoroxanyl) [1,1'-bibenyl] -2-yl] methyl] -3, 5-dimethoxy-N-methylphenylhydrazone Amine (Please read the precautions on the back before filling out this page) Gujiajia County (⑽) (Danguili) 517057 A7 B7 Paper Specifications 344 Printed by the Central Consumers Bureau of the Ministry of Economic Affairs Cl OMe 5-chloro-N- [[2 '-[[(3, 4-dimethyl-5-isooxazolyl) amino] sulfofluorene] -4- (2-oxazolyl) [1 , Γ -bibenyl] -2-yl] methyl] -2-methoxymethylbenzidine 7.9 2, 6-dichloro-N- [[2 '-[[(3, 4-Di Methyl-5-7.6 ★ Cl isoxazolyl) amino] sulfofluorenyl] -4- (2-oxazolyl) [1 '1'-bibenyl] -2-yl] fluorenyl] -N- Methyl-3 -pyridamidine 264 Me ΗΓΤ ^ Ο A 3- (acetamido) -N-[[2 '-[[(3, 4-dimethyl-5-isoxazolyl) amine [Alkyl] pyridyl] -4- (2-oxafluorenyl) [1 '1'-bibenyl] -2-yl] methyl] -N, 4-monomethylbenzylamine 7.0 265 Me 3 N -[[2 '-[[(3, 4-Dimethyl-5-isooxazolyl) amino] sulfofluorene] -4- (2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -N, 5- — ^ ►methyl-1-benzyl-1H-pyrazole-4-carboxamide 7.6 266 OMe N- [[2 '-[[(3, 4-Dimethyl-5-isooxazolyl) amino] sulfofluorene] -4- (2-oxafluorenyl) [1,1'-biphenyl ] -2-yl] methyl] -4-methoxy-N-methyl-2-quinolinecarboxamide 7.7 297 mm) (Please read the notes on the back before filling in this page) Rule paper Applicable Standards for National Standards -347 — 517057 A7 B7 V. Description of Invention (345) Printed by the Consumer Cooperatives of the Central Standards Bureau, Ministry of Economic Affairs, 267 Me Ν- [[2 '-[[(3, 4-dimethyl- 5-Isoxazolyl) amino] sulfofluorenyl] -4- (2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl] _N, 5_ — * methyl_2 _ Benzo-2H -1,2,3-triazole-4-carboxamide 8.5 268 σ. N-[[2 '-[[(3, 4-dimethyl-5-isoxazolyl) amino] sulfofluorene] -4- (2-oxazolyl) [1,1'-biphenyl ] -2-yl] methyl] -N-methyl-2-phenoxy-3-pyridinecarboxamide 7.6 269 ET ° N- [[2 '-[[(3,4-dimethyl-5 -Isoxazolyl) amino] sulfofluorenyl] -4- (2-oxazolyl) [1, Γ-biphenyl] -2-yl] methyl] -N ', N'-diethyl- N-methyl-1,2-xylylenediamine 7.6 270 N- [[2 '-[[(3,4-Dimethyl-5-isoxazolyl) amino] sulfofluorene] -4- (2-oxafluorenyl) [1, Γ-biphenyl] -2-yl] methyl] -N-methyl-9H-fluorene-9-propylamine 8.8 1 (Please read the precautions on the back before (Fill in this page) Rule paper

(CNS) A4 specification (210X 297 mm) 348 517057 A7 __B7 V. Description of the invention (346) △ High-performance liquid color separation status: Column: YMC S3 ODS 4. 6x50 mm in 8 minutes 0-1 0 0 % B gradient elution and hold at 100% B for 3 minutes. Flow rate: 2.5 ml / min A: 10% methanol-90% water-0.2% phosphoric acid B: 90% methanol-10% water-0.2% phosphoric acid, verification wavelength: 254 nm Example 271-2ft3 Examples 2 7 1-2 8 3 The compounds have the structure shown below, where, for each compound, R * is the part shown in the following Table II. These compounds were prepared by a method similar to that described in Example 164. (Please read the notes on the back before filling this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Γ = \

This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) -349 ~ 517057 A7 B7 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (347) Table nr Example r Compound name High-performance liquid color Dwell time of number layer separation (minutes) △ 271 I, 2 '-[[[1- (1,1-dimethylethyl) -3-methyl-1H 11.0ΔΔ yi / pyrazol-5-yl] Amine] methyl] -N- (3,4-dimethyl-methyl-5-isooxazolyl)]-4 '-(2-oxazolyl) [1,1'-biphenyl] -2-Sulfamethoxamine 272 N- (3, 4-dimethyl-5-isoxanthene) -4 '-(2-oxazolyl) -2'-[(1H-D Methylamino) methyl] [1,1'-biphenyl] -2-sulfonylamine 5.5 273 N- / "N N- (3, 4-dimethyl-5-isoxamidino) -4 '-(2-oxa5.3 B oxazolyl) -2'-[(1H-1, 2, 4-triazol-3-ylamino) methyl] [1, Γ-biphenyl] -2-sulfo Hydrazine 274 Ν- (3,4-dimethyl-5-isoxazolyl) -2 '_ [[(5- 6.8methyl-3-oxafluorenyl) amino] phenyl] -4'- (2-oxazolyl) [1,1'-biphenyl] -2-sulfonamide 275 NC% n 2 '-[[(4-cyano-1'-pyridine Azole-3-yl) amino] methyl 6.4 X / K group] -N- (3,4-: ~ * methyl-5-isospirofluorenyl) -4 '-(2-Βoxanyl) [ 1,1'-biphenyl] -2-basic amine (Please read the precautions on the back before filling this page) This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) -350- 517057 A7 B7 V. Description of the invention (348) 276 people printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs J N- (3, 4-dimethyl-5-isooxazolyl) -2 '-[[(3, 5-dimethyl-2-corazinyl) amino] methyl] -4 '-(2-oxafluorenyl) [1, Γ-biphenyl] -2-sulfonamide 6.5 277 N- (3 , 4-dimethyl-5-isoxanthene) -2 '-[[(3, 5-dimethyl-2-pyrimidinyl) amino] methyl] -4'-(2-oxazolyl ) [1, Γ-biphenyl-2-sulfonamide 5.9 278 ^ VN N-(3,4-dimethyl-5-isoxazolyl) -2 '-[[(5-ethyl-1 , 3,4-Pedadiazol-2-yl) amino] methyl] -4 '-(2-oxazolyl) [1,1'-biphenyl] -2-sulfonamide 6.5 279 σΗ 2 '-[(2-benzothiazolylamino) methyl] -N- (3, 4-dimethyl-5-isooxazolyl) -4'-(2-oxazolyl) [1 ' 1'-biphenyl] -2-propanamine 6.8 280 s 2 '-[[(4-Molyl-1H-D Fluoren-3-yl) methylene] methyl] -N- (3,4- ~~ ^ methyl-5-isoamyl) -4 '-(2-oxazolyl) [1, Γ- Biphenyl] -2-sulfonamide 6.9 281 '-s H N- (3, 4-dimethyl-5-isooxazolyl) -4'-(2-oxazolyl) -2 '-[ [[5- (2-P Sephenyl) -1'-pyrazol-3 -yl] amino] methyl] [1,1'-biphenyl] -2-sulfonamide 6.7 OX 297 mm) (CNS) A4 specification (21 (Please read the notes on the back before filling in this page) Appropriate size paper on standard rulers and national schools 351-517057 A7 B7 V. Description of the invention (349) Employees of Central Bureau of Standards, Ministry of Economic Affairs Printed by a cooperative

(Please read the precautions on the back before filling this page) This paper size applies Chinese national standard (milk) 8 4 specifications (210 '乂 297 mm) _ 517057 A7 B7 V. Description of the invention (35〇) △ High performance Liquid chromatographic separation status: Column: YMC S3 〇 DS 4. 6X50 mm (please read the precautions on the back before filling this page) Perform gradient gradient of 0-1 0 0% B 'in 8 minutes and keep it at 100 % B for 3 minutes. Flow rate: 2.5 ml / min A: 10% methanol-90% water-0_ 2% phosphoric acid B: 90% methanol-10% water 0 2% phosphoric acid Verification wavelength: 217 nm △ △ high-performance liquid color layer Separation status: Column: YMC S3 0 DS 4. 6x150 mm was subjected to a gradient gradient of 40 to 100% B during 25 minutes and held at 100% B for 5 minutes. Flow rate: 1.5 ml / min. A: 10% methanol—90% water—0.2% phosphoric acid B: 90% methanol—10% water—0.2% phosphoric acid Verification wavelength: 2 17 nm. Example of printing of employee cooperatives by the Central Bureau of Standards of the Ministry of Economic Affairs 2 8 4 N — (4,5 —dimethyl — 3 —rizozolyl) — 4, 1, (2_bis — oxazolyl) — 2, 1, ί [3- — (trifluoromethyl) — 1H. Didipyrazole — 1 — a] A 1 1 Γ1, 1 'diphenyl I] 2 — expanded amines The paper size is applicable to the Chinese National Standard (CNS) Α4 Specifications (210X297 mm) _ 353 517057 A7 B7 V. Description of the invention (351) r = \

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

CHS A · 4,5 -dimethyl-1,3 -isoxazolamide phosphonate-100 ml of 4 equivalents of hydrochloric acid dioxane solution was added to Methyl 3-isoxazolyl) carbamic acid 1, 1-dimethyl ethyl ester (25.0 g, 117.79 mmol,

Konoike, T. et al., Tet. Lett., 3 7 ′ 3 3 3 9 -3342 (1996)). The mixture was stirred at room temperature for 5 hours and then concentrated to give the title compound in this step as a solid, which was used in the next step without further purification. B. 2-Bromo-N- (4,5_dimethyl-1 3-isoxazole) benzamidine The Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs printed the 0-bromo group at 0 ° C Toluenesulfonyl chloride (28.59 g, 1 1.1.9 mmol) was added to the solid solid obtained in step A and 4-dimethylaminopyridine (14 4 g, 11.78 mmol) in 79 ml of pyridine solution. The mixture was stirred at 40 ° C for 6.5 hours and concentrated. The residue was then dissolved in 300 ml of methanol, 1000 ml of a 3% aqueous sodium bicarbonate solution was added, and the mixture was concentrated in vacuo to remove most of the methanol. And this paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm)-354 517057 Printed by A7 _____B7 of the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. After the description of the invention (352), the solid matter is filtered out, and then the The aqueous filtrate was acidified to pH 1 with 6 equivalents of hydrochloric acid at 0 ° C and extracted with ethyl acetate (2 x 400 mL). Then, the extract was washed with 100 ml of 1 equivalent strength hydrochloric acid, 100 ml of water and 100 ml of brine, and dried and concentrated to obtain the title compound (34.32 g, about 95%) in this step. % Purity, 84% yield in two steps) ° Rf = 0.57, silica gel, 1: 1 hexane / ethyl acetate. C. 2 —bromo-N — (4,5—dimethyl-1, 3 —isoxazole) —N — [(2_methylargon, ethaneargon, dimethyl), benzylsulfonamide at 0 ° C Next, sodium hydride (60% mineral oil solution, 4.93 g '123.34 mmol) was added portionwise to 343 ml of the title compound of Step B (3 2. 60 g, 102. 78 mmol). Dimethylformamide solution. After stirring at room temperature for 30 minutes, the mixture was cooled in an ice-salt bath (-15 ° C), and then 2-methoxyethoxymethyl chloride (16. 00 g, 128. 48 mmol) Ear) Add dropwise over a 20 minute period. 5 小时。 Then the reaction was stirred under ice-salt bath for 20 minutes, and then stirred at room temperature for 1.5 hours. Then 1400 ml of 1: 1 hexane / ethyl acetate was added to the reaction mixture. The organic layer was separated, washed with 2 X 800 ml of water, 400 ml of brine, and dried and concentrated. Then, the residue was separated on a silica gel using 2.5: 1 hexane / ethyl acetate for color separation to obtain the title compound (32.12 g, 75%) as an oil in this step. This & Zhang scale is applicable to China National Standard (CNS) A4 specifications (210X297 mm) — -355-II Order I (Please read the precautions on the back before filling this page) 517057 A7 B7 Staff Consumer Cooperatives, Central Standards Bureau, Ministry of Economic Affairs Printed 5. Description of the invention (353) 1 1 DN — (4 Pi _ dimethyl_ 3 _ isoxazolyl) 2 &gt; mono-methyl 1 sugar N Γ (2 methoxyethoxy) methyl] 1-4 &gt; -1 (1 1 2 Moxa group 1 r 1 1 -biphenyl)-2: 1 1 n-butyllithium (2 moles of pentane solution at-9 5 V m first read% 1 1 2 9 0 7 ml 5 8 1 4 mmol) to step C 1 1 I compound (2 2 1 6 g 5 2 8 5 mmol) 2 6 4 ml Caution 1 1 in tetrahydrofuran solution. Stir the mixture at -9 5 ° C for 10 minutes and fill in 1 again. Then write dimethyl borate (6 5 9 g, 6 3 • 4 2 mmol). W | Add to this page and stir at — 7 8 ° C for 1 5 minutes 〇 Then remove the cold bath, slowly warm the mixture to room temperature, and stir at room temperature for 0 5 hours y 1 1 I, then cool the mixture to 0 ° C and then 100 ml of 3 equivalent hydrogen 1 1 Add chloric acid dropwise, add 0, stir for 30 minutes, extract the mixture with dichloromethane (130, 100 ml, 100 ml), and then extract the combined organic extract, 1 1 and 30 ml of TTTt. Washed with water, dried and concentrated to give a gelatinous 2 1 I dihydroxyboryl — N — (4 5 —dimethyl — 3 — isoxazolyl) — N — C (2 — methoxyethyl (Oxy) methyl) benzamidine 〇1 1 1 106 ml 2 mol concentration aqueous sodium carbonate and diphenylphosphine (diphenylphosphine) 1 1 palladium (〇) (6 1 1 g 5 2 9 mmol) Add to 2-dihydroxy 1 1 boryl-N-(4 9 5-dimethyl-3-isoxazolyl)-N-C 1 1 (2-methoxyethoxy ) Methyl) benzamidine and Example 2 1 Step D 1 | Title compound (1 3 3 2 g &gt; 5 8 1 4 mmol) 1 I 2 6 4 ml toluene and 1 3 2 ml 9 5 % Ethanol solution &gt; The reaction 1 1 I mixture was further heated at 85 ° C for 4 hours under cooling and diluted with 2 0 0 1 1 1 ml of ethyl acetate and then the organic layer was separated &gt; 0 0 milliliters of water 1 1 Make paper hate people Tongzhou T country national grave standard (CNS) A4 specifications (210 X 297 mm) -356-517057 A7 B7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 354) Washed with 1 I and 50 ml of brine, dried and concentrated. Then the residue was separated on a silica 1 1 I gel using 1: 1 hexane / ethyl acetate to separate the chromatographic layers &gt; to obtain dnii color 1 1 The title compound in this step in a gelatinous form (1 6 9 5 g in two steps yields 1 I Please 1 | 6 2 7%) ° Read 1 I Read 1 Back I 1 I EN — (4, fj — dimethyl — 3 — isoDoxazolyl) — 2, — — &lt; (Note 1 hydroxymethyl)-N [(2 methoxyethoxy Base) methyl] | item 1 1 4 9 a (2--H corn beer)],,]] Bipinji) -2 expand the boat t write f 1 hydrazine on this page ^ — ✓ 1 at room temperature, Add sodium borohydride (0.035 g &gt; 0.93 mmol 1 1 mole) to 10 ml of step D of the title compound (0.37 g &gt; 0.76 mmol 1 1 mole) The mixture was stirred for a further 2 hours in the methanol solution. The clear solution was then concentrated to 5 ml &gt; and diluted 1 100 with 100 ml of water. The aqueous solution was then extracted with 3 × 100 ml of ethyl acetate. The organic extract of the compound 1 1 I was washed once with water, dried and evaporated to obtain 1 λ 0 3 g (95%) ifirr m colored gel-like title compound of this step. 0 W 1 1 F 2 9 mono (bromomethyl) 1--N-(4,1 5--dimethyl- -3 -iso-iso 1 1 evil) -N (2 methoxyethoxy) methyl]-4 &gt; 1 1 (2-oxazolyl) 1 1 -biphenyl:)-_ £ 1 monoamidine 1 1 amine 1 1 at 5 ° C, triphenylphosphine (0 2 8 3 g 1 0 8 milli Mo 1 1 ear) and carbon tetrabromide (0 3 5 8 g 1 0 8 mmol) to 1 1 Step E of the title compound (0 37 g 0 7 2 mmol) 5 1 1 Guozhongzhong used a suitable paper sheet centimeter 7 9 2 517057 A7 B7 V. Description of the invention (355) ml of dimethylformamide solution, and the mixture was stirred for 5 hours. Then the solution was diluted with 100 ml of water 'and the aqueous solution was extracted with 3 X 100 ml of ethyl acetate. The combined organic extracts were then washed once with water and dried and evaporated. The resulting residue was separated on 20 g of silica gel using 2: 1 hexane / ethyl acetate for color separation, to obtain 0.285 g (69%) of the title compound of this step. G. 2 '一 ί ,,, dihydro- 3-(trifluoromethyl)-1 Η -pyrazole- 1 -some] methyl] -N — (4,5 —dimethyl-3 — Isethionyl) -N-[(2-methoxyethoxy) methyl] -4 '-(2-oxazolyl) [1, fluorene'-biphenyl] -2-fluorenamine ( (Please read the notes on the back before filling this page) f = \ η κι

Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs, adding sodium hydride (60% mineral oil suspension, 0.0125 g, 0 ·, 3 12 mmol) to 3-trifluoromethylpyrazole G, 0.312 mmol) in 1 ml of dimethylformamide solution, and the mixture was stirred at room temperature under argon for 10 minutes. The title compound of Step F (0.12 g, 0.208 mmol) was then added and the mixture was stirred for another 16 hours. Then add the mixture to the paper size to apply Chinese National Standard (CNS) A4 specifications (210X297 mm) -358-517057 Printed by A7 B7, Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (356) to 20 ml of water and The solution was extracted with 3 × 2 5 ml of ethyl acetate. The combined organic extract was washed with water, dried and evaporated to obtain 0.13 g (100%) of the title compound in this step as a colorless gel. Η Ν — (4,5 —dimethyl — 3 —Isorexyl) ~~ 4 '— (2 —Very violent) —2′—ί Γ 3-(trifluoromethyl) —1 Η —pyrazole—1—an]] A and 1 1 Γ 1 Add 1 ml of 6 'equivalent aqueous hydrochloric acid to 10 ml of 95% aqueous ethanol solution of the title compound of Step G (0.13 g, 0 31 mmol). The mixture was refluxed for an additional hour, after which the mixture was diluted with 25 ml of water and extracted with 3 × 2 5 ml of ethyl acetate. The combined organic extracts were then washed once with water, dried and evaporated. The residue was borrowed on a 30X500 mm ODS S10 column for reverse-phase preparative high-performance liquid chromatography and used 78% solvent B (90% methanol, 10% water, 0.1% trifluoroacetic acid) and 22 % Solvent A (10% methanol, 90% water, 0.1% trifluoroacetic acid) was eluted and purified. The appropriate fractions were collected, neutralized to pH 7 with aqueous sodium bicarbonate, and concentrated to 5 ml. Then, the solution was acidified to p 水性 2 with aqueous sodium hydrogen sulfate, and then the white solid was filtered and dried to obtain 0.063 g (89%) of the title compound in this step as a white solid, m.p. 89-99 ° C (Amorphous). This paper size applies to the Chinese National Standard (see 0) 8 4 specifications (210 father 297 mm) _ ----------- (Please read the precautions on the back before filling this page) Order

Claims (1)

517057 A8 B8 C8 D8 Patent Application Scope Annex 1 U): Patent Application No. 86101898 ~ ......- 一 --1 1 Chinese Patent Application Range Amendment Bu Xiuyu 1 : ¾¾ fL A compound of the Republic of China 9 Amended in February 1 5 R1 or its diastereomer or pharmacologically acceptable, accept the salt, one of X and Υ is Ν, the other is 0; (Please read the precautions on the back before filling this page) Economy Ministry of Intellectual Property Bureau's Consumer Cooperatives printed R 1 and R 2 as Η, C 1-4, 垸… C—N Η 2; R 3 and R 4 are C 1-4 alkyl; R 11, • R 13 And R η 1 is Η; R 12 is Η, C 1-4. Alkyl (substituted by 1 Z i if necessary), hydroxyl, -C-10R cy 0 C 2-βalkenyl (substituted by 1 if necessary) Phenyl substituted) R1 oxazolyl; this paper size is in accordance with China National Standard (CNS) A4 specification (210 × 297 mm) 517057 A8 B8 C8 D8, patent application scope g? 9? 0 ^ 7 θ -M-C -Rb »-CN-Re, -S-Rc, -NCN-Rt *, -NH-S-Ro, '11 RjL u 〇U ^ 0 alkyl, hydroxyl, benzene Cb6 alkyl, C P6 alkoxy, Phenoxy (may be substituted by one phenyl group), oxazolyl (may be substituted with 1 phenyl group if necessary), triazolyl (may be substituted with 1 phenyl group if necessary), imidazolyl (if necessary with 1 ci — 6 alkyl, phenyl substituted), pyrazolyl ( If necessary, a phenyl group, a halo-c alkyl group, a pyrazinyl group substituted with a C 1-4 alkyl group, a pyridyl group substituted with a C 1-4 alkyl group, a piperazinyl group (if necessary, } C 6 alkyl, halo c'-6 alkyl, C 4 alkylcarbonyl, phenyl substituted), oxyimidazolidinyl (optionally substituted with 1 C 6 alkyl, phenyl), Tetrazolyl (optionally substituted with 1 phenyl, C6 alkyl), morpholinyl, pyrrolidyl (optionally substituted with 1 to 2 halogens), oxypyrrolidyl (optionally substituted with 1 — 2 alkyl substituted), 2, 3 —dichloro-1 Η · one dioxin — 2Η-iso-earthylpyridyl, 1,2,3,4 -tetrahydrodarkinyl, isoxazolyl Amine group (optionally substituted by 1 to 2 alkyl groups), oxypiperidinyl group (optionally substituted by 1 to 2 (: 1-4 alkyl groups), oxyisoxazolyl group (optionally required) 1 to 2 &lt;: 1-4 alkyl substitution), 2, --------- install ------ order ------ (Please read the precautions on the back before filling this page) Economy Printed by the Consumer Cooperatives of the Ministry of Intellectual Property Bureau of the People's Republic of China. 3-Dihydrol-2-Oxyl-1 Η-Indylazolyl, 1,2, 3, 4-Tetrahydrol-1-1-1 Imidyl ~ 2-isoquinolinyl, 1,3-dihydrol-1, 1-oxyl-2H-isophoryl, benzotriazolyl, 1 '2,3-triazolo [4,5 — B} π ratio, 3,4 -dihydro- 2 -pyrido [3,261 ,,, J 1, 4 -oxazolyl, imidazo [4,5-b] pyridyl, 2, q ~ — 赵 宜 ϋ ~ —Hydrogen I 碁 a 2 —Hydroxyl 邛 跺 a 邛 跺 yl (substituted by 1-2 halogens if necessary}, 2 This paper is also applicable to China National Standard (CNS) Α4 specification (210X297 (Mm) 517057 A8 B8 C8 D8 6. Scope of patent application, 3-dihydro-2-oxo-benzoxazolyl group; Ra is fluorene, Ci-6 alkyl, halogen Ci-6 alkyl, C3 -7 cycloalkyl; (Please read the notes on the back before filling this page) Rb is Η, Ci-6 alkyl, halo Ci-6 alkyl, C3_7 cycloalkyl , Indino, 15-dihydro, phenoxy, and benzene C 6 alkyl (benzene ring may be substituted with 1-2 halogen and phenyl if necessary); Rc is Ci-6 group; R d is Η , C 1-6 alkyl; R e is fluorene, C 6 alkyl; R f is phenyl, C i -6 alkyl; 11 «is 11, (: 1-6 alkyl, benzyl; Rh Is alkyl, halo-C6 alkyl, pyrimidinyl, phenyl (wherein the benzene ring may be substituted with 1 Ci-4 alkoxy group as required); j is 0, S, N, NR15; R15 is Η, Ci-6 alkyl, hydroxyethoxymethyl, methoxyethoxymethyl; P is 0,1,2; K and L are printed as N or C by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs, but K Or at least one of L is C. 2.  The compound according to item 1 of the scope of patent application, wherein R1 and R2 are each a C alkyl group or hydrogen. 3.  The compound according to item 1 of the patent application, wherein the ring containing L, J and K is 2-oxazole. 4. The compound according to item 1 of the application, wherein p is zero. 5. The compound according to item 6 of the scope of patent application, among which R11, this paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) One 3-517057 A8 B8 C8 D8 Six, the scope of patent application R12, R13 and R14 is hydrogen. (Please read the notes on the back before filling out this page) 6. The compound according to item 1 of the scope of patent application, wherein R3 and R4 are each methyl. 7. The compound according to item 1 of the scope of patent application, wherein X is 0 and Y is N. 8 . The compound according to item 1 of the application, wherein X is N and Y is 0. 9 . The compound according to item 1 of the scope of patent application is selected from the group of the following compounds: ·· N— (3,4-dimethyl-1—5-isooxazolyl) —4 ′ — (2-oxazole Group) —2 ′ — [[(2,2,2-trifluoroethyl) amino] methyl] [1,1′-biphenyl] —2-sulfanilamide; N— (3,4 — Dimethyl- 5 -isoxazolyl)-4 '(2 -oxazolyl)-2'-[[(2,2,2-trifluoroethyl) amino] methyl] [1,1 ' 1-biphenyl]-2-sulfamethoxamine, monohydrochloride; printed by N- (3,4-dimethyl-1,5-isoxazolyl)-2 '1 [[Methyl ((2,2,2-trifluoroethyl) amino] methyl] methyl]-4 '-(2-oxazolyl) [1,1'-biphenyl] -2-sulfanilamide , Trifluoroacetate (1: 1); N-[[2 '-[[(3,4-Dimethyl-5-isoxazolyl) amino] sulfofluorene]-4-(2-oxazole (Yl) [1,1'-biphenyl] -2-yl] methyl] -3,3,3-trifluoro -N—Methylpropanamide; This paper size applies to China National Standard (CNS) A4 (210X297 mm) 4-517057 A8 B8 C8 D8 VI. Patent Application Scope N — [〔2 '一 [[( 3,4 dimethyl-1 5-isoxazolyl) amino group] sulfofluorene] -4 4- (2-oxazolyl) [1,1 'unit (please read the precautions on the back before filling this page) ) Phenyl]-2-yl] methyl] -4 4-fluoro-N-methylbenzylamine; N — [[2 '-[[(3,4 -dimethyl- 5 -isoxazolyl ) Amine]] sulfonyl]] 4- (2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -2-fluoro-N-methylphenylhydrazine; N — [[2 '-[[(3,4 -Dimethyl-5 -isoxazolyl) amino] sulfofluorene] -4 (2 -oxazolyl) [1,1'biphenyl] —2 —yl] methyl] -3-fluoro-'N-methylbenzimidamine; 4-chloro-N-[[2 '-[[(3,4-dimethyl-5—isoxamine Oxazolyl) amino] sulfonyl]] 4 4 (2 -oxa (), [1,1'-biphenyl] -2-yl] methyl] -N -methylbenzimidamine; N-(3,4-dimethyl-5 -isoxazolyl) -2 ' [[[Ethyl (2,2,2-trifluoroethyl) amino] methyl-1,4 '-(2-oxazolyl) [1,1'-biphenyl] -2-sulfanilamide; 2 —chloro-N — [[2 '— [[3,4-dimethyl-1,5-isoxazolyl) amino] sulfonyl] —4— (2-oxazolyl) [1, Ministry of Economic Affairs Printed by the Intellectual Property Bureau's Consumer Cooperatives 1′-Biphenyl] -2-yl] methyl] -N-methylbenzidine; 2,4-dichloro-N— [[2 '-[[( 3,4-dimethyl-1, 5-isoxazolyl) amino] sulfonyl]] 4-(2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl]- N —methylbenzidine; N — [[2 '1 [[(3,4 dimethyl-5 isoxazolyl) amino] sulfonyl]] 4 4 (2-oxazolyl) [ 1,1 'Paper size for China National Standards (CNS) A4 (210X297 mm) -5-517057 A8 B8 C8 D8 6. Scope of patent application Phenyl]-2 -yl] methyl] -3,4 -difluoro-N -methylphenylmamine; (Please read the precautions on the back before filling this page) N — (3,4 dimethyl-5—isoxazolyl) —4 ′ — (2 —Oxazolyl) —2 ′-[[(benzyl) (2,2,2-trifluoroethyl) amino] methyl] [1,1′-biphenyl] —2-sulfanilamide ; N— (3,4—dimethyl—5—isooxazolyl) —2 ′ — [(3,3—dimethyl—2—hexyl—1—B than acryl) methyl] -4 '-(2-oxazolyl-bi, phenyl) -2-sulfamethoxamine; N- (3,4-dimethyl-5-isoxazolyl)-2'-[[(4- Methoxyphenyl) methylamino] methyl] -4 '-(2-oxazolyl) [1,1'-biphenyl]-2-sulfonamide, monohydrochloride t N — [ (3,3-difluoro-1,1-pyrrolidinyl) methyl] -N- (3,4-dimethyl-1,5-isoxazolyl) -4. 'One (2 — oxazolyl) [1,1' one biphenyl] — 2-sulfamethoxamine, monohydrochloric acid, printed by the Consumers ’Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs; N — [[2 'one [ [(3,4, dimethyl-1,5-isoxazolyl) amino] sulfofluorene] -4 (2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl ]] N-methyl-2 2-pyrazinemidine; N— [[21— [[(3,4 dimethyl-5—isoxazolyl) amino] sulfonyl]] 4 4 (2 -Oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -N, 3-dimethyl-2 -thiophene This paper applies Chinese National Standard (CNS) A4 specifications ( 2l0X297mm) 517057 A8 B8 C8 D8 VI. Patent application scope fluoramide; (Please read the precautions on the back before filling out this page) 3 — Cyano-N — [[2 'One [[(3' 4 —Dimethyl-5 —isoxazolyl) amino] sulfofluorene] -4 4- (2-oxazolyl) [1,1′-biphenyl] -2-yl] methyl] -N-formyl Benzamidine; N — [[2 ' [[(3,4 dimethyl-5 —isoxazolyl) amino] sulfofluorene] -4 (2-oxazolyl) [1,1'-biphenyl] -2 -yl] Group]-2 -methoxy-N -methylbenzimidamine> N-[[2 '1 [[(3,4 -dimethyl- 5 -isoxazolyl) amino] sulfonyl]] 4 mono (2-oxazolyl) [1,1 'monobiphenyl] 2- 2-yl] methyl] 2- 2-fluoro-N-methylphenethylamine 1 N — [[2'-[ [(3,4, dimethyl-1,5-isoxazolyl) amino] sulfofluorene] -4 (2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl 〕 -N-methyl-1,3-benzobenzoxan-5-methanamine; printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs (R) — N — [[2, 1 Dimethyl-5 oxazolyl) amino] sulfonyl]] 4 4- (2-oxazolyl) [1, 1'-biphenyl] -2-yl] methyl] -α-methoxy -N-methylphenethylamine; Ν-[[2 '— [[(3,4-dimethyl -5-isoxazolyl) amino] sulfofluorene] -4-(2-oxazolyl) [1,1 '-biphenyl] -2 -yl] methyl] -N -methyl -2- Thiopheneamine; Ν — [[2, 1 [[(3,4 dimethyl-5 — isoxazole) The standard paper is applicable to the China National Standard (CNS) A4 specification (210 × 297 mm) -Ί -517057 A8 B8 C8 D8 VI. Patent application scope group) Amine group] sulfofluorene]-4 1 (2-oxazolyl) [1 '1' biphenyl]-2 -yl] methyl] 3, 4,5 —trifluoro-N-methyl (please read the precautions on the back before filling this page) phenylbenzidine; N — [〔2 '〔〔(3,4 dimethyl dimethyl 5 —iso Oxazolyl) amino] sulfonyl]] 4- (2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -2,4,6-trifluoro-N —Methylbenzidine; N — [[2, 1 [[(3,4 dimethyl-5 isoxazolyl) amino] sulfonyl]] 4 4- (2-oxazolyl ') [ 1,1'-biphenyl] -2-yl] methyl] 4 a Methoxy-N-methamphetamine Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs-8-517057 A8 B8 C8 D8 VI. Patent application scope) Amine] Sulfo]] 4 4 (2 -Evil Oxazolyl) [1,1'-bi (please read the notes on the back before filling in this page) phenyl]-2-yl] methyl] tetrahydro-N -methyl-2 -furanamide; N — [[2 '1 [[(3,4 dimethyl-5 —isoxazolyl) amino] sulfonyl]] 4- (2-oxazolyl) [1,1' biphenyl ] 2-methyl] methyl] —N —methyl — 4-pyridinecarboxamide; N — [[2 '-[[(3,4 dimethyl-5 —isoxazolyl) amino] Sulfonium]-4-(2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -N -methylmono, 3-pyridinecarboxamide; N — [[2 'One [[(3,4-Dimethyl-5 -isoxazolyl) amino] sulfofluorene] -4 (2-oxazolyl) [1,1' -biphenyl] -2-yl ] Methyl] -N-methyl-2 2-pyridine Hydrazine; N — [[2 '1 [[(3,4 dimethyl-5 isoxazolyl) amino] sulfonyl]] 4 4 (2-oxazolyl) [1,1' 1 Biphenyl] -2-yl] methyl] -N-methyl-1,2,3-thiadiazole-4methylformamide; N — [[2, 1 [[(3,4,1,2dimethyl) Base 5 — Isoxazole Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs, Employees' Cooperatives) Amine] Sulfo]] 4 4- (2-oxazolyl) [1,1'-biphenyl]-2-yl] Methyl] -N, 1,5-trimethyl-1H-pyrazole-3methylformamide; N-[[2, 1 [[(3,4 dimethyl-5 -isoxazolyl) Amine] sulfofluorene] -4 (2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -N, 3,5-trimethyl-4 4-isoxazole Formamidine; This paper size applies to China National Standards (CNS) A4 (210X297 mm)-9-517057 A8 BS C8 D8 VI. Patent Application Scope N — [[2 '1 [[(3, 4 12 Methyl-5 —isoxazole (Please read the note on the back first Please fill in this page again for this item) Group) Amine group] Sulfonyl]] 4- (2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -N-methylbicyclo [ 4.  2.  0] octane-1,3,5-triene-7-formamidine; N — [[2,1 [[(3,4 dimethyl-5 —isoxazolyl) amino] sulfonyl]] -4- (2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -3-methoxy-N-methylbenzylamine f N — [[2'- [[(3,4-Dimethyl-5-isoxazolyl) amino] sulfonyl]] 4- (2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl Group] -2,5-difluoro-N-methylbenzylamine; N-[[2, 1 [[(3,4-Dimethyl-5-isoxazolyl) amino] sulfonyl] One 4 one (2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -3,5-difluoro-N-methylphenylhydrazine; N — [[2 , [[(3,4 dimethyl-5 — isoxazole, Intellectual Property Bureau of the Ministry of Economic Affairs, Employees, Cooperative Co., Ltd., printing base) amine] sulfo]] 4 (2 -oxazolyl) [1, 1′-biphenyl] -2-yl] methyl] -N-methyl-1 1-phenylcyclopropaneformamide ; 3- (dimethylamino) -N-[[2 '-[[((3'4-dimethyl-2-5-isoxazolyl) amino] sulfofluorene]] 4- (2-oxazolyl ) [1,1'-biphenyl]-2-methyl] methyl] -N-methylphenylhydrazine; ^ Paper size applies to China National Standard (CNS) A4 (210X297 mm) -10-517057 Printed by the staff of the Intellectual Property Bureau of the Ministry of Economic Affairs, the Yellow Cooperative, A8 B8 C8 D8 'Application for patents N ~ [[2, 1 [[(3, 4 -dimethyl-5 -isoxazolyl) amino] sulfonyl] One 4 one (2-oxazolyl) [1,1, biphenyl] ~ 2-yl] methyl] -N, 2,2-trimethyl-1 3- (2 ~ methyl-1 1-propene Methyl) cyclopropanecarboxamide; N — [[2, 1 [[(3,4 dimethyl-5 —isoxazolyl) amino] sulfonyl]] 4 4 (2-_azolyl) [ 1,1,1-benzyl] -2-yl] methyl] -N-methyl-2-D-pyridineacetamide, trifluoroacetate (1: 1); N — [[2,1 [ 〔(3,4, dimethyl-1,5—iso_hydrocarbyl) amine ] 礞 醯] -4- (2-oxazolyl) [1,1, -biphenyl] -2-yl] methyl] -N-methyl-1 4-pyridineacetamide, trifluoroacetate ( 1: 1); N— [[2, 1 [[(3,4 dimethyl-5 —isoxazolyl) amino] sulfonyl]] 4 4 (2-oxazolyl) [1,1 'One biphenyl] -2-yl] methyl] -N-methyl-1 3-pyridineacetamide, trifluoroacetate (1: 1); N — [[2, 1 [[(3, 4 Monodimethyl-1 5-isoxazolyl) amino] sulfonyl] -4— (2-oxazolyl) [1,1′-biphenyl] -2-yl] methyl] -N, 1 Monomethyl-1H-indoxdol-2-methylamidine; N-[[2, 1 [[(3,4-dimethyl-5-isoxazolyl) amino] sulfonyl]]-4 Mono (2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -2,3,6-trifluoro-N-methylbenzidine; this paper is for China National Standards (CNS) A4 Specification (210X297mm) Awl Order (Please read the precautions on the back before filling in this ) -11-517057 A8 B8 C8 D8 6. Scope of patent application N — [[2 '1 [[(3,4 dimethyl-5 — isoxazole) (Please read the precautions on the back before filling in this page) (Amino) amino] sulfonyl]] 4- (2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -1,2,3,4, tetrahydro-N Monomethyl-2-some formamidine; N-[[2 '-[[(3,4 dimethyl-5 -isoxazolyl) amino] sulfofluorene] -4 1 (2-oxazole [], [1,1 '-biphenyl] -2-yl] methyl] -N, 2,4,6-tetramethylphenethylamine; N-[[2'-[[(3,4 Mono-dimethyl-5-isoxazolyl) amino] sulfonyl]] 4- (2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -N-formyl Phenyl-1,3-benzodioxo-5-methylacetamide; N-[[2 '-[[(3,4 dimethyl-5 -isoxazolyl) amino] sulfonyl]]-4 Mono (2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -N —Methyl-4 4- (1-methylethoxy) benzidine; N — [〔2 ′ 〔[(3,4-dimethyl-2—5—isoxazole, Intellectual Property Bureau, Ministry of Economic Affairs, Employee Consumption Cooperative) Printed group) amine group] sulfonyl]] 4- (2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -2,3-dimethoxy-N — Toluidine; 1— (1,1,2-dimethyl) —N— [[2 ′ — [[(3,4—Dimethyl-5—isoxazolyl) amino] sulfonyl]] 4- (2,1-oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -N, 3-dimethyl-1H-pyrazole-5-formamidine; Applicable to Chinese national standards Γ〇Ν5) Α4 specifications (210X297 gong) ~ -12-517057 AS B8 C8 D8 6. Application scope of patents N — [〔2 ′ 〔〔(3, 4 dimethyl dimethyl 5 · -Isoxazole (please read the notes on the back before filling in this page) Base) Amine]] Sulfa]] 4 (2 -oxazolyl) [1 '1' Biphenyl]-2 -yl ] Methyl] -N -methyl-3- Trifluoromethyl) benzylamine; Ν — [[2 '-[[(3,4 -dimethyl-5 —isoxazolyl) amino] sulfonyl]] 4-(2 -oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -4-fluorofluoro-N-methyl-1-methylformamide; 3,5-dichloro-N-[[2 ' — T [(3,4-monomethyl-5-isoxazolyl) amino] sulfonyl]] 4- (2-oxazolyl) [1,1'-biphenyl] -2-yl] Methyl] -N-methylbenzidine; 3,4-dichloro-N-[[2 '— [[(3,4-dimethyl-5'-isoxazolyl) amino]] sulfonium ] 4-(2-oxazolyl) [1,1 'monobiphenyl]-2 -yl] methyl] -N -methylbenzidine; N-[[2'-[[(3, 4-Dimethyl-5 —Isoxazole Consumer Cooperation of the Intellectual Property Bureau of the Ministry of Economic Affairs Du Yinji] Amine] Sulfo]] 4- (2-oxazolyl) [1,1'-biphenyl] -2 -yl] methyl] -1-(4-methoxyphenyl) -N-methylcyclopropaneformamide N — [[2 '-[[(3,4 dimethyl-5 —isoxazolyl) amino] sulfonyl]] 4- (2-oxazolyl) [1,1' biphenyl 〕 —2 —yl] methyl] -2,3,5,6-tetrafluoro-N-methylbenzidine; This paper size applies to China National Standard (CNS) A4 (210X297 mm) -13 -517057 A8 B8 C8 D8 6. Scope of patent application N — [[2 '— [[(3,4-dimethyl-1—5-isoxazolyl) amino] sulfonyl]] — 4— (2-oxazole (1,1'-bi (please read the precautions on the back before filling out this page) Phenyl] -2 -yl] methyl] -N -methyl-4 (trifluoromethyl) phenylethylfluorene Amine; 2,6-dichloro-N— [[2 '-[[(3,4-dimethyl- 5 -isoxazolyl) amino] sulfonyl]] 4-(2 -oxazolyl ) [1,1'-biphenyl] -2-yl] methyl] -N-methylphenethylamine; N-[[2 '-[[(3,4-dimethyl-5-iso Oxazolyl) amino] sulfonyl] -4— (2-oxazolyl) [1,1 '—Biphenyl] —2-yl] methyl] —3—fluoro—N—methyl—5- (trifluoromethyl) benzidine; N — [[2, 1 [[(3, 4 Monodimethyl- 5 -isoxazolyl) amino] sulfofluorene] -4 4- (2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -4-fluoro N-methyl- 2-(trifluoromethyl) benzamidine; N — [[2'- Printed group) amine group] sulfonyl]] 4- (2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -N-methyl-α-phenylphenylethyl Amidamine t 2 — (2-chlorophenoxy) —N — [[2 '1 [[(3,4 dimethyl-5 —isoxazolyl) amino] sulfonyl]] 4 1 ( 2 monomethyl) [1,1 'monobiphenyl] -2-yl] methyl] -N, 2-dimethylpropanamide; this paper size applies to China National Standard (CNS) A4 specifications ( 210X297 mm) -14-517057 A8 B8 C8 D8 2 — chloro-N — [[2 '1 [[(3,4 dimethyl one (please read the notes on the back before filling out this page) 5-isoxazolyl) amino] sulfo]] a 4- (2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -3,4-dimethoxy-N-methylbenzidine; 2-(2, 4-dichlorophenoxy) N— [[2 '-[[(3,4-dimethyl-1,5-isoxazolyl) amino] sulfonyl]] 4- (2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl] —N —methylacetamide; 2 —chloro-N — [[2 '— [[(3' 4 —monomethyl— 5 -Isoxazolyl) amino] sulfonyl]] 4- 4 (2-oxazolyl) [1,1 '-biphenyl] -2-yl] methyl] -N -methyl-5-( Trifluoromethyl) benzidine; N — (3,4-dimethyl-1—5-oxazolyl) —2 ′-[hydroxy (5-phenyl-1—oxazolyl) methyl] —4 '— (2 —oxoyl) [1,1 ′ —biphenyl] — 2 —pyrimidine; N — (3, 4 —dimethyl — 5 — (Methenyl) —4 ′ — (2 —oxazolyl) —2 ′ — [(5-phenyl-2-oxazolyl) methyl Printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs] [1,1 ' —Biphenyl] -2-sulfanilamide; 2 '— [[(2,2-difluoroyl-2-phenethyl) amino] methyl] -N— (3,4-dimethyl-1 5 —Isoxazolyl)-4 '-(2-Chrysyl) [1,1' monobiphenyl]-2-Hydroxyamine, monohydrochloride; N-(3, 4-Dimethyl Base 5 —Isochrylyl) —2 ′ — (1H-imidazol—1-ylmethyl) —4 ′ — (2-oxazolyl) [1 ^ Paper scale is applicable to China National Standards (CNS) A4 Specification (210X297 mm) -15-517057 A8 B8 C8 D8 6. Application scope of patent, 1, monobiphenyl]-2-sulfamethoxamine, monohydrochloride; N- (3, 4-dimethyl One 5 —Isoxazolyl) One 4'One ((Please read the notes on the back before filling out this page) 2 —oxazolyl) One 2 'One [(4-Phenyl-1 Piperazinyl) A [], [1,1'-biphenyl]-2-sulfonamide; 2 '-[(2 , 3-Dichloro-1H — σ Lead! I- 1 -yl) methyl] -N-(3,4 -dimethyl-5 -isoxazolyl) -4 '-(2-oxazolyl) [1,1' -biphenyl] —2 —Sulfonamide, monohydrochloride; Ν-(3,4-dimethyl-5 -iso and oxazolyl)-4 '-(2 -oxazolyl)-2, ([2- Phenyl-1'-imidazole- 1-yl) methyl] [1,1'-biphenyl] -2-sulfamidamine'monohydrochloride; 2,-[(1,3-dihydro- 1, 3 -Hydroxy-2, 1-isopropyl- 2 -yl] methyl] -N-(3,4 -dimethyl-5 -isoxazolyl) -4 '-(2 -oxazole (1,1'-biphenyl) -2-sulfanilamide; Ν— (3,4-dimethyl-5—isoxazolyl) —4 '— (Poverty alleviation of employees of the Intellectual Property Bureau of the Ministry of Economic Affairs Cooperative prints 2-oxazolyl) -2,-[(1,2,3,4-tetrahydro-1-1-quinolinyl) methyl] [1,1'-biphenyl] -2-sulfo Amidine; Ν-(3,4 dimethyl-5-isoxazolyl)-2 '-[[(1-methylethyl) (2, 2, 2, 2 —Trifluoroethyl) amino] methyl] -4,1- (2-oxazolyl) [1,1 · -biphenyl] -2-sulfonamide; Ν— (3,4-dimethyl 5 —Isoxazolyl) 1 4 '1 (This paper size is applicable to China National Standards (CNS) A4 specifications (210X 297 mm) 517057 A8 B8 C8 D8 6. Application for patent scope 2-oxazolyl) 1 2 '-[[[1- (Digasmethyl) ethyl] amino] methyl]-[1,1'-biphenyl]-2 -sulfamethoxamine; (Please read the precautions on the back first (Fill in this page) N — (3, 4-dimethyl-1, 5-oxazolyl) — 4 '— (2-spiroyl) — 2' — [(3-phenyl-1H-B than fluorene — 1 1-yl) methyl] [1,1'-biphenyl] -2-sulfamethoxamine; N- (3,4-dimethyl-5-isoxazolyl) -4 '-(2-oxo Oxazolyl) -2 '-(1H-pyrazole-1 monomethyl) [1,1'-biphenyl] -2-sulfamidamide; 2,1-[(1,3-dihydrol-1 1-Hydroxy-2H-isopropyl-2-methyl) methyl] -N — (3,4- Methyl- 5 -isoxazolyl) -4 '-(2-oxazolyl) [1,1'-biphenyl] -2 -sulfamethoxamine; N- (3,4 -dimethyl-5 —Isoxazolyl) -2 ′-[[((3,4-Dimethyl-5—isoxazolyl) amino] methyl] -4,1- (2-oxazolyl) [1,1 ' —Biphenyl] —2—sulfamethoxamine N— (3,4—dimethyl—5—isoxazolyl) —4, 1 (printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 2—oxazolyl ) -2,1- (2H-1,2,3-triazol-2-ylmethyl) [1,1'-biphenyl] -2-sulfonamide; N- (3,4-dimethyl One 5 -isoxazolyl) one 4 'one (2 -oxazolyl) one 2,-[1H-1, 2, 3-triazole one 1 -ylmethyl) [1,1' one biphenyl ] 2-sulfamethoxamine; N-(3,4-dimethyl-5-isoxazolyl)-2 '-{(3, 3-dimethyl-2-oxo-1-piperidine (Methyl) methyl] a paper size applicable to China National Standard (CNS) A4 (210X297 mm) -17-517057 A8 δ C8 D8 VI. Application scope of patent 4 '-(2-oxazolyl) [1,1'-biphenyl]-2 -sulfamethoxamine (please read the precautions on the back before filling this page) N — [ [2 '-[[(3,4-Dimethyl-5-isoxazolyl) amino] sulfonyl]] 4 4- (2-oxazolyl) [1,1'-biphenyl] -2 —Yl] methyl] —N—methyl—2—phenoxyacetamidamine; and N— (3,4-dimethyl-5—isoxazolyl) —2 ′ — [(4,4 — Dimethyl-3-oxooxy-2 isoxazolyl) methyl] -4,1- (2-oxazolyl) [1,1'-biphenyl] -2-sulfanilamide; 1 0 . The compound according to item 1 of the scope of patent application is selected from the following group of compounds: N — (3,4 dimethyl-5 —isoxazolyl) — 2 '— [[2 — (1— (Methylethyl)-1H-imidazol- 1-yl] methyl] -4'-2 -oxazolyl) [1,1 '-biphenyl]-. 2 —Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs of Sulfamethoxamine N— (3,4—dimethyl—5—isospironyl) —4 ′ — (2 —oxazolyl) — 2 ′ — [( 5-phenyl-2H-tetrazol-2-yl) methyl] [1,1'-biphenyl] '-2-sulfonamide; N- (3,4-dimethyl-5-isoxyl Oxazolyl)-2 '-[(5-methyl-1H-tetrazol-1-yl) methyl] -4,1- (2-oxazolyl) [1,1'-biphenyl]-2- Sulfonamide; N— (3,4—dimethyl—5—isoxazolyl) —2 ′ — [This paper size applies to China National Standards (CNS) 8 4 grid (2H) X297 mm)- 18-517057 A8 B8 C8 D8 6. Scope of patent application (5-methyl-1 2H-tetramethyl-2-yl) methyl] 4 '1 (2 oxazolyl) [1, 1' biphenyl ] 2-sulfamethoxamine; (Please read the precautions on the back before filling out this page) N— (3,4 dimethyl-5—isochelyl) —4 'one (2-spirofluorenyl) -2 '— [(5-phenyl-2H-1, 2,4 -triazol-2-yl ) Methyl] [1,1'-biphenyl]-2-sulfamethoxamine; N- (3,4-dimethyl-5-isoxazolyl)-4 '-(2-oxazolyl) 1 2 '— [[3 — (trifluoromethyl) -1 1 Η-pyrazole-1 1-yl] methyl] [1, 1' -biphenyl]-2 -sulfonamide &gt; Ν— (3 , 4-dimethyl-2, 5-isoxazolyl) -2 '-[[3- (3-methyl-3, 2-pyrazinyl) -1, -pyrazol-1, 1-yl] methyl]-4' Mono (2-oxazolyl) [1,1'-biphenyl] -2-sulfamethoxamine; Ν- (3,4-dimethyl-5-isoxazolyl)-2 '-[Ministry of Economics Printed by the Intellectual Property Bureau's Consumer Cooperatives [3- — (2-methyl-5 —pyridyl) — 1 Η —pyrazol — 1 —yl] methyl] — 4 '— (2-oxazolyl) [1, 1'-biphenyl]-2-sulfamethoxamine; 2 '-(1'-benzotriazole- 1-ylmethyl) -N- (3,4-dimethyl-5 -isoxazolyl) -4 '-(2-oxazolyl) [1,1'-biphenyl] -2-sulfamidamide; Ν— (3,4-dimethyl-5 —Isoxazolyl) —4 ′ — (2-oxazolyl) —2, — [(1,2,3-triazolo [4,5—b] tl is more than α-amidyl) methyl] [1, 1 'one biphenyl] one 2-base basis This paper is applicable to Chinese National Standards (CNS) A4 specifications (210 × 297 mm): one 19 one 517057 A8 B8 C8 D8 And B; (Please read the notes on the back before filling out this page) 2, a [(3,4 -dihydro-211-pyrido [3,2 -b]-1, 4-chew-4- (Methyl) methyl] —N — (3,4 dimethyl-5 —isoxazolyl) — 4 ′ mono (2-oxazolyl) [1,1 ′ —biphenyl] — 2-sulfofluorene Amine; N— (3,4—dimethyl-5-isospirofluorenyl) —4 ′ — (2-oxazolyl) —2 ′ — [(imidazo [4,5-b] —pyridyl) Methyl] — [1,1′-biphenyl] -2-sulfanilamide, isomers A and B; '2'-[(3,3-difluoro-2,3-dihydro-1 2-Hydoxy-1H-, 0-dio-1-yl) methyl] -N- (3,4-dimethyl —5 —Isoxazolyl) —4 ′ — (2-oxazolyl) [1, 1′-biphenyl] -2 —-sulfonamide; N— (3,4—dimethyl—5— Isoxazolyl) -2 '-[(4-pyrimidinylamino) methyl] -4'-(2-oxazolyl) [1,1'-biphenyl] -2 -sulfonamide; N — (3,4 dimethyl-5—iso_fluorenyl) —2 '— [Printed by (4—morpholinylmethyl) —4' — (2—oxazole Group) [1,1'-biphenyl]-2-sulfamethoxamine; N-(3,4-dimethyl-1 5-isoxazolyl) -2, one [(4 -methyl-1 1- Piperazinyl) methyl] -4 '-(2-Metazolyl) [1,1'-biphenyl] -2-sulfamidazine; 1-ethylamidine-4 4 [[2' 1 [[( 3,4-Dimethyl-5-isoxazolyl) amino group] sulfofluorene] -1 4 one (2-oxazolyl) [1 The paper scale is applicable to China National Standards (CNS) A4 Washer (210X297) %): ~--20-517057 A8 B8 C8 D8 VI. Application scope of patents, 1'-biphenyl] -2-yl] A ] Piperazine; N— (3,4—dimethyl—5—isoxazolyl) —4 ′ — ((Please read the notes on the back before filling in this page) 2—oxazolyl) —2 '— [[4-— (2,2,2-trifluoroethyl)-1-piperazinyl] methyl] [1,1′-biphenyl]-2-sulfamidazine dihydrochloride; N — [[2, — [[(3,4-Dimethyl-5 —isoxazolyl) amino] sulfonyl]] 4-(2-oxazolyl) [1,1'biphenyl]- 2 -yl] methyl] -N -methyl -1H-mouth introduction flower 2 -formamidine; 'N — [[2, 1 [[(3,4-Dimethyl-5 —isoxazolyl) amino] sulfonyl]] 4- 4 (2-oxazolyl) [1' 1 'monobiphenyl Yl] -2 -yl] methyl] -2,3-dihydro-N-methyl- 1 fluorene-fluorene -2 -methylamine; Ν-(3,4-dimethyl-5 -isoxamine (Oxazolyl) -4 '-(2-oxazolyl) -2'-[(1,2,3,4-tetrahydrol-1 1-oxyl 2-isoquinolinyl) methyl] [1 , 1'-biphenyl]-2-sulfamethoxamine; printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, 2 '-(1Η-benzimidazole-1 monomethyl)-N-(3, 4-12 Methyl- 5 -isoxazolyl) -4 '-(2-oxazolyl) [1,1'-biphenyl]-2-sulfamidamide; 2, 1 [(2,3-dihydroyl) -2-Hydoxy-3-benzoxazolyl) methyl] -N- (3,4-dimethyl-5-isoxazolyl) -4,-(2-oxazolyl) [1 , 1'-biphenyl]-2 -sulfamethoxamine; this paper size applies to China National Standard (CNS) A4 (210X297) ) 、 -21-517057 A8 B8 C8 D8 VI. Application scope of patent 2 '-[(2,3 —dihydro- 2 -oxyl —1H — quotation (please read the precautions on the back before filling in this Page) fluorene- 1-yl) methyl] -N — (3 ′ 4 dimethyl-5 —isoxazolyl) — 4 ′-(2-oxazolyl) [1,1 ′ —biphenyl 〕 -2 monosulfonamide; N- (3,4-dimethyl-1,5-isospirofluorenyl) -2 '-[[4,4-dimethyl-1, 2-oxo-1, pyrrolidine A)]] 4 '-(2-oxazolyl) [1,1'-biphenyl]-2 -sulfamethoxamine IN-[[2, 1 [[(3, 4-dimethyl-5 — Isoxazolyl) amino] sulfonyl]] 4- (2-oxazolyl) [1,1′-biphenyl] -2-yl] methyl] -N, 1,3-trimethyl -1H-pyrazole-5-formamidine; N-[[2 '-[[(3,4-dimethyl- 5 -isoxazolyl) amino] sulfofluorene]-4-(2 -oxa Oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -N, 2-dimethylphenethylhydrazone Amine; N — [[2,1 [[(3,4-Dimethyl-5 —isoxazolyl) amino] sulfonyl]] 4— (2-oxazolyl) [1,1 'unit Printed by the Consumers ’Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, Phenyl]-2 -yl] methyl]-1 -ethyl -N, 3 -dimethyl-1 Η -pyrazole-5 -methanamine; Ν- [[2, 1 [[(3,4 dimethyl-5 -isoxazolyl) amino] sulfonyl]] 4-(2-oxazolyl) [1,1 'biphenyl]- 2-methyl] methyl] -1,1-ethyl-N, 1,3,5-tetramethyl-1, 1-pyrazol-4, methylamine; Ν- [[2, 1 [[(3, 4 Monodimethyl-5 — Isoxazole This paper is compliant with China National Standards (CNS) A4 specifications (210X297 mm)-22-517057 A8 B8 C8 D8 6. Scope of patent application (please read the precautions on the back first) (Fill in this page) Group) Amino group] Sulfafluorene]-4 1 (2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -2,6-difluoro-N —Methylbenzidine; N — [ 2 '-[[(3,4-Dimethyl-5-isoxazolyl) amino] sulfofluorene] -4 4- (2-oxazolyl) [1,1'-biphenyl] -1 2- []] Methyl] -2-methoxy-N-methylphenethylamine; N — [[2 '-[[(3,4-dimethyl-1,5-isoxazolyl) amino] sulfonyl]醯] a 4- (2-oxazolyl ') [1,1'-biphenyl] -2-yl] methyl] -3-methoxy-N-methylphenethylfluorene. Amine; N — [[2 '1 [[(3,4-Dimethyl-5 —isoxazolyl) amino] sulfonyl]] 4 4- (2-oxazolyl) [1,1' Phenyl]-2-yl] methyl] -4 4-methoxy-N-methylbenzamide; 4-chloro-N- [[2 '-[[(3,4-dimethyl-economic Ministry of Intellectual Property Bureau Employees' Cooperatives Printed 5-Isoxazolyl) Amine] Sulfo]] 4- 4 (2-oxazolyl) [1,1'-biphenyl]-2 -yl] methyl] Mono-N-methylphenethylamine 2-chloro-mono-N — [[2 'mono [[(3,4-dimethyl-5 -isoxazolyl) amino] sulfofluorene] -4 mono (2 -Oxazolyl) [1,1,1-biphenyl] -2-yl] methyl] -N-methylphenylethylamine f N — [[2, 1 [[(3,4 dimethyl 5—Isoxazole This paper size is applicable to China National Standards (CNS) A4 (210X297 mm) -23-517057 A8 B8 C8 D8 6. Application scope of patents) Amine] Sulfo]] 4 1 (2 —Oxazolyl] [1, 1 '(read first Note on the back page, please fill in this page again) Phenyl] -2-yl] methyl] -2,6-difluoro-N-methylphenylacetamide; N-[[2 '-[[(3, 4 dimethyl-1 5-isoxazolyl) amino] sulfofluorene] -4 4- (2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -3, 5-difluoromono-N-methylphenethylamine; N— [[2 '-[[(3,4-dimethyl-2-5-isoxazolyl) amino] sulfonyl]] 4 — ( 2 -oxazolyl ') [1,1'-biphenyl] -2-yl] methyl] -2,5-difluoro-N-methylphenethylhydrazine; N — [[2, 1 [[(3,4 dimethyl-5 isoxazolyl) amino] sulfonyl]] 4 4- (2-oxazolyl) [1,1'-biphenyl]-2-yl] methyl Group] -2,4-difluoro-N-methylphenethylhydrazine; N-[[2,1 [[(3,4-dimethyl-1-5-isoxazolyl) amino] sulfonyl] ] 1-4 (2 -oxazolyl) [1,1 'Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Phenyl]-2 -yl] methyl] -N -methyl-4 4-blindolinamidoxamine; N — [[2 '-[[(3,4-dimethyl-2—isoxazolyl) Amine] sulfofluorene] -4 mono (2-oxazolyl) [1,1 'monobiphenyl] -2-yl] methyl] -N-methyl-6-benzoxazomethoxamine ; 3— (1,1-dimethylethyl) -N — [[2 '— [[(3,4-dimethyl-2—5-oxazolyl) amino] sulfonyl]] 4 Paper size applies to China National Standards (CNS) A4 (210X297 mm 1 -24-517057 A8 B8 C8 D8) 6. Scope of patent application (2-oxazolyl) [1,1'-biphenyl] —2— Group] methyl] -N, 1-dimethyl-1 1 Η -pyrazole-5 -formamidine; (Please read the precautions on the back before filling this page) 4-chloro-N-[[2 ' [[(3'4-Dimethyl-5-isoxazolyl) amino] sulfonyl]] 4- (2-oxazolyl) [1,1'biphenyl] -2-yl] Methyl] -2-methoxy-N-methylbenzidine; 3- (1, 1-bis (Methylethyl) -N — [[2 ′-[[(3,4-dimethyl-1,5-isoxazolyl) amino] sulfonyl]] 4— (2-chrylyl) [1, 1′-biphenyl] di-2-yl] methyl] -N-methyl-1-phenyl-1,1-fluorene-1,2,3-triazole-5-methylformamide; 2,3-dihydroyl 1N— [[2 '— [[(3,4 Dimethyl-5-isoxazolyl) amino] sulfonyl]] 4— (2-oxazolyl) [1,1 ′ biphenyl [Group]-2 -yl] methyl] -N, 4 -dimethyl-2 -thio-3-3-pyrazolacetamide; Ν-[[2 '-[[(3,4-dimethyl 5 — isoxazolyl) amine] sulfonyl]] 4 1 (2-oxazolyl) [1, 1 'printed by the Consumers ’Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, a phenyl group] a 2 —yl] Group] -N, 3-dimethyl-1 5- (trifluoromethyl) -4 4-isoxazolecarboxamide; 3- (1,1 -dimethylethyl) -N-[[2 '- [[(3,4 dimethyl-5'-isoxazolyl) amino] sulfonyl]] 4 4- (2-fluorenyl) [1 1′-biphenyl] -2-yl] methyl] -1 1-ethyl-N-methyl-1 1-pyrazole-5 methylamine; Ν- [[2, a [[(3, 4 Dimethyl-5 — Isoxazole This paper is sized for China National Standards (CNS) A4 (210 × 297 mm)-25-517057 A8 B8 C8 D8 7. Amino group for patent application] Amine group] ] 4- (2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -N-methyl-5- (1-pyrrolidinyl) -2H-tetrazole-1 2 —Acetylamine; (Please read the precautions on the back before filling out this page) N — [[2 '1 [[(3,4 dimethyl-5 —isoxazolyl) amino] sulfonyl] One 4 one (2-oxazolyl) [1 '1'-biphenyl] one 2-yl] methyl] one 3- (trifluoromethyl) phenylacetamide; N — [[2, one [ [(3,4-Dimethyl-5-isoxazolyl) amino] sulfofluorene] -4-mono (2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl 〕 -N-methyl-1,2- (trifluoromethyl) Phenylacetamide; N — [〔2, a 〔. [(3,4-Dimethyl-5'-isoxazolyl) amino group] Basic group] 4- (2-oxazolyl) [1 '1'-biphenyl]-2-yl] methyl ] -N, 1-dimethyl-1H-benzimidazole-2-propanamidine; N- [[2,1 [[(3,4-dimethyl-1,5-isoxazole) Bureau of Intellectual Property, Ministry of Economic Affairs Employee Consumer Cooperative Printed Group) Amine] Sulfofluorene]-4 1 (2-oxazolyl) [1,1 'monobiphenyl]-2 -yl] methyl] -N, 2-dimethyl-1 4 mono (trifluoromethyl) -3-pyridinecarboxamide; N — [[2, 1 [[(3,4-Dimethyl-5 —isoxazolyl) amino] sulfonyl]] 4— (2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -N-methyl-5-(2-pyridyl) -2 -benzophenamidine; N- [[2, 1 [[(3,4-Dimethyl-5 -isoxazolyl) amino] sulfonyl]] 4- (2 -oxazolyl) [1,1 'One paper size applies China National Standards (CNS) A4 (210X297 mm) -26-517057 A8 B8 C8 D 8 6. Scope of patent application: Phenyl]-2 -yl] methyl] -N-methyl-4 -phenyl -1,2,3-thiadiazole-5 -methanamine; (Please read the Please fill in this page again for attention) N — [[2 '1 [[(3,4 -Dimethyl-5 —isoxazolyl) amino] sulfofluorene] -4 (2 -oxazolyl) [1 , 1'-biphenyl]-2-yl] methyl]-N-methyl-4-(1 '2, 3-thiadiazole-4-yl) benzamidine; N-[[2'- [[(3,4-Dimethyl-5-isoxazolyl) amino] sulfofluorene] -4 4- (2-oxazolyl) [1'1'biphenyl]-2-yl] A Group] -N-methyl-'2-hydoxy-'3 (2H) -benzospiro. Zolpropramine; N — [[2, 1 [[(3,4-Dimethyl-5 —Isoxazolyl) amino]]] [4 — (2-oxazolyl) [1,1 '-Biphenyl] -2-yl] methyl] -N, 5-dimethyl-2 -phenyl -4 -oxazoleacetamide; N-[[2, 1 [[(3, 4 — Dimethyl- 5 -isoxazolyl) amino] sulfofluorene] -4 4- (2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -N-methyl Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs of the Ministry of Economic Affairs, 1,4-Dithione [4,5] decane-8-methanamine; 4-chloro-N- [[2 '-[[(3, 4 dimethyl-1 5-isospirofluorenyl) amino] fluorene] _4 mono (2-chrysinyl) [1,1, monobiphenyl] 2- 2-yl] methyl] -N, 1 , 3-trimethyl-1 1 — [I than pyrene [3, 4-b] H than n-determined 5-methylformamide; N — [[2, 1 [[(3, 4-dimethyl One 5-isoxazolyl) amino group] sulfofluorene] One 4-one (2-oxazolyl) [1,1 ' Using China National Standards (CNS) A4 specifications (210X297 male shame 1 27-517057 A8 B8 C8 D8 Six, patent application scope phenyl]-2 -yl] methyl]-N-methyl-1-phenyl- 5-propyl-1H-pyrazole-4 acetamidine; (Please read the precautions on the back before filling out this page) N— [〔2 '一 〔[(3,4-dimethyl-5-iso Oxazolyl) amino] sulfonyl]] 4- (2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -N-methyl-1 3-[(4- Methoxyphenoxy) methyl] benzidine; N — [[2, 1 [[(3,4 dimethyl-5 —isoxazolyl) amino] sulfonyl]] 4 4 (2- Oxazolyl) [1, I-biphenyl] -2-yl] methyl] -N-methyl-1'5- [3- (trifluoromethyl) phenyl] -2H-tetrazole-2 —Acetylamine; N — [[2 '-[[(3,4-Dimethyl-5-isoxazolyl) amino] sulfofluorene] -4 4- (2-oxazolyl) [1,1 'Biphenyl] -2-yl] methyl] -N-methyl-5 1-methyl- 3-(trifluoromethyl)-1H-B is more than 5-a-methyl]-2 -phenanthidine; N-[[2 '-[[(3,4-dimethyl 5 —Isoxazolyl) amino] sulfofluorene] -4 — (2 —oxazolyl) [1,1 ′ —Phenyl printed by the Consumers ’Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs] —2— Methyl] -N, 4-dimethyl-5- [3- (trifluoromethyl) phenyl] -5-thiazoleacetamide; 1- (4-chlorophenyl) -N-[[2 ' One [[(3,4 dimethyl-5 isoxazolyl) amino] sulfofluorene] a 4- (2-oxazolyl) [1,1'biphenyl] a 2-yl] Methyl] -N -methyl-5-(trifluoromethyl) -1H -pyrazole -4-methylamidine; N-[[2 '-[((3,4 -dimethyl-5 -iso The oxazole paper paper scale is applicable to China National Standards (CNS) A4 (210X297 mm) -28-517057 A8 38 C8 D8 VI. Patent application scope) Amine] Sulfo]] 4 4 (2 -oxazolyl ) 〔1, 1 '(Please read the precautions on the back before (Write this page) Phenyl] -2-yl] methyl] -N, 6-dimethyl-2 -pyridinecarboxamide; N-[[2 '-[[(3,4-dimethyl-1 5 —Isoxazolyl) amino] sulfonyl]] 4- (2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -N-methyl-2 -thienylethyl Amidamine; N — [[2, 1 [[(3,4 dimethyl-5 —isoxazolyl) amino] sulfonyl]]-4 4 (2 -oxazolyl) [1 '1' 1 Biphenyl] -2-yl] methyl] -N-methyl-'2- (phenylmethoxy) phenethylhydrazine; 3- (2-chloro-6-fluorophenyl) -N- [[2 '— [[(3,4 dimethyl-5'-isoxazolyl) amino] sulfonyl]] 4-(2 -oxazolyl) [1,1'biphenyl]- 2 -yl] methyl] -N, 5-dimethyl-4 4-isoxazole formamidine; N — [[2, 1 [[(3,4-dimethyl-2—5-isoxazole) Ministry of Economic Affairs Printed by the Intellectual Property Bureau Employee Cooperatives Co., Ltd.) Amine] Sulfo]] 4 4 (2-oxazolyl) [1 '1' Biphenyl ] 2- 2-yl] methyl] -N, 1-dimethyl- 1H-pyrazole-4 monomethylamine; N — [[2, 1 [[(3,4 -dimethyl-5 —iso Oxazolyl) amino] sulfonyl]] 4- (2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -N, 5-dimethyl-1H-pyridine Azole_ 3 -methoxamine; N-[[2, 1 [[(3,4 dimethyl-5 -isoxazolyl) amino] sulfofluorene] -4 1 (2-oxazolyl) [ 1, 1 'One copy of this standard is applicable to China National Standards (CNS) A4 specifications (210X297 mm) -29-517057 A8 B8 C8 D8 6. Application scope of patents phenyl]-2 -yl] methyl]- N —methyl — 2 — P stilbenamidamine; N — [[2 '1 [[(3,4 dimethyl-5 —isoxazole) (Please read the precautions on the back before filling in this page) Aminyl) amine] sulfonyl]] 4- (2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -N-methyl-1 3-thienothalamide; 6 —Chloro-N — [[2 'one [[(3,4 dimethyl -5 -Isoxazolyl) amino] sulfofluorene] -4-(2-oxazolyl) [1,1'-biphenyl] -2 -yl] methyl] -N -methyl -3- D pyridamidine; N — [[2 '1 [[(3,4 dimethyl-5 —isoxazolyl) amino] sulfonyl]] 4- (2 -oxazolyl) [1 '1' —Biphenyl] —2-yl] methyl] —N-methyl—1H—N-methyl-5—formamidine; 2—Chloro—N— [[2 '— [. [(3,4-Dimethyl-5-isoxazolyl) amino] sulfofluorene] -4 (2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl 〕 -N, 6-dimethyl-1,4-pyridamidine; N— [〔2 ′ 一 ［〔(3,4-dimethyl-2-5—Isoxazole Printed by Employees ’Cooperative of Intellectual Property Bureau, Ministry of Economic Affairs (Amino) amino] sulfonyl] -4 (2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -N-methyl-4-pyridinocarboxamidine; N — [[2 '1 [[(3,4-dimethyl-5 —iso-fluorenyl) amino] sulfonyl]]-4 (2 -oxazolyl) [1,1' biphenyl 〕 -2—Methyl] methyl] -N-methyl-1 1 Η 跺 一 -1 monoethylamine; Ν — [〔2 ′ 〔〔(3,4-dimethyl-1 5 — isoxic The paper size is based on the Chinese National Standard (CNS) A4 specification (210 × 297 public ίΠ -30-517057 B8 C8 D8) 6. Scope of patent application (please read the precautions on the back before filling this page) Base) Amine] Sulfur醯] a 4 — (2-oxazolyl) [1, 1 Monobiphenyl] -2-yl] methyl] -N-methyl-1H- hydrazone-3 acetamidine; 2,3-dihydro-mono-N- [[2 '— [[(3 , 4-Dimethyl-5'-isoxazolyl) amino] sulfonyl]] 4- 4- (2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -N —Methyl-1H—fluorene-2—ethanamide; N— [[2 ′ — [[(3,4-dimethyl-1—5—oxazolyl) amino] sulfonyl]]-4— (2 -Oxazolyl) [1,1'-biphenyl]-2-yl] methyl]-5-fluoro-N -methyl -1H-indyl 2 -carboxamide; N-[[ 2 '-[[(3,4-Dimethyl-5-isoxazolyl) amino] sulfofluorene] -4 4- (2-oxazolyl) [1,1'-biphenyl] -2- Group] methyl] -3,5-dimethoxy-N-methylbenzidine; printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, 5-chloro-N— [[2, 1 [[(3, 4-dimethyl-1,5-isoxazolyl) amino] sulfonyl]] 4 4- (2-oxazolyl) [1,1'- Phenyl] 2-yl] methyl] 2-methoxy-N-methylbenzidine; 2,6-dichloro-N-[[2 'one [[(3,4 one dimethyl -5-isoxazolyl) amino] sulfofluorene]-4-(2-oxazolyl) [1,1 'biphenyl]-2 -yl] methyl]-N-methyl-3 —Pyridamidine; 3 — (acetamido) —N — [〔2 '〔[(3,4 — This paper size applies to China National Standard (CNS) A4 (210X297 mm) -31-517057 A8 B8 C8 D8 VI. Scope of patent application dimethyl-5 -isoxazolyl) amino] sulfonyl]] 4 4 (2 -oxazolyl) [1,1 '-biphenyl] -2 -yl 〕 Methyl] —N, 4 — (please read the precautions on the back before filling this page) dimethylbenzidine; N — [[2 'one [[(3,4 one dimethyl one 5 —iso Oxazolyl) amino] sulfonyl]] 4-mono (2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -N, 5-dimethyl-1 1-benzene Yl-1 fluorene-pyrazole-4 methylformamide; Ν- [〔2 One [[(3,4 dimethyl-5 -isoxazolyl) amino] sulfonyl] -4- (2-oxazolyl) [1,1'biphenyl] -2-yl] Methyl]-4'-methoxy-N-methyl-2-quinolinolamidine; Ν-[[2 '-[[(3,4-dimethyl-2-5-isoxazolyl) amine []] Sulfofluorene] -4 (2-oxazolyl) [1,1 '-biphenyl] -2 -yl] methyl] -N, 5-dimethyl-2 -phenyl-2-1-1 ， 2,3-triazol-4 monomethylamine; Ν-[[2 '-[[(3,4-dimethyl-2-5-isoxazolyl) amino] sulfonyl]] 4-(2 —Oxazolyl] [1,1 '—Phenyl printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs] -2 -yl] methyl] -N -methyl -2 -phenoxy -3 -pyridine Amines; Ν — [[2 '-[[(3,4 dimethyl-5-isoxazolyl) amino] sulfonyl]] 4-(2 -oxazolyl) [1,1'- Phenyl] -2-yl] methyl] -N ', N'-diethyl-N-methyl 1,2—xylylenediamine; Ν — [〔2 * — [[(3,4 dimethyl-5—isoxazole) This paper is in accordance with China National Standard (CNS) A4 (210X297) (%) -32-517057 A8 B8 C8 D8 6. Scope of patent application (please read the notes on the back before filling in this page) Base) Amine group] Sulfonium] 1 4 1 (2-oxazolyl) [1'1 '1 biphenyl]-2 -yl] methyl]-N-methyl-9H-hydrazine 9-propanamide;' 2 '-[[(1 1 (1, 1-dimethylethyl) -3-methyl-1H-pyrazol-5-yl] amino] methyl] -N- (3,4-dimethyl-5-isooxazolyl)-4 '-(2-oxazolyl ) [1,1'-biphenyl]-2-sulfamethoxamine; N — (3,4 —dimethyl — 5 —oxazolyl) — 4 '— (2-oxazolyl) — 2' Mono-[(1H-pyrazoldi-3-ylamino) 'methyl]-[1,1'-biphenyl] -2-sulfamidamide; N--3,4-dimethyl-6-iso Evilyl) -4, 1 (2-oxazolyl)-2 '-[(1H-1, 2 , 4-triazol-3-ylamino) methyl]-[1,1'-biphenyl] -2-sulfonamido f N — (3,4-dimethyl-2—isoxazolyl ) 2 ′-[[((5-methyl-1,3-oxazolyl) amino] methyl] a. 4 '1 (2 -oxazolyl) [1,1' -biphenyl]-2 -sulfamethoxamine; printed by the Yellow Cooperative of Employees of the Intellectual Property Bureau of the Ministry of Economic Affairs —Pyrazol-3-yl) amino] methyl] -N — (3,4 dimethyl-5—isoxazolyl) —4, 1 (2-oxazolyl) [1,1′— Biphenyl]-2-sulfamethoxamine f N — (3,4 -dimethyl-5 -isoamyl) -2 '-[(3,5 -dimethyl-2 -pyrazinyl] amine [Methyl] methyl] -4 '-(2-oxazolyl) [1,1'-biphenyl] -2-sulfanilamide; This paper size applies to China National Standard (CNS) A4 (210X297 mm) ) -33-517057 A8 B8 C8 D8 VI. Patent application scope N — (3,4 dimethyl-5 —isoxazolyl) 1 2 'one [(Please read the precautions on the back before filling this page) (3,5-Dimethyl-2-pyrimidinyl) amino] methyl] -4 '-(2-oxazolyl) [1,1'-biphenyl] -2-sulfamethoxamine; N- (3,4 dimethyl-5'-oxazolyl) -2 '-[(5 —Ethyl-1,3,4—thiadifluoren-2-yl) amino] methyl] -4 ′-(2-spirowayl) [1,1′-biphenyl] —21-sulfofluorene Amines; 2 '-[(2-benzothiazolylamino) methyl] -N- (3,4-dimethyl-5-isoxazolyl) -4. '^ (2-oxazolyl) [1,1'-biphenyl]-2-fluorenamine; 2'-[[(4-Molyl- 1H-hydrazone-3 -yl) amino] Methyl] -N- (3,4-dimethyl-5-isooxazolyl) -4 '-(2-oxazolyl) [1, P-biphenyl]-2-sulfamethoxamine t N — (3,4-dimethyl-5—isoxazolyl) —4, — (2-oxazolyl) —2 ′ — [[[[5-(2-thienyl) —1H—pyrazole—3 —Yl] amino] methyl] [1,1'-biphenyl] — printed by the Consumers ’Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 2-Sulmonylamine; N — (3,4 —dimethyl-5 —iso Oxazolyl) -2 '-[[((6-methoxy-2-benzothiazolyl) amino] methyl] -4'-(2-oxazolyl) [1,1'-biphenyl ]-2 -sulfamethoxamine I 2 '-[[[4-((4-chlorophenyl) -6-ethoxy-2 -pyrimidinyl] amino] methyl] -N-(3,4 -2 Methyl-5 — This paper is suitable for China National Standards (CNS) A4 standard (210X297 male thin 1 —34-517057 A8 Βδ C8 D8 6. Scope of patent application: Isoxazolyl)-4 '-(2-oxazolyl) [1, 1'-biphenyl]-2-sulfamethoxamine; and (Please read the notes on the back before filling in this Page) N— (4,5—Dimethyl—3—Isoamidine) —4 ′ — (2-oxazolyl) —2 ′ — [[3 — (Trifluoromethyl) —1—pyridine Azole- 1-yl] methyl] [1,1'-biphenyl] -2-sulfamethoxamine 01. The compound according to item 1 of the scope of patent application is selected from the following group of compounds: Ν-[[2 '— [[(3,4 -Dishenyl-5 -isoxazolyl) amino] sulfonic acid]醯]-4 (2-oxazolyl) [1,1'-biphenyl]-2 -yl] methyl] -N-(1 -methylethyl)-2, 2-dimethylpropane Hydrazine; Ν — [[2 '1 [[(3,4 dimethyl-5 —isoxazolyl) amino] sulfonyl]] 4 4 (2 -oxazolyl) [1,1' 1 Biphenyl]-2 -yl] methyl] -N — (1 -methylethyl) propanamine j Printed by 2 '-(cyanomethyl) -N — ( 3,4 dimethyl-5 —isoxazolyl) -4 '— (2-oxazolyl) [1,1' monobiphenyl] -2-sulfonamide; Ν— (1,1- Dimethylethyl)-2 '-[[((3,4-dimethyl- 5-isoxazolyl) amino] sulfofluorene]] 4- (2-oxazolyl) [1,1' one Biphenyl] 2-acetamidine; 2 'one [[(3, 4 one two 5—Isoxazolyl) amino] sulfonyl]] N, N—dimethyl—4- (2-oxazolyl) [1, this paper is applicable to China National Standards (CNS) A4 (210 × 297 mm) -35-517057 A8 B8 C8 D8 6. Application scope of patent 1'-biphenyl]-2-acetamide; (Please read the precautions on the back before filling this page) N-Cyclopropyl One N. — [[2 '-[[(3,4-Dimethyl-5-isoxazolyl) amino] sulfonyl]]-4 4- (2-oxazolyl) [1,1'biphenyl] Mono-2-methyl] methyl] 2-methylpropanamide »N-(3,4 dimethyl-5-isoxazolyl) -2, [[(1-methylethyl) amine []] Methyl]-4 'mono (2-oxazolyl) [1,1' monobiphenyl]-2-sulfosulfanilamide; N-[[2 'one [[(3,4-disynyl —5 —Isoxazolyl) amino] sulfonyl]] 4 4- (2-oxazolyl) [1 '1' biphenyl] 2- 2-yl] methyl] -N-methylcyclopropanemethyl Amidoamine; N — (3,4 dimethyl-5—isoxazolyl) —2 ′ — [[(2-methylpropyl) sulfonyl] methyl] —4 ’— (2-oxazole [], [1,1'-biphenyl]-2-sulfonylamine; N — [[2 '-[[(3,4 -Dimethyl-5-isoxazolyl) amino] sulfonyl] -4- (2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -N, 2-dimethylpropanamide; Ministry of Economic Affairs Printed by the Intellectual Property Cooperative Employee Co-operative Cooperative N— (3,4 dimethyl-5—isospirofluorenyl) —2 ^ [[[methyl (2-methylpropyl) amino] methyl] —4 'Mono (2-oxazolyl) [1,1' monobiphenyl] -2-sulfanilamide; N- [[2 'one [[(3,4-dimethyl-1,5-isoxazolyl ) Amine]] sulfonyl]] 4- (2-oxazolyl) [1'1'-biphenyl] -2-yl] methyl] -N-methylphenethylamine; N— (3, 4 Dimethyl-5 -isoxazolyl) 2 '-[This paper size applies to China National Standard (CNS) A4 (210X297 mm) -36-517057 A8 B8 C8 D8 6. Scope of patent application ( Tolylamino) methyl] -4 '-(2-oxazolyl) [1,1'-biphenyl] -2-sulfamidamide, trifluoroacetate (1; 1); (Please read first Note on the back, please fill out this page again) N — [[2 '1 [[(3,4 dimethyl-5 —isoxazolyl) amino] sulfonyl]] 4 (2 -oxazolyl) [1,1'-biphenyl] -2-yl] methyl]- N, α, α —trimethylphenethylamine »N — (3,4 dimethyl-5 —isoamyl)-2 ′-[(1-methylethoxy) methyl]- 4 'mono (2-oxazolyl) [1,1'-biphenyl]-2-sulfamethoxamine;' N — [[2 '-[[(3, 4-dimethyl-5-isoxic Oxazolyl) amino] sulfofluorene] -4 mono (2-spirazolyl) [1,1'-biphenyl] -2-yl] methyl] _N -methamphetamine; N — [[ 2, [[((3,4, dimethyl-1,5-isoxazolyl) amino] sulfonyl]]-4 ((2-oxazolyl) [1,1'-biphenyl]] 2— [Methyl] methyl] -N-methylcyclopentanecarboxamide; N-[[2 '-[[(3,4-dimethyl-1-5-isoxazolyl) amino] sulfonyl]]-4 Mono (2-oxazolyl) [1,1 '—Phenyl printed by the staff of the Intellectual Property Bureau of the Ministry of Economic Affairs of the United Nations]-2-methyl] methyl] -N -methylcyclohexanemethane; N — [[2, 1 [[(3,4 dimethyl-5 —isoxazolyl) amino] sulfonyl]] 4 (2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -N-methylcyclohexanepropanamide; N — [[2 '-[[(3,4 Monodimethyl- 5 -isoxazolyl) amino] sulfofluorene] -4-(2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -N -formyl Base 1-Ethylamine; This paper size applies to China National Standard (CNS) A4 (210X297 mm)-37-517057 A8 B8 C8 D8, application for patent worship N-[〔2 '〔〔〔 (3,4 dimethyl-5 —isoxazole (please read the notes on the back before filling this page) group) amine group] sulfonyl]] 4 4 (2-oxazolyl) [1, 1 ' Monobiphenyl] -2-yl] methyl] -N-methylcyclopropaneacetamidamine; N-[[2 '-[[(3,4 dimethyl-5-isoxazolyl) amine []] Sulfonyl]] 4- (2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -N, 3,3-trimethylbutyramide; N — [ [2 '-[[(3,4-Dimethyl-5'-isoxazolyl) Amine] sulfofluorene] -4- (2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -N-methylcyclo'pentaneacetamidamine; · N- [[2 '-[[(3,4-Dimethyl-5 -isoxazolyl) amino] sulfonyl]] 4-(2-oxazolyl) [1,1' -biphenyl]- 2-yl] methyl] -N-methylcyclohexaneacetamidamine; N-[[2 '-[[(3,4-dimethyl-5-isoxazolyl) amino] sulfonyl] One 4 one (2-oxazolyl) [1,1'-biphenyl] one 2-yl] methyl] one N-methyl one one one methylamine; N— (3,4 one dimethyl A 5-isoxazolyl). 4 '— (2 -oxazolyl) — 2' 1 (3-phenylpropoxy) [1,1 '—Phenyl printed by the Consumers ’Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs] -2 —Phenylamine ; N — (3,4 dimethyl-5—isooxazolyl) —4 ′ — (2-oxazolyl) —2 ’— (3-phenylpropoxy) [1, 1 ' Phenyl] -2-mineralamine; 2 '— [[(1,1biphenyl) -4-yloxy) methyl] -N — (3,4 dimethyl-5—isoxamine Zolyl)-4 '-(2-oxazolyl) [1,1'-biphenyl]-2 -sulfamethoxamine; this paper uses China National Standard (CNS) A4 (210X297 mm) -38-517057 A8 B8 C8 D8 6. Scope of patent application N — [〔2 '一 〔[(3,4 dimethyl-5—isoxazole (Please read the precautions on the back before filling this page)) ) Amine] sulfofluorene] -4- (2-oxazolyl) [1,1'-biphenyl] -2-yl] methyl] -N-methyl [1,1'-biphenyl] -4-formamidine; N-(3, 4-dimethyl- 5-isospirofluorenyl) -2 '-(2-hydroxy-4 monophenylbutyl) -4'-(2-oxazolyl) [1, 1'-biphenyl]-2-sulfamethoxamine, Isomer A; N— (3,4—dimethyl—5—isoηoxanyl) —2 ′ — (2-hydroxy-4—phenylbutyl) —4 ′ — (2dioxazolyl) [1, 1'-biphenyl] 2-sulfamidamide, isomer B; N — [[2 '-[[(3,4 dimethyl-5 —isoxazolyl) amino] Sulfonium]-4-(2-oxazolyl) [1,1 '-biphenyl]-2 -yl] ethyl] -N -methylphenethylamine; Ν-(3,4 -dimethylformamide) 5-5 isoxazolyl) -2 '-[(anilino) methyl] -4'-(2-oxazolyl) [1,1'-biphenyl] -2-basalamide; [ [2 'One [[(3,4 Dimethyl-5 —isoxazolyl) Amino group printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs] Sulfur]] 4 (2 -oxazolyl) [1 , 1'-biphenyl] -2-yl] methyl] methylaminocarboxylic acid, phenyl ester; [[2, 1 [ (3,4 dimethyl-5 —isoxazolyl) amine] sulfonyl]] 4-(2-oxazolyl) [1,1 '-biphenyl] -2 -yl] methyl] Methylaminocarboxylic acid, benzyl methyl ester; Ν — (3,4 dimethyl-5—isospirofluorenyl) —2 ′ — [[methyl (benzyl) amino] methyl] —4 ′ One (2-oxazolyl) This paper size is applicable to China National Standard (CNS) A4 specification (210 × 297 mm) -39-517057 A8 B8 C8 D8 VI. Application scope of patent [1,1'-biphenyl]- 2-sulfamethoxamine; N-(3,4 dimethyl-5-isoxazolyl)-2 '-[(Please read the precautions on the back before filling this page) [methyl (2-phenylethyl (Amino) amino] methyl] -4 '-(2-oxazolyl) [1,1'-biphenyl] -2-sulfamethoxamine; 1 ^, 1 ^, 1 ^, trimethyl 1 ^, one [[2 '-[[(3, 4 dimethyl- 5 -iso-n-oxanyl) amino] sulfonyl]] 4-(2-glutamyl) [1,1' one Biphenyl] -2-yl] methyl] urea; Ν— (3,4, dimethyl-2,5—iso Oxazolyl) -4 '-(2-oxazolyl) -2'-[[3-phenyl-1, 2-oxo-1, 1-imidazolidinyl) methyl] [1,1'-biphenyl ] 2-sulfonamide N-(3,4-dimethyl-5-isoxazolyl)-4 '-(2-chrysyl)-2'-[(2-Hydoxy-3- Methyl-1-imidazolidinyl) methyl] [1,1'-biphenyl]-2-sulfanilamide; N- (3,4-dimethyl- 5 -isospirofluorenyl) -4 ' Mono (2-oxazolyl) -2 '-[[2-hydoxy-3- (1-methylethyl)-1-imidazolidinyl] methyl] [1,1'-biphenyl] Printed by the employee ’s cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, 2-sulfamethoxamine; I NR — [[2, 1 [[(3,4-dimethyl-5—isoxazolyl) amino] sulfonyl]] _4 mono (2-oxazolyl) [1,1 'monobiphenyl] -2-yl] methyl] -N, 3-dimethylbutyramide; Ν — [[2' one [[(4 , 5-dimethyl-1, 3-isoxazolyl) amino] sulfonyl]] 4-(2-oxazolyl) [1, 1 ' A copy of this paper is applicable to China National Standards (CNS) A4 specifications (210X297 mm) 517057 A8 B8 C8 D8 C, patent application: Phenyl]-2 -yl] methyl]-N, 4, 4, 13 Methylpentamidine; N — [[2, 1 [[(3,4 dimethyl-5 isoxazolyl) amino] sulfonyl]] 4- (2-oxazolyl) [1, 1'-biphenyl]-2-yl] methyl] -N-methylcyclobutanemidine; N — [[2 '1 [[(3,4-dimethyl-1,5-isoxazole Group) amine group] sulfofluorene] -4 4- (2-oxazolyl) [1,1'-biphenyl] -2 2-yl] methyl] -N-methylphentermine; and N- [ [2 '-[[(3,4-Dimethyl-5-isoxazolyl) amino] sulfonyl]] 4 4- (2-oxazolyl) [1,1'-biphenyl] -1 2 —M]] methyl] -N-methyl [1,1'-biphenyl] -2 methylformamide. (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs This paper size applies to China National Standard (CNS) A4 (210X297 mm) -41 *