TWI291951B - Benzothiazine derivatives, preparation process thereof, and pharmaceutical compositions comprising the same - Google Patents

Description

1291951 A7 B7 V. INSTRUCTION DESCRIPTION (1) The present invention relates to a benzothiazepine heptaene derivative, or a pharmaceutically acceptable salt, solvate thereof, a solvate thereof, and a prodrug thereof . These benzoquinones, heptaerythritols have ileal bile acid delivery (IB AT) inhibitory activity and are therefore valuable in the treatment of disease states associated with symptoms of hyperlipidemia, and are useful in the treatment of warm-blooded animals such as humans. Method. The present invention also relates to a process for the manufacture of the benzoquinone heptaerythritol derivative, a pharmaceutical composition thereof, and the use thereof for the manufacture of a medicament for inhibiting IB AT in a warm-blooded animal such as a human. It is known that hyperlipidemia associated with high concentrations of total cholesterol and low-density lipoprotein cholesterol is a major risk factor for cardiac and vascular atherosclerotic diseases (eg, π coronary heart disease: reducing its risk; The world is a point of view", Assman G., Carmena R. Cullen Ρ. et al; Journal of Revolving Journals 1999, 100, 1930-1938, and "Diabetes and Heart and Vascular Diseases · Statement to the American Heart Association Health Specialist n, Grundy S, Benjamin I., Burke G. et al.; Journal of Cycling 1999, 100, 1134-46). It has been found that interfering with the circulation of bile acids in the intestinal lumen reduces cholesterol levels. Therapies previously established to lower cholesterol concentrations relate, for example, to treatment with HMG-CoA reductase inhibitors, preferably bacteriocins, such as simvastatin and fluvastatin, Or a bile acid binder such as a resin; Commonly used bile acid binders are, for example, cholestyramine and cholesipol. A recently proposed therapy (''Bile Acid and Lipoprotein Metabolism: Resurrection of Bile Acid in the Post-Cytocin Era", Angelin B, Eriksson M, Rudling Μ; Modern Insights on Fatty, 1999, 10, 269-74) relates to treatment with a substance having an inhibitory effect on sputum. ___ This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

1291951 A7 _B7._._ V. INSTRUCTIONS (2) Reabsorption of bile acids from the gastrointestinal tract is a normal physiological process that occurs primarily in the ileum by the IBAT mechanism. Inhibitors of IBAT can be used to treat hypercholesterolemia (see, for example, "The interaction of bile acids and cholesterol with non-systemic agents with low blood cholesterol properties", Biochemica et Biophysica Acta, 1210 (1994) 255-287). Such a compound having such an inhibitory activity against IBAT can also be used for the treatment of hyperlipidemia. A compound having such an inhibitory activity has been described, for example, in WO 93/16055, WO 94/18183, WO 94/18184, WO. 96/05188, WO 96/08484, WO 96/16051, W〇97/33882, WO 98/38182, WO 99/35135, WO 98/40375, WO 99/35153, WO 99/64409, WO 99/64410, WO 00/01687, WO 00/47568, WO 00/61568, WO 01/68906, DE 19825804, WO 00/38725, WO 00/38726, WO 00/38727, WO 00/38728, WO 00/38729, WO 01 Compounds of the formula 68/86906 and EP 0 864 582. In another aspect, the invention relates to the use of a compound of the invention for the treatment of adverse symptoms and conditions of lipemia, such as hyperlipidemia, hypertriglyceridemia, high Lualgglutinemia (high LDL), high pre-lipoproteinemia (high VLDL), excessive chylomicrons in blood, blood Low protein, hypercholesterolemia, hyperlipoproteinemia, and low alpha lipoproteinemia (low HDL). In addition, these compounds are expected to be used to prevent and treat different clinical symptoms such as atherosclerosis, arteriosclerosis, and rhythm. Qi, high thrombosis symptoms, vascular dysfunction, endothelial dysfunction, heart failure, coronary heart disease, heart and vascular disease, myocardial infarction, palpitations, peripheral vascular disease, inflammation of heart and blood vessels, such as heart, valve, Vascular distribution, arteries and veins, aneurysms, stenosis, restenosis, vascular plaques, vascular fat streaks, white blood cells, single cells and a _____-5-_ This paper scale applies to China National Standard (CNS) Α 4 specifications (210χ297 PCT)

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1291951 A7 B7

/ or macrophage infiltration, endothelium increase and surgical trauma and vascular thrombosis, stroke and temporary \^ =, infection: the invention is based on the discovery of certain benzoquinone sulphur nitrogen seven gardens. Suppress IBAT. It is expected that this property is related to the symptoms of hyperlipidemia in the disease state of the deaf person. Therefore, the present invention provides the compound of the formula (1).

(I)

Wherein: ... and ... are independently selected from hydrogen or Ch6 alkyl; R1 and R2 are independently selected from C1-6 alkyl; π and Ry are independently selected from hydrogen or Ci-0 alkyl, or ... and one is hydrogen or c a 6 alkyl group, and the other is a hydroxyl group or a c 6 alkoxy group;

Rz is selected from the group consisting of fluorenyl, nitro, cyano, hydroxy, amine, carboxyl, amine yl, fluorenyl, sulfonyl, q.6 alkyl, A"alkenyl, alkynyl, cb6 Alkoxy, Ch alkyl fluorenyl, c oxacarbonyloxy, N_(q-6 alkyl) amine, NXC!.6 alkyl h-amino, Ci. 6 alkanoyl, Ν乂Ch alkyl) Aminomethyl sulfonyl, N,N-(C^6 alkyl)2 amine carbaryl, oxime 6 alkyl s(〇)a, where a is the standard of Chinese paper (CNS) A4 specification ( 210 X 297 mm) 1291951 A7 ____Β7_.___ V. Inventive Note (4) to 2 'Cb6 alkoxycarbonyl, C!-6 alkoxycarbonylamino, ureido, anthracene ((: 1-6 alkyl)) Base, N-(Ch alkyl) treadyl, Ν', Ν, ((ν6 alkyl) 2 ureido, NHCu)-N-% -6 alkyl, NW! · 6 alkyl) 2 Kq-6 alkyl), N-(ci.6 alkyl)aminesulfonyl and N,N-(Ci.6 alkyl)2aminesulfonyl; v is 〇-5; R4 and R5 One is the formula (IA) group:

R3 and R6, and the other of R4 and R5, independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amine, carboxyl, amine carbaryl, fluorenyl, sulfonyl, (: 4 alkyl, C 2 4 fluorenyl, (: 2 · 4 alkynyl, cl M decyloxy, Ch alkyl fluorenyl, Ch alkyl decyloxy, N-(C! 4 alkyl) amine, n, n _ (Ch Alkyl) 2 amine group, Ch sulphonylamino group, N-(Ch alkyl) amine carbaryl group, n, N-(Ch alkyl) 2 amine carbaryl group, C ** 4 alkyl s (〇) a, wherein a is 0 to 2, cl-4 oxime, N-(Ch alkyl)amine sulfonyl and N,N-(Ci-4 alkyl &amine sulfonyl; wherein R3 and R6 And another of R4 and R5 may be substituted on the carbon by one or more R16; D is -〇·, -N(Ra)-, -S(〇V or -CH(Ra)·; Ra is hydrogen or CM alkyl, and b is 0-2; ring A is aryl or heteroaryl; wherein ring A is optionally substituted by a substituent of R17; selected from the paper scale applicable to Chinese national standard (CNS) ) A4 size (210 X 297 mm)

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1291951 A7 B7 V. INSTRUCTIONS (5) R7 is hydrogen, alkyl, carbocyclyl or heterocyclic; wherein R7 is optionally substituted by one or more substituents selected from R18; R8 is hydrogen or alkyl R9 is hydrogen or <^.4 alkyl·, R1 G is hydrogen, C! _4 alkyl, carbocyclyl or heterocyclic; wherein R1 is optionally substituted by one or more selected from Rl 9 Substituent; R11 is carboxyl, sulfonate, sulfinyl, phosphonic acid, tetrazolyl, -P(0)(0Rc.)(0Rd), -P(0)(0H)(0Rc), - P(〇)(〇H)(Rd) or -p(Q)(〇Rc)(Rd), of which 11. Independently selected from the group consisting of CV6 alkyl groups; or Rii is a group of formula (IB):

B) wherein: X is -N(Rq)-, -N(Rq)C(0)-, -0-, and -S(0)a -; wherein a is 0-2, and Rq is hydrogen or Ci. 4 alkyl; R12 is hydrogen or c1M alkyl; R13 and R14 are independently selected from hydrogen, c1M alkyl, carbocyclyl, heterocyclyl or R23; wherein the C4 alkyl, carbocyclyl or heterocyclic group It may be independently substituted with one or more substituents selected from R20; R15 is a carboxyl group, a sulfonic acid group, a sulfinyl group, a phosphonic acid group, a tetrazolyl group, -P(0)(0Re)(0Rf), -P(〇)(〇H)(ORe), -P(0)(0H)(Re)4 -P(〇)(〇Re)(Rf) , wherein Re and the lanthanide are independently selected from an alkyl group; R15 is a formula (IC) group·· -8 - __ — This paper scale applies to China National Standard (CNS) A4 specification (21〇x4 7 public) A7 B7 1291951 V. Invention description (6) Sound (1C) Wherein: R24 is selected from hydrogen or q.4 alkyl; R25 is selected from hydrogen, q.4 alkyl, carbocyclyl, heterocyclyl or R27; wherein the Ci-4 thiol, carbocyclyl or heterocycle The group may be independently substituted with one or more substituents selected from R28; R26 is selected from the group consisting of a carboxyl group, a sulfonic acid group, a sulfinyl group, a phosphonic acid group, a tetrazolyl group, -P(0) (0R§) (0Rh) > -P(〇)(〇H)(ORg) s .P(〇)(〇H)(R8) -P (〇)(〇Rg )(Rh) wherein Rg and Rh are independently selected from Cl-6 alkyl; p is 1-3; wherein Rl 3 may be the same or different; q is 0-1; r is 0. 3; wherein the meaning of Rl 4 may be the same or different; m is 0-2; wherein the meaning of R1〇 may be the same or different; η is I-3; wherein the meaning of R7 may be the same or different; ζ is 0- 3; wherein the meaning of R25 may be the same or different; R1 6, R1 7 and R1 8 are independently selected from halo, schwitz, cyano, hydroxy, amine, carboxyl, amide, fluorenyl, sulfonyl , q μalkyl, fluorenyl, c: 2·4 alkynyl, Ci-4 alkoxy, alkanoyl, alkoxy, N-(C1M alkyl)amine, n,n_(Ci_4 alkyl &amine,Ch-alkylamino, N-(C!-4 alkyl)amine,carboxylidene, N,N-(C^alkyl&amine,carbyl,alkyl S(〇)' For the oxime to 2, CH alkoxycarbonyl, N-(Ch decyl)amine sulfonate paper size applicable to China National Standard (CNS) A4 specification (210X 297 mm) 1291951 A7 ______ B7 V. Description of invention (7) And NXq-4 alkyl)2aminesulfonyl; wherein R16, R17 and R1S may be independently substituted on the carbon by one or more R2 1 ; 9. R2 0, r23, R2 7& R28 are independently selected from the group consisting of halo, nitro, cyano, hydroxy, amine, carboxyl, amine fluorenyl, fluorenyl, sulfonyl, clM fluorenyl, C2-4 Alkenyl, C2-4 alkynyl, Ci-4 alkoxy, C1M alkyl fluorenyl, A. 4 alkyl alkoxy, N-(Ch alkyl) amine, N,N-(Ch alkyl) 2 amine a C,4 alkyl amidino group, an N-(Ci-4 alkyl)aminecarbamyl group, an alkyl)2 amine fluorenyl group, a Ch alkyl S(0)a, wherein a is 0 to 2, Ch alkoxycarbonyl, N_(Ay alkyl)aminesulfonyl, N,N-(Ci_4 alkyl)2aminesulfonyl, carbocyclyl, heterocyclyl, sulfonate, sulfinyl, formazan Base, phosphonic acid group, ^>(〇)(〇RaX〇Rb), -P(0)(0H)(0Ra), -P(〇)(〇H)(Ra) or -P(0)( 0Ra)(Rb), wherein {^ and oxime are independently selected from (: 6 alkyl; wherein Rl 9 'r2 0, R2 3, R2 7 and R2 8 may be independently or on the carbon by one or more R22 Substituted; R21 and R22 are independently selected from the group consisting of halo, hydroxy, cyano, amidino, ureido, amine, nitro, alkoxy, carbamoyl, fluorenyl, amide, trifluoromethyl , trifluoromethoxy, decyl, ethyl, methoxy, ethoxy, acetamidine , allyl, ethynyl, methoxycarbonyl, methionyl, ethyl hydrazino, amylamine, etidinyl, ethoxylated, decylamino, dimethylamino, N-methylamine Sulfhydryl, N,N-dimethylaminecarbamyl, methylthio, methylsulfinyl, ketonesulfonyl, N-methylaminesulfonyl and N,N-dimethylamine A sulfhydryl group; or a pharmaceutically acceptable salt, solvate thereof, a solvate of such a salt, or a prodrug thereof. According to another aspect of the present invention, a compound of the formula (Γ) is provided: _______ 10_ The standard of the paper scale s (CNS) Si: grid (can X 297 dongdong) 1291951 A7 B7 V. Description of invention (8

(Γ) where: R1 and R2 are independently selected from Cb6 alkyl; one of R4 and R5 is a group of formula (LV):

R3 and R6, and the other of R4 and R5 are independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amine, carboxy, aminemethanyl, fluorenyl, sulfonyl, Ci-4 Base, c2-4 fluorenyl, c2-4 alkynyl, Ci 4 alkoxy, C1_4 broth, Ch oxy, N-(Cl-4 alkyl)amine, N,N_(Ci4 alkyl ) 2 Amino, C 4 alkanoguanidino, N-(C丨_4 alkyl)aminecarbamyl, N,N_(C 4 alkyl) 2 Aminocarboxamidine, Ci·4 alkyl s (0) a, wherein 3 is 0 to 2, Ci 4 alkoxycarbonyl, N-(Ch alkyl)amine sulfonyl and n,n-(Ch alkyl) 2 amine sulfonyl; And another of R4 and R5 may be substituted on the carbon by one or more Ri2; the horse atom or heteroaryl; the oxime ring A is optionally used _ or more than -11 - the paper scale applies to the Chinese country Standard (CNS) A4 size (210 X 297 mm) 1291951 A7 B7 V. Description of invention (9) Substituent substitution of R1 3; R7 is hydrogen, q.4 alkyl, carbocyclyl or heterocyclic; Depending on the situation, the brother is replaced by one or more substituents selected from R14, · R8 is hydrogen, C. 4 alkyl, anthracenyl or heterocyclic; One or more substituents selected from R15 are substituted; R9 is a carboxyl group, a carboxylic acid group, a sulfinyl group, a phosphonic acid group, _p(〇x〇RC)(()Rd), -P(〇)(OH) (ORc), -P(〇X〇HXRd) or -P(0)(〇RC)(Rd), wherein 俨 and 以 are independent from q-alkyl; or R9 is a group of formula (IB,): F° 〇(IB,) wherein: R10 is hydrogen, q μalkyl, carbocyclyl or heterocyclyl; wherein R1 is optionally substituted by one or more substituents selected from Ri 6; R is known: Base, acid group, diazonium group, phosphonic acid group, _p(〇)(〇Re)(〇Rf), -P(0)(0H)(0Re), -P(0)(0H)(Re Or _p(〇)(〇Re)(Rf), wherein the lanthanide is independently selected from Cb6 alkyl; P is I-3; wherein R10 may be the same or different; m is 0-2; The meaning of R8 may be the same or different; η is 1_3; wherein the meaning of R7 may be the same or different;

Rl=RU and Ri4 are independently selected from the group consisting of a nitro group, a nitro group, a cyano group, a hydroxyl group, an amine group, a carboxyl group, an amine carbaryl group, a fluorenyl group, an amine sulfonyl group, a Ci sinyl group, an alkenyl group, a C2_4 alkynyl group, and a Ciy group. Alkoxy, alkanoyl, alkynyloxy The paper scale is applicable to China National Standard (CNS) A4 specification (210x297 mm) 1291951 A7 B7 V. Description of invention (1〇), 沁((^_4 alkyl)amine group , n,N-(C 4 alkyl) 2 amine group, Cb 4 alkanoylamino group, Ν-((ν4 alkyl)amine methyl sulfonyl group, ν, Ν-Αμ alkyl group) 2 amine mercapto group, Ci -4 alkyl S(0)a, wherein a is hydrazine to 2, q-4 alkoxycarbonyl, alkyl)amine sulfonyl and N,N-(C1-4alkyl)2amine sulfonyl; R1 2, R1 3 and R1 4 may be substituted on the carbon by one or more Rl 7 depending on the case;

Rl 5 and Rl 6 are independently selected from the group consisting of fluorenyl, nitro, cyano, hydroxy, amine, ruthenium, amine mercapto, cyclyl, amine fluorenyl, q-4 cyclyl, C 2-4 alkenyl , 〇 2_4 block base, (^ Bu 4 alkoxy, (1: Bu 4 纟 醯 匚, 匚 1-4 醯 醯 醯, 1 ^ - (Ci-4 alkyl) amine group, ν, Ν - Αμalkyl) 2 amine group, Ci_4 alkyl amidino group, N-(CV4 alkyl) amine methyl sulfonyl group, N, N-(Ci_4 alkyl) 2 amine methyl fluorenyl group, (: 1-4 alkyl S ( 0) a, wherein a is 〇 to 2, Ci-4 alkoxycarbonyl, N-(C1M alkyl)amine sulfonyl and N,N-(C1-4 alkyl)2 sulfonyl, sulfonate , sulfinyl, fluorenyl, phosphonic acid, -P(〇)(〇Ra)(ORb), -P(〇)(〇Hx〇Ra), -P(〇)(〇H)(Ra Or P(0)(0Ra)(Rb), wherein 1^ and the oxime are independently selected from Ci 6 alkyl; wherein Rl5 and R16 may be independently substituted on the carbon by one or more Ris; R1 7 and R1 8 is independently selected from the group consisting of halo, hydroxy, cyano, amine, mercapto, urethra, amine, nitro, carboxy, carbamoyl, fluorenyl, sulfonyl, trifluoromethyl, tri Fluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, acetylene , methoxycarbonyl, decyl, ethyl hydrazino, formazanyl, acetamido, ethoxylated, methylamino, dimethylamino, N-methylamine, fluorenyl, N, N - dimethylamine-methyl sulfhydryl, methylthio, decylsulfinyl, methyl sulfonyl, N-decylamine sulfonyl and n,N-dimethylamine sulfonyl; or a pharmaceutical thereof An acceptable salt, solvate, solvate of such a salt, or a prodrug thereof. ---- -13- This paper size is suitable for the standard of wealth (CNS) A4 specification (210X297 mm 5 - One -

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DESCRIPTION OF THE INVENTION ----- According to another aspect of the present invention, a compound of the formula (Γ) is provided:

Wherein: R and R2 are independently selected from C1-6 alkyl; one of R4 and R5 is a group of formula (IA"):

(IA,,) R3 and R6, and the other of 圮 and R5 are independently selected from the group consisting of hydrogen, halo, nitrocyano, benzyl, amine, alkyl, amidyl, fluorenyl, and amine. Base, C1M alkyl, c2-4 alkenyl, c2-4 alkynyl, alkoxy, Α·4 alkyl decyl, Ch alkyl decyloxy, n-(Ch alkyl) amine, N, NKci-4 2)amino group, Ch alkanoylamino group, N-(CH alkyl)amine mercapto group, N,N-(Ch alkylamine methyl, C!·4 alkyl S(0)a, wherein a is 〇 to 2, Ci 4 alkoxycarbonyl, Ν-%·4 alkyl) sulfonamide and N,N-(CH alkyl) 2 amine sulfonyl; wherein R3 and R6, and R4 and R5 Another case may be substituted on the carbon by one or more Rl 6; ring A is an aryl or heteroaryl group; wherein ring a is optionally one or more selected from the group consisting of _____-_ -14 - paper scale Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1291951

V. Description of the invention (A7 B7 12)

Substituted by a substituent of R17; R7 is hydrogen., q_4 alkyl, carbocyclyl or heterocyclyl; wherein R7 is regarded as being, the brother is substituted by one or more substituents selected from R1 8; R8 is hydrogen or Q.4 alkyl; R9 is hydrogen or alkyl; R10 is hydrogen, q.4 alkyl, carbocyclyl or heterocyclic; wherein R.sup.1 is optionally substituted by one or more substituents selected from R19; R11 is a carboxyl group, a sulfonic acid group, a sulfinyl group, a phosphonic acid group, -P(〇x〇RCX〇Rd), -P(0)(0H)(0Rc), -P(0)(0H)(Rd Or -P(0)(〇Rc)(Rd), wherein Rc^Rd is independently selected from Ci-6 alkyl; or R11 is a group of formula (IB"):

(IB") where: X -N(RQ)-, -N(Rq )C(0)-, -0-, and -S(0)a -; where a is 0-2 and Rq is hydrogen or (^_4 alkyl, · R12 is hydrogen or c^.4 yard base;

Rl3 and R14 are independently selected from hydrogen, (^-4 alkyl, carbocyclyl or heterocyclic; wherein R13 and R14 may be independently substituted by one or more substituents selected from r2?; - R15 is a carboxyl group; , sulfonic acid group, sulfinyl group, phosphonic acid group, -P(0)(0Re)(0Rf), -P(0)(〇H)(0Re), -P(〇)(〇H)(Re ) or -P(0)(0Re)(Rf), where Re and r/system ____ -15- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm)

Line 1291951 A7 _____ _B7 V. Inventive Note (13) Independently selected from C1-6 alkyl; P is I·3 ·, where Rl 3 can be the same or different; q is 0,1; r is 0-3 Wherein the meaning of Ri4 may be the same or different; m is 0-2; wherein the meaning of Ri 〇 may be the same or different; η is 1-3; wherein the meaning of R7 may be the same or different; R1 6, R1 7 and R18 is independently selected from the group consisting of a 13⁄4 group, a nitro group, a cyano group, a hydroxyl group, an amine group, a carboxyl group, an amine group, a fluorenyl group, an amine sulfonyl group, a Ch alkyl group, a C2i fluorenyl group, a c^4 group, and a C^4 group. Pitoxy, Ci-4, decyl, Cn decyloxy, N-(CV4 alkyl)amino, alkyl) 2 amine, Ci-4 alkanoyl, N-(CV4 alkyl)amine Mercapto, n, n-(cv4 alkyl) 2 amine methyl sulfonyl, C1M alkyl S(0)a, wherein a is 0 to 2, q-4 alkoxycarbonyl, N-(C tetraalkyl) Amine thiol and N,N-(C 4 alkyl) 2 amine sulfonyl; wherein R 6 , Ri 7 and Ris may be independently substituted on the carbon by one or more R 2 1; R 1 9 and R2G is independently selected from the group consisting of halo, nitro, cyano, hydroxy, amine, benzyl, carbamoyl, carbyl, amine hydrazino, Ci_4 alkyl, c2_4 alkenyl, c2-4 Block group, q - 4hoxyoxy, q_4, S, S, C, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4 4-alkaneamine, N-(Ci-4 alkyl)amine fluorenyl, hydrazine, hydrazine-% μalkyl)2-aminocarboxamidine, q -4 alkyl S(0)a, wherein a is 0 To 2, C! · 4 alkoxycarbonyl, N-% _4 alkyl) sulfonyl, N,N-(C)-4 alkyl) 2 sulfonyl, carbocyclyl, heterocyclyl, sulfonate Acid group, sulfinyl group, formazan group, phosphonic acid group, -P(〇)(〇Ra)(〇Rb), two P(〇x〇Hx〇Ra), -P(〇)(〇H) (Ra) or -P(0)(〇Ra)(Rb), wherein Ra and Rb are independently selected from Ci-6 alkyl; wherein R19 and R21 may be independently substituted on the carbon by one or more R22; — -16 ~ This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) 1291951 A7 B7 V. Description of invention (14 R2 1 and R2 2 are independently selected from halo, sulfhydryl, cyano, and amine Sulfhydryl, urethra, amine, nitro, carboxyl, amine carbaryl, sulfhydryl, sulfonyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, B Oxyl, vinyl, allyl, ethynyl, anthracenyloxy, methyl sulfhydryl Ethyl, methionine, etidinyl, ethoxylated, decylamino, dimethylamino, benzylamine, hydrazine, hydrazine-didecylamine sulfhydryl, methyl sulphide a group, a sulfhydryl group, a sulfonyl sulfonyl group, a hydrazine-methylamine sulfonyl group, and an anthracene-dimethylamine hydrazide group; or a pharmaceutically acceptable salt or solvate thereof a salt solvate, or a prodrug thereof. In the following paragraphs of Zhu Mingyi I, and in the scope of the patent application, in the case of the reference to the compound of formula (I), it should be understood that this aspect also relates to the compound of formula (7) and the compound of formula (Γ). Further, the skilled person will understand that the numbering system between the compound of the formula (1) and the compound of the formula (Γ) is different. The numbering system used hereinafter refers to the compound of formula (1)' but it should be understood that these statements also apply to the corresponding meanings in formula (1). In this patent specification, the term "thiol" includes both straight-chain and branched-chain singular groups, but for individual alkyl, such as "propyl", it refers to a straight-chain variant. For example, &quot ; cl-6 垸基" is included, burnt base, complete base 'propyl, 'propyl', which refers to straight clocks and sputum and P, and only for individual branched chain alkyl ^ ^ private s such as isopropyl 4 ' is specifically a branching bond variant. Similar to the conventional m system is applicable to other ", for example, "benzene" based system including phenyl Ci. 4 k base, + base, 1-phenylethyl And its ^ 丞 2 winter base ethyl. The word "from the base" refers to the gas base, rolling base, '/ odor base and base. Isopropyl and second-butyl. However, for the reference of individual appearance base, 譬 & Zhang scale suitable wealth g g home standard (CNS) 1291951 A7

β, this * is selected from the "one or more, · group, it should be understood that the genus includes all substituents selected from the specified group _ ', or the substituent is selected from the specified group Two or more of the group. 1 '

The cycloheteroaryl group to 1 is a fully unsaturated mono- or bicyclic ring containing 3 to 12 atoms, and at least one of the atoms is selected from nitrogen, sulfur or oxygen, and unless otherwise, it may be bonded via carbon or nitrogen. "heteroaryl 浐I 屌早夕士 into the τ from &; 你 你 你 你 你 你 你 你 你 你 你 你 你 你 你 你 你 你 你 你 你 你 你 你 你 你 你 你 你 你 你 王 王 王 王 王 王 王 王 王 王It is selected from λ, sulphur or oxygen unless otherwise: 'otherwise it can be attached via carbon or nitrogen. Another divisor of the present invention: another, has, =; group: a fully unsaturated monocyclic ring containing 5 or 6 atoms, or a U: sub-ring ring, at least - Selection: Heterofang 22 is otherwise specified, otherwise it may be linked by carbon or nitrogen. "Ice syllabic terminology and appropriate meaning are porphinyl, rimidyl, pyrrolyl, oxadiazolyl, isoxazolyl:, yl..." "yl, yl, ..." The term "aryl" preferably refers to a pyrenyl or a 4-indenyl group. A sulphate-based group: or a bicyclic carbocyclic ring contains 3,12 atoms and a univalent group of horses having a single ring of 5 or 6 atoms. Ring, a double ring of 10 atoms. The appropriate meaning of aryl group (9). Dimensions. Specific, aryl group is phenyl. Α Α ""heterocyclic" is saturated 'partially saturated or unsaturated with 3-12 atoms, or at least one of which is selected from nitrogen, stone... :: otherwise specified, otherwise it can be Carbon or nitrogen connection, where _' base; visible h condition is replaced by -qo), or ring (four) sub-sense is oxidized, Μ成^_

1291951 A7 --~------- B7 V. INSTRUCTION DESCRIPTION - e-heterocyclic group is preferably saturated, partially saturated or unsaturated, single or double, in %, containing 5 or 6 atoms, at least An atomic system selected from the group consisting of nitrogen, sulfur or oxygen' may be linked via carbon or nitrogen unless otherwise specified, where

The group may optionally be replaced by -c(o)-, or the ring sulfur atom may be oxidized as appropriate to form an S-oxide. Examples of "heterocyclyl" terms and their appropriate meanings are thiazolyl, tetrahydropyrrolyl, dihydropyrrolyl, anthracene tetrahydropyrrolidone, 2,5-didecyltetrahydroppyryl, 2-phenylene Oxazolinone, anthracene, diketone tetrahydroquinolyl, 2,4-dione imidazolidinyl, 2-keto-l,3,4-(4-triazolinyl), 2-oxazolidinone, 5,6-dihydrouracil, anthracene, 3-benzodioxanyl, m-i-l-, and 2-azabicyclo[2·2·1] Heptyl, 4-pyrazolone, flufenyl, 2-ketotetrahydrofuranyl, tetrahydrofuranyl, 2,3-dihydrobenzofuranyl, benzoquinone, tetrahydropyranyl, hexahydropyridine Ketone, keto-yl, 1,3-dihydroisodecyl, hexahydropyridinyl, thiomorpholine, diketothiomorpholinyl, tetrahydropyranyl, 1,3- Dioxinyl, high hexahydropyridinyl, thienyl, isoxazolyl, mito, pyrhadyl, p-oxadiazolyl, iso-p-decyl, H'. Sitting base, 1, 3, 4-three. Sit-base, shouting squirrel, sputum base, u-dense base, 4 squat base, ton base, tower tillage, ϊτ than decidyl, 4-p than bite g, base, and p check P ketone group. The n carbocyclyl group n is a saturated, partially saturated or unsaturated mono- or bicyclic carbocyclic ring containing 3-12 atoms; wherein the -CHr group may be replaced by _c(〇>, carbocyclyl Preferably, it is a monocyclic ring containing 5 or 6 atoms, or a bicyclic ring containing 9 or 1 atom. The appropriate meaning of "carbocyclyl" includes cyclopropyl, cyclobutyl, 1-ketone. Cyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl, decyl, tetrahydroindenyl, hydroquinone or cyanohydrazinyl. -19- Applicable to Chinese National Standard (CNS) Α4 Specification (210X 297 public) ' ' - 1291951 A7 B7 V. Description of Invention (17 ) Specific "carbocyclyl" is cyclopropyl, cyclobutyl, 1-ketocyclopentyl , cyclopentyl, cyclopentyl, cyclohexyl, cyclohexenyl, phenyl or 1-ketohydroindenyl. Examples of "c!-6 alkoxy" and alkoxy" are Examples of "q.6 alkoxycarbonyl" and alkoxycarbonyl" include methoxycarbonyl, ethoxycarbonyl, n- and tert-butoxycarbonyl.” (: 6 alkoxy, And, (:Bu 4 alkoxy) examples, including Examples of the oxy, ethoxy, and propoxy groups. "Cl_6 alkanoylamino" and f'c1-4 amidoxime include guanylamino, acetamido and propylamine. (: 6 alkyl s(0)a, wherein a is 0 to 2', and, Ci-4 alkyl S(〇)a, wherein a is 0 to 2" examples, including thiol, B Examples of a thio group, a methylsulfinyl group, an ethylsulfinyl group, a decanesulfonyl group, and an ethylsulfonyl group. Examples of alkanoyl group and "(-4 alkynyl)" include c1-3 An alkanoyl group, a propyl fluorenyl group and an ethyl fluorenyl group. "N-fualkyl"amino group" and "N-(Cle4 alkyl) amine group, and examples thereof include a methylamino group and an ethylamino group." Examples of Ν-Αι alkyl) 2 amino" and "n, N-(Ch alkyl) 2 amine", including di-N-methylamino, diethyl)amine and N-ethylmethylamine Examples of "c2-6 fluorenyl" and "C2_4 fluorenyl" are vinyl, allyl and 1-propenyl. Examples of c2_6 alkynyl and "c2_4 alkynyl" are ethynyl, 1- Propynyl and 2-propynyl. "N-% _ 6 alkyl)amine hydrazide" with nN-(Ci ·4 alkyl)amine sulfonyl, an example of which is N-(Cl _3 alkane Amine sulfonate , N-(methyl)amine sulfonyl and N-(ethyl)amine sulfonyl. "N-(Ch alkyl) 2 amine sulfonyl π and nN-(C 4 alkyl) 2 amine sulfonate An example of a fluorenyl group, n,N-(dimethyl)amine sulfonyl and N-(methyl>N-(ethyl)amine sulfonyl."^((^-6 alkyl)amine Examples of the methylmercapto, and ''N-%-4 alkyl)amine thiol group are methylaminocarbonyl and ethylaminocarbonyl. "Ν,Ν-βυalkyl)2aminecarbamyl" Examples of the "N,N-(Cl_4 alkyl) 2 amine fluorenyl group" are dimethylaminocarbonyl and methylethylaminocarbonyl. "(3^6 alkoxycarbonyl _ -20- This paper scale applies to China National Standard (CNS) A4 specification (2ΐί) X 297 public)

Binding

Line 5. Inventive Description (18) Examples of the amine group '' are an ethoxycarbonylamino group and a third-butoxycarbonylamino group. An example of "N, (Ch alkyl)ureido" is N, _methylureido and n, _ethylureido.,, N (C 6 alkyl) leg bases. Examples of methylurea groups and groups of ethylureido groups, , oxime |, oxime, (Cu alkyl hureido) are oxime, oxime, dimethylurea and decylethylureido. Examples of 'Ν'%·6 alkylyl group" are Ν,·曱基·Ν-mercaptourea and hydrazine, _propyl·Ν_methylureido."n,,n,_ An example of a (Ci^)-based 2_n_(Ch alkyl)ureido group is N, dimethyl-N•methylureido and nl methyl.ethyl-N-propyl gland. Suitable pharmaceutically acceptable salts are, for example, sufficient acid I addition salts of the compounds of the invention, such as acid addition salts with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluorocarbon A suitable orally acceptable salt of a compound of the invention which is sufficiently acidic, such as a metal, such as a sodium or a salt, an alkaline earth to a genus, for example Calcium or magnesium salts, normal salts, & and organic bases which provide physiologically acceptable cations a salt, for example, a salt with methylamine, dimethylamine, trimethylamine "hydropyridinium, morpholine or cis-(2-hydroxyethyl)amine. The compound of formula (I) can be administered in the form of a prodrug, Compounds of formula (1) are obtained by human or mobilization. Examples of prodrugs include: hydrolyzed vinegar in vivo and hydrolyzable amine in vivo. Example: In vivo hydrolysis of a compound of formula (1) The ester is a pharmaceutically acceptable ester which is hydrolyzed in the body to produce a parent acid or an alcohol; a suitable pharmaceutically acceptable ester of the thiol group, which is included. Methyl, I6, oxymethyl acetonate, such as dimethyl ethinyloxymethyl, fluorenyl hydrazine, % cycloalkyloxycarbonyl 1291951 A7 B7 V. Description of the invention (19-hydroxy octanane) Base esters, such as 丨-cyclohexylcarbonyloxyethyl; i, 3 • dioxol-2-one methyl esters, such as 5-methyl], 3_dioxos; Methyl, and 6 alkoxycarbonyloxyethyl esters, such as 丨-曱 oxycarbonyloxyethyl, may be formed on any of the carboxyl groups in the compounds of the invention. Formula (I) containing a hydroxy group Hydrolyzable esters in vivo, including inorganic ester jaws, such as phosphates and cardiopuroxyalkyl ethers, and related compounds, which are decomposed by in vivo hydrolysis of vinegar to obtain the parent hydroxyl group. Examples of alkyl ethers include ethoxymethoxymethoxy and 2,2-dimethylpropoxy-decyloxy. The in vivo hydrolysis of the (IV) group is selected to form a group, including Alkyl-based benzoyl, phenylethyl and substituted phenyl fluorenyl and phenylethyl, oxiranyl (obtained fluorenyl (4)), diamylaminomethyl and N-d amine Ethyl) ylamine carbenyl group (for urethane hydrazide), diamined amine aryl group and carboxyethyl fluorenyl group. Examples of the substituents on the benzoyl group include a porphyrin group and a hexahydropyridyl group from the ring nitrogen atom via a methylene group to the 3- or 4-position of the benzoyl group. Treasure, having a lean base formula (1), a compound hydrolyzable amine in vivo, which is suitable for me, such as N-Cl.6: Fe-based or hydrazine, Ν-di-C, 垸, 垸, 酿, ν Methyl, hydrazine, dimethyl, hydrazine or ethyl phthalamide. - Some of the compounds of formula (1) may have a palm center and/or geometric isomerization center (Ε_ and Ζ-isomer), and it should be understood that 'the invention covers all such optical, non-inhibiting activities. Enantiomers and geometric isomers, the invention relates to any and all tautomeric forms of the compounds having inhibitory activity. -twenty two-

1291951 A7

B7 should also be understood to have a wide variety of forms: 'some' (1) compounds may be solvated as well as undissolved to have a _A;f, such as a hydrated form. It should be understood that the present invention is all such solvated forms of the activity of Ri, /=. Love, brother,; ^, R5 and R6 have the following meanings. This meaning may be used to properly implement any definition, patent application scope or use as defined below. Preferably, R and R2 are independently selected from the group consisting of 4 alkyl groups. R and R2 are preferably independently selected from ethyl or butyl groups. R and Han are better selected from the group consisting of B. In the aspect of the present invention, the specific R1 and R2 are both butyl. In another aspect of the invention, the specific R1 and R2 are both propyl. In the present invention, the other aspect Specifically, one of R1 and R2 is an ethyl group, and the other is a butyl group.

Rx and Ry are preferably independently selected from hydrogen or q6 alkyl. RX and Ry are both better hydrogen. Preferably, R I is selected from the group consisting of an anthracenyl group, an amine group, a C1-6 alkyl group, a q-6 alkoxycarbonylamino group *NL(C1·6 alkyl group)|urea group. More preferably, the oxime is selected from the group consisting of a gas group, an amine group, a third butyl group, a third-butoxycarbonylamino group or an N,-(Third-butyl) choline group. V is preferably 〇 or 1. In one aspect of the invention, V is more preferably 0: In one aspect of the invention, v is more preferably 1. In one aspect of the invention, R4 is preferably a group of formula (IA) (as described above ___ -23- This paper scale applies to the Chinese National Standard (CNS) A4 specification (21〇X297 mm) 1291951 A7 _________B7 Five, month (21) painted). In another aspect of the invention, R5 is preferably a group of formula (IA) (as depicted above). R3 and R6 are preferably hydrogen. Preferably, the other of R4 and R5 which is not a group of formula (IA) is selected from halo, c a 4 alkoxy or C1M alkyl s(0)a, wherein a is 0 to 2 Wherein R4 or R5 may optionally be substituted on the carbon with one or more r16; wherein R16 is independently selected from the group consisting of hydroxy and hydrazine, 烷基alkyl)2 amine. More preferably, the other of R4 and R5, which is not a group of the formula (ΙΑ), is selected from the group consisting of bromo, methoxy, isopropoxy, methylthio, ethylthio, isopropylthio or A singular cross S&base; wherein R4 or R5 may be optionally substituted on the carbon with one or more R16; wherein R16 is independently selected from hydroxy and N,N-dimethylamino. In particular, the other of R4 and R5 which is not a group of formula (IA) is selected from the group consisting of bromo, methoxy, isopropoxy, methylthio, ethylthio, isopropylthio, 2 - hydroxyethylthio, 2-(N,N-dimethylamino)ethylthio or methanesulfonyl. More specifically, the other of R4 and R5, which is not a group of the formula (IA), is a methylthio group. Preferably, the other of R4 and R5, which is not a group of formula (IA), is selected from the group consisting of hydrogen, fluorenyl, C 4 methoxy or c 1-4 s (〇) a, wherein a It is 〇 to 2; wherein R4 or R5 may optionally be substituted on the carbon by one or more sizing 16; wherein the sizing 10 is independently selected from the group consisting of a carbyl group, a carboxy group and an N,N-(Ci.4 alkyl) 2 amine group. More preferably!! The other one of R4 and R5, which is not a group of the formula (ΙΑ), is selected from the group consisting of hydrogen, bromo, methoxy, isopropoxy, methylthio, ethylthio, Isopropylthio or methanesulfonyl; wherein &4 or R5 may be one or more on carbon - optionally - this paper scale applies to China National Standard (CNS) A4 (210 X 297 public)

Binding

1291951 A7 B7 V. Description of the invention (22) R1 6 substituted; wherein R1 6 is independently selected from the group consisting of a hydroxyl group, a carboxyl group and an N,N-dimethylamino group. Specifically, the other of R4 and R5 which is not a group of formula (IA) is selected from the group consisting of hydrogen, bromo, methoxy, isopropoxy, sulfonylthio, carboxymethylthio, ethyl sulphide Base, isopropylthio, 2-hydroxyethylthio, 2-(N,N-dimethylamino)ethylthio or methanesulfonyl. In another aspect of the invention, it is more preferred that the other of R4 and R5, which is not a group of formula (IA), is selected from the group consisting of hydrogen, chloro, bromo, methoxy, isopropoxy, Methylthio, ethylthio or isopropylthio; wherein R4 or R5 may be optionally substituted on the carbon with one or more R16; wherein R16 is independently selected from hydroxy, carboxy and N,N-dimethylamino . In another aspect of the invention, specifically, the other of R4 and R5, which is not a group of formula (IA), is selected from the group consisting of hydrogen, chloro, bromo, methoxy, isopropoxy, and Sulfuryl, carboxymethylthio, ethylthio, isopropylthio, 2-hydroxyethylthio or 2-(N,N-diamino)ethylthio. In another aspect of the invention, more particularly, the other of R4 and R5, which is not a group of formula (IA), is a bromo or chloro group. In another aspect of the invention, more particularly, the other of R4 and R5, which is not a group of formula (IA), is methoxy. In one aspect of the invention, Ring A is preferably an aryl group. In another aspect of the invention, Ring A is preferably a heteroaryl group. When ring A is an aryl group, it is preferred that ring A is a benzene group. When ring A is a heteroaryl group, it is preferred that ring A is a thienyl group or a fluorenyl group. Ring A is preferably an aryl or heteroaryl group; wherein ring A is optionally treated by one or more -25- paper scales in accordance with the Chinese National Standard (CNS) A4 specification (210X 297 mm)

Binding

1291951 A7 A_B7 V. INSTRUCTION DESCRIPTION (23) Substituent substitutions selected from R1 7 wherein R17 is selected from decyl, hydroxy or q-4 alkyl; wherein ri 7 may optionally be one or more on carbon 1 substituted; wherein R21 is selected from halo. D is preferably -〇- or -S-. In one aspect of the invention, more preferably D is -〇-. In one aspect of the invention, more preferably D is -S-. More preferably, the soil A is a phenyl group, a porphinyl group or a fluorenyl group; wherein the ring a is optionally substituted with a plurality of substituents selected from the group consisting of a benzyl group, a trans group or a trifluoromethyl group. Specifically, ring A is selected from the group consisting of phenyl, 4-phenyl, π-cephen-2-yl, 4-trimethylphenyl, 3-hydroxyphenyl, 2-fluorophenyl, 2, 3-dihydroxyphenyl or indol-3-yl. More specifically, ring A is a phenyl group. In another aspect of the invention, preferred ring A is aryl or heteroaryl; wherein ring A is optionally substituted with one or more substituents selected from Ri 7; wherein R17 is selected from thiol, hydroxy C1 -4 alkyl or C1-4 alkoxy; wherein Ri7 may optionally be substituted on the carbon with one or more R2<1>; wherein R2<1> is selected from halo. In another aspect of the invention, more preferred ring A is phenyl, pyrenyl or fluorenyl; wherein ring A is optionally substituted with one or more substituents selected from halo, thio, methoxy Or trifluoromethyl. In another aspect of the invention, specifically, ring A is selected from the group consisting of phenyl, 4, 2 phenyl, 4-nonyloxyphenyl, thiophene 1 , present trifluoromethylphenyl, fluorenyl phenyl, 2-fluorophenyl, 2,3-dihydroxyphenyl or fluorenyl-3-yl. X 297 mm) 1291951 A7 B7 V. INSTRUCTION DESCRIPTION (24) In another aspect of the invention, specifically, ring A is selected from the group consisting of phenyl, 4-hydroxyphenyl, 4-methoxyphenyl, thiophene- 2-Based, 4-trifluoromethylphenyl, 3-hydroxyphenyl, 2-fluorophenyl, 4-fluorophenyl, 2,3-dihydroxyphenyl or indol-3-yl. R7 is preferably hydrogen, q_4 alkyl or carbocyclyl. R7 is more preferably hydrogen, methyl or phenyl. In particular, R7 is hydrogen. In one aspect of the invention, preferably R8 is hydrogen. In another aspect of the invention, preferably R8 is Cp4 alkyl. In another aspect of the invention, more preferably R8 is hydrogen or methyl. In one aspect of the invention, preferably R9 is hydrogen. In another aspect of the invention, preferably R9 is Cp4 alkyl. In another aspect of the invention, more preferably R9 is hydrogen or methyl. R1G is preferably hydrogen. In one aspect of the invention, preferably R11 is a carboxyl group, a sulfonic acid group, a sulfinyl group, a phosphonic acid group, -P(0)(0Rc)(0Rd), -P(0)(0H)(0Rc), -P(0)(0H)(Rd) or -P(0)(0Rc)(Rd), wherein ^ is independently selected from C1-6 alkyl. In another aspect of the invention, preferably Ri1 is a group of formula (IB) (as depicted above). R1 1 is preferably a carboxyl group, -P(0)(〇H)(0Rc) or a group of formula (IB) (as described above). R1 1 is more preferably a carboxyl group, -P(〇)(〇H)(OEt) or a group of formula (IB) (as described above). In another aspect of the invention, preferably R11 is carboxy, sulfonic acid, -P(0)(0H)(0Re), wherein Rc is selected from the group consisting of q-4 alkyl or a group of formula (IB) (eg above -27 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

Binding

1291951

The description will be). X is preferably -NH- or -NHC(O)-〇 x is more preferably -NHC(O)-. In one aspect of the invention, preferably R12 is hydrogen. In another aspect of the invention, preferably R12 is Ci alkyl. In another aspect of the invention, more preferably Rl 2 is hydrogen or methyl.

Rl 3 is preferably hydrogen, C!.4 alkyl or carbocyclyl; wherein R!3 is optionally substituted with one or more substituents selected from R2? wherein R2() is a hydroxyl group. R13 is more preferably hydrogen, methyl or phenyl; wherein R 3 is optionally substituted by one or more substituents selected from R 2 oxime; wherein R 2 () is a hydroxyl group. In particular, R1 3 is hydrogen, hydroxymethyl or phenyl. More specifically, R1 3 is hydrogen or a methyl group. In another aspect of the invention, R13 is preferably hydrogen, C1-4 alkyl or carbocyclyl; wherein R13 is optionally substituted with one or more substituents selected from R20; wherein R20 is a number of a group, a ring or an amine group; wherein R2 is optionally substituted on the carbon by one or more R22; R2 2 is a light group. In another aspect of the invention, more preferably R 3 is hydrogen, methyl, ethyl, butyl or stupid; wherein R! 3 is optionally substituted with one or more substituents selected from R 2 fluorene; R 〇 is per base, carboxyl group, phenyl or amine group; wherein r20 may be substituted on the carbon by one or more R22; L _28· The paper size is suitable for the middle material (CNS) Α4 χ 297 mm)

Binding

1291951 A7 '*-----___Β7___ V. Description of the invention (26) R22 is a hydroxyl group. In another aspect of the invention, specifically, R13 is hydrogen, hydroxydecyl, 4-aminobutyl, 2-carboxyethyl, 4-hydroxybenzyl or phenyl. In another aspect of the invention, preferably R!3 is hydrogen, Ci-4 alkyl or carbocyclyl' wherein R13 is optionally substituted with one or more substituents selected from R2? wherein R2() is fluorenyl a carboxyl group, a carbocyclic group, a heterocyclic group or an amine group; wherein r2 is optionally substituted on the carbon by one or more R22; and R22 is a hydroxyl group. In another aspect of the invention, more preferably Ri3 is hydrogen, methyl, ethyl, butyl or phenyl; wherein Rl3 is optionally substituted with one or more substituents selected from R20; wherein R20 is a trans-group And a carboxyl group, a phenyl group, an imidazolyl group or an amine group; wherein R 2 〇 is optionally substituted on the carbon by one or more R 2 2 ; R 22 is a hydroxyl group. In another aspect of the invention, in particular, R13 is hydrogen, light methyl, 4-aminobutyl, 2-carboxyethyl, 4-hydroxyindenyl, imidazolyl-5-ylmethyl or phenyl. In still another aspect of the invention, preferably R13 is hydrogen, C1-4 alkyl, cyclyl or R23; wherein R13 is optionally substituted with one or more substituents selected from R2; wherein R20 is hydroxy a Ci-4 alkyl S(0)a wherein a is 0, a C1M alkoxy group, an amine group, a carbocyclic group, a heterocyclic group or a mirror group; wherein R2 G can be independently or on the carbon by one or more R2 2 is substituted; ~ R22 is selected from a hydroxyl group; and R23 is a carboxyl group. -29- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm)

Binding

1291951 A7 B7 V. INSTRUCTION DESCRIPTION (27) In yet another aspect of the invention, more preferably RU is hydrogen, methyl, ethyl, butyl or phenyl or R23; wherein Ri 3 is optionally one or more Substituted by a substituent selected from R 2 oxime; wherein R 2 0 is a sulfhydryl group, a methylthio group, a methoxy group, an amine group, an imidazolyl group or a mercapto group; wherein R is independently represented by one or more R 2 2 on the carbon Substituted; R22 is selected from a hydroxyl group; and R2 3 is a group. In yet another aspect of the invention, specifically, R13 is hydrogen, carboxy, hydroxymethyl, decylmethyl, methoxymethyl, methylthiomethyl, 2-methylthioethyl, 4- Aminobutyl, 4-hydroxybenzyl, imidazolium-5-ylmethyl or phenyl. On the other hand, more specifically, Rl 3 is methylthiomethyl, methylsulfinylmethyl or methylsulfonylmethyl. R14 is preferably hydrogen. In another aspect of the invention, preferably R14 is selected from hydrogen, C14 alkyl or carbocyclyl; wherein the C!-4 alkyl or carbocyclyl is optionally substituted by one or more substituents selected from R20 And R2Q is a hydroxyl group. In another aspect of the invention, more preferably Rl 4 is selected from the group consisting of hydrogen, methyl or phenyl; wherein the fluorenyl or phenyl group is optionally substituted with one or more substituents selected from R20; and R2() is Hydroxyl. In another aspect of the invention, specifically, R14 is hydrogen, phenyl or hydroxyindenyl. In particular, Ri5 is a carboxyl group or a sulfonic acid group. ________-30- This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm)

Binding

1291951 A7 B7 V. INSTRUCTION DESCRIPTION (28) In one aspect of the invention, more specifically, R15 is a carboxyl group. In another aspect of the invention, more particularly, R15 is a sulfonic acid group. R15 is preferably a carboxyl group, a sulfonic acid group, -P(〇)(〇Re)(〇Rf), -P(0)(0H)(〇Re), ·Ρ(0)(0Η)(ΐη or -P) (0) (0Re)(Rf), wherein Re and Rf are independently selected from Ci-4 alkyl. R15 is more preferably carboxyl, sulfonate, -P(〇)(〇Re)(〇Rf), -P (0) (0H) (0Re), -P(0)(0H)(Re) or -P(0)(0Re)(Rf), wherein "and R/ are independently selected from methyl or ethyl. R15 Preferred is a carboxyl group, a sulfonic acid group, -P(0)(0Et)(0Et), -P(0)(0H)(0Et), -P(0)(0H)(Me) or -P(0) (0Et)(Me). 1115 is preferably a carboxyl group, a sulfonic acid group, a phosphonic acid group, -?(0)(01^)(01{;), -P(0)(0H)(0Re), -P (〇) (〇H)(Re) or -P(0)(Re)(Rf), wherein 1^ and the oxime are independently selected from Ci_4 alkyl, or R15 is a group of formula (1C) (as depicted above) R15 is more preferably a carboxyl group, a sulfonic acid group, a phosphonic acid group, -卩(0)(01^)(01^), -P(0)(0H)(0Re), -P(〇)(〇H (Re) or -P(0)(0Re)(Rf), wherein Re and R/ are independently selected from methyl or ethyl, or R15 is a group of formula (1C) (as depicted above). Preferred are carboxyl group, sulfonic acid group, phosphonic acid group, 4(0)(€^)(0£1), -P(0)(0t-Bu)(0t-Bu), -P(0)(0H ) (0Et), -P(0)(0H)(Me) or -P(0)(0Et)(Me) , R15 is a group of formula (1C) (as depicted above). In one aspect of the invention, preferably R15 is a group of formula (1C) (as depicted above). In another aspect of the invention, preferably R1 5 is not a group of the formula (1C) (as depicted above). In one aspect of the invention, preferably R1 5 is a group. In another aspect of the invention, preferably R15 is a sulfonic acid group. -31 -__ This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

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1291951 A7 Description of the Invention In another aspect of the invention, preferably R15 is -P(0)(0H)(0Et). In another aspect of the invention, preferably Rl 5 is -P(〇)(〇H)(Me). In another aspect of the invention, preferably R15 is -P(0)(0Et)(Me). In one aspect of the invention, preferably R24 is hydrogen. In another aspect of the invention, preferably R24 is cbu*alkyl. R25 is preferably hydrogen. R26 is preferably a carboxyl group. P軚佳马1 or 2 ·' wherein Rl 3 can be the same or different. Is it better in one aspect of the invention? Is 1. In still another aspect of the invention, more preferably P is 2; wherein the meaning of R13 may be the same or different. In another aspect of the invention, more preferably #3; wherein the meaning of Rl3 may be the same or different. In one aspect of the invention, preferably q is hydrazine. In another aspect of the invention, preferably 〇1 is i. In one aspect of the invention, preferred is 〇. In one aspect of the invention, it is more preferred to be one. In another aspect of the invention, more preferably r is 2; wherein the meaning of rM can be the same or different. In another aspect of the invention, more preferably 1 &lt;3; wherein the meaning of rM can be the same or different. Preferably m is 〇. In another aspect of the invention, it is preferred to be 〇 or 1. Preferably η is i. ____-32- This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

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Line 1291951 A7 ________IB? V. Description of the Invention (30) ^~ In another aspect of the invention, preferably η is 1 or 2. Preferably, it is 1. a group of the formula (IAf) wherein R 7 is hydrogen, methyl or phenyl, 11 is 1, and ring VIII is phenyl, thienyl or fluorenyl; wherein ring A is optionally substituted by one or more substituents, It is selected from a halogen group, a hydroxyl group or a trifluoromethyl group, m is oxime, and R9 is a group, -P(0)(0H)(0Rc) or a group of formula (IB). a group of formula (IA) wherein: D is -0- or -S-; ring A is phenyl, thienyl or fluorenyl; wherein ring a is optionally substituted with one or more substituents selected from hydrazine Base, hydroxy, methoxy or trifluoromethyl; R7 is hydrogen, methyl or phenyl; R8 is hydrogen or methyl; R9 is hydrogen or methyl; R1 G is hydrogen; m is 0-2, of which Rio The meaning may be the same or different; and R1 1 is a carboxyl group, -P(0)(0H)(0Et) or a group of formula (IB) (as described in the first item of the patent application); a group wherein Rio is hydrogen, hydroxymethyl or phenyl, p is 1 or 2; wherein R10 may be the same or different and Ri is a carboxy or sulfonic acid group. a group of formula (IB) wherein: R12 is hydrogen or fluorenyl; R1 3 is hydrogen, methyl, ethyl, butyl or phenyl or R23; wherein Rl3 is optionally substituted by one or more selected from Substituent; R2〇 is hydroxy, methylthio, methoxy, amine, imidazolyl or mirror; wherein R2 0 can be used independently - 33 _ This paper scale is suitable for g @家标准(CNS) A4 ;A grid (21QX297 public love)'

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1291951 A7 ----------B7 V. INSTRUCTION DESCRIPTION (31) Substituted by one or more hydroxyl groups on carbon; R23 is a carboxyl group; X is -NH- or; R is selected from hydrogen, methyl Or a phenyl group; wherein the methyl or phenyl group may be optionally substituted by one or more substituents selected from a hydroxyl group; R15 uronyl, sulfonic acid group, phosphonic acid group, -p(〇)(〇Re)(〇Rf) ), _p(〇)(〇H)(〇Re), -P(0)(0H)(Re) or AQxoRexRf), wherein ^ and Rf are independently selected from methyl or ethyl, or Rl5 is formula (1C) a group (as described in the scope of the patent application); P is I-3, wherein the meaning of R13 may be the same or different; q is 〇-1; and r is 0-3, of which meaning The same or different; a group of the formula (1C) wherein R 2 4 is hydrogen; R 2 5 is hydrogen; r 2 6 is a certain group; and z is 1; or a pharmaceutically acceptable salt or solvate thereof a solvate of a salt, or a prodrug thereof. Accordingly, in another aspect of the invention there is provided a compound of formula (I') as depicted above, wherein: R1 and R2 are independently selected from ethyl or butyl; R3 and R6 are hydrogen; 'R4 is selected from Halo, CV4 alkoxy or Cw alkyl s(〇)a, wherein a is 〇 to 2 'wherein R4 may optionally be substituted on the carbon by one or more 丨6; wherein y 6 ___ -34- paper尺钱财® S House (CNS) A4 specification (210 X 297 public)-------- 1291951 A7 B7 V. Description of invention (32) is independently selected from hydroxyl and N, N-(C 4 alkyl) 2 amine; R 5 is a group of formula (DV); ring A is aryl or heteroaryl; wherein ring A is optionally substituted by one or more substituents selected from R 17 ; From thiol, hydroxy or Cl 4 alkyl; wherein Rl 7 may be optionally substituted on the carbon with one or more R 2 1 ; wherein R 21 is selected from halo; R 7 is argon, 〇 4 4 alkyl or carbocyclyl; 1 is a carboxyl group, -P(0)(0H)(0RC) or a group of formula (IB,) (as depicted above); R13 is hydrogen, c _4 alkyl or carbocyclyl; wherein RU is optionally Or a plurality of substituents selected from the group consisting of r2〇; wherein one R 2 ^ is a trans group; R 15 is a few Or an acid group; P is 1 or 2; wherein Rl 3 may be the same or different; m is hydrazine; and η is 1; or a pharmaceutically acceptable salt, solvate thereof, or a solvent thereof , or its prodrug. Thus, in another aspect of the invention, there is provided a compound as described above, wherein: R1 and R2 are both butyl, or one of r^R2 is ethyl and the other group; For order

R4 is methylthio; R5 is a group of formula (IA') (as described above); this paper scale is suitable for g g home standard (CNS) A4 specification -35· 1291951 A7

R3 and R6 are hydrogen; ring A is phenyl; R7 is nitrogen; R is a group of formula (IB,) (as illustrated above); R13 is hydrogen or hydroxymethyl, and R15 is a complex or a reductive group. ; P is 1 or 2; Mr&quot; may mean the same or not m is 〇; η is 1; or a pharmaceutically acceptable salt thereof or a prodrug thereof. a compound of the salt, a solvate of such a salt, and thus, in another aspect of the invention, a compound of the formula (Ιπ), wherein: R1 and R2, as described above, are independently selected from ethyl or butyl R3 and R6 are hydrogen; R4 is selected from i group, Cl-4 decyloxy or Ci4 alkyl s(〇)a, wherein 3 is 〇 to 2; wherein R4 may optionally be one or more on carbon Rl 6 substituted; wherein R 6 is independently selected from the group consisting of a hydroxyl group and a HN-CC 4 alkyl) 2 amine group; R 5 is a group of the formula (ΙΑ)); 'cyclopentane is an aryl or heteroaryl group; Depending on the case, it may be substituted by one or more substituents selected from R17; _ R7 is hydrogen, C1 -4 or carbocyclyl; R8 is hydrogen or methyl; -36- This paper scale applies to Chinese national standards (CNS) A4 size (210X297 mm) 1291951 A7 B7 V. Description of invention (34) R9 is hydrogen or methyl; R11 is carboxyl, -P(〇)(〇H)(〇Rc) or formula (IB") group (as described above); X is -NH- or -NHC(O)-; R12 is hydrogen or methyl; R13 is hydrogen, h-4, or carbocyclyl' wherein R13 is optionally taken a plurality of substituents selected from R 2 G are substituted; R 14 is hydrogen;

Ri5 is a thiol or a reductive acid group; R17 is selected from the group consisting of a radical, a thiol group, a C1-4fe group or a c1-4 alkoxy group; wherein Ri7 may optionally be substituted on the carbon by one or more R2 1; R 2 G is An Ik group, a complex group, a carbocyclic group or an amine group; wherein r2 is optionally substituted on the carbon by one or more R2 2; R21 is selected from a halogen group; R2 2 is a mesogenic group; p is I·3; The meaning of Rl 3 can be the same or different. q is 0-1; r is 0-3; wherein the meaning of Rl 4 may be the same or different; and if &lt;, then r is not 〇; Π1 is 0-2; and η is 1-3; A pharmaceutically acceptable salt, solvate, solvate of such a salt, or a prodrug thereof. Accordingly, in still another aspect of the invention, there is provided a compound of formula (I) as hereinbefore described, wherein: 37- the paper size is suitable for the family and is broken ^&gt; 297 gong 1291951 A7 _______B7 V. Description of the invention (35 1' RV and RW are both hydrogen; R1 and R2 are independently selected from Ci. 4 alkyl;

Rx and Ry are both hydrogen; P is selected from i-based 'amine group, Ci_6 fluorenyl group, oxycarbylamino group or N,-(Cb6 alkyl)ureido group; V is 0 or 1; R3 and R6 are hydrogen; One of R4 and R5 is a group of formula (IA) (as depicted above), and the other is selected from the group consisting of hydrogen, halo, &lt;:4 alkoxy or aza alkyl s(〇)a, Wherein a is 0 to 2; wherein R4 or R5 may be optionally substituted on the carbon with one or more R16; wherein R1 6 is independently selected from hydroxy, carboxy and NXq-4 alkyl) 2 amine; D is -〇 - or -S-; R7 is hydrogen, methyl or phenyl; R8 is hydrogen or methyl; ring A is aryl or heteroaryl; wherein ring A is optionally substituted by one or more substituents selected from R17 Substituent; wherein R17 is selected from the group consisting of a hydroxy group, a hydroxy group, a C1-4 alkyl group or a Ci_* oxy group, wherein Rl7 may optionally be substituted on the carbon by one or more R2<1>; wherein R2<1> is selected from halo R9 is hydrogen or fluorenyl; R1G is hydrogen; R1 1 is carboxy, -P(〇)(〇H)(ORc), wherein Rc is selected from a Ci_4 alkyl group or a group of formula (IB) (as above) Depicted); R1 2 is hydrogen or methyl; X is -NH- or -NHC(O)-; -38- This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 1291951 A7 B7 V. INSTRUCTION DESCRIPTION (36) R13 is hydrogen, Ci_4 alkyl, carbocyclyl or R23; wherein r]3 is optionally substituted by one or more substituents selected from R20, and its tR2〇 is a hydroxy group, an alkyl group S(0)a, wherein a is 0, C!·4 alkoxy, an amine group, a carbocyclic group, a heterocyclic group or a fluorenyl group; wherein R20 can be independently or on the carbon by one or more R22 is substituted; R22 is selected from a hydroxyl group; and R23 is a carboxyl group; R14 is selected from the group consisting of hydrogen, C1M alkyl or carbocyclyl; wherein the alkyl, carbocyclic or carbocyclic group may be optionally selected from R2 by one or more a substituent substituted with hydrazine; and R 2 〇 is a hydroxyl group; R is: a group, a 26 acid group, a phosphonic acid group, _p(Q)(〇Re )(〇Rf), p(Q)(〇H)(〇Re , -P(0)(0H)(Re) or _P(〇)(〇Re)(Rf), wherein Rf is independently selected from a C1 alkyl group, or R15 is a group of formula (1C) (as above) R24 is hydrogen; R25 is hydrogen; R2 6 is a few groups; p is 1-3; wherein R!3 can be the same or different; q is 0-1; r is 0-3; The meaning may be the same or different; m is 0_2; wherein the meaning of Ri 〇 may be the same or different; η is I-2; wherein the meaning of R7 may be the same or different; ζ is 0-1; wherein R 2 5 may be the same or different; or a pharmaceutically acceptable salt, solvate thereof, solvate of such a salt, or a prodrug thereof. In another aspect of the invention, preferred compounds of the invention are any one of the examples, or a pharmaceutically acceptable salt or solvate thereof, such a salt

1291951 A7 B7 V. INSTRUCTIONS (37) Solvates, or prodrugs thereof. One aspect of the invention provides a compound of formula (I), selected from the group consisting of Examples 8, 9, 46, 56, 59, 60, 61, 62, 66 and 69, or a pharmaceutically acceptable salt or solvate thereof, a salt solvate, or a prodrug thereof. In another aspect of the invention there is provided a compound of formula (1) which is examples 73, 74, 95, 96, 97, 98, 99 and 100, or a pharmaceutically acceptable salt, solvate thereof, such a salt a solvate, or a prodrug thereof. In another aspect of the invention, the preferred compound of the invention is any one of Examples 43, 50, 51 and 52, or a pharmaceutically acceptable salt, solvate thereof, solvate thereof, Or its prodrug. In still other aspects of the invention, preferred compounds of the invention are Examples 43, 46, 50, 51, 56, 58, 59, 61, 62, 63, 69, 81, 83, 85, 94, 97, Any of 98, 108, 109, 110, 111 or 117. A preferred aspect of the invention is related to a compound of formula (1) or a pharmaceutically acceptable salt thereof. Another aspect of the invention provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, solvate of such a salt, or a prodrug thereof, wherein the variable group Unless otherwise specified, as defined in formula (I)): 才 method α · · 式 幷 幷 幷 幷 圜 圜 圜 · · · · - 40 - This paper scale applies to Chinese national standards (CNS ) Α 4 specifications (210X297 mm)

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1291951 A7 B7

1291951 A7 _ B7 V. INSTRUCTION DESCRIPTION (39) wherein L is a displaceable group; a method of "" is to make a formula (Va) or (Vb) acid:

(VI); A method of reacting a compound of formula (I) wherein R11 is a group of formula (IB); wherein a compound of formula (I) wherein R11 is a group, reacts with an amine of formula (VII):

In the case of the compound of formula (I), where RH is a carboxyl group; ^ ^ (Villa) _____-42- This paper scale applies to the Chinese National Standard (CNS) Α4 specification (210 x 297 dong) a 1291951 A7 B7

1291951 .- A7 B7

1291951 A7 B7 V. Description of invention (42)

Wherein L is a replaceable group; reacted with a formula (χι) thiol:

Ry-H , (XI) wherein is a q 4 alkylthio group, optionally substituted on the carbon by one or more R 16 ; Method 8): a compound of formula (I) wherein R 5 is a group of formula (IC) In the case of the compound of the formula (IXa) or (IXb), wherein Rp is hydrogen, reacts with a compound of the formula (χπ); R25

R24 (XII) is a compound of formula (I) wherein R1 is a group of formula (ΙΒ) and Rl 5 is a group of formula (IC) and R26 is a group; : —_______· 45 - This paper ruler Wei Cai @ g家标准(CNS) ΜSpecifications (21GX297^y 1291951 A7 B7

(Rz)v (Xllla) or (Xlllb) compound removal protection: p0

R2IN R14 Bu

(Rz)v (Xlllb) wherein RP is (: 4 alkyl; a compound of formula (1), wherein X is -N(Rq)C(0)-; let formula (XlVa): -46 - This paper size applies to Chinese National Standard (CNS) A4 specification (21Q x 297 mm) 1291951 A7 B7

1291951 A7 B7 V. INSTRUCTION DESCRIPTION (45) i) converting a compound of formula (I) to another compound of formula (I); ii) removing any protecting groups; iii) forming pharmaceutically acceptable salts, solvates, a solvate of such a salt, or a prodrug. It will also be apparent to those skilled in the art that similar methods to the above methods can be used to prepare compounds of the formula (Γ) and formula (Γ) in which the definition of the variable group may differ. L is a replaceable group, and the appropriate meaning of L is, for example, a radical or a sulfonyloxy group such as a chloro group, a bromo group, a methanesulfonyloxy group or a toluene-4-sulfonyloxy group. RP is a Ci_4 alkyl group. Preferably, RP is a mercapto group or an ethyl group. More preferably, RP is a methyl group. The specific reaction conditions of the above reaction are as follows. Process 1): The benzoquinone sulphide heptaerythrene of the formula (II) can be oxidized under standard sulfur oxidation conditions; for example, hydrogen peroxide and trifluoroacetic acid are used, preferably at a temperature ranging from 0 ° C to reflux. It is at or near room temperature. For the compound of formula (I) wherein Rx and Ry are hydrogen, the compound of formula (Π) can be prepared according to Scheme 1. It will be apparent to those skilled in the art that Rx and Ry are not all hydrogen, and the following synthetic routes must be performed using procedures known to those skilled in the art. -48 - This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) 1291951 A7 B7

1291951

Such as halogen. The compounds of formula (Ila) and (Ik) are commercially available compounds, or are known in the literature or are made by standard methods known in the art. Method 2): The compound of the formula (IIIa) or (mb) can be reacted with a compound of the formula (IV) in the presence of, for example, a seed drill, such as a carbon steel, or an organic test, such as = unig S-base, in a suitable solvent. In the presence of, for example, acetonitrile, di-methane or tetrahydrofuran, at temperatures ranging from TC to reflux, preferably at or near reflux. Compounds of formula (Ilia) or (Illb) may be analogous to formula (π) (but It is prepared in such a manner that R4 or r5 is a hydroxy group, followed by an oxidation step of the method 丨). The compound of formula (IV) is a commercially available compound, or is known in the literature or is prepared by standard methods known in the art. Method 3) Method, Method 8) and Method 1): The acid and the amine can be coupled together in the presence of a suitable coupling reagent. Standard peptide coupling reagents known in the art can be employed as suitable coupling reagents, or, for example, carbonyldiimidazole and dicyclohexylcarbodiimide, optionally in the presence of a catalyst, such as dimethylaminopyridine or 4-tetra Hydropyrrolidylpyridine, optionally in the presence of a base, such as triethylamine, pyridine or 2,6-dialkylpyridine, such as 2,6-lutidine or 2,6-di-t-butyl Pyridine. Suitable solvents include dimethylacetamide, methylene chloride, benzene, tetrahydrofuran and dimethylformamide. This coupling reaction can be suitably carried out at a temperature ranging from -40 to 40 °C. Suitable activated acid derivatives include antimony tellurides such as gasified antimony, and active esters such as pentafluorophenyl esters. The reaction of these types of compounds with amines is well known in the art, for example, in the presence of a base such as the above. • 50. This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 complex)-

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1291951 A7 _B7^_._ V. Description of the invention (48), and reacting in a suitable solvent such as the above. This reaction can conveniently be carried out at a temperature ranging from -40 to 40 °C. A compound of the formula (Va) or (Vb) wherein D is -0-, -NRa- or -S- can be prepared according to Scheme 2:

NaC03 MeCN (Ilia)_) Scheme 2 wherein L is a replaceable group as defined above. Compounds of the formulae (Va) and (Vb) wherein D is -SO- or -S02-, can be oxidized by the formation of compounds of formula (Va) and (Vb) from Figure 2 wherein D is -S- production. A compound of formula (Va) or (Vb) wherein D is -CH2- can be prepared according to Scheme 3. (Va) (Vc) (Vb)

NaC03 MeCN

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-51 - This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1291951 A7 B7

This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1291951 A7 B7 V. Invention description (50) / Formula (Vc), (VI), (VII), (XII), (XV) and The XVI) compound is a commercially available compound, or is known in the literature, or it is made by standard methods known in the art. Method 5), Method 6) and Method 9) · · (Villa), (Vlllb), (IXa), (IXb), (Xllla) and (Xlllb) esters, can be removed under standard conditions, as follows Said, for example, it can remove the protection at room temperature in sodium hydroxide in decyl alcohol. The formula (Villa), (Vlllb), (IXa), (IXb), (Xllla) and (Xlllb) esters can be prepared by any of the procedures described above for the preparation of the compound of formula (1), but wherein R1 1, R15 or R26 is a Ci_4 alkoxycarbonyl group. Process 7): Compounds of formula (Xa) and (Xb) can be reacted with a thiol of formula (XI) in the presence of a base, such as an inorganic test, such as sodium carbonate, or an organic test, such as Hunigs' base, in the presence of a suitable solvent. For example, DMF or THF, at a temperature ranging from 0 ° C to reflux. Compounds of formula (Xa) and (Xb) can be prepared by any of the procedures above for the preparation of compounds of formula (I), but wherein one of R4 and R5 is L. The compound of formula (XI) is a commercially available compound, or is known in the literature, or it is made by standard methods known in the art. It will be appreciated that certain different ring substituents in the compounds of the invention may be introduced by standard aromatic substitution reactions or by modification of functional groups, either prior to or immediately prior to the methods indicated above. Subsequent to this, and by itself is included in the aspect of the method of the invention. Such reactions and modifications include, for example, the introduction of an aromatic substitution reaction by a substituent, the reduction of a substituent, the alkylation of a substituent, and the oxidation of a substituent. The reagents and reaction conditions for such procedures are well known in the art of chemistry. Specificity of Aromatic Substitution Reaction-53- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1291951 A7 B7 V. Description of invention (51) Examples, including the introduction of nitrate by using concentrated nitric acid, The use of, for example, ruthenium halide and Lewis acid (such as trichlorinated) to introduce a sulfhydryl group under Friedel Crafts conditions; using an alkyl halide and a Lewis acid (such as trichlorinated) to introduce an alkyl group under Friedel Crafts conditions And specific examples of upgrading, including reduction of the nitro group to an amine group, by, for example, catalytic hydrogenation, using a nickel catalyst, or in the presence of hydrochloric acid, treated with iron, and heated; oxidation of the alkylthio group to alkyl sulfinium Base or alkyl group. It should also be understood that in some of the reactions mentioned herein, it may be necessary/want to protect any sensitive groups in the compound. Where protection is necessary or desirable, and appropriate methods of protection are known to those skilled in the art. Conventional protecting groups can be used according to standard practice (for an illustration, see T. W. Green, Protective Groups for Organic Synthesis, John Wiley &amp; Sons, 1991). Thus, if the reactant contains a group such as an amine group, a carboxyl group or a hydroxyl group, it may be desirable to protect the group in some of the reactions mentioned herein. Suitable protecting groups for an amino group or an alkylamino group are, for example, anthracenyl groups such as an alkano group, for example an ethoxy group, an alkoxycarbonyl group such as a methoxycarbonyl group, an ethoxycarbonyl group or a tert-butoxycarbonyl group, an aryl group. A methoxycarbonyl group, such as an oxime carbonyl group, or an aryl fluorenyl group, such as a benzamidine group. The deprotection conditions of the above protecting groups must be changed with the choice of protecting groups. Thus, for example, an anthracenyl group such as an alkane group or a pyrolysine or an aryl group can be removed by, for example, hydrolysis, using a suitable test such as a metal hydroxide such as hydrogen peroxide II or sodium. Alternatively, a mercapto group such as a tert-butoxycarbonyl group can be removed, for example, by treatment with a suitable acid such as hydrochloric acid, sulfuric acid or phosphoric acid or trifluoroacetic acid, and an arylmethoxycarbonyl group such as an anthraceneoxycarbonyl group can be used. For example, hydrogen on a catalyst such as palladium on carbon-54- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1291951 A7 B7 V. Invention description (52) Chemical effect, or via Louis The acid is removed by treatment with borax (trifluoroacetate) boron. Suitable alternative protecting groups for the primary amine group are, for example, sulfhydryl groups which can be removed via treatment with an alkylamine such as dimethylaminopropylamine or with hydrazine. Suitable protecting groups for the hydroxy group are, for example, anthracenyl groups such as an alkano group, such as an ethyl fluorenyl group, an aryl fluorenyl group such as a benzamidine group, or an arylmethyl group such as a benzyl group. The deprotection conditions of the above protecting groups must be changed with the choice of protecting groups. Thus, for example, an anthracene group such as a decyl group or an aryl group can be removed by, for example, hydrolysis, using a suitable base such as an alkali metal hydroxide such as lithium hydroxide or sodium. Alternatively, an arylmethyl group, such as a fluorenyl group, can be removed by hydrogenation, for example, on a catalyst such as palladium on carbon. A suitable protecting group for a carboxyl group is, for example, an esterifying group such as a mercapto group or an ethyl group which can be removed by, for example, hydrolysis, using a base such as sodium hydroxide or, for example, a third-butyl group, It can be removed, for example, by treatment with an acid such as an organic acid such as trifluoroacetic acid, or, for example, a sulfhydryl group, which can be removed by, for example, nitriding, such as nitridation on 4 bar/carbon. Such protecting groups can be removed at any convenient stage in the synthesis using conventional techniques known in the art of chemistry. As described above, the compound defined in the present invention has IB AT inhibitory activity. These properties can be assessed, for example, using in vitro assays to study the effects of bile acid absorption in IB AT transfected cells (Smith L.5 Price-Jones MJ5 Hugnes KT Ά. Jones Ν. RA; J Biomolecular Screening, 3, 227-230), or in vivo in mice/mouse, by studying the effect of radiolabeling on bile acid absorption (Lewis MC, Brieaddy LE • 55- This paper scale applies to Chinese national standards (CNS) A4 size (210x 297 mm) 1291951

And Root C. J" J Lip Res 1995, 36, 1〇 9811〇5). In another aspect of the invention, there is provided a pharmaceutical composition comprising: a compound of formula (1) Or a pharmaceutically acceptable salt, solvent &amp; solvate of such a salt, or a prodrug thereof, accompanied by a pharmaceutically acceptable diluent or carrier. The form of administration, for example, as a tablet or sac: suitable for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or =) (form, as a sterile m float or emulsion, suitable for topical: 'made as a soft palate or cream, or suitable for rectal administration, as a suppository. System: As usual, the above composition can be prepared in a conventional manner, using a conventional formula, or a compound or a pharmaceutically acceptable compound thereof. Salts, solvates, "salts of such salts, or their prodrugs, usually in unit doses, in the range of 5 to 5000 mg of rice body sa" means ~ about ,I. Under the jin, the technique is given to warm-blooded animals, and this is provided in the case of a hanging crane; A Gong Gu #令丨田于ί疋供/口Therapeutic Effective Agent I. One unit dosage form, such as: or capsules, often contains, for example, (four) milligrams of active ingredient. Preferably, the county: in the range of (four) mg ▲ / kg, on the other hand, π The daily dose used in the range of 0.02-20 pg/kg must be changed according to the treatment of 瘵夕广, 仏, ^ 潦佰王, special foot administration and the diseased disease. ^ Person's Practitioner's Decision I (Four) Amount can be treated according to another aspect of the invention for treating any particular disease.

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1291951 A7 B7 V. Description of the invention (54) or a pharmaceutically acceptable salt, solvate thereof, solvate of such a salt, or a prodrug thereof, for use in the prevention or treatment of a warm-blooded animal such as a human The method. We have found that a compound as defined in the present invention, or a pharmaceutically acceptable salt, solvate thereof, a solvate of such a salt, or a prodrug thereof, is an effective IB AT inhibitor, and thus is in treatment and blood. There is a price hazard in the disease state associated with excess fat symptoms. Thus, according to this aspect of the invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt, solvate thereof, solvate of such a salt, or a prodrug thereof, as defined above, as a medicament use. According to another feature of the invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt, solvate thereof, solvate of such a salt, or a prodrug thereof, as defined hereinbefore, in the manufacture of a medicament For use, the agent is used to produce IB AT inhibition in a warm-blooded animal such as a human. According to another feature of the invention, there is provided a compound of formula (1), or a pharmaceutically acceptable salt, solvate thereof, solvate of such a salt, or a prodrug thereof, as defined above, in the manufacture of a medicament Use, this medicine is used to treat symptoms of hyperlipidemia in warm-blooded animals such as humans. According to another feature of the invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt, solvate thereof, solvate of such a salt, or a prodrug thereof, as defined hereinbefore, in the manufacture of a medicament For the purpose of the above, the medicament is used in the treatment of adverse symptoms and diseases of lipemia in warm-blooded animals such as humans, such as hyperlipidemia, hypertriglyceridemia, hyperlipoproteinemia (high LDL), high pre-lipoprotein Hyperemia (high VLDL), excessive chylomicrons in the blood, and low serum lipoprotein-57- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm)

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1291951 A7 B7 V. INSTRUCTIONS (55), hypercholesterolemia, hyperlipoproteinemia, and low alpha lipoproteinemia (low HDL).

According to another feature of the invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt, solvate thereof, a solvate of such a salt, or a prodrug thereof, as defined hereinbefore For manufacturing purposes, this agent is used to treat different clinical symptoms in warm-blooded animals such as humans, such as atherosclerosis, arteriosclerosis, arrhythmia, hyperthrombotic symptoms, vascular dysfunction, endothelial dysfunction, heart failure , coronary heart disease, heart and vascular disease, myocardial infarction, palpitations, peripheral vascular disease, inflammation of heart and blood vessels, such as heart, valve, blood vessel distribution, arteries and veins, aneurysms, stenosis, restenosis, vascular plaque Vascular lipid streaks, white blood cells, single-cell and/or giant sputum cell infiltration, intimal thickening, thinning of the middle vascular layer, infection and surgical trauma and vascular thrombosis, stroke and temporary episodes of seizures. According to another feature of the invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt, solvate thereof, solvate of such a salt, or a prodrug thereof, as defined hereinbefore, in the manufacture of a medicament For use, the medicament is for the treatment of atherosclerosis, coronary heart disease, myocardial infarction, palpitations, peripheral vascular disease, stroke and temporary episodes of seizures. According to a further feature of this aspect of the invention, there is provided a method of producing IB AT inhibition in a warm-blooded animal, such as a human, in need of treatment, comprising administering to the animal an effective amount of a compound of formula (I) or a pharmaceutical thereof An acceptable salt, solvate, solvate of such a salt, or a prodrug thereof. According to a further feature of this aspect of the invention, there is provided a method of treating hyperlipidemia in a warm-blooded animal, such as a human, in need of treatment, -58- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 1291951 A7 B7 V. INSTRUCTION DESCRIPTION (56) It comprises administering to the animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate thereof, solvate of such a salt, or a compound thereof Body medicine. According to a further feature of this aspect of the invention, there is provided a method of treating a lipemia adverse symptom and condition in a warm-blooded animal, such as a human, in need of treatment, such as hyperlipidemia, high glycerol S-type hyperemia, high 0 lipoproteinemia (high LDL), high pre-lipoproteinemia (high VLDL), excessive chylomicrons in blood, hypolipoproteinemia, hypercholesterolemia, hyperlipoproteinemia, and hypolipoproteinemia (low HDL) which comprises administering to the animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate thereof, solvate of such a salt, or a prodrug thereof. According to a further feature of this aspect of the invention, there is provided a method of treating different clinical conditions in a warm-blooded animal, such as a human, in need of treatment, such as atherosclerosis, arteriosclerosis, arrhythmia, hyperthrombotic symptoms, Vascular dysfunction, endothelial dysfunction, heart failure, coronary heart disease, heart and vascular disease, myocardial infarction, palpitations, peripheral vascular disease, inflammation of heart and blood vessels, such as heart, valve, blood vessel distribution, arteries and veins, Aneurysm, stenosis, restenosis, vascular plaque, vascular fat streaks, leukocyte, single cell and/or macrophage infiltration, intimal thickening, thinning of the middle vascular layer, infection and surgical trauma and vascular thrombosis, stroke and temporary An episode of episodes comprising administering to the animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate thereof, such salt solvate, or a prodrug thereof. According to a further feature of this aspect of the invention, there is provided a method for treating atherosclerosis in a warm-blooded animal such as a human in need of treatment, a coronary heart-59-this paper scale applicable to the Chinese National Standard (CNS) A4 specification (210 X 297) 1291951 A7 B7 V. Description of the invention (57) A method of disease, myocardial infarction, palpitations, peripheral vascular disease, stroke, and temporary episodes of episodes, which comprises administering to the animal an effective amount of a compound of formula (I) Or a pharmaceutically acceptable salt, solvate thereof, solvate of such a salt, or a prodrug thereof. There is evidence that IB AT inhibitors may be effective for the treatment and/or prevention of gallstones. According to a further feature of this aspect of the invention, there is provided a method of treating and/or preventing gallstones in a warm-blooded animal, such as a human, in need of treatment, comprising administering to the animal an effective amount of a compound of formula (I) or a pharmaceutical An acceptable salt, solvate, solvate of such a salt, or a prodrug thereof. The amount of dose required for treatment or prophylaxis must vary depending on the host to be treated, the route of administration, and the severity of the condition being treated. It is contemplated that the unit dosage is, for example, in the range of from 1 to 100 mg/kg, preferably from 1 to 50 mg/kg. The IBAT inhibitory activity defined above may be applied as a sole therapy or may involve one or more other substances and/or therapeutic agents in addition to the compounds of the present invention. Such co-therapy can be achieved by simultaneous, sequential or individual administration of the individual components of the treatment. According to this aspect of the invention, there is provided a pharmaceutical product comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate thereof, solvate of such a salt, or a prodrug thereof, as hereinbefore defined And another IB AT inhibitor as defined above, and another low-lipidemia for co-treatment of hyperlipidemia. In another aspect of the invention, a compound of formula (I), or a pharmaceutically acceptable salt, solvate thereof, solvate of such a salt, or a prodrug thereof, may be used with a -60- paper scale China National Standard (CNS) A4 specification (210 X 297 mm)

Binding

1291951 A7 B7 V. INSTRUCTION DESCRIPTION (58) A HMG Co-A reductase inhibitor, or a pharmaceutically acceptable salt, solvate thereof, a solvate of such a salt, or a prodrug thereof is administered together. A suitable HMG Co-A reductase inhibitor, a pharmaceutically acceptable salt, solvate thereof, a solvate of such a salt, or a prodrug thereof, is a bacteriocin known in the art. Specific bacteriocins are fluvastatin, lovastatin, pravastatin, simvastatin, and atovamycin ( Atorvastatin), cerivastatin, bervastatin, dalvastatin, mevastatin, and (Ε)·7-[4-( 4-fluorophenyl)-6-isopropyl-2-[methyl(indolylsulfonyl)amino]pyrimidin-5-yl](3R,5S&gt;3,5-dihydroxyhept-6-oxime An acid (rosuvastatin), or a pharmaceutically acceptable salt, solvate thereof, a solvate of such a salt, or a prodrug thereof. The specific bacteriocin is an Atowa bacterium Illustravastatin or a pharmaceutically acceptable salt, solvate thereof, solvate of such a salt, or a prodrug thereof. More specific bacteriostatin is an atorvastatin salt. A specific bacteriocin is (E)-7-[4-(4-fluorophenyl)isopropyl-5-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R) , 5S)-3,5-di-transgepta-5-enoic acid (rosuvastatin) Or a pharmaceutically acceptable salt, solvate thereof, solvate of such a salt, or a prodrug thereof. Preferably, the specific bacteriocin is a rosuvastatin about salt. In another aspect, the compound of formula (I), or a pharmaceutically acceptable salt, solvate thereof, solvate of such a salt, or a prodrug thereof, may be accompanied by an HMG Co-A reductase inhibitor or a pharmaceutical thereof An acceptable salt, solvate, solvate of such a salt, or a prodrug thereof, and/or a bile acid binder, to avoid the inhibition of the ileal bile acid delivery system The scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1291951

Fifth, the invention description (59 into the colon in excess of bile acid ^ towel, this danger. Over 1 bile acid contained in the internal organs! L, :::: Therefore, the present invention is also provided in patients, in the package Human: a substance or a salt thereof, a solvate thereof, which is used in the treatment of a drip or a medicinal drug thereof, for the treatment of possible by-crops ==;::: pharmaceutically acceptable The accepted salt 'endogenous cholesterol for solvent synthesis, and when used in combination with a salt of a double salt, a solvate, a solvate of such a salt, or a fa melody thereof, has an additive effect on lipid reduction. The appropriate bile acid binder for the two combination therapies is a resin, = amine and gallstone (code - item (10) tincture I can be lower than the one containing only bile acid binder - with 1 = cholesterol The therapeutic dose can also be avoided by the low-dose bile acid-adhesive action. The head-to-head is made into any of the features of the present invention, which is provided in the treatment of warm-blooded animals. For example, a method for producing a suppressive effect in humans, including the method of administering an effective amount to the animal (1) Or a pharmaceutically acceptable pharmaceutically acceptable solvate thereof, a solvate of such a salt, or a prodrug thereof, 2 = two = fixed dose of an effective amount of η, · α reductase inhibits its head a sensible salt, a solvate, or a prodrug of such a salt. 】 a mouthpiece, or thus 'in the other feature of the invention, which is provided in a need. ® National Standard (CNS) A4 Specification (210 X 297 Public 1291951 A7

A method for producing a sputum inhibitory effect in a warm-blooded animal, such as a human, which comprises administering to a mammal an effective amount of a compound of the formula (1) or a pharmaceutically acceptable salt thereof, a falling-formulation compound, and a solvent of such a salt. a drug, or a prodrug thereof, and simultaneously, sequentially or separately administered a bile acid binder. Δ, therefore, in another feature of the invention, it provides a method of producing IBAT inhibition in a needy/oral treatment of a blood-blooded animal such as a human, which comprises administering an effective amount to a child (1) a compound or hydrazine pharmaceutically acceptable <salt, solvate, solvate of such a salt, or a prodrug thereof, and the same, sequential or individual administration of an effective amount of HMG c〇_A reductase inhibitor Or a salt, a falling composition, a solvate of such a salt, or a pharmaceutically acceptable drug thereof, and a bile acid binder may be administered simultaneously, sequentially or separately. ▲ Accordingly, in another feature of the invention, there is provided a method of treating hyperlipidemia in a warm-blooded animal, such as a human, in need of treatment, comprising administering to the animal an effective amount of a compound of formula 1 or A pharmaceutically acceptable salt, solvate, solvate of such a salt, or a prodrug thereof, and the same, sequential or individual administration of an effective amount of a hmgc〇_a reductase inhibitor or its pharmaceutically effective An acceptable salt, solvate, solvate of such a salt or a prodrug thereof. Thus, in another feature of the invention, there is provided a method of treating hyperlipidemia in a warm-blooded animal, such as a human, in need of treatment, comprising administering to the animal an effective amount of a compound of formula (1) Or a pharmaceutically acceptable salt, solvate thereof, a solvate of such a salt, or a prodrug thereof, and an effective amount of a bile acid binder is administered simultaneously, sequentially or separately. Therefore, in another feature of the present invention, it provides

Binding

1291951 A7 B7 V. INSTRUCTION DESCRIPTION (61) A method of treating a symptom of hyperlipidemia in a warm-blooded animal, such as a human, comprising administering to the animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, a solvate, a solvate of such a salt, or a prodrug thereof, and an effective amount of an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable salt or solvate thereof, simultaneously, sequentially or separately. A solvate of such a salt, or a prodrug thereof, and a bile acid binder is administered simultaneously, sequentially or separately. According to another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt, solvate thereof, a solvate of such a salt, or a prodrug thereof, and The HMG Co-A reductase inhibitor, or a pharmaceutically acceptable salt, solvate thereof, solvate of such a salt, or a prodrug thereof, is accompanied by a pharmaceutically acceptable diluent or carrier. According to another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt, solvate thereof, a solvate of such a salt, or a prodrug thereof, and A bile acid binder, accompanied by a pharmaceutically acceptable diluent or carrier. According to another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate thereof, solvate of such a salt, or a prodrug thereof, And a pharmaceutically acceptable salt thereof with an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable salt, solvate thereof, a solvate thereof, or a prodrug thereof, and a bile acid binder Agent or carrier. According to another aspect of the present invention, there is provided a kit comprising a compound of the formula (I) or a pharmaceutically acceptable salt, solvate thereof, a solvate of such a salt, or a prodrug thereof, and HMG Co -A reductase inhibitor or its pharmaceutical-64-paper scale applicable to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1291951 A7 B7 V. Description of invention (62) Acceptable salts, solvates, a solvate of such a salt, or a prodrug thereof. According to another aspect of the present invention, there is provided a kit comprising a compound of the formula (I) or a pharmaceutically acceptable salt, solvate thereof, a solvate of such a salt, or a prodrug thereof, and a bile acid Adhesive. According to another aspect of the present invention, there is provided a kit comprising a compound of the formula (I) or a pharmaceutically acceptable salt, solvate thereof, a solvate of such a salt, or a prodrug thereof, and HMG Co An A reductase inhibitor, or a pharmaceutically acceptable salt, solvate thereof, a solvate of such a salt, or a prodrug thereof, and a bile acid binder. According to another aspect of the present invention, there is provided a kit comprising: a) a compound of formula (I), or a pharmaceutically acceptable salt, solvate thereof, a solvate thereof, or a prodrug thereof, In the first unit dosage form; b) an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable salt, solvate thereof, a solvate thereof, or a prodrug thereof; Dosage form; and c) a container device for containing the first and second dosage forms. According to another aspect of the present invention, there is provided a kit comprising: a) a compound of formula (I) or a pharmaceutically acceptable pharmaceutically acceptable solvate thereof, a solvate thereof, or a prodrug thereof , in the first unit dosage form; b) a bile acid binder; in a second unit dosage form; and c) a container device for containing the first and second dosage forms. According to another aspect of the present invention, there is provided a kit comprising: a) a compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof, the salt-65- the paper scale is applicable to the Chinese national standard ( CNS) A4 size (210 X 297 mm) 1291951 A7 B7 V. The solvate of the invention (63), or its prodrug, is in the first unit dosage form; b) HMG Co-A reductase inhibitor Or a pharmaceutically acceptable salt, solvate thereof, a solvate of such a salt, or a prodrug thereof; in a second unit dosage form; c) a bile acid binder; in a third unit dosage form; And d) a container for containing the first, second and third dosage forms

According to another aspect of the present invention, there is provided a kit comprising: a) a compound of formula (I), or a pharmaceutically acceptable salt, solvate thereof, a solvate thereof, or a prodrug thereof, a first unit dosage form with a pharmaceutically acceptable diluent or carrier; b) an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable salt, solvate thereof, or a solvent thereof Or a prodrug thereof, in a second unit dosage form; and c) a container device for containing the first and second dosage forms. According to another aspect of the present invention, there is provided a kit comprising: a) a compound of formula (I), or a pharmaceutically acceptable salt, solvate thereof, a solvate thereof, or a prodrug thereof, a first unit dosage form with a pharmaceutically acceptable diluent or carrier; _b) a bile acid binder in a second unit dosage form; and c) for containing the first and second dosage forms A container device in the form of a dosage form. According to another aspect of the present invention, there is provided a kit comprising: a) a compound of the formula (1) or a pharmaceutically acceptable salt, solvate thereof, a solvate of such a salt, or a prodrug thereof, accompanied by Pharmaceutically acceptable dilution -66- This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1291951 A7

Agent or carrier, in the first unit dosage form; : HMGCo-A reductase inhibitor or a pharmaceutically acceptable substance thereof, a solvate of such a salt, or a mouth-filled J mouth form and a body music, Wang Hao two unit agents c) bile acid binder; d) to accommodate the first unit in a third unit dosage form; and a younger brother and two dose forms of the container according to Another feature of the present invention provides a compound of the formula (1) or a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of such a salt, or a prodrug thereof and an HMG Co-A reductase inhibitor Or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt thereof, a solvate of such a salt, or a prodrug thereof, for use in the manufacture of a medicament for use in the production of a warm-blooded animal such as a human IB AT inhibition. According to another feature of the invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt, solvate thereof, solvate of such a salt, or a prodrug thereof, with a bile acid binder, For pharmaceutical manufacturing purposes, the agent is used to produce IB A inhibitory effects in warm-blooded animals such as humans. According to another feature of the invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt, solvate thereof, solvate of such a salt, or a prodrug thereof, and HMG Co-A reductase An inhibitor, or a pharmaceutically acceptable salt, solvate thereof, a solvate thereof, or a prodrug thereof, and a bile acid binder, for use in the manufacture of a medicament, such as in a warm-blooded animal Used in humans to produce IB AT inhibition. According to another feature of the invention, it is provided that the compound of formula (1) or its pharmaceutical-67-paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 1291951 A7 B7 5. The invention description (65) is acceptable a salt, a solvate, a solvate of such a salt, or a prodrug thereof, an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable salt, solvate thereof, a solvate thereof, Or a prodrug thereof for use in the manufacture of a medicament for the treatment of hyperlipidemia in a warm-blooded animal such as a human. According to another feature of the invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt, solvate thereof, solvate of such a salt, or a prodrug thereof, a bile acid binder, in a medicament For manufacturing purposes, the agent is used to treat hyperlipidemia in warm-blooded animals such as humans. According to another feature of the invention, there is provided a compound of formula (1), or a pharmaceutically acceptable salt, solvate thereof, solvate of such a salt, or a prodrug thereof, HMG Co-A reductase inhibitor or a pharmaceutically acceptable salt, a solvate thereof, a solvate of such a salt, or a prodrug thereof, and a bile acid binder, for use in the manufacture of a medicament, which is in a warm-blooded animal such as a human. For the treatment of hyperlipidemia symptoms. According to another aspect of the present invention, there is provided a combination therapy comprising administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, to a warm-blooded animal, such as a human, in need of treatment. a solvate of such a salt, or a prodrug thereof, optionally accompanied by a pharmaceutically acceptable diluent or carrier, and simultaneously, sequentially or separately administered an effective amount of an HMG Co-A reductase inhibitor or A pharmaceutically acceptable salt, solvate, solvate of such a salt, or a prodrug thereof, optionally accompanied by a pharmaceutically acceptable diluent or carrier. According to another aspect of the present invention, a combination treatment is provided, which is packaged in a Chinese standard (CNS) A4 size (210X 297 mm) 1291951 A7 B7 5. Inventive Note (66) An effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate thereof, a solvate of such a salt, or a prodrug thereof, is administered to a warm-blooded animal, such as a human, in need of treatment, as appropriate A pharmaceutically acceptable diluent or carrier is administered, and an effective amount of the bile acid binder is administered simultaneously, sequentially or separately, optionally with a pharmaceutically acceptable diluent or carrier.

According to another aspect of the present invention, there is provided a combination therapy comprising administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, to a warm-blooded animal, such as a human, in need of treatment. a solvate of such a salt, or a prodrug thereof, optionally accompanied by a pharmaceutically acceptable diluent or carrier, and simultaneously, sequentially or separately administered an effective amount of an HMG Co-A reductase inhibitor or A pharmaceutically acceptable salt, solvate, solvate of such a salt, or a prodrug thereof, optionally accompanied by a pharmaceutically acceptable excipient, and administered simultaneously, sequentially or separately, in an effective amount of bile The acid binder is optionally accompanied by a pharmaceutically acceptable diluent or carrier. According to still another aspect of the present invention, there is provided a combination therapy comprising administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, to a warm-blooded animal, such as a human, in need of treatment. a solvate of such a salt, or a prodrug thereof, optionally accompanied by a pharmaceutically acceptable diluent or carrier, and simultaneously, sequentially or separately administered one or more of the following agents, selected from: &gt; CETP (cholesteryl ester transfer protein) inhibitors, for example, as described and described in WO 00/38725, page 7, line 22 - page 10, line 17, which is incorporated herein by reference.

&gt;Cholesterol absorption antagonists, such as nitroxanthone, such as SCH-69- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1291951 A7 ------ B7_^ _ V. </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; 54, as described in 1998, which is incorporated herein by reference; &gt; fibric acid derivatives; for example, clofibrate, gemfibrozil, fenofibrate, Ciprofibrate and bezafibrate; &gt;nicotinic acid derivatives such as nicotinic acid (nicotinic acid), acipimox and acid pentaerythritol@ &gt; phytosterol compounds, such as stanol; &gt;probucol;&gt; anti-obesity compounds, such as 〇rlistat (EP 129, 748) and Heb Sibutramine (GB 2,184,122 and US 4,929,629); &gt; antihypertensive compounds such as angiotensin converting enzyme (ACE) Agent, angiotensin II receptor antagonist, adrenergic blocker, alpha adrenergic blocker, adrenergic blocker, mixed alpha/cold adrenergic blocker, adrenergic stimulant, Calcium channel blockers, diuretics or vasodilators; &gt;Insulin;&gt; Continued guanylureas, including glyburide, sulfobutamide, etc.; &gt;Metformin; and/or &gt; Acarbose Or a pharmaceutically acceptable salt, solvate thereof, solvate of such a salt, or a pharmaceutically acceptable drug thereof, optionally accompanied by a pharmaceutically acceptable diluent or carrier 0 ___ -70- the paper The scale applies to China National Standard (CNS) A4 specification (21〇x297 mm) 1291951 A7 B7 V. Description of invention (68) Specific ACE inhibitor or its pharmaceutically acceptable salt, solvate, solvent combination of such salt And a prodrug thereof, comprising an active metabolic product, which may be used in combination with a compound of formula (I), including but not limited to the following compounds: aracepril, alatriopril, alteop.利 (altiopril) mom, Anke Zining (ancov Enin), benazepril, benazepril hydrochloride, benazeprilat, benzoylcaptopril, cappuccino Captopril, captopril-cysteine, captopril-glutabolin, ceranapril, ceranopril ), ceronapril, cilazapril, cilazaprilat, delapril, delaipl-diacid, ampere Nellapril, enalaprilat, enapril, epipaptopril, foroxymithine, and versatile Fosfenopril), fosenopril, fosenopril sodium, fosinopril, fosinopril sodium, fosinoprilat, fosinoprilat New language, fosinoprilic acid, glycolyril, hemorphin-4, idrapril ), imidapril, indolapril, indolaprilat, libenzapril, lisinopril, come west Ming (lydumin) A, lyciumin B, mixanpril, moexipril, moexiprilat, movertipril , muracein A, muracein B, muracein C, pent〇pril, perindopril, Palindo Perindoprilat, pivalopril, Pipouli ____-71 -_ This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1291951 A7 B7 V. Description of invention (69) (pivopril), quinapril, quinapril hydrochloride, quinaprilat, ramipril, ramipril (ramiprilat) ), history p raprapril, history ^: spirapril hydrochloride, schizoprilat, history Spiropril, spiropril hydrochloride, temocapril, temocapril hydrochloride, dermatitis, tellan Trandolapril, trandolaprilat, utibapril, zabicipril, zabiciprilat, febupripril (zofenoprii) and sitting on non-professional (zofenoprilat). Preferred ACE inhibitors for use in the present invention are ramipril, ramiprilat, lisinopril, enalapril and anna Laplet (enalaprilat). Preferred ace inhibitors for use in the present invention are ramipril and ramiprilat. Preferred angiotensin II antagonists for use in combination with a compound of formula (I), pharmaceutically acceptable salts, solvates thereof, solvates of such salts, or prodrugs thereof, include but are not limited to the following compounds : candesartan, candesartan cilexetil, losartan, valsartan, irbesartan, tasolartan (tassartan) Tasosartan), telmisartan and eprosartan. A particularly preferred angiotensin antagonist antagonist or a pharmaceutically acceptable derivative thereof for use in the present invention is candesartan and candesartan cilexetil In another aspect of the invention, the compound of the formula (I) or a pharmaceutically acceptable salt, solvate thereof, a solvate of the salt, or a prodrug thereof, may be accompanied by PPAR α and/or r Activator or its pharmaceutically acceptable salt, solvent __-72- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1291951 A7 B7__._ V. Invention description (7Q) A solvate of such a salt, or a prodrug thereof, is administered together. Suitable PPAR alpha and/or r agonists, pharmaceutically acceptable salts, solvates, solvates thereof, or prodrugs thereof, are known in the art. It is included in W0 01/12187, W0 01/12612, W0 99/62870, W0 99/62872, WO 99/62871, WO 98/57941, WO 01/40170, J Med Chem. 1996, 39, The treatment of patents, 10 (5), 623-634 (especially the compounds described in the patent application listed on page 634) and the compounds described in J Med Chem. 2000, 43, 527, All of them are incorporated herein by reference. In particular, PPAR and/or r catalyzers refer to WY-14643, chlorophenyl butyl ketone, fenofibrate, bezafibrate, GW 9578, Zhuo Ge Ta Zong ( Troglitazone), pioglitazone, rosiglitazone, eglitazone, proglitazone, BRL-49634, KRP-297, JTT-501, SB 213068, GW 1929, GW 7845, 0”0207, 1^796449, 1^165041 and 0 。 2433. In particular, α and/or r catalyzer means (S)-2-ethoxy Base-3-[4-(2-{4-decanesulfonyloxyphenyl}ethoxy)phenyl]propionic acid and pharmaceutically acceptable salts thereof] Therefore, another aspect of the invention In a feature, it provides a method of producing IBAT inhibition in a warm-blooded animal, such as a human, in need of treatment, comprising administering to the animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, a solvent composition, a solvate of such a salt, or a prodrug thereof, and an effective amount of PPAR α and/or r agonist or a pharmaceutically acceptable salt thereof, simultaneously, sequentially or separately, a solvate, a solvate of such a salt, or a prodrug thereof. Therefore, in another feature of the present invention, it provides a Chinese National Standard (CNS) for use on a paper scale of _-73- A4 size (210X297 mm) 1291951 A7 B7 V. Description of the invention (71) A method for treating a symptom of hyperlipidemia in a warm-blooded animal, such as a human, comprising administering to the animal an effective amount of a compound of formula (I) or A pharmaceutically acceptable salt, solvate, solvate of such a salt, or a prodrug thereof, and administered simultaneously, sequentially or separately, in an effective amount of a PPAR π and/or r agonist or pharmaceutically acceptable a salt, a solvate, a solvate of such a salt, or a prodrug thereof. According to another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable compound thereof a salt, a solvate, a solvate of such a salt, or a prodrug thereof, in combination with a PPAR alpha and/or r agonist or a pharmaceutically acceptable salt, solvate thereof, or a solvent thereof Drug, or its prodrug, accompanied by pharmaceutically acceptable A release or carrier. According to another aspect of the invention there is provided a kit comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate thereof, solvate thereof, or a prodrug, and a PPAR alpha and/or r agonist, or a pharmaceutically acceptable salt, solvate thereof, a solvate thereof, or a prodrug thereof. According to another aspect of the invention, Provided is a kit comprising: a) a compound of formula (I), or a pharmaceutically acceptable salt, solvate thereof, solvate of such a salt, or a prodrug thereof, in a first unit dosage form; b) a PPAR alpha and/or r agonist, or a pharmaceutically acceptable salt, solvate thereof, a solvate thereof, or a prodrug thereof; in a second unit dosage form; and c) To accommodate the container means of the first and second dosage forms. According to another aspect of the present invention, there is provided a kit comprising: -74- The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X 297 mm)

1291951 A7 B7 V. INSTRUCTION DESCRIPTION (72) a) a compound of formula (I), or a pharmaceutically acceptable salt, solvate thereof, solvate of such a salt, or a prodrug thereof, accompanied by pharmaceutically acceptable a diluent or carrier in the first unit dosage form; b) a PPAR alpha and/or r agonist or a pharmaceutically acceptable salt, solvate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof a body drug in a second unit dosage form; and c) a container device for containing the first and second dosage forms. According to another feature of the invention, there is provided a compound of formula (1), or a pharmaceutically acceptable salt, solvate thereof, solvate of such a salt, or a prodrug thereof, with PPAR alpha and/or r Or a pharmaceutically acceptable salt, solvate thereof, solvate of such a salt, or a prodrug thereof, for use in the manufacture of a medicament for the production of IB AT in a warm-blooded animal such as a human Inhibition. According to another feature of the invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt, solvate thereof, solvate of such a salt, or a prodrug thereof, PPAR alpha and/or r An agent or a pharmaceutically acceptable salt, solvate thereof, a solvate of such a salt, or a prodrug thereof, for use in the manufacture of a medicament for the treatment of blood in a warm-blooded animal such as a human. Excessive symptoms of fat. According to another aspect of the present invention, there is provided a combination therapy comprising administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, to a warm-blooded animal, such as a human, in need of treatment. A solvate of such a salt, or a prodrug thereof, optionally accompanied by a pharmaceutically acceptable diluent or carrier, and administered simultaneously, sequentially or separately, in an effective amount of PPAR alpha and /75. Applicable to Chinese National Standard (CNS) Α4 Specification (210X 297 mm) 1291951 A7 _____B7 V. Description of Invention (73) or r-catalyst or its pharmaceutically acceptable salt, solvate, solvate of such a salt, Or a prodrug thereof, optionally accompanied by a pharmaceutically acceptable diluent or carrier. a compound of the formula (I), or a pharmaceutically acceptable salt, solvate thereof, a solvate thereof, or a prodrug thereof, in addition to its use in therapeutic medicine, may be in vitro and in vivo. Test System i was developed and standardized as a pharmacological tool to assess the role of IB AT inhibitors in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice as part of a search for new therapeutic agents . Many of the intermediates described herein are novel and are therefore provided as another feature of the invention. For example, the compounds of the formula (Villa), (vnib), (IXa), (IXb), (Xllla) and (Xlllb), when tested in the in vitro test described above, show IB AT inhibitory activity, thus The request is another feature of the invention. Thus, in another feature of the invention, there is provided a compound of formula (VIIIa), (Vlllb), (IXa), (IXb), (Xllla) or (Xlllb), or a pharmaceutically acceptable salt thereof, a solvate, a solvate of such a salt, or a prodrug thereof. Thus, according to another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound (Villa), (Vlllb), (IXa), (IXb), (X_IHa) or (Xlllb) compound as defined above, Or a pharmaceutically acceptable lysine, solvate, solvate of such a salt, or a prodrug thereof, accompanied by a pharmaceutically acceptable diluent or carrier. According to another aspect of the present invention, there is provided a compound of the formula (Villa), (Vlllb), (IXa), (IXb), (Xllla) or (X11lb), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, Solvate, solvate of this salt, or its prodrug-76- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) ' '

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k 1291951 A7 B7 V. INSTRUCTIONS (74) For use in methods for the prevention or treatment of warm-blooded animals such as humans. Thus, according to this aspect of the invention, there is provided a compound of the formula (Villa), (Vlllb), (IXa), (IXb), (Xllla) or (X11lb) as defined above, or a pharmaceutically acceptable salt thereof A solvate, a solvate of such a salt, or a prodrug thereof, for use as a medicament. According to another feature of the invention, there is provided a compound of the formula (Villa), (Vlllb), (IXa), (IXb), (Xllla) or (X11lb), or a pharmaceutically acceptable salt thereof, or a solvent thereof A compound, a solvate of such a salt, or a prodrug thereof, for use in the manufacture of a medicament for the production of IB AT inhibition in a warm-blooded animal such as a human. According to another feature of the invention, there is provided a compound of the formula (Villa), (Vlllb), (IXa), (IXb), (Xllla) or (X11lb), or a pharmaceutically acceptable salt thereof, as hereinbefore defined A solvate, a solvate of such a salt, or a prodrug thereof, for use in the manufacture of a medicament for the treatment of hyperlipidemia in a warm-blooded animal such as a human. According to a further feature of this aspect of the invention, there is provided a method of producing an inhibitor of IB A in a warm-blooded animal, such as a human, in need of treatment, comprising administering to the animal an effective amount of a formula (Villa), ( Vlllb), (IXa), (IXb), (Xllla) or (Xlllb) a compound, or a pharmaceutically acceptable winter salt, solvate thereof, a solvate of such a salt, or a prodrug thereof. According to a further feature of this aspect of the invention, there is provided a method of treating hyperlipidemia in a warm-blooded animal, such as a human, in need of treatment, comprising administering to the animal an effective amount of a Villa, (Vlllb), (IXa), (IXb), (Xllla) or (Xlllb) compound, or a pharmaceutically acceptable salt or solvate thereof ____-77-_ This paper scale applies to China National Standard (CNS) A4 specification (210X297 PCT)

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1291951 A7 B7 V. INSTRUCTIONS (75), a solvate of such a salt, or a prodrug thereof. Among the other pharmaceutical compositions, processes, methods, uses, and pharmaceutical manufacturing characteristics described above, alternatives and preferred embodiments of the compounds of the invention described herein are also applicable. EXAMPLES The invention will now be illustrated in the following non-limiting examples, in which standard techniques known to the skilled chemist, and techniques similar to those described in the examples, may be used where appropriate, and wherein, unless otherwise stated, : (i) Evaporation is carried out in the open air by rotary evaporation, and the treatment is carried out after filtration to remove residual solids such as desiccant; (ii) all reactions are carried out under inert atmosphere at ambient temperature, typically The upper system is in the range of 18-25 ° C, using HPLC grade solvent, under anhydrous conditions, unless otherwise stated; (iii) Column chromatography (by rapid procedure) is based on silicone 40-63 micron ( (iv) The yields given are for illustrative purposes only and are not necessarily the maximum achievable enthalpy; (7) The structure of the final product of formula (I) is generally by nuclear (usually proton) magnetic resonance (NMR) Confirmed with mass spectrometry; the magnetic resonance chemical shift enthalpy is measured in deuterated CDC13 (unless otherwise stated) on the d scale (ppm from the low magnetic field of tetramethyl decane); proton data is quoted unless otherwise Said; the spectrum is recorded Varian Mercury-300 MHz, Varian Unity plus-400 MHz, Varian Unity plus-600 MHz, or on a Varian Inova-500 MHz spectrometer, unless otherwise noted, data is recorded at 400 MHz; and absorption peak multiplicity Displayed as follows: s, single peak; d, double peak; dd, double doublet; t, three-78- This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm)

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1291951 A7 B7 V. Invention description (76) Heavy peak; tt, triple triplet; q, quadruple peak; tq, triple quadruple peak; m, multiple peak; br, broad; ABq, AB quadruple ; ABd, AB double peak, ABdd, AB doublet double peak; dABq, AB quadruple peak; LCMS system green on Waters ZMD, LC column xTerra MS C8 (Waters), installed HP 1100 MS-detector diode array detection; mass spectrometry (MS) (loop) is recorded on VG Platform II (Fisons instrument) with HP-1100 MS-detector diode array; It is also mentioned that otherwise the mass ion referred to is (MH+); unless further details are specified herein, No. 1J Analytical High Performance Liquid Chromatography (HPLC) is based on Prep LC 2000 (Waters), Cromasil C8, 7 micron (Akzo Nobel); MeCN and deionized water 10 mM ammonium acetate as mobile phase, with appropriate composition; (vii) Intermediates are usually not fully characterized, and purity is by thin layer Evaluation by analytical (TLC), HPLC, infrared (IR), MS or NMR analysis; (viii) in the case of dehydration of the solution, Sodium is a desiccant; (ix) in the case of the reference &quot;ISOLUTE" column, this means that the column contains 2 grams of silicone, which is contained in a 6 ml disposable syringe and 54 A pore size porous disc support, "is〇LUTE, the name is obtained from International Sorbent Technology Company; &quot;ISOLUTE, is a registered trademark; (8) The following abbreviations can be used in the previous or following: DCM di-methane; DMF N,N-dimethylformamide; TBTU tetrafluoroborate o-benzotriazole small group with vanadyl 1 ^-tetramethyl hydrazine;

EtOAc EtOAC ;

MeCN acetonitrile; _ -79- — This paper scale applies to China National Standard (CNS) A4 specification (2i〇X297 mm)

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1291951 B7

1291951 A7 B7 V. INSTRUCTIONS (78 3 H each bd6〇c: 4 ό (300 MHz, CD3OD) 0.75-0.85 (m, 6H), 1.0-1.6 (m, 12H), 2.2 (s, 3H), 3.75 (brs, 2H), 3.25 (s, 2H), 4.6-4.7 (m, 2H), 5.7^s, 1H), 6.7 (s, 1H), 6.9-7.3 (m, 8H), 7.4 (s, 1H Method 31 4 FF F 4 ό (300 MHz, CD30D) 0.75-0.9 (m, 6H), 1.0-1.6 (m, 12H), 2.2 (s, 3H), 3.25 (s, 2H), 3.75 (brs , 2H), 4.6-4.8 (m, 2H), 5.45 (s, .1H), 6.7 (s, 1H), 6.95-7.3 (m, 5H), 7.4 (s, 1H), 7.6 (s, 4H) Method 32 5 HO 〇0, PX〇cC ό (500 MHz) 0.7-0.8 (m, 6H), 1.0-1.6 (m, 12H), 3.2 (brs, 2H), 3.6 (brs, 2H), 4.48 (m , 2H), 5.0 (s, 1H), 6.5 (d, 1H), 6.7-7.4 (m, 10H), 7.9 (s, 1H) Method 39 6 ό (DMSO-d^) 0.7-0.8 (m, 6H ), 0.9-1.6 (m, 12H), 3.2 (brs, 2H), 3.7 (brs, 2H), 4.6-4.8 (m, 3H), 6.6 (d, 2H), 6.9-7.3 (m, 8H), 7.4 (s, 1H), 8.3 (d, 1H) Method 40 7 M/z = 768.9 Method 67 Pack 1 81 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public) 1291951 A7 -- ----—___________B7_ V. Description of invention (79) (300 MHz, CD3〇D) 0.75-0.9 million

(m, 6H), 1.0-1.25 (m, 4H), 1.4-42 1.6 (m, 4H), 2.15 (s, 3H), 3.1-3.3 (m, 4H), 3.5-3.8 (m, 5H), 4.75 (ABq, 2H), 5.45 (s, 2H),

rN^0 6.75 (s, 1H), 6.95-7.5 (11H); m/z 711.3

(500 MHz, DMSO-d6) 0.7-0.8 (m, 6H), 0.9-L6 (m, 12H), 2.2 (s, 3H) 3.2-3.8 (m, 8H), 4.8 (ABq, 2H), 5.6 ( d, 1H), 6.7 (s, 1H), 6.8-7.5 (m, 11H), 7.8 (brs, 1H), 8.6 (d, 1H), 8.8 (t, 1H) Ethanol instead of HPLC1 purification, using MeCN Example 1 with a buffer of acetic acid 1 (55: 45) as a dissolving agent. 10 phenyl-7-bromo, -indolyl]ethyl 5-tetrahydro-1,5-alum, sulphur, heptadecene -Diketo-3-butyl-3-ethylphenylphenylj-bromo-based winter {1W(RHL phenyl)-polymethoxycarbonylmethyl)amine-methylidene]ethoxy brom 2,3,4&gt; Tetrahydro '5-benzothiazepine heptarene (Method 33; 1 〇 3 mg, 0.15 mmol) was dissolved in a mixture of Ding and Qiao ^ 3 mL). Li〇H (7 mg, 〇·3 mmol) was added and the mixture was stirred at ambient temperature for 7 hours. Most of the solvent was removed under reduced pressure, and the crude product was purified by preparative HPLC using EtOAc (EtOAc: EtOAc (EtOAc: EtOAc) The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1291951 A7 B7 V. Description of invention (80) NMR (DMSO-d6) 0.60-0.80 (m, 6H), 0.90- 1.60 (m, 11H), 3.15-3.45 (m, 2H), 3.50-3.90 (m, 2H), 4.95-5.25 (m, 2H), 6.85-7.55 (m, 12H), 8.55-8.95 (m, 1H) Example 11-16 The following compounds were synthesized by the procedure of Example 10 using the appropriate starting materials. 0 -83- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1291951 V A7 B7 DESCRIPTION OF THE INVENTION (81) Example compound NMR SM 11 ° 〇c〇c,... ό ((CD3)2CO) 0.70-0.90 (m, 6H), 0.95-1.35 (m, 4H), 1.40-1.75 (m , 4H), 3.15-3.35 (m, 2H), 3.80 (brs, 2H), 5.40 (d, 1H), 5.90-6.15 (2s, 1H), 6.95-7.75 (m, 18H) Method 34 12 9. 〇C〇C ό (CD3OD) 0.75-0,85 (m, 6H), L00-1.30 (m, 8H), 1.35-1.55 (m, 4H), 3.20 (s, 2H), 3.60 (s, 3H) , 3.75 (brs, 2H), 4.60 (ABq, 2H), 5.40 (s, 1H), 6.50 (s, 1H), 6.95-7.45 (m, 10H), 7.55 (s, 1H) Method 35 13 ho^nY^ n^, qp ° 〇C〇cC ό (CD3OD) 0.75-0.85 (m, 6H), 1.00-L30 (m, 8H), 1.35-1.55 (m, 4H), 3.20 (s, 2H), 3.55 (s , 3H), 3.75 (brs, 2H), 3.90 (ABq, 2H), 4.60 (ABq, 2H), 5.60 (s, 1H), 6.50 (s, 1H), 6.95-7.45*(m, 10H), 7.55 (s, 1H) Method 36 14 ° CC〇cC ό · (CD3OD) 0.75-0.85 (m, 6H), 1.00-L30 (m; 8H), 1.35-1.60 (m, 4H), 3.20 (s, 2H) , 3.60 (s, 3H), 3.75 (brs, 2H), 4.55 (ABq, 2H), 5.55 (s, 1H), 6.50 (s, 1H), 6.95-7.45 (m, 9H), 7.50 (s, lH · Method 37 -84- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1291951 A7 B7 V. Invention description (82) 15 ^0. 0〇〇cC ό - (CD3OD) 0.75-0.85 (m, 6H), 1.00-1.30 (m, 8H), 1.35-1.60 (m, 4H), 2.15 (s, 3H), 3.25 (s, 2H), 3.75 (brs, 2H), 4.65 (ABq, 2H), 5.60 (s, 1H), 6.70 (s, 1H), 6.90-7.45 (m, 10H) Method 38 16 .ό (CD3OD) 7.55-7.41 (3H, m), 7.35-7.20 (5H, m), 7.15-7Ό8 (3H, m), 7.04-6.98 (1H, m), 548-5.32 (1H, m), 4.80-4.60 (2H, m), 4.00- 3.56 (4H, m), 3.27-3,22 (2H, m), 1.61-LOO (11H, m), 0.83-0.74 (6H, m) Method 70 Example 17 1,_1-diketo-3-butene -3-ethyl-5-phenyl•7-bromo-8-rN-((SH'-phenylcarboxymethyl)_-)methanylmethyl chloride 1-2,3,4,5 -tetrahydro-1,5-benzoquinonesulfazytitol, 1,1-diketo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-[N-( (S)-r-phenyl-1,-methoxycarbonylmethyl)amine-mercaptomethoxy]-2,3,4,5-tetrahydro-1,5-benzoquinonesulfurium heptadecene ( Method 46; 60 mg, 0.091 mmol, dissolved in THF (1 mL) and added to lithium hydroxide monohydrate (12.6 mg, 0·29 mmol) in water (1 mL) Within the solution, the mixture was occasionally stirred for 30 minutes. Add 2 Μ HC1 solution (0.3 The aqueous layer was extracted with EtOAc (EtOAc) (EtOAc). -0·84(m,6H),l·0- 1.6 (m, 8H), 3.27 (brs, 2H), 3.60-3..90 (m5 2H), 4.71 (ABq, 2H)5 5.47-5.55 ( m, ___-85-__ This paper size is applicable to China National Standard (CNS) A4 specification (210 x 297 mm) 1291951 A7 B7 V. Invention description (83) 1H), 7.02 (brt, 1H), 7.08-7.17 ( m, 3H), 7.25-7.46 (m, 7H), 7.52 (s, 1H), 8.43 (d, NH); m/z 643.5. Example 18-21 The following compounds were prepared by the procedure of Example 17 Start material synthesis. -86- This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1291951 A7 B7 V. Description of invention (84) Example compound NMR or m/z SM 18 1 〇〇Μ/ζ 670 (Μ +ΝΗ/) Method 43 19 2, / 1 0 (CD30D) 0.7CWX90 (m,6Η),1·0· 1·32 (m,4Η), 1.32-1.70 (m,4Η), 2.15 (s, 3H ), 2.85 (brs, 3H), 3.23 (brs, 2H), 3.53-3.93 (m, 2H), 4.99 (ABq, 2H), 6.27 (s, 1H), 6.71 (s, 1H), 6.94 (t, 1H), 7Ό7 (d, 2H), 7.25 (t, 2H), 7.3-7.47 (m, 6H); m/z 625.3 Method 62 20 ο (CD30D) 0.75-0.84 (m, 6H), L0-1.29 ( m, 4H), 1.36-L65 (m, 4H), 2.15 (s, 3H), 2.82-2.97 (m, 2H), 3.22 (brs, 2H), 3.6-3.85 (m, 2H), 4.66 (ABq, (2, H) 625.4 Method 112 21 Ο (600 MHz, CD3OD) 0,77-0.88 (m, 6H), 1.0-132 (m, 4H), 1.39-L70 (m, 4H), 2.16 (s, 3H), 2.88 (brs , 3H), 3.25 (brs, 2H), 3,52-3·93 (m, 2H), 5.03 (ABq, 2H), 6.28 (s, 1H), 6.73 (s, 1H), 6.96 (t, 1H ), 7.09 (brd, 2H), 7-27 (t, 2H), 7.32-7.46 (m, 6H) · Method 79 _ - 87- This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1291951 A7 B7 V. Description of invention (85) 1 2.2 equivalent of LiOH in THF / water (4 / 1) 2 by preparatory HPLC Purification, using MeCN / ammonium acetate buffer gradient (5/95 to contact / oxime) as the dissolving agent example 22 U·-diketo-3-butyl-3-ethyl-5-phenyl; bromo- 8-rN-((R)-l,-phenyl-1,-carboxymethylamine-methyl methoxyl 1-2,3,4,5-tetrahydro-1,5- stupid #thiazeazin The title compound is derived from 1,1-dione-3-but-3-ethyl-5-phenyl-7-bromo each [N-((R)-lf-phenyl-1L methoxycarbonyl) Methyl) Aminomethyl methoxymethyl 3,4,5-tetrahydro-1 1,5-benzothiazepine sulphate (Method 61), synthesized by the procedure of Example 17, except that the aqueous layer was extracted with EtOAc . The product was purified by preparative HPLC using a MeCN / ammonium acetate buffer gradient (5/95 to 100/0) as the solvent. NMR 0.75-0.83 (m, 6H), 1.0-1.25 (m, 4H), 1.32-1.52 (m, 3H), 1.55-1.70 (m, 1H), 3.20 (ABq, 2H), 3_65-3.83 (m, 2H), 4.62 (ABq52H), 5.68 (d, lH), 7.04-7.15 (m, 4H), 7.3-7.5 (m, 8H), 7.87 (brd, 1H); m/z 643.1 · Example 23 1,1 -Diketo-3-butylethylethyl-5-phenyl-7-bromo-8-(N-indole (SH,- phenyl) (2- continued 1-ylethyl)amine carbhydryl 1丨 丨 醯 醯 甲 methoxy) 2,3,4,5-tetra-1 1,5-benzoquinone sulphide heptadecene ammonium salt U-diketo-3-butyl-3-ethyl- 5-phenyl-7-.glycine-8-[N-((S)-l,-phenylheptacarboxymethyl)amine-carbenylmethoxy]-2,3,4,5-tetrahydro -1,5-benzoquinonesulfurium heptadecene (Example 17; 48 mg, 0.075 mmol) and 2-aminoethanesulfonic acid (17 mg, 0·Μ mmol) dissolved in DMF (2 mL) ) with DIPEA (0.052 ml, 〇·3 〇亳 Mo). The mixture was stirred at 60 ° C for 15 minutes. TBTU (31 gram, 0.097 mmol) was added and the mixture was at 60 ° C. Stir for 2 hours.

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-88- 1291951 A7 B7 V. Evaporation of solvent under invention (86). The residue was purified by preparative HPLC using a MeCN / ammonium acetate buffer gradient (5/95 to 100/0) as a solvent. Lyophilized to give the title compound 4 mg (7 %). NMR (CD3 OD) 0.75-0.83 (m, 6H), 0.95-1.65 (m, 8H), 2.85-3.0 (m, 2H), 3.27 (brs, 2H), 3.5-3.9 (m, 4H), 4.72 ( ABq, 2H), 5.48 (s, 1H), 7.02 (brt, 1H), 7.09-7.15 (m, 3H), 7.25-7.52 (m, 8H); m/z 750.3. Example 24-37 Made by the same procedure. This acid (1 eq.) was dissolved in THF (1 mL) and taken to a solution of lithium hydroxide monohydrate (12.6 mg, 2.9-6.6 eq.) in water (1 mL). The mixture was occasionally stirred and deprotected (according to LC-MS) after 1.5-6 hours. Add 2M HCl solution (〇·3 ml). Examples 24-33 The reaction mixture was placed on a hydramatrix® filled syringe. The product was dissolved in DCM. The DCM was dried under reduced pressure, filtered and evaporated under reduced pressure. The product was purified by preparative HPLC using a MeCN / ammonium acetate buffer gradient (5/95 to 100/0) as the solvent. -89- The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1291951 A7 B7 V. Description of the invention (87) Example 34-37 The aqueous layer was extracted twice with DCM. The organic layer was dried under reduced pressure, filtered and evaporated under reduced pressure. EXAMPLES Compound NMR (CD3OD) m/z SM 24 9. . . 0 0.75-0.84 (m, 6H), 1.0-1.25 (m, 4H), 1.37-1.65 (m, 4H), 3.20 (brs, 2H), 3.55-3.90 (m, 5H), 4.58 (ABq, 2H) , 5.33 (s, 1H), 6.51 (s, 1H), 6.97 (brt, 1H), 7.12 (brd, 2H), 7.2-7.33 (m, 5H), 7.41 (brd, 2H), 7.54 (s, 1H 595.4 Method 47 25 0〇- 〇〇ό 0.73-0.85 (m, 6H), 1.0-1.3 (m, 4H), L35-1.65 (m, 4H), 2.17 (s, 3H), 3.23 (brs, 2H) ), 3.55-3.90 (m, 2H), 4.71 (ABq, 2H), 5.49-5.52 (m, 1H), 6.73 (s, 1H), 6.96 (brt, 1H), 7.10 (brd, 2H), 7.23- 7.45 (m, 8H), 836 (brd) NH) 611.2 Method 48 _-90- This paper scale applies to Chinese National Standard (CNS) A4 size (210 X 297 mm) 1291951 A7 B7 V. Description of invention (88) 26 . 9. . . ό 0.74-0.84 (m, 6Η), 1.0-1.3 (m? 8H), 1.37-1.54 (m, 4H), 3.28 (brs, 2H), 3.65-3.85 (m, 2H), 4.72 (ABq, 2H) , 5.49-5.52 (m, 1H), 7.04 (brt, 1H), 7.09-7,18 (m, 3H), 7.28-7.46 (m, 7H), 7.52 (s, 1H), 8.45 (brd, NH) 671.2 Method 49 27 Each. ό 0.74-0.84 (m, 6H), 1.0-1.3 (m, .4H), 1.35-1.65 (m, 4H), 3.21 (brs, 2H), 3.59 (s, 3H), 3.62-3.90 (m, 2H) ), 4.62 (ABq, 2H), 5.49 (s, 1H), 6.50 (s, 1H) 6.98 (brt, 1H), 7.12 (brd, 2H), 7.24-7, 43 (m, 7H), 7.54 (s , 1H) 595.3 Method 50 28 each; λό 0.74-0.85 (m, 6H), 0.85-L65 (m, 14H), 3.21 (brs, 2H), 3.6-3.9 (m, 2H), 4.25-436 (m, 1H), 4.53-4.66 (m, 2H), 5.49 (s, 1H), 6.47 (s, 1H) 6.91-7.0 (m, 1H), 7.04-7.16 (m, 2H), 7.22-7,46 (m , 7H), 7.51 (s, 1H) 623.3 Method 51 29 ; 〇r0 0.73-0.85 (m, 6H), 0.85-1.65 (m, 8H), 3.24 (brs, 3H), 3.34 (brs, 2H), 3.6 -3.95 (m, 2H), 4.8-4.95 (m, 2H), 5.52 (s, 1H), 7Ό6 (brt, 1H), 7.17 (brd, 2H), 7.27-7.40 (m, 5H), 7.40-7.50 (m, 3H), 7.69 (s, 1H) ~ 643.3 Method 52 ___-91 - This paper size applies to Chinese National Standard (CNS) A4 specification (21〇x297 mm) 1291951 A7 B7 V. Invention description (89) 30 Wu x56〇C ό 0.74-0.84 (m,6Η), 0.85-1.55 (m, 12Η), 3.24-3.33 (m, 2Η), 3.65-3.85 (m, 2H), 4.65-4.78 (m, 2H), 5.50 (brs, 1H), 6.99-7.2 (m, 4H), 7.25-7.48 (m, 7H), 7.51 (s, 1H) 671.2 Method 53 31 .ό 0.72-0.84 (m, 6H), 0.85-L65 (m, 8H), 3.27 (brs, 2H), 3.54-3.9 (m, 2H), 4.70 (ABq, 2H), 5.70 (s, 1H), 6.63-6.69 (m, 1H), 6.71-6.77 (m, 2H), 7.02 (bit, 1H), 7.08-7.17 (m, 3H), 7.30 (brt, 2H), 7.52 (s , 1H) 675.4 Method 54 32 ί人. I56cr ό 0.72-0.84 (m, 6H), 0.98-1.67 (m, 8H), 3.21 (brs, 2H), 3.54-3.9 (m, 5H), 4.62 (ABq, 2H), 5.57 (s, 1H), 6.51 (s, 1H), 6.59-6.73 (m, 3H), 6.97 (bit, 1H), 7.12 (brd, 2H), 7.28 (brt, 2H), 7.56 (s, 1H) 627.5 Method 55 33 .ό 0.73 -0.86 (m, 6H), 1.0-1.68 (m, 8H), 2.19 (s, 3H), 3.24 (brs, 2H), 3.55-3.9 (m, 2H), 4.71 (ABq, 2H), 5.53 (s , 1H), 6.60-6.73 (m, 3H), 6.75 (s, 1H), 6.96 (brt, 1H), 7.10 (brd, 2H), 1.21 (brt, 2H), 7.44 (s, 1H) 643.4 Method 56 _-92- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1291951 A7 B7 V. Invention description (9Q) 34 ό 0.74-0.86 (m, 6Η), 1.0-1.3 (m, 8Η), 1.35-1.57 (m, 4H), 2.19 (s, 3H), 3.23 (brs, 2H), 3.62-3.85 (m7 2H), 4.65 (ABq, 2H), 5.28 (s, 1H), 6.72 ( s, 1H), 6.94-7.05 (m, 3H), 7.12 (brd, 2H), 7.28 (brt, 2H), 7.39 (s, 1H), 7.43 (dd, 2H) 657.3 Method 57 35 ό 0.75-0.86 ( m, 6H), 1.0-1.3 (m, 8H), 1.35-1.55 (m, 4H), 2.01 (s, 3H), 3.11-3.26 (ABq, 2H), 3.6-3.8 (m, 2H), 4.58 ( d, 1H), 4.70 (d, 1H), 5.64 (s, 1H), 6.62 (s, 1H), 6.91-7 .0 (m, 2H), 7.01-7.12 (m, 3H), 7.23-7.33 (m, 4H), 7.37 (s, 1H), 7.69 (brd, 1H) 678.4 Method 58 36 ό 0.76-0.84 (m, 6H), L0-1.3 (m, 8H), 1.36-1.53 (m, 4H), 3.21 (brs, 2H), 3.64 (s, 3H), 3.67-3.87 (m, 2H), 4.57 (ABq, 2H) , 531 (s, 1H), 6.50 (s; 1H), 6.95-7.06 (m, 3H), 7.14 (brd, 2H), 7.28 (bit, 2H), 7.38-7.46 (m, 2H), 7.51 (s , 1H) 641.4 Method 59 37 • ό 0.75-0.87 (m, 6H), 1.0-1.3 (m, 8H), 1.34-L53 (m, 4H), 3.18 (ABq, 2H), 3.27 (s, 3H), 3.65-3.85 (m, 2H), 4.52 (d, 1H), 4.65 (d, 1H), 5.66 (s, 1H), 6.30 (s, 1H), 6.90-7Ό2 (m, 2H), 7.03-7.16 ( m, 3H), 7.23-7.34 (m, 4H), 7.50'(s, 1H), 7.59 (brd, 1H) 662.4 Method 60 _ -93- This paper scale applies to China National Standard (CNS) A4 specification (210X297 PCT) 1291951 A7 ___ B7 V. INSTRUCTIONS (91) MAIN EXAMPLE 38 -Lj&quot;-Mercapto-3-butyl-3-ethyl-5-phenyl-7-methyl fluorenyl-8-[N- ((RVl,-phenyl-indole-amine oxime oxime 1-2,3,4,5-tetrahydro-1,5- stupyl# sulphur heptadecene to U-diketo-3 -butyl-3-ethyl-5-phenyl-7-bromo-8-[N-((R)]lphenyl], _ dimethyl)amine carbhydryl Oxy] tetrahydro-1,5-phenylene _2,3,4,5- diltiazem Bing won seven Xi (Examples 22; 50 mg, 0.078 mmol) was dissolved in DMF (1.5 mL). Sodium methanethiolate (20 mg, 0.29 mmol) was added and the mixture was at 5 Torr. Mix for 1.5 hours. Acetic acid (40 mg) was added and the solvent was evaporated under reduced pressure. The residue was purified by preparative HPLC using &lt;RTI ID=0.0&gt;&gt; NMR (DMSO-d6): 0.7-0.8 (m, 6H), 0.9-1.6 (m, 8H), 2.2 (s, 3H), 3· 1-3.7 (m, 4H), 4.6-4.8 (m, 3H) ), 6·7 (s, 1H), 6·8-7·4 (m, 11H), 8·3 (d, 1H)· Example 39 monomethyl-3-butyl-3-ethyl- 5-phenyl-7-ethylthio-8-indole-((ΙΙ)-Γ-phenyl-i,- complex H)amine methyl methoxy 1-2,3,4&gt;tetrahydro-1 ,5- alum, sulphur, heptadecene, 1,1-dione-3-butyl-3-ethyl-5-phenyl-7-formyl-8-[N-((R)-l ,-phenyl_1,_monomethyl)amine carbhydryl methoxy]-2,3,4,5-tetrahydro-l,5-benzoquinone sulphide sulphate (example 22, 50 gram , 0.078 φ mol), ethanethiol (99 mg, ι·59 mmol) and cesium carbonate (253 mg, 0.78 mmol) were added to 〇MF (5 mL), and the compound was obtained at 44 C fell for 30 hours. The solvent was quenched and evaporated under reduced pressure. EtOAc was purified from EtOAc EtOAc (EtOAc) The residue was purified by EtOAc EtOAc EtOAc:EtOAc Nmr(3〇〇MHz, CD3 OD) 0.7-0.85 (m,6H),1.0-1 ·6 (m,11H),2.65 (q,2H),3·2 (s,2H), -94- Paper scale applicable towel SS standard (CNS) A4 specification (21GX297 official) ~------- 1291951 A7 ____B7 V. Invention description (92) Mildew &quot;&quot; ' 3.7 (birs, 2H), 4.6 ( q, 2H), 5.3 (s, 1H), 6.75 (s, 1H), 6.9-7.5 (m, 11H). Example 40 U_-Diketo-3-butyl-3_ethyl-5-phenyl -7-(2-hydroxyethylthio-carboxymethyl)amine-methyl methoxyl 1-2,3,4,5-tetrahydro-1,5-benzothiazepine will 1,1- Diketo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-[N-((RH,-phenyl-!,·methyl)&amp; Base]-2,3,4,5-tetrahydro-1,5-phenylindolesulfonium sulphate (Example 22; 50 mg, 0.078 mmol), 2-mercaptoethanol (281 mg, 3.59 Torr) And dimethyl carbonate (228 mg, 0.7 mmol) was added to DMF (5 mL), and the mixture was stirred at 70 ° C for 9 hours. The solvent was evaporated under reduced pressure. MeCN / ammonium acetate buffer (45: 55) was used as the dissolving agent. The collected fractions were lyophilized and the standards were obtained. Compound 20 mg (40%). NMR (300 MHz, CD3 OD) 0.75-0.85 (m5 6H), 1·〇-1·6 (m, 8Η), 2·9 (t, 2Η), 3·2 ( s, 2Η), 3·55 (t, 2Η), 3.7 (brs, 2Η), 4.65 (q, 2Η), 5·3 (s, 1Η), 6.9 (s, 1H), 6.95-7.5 (m, 11H). Example 41 U-diketo-3-butyl-3-ethyl-5-phenyl-7-(2-N',N'-dimethylaminoethylthio-V8-late-((8) -Γ-phenyl-indole-carboxymethyl)amine,carboxymethylmethoxy, 1_2,3,4,5-tetrahydrophenyl sulfonium, heptaerythrene, 1,1-dione-3-butyl- 3-ethyl-5-phenyl-7-indolyl-8-[N-((R)-l,-phenyl-1,-indolyl)amine fluorenylmethoxy]-2,3 , 4,5-tetrahydro-1,5-benzoquinonesulfurium heptadecene (Example 22; 50 mg, 0.078 mmol), dimethylaminoethanethiol hydrochloride (99 mg, 0.94 mmol) ), potassium carbonate (129 mg, 0.94 mmol), DIPEA (100 mg, 0. 77 mmol) and sodium borohydride (35 mg, 〇.93 mmol) were added to DMF (10 mL). And the mixture is at 85. (:Under 24 hours. __ -95- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1291951 A7 ____B7 V. Invention description (93) Filtering agent, and reducing Evaporation was carried out, and the residue was purified twice by preparative HpLC using MeCN / ammonium acetate buffer (40··6 〇) as a dissolving agent. The collected fractions were lyophilized to give the title compound 15 mg (3). 〇%). (300 MHz, CD3 OD) 0.75-0.85 (m, 6H), 1.0-1.65 (m, 8H), 2.65 (s, 6H), 3.05 (t, 2H), 3.2 (t, 2H), 3.3(s, 2H), 3.75 (brs, 2H), 4.75 (s, 2H), 5.2 (s, lH), 6.95- 7.4 (m, ll), 7.5 (s, 1H). Example 42

M: di-branched 1-yl-3-butylethylethyl-5-phenyl-7-isopropylsulfanyl bromide lj&gt;_隹methyl)aminecarboxymethylmethoxy 1-2,3,4 ,5-tetrahydro-L5-benzothiazepine hepeneene 1,1-dione-3-butyl-3-ethyl-5-phenyl-7-bromo-8-[N-( (R)-l,-phenyl-1,-carboxymethyl)amine,carboxymethylmethoxy]-2,3,4,5-tetrahydro-1,5-benzoquinonesulfurium heptadecene (example) 22 '50 Dang' 0.078 Amor), 2-propene: sulphur (126 mg, 1.65 mmol), cesium carbonate (152 mg, 0.47 mmol), sodium borohydride (25 mg, 〇·66) Millol) was added to DMF (5 mL) and the mixture was at 1 Torr. (3 stirring for 5 minutes. Evaporate the solvent under reduced pressure. The residue was purified by preparative HPLC using MeCN / ammonium acetate buffer (45: 55) as a solvent. The collected fractions were lyophilized to give The title compound is 15 mg (30%). NMR (300 MHz, DMSO-d6) 0.7-0.85 (m, 6H), 0.95-1.65 (m, 14H), 3.3 (s5 2H), 3·7 (brs, 2H) , 4.75 (dd5 2H), 5.05 (brs, 1H), 6.75-7.4 (m, 12H), 8·5 (brs, 1H)· Example 43 1,1-dione-3,3-dibutyl- 5-phenyl-7-methylthiophenyl-indole-indole 4 carboxymethyl)amine carbaryl 1 hydrazinylmethyl methoxy)-2,3,4,5-tetrahydro-1, 5-莫# sulphur nitrogen heptarene makes 1,1-diketo-3,3-dibutyl-5-phenyl-7-fluorenyl-8-(N-{(R)-l·- Phenyl-1,- _ -96- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1291951 A7 _______ B7 V. Description of invention (94 ) [N (first · butoxycarbonyl) Methyl)aminomercapto]methylammonium decyloxy)_ 2,3,4,5-tetrahydro-1,5-benzoquinone heptadecene (Method 63; ι 2 mg, ο”? millimolar) in DCM (2 ml). TFA (〇7 ml) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was evaporated under reduced pressure. The residue was purified by preparative HPLC using &lt;RTI ID=0.0&gt;&gt;&gt; NMR (3〇〇DMSO-d6) 0.7-0.8 (m3 6H)3 0.9-1.6 (m, 12H), 2.2 (s5 3H) 3.2-3.3 (m, 2H), 3.5-3.8 (m5 4H)5 4.8 ( ABq, 2H), 5.6 (d; 1H), 6.7 (s? 1H)? 6.8-7.5 (m, 11H), 8.5-8.7 (m, 2H). Examples 44-49 The following compounds are by the procedure of Example 43 , using the appropriate starting material to synthesize 0. Example compound NMR or m/z SM 14 ° eXC&gt;r- ό (300 MHz) 0.7-0.9 (m, 6H), 1.0-L7 (m, 8H), 3.2 (m, 2H), 3.75 (brs, 2H), 3.9-4.0 (m, 1H), 4.15-4.25 (m, 1H), 4.5-4.7 (m, 2H), 5.75-5.9 (m, 1H), 7.05- 7.2 ( m, 4H), 7.25-7.4 (m, 5H), 7.45-7.55 (m, 3H), 8.2 (d, 1H) Method 64 45 JQ CC〇cC .0 (CD3OD) 0.70-0.90 (m, 6H), 1.00-1.30 (m, 8H), 1.35-L55 (m7 4H), 3.20 (s, 2H), 3.55 (s, 3H), 3.75 (brs, 2H), 3.80-4.00 (m, 2H), 4.40-4.70 (m, 3H), 5,65 (s, 1H), 6.50 (s,1H), 6.95-7.50 (m, 10H), 7.55 (s, 1H) Method 41 ---.. _______-97- This paper The scale applies to China National Standard (CNS) A4 specification (210X297 mm) A7 B7 1291951 V. Description of invention

783.5 802.7 (300 MHz, CD3OD) 0.75-0.85 (m, 6H), 1.05-1.3 (m, 8H), 1.4-1.6 (m, 4Η), 22 (s, 3H), 3.25 (2H), 3.7-3.95 (m, 4H), 4.7 (ABq, 2H), 5.5 (s, 1H), 6.7 (s, 1H), 6.75-7.35 (m, 9H), 7.4 (s, 1H) (500 MHz, CD3OD) 0.82 ( Brt, 6H), 1.05-L26 (m, 8H), 1.42-L56 (m, 4H), 3.27 (brs, 2H), 3,6-3.75 (m, 2H), 4.58 (ABq, 2H), 5.41 ( s, 1H), 6.73-6.82 (m, 3H), 7.0 (d, 2H), 7.05 (dd, 1H), 7.25-7.36 (m, 3H), 7.41 (brd, 2H), 7.48 (d, 1H) m/z 608.3 Method 65 Method 66 Method 68 Example 119 t -Hsn Iso 2,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-benzene Base-1·-[Gentosylethyl)amine-methylmethyl 1methyl}amine-methylhydrazine oxy)-2,3,4,5-tetrahydro-1^: pen nitrogen heptadecene ammonium salt -98 Paper Size Standards (CNS) ΜSpecifications ((10)χ 297 公爱) 129195 i A7 B7 V. Description of Invention (96) 1,1-One-Ketyl-3,3-Dibutyl-5 -Phenyl-7-fluorenylthio-recreating methoxy-2.3.4.5- Tetrahydro-1,5-benzoquinonesulfuryl sulphate (Method 22; ι 5 〇 mg, 〇·3 〇 millimolar) With 2-((2fR)-2f-amino-2f-phenylethenylamino)ethanesulfonate (Method 28; containing DIPEA hydrochloride '150 mg, 0.36 mmol) was dissolved in DMF (6 ml). DIPEA (0.2* liter, 1J5 millimolar) and butyl BTU (n4 mg, 〇·36 耄mol) were added, and the mixture was stirred at room temperature for 2 hours. The falling agent was evaporated under reduced pressure. The residue was purified by preparative HPLC using EtOAc (EtOAc:EtOAc:EtOAc: NMR (CD3 〇D) 0.75-0.85 (m,6H), 1.0-1.3 (m,8H),1·3-1·6 (m, 4Η), 2.16 (s,3Η), 2.85-3.0 (m, 2Η),3·24 (brs,2Η) 3.5-3.85 (m,4Η), 4.70 (ABq, 2H), 5.47 (s5 1H)5 6.71 (S) 1H), 6.97 (brt, 1H), 7.11 (brd , 2H)? 7.23-7.45 (m, 8H); m/z 746.2. Example 51 keto-keto-3-butyl _3·ethyl iphenyl fluorenylmethyl sulphate -8 ((8)·丨, _Phenyl·Bu K2·Continuous acid ethyl hydrazide) Aminomethyl group 1 曱 丨 丨 醯 醯 醯 甲 甲 -2 -2 2,3,4,5_4 jL -1,5-benzoquinone U-dione-3-butylethyl-5-phenyl methoxymethyl carboxymethoxy _ 2.3.4.5-tetrahydro-1,5-benzoquinone sulphide Alkene (Method 17; 49 mg, 〇1 〇 mmol) and 2-((2'R&gt;2'-Amino-2,-phenylethenylamino)ethanesulfonic acid (Method 28; DIPEA hydrochloride; 52 mg, 0.12 mmol, dissolved in DMF (2 mL). Add DIPEA (0.071 mL, 〇·4 ΐmol) with TBTU (39 mg, 〇12 耄mol) and The mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure. MeCN / ammonium acetate buffer gradient (5 / 95 to 100 / 0) as a dissolving agent, and the title compound 59 papers Chinese National Standard (CNS) M specifications ((10) χ 29? public love) -- 1291951 A7 ______B7 (97) gram (78%). NMR (CD3 OD) 0.74-0.90 (m, 6H), 0.98-1.3 (m, 4H), 1.35-1.67 (m, 4H), 2.16 (s, 3H), 2.85-3.02 (m, 2H), 3·23 (brs, 2H) 3.52-3.90 (m, 4H), 4.70 (ABq, 2H), 5.47 (s, lH), 6.71 (s, lH), 6.96 (brt , lH), 7.09 (brd, 2H), 7.21-7.48 (m, 8H); m/z 718.4. Example 52 U-dikedo-3-butyl-3-ethyl-5-phenyl-7- Methylthio-8-(N-UR)-r-phenyl-1L 0((carboxymethyl)amine fluorenyl 1 methyl}amine fluorenyloxy)-2,3,4,5- Tetrahydro-1,5-benzothiazepine heptarene makes U-diketo-3-butyl-3-ethyl-5-phenyl-7-sulfonylthio-8-(N-{(R )-r-phenyl-indole-[Ν-(ethoxycarbonylmethyl)amine hydrazino]methyl decylcarbamyl methoxy)-2,3,4,5-tetrahydro-1,5 - Benzothiazepine heptarene (Method 72; 44 mg, 0.063 mmol) was dissolved in THF: Η20, 1 : 1, (2 mL) and NaOH (1 Μ, 0.126 mmol). The mixture was stirred at ambient temperature for 1 hour. The reaction mixture was acidified with HCl (1 Μ), diluted to 10 mL and extracted with DCM (3 X 10 mL). The combined organic layers were dried (MgSO4). NMR (300 MHz) 0.78-0.85 (m, 6H), 1.02-1-70 (m, 8H), 2.20 (s, 3H), 3.15/3.21 (ABq, 2H), 3.78 (m, 2H), 3· 94/4·20 (dABq, 2H), 4.64 (q, 2H), 5.91 (d, 1H), 6.65 (s, 1H), 6.98-7.52 (m, 11H), 8.17 (d, 1H). Example 53 i,l-Diketo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N](R)-l,-phenyl-oxime-late- (1'carboxy-indole-phenylmethyl)amine-methylmethyl 1 methyl decyl carbyl methoxy) — 2,3,4,5-tetrahydro-1,5-benzoquinone The title compound of decene is 1,1-diketo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-l·-phenyl曱 羰 carbonyl] phenylmethyl) amine mercapto] methyl} -100- This paper size applies to Chinese National Standard (CNS) Α 4 specifications (210 X 297 mm) Binding

1291951 A7 ___ B7 V. INSTRUCTIONS (98) ^ Aminomethyl methoxy)-2,3,4,5-tetrahydro-1,5-benzoquinone sulphide heptarene (Method 73), by way of example 52 program synthesis. NMR (500 MHz) 0.76-0.84 (m, 6H), 1.05-1.73 (m, 8H), 2.14 (s, 3H), 3·16 (m, 2H), 3.74 (m5 2H), 4.48 (m, 2H) ),5·53 (d,2H), 5.96 (d5 2H), 6.63 (s,1H), 6.97-7.48 (m5 13H), 7.86 (m5 1H), 8.17 (m,1H)· Example 54 U-II Keto-3-ethyl-3-butyl-5-phenyl-7-methylthio-8]l-rN-((RV 勒 芏 ) ) 胺 胺 胺 胺 胺 胺 胺 胺 乙 乙 乙 乙 乙 乙 乙 乙 乙,3,4,5-tetrahydro-1,5-alum sulphide heptadecene in 1,1-indolyl-3-butyl-3-ethyl-5-phenyl-7-bromo- 8-{l-[N-((R)-l,-phenyl-indole-carboxymethyl)aminemethanyl]ethoxy}-2,3,4,5-tetrahydro-1,5- Benzothiazolidine (Example 10, 0.050 g, 7.6 x 10 0.5 mol) in a solution of DMF (4 ml), sodium thiomethoxide (〇·〇 21 g, 3·0χ1 (Γ4 Mo) Ear), and the solution was simmered at % temperature for 4 hours. The mixture was concentrated and the residue was partitioned between water and ether. The aqueous phase was extracted twice with ether and combined. The organic extract was dried (MgSO4), concentrated and purified by HPLC to give a white solid (0.03 g (63%) of 'yield title compound' as a white solid. njvjr (CD, OD) 0. 75-0.90 (m, 6H), 1.00-1.30 (m, ffi), 1.40-1.70 (m, 7H), 2.15 (d, 3H), 3.10-3·30 (m, 2H), 3·55-3 · 95 (m5 2H), 4.80-4.95 (m, 2H), 5·30 (d, 1H), 6·70-7·50 (m, 12H); m/z 625.3. Example 55 U:-keto group 3-ethyl-3-butyl-5-phenyl-7-fluorenyl sulphate) amine carbazyl yl} oxy}-2,3,4,5-tetrahydro-1,5- Benzopyrene | heptarene ^ 1,1-dione-3-ethyl-3-butyl-5-phenyl-7-methylthio·8·{...[Ν·((Ιι)ι -Carboxybenzyl)amine-mercapto]iodo}-2,3,4,5-tetrahydro-1,5-benzoquinonesulfur-7-vegetation (Example 11; 0.018 g, 2·5χ1 (Γ 5 Mohr) in solution in DMF (3 ml) -101- 冢 paper scale applicable to Chinese National Standard (CNS) Α4 specification (210 X 297 mm) 1 --- 1291951 A7 B7 V. Invention description (99 ) ' Sodium thiomethoxide (7 g, 丨〇χ1〇-4 mol) was added and the solution was stirred at ambient temperature for 4 hours. The mixture was concentrated and the residue was partitioned between water and ether. The aqueous phase was re-extracted twice with ether and the combined organic extracts were dried (MgSO.sub.4), concentrated and purified by HPLC. The title compound was obtained as a white solid. NMR (CD3 〇D) 0.70-0.85 (m5 6H)5 1.00-1.25 (m5 4H), L35-1.65 (m5 4H)5 2.20 (d? 3H)5 3.10- 3·20 (m, 2H), 3.50- 3.85 (m, 2H), 5.30 (d, 1H), 5.80 (d, 1H), 6.70 (s, 1H), 6.90- 7.65 (m, 16H). Example 56 Let dimercapto-3,3-dibutyl Base-5-styl-7-nonylthio-8-(N-UR)w-rN,-(2-pic acid) anthranilyl 1 ice via a certain amine methoxymethyl methoxy V2,3A5-tetrahydro-1,5-alum sulphide heptadecene 2-{[(2R)-2-amino-2-(4-hydroxyphenyl)ethenyl]amino}ethane Sulfonic acid (Method 80; 32.5 mg, 0.119 mmol) was mixed with DMF (4 liters) and N-methylmorpholine (30 μL '0.272 Amor). Obtaining a clear solution and continuously adding 1,1-monoindole-3,3-butyl-5-winter-7-methylthio-8-yloxycarbonyl-2,3,4,5 - Tetrahydro-1,5-benzoquinonesulfurium sulphate (Method 22; 50 mg, 0.099 mmol) with TBTU (38 mg, 0.119 mmol). The reaction was stirred at ambient temperature for 30 minutes and DMF was removed. The crude product was purified by preparative HPLC using MeCN / ammonium acetate buffer (1:1). Freeze-drying gave 55 mg of the title compound (71%). NMR (500 MHz, MeOD) 0.78-0.86 (m, 6H), 1.0-1.3 (m, 8H), 1.4-1.6 (m5 4H), 2·15 (s, 3H), 2.85-3.00 (m, 2H) , 3.25 (s, 2H), 3.55-3.68 (m, 2H), 3.75 (brs, 2H), 4.65 (ABq, 2H), 5.36 (s, 1H), 6.70 (s, 1H), 6·75 (d , 2H), 6.98 (t, 1H), 7.12 (d, 2H), 7.22 (d, 2H) 7.28 (t5 2H), 7.4 (s, 1H) ; m/z 762. -102- This paper size applies China National Standard (CNS) A4 Specification (210X 297 mm) 1291951 A7 B7 V. INSTRUCTIONS (100) EXAMPLES 57-58 The following compounds were synthesized by the procedure of Example 56 using the appropriate starting materials, except that the reactants were The indwell was carried out for 64 hours (Example 57) or 2 hours (Example 58) and the product was purified by preparative HPLC using a MeCN / ammonium acetate buffer gradient (45/55 to 66/40) as the dissolving agent. Example compound NMR (CD3OD) with m/z SM 57 ' ό palmar isomer 1 0.75-0.84 (m, 6H) 1.00-1.27 (m, 4H), 1.37-1·64 (m, 4H) 2.14 (s, 3H), 2,86-3.00 (m, 2H), 3.22 (s, 2H), 3.53-3.68 (m, 2H), 3.85 brd, 2H), 4.68 (ABq, 2H); 5.35 (s, 1H), 6.70 (s, 1H), 6.75 (d, 2H), 6.95 (t,. 1H), 7.08 (d, 2H), 7.20-7.29 (m, 4H), 7.37 (s, lH); m/ z 751 _NH/) Method 23 58 . What 1 ~ WS / N'. . :χχ:χΓ ' ό Palm to the isomer 2 0.77-0.85 (m, 6H) 1.06-1.27 (m, 4H), 1.40-1,62 (m, 4H) 2.17 (s, 3H), 2.87-3.00 ( m, 2H), 3.24 (s, 2H), 3.56-3.68 (m, 2H), 3.75 (brd, 2H), 4.71 (ABq, 2H), 537 (s, 1H), 6.72 (s, 1H), 6.77 (d, 2H), 6.97 (t, 1H), 7.10 (d, 2H), 7.23 (d, 2H), 7.28 (t, 2H), 7.40 (s, 1H); m/z 751 Method 24 __ -103 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 1291951 A7

ijH 59

^^_) Amine 曱醯.棊.Jy base} Aminomethyl hydrazino oxime V2,3A5-tetrahydro-1,5-mole saponin, 1,1-dione-3-butyl- 3-ethyl-5-phenyl-7-indolyl-8-[N-((R)-a-methyl-indenyl)amine-methylcarbonyl]-2,3,4,5- Tetrahydro-1,5-phenylindolesulfonium heptadecene (Example 38; 66.8 mg, 0.109 mmol) and ethyl f-alanine hydrochloride (23 mg mg 0.15 mmol) dissolved in DCM (2.5 In ML), add N-methyl whipped cream (0.07 ml, 0·64 mmol). After stirring at ambient temperature for 5 minutes, TBTU (45.6 mg, 0.142 mmol) was added, followed by stirring for 2 hours. The reaction mixture was filtered through a short column and concentrated. The crude ester was dissolved in THF (15 mL) and water (1. 5 mL) and NaOH (1 Μ, 0.20 mmol). After stirring at ambient temperature for 1 hour, the reaction was quenched with 1 MHC1. The reaction mixture was diluted with water (10 mL)EtOAc The organic layer was concentrated and purified by preparative HPLC to give the title compound (6 <RTIgt; NMR (300 MHz) 0.80 (m, 6 Η), L00-1.70 (m, 8 Η), 2·17 (s, 3 Η), 2·48 (m, 2 Η), 3.17 (ABq, 2 Η), 3.35 (m, 1Η),3·57 (m,1Η), 3.70 (m,2Η),4·62 (ABq, 2H),5·77 (d,1H),6·64 (s5 1H),6.98 (t,1H) ), 7.06 (d, 2H), 7, 28 (m, 4H), 7.42 (m, 3H), 7.56 (m, 1H), 8, 10 (m, 1H). -104- This paper scale applies to China Standard (CNS) A4 size (210 X 297 mm) 1291951 A7 B7 V. INSTRUCTIONS (1(32) EXAMPLES 60-63 The following compounds were synthesized by the procedure of Example 59 using the appropriate starting materials. 60 HN into L 0 HO 0:81 (m, 6H), L00-1.95 (m, 10H), 2.22 (s, 3H), 3.37 (m, 2H), 3.18 (ABq, 2H), 3.48 (m, 2H ), 3.75 (m, 2H), 4.66 (q, 2H), 5.75 (d, 1H), 6.67 (s, 1H), 7.00 (t, 1H), 7.09 (m, 2H), 7.20 (m, 1H) , 7.30 (m, 4H), 7.44 (m, 2H), 8.25 (m, 1H) Example 38 61 j 0 6 OH (300 MHz, DMSO-d^) 0.74 (m, 6H), 0.95-L50 (m, 12H), 2.16 (s, 3H), 2.28 (t, 2H), 3.24 (m, 2H), 4.74 (q, 2H), 5.33 (d, 1H), 6.69 (m, 2H), 6.85 (t, 1H ), 6.99 (m, 2H), 7.16 (m, 4H), 8.33-8.45 (m, 2H) Example 2 62 χ° ό i'. · HO . (300 MHz) 0.81 (m, 6H), 1.00-1.74 (m, 14H), 2.22 (s, 3H), 2.31 (m, 2H), 3.10- 3.35 (m, 4H), 3.73 (m, 2H), 4.62 (ABq, 2H), 5.64 (d, 1H), 639 (brs, 1H)V6.67 (s, 1H), 6.96-7.10 (m, 3H ), 7.25-7.48 (m, 7H), 8.21 (d, 1H) Example 38 ___-105- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1291951 A7 B7 V. Description of invention ( 103 ) 63 0.81 (m, 6H), 1.03-1.55 (m, 12H), Example 2.19 (s, 3H), 2.55 (m, 2H), 3.18 (m, 1 2H), 3.46 (m, 1H), 3.58 (m, 1H), ΝΗ ό 3·74 (m, 2H), 4.64 (ABq, 2H), 5.80 0=\ ΟΗ (m, 1H), 6.64 (s, 1H), 7.01 (t, 1H), 7 · 08 (d, 2H), 7·30 (m, 5H), 7.44 (m, 3H), 8.11 (m, 1H) * Example 64 1,1-dione-3-butyl-3-ethyl -5-phenyl-7-sulfonylthio-84N-((R)-a-carboxy-4-methoxyindolyl)amine-branthylmethyl-based -2,3,4,5-four wind -1,5-benzosulfur gas

1,1-di@同基-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-{N-[(R)-α-(tris-butoxycarbonyl) 4-hydroxyindolyl]amine-methylmercaptomethoxy}-2,3,4,5-tetrahydro-1,5-benzoquinonesulfurium heptadecene (Method 78; 48 mg, 0.070 mmol) ), bromoethyl (trimethylammonium bromide) (57 mg, 0. 230 mmol), tetrabutylammonium bromide (3 mg, 0.009 mmol) and Cs2C03 (71 mg, 0.22 mmol) The ear was added to CH.sub.3CN (1.0 mL). The solvent was evaporated, and the residue was crystalljjjjjjjjjjjjjj The crude ester was dissolved in EtOAc (EtOAc)EtOAc. The solvent was evaporated, and the title compound wasjjjjjjjjj NMR (DMSO-d6) 0.74 (m, 6H), 0·94-1·60 (m, 8H), 2.17 (s, 3H), 3·25 (m, 2H), 3.69 (s, 3H), 4.70 (ABq, 2H), 4.95 (brs, 1H), 6.71 (s, IH), 6.83 (m, 3H), 6.97 (d, 2H), 7.20 (m, 4H), 7.27 (s, 1H), 8· 37 (brs, 1H). Example 65 1,1-Diketo-3,3-dibutyl-5-phenyl-7-methylsulfanyl acid B_~ 1QR -_;__ This paper size applies China National Standard (CNS) A4 Specification (210 X 297 mm) 1291951 A7 —_ B7 V. Description of Invention (104) Production of 醯 醯 棊 棊 · · · · · · · · · · · · · · τ τ τ τ τ τ τ τ τ τ τ τ Benzene sulfonium sulphide sulphate ammonium salt 1,1 -diketo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N------methyl Mercapto)methylmercaptomethoxy i ]-2,3,4,5-tetrahydro-1,5-benzothiazepine hepene (Example 18; 27 mg, 0·041 mmol) is soluble In DCM (2 ml). Tetrabutylammonium taurate (45 mg, 0.123 mmol) was added continuously with TBTU (16 mg, 0.050 mmol) and the mixture was stirred at ambient temperature for 5 hours. The solution was evaporated and the product was purified by preparative HPLC using MeCN / ammonium acetate buffer (50/50) as solvent. The title compound was obtained in EtOAc (EtOAc). NMR showed that 16% of the product was left as a tetrabutylammonium salt. NMR (500 MHz) 0.75-0.9 (m, 6H), 1.0-1.3 (m, 8H), 1·3-1.6 (m, 4H), 1.95 (s, 3Η), 2_1 (s, 3Η), 2.9 ( Brs,2Η),3·05 (brs,2Η),3·55 (ABd,2Η),3·75 (brs,2Η), 4·55 (ABq,2H),6.6 (s,1H),6.9- 7.6 (m, 12H), 8·2-8·3 (brs, 1H); m/z 777 (M+NH4+). Examples 66-67 The following compounds were synthesized by the procedure of Example 65 using the appropriate starting materials. . ______- 1Π7 , This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1291951

Jade, invention description (1Q5

67 0.75-0.85 (m, 6Η),1·02 (U2H), 1.05-1.3 (m, 4Η), L3-1.7 (m, 20H), 2.17 (s, 3H), 2.85-2.99 (m, 2H) , 3.19-3,26 (m, 10H), 3.52-3.92 (m, 4H), 4.71 (ABq, 2H), 5.47 (s, 1H), 6.72 (s, 1H), 6.96 (t, 1H), 7.09 (brd, 2H), 7.23:7.44 (m, 8H); m/z 735.2 (M+NH4, example 68

Li^·酉同基-3,3^. 基·7-Methylthio-carboxymethyl)amine]·....A.indolyloxy)-2,3,4,5-tetrahydro- 1,5-benzoquinonesulfurium heptadecene gives 1,1-diketo-3,3-dibutyl iphenyl sulfonylthiol_8_(N_{...[ν,_(methoxycarbonylmethyl) Aminomethyl]-...methylbenzyl decyl carbyl methoxy) 2,3,4,5-tetrahydro-i,5-benzoquinone sulphide heptarene (Method 44; 20 mg _ , 0.028 mmol) dissolved in 2.5 liters of THF / water mixture (4/1). LiOH (2 mg, 0.084 mmol) was added and the mixture was stirred at ambient temperature for a few hours. The title compound was purified by preparative HPLC using MeCN / ammonium acetate buffer (50/50) as solvent. MeCN was evaporated and the residual buffer was acidified with acetic acid. Freeze-dryed to obtain 1 mg of product (51%). NMR 0.7-0.9 (m, 6H), 1.0-1.35 (m, 8H), this paper scale applies to Chinese National Standard (CNS) A4 specification (210χ297 mm) 1291951 A7 __ _ B7^__ V. Description of invention (106 ) 1.35-1.6 (m, 4H), 2.0 (s, 3H), 2.2 (s, 3H), 3.2 (brs, 2H), 3·65-3·85 (brs, 2H), 3.9-4.1 (d, 2Η),4·5-4·7 (ABq,2Η),6·6 (s,1Η), 6.8 (brs,1Η),6·9-7·5 (m,11Η), 8·1 (s , 1H) ; m/z 727 (M+NH4+)· Example 69 U-diketo-3,3-dibutyl-5-styl-7-methylthio-α-[Ν,·(2-sulfonic acid Ethyl ethyl)amine carbaryl 1-2-fluoro fluorenyl}amine carbhydryl methoxy)-2,3,4,5-tetrahydro-1,5-phenyl sulfonium sulphate酉-yl-3,3-tert-butyl-5-winter-7-methylthio-8-{Ν-[...indolyl-2-ylbenzyl]amine-methyl methoxy}-2 , 3,4,5-tetrahydro-1,5-benzoquinonesulfurium heptadecene (Example 15; 20 mg, 0.030 mmol), tetrabutylammonium taurate (2 mg mg '0.054 mmol Ear) and DIPEA (25 mg, 0.19 mmol) dissolved in DMF (0.4 liters). TBTU (15 mg, 0.047 mmol) was added and the mixture was stirred at room temperature for 30 minutes. The product was separated from the reaction mixture by preparative HPLC using MeCN/ammonium acetate buffer (50:50) as the dissolving agent. 7 mg (29%) of the title compound was obtained. m/z = 764.5. Example 70]^1-indenyl-3,3-dibutyl-5-phenyl-7-methylthio-8-〇1-(11&gt;)-{&lt;^ -『(]^,-(1^&gt;)-{心呀'-(several fluorenyl)amine hydrazino}amine-branched)methylamine-methyl thiol-yl group} _?醯基甲Oxy)-2,3,4,5-tetrahydro-1,5-stupyl #thioxinshitongping 1,1-dione-3,3-dibutyl-5-phenyl-7- Sulfosyl-8-(N-{(R)-l.-phenyl-indole-[Ν'·(carboxymethyl)amine-methylmethyl)-yl}amine-methylmethyl)-2, 3,4,5_tetrahydro", 5-benzoquinonesulfurium heptadecene (Example 43; 35 mg, 0.050 mmol) and (R)_heart with (t-butoxycarbonylmethyl)amine oxime醯 ] ] ( (method 86; 2 〇 _ mg, 〇〇 76 mmol) dissolved in DCM (2 ml), and added 2,6-lutidine (〇〇3 毫-109- paper) The scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)--- 1291951 A7 _ B7 V. Invention description (1Q7) l '0·26 millimoles). After stirring for 5 minutes at ambient temperature, butyl btu (20 mg, 0.062 mmol) was added and stirring was continued for 3 hours. The reaction mixture was filtered through a pad using DCM:EtOAcEtOAc Then, the third-butyl ester was dissolved in DCM (6 ml), and THF (1 mL) was added. After stirring overnight at ambient temperature, the solvent was evaporated. Add toluene and evaporate twice. The product was further purified to give the title compound (40 mg, 93%). NMR (500 MHz, DMSO-d6) 0.75 (m, 6H), 0·95-1·50 (m, 12H), 2.16 (s, 3H), 3·25 (m, 2Η), 3·75 (m , 2Η), 3·90 (dd, 1Η), 4.73/4.84 (ABq, 2Η), 5·54 (m, 2Η), 5.58 (d, 1H), 6.68 (s, 1H), 6.85 (t, 1H) ), 6.99 (d, 2H), 7.18-7.46 (m, 13H), 8. 51- 8.73 (m, 4H). Example 71 U-g-glysyl-3,3-dibutylphenylmethylthio Each p(8) carboxy-ice serotonin) Aminomethyl methoxy 1-2,3,4,5-tetrahydro-1,5-phenyl sulfonium hexadecene gives 1,1-dione-3, 3-Dibutyl-5-phenyl-7-methylthio-8-methyloxy-2,3,4,5-tetrahydro-1,5-benzothiazepine hepene (Method 22 ; 61 mg, 0.12 mmol, and (2S)-amino-(4-indolyl) methyl acetate hydrochloride (31 mg, 〇14 mmol) in DCM (4 mL) 2,6·lutidine (0.04 ml, 〇·34 mmol) was added. After stirring at room temperature for 5 minutes, TBTU (7 mg mg, 0·17 mmol) was added and stirring was continued for 2 hours. The reaction mixture was filtered through a short column. The crude methyl ester was dissolved in hexane HF (1.5 liters) and water (1 liters), and NaOH (aqueous solution, 1 Torr, 0.39 mmol) was added. The reaction mixture was stirred at room temperature for 8 hr then EtOAc (EtOAc) The collected organic layer was concentrated and purified by preparative ,ριχ using MeCN / ammonium acetate buffer (50 ··5 〇) to give the title compound ______- 110- This paper scale applies to Chinese National Standard (CNS) A4 Specifications (21〇X297 mm) -—-- 1291951 A7 ___B7\_, V. Description of invention (108) (57 mg, 72%). NMR (500 MHz, CD3 0D) 0·81 (m, 6H), 1.05-1.26 (m, 8H), 1.40-1.55 (m, 4H)5 2.17 (s, 3H), 3.24 (brs, 2H), 3.74 (brs5 1H)5 4.66 (ABq? 2H), 6.70-6.75 (m,3H),6·99 (t,1H), 7.11 (d,2H), 7.22-7.30 (m,4H), 7.40 (s, 1H). Example 72 1,1-Diketo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-(SM &amp; ΓΝ,-(2-) acid group 4-yl)aminomethane 1-4. fluorenyl}amine carbaryloxy)-2,3Α5-tetramyl-L5-indole sulphide sulphate ammonium salt 1,1-dione -3,3-dibutyl-5-phenyl-7-methylthio-[N-(S)-indole-enyl-4-methylindolyl)amine-m-methoxy]-2,3 , 4,5-tetraqi-1,5-benzene-pyrazine nitrogen sulphate (Example 71; 31 mg, 0.047 mmol) and tetrabutylammonium taurate (57 mg, 0.155 mmol) In DCM (2 ml). After stirring for 5 minutes at room temperature, TBTU (24 mg, 0.075 mmol) was added and stirring was continued for 6 hours. The solvent was evaporated and the residue was purified EtOAc EtOAcjjjjjjjj m/z 762.2. Example 73 and Example 74 lil: diketo-3-(R/S)-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N- (RV{Xim Mg-Mimi-5-yl-1-carboxyethyl)aminemethanyl]octyl}amine methyl hydrazine a certain nitrogen ν 么 1,4,5-tetrahydro-1,5-benzene幷Sulphur heptaerythrene 1,1 -diketo-3-butyl-3-ethyl-5-phenyl-7-sulfonyl-8-[N-((R)-l,-benzene -1-1·-carboxymethyl)amine fluorenylmethoxy]-2,3,4,5-tetrahydro-1,5-phenylindolesulfinyl heptadecene (Example 38; 56.4 mg, 〇·〇 Add to NCM (3 ml) with D-histamine methyl ester dihydrochloride (25.2 mg, 〇·1 〇 4 mmol). Add N_甲—____- 111 - paper The scale applies to the g H family standard (CNS) A4 specification (; 1 () &gt;&lt; 297 public love 5 - 1291951

Keifofine (0.05 ml, 0.41 mmol) followed by TBTU (4 mg, 0.12 mmol). The reaction mixture was stirred at 4 Torr for 3 minutes and at room temperature for 3 hours. More TBTU (15 mg, 〇·〇 47 mmol) and DIPEA (0.025 mL, 0.14 mmol) were added and the reaction mixture was stirred at room temperature; The solvent was evaporated and the residue was filtered through a short column using MeOH as solvent. The crude oxime ester was dissolved in THF (1 mL) and water (1.0 liter) and NaOH (aq., 1 s, 0.15 mM). The reaction mixture was stirred at room temperature for 2 hours and quenched with HCl (1 EtOAc). The solvent was evaporated and the residue was purified using EtOAc EtOAc EtOAc. The compound was dropped into two peaks, presumed to be two diastereomers. The first spike (10 mg, 14%). The second peak (16. 8 mg, 24%). The first peak NMR (DMSO-d6) 0.74 (m, 6H), 0.95-1 · 60 (m, 8 Η), 2.17 (s, 3 Η), 2.82 (m, 2 Η), 3·23 (m, 2Η), 4.27 (m, 1Η), 4.80 (ABq, 2H), 5.60 (d, lH), 6.55 (brs, lH), 6.70 (s, lH), 6.84 (t, lH), 6.96 (d, 2H) ), 7.14· 7.28 (m, 6H), 7.33 (s, 1H), 7.44 (brs, 1H), 8.54 (d, 1H), 8.60 (brs, 1H); m/z 748.4. The second peak: NMR (DMSO-d6) 0.74 (m5 6H), 0.95-1.60 (m, 8H), 2.17 (s, 3H), 2.92 (dABq, 2H), 3.23 (m, 2H), 4.41 (m) , 1H), 4.79 (ABq, 2H), 5.60 (d5 1H), 6.70 (s5 1H), 6.78 (s, 1H), 6.84 (t, 1H), 6.96 (d, 2H), 7.16-7.34 (m, 6H), 7.40 (m, 2H), 7.55 (s, 1H), 8·55 (d, 1H), 8.71 (d, 1H); m/z 748.4. Example 75 1,1-dione-3, 3-Dibutyl-5-(4-t-butylphenyl)-7-methylsulfanyl-8-oxime-{(11)-shen-[Ν'-(carboxymethyl)aminecarboxamide The title compound is in 1,1-dimercapto-3, the title compound is hydrazinyl}aminomethane methoxy)-2,3,4,5-tetrahydro-1,5-phenyl sulfonium heptadecene. 3-Dibutyl-5-phenyl-7-methylthio-8-(N--112- This paper scale is applicable to China National Standard (CNS) A4 specification (210X 297 mm) 1291951 A7 B7 V. Description of invention (110 ) {(R)-l·-Phenyl-1··[ΝΗcarboxymethyl]aminemethanyl]methyl}aminecarboxymethylmethoxy)- 2.3.4.5-tetrahydro-1,5 In the synthesis of benzoquinone sulphide sulphate (Example 43), by-products were isolated. Approximately 1 gram of this compound was purified by preparative HPLC (MeCN / EtOAc (50.50). MHz, DMSO-d6) 0.73 (m, 6H), 0.90-1.40 (m, 12H), 1.24 (s, 9H), 2·16 (s, 3H), 3·23 (m, 2H), 3.65/3.75 (dABq, 2H), 4.72/4.82 (ABq, 2H), 5.60 (d, 1H), 6.65 (s, 1H)5 6.97 (d5 2H)5 7.23-7.35 (m5 6H)5 7.45 (d5 2H), 8.58 (d5 1H), 8.62 (t, 1H). Example 76 1,1-diketo-3-butyl-3-ethyl-5-phenyl·7-(Ν-((ΙΙ)-以-read Base: f-based) amine-mercaptomethylthio)-methyleneoxy-2,3,4,5-tetrahydro-1,5-benzene#thiol heptadecene to 1,1-dione-3 -butyl-3-ethyl-5-phenyl-7-carboxymethylthiomethyloxy-2.3.4.5-tetrahydro-1,5-benzoquinonesulfurium heptadecene (Method 81; 38 mg , 0.080 mmol, and D-phenylglycine methyl ester hydrochloride (24 mg, 0.12 mmol) dissolved in DCM (2 mL), and N-methyl. 5 ml, 0.42 millimoles). After stirring at room temperature for 5 minutes, TBTU (44 mg, 0.14 mmol) was added and stirring was continued for 2 hours. The reaction mixture was filtered through a short column. The product was dissolved in THF (1 mL) and water (1 mL). The reaction was quenched with EtOAc (1 M), diluted with water (10 mL) Purification by preparative HPLC gave the title compound (40 mg, 82%). NMR (DMSO-d6) 0.75 (m, 6H), 0.96-1.60 (m, 8H), 3·22 (m, 2H), 3·56 (ABq, 2H), 3.89 (s, 3H), 4·81 (d,1H), 6.78 (t,1H), 6.83 (d,2H), 6.89 (s,1H),7.11-7.23 (m,7H),7·31 (s,1H),8.37 (m,1H) )· Example 77 -113- This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm)

Binding

k 1291951 A7 ___ B7 V. INSTRUCTION DESCRIPTION (111) ~ A JJ-monoketo-3-butyl-3-ethyl-5-phenyl-7-carboxymethylthio...carboxyindole) Amidamide Methoxy 1-2,3,4,5-tetrahydro-1,5-phenylindolesulfinyl heptadecene U-diketo-3-butyl-3-ethyl-5-phenyl- 7-Ethoxycarbonylmethylthio-8-carboxymethyllactyl-2,3,4,5-tetraindole-1,5-phenylindolesulfonium sulphate (Method 82; 21 mg, 0.038 Amor) It was dissolved in DCM (1.5 ml) with phenylglycine methylation hydrochloride (I] mg, 0061 mmol), and N-methylmorpholine (0.02 ml, 〇·19耄) was added. Moore). After stirring at ambient temperature for 5 minutes, TBTU (18 mg '0.056 mmol) was added and stirring was continued for 2 hours. The reaction mixture was filtered through a short column. The crude g was dissolved in THF (1 liter) and water (1 mL), and NaOH (aqueous solution, 1 ml, 1 M) was added. The reaction mixture was stirred at rt EtOAc (EtOAc) (EtOAc) The collected organic layer was concentrated and purified with EtOAc EtOAcjjjjjj NMR (CD3 OD) 0·80 (m, 6H), 1.03-1.26 (m, 4H), 1.38-1·65 (m, 4H), 1.96 (s, 3H), 3·20 (s, 2H) ), 3.44 (s, 2H), 3.67 (brs, 1H), 3.76 (brs, 1H), 4·67 (ABq, 2H), 5.29 (s, 1H), 6.89 (s, 1H), 6.92 (t, 1H), 7.05 (d, 2H), 7·19-7·32 (m, 5H), 7.41 (s, 1H), 7.45 (d, 2H). Example 78 1,1-dione-3,3 -Dibutyl-5-phenyl-7-sulfonylthio-8-[N-(RH ... {N'-"(R)-NV2-hydroxy-1-carboxyethyl)amine mercaptomethyl 1 Aminomethyl benzyl}benzyl)amine fluorenylmethyl]-2,3,4,5-tetra-1,5-benzoquinone sulphide sulphate gives 1,1-dione _3, 3_Dibutyl-5-phenyl-7-indolethio-8-(N-{(R)-r-phenyl-1,-[N'-(carboxymethyl)aminecarbamyl]anthracene Aminomethylmercaptomethoxy-2,3,4,5-tetrahydro-1,5-benzoquinonesulfurium heptadecene (Example 43; 50 mg, 0.072 mmol), 〇-(第Three _ -114- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1291951 A7 B7 V. Description of invention (112) Butyl)-D-serine third-butyl ester hydrochloride Salt (22 mg, 0. 087 mmol) and N-mercapto-Fallin (40 mg, 0. 40 mil) It was dissolved in DCM (1 mL). TBTU (29 mg '0.090 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated and the residue was taken to abr. (d. The obtained material (about 60 mg) was dissolved in DCM (1 mL). TFA (0.59 g, 5.2 mmol) was added, and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated, and the residue was purified by preparative HPLC using MeCN / ammonium acetate buffer (50: 50) as solvent. 38 mg (720/.) of the title compound was obtained. :^^01(300 顺2,0乂80-(16)0.7-0.8(111,611),0.9-1.5 (m,12H),2.2 (s,3H),3.2-3.9 (m,10H ), 4.2 (brs, 1H), 4.8 (ABq, 2H), 5.6 (d, 1H), 6.7 (s, 1H), 6·87·5 (m, 11H), 8.0 (d, 1H), 8.6 ( d,1H),8.7 (t,1H)· Example 79 1,1-indenyl-3,3-butyl-5-winter-7-methylthio-8-fN-(R)- (a-{N,-|YSVNn-(2-hydroxy-1-carboxyethyl)aminemethylmercaptomethyl1amine-methylhydrazino}-based)amine-carboxamidine-based 1-2,3,4 ,5-tetranitro-1,5-penelopeite nitrogen-filled heptazone, 1,1-dione-3,3-dibutyl-5-phenyl-7-sulfonyl-8-(N -{(R)-l,-phenyl],_[N'-(decyl)aminoindenyl]methyl}amine-methylcarbonyloxy)-2,3,4,5-tetrahydro -u-benzoquinonesulfurium heptasulfonate (Example 43; 50 mg, 0.072 mmol), 〇-(Third-butyl)-1-serine tris-butyl ester hydrochloride (22 mg, 0.087 millimolar) and N-methylmorpholine (40 mg, 0. 40 mmol) dissolved in DCM (1 mL). Add TBTU (29 gram '0.090 Amor) and mix in Stir for 1 hour at room temperature. Evaporate the reaction mixture and allow the residue to pass short Column (DCM: EtOAc, 1 : 4). The obtained material (~ 60 mg) was dissolved in DCM (1 mL). TFA (0.44 g, 3.9 mM) was added and mixed -115- This paper size applies to the SS standard (CNS) A4 specification (21GX297 public) &quot; -- 1291951 A7 _______ B7 V. Inventive Note (113) Stir at room temperature for 18 hours. Evaporate the solvent and lend the residue Prepare for HPLC purification using MeCN / ammonium acetate buffer (5 〇: 50) as the solvent. Obtained 33 mg (63%) of the title compound. NMR (300 MHz, DMSO-d6) 0.7-0.8 (m, 6H) , 0.9-1.5 (m, 12H), 2.2 (s, 3H), 3·2-3·9 (m, 10H), 4.2 (m, 1H), 4.8 (ABq, 2H), 5·6 (d, 1H),6·7 (s,1H),6·87·5 (m,11H),7·9 (d,1H),8·6 (d,1H), 8.7 (t,1H). Example 80 1"1-diketo-3-butyl-3-ethyl-5-phenyl-7-methylthio...ΓΝ,-Π,1-dicarboxymethyl)aminecarboxamide Mercaptomethyl-based V2.3A5-tetrahydro-1,5-jasmium sulphide heptadecene gives 1,1·monoketo-3-butyl-3-ethyl-5-phenyl-7- Thioyl-8-[N-"R)-π-monohydrazino)aminomethane methoxy]- 2,3,4,5-tetrahydro-1,5-benzothiazepine hepene (Example 38; 50 mg, 0.082 mmol), dimethyl amalonate (6 mg, 0.13 m) Mol) and N-methylphenoflline (55 μL, 0.5 mmol) were dissolved in DCM (3 mL), TBTU (42 mg, 0.13 mmol) was added and the mixture was dropped for 15 minutes. The solvent was evaporated under reduced pressure. The residue was dissolved in ethanol (95%) (2 mL) and EtOAc (EtOAc (EtOAc) The reaction mixture was decanted; it was dropped for 4 hours. The mixture was neutralized with acetic acid. The solvent was evaporated under reduced pressure, and the residue was purified by preparative HPLC using MeCN / ammonium acetate buffer (40: 60) as a solvent. The collected fractions were lyophilized to give 4 mg (7 %) of the title compound. NMR (300 MHz, CD3 OD) 0.75-0.9 (m, 6H), 1·0-1·3 (m, 4H), 1.4-1.65 (m, 4H), 2.15 (s, 3H), 3.25 (s, 2H), 3.7 (brs, 2H), 4.65-4.8 (m, 2H), 5.75 (s, lH), 6.75 (s, lH), 6.9-7.55 (m, 11H) · -116- This paper scale applies to China National Standard (CNS) A4 Specification (210 X 297 mm) 1291951 A7 B7 V. INSTRUCTIONS (114) EXAMPLES 81-87 The following compounds were synthesized by the procedure of Example 80 using the appropriate starting materials, using 2,6 - Dimercaptopyridine instead of N-methylmorpholine, and the dispersant is given a MeCN / ammonium acetate buffer (45: 55). The reaction time at each stage was slightly changed. -117- This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm)

Binding

line

1291951 A7 B7 Γ---7^115 V. INSTRUCTIONS ( ) ^------------ Example compound NMR (300 MHz, CD3OD) SM~ 38 81 ύ —------ (500 MHz) 0.8-0.95 (m, 6H), 1.05-1.35 (m, 4H), 1.4-1.7 (m, 4H), 2.2 (s, 3H), 3.25 (s, 2H), 3.7-3.9 (m , 4H), 4.4-4.45 (m, 1H), 4.7-4.8 (m, 2H), 5.7 (s, 1H), 6.75 (s, 1H), 6.95-7.6 (m, 11H) 82 ο 0.75-0.9 ( m, 6H), 1.05-1.3 (m, 4H), L4-1.6 (m, 4H), 2.15 (s, 3H), 3.25 (s, 2H), 3.7-3.95 (m, 4H), 4.25-4.3 ( m, 1H), 4.75 (ABq, 2H), 5.65 (s, 1H), 6.75 (s, 1H), 7.95-7.55 (m, 11H) Example 38 83 Ο __——----. 0.75-0.9 ( m, 6H),1·05-1·35 (m,8H), 1.4-1.6 (m, 4H), 2.15 (s, 3H), 3.25 (s, 2H), 3.7-3.9 (m, 4H), 4.35-4.45 (m, 1H), 4.7 (ABq, 2H), 5.7 (s, 1H), 6.75 (s, 1H), 6.95-7.55 (m, 11H) Example 1 84 1 0.75-0.9 (m, 6H) , 1.05-L3 (m, 8H), 1.4-1.6 (m, 4H), 2.15 (s, 3H), 3.25 (s, 2H), 3.7-3.9 (m, 4H), 3.3-3.4 (m, 1H) , 4.7 (ABq, 2H), 5.65 (s, 1H), 6.7 (s, 1H), 6.95-7.55 (m, 11H) Example 1 85 2 d ό ηοΛ-ν ηΙ HO^ · 0.75-0.9 (m, 6H ), 1.05-1.3 (m, 8H), 1.4-1.6 (m, 4H), 3.25 (s, 3H), 3.6-3.9 (m, 6H), 43-4.5 (m, 2H), 4.7 (ABq, 2H), 5.65 (s, 1H), 6.7 (s, 1H), 6.95 -7.5 (m, 11H)^ Example 83 -118- A paper scale applies to China National Standard (CNS) A4 size (210 x 297 mm) 1291951 A7 B7 V. Invention description (116) 86 3 °ΧΤ〇^&lt ;: ^ 0 ΗΟ^ 0.75-0.9 (m, 6H), 1.05-1.3 (m, 8H), 1.4-1.6 (m, 4H), 2.15 (s, 3H), 3.25 (s, 2H), 3.6-3.9 (m, 6H), 4.35-4.5 (m, 2H), 4.7 (ABq, 2H), 5.6 (s, 1H), 6.7 (s, 1H), 6.95-7.55 (m, 11H) Example 83 87 0.75-0.9 (m, 6H), 1.Q5-1.3 (m, 8H), Example 1_ 4 ^C(3cT L4-1.6 (m, 4H), 2.2 (d, 3H), 3.15- 335 (m, 5H), 3.5 -3.85 (4H), 4.4-4.5 °γ\ ζ^) (m, 1H), 4.6-4.7 (m, 2H), 5.6 (s, 1H), JX 6.7 (s, 1H), 6.95^7.55 (m , 11H) 1 ratio of dissolving agent (55: 45); 2 ratio of dissolving agent - variable gradient liquid; ratio of 3 dissolving agent (50: 50); ratio of dissolving agent (60: 40) Example 88 1,1-dione Benzyl-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-(S)-(-------------- ,4,5-tetrahydro-1,5-stupyl#sulfuric heptadecene makes 1,1-one-keto-3,3-dibutyl 5-5-phenyl-7-sulfonylthio-8-[N-(s)-(...methoxybenzyl benzyl)amine decyl decyloxy]-2,3,4,5-tetrahydro- 1,5-Benzene sulfonium sulfoxide (Method 87; 55.2 mg, 0.064 mmol) was dissolved in THF (2 mL) and 〇.5 liters of water. LiOH (3.1 mg, 0.127 mmol) was added and the mixture was stirred for 1 hour. Water (1 mL) was added and the mixture was acidified with EtOAc EtOAc (EtOAc) The DCM phase was dehydrated, dried and concentrated. The solid product was co-evaporated with diethyl ether and dissolved in HPLC grade water. The title compound was obtained as a white solid (yield: 28 mg). Nmr 0.77-0 : 85-(m,6H),1.03-1.25 (m,8H),1.34-1.57 (m,4H),2.16 (s,3H) 3 18

1291951 A7 B7 V. INSTRUCTIONS (117) (brs, 2H), 3.75 (brs, 2H), 4.65 (ABq, 2H), 5.7 (d, 1H), 6.63 (s, 1H), 7.0 (t, 1H) , 7.1 (d, 2H), 7.26-7.48 (m, 8H), 7.85 (d, 1H); m/z 639. Example 89 1,1-dione-3,3-dibutyl-5-benzene -7-methylthio-8-nSM (SVa-[N'-(carboxy hydrazine, amine hydrazino 1 tea decyl carbhydryl methoxy 1-2,3,4,5-tetrahydro) -1,5-benzoquinone oxime hydrazide, 1,1-dione-3,3-dibutyl-5-phenyl-7-fluorenyl-8-[N-{(S) -...[N,-(methoxycarbonylmethyl)aminemethylmercapto]ylamino}aminomethyl methoxy]-2,3,4,5-tetrahydro-1,5-phenyl sulfonium sulphide The terpene (Method 88; 19 mg, 0.027 mmol) was hydrolyzed in THF (1 mL) and water (3·3 mL) with LiOH (1·3 mg, 0·054 mmol). Water (3 ml) was added, and the mixture was crystallised eluted eluted elut elut elut elut elut elut elut elut elut NMR 0.77-0.85 (m, 6 Η), 1.0-1.3 (m3 8H)? 1.34-1.57 (m5 4H), 2.17 (s, 3H), 3.18 (s, 2H), 3.75 (b Rs, 2H), 3.90-4.20 (m, 2H), 4.65 (ABq, 2H), 5.87 (m, 1H), 6·63 (s, 1H), 6.98-7.50 (m, 12H), 8.12-8.20 ( m,1H) ; m/z 696. Example 90 diketo·3,3-dibutyl-5-phenyl-7-methylthio...indole,-(2-sulfonic acid methylamine) Aminomethyl methoxy [2JA5-tetraindole-1,5-stupyl] sulphide sulphate steel salt 1,1-dione-3,3-dibutyl-5-phenyl -7-Methylthio-8-[N-(S)-(cardocarboxymethyl)amine-based methylmeryl]-2,3,4,5-tetraki-1,5-winter sulfur The saponin (Example 88; 41 mg, 0.064 mmol) was dissolved in 3 mL of DCM. Continuous addition of tetrabutylammonium borate (70 mg, 0.191 mmol) with TBTU (25 mg, 0.078 ____-) 120- The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1291951 A7 B7 V. Description of the invention (118) millimolar) and the mixture is stirred at ambient temperature overnight. The solvent was evaporated, and the product was purified by preparative HPLC using MeCN / ammonium acetate buffer gradient (45/55 to 55/45) as a solvent. The collected fractions were lyophilized, followed by ion exchange chromatography on 4 g of Amberlite CG 120, Na+-form to give the title compound, 85% yield (42 mg). NMR 0.7-0.8 (m, 6H), 0.9-1.2 (m, 8H), 1.3-1.5 (m, 4H), 2.0 (s, 3H), 2.9-3.2 (m, 2H+2H), 3.3-3.8 (m, 2H+2H), 4.4-4.7 (m, 2H), 5.6 (m, 1H), 6.57 (s, 1H), 6.9-7.5 (m, 11H), 7.8-8.1 (m, 2H) ; m /z 746. Example 91 The following compound was synthesized by the procedure of Example 90 using the appropriate starting material, except that the product was purified using a 40/60 to 70/30 buffer gradient and then dried to dryness. Examples Compound NMR (CD3OD) and m/z

SM 91

NH, 0.76-0.84 (m, 6H), 1.03-1.27 (m, 8H), 1.38-1.55 (m, 4H), 2.15 (s, 3H), 2.95 (t, 2H), 3.24 (s, 2H), 3.58 (dt, 2H), 3.75 (brs, 2H), 3.85 (ABdd, 2H), 4 J2 (ABq, 2H), 5.51 (s, 1H), 6.70 (s7 1H), 6.97 (t, 1H), 7.11 (d, 2H), 7.25-7.40 (m, 6H), 7.46 (d, 2H); m/z 803 Example 43 Example 92 1,1-dione, 3-butyl-3-ethyl-5- Phenyl-7-[N-{(R)-...W carboxymethyl)aminemethanyl 1henylguanamine-methylhydrazine oxyl 1-2,3,4,5-tetrahydro-1,5 - Benzene sulphide heptahexene sodium salt 1,1 -diketo-3-butyl-3-ethyl-5-phenyl- -171 which has been dissolved in DCM (4 ml) China National Standard (CNS) A4 Specification (210 X 297 mm) 1291951 A7 B7 V. Description of Invention (119) 7-Carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzoquinone Sulfur Sodium heptadecene sodium salt (\¥〇01/66533; 120 mg, 0.278 mmol), added to the heart [N-(Thrs-butoxycarbonylmethyl)amine indolyl]guanamine (Method 86; 90%, 150 mg, 0.511 mmol) in DCM (3 mL). 2,6-Dimethylpyridine (65 mL, 0.559 mmol) was added with TBTU (137 mg, 0.427 mmol), and the reaction mixture was stirred at ambient temperature overnight. The solution was filtered using DCM / EtOAc (8/2) as solvent. Evaporate the solvent. DCM (4 mL) was added with TFA (0.6 mL), and mixture was stirred overnight. The solvent was evaporated and the crude product was taken on a Chromasil </ br </ br> column, and purified by preparative HPLC using &lt;RTIgt;&lt;/RTI&gt;&lt;/RTI&gt;&gt;MeCN / ammonium sulphate buffer gradient (50/50 to 100/0) as mobile phase. The MeCN was evaporated and lyophilized to give the title compound, 36%. &gt;^110.73-0.82 (m,6H),1.00-1.23 (m,4H),1.30-1.65 (m,4H),3.05-3.18 (m,2H),3.65 (brs,2H),3.75 (ABdd, 2H), 4.46 (ABq, 2H), 5.70 (d, 1H), 6.79-7.24 (m, 10H), 7.36 (d, 2H), 7.46 (d, 1H), 7·83 (d, 1H), 8.00 (brs, 1H); m/z 622. Examples 93-94 The following compounds were synthesized by the procedure of Example 92 using the appropriate starting material, but HPLC-chromatography was carried out on a Chromasil C8 column with a solvant gradient The liquid is from 45/55 to 60/40. __-122- This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1291951 A7 B7 V. Description of invention (12Q) Example compound NMR (CD3OD) and m/z SM 93 9 〇', /? NH / Γ 〇^OH 0 to palm isomer 1 0.75-0.84 (m, 6H) 1.00-1.27 (m, 4H), 1.38-1.66 (m, 4H) 2.15(s, 3H), 3.22 (s, 2H ), 3.75 (brs, 2H), 3.83 (ABdd, 2H), 4.69 (ABq, 2H), 5.60 (s, 1H), 6.71 (s, lH), 6.96 (t, 1H), 7.09 (d, 2H) , 7.23-7.37 (m,. 5H), 7.39 (s, 1H), 7.46 (d, 2H); m/z 668 Method 23; Method 86 94 〇Anh 0L 0 to palm isomer 2 0.78-0.85 (m , 6H) 1.04-1.27 (m, 4H), 1.41-1.65 (m, 4H) 2.17 (s, 3H), 3.24 (s, 2H), 3,68 (brs, 2H), 3.89 (ABdd, 2H), 4.72 (ABq, 2H), 5.62 (s, 1H), 6.73 (s, 1H), 6.97 (t, 1H), 7.11 (d, 2H), 7.26-738 (m, 5H), 7.41 (s, 1H) , 7.48 (d, 2H); m/z 668 Method 24; Method 86 Example 95 1,1-dione-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- {N-"(R)-heart "(ethoxy X methyl) phosphonium 1 ethyl} amine formazan base 1 amine methyl methoxy}-2,3,4,5-four Hydrogen-1,5-phenylindolesulfonium sulphate in 2-[(methyl)(ethyl) Phosphonic acid] ethylamine (Helv. Chim. Acta; GE; 75; 8; 1992; 2545-2552; 16 mg, 0.106 mmol) in DCM (2 mL) in 〇 ° C and argon Addition of 1,1-diketo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-[N-((R)-l'-phenyl-1' -carboxymethyl)amine-mercaptomethoxyoxy]-2,3,4,5-tetrahydro-1,5-benzoquinonesulfazinardecene (Example 38; 50 mg, 0.082 mmol), DIPEA (42 mg, 0·328 mmol) and TBTU (34 mg, 0.106 mmol) -123- This paper size applies to Chinese National Standard (CNS) Α4 size (210 X 297 mm) 1291951 A7 B7 V. Description of the invention (121). The reaction mixture was stirred at room temperature for 110 min then DCM was added and the solution was washed with NaHC03 (aq. The organic layer was dehydrated and the solvent was evaporated under reduced pressure. The residue was purified by chromatography and the product was dissolved in DCM / methanol (100: 5). Yield 43 mg (71%). NMR (500 MHz) 0.78-0.85 (m5 6H), 1.02-1.54 (m, 12H), 1.6-1.75 (br, 1H), 1.8-2.10 (m5 3H), 2·21 (s, 3H), 3.10- 3.25 (m, 2H), 3.51-3.84 (m, 4H), 3.9-3.99 (m, 1H), 4.01-4.09 (m, 1H), 4.54-4.69 (dd, 2H), 5·51 (d, 1H) ), 6.68 (s, 1H), 6.96-7.02 (m, 1H), 7.03-7.18 (m, 3H), 7.25-7.42 (m, 6H), 7.43-7.48 (m, 2H), 8.05-8.15 (m , 1H). Examples 96-97 The following compounds were synthesized by the procedure of Example 95 using the appropriate starting material. Example compound NMR or m/z SM 96 l r r N · &lt; CUD 0.76-0.85 (m, 6H), LOO-1.52 (m, 12H), L55-1.75 (m, 1H), 1.95-2.12 (br, 1H ), 2,20 (s, 3H), 3.10-3.25 (m, 2H), 3.55-3.85 (m, 4H), 3.85-4.00 (m, 2H), 4.03-4.13 (m, 2H), 4.6 (q , 2H), 5.64 (d, 1H), 6.66 (s, 1H), 7.78 (br, 1H), 6.95-7.10 (m, 3H), 7.23-7.40 (m, 6H), 7.43-7.49 (m, 2H ), 8Ό7 (d, 1H); m/z 760.3 Example 38 97 ^ rN , '&lt; (600 MHz) 0.75-0.82 (m, 6H), 1.0-1.42 Example 1 pc--L (m, 13H), 1.64 (brs, 1H), 2.18 (s, 3H), 3.08-3.24 (m, 2H), 3.50-3.84 (m, 4H), 3.87-4.13 (m, 2H), 4.54-4.68 (m, 2H), 5.56-5.62 (m, 1H), 6.63 (s, 1H), 6.87-7.10 (m, 3H), 7.24-7.40 (m, 7H), 7.43-7.49 (m, 2H), 7.98-8.05 (m, 1H) ); m/z 730.5 38 -124- This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

1291951 A7 ____B7 V. Description of invention (122) &quot; '1 amine: Tetrahedron; EN; 49; 47; 1993; 11055-11064 Example 98 U-diketo-3-butyl-3-Ethyl-7-7 Methylthio group·8·{Ν_Γ(Κ)-heart sigh_(2 small borrowing cover) (methyl) 嶙S&amp; base 1 ethyl fluorenyl) fluorenyl 1 amine carbamyl guanidine 2.3.4.5- four Hydrogen-1,5-phenylindolesulfonium sulphate in 1,1-dione-3-but-3-yl-5-phenyl-7-methylthio-8-{N-[( R)+(N,-{2-[(ethoxy)(methyl)phosphonium]ethyl}amine-methylmethyl)-amino]aminomethylcarbonyl}-2,3,4, 5-Tetrahydro-1,5-phenylindolesulfonium heptadecene (Example 95; 27 mg, 0.036 mmol) in a solution of ethanol (1·5 mL). A 2 μl aqueous solution of NaOH (〇·22 ml, 〇·44 mmol) was added under the arm. The reaction mixture was stirred at room temperature for 24 hours. Add acetic acid (1) · 2 ml). The solvent was evaporated under reduced pressure and the residue was purified eluting eluting The DCM layer was separated, washed with brine, dried and dried and evaporated. The residue was recrystallized from DCM / ether / petroleum ether toield NMR (600 MHz) 0.74-0.82 (m, 6H), 1.0-1.70 (m, llH), 1.90-2.09 (m, 2H), 2.16 (s, 3H), 3.05-3.24 (m, 2H), 3.40- 3.85 (m, 4H), 4·5 (Μ·65 (dd, 2H), 5.55 (d, 1H), 6.63 (s, 1H), 6.93-7.07 (m, 3H), 7.20-7, 50 (m , 9H), 8.10 (d, 1H); m/z 716.3. Example 99 1,1-di-S-yl-3-butyl-3-ethyl-5-phenyl-7-methylthiohydroxy) L Ethoxy)phosphorylmethyl 1amine-based fluorenyl-amino-yl-1,3,4,5-ghydro-1,5-benzoquinone sulphide 1,1-diketo-3-butylungyl-5-phenyl-7-sulfonyl-8-[N-((R)-a-{N,-[(diethoxy))嶙醯 曱 ] ] 胺 } } } } } } } } 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( Mo _ -125- This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) 1291951 A7 ___Β7__ V. Invention description (123) 'Ear) Add 1 in drop to solution in MeCN (0.5 ml) Aqueous solution of μ LiOH (0.171 ml, · 0.171 mmol). The reaction mixture was stirred at room temperature for 3 days. Acetic acid was added and the solvent was evaporated under reduced pressure. The crude product was purified by preparative HPLC using EtOAc (EtOAc: EtOAc) _411(60〇]^2, €0300) 0.77- 0.84 (m, 6H), 1.00-1.30 (m, 7H), 1.40-1.65 (m, 4H), 2.17 (s, 3H), 3.23 (brs, 2H) ), 3.51 (d, 2H), 3.6-3.85 (m, 4H), 4.70 (dd, 2H), 5.57 (s, 1H), 6.72 (s, 1H), 6.96 (t, 1H), 7.09 (d, 2H),7·25-7·31 (m,3H),7·32-7·36 (m5 2H), 7.40 (s,1H), 7.45 (d, 2H) ; m/z 732.4. Example 100 II Ketopropyl-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-fN-((R)-...丨N'-[(hydroxy)β-yl)phosphoniummethyl Aminomethyl hydrazino)1,3,4,5-tetrahydro-1,5-benzothiazepine quinone is attached to 1,1-one keto-3-butene 3-ethyl-5-phenyl-7-fluorenyl-8-[N-((R)-α-{Ν'-[(ethoxy)(methyl)phosphonium fluorenyl] Aminomethyl hydrazino} decyl) amine carbaryl methoxy]- 2,3,4,5-tetrahydro-1,5-benzothiazepine hepene (Example 97; 85 mg, 0.12 mmol) ) in a solution in MeCN (2.4 ml), in hydrazine. A 1 μL aqueous solution of Li (U7 mL, U7 mmol) was added dropwise under the arm. The reaction mixture was stirred at room temperature for 20 hours. Acetic acid was added and the solvent was evaporated under reduced sound. The crude product was purified by EtOAc EtOAc EtOAc EtOAc EtOAc Nmr (CD3 OD) 0.75-0.84 (m, 6H), 1.0-1.70 (m, 11H), 2.15 (s, 3H), 3.22 (brs, 2H), 3.35 (d, 2H), 3.60-3.90 (m, 2H), 4·70 (dd, 2H), 3·55 (s, 1H), 6.71 (s, 1H), 6.96 (t, 1H), 7.09 (d, 2H), 7·23-7· 38 (m,5H), 7.40 (s,1H), 7.46 (d,2H) ; m/z 702.3 _______ -126- This paper size applies to Chinese National Standard (CNS) A4 size (210X297 mm) 1291951 A7 B7 5Γ , Description of the Invention (Example 101 The following compounds were synthesized by using the appropriate starting materials by the procedure of Shentian Example 100

NMR (600 MHz, CD3OD) and m/z 0^6-0.83 (m, 6H), 1.05-1.55 (m, 15H)T 1.91-1.99 (m, 2H), 2.15 (s, 3H), 3.24 (brs , 2H), 3.40-3.50 (m, 2H), 3.66-3.86 (m, 2H), 4.69 (dd, 2H), 5.42 (s, 1H), 6.70 (s, lH), 6, 92 (UH), 7.11(d,2H), 7.25-7.39 (m, 6H), 7.43 (d, 2H); m/z 744* 3 Example 102 - light-based 3 Dingham-5-phenyl-7-methylthio -8-[Ν-((ΙΙ)-二-(第-兵-丁氧胺甲醯基戌基)amine-carbamoylmethoxy&gt; 2^5: tetrahydro-1, sulfonium thiol Hexetylene in 1,1-dione-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-[N-((R)-l,-phenyl-fluorene -carboxymethyl)amine-mercaptomethoxy]-2,3,4, Hongtetrahydro-: 1,5-benzothiazepine hepene (Example 38; 80 mg, 〇·ΐ 31 mmol) ) with bis(tris-butoxy) fluorenyl decylamine (Tet. Lett· ; ΕΝ '· 33 ; 1 ; 1992 ; 77-80 ; 37 mg, 0.164 mmol) in DCM (5 ml) 2,6'-dimethylpyridine (28 mg, 0.262 mmol) and TBTU (53 mg, 0.164 mmol) were added to the solution. The reaction mixture was stirred at room temperature for 2 hours and 50 minutes. Evaporating the solvent under reduced pressure and The crude product was purified by flash chromatography eluting elut elut elut elut elut elut elut elut elut elut elut elut elut elut elut eluts elut (m, 26H), 2.22 (s, 3H), 2.10-2.25 (m, 2H), 3.45-3.90 (m, ____- 127-___ This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 x 297) PCT) 1291951 A7 ____B7_ ·___ V. Description of invention (125) 4H), 4.61 (dd, 2H), 5.52 (d, 1H), 5.94 (brs, 1H), 6.67 (s, 1H), 7.0 (t, 1H ),7·07 ( d,2H),7·26-7·48 (m5 8H), 8.12 (d,1H) ; m/z 704.22 [M-2(Third-Butyl)+2H]· Example 103 1,1-diketo-3-butylethyl 5-phenyl-7-methylthio-8-rN-((R)-heart {N,-"di-(hydroxy)phosphonium Methyl]aminoindenyl}mercapto)amine-methylmercaptomethoxy 1_2,3,4,5-tetrahydro-1,5-benzoquinonesulfury-septene in 1,1-dione- 3-butyl-3-ethyl-5-phenyl-7-fluorenyl-8-[N-((R)-...{N,-[bis-(t-butoxy)phosphonium) Aminomethyl hydrazinyl fluorenyl hydrazinyl hydrazinyl hydrazinyl hydrazinyl hydrazinyl hydrazide hydrazide Milli Ear) in the inner was added TFA at square ° c in DCM (4 ml) (1 ml). The reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and the residue was purified eluting eluting The organic layer was separated, washed with brine, dried and dried and evaporated. The residue was suspended in ether and crystall crystals crystals crystals NMR (500 MHZ, DMSO-d6) 0.70-0.80 (m, 6H), 0.99-1.61 (m, 8H), 2.18 (s, 3H), 2·80-4·0 (m, 6H), 4.80 (dd , 2H), 5.65 (d, 1H), 6·71 (s, 1H), 6·80-7·02·(πι, 3H), 7·15-7·35 (m, 6H), 7.48 (d , 2H), 8.50-9.20 (m, 2H); m/z 704.3 Example 104 1,1-diketo-3,3-dibutyl-5-phenyl-7-methylthiomethylfuran (B ) 基 基 』 』 』 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 1 1 1 1 1 1 1 1 1 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四, 3-monobutyl-5-phenyl-7-decylthio-8-[N-((R)-l,-phenylcarboxymethyl)aminecarboxylideneoxy]-2,3, 4,5-tetrahydrophenyl sulfonium sulphide sulphate (example 1; 60 mg, 0·094 mmol) and 2-[(methyl)(ethyl)indenyl]ethylamine-128- paper The scale applies to the country's S standard (CNS) Α 4 specifications (210X297 public) ' --- 1291951 A7 B7 V. Inventions (126 (Helv. Chim. Acta ; GE ; 75 ; 8 ; 1992 ; 2545-2552 ; Add 2,6-lutidine (20 mg, 0.19 mmol) to TBTU (39 mg, 0.121) in a solution of 20 mg, 0.132 mmol) under 〇 ° C and argon. The reaction mixture was stirred at room temperature for 70 minutes, then DCM was added, and the solution was washed with water and brine. The organic layer was dried and evaporated, and the solvent was evaporated under reduced pressure. Chromatography, EtOAc (EtOAc: EtOAc (EtOAc) , 1.80-2.05 (m, 2H), 2·20 (s, 3H), 2·17 (s, 2H), 3.47-3.80 (m, 4H), 3.88-4.10 (dd, 2H), 5.52 (d, lH), 6.65 (s, lH), 6.95-7.12 (m, 3 Η), 7.13-7.42 (m, 7 Η), 7.43-7.49 (m, 2 Η), 8.05-8.16 (m, 1 Η); m/z 772.4 Example 105 1,1-diketo-3,3-dibutyl-5-phenyl-7-fluorenyl-8-〇^{(11&gt;heart [^-(2-mercaptocarboxyl) Aminomethyl hydrazino 1 benzylamine carbazyl methoxy)-2,3,4,5-tetrahydro-1,5-stump # sulphide sulphate in U-diketonyl-3, 3-dibutyl-5-phenyl-7-indolethio-8-[N-((R)-heart {N,-[2-(tritylmethylthio)) small (third-butoxy) Carbonyl)ethyl]aminemethylmercapto}indenyl)amine fluorenyloxy]-2,3,4,5-tetrahydro-1,5-phenylindolesulfinyl hepene (Method 91; 37 Milligrams (0.036 mmol) in DCM (1 mL), EtOAc over EtOAc. The ice bath was removed and triethyl oxalate (42 mg, 0.36 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. Then the solvent was evaporated under reduced pressure. The crude product was purified by preparative HPLC using EtOAc (EtOAc:EtOAc) NMR (500 MHz, CD3 〇D) 0.76- -129- This paper size applies to Chinese National Standard (CNS) A4 size (210 X 297 mm) m\

Line 1291951 A7 B7 jade, invention description (127) 0.85 (m, 6H), 1.05-1.60 (m, 12H), 2.17 (s, 3H), 2.77-2.92 (m, 2H), 3.24 (brs, 2H)? 3.613.88 (m5 2H)3 4.56 (t, 1H), 4.70 (dd, 2H), 5.65 (s, 1H)3 6.71 (s5 1H), 6.98 (t,1H), 7.12 (d,2H), 7.25 -7.43 (m, 6H), 7.50 (d, 2H); m/z 742.4. Example 106 The following compound was synthesized by the procedure of Example 1-5, using the appropriate starting material to synthesize the example compound NMR (500 MHz, CD3OD) m/z

SM _ 106

0.77-0.85 (m, 6H), 1.03-L28 (m, 8H), method L38-1.58 (m, 4H), 2.15 (s, 3H), 2.87- 93 3.5 (m, 2H), 3.25 (s, 2H ), 3.75 (brs, 2H), 4.55. (s, 1H), 4.71 (dd, 2H), 5.66 (s, 1H), 6.71 (s, 1H), 6·98 (t, 1H), 7· 12 (d, 2H), 7.25-7.43 (m, 6H), 7.49 (d, 2H); m/z 742.28 Example 107 D-butyl-butyl-butylethyl-5-phenyl-7-bromo- 8-(2-{N-〖(RV-heart (carboxyl)amine-carbamoyl}ethoxy V2,3,4,5-tetrahydro-1,5-benzothiazepine hepene on 1,1 -Diketo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-(2-{N-[(R)-a-(tris-butoxycarbonyl)) Aminyl}}ethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine hepene (Method 90; 77 mg, 0.108 mmol) in DCM (3 TFA (0.75 ml) was added to the solution in cc. The reaction mixture was stirred at room/dish for 2 hours and 45 minutes. The solvent was evaporated under reduced pressure and the crude material was taken from preparative HPLC. Purification, using MeCN and ammonium acetate buffer (4 〇: 60 to 5 〇: 50) as the eliminating agent to obtain the title compound 6 〇 mg (82%). -130- m This paper scale is applicable to China Standard (CNS) A4 size (210 X 297 mm) A7 B7 1291951 State, invention description (128) NMR (500 MHz, CD3 〇D) 0.75-0.85 (m, 6H), 1.0-1.25 (m, 4H), 1.40-L64 (m, 4H), 2.75-2.90 (m, 2H), 3.26 (s, 2H), 3·50-3·90 (m, 2H), 4·30-4·41 (m, 2H) , 5.43 (s, 1H), 6.99 (t5 1H), 7.05-7.13 (m, 3H), 7·23-7·34 (m, 5H), 7.45 (d, 2H), 7.52 (s, 1H); m/z 658. Example 108 The following compound was synthesized by the procedure of Example 107 using the appropriate starting material.

f example | complexes | NMR (SOO MHz, CD3OD) with m/z | SM

0·78-0·85 (m, 6Η), 1Ό2-1.30 (m, square: 8H), 1.38-1·58 (m, 4H), 1·87 (s, 3H), 92 2.15 (s , 3H), 2.77-2.83 (m, 1H), 2,87-2.94 (m, 1H), 3.24 (s, 2H), 3.74 (brs, 2H), 4.53-4,59 (m, 1H), 4.68 (dd, 2H), 5.66 (s, 1H), 6.71 (s, 1H), 6.98 (t, 1H), 7.12 (d, 2H), 7.25-731 (m, 3H), 7·32-7·36 (m, 2H), 7.40 (s, 1H), 7.49 (d, 2H); m/z 756.23 Example 109 1-keto-j-s-butyl-5-phenyl-7-methylthio-8- {Nf(R)-π_(Ν'-{2-『(曱))[Ethyl)phospho-based]ethyl}amine fluorenyl)-4-thiol-amine 1 amine-methyl hydrazine 2,3,4,5-tetrahydro-1,5-benzoquinonesulfurium heptadecene in 1,1-dione-3,3-dibutyl-5-phenyl-7·decylthio- 8-[N-((R)-iso-yl-glycolyl)amine-carbenylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine (Example 2; 80 mg, 0.122 mmol) and 2-[(indenyl)(ethyl)phosphonium]ethylamine (Helv. Chim. Acta,; GE; 75; 8; 1992; 2545-2552; 24 mg, 〇·159 ___-131 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1291951 A7 B7 V. Invention (129) Millol) In a solution of DCM (2 mL), 2,6-dimercaptopyridine (26 mg, 〇·244 mmol) and TBTU (51 mg, 0.159 m) were added under argon. Moor). The reaction mixture was stirred at room temperature for 60 min then diluted with DCM. This solution was washed with water, brine, dried over water and evaporated. The residue was purified by EtOAc EtOAc EtOAc EtOAc EtOAc -1.55 (m5 18H), 1.82-1-98 (m5 2H), 2.15 (s, 3H), 3.14 (brs, 2H), 3.40-3.56 (m, 2H), 3·70 (brs, 2H), 3.89 -4.02 (m, 2H), 4.51 (dd5 2H), 5.33 (t, 1H), 6.61 (s, 1H), 6.65-6.72 (m5 2H), 6.95 (t, 1H), 7.03 (d, 2H), 7·12· 7.19 (m, 3H), 7.22-7.26 (m, 2H), 7.32 (s, 1H), 8.11 (t, 1H); m/z 788.56. Example 110 1"1-dione-3 ,3-dibutyl-5-phenyl-7-methylthio-8-{N-"(R)-sink-(N,-{2-"(methyl)(#yl)] thiol] Ethyl}amine-mercapto)-4-pyridyl 1amine-methylhydrazine methoxy^2,3,4,5-tetrahydro-1,5-benzoquinonesulfazin-7-ene in 1,1- Diketo-3,3-dibutyl-5-phenyl-7-methylthio-8-{N-[(R&gt; α-(Ν,-{2-[(methyl)(ethyl))) Mercapto]ethyl}amine-mercapto)-4-benzylbenzylamine-methylmercaptomethoxy}-2,3,4,5-tetrahydro-1,5-benzoquinone (Example 1〇4; 37 mg, 〇.〇47 mmol) in a solution of MeCN/MeOH (4 mL, 1:1) A 1 μL aqueous solution of LiOH (0.8 liters, 0.8 mmol) was added. The reaction mixture was stirred at room temperature for 40 min shovel. Acetic acid was added and the solvent was evaporated under reduced pressure. The crude product was purified by preparative HPLC. The title compound 35 mg (96%) was obtained with the ammonium acetate buffer (4 〇: 60 and 45: 55) as the eliminating agent. NMR (500 MHz, CD3 OD) 0.78-0.85 (m, 6H)5 1.06- 1.28 (m5 11H)5 1.39-1.57 (m5 4H)? 1.72-1.85 (m,2H), 2.16 (s,3H)5 2.24 (s,2H), 3.40-3.50 (m,2H), 3.65-3.84 ( m, -132 This paper size applies to Chinese National Standard (CNS) A4 specification (210x 297 mm) Binding

Line 1291951 A7 B7 V. Description of invention (13Q) 2H), 4.69 (dd, 2H), 5.36 (s, 1H), 6.71 (s, 1H), 6.76 (d, 2H), 6.99 (t, 1H), 7.13 (d5 2H), 7·22-7.33 (m, 4H), 7.39 (s, 1H); m/z 760.27 Example 111 1,1-dione-3,3-dibutyl-5-phenyl- 7-Methylthio-8-(N-{(RV--ΚΚΟ-Ν'β-methylsulfinyl carboxyethyl)amine fluorenyl 1 fluorenyl}amine-methyl methoxy)- 2.3.4.5- Tetrahydro-1,5-benzoquinonesulfazin-7-decene The title compound was isolated as a by-product from Synthesis Example 108. NMR (500 MHz, CD3 0D) 0.78-0.85 (m, 6H), 1.02-1.60 (m, 12H), 2.16 (d, 3H), 2.53 (d, 3H), 3·08-3.18 (m, 1H) ,3·24 (s,2H),3·35 (v br,1H),3·75 (v br,2H),4.62 (v br,1H),4.71 (dd,2H),5.60 (d,1H) ), 7.71 (s, 1H), 6.98 (t, 1H), 7.12 (d, 2H), 7.25-7.42 (m, 6H), 7.47 (d, 2H); m/z 772.25. Example 112 !, 1-diketo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-heart "(S)-N,-(3-methylthio) -2-carboxypropyl)amine carbaryl 1 fluorenyl}amine carbaryl methoxy) 2,3,4,5-tetrahydro-1,5-benzoquinone sulphide sulphate in 1,1- Diketo-3,3-dibutyl-5-phenyl-7-fluorenyl-8-(N-{(R)-...[(S)-N,-(3-methylthio-2) -Methoxycarbonylpropyl)amine fluorenylmethylamine 2.3.4.5-tetrahydro-1,5-benzoquinone sulphide sulphate (Method 94; 68 mg, 0.087 mmol) NaOH (9 mg in 0.4 ml of water) was added to a solution in ethanol (5 mL). The reaction mixture was stirred at room temperature for 2.5 hr. Solvent. The crude product is prepared by HPLC. Using MeCN and ammonium acetate buffer (40 ··60 to 60:40) as the dissolving agent, the title compound 52 mg (76%) was obtained. 1^411 (500)^2, €3〇) 0.79- 〇·86 (m,6H),1.05-1.29 (m,8H),1.40-1.58 (m,4H),1.84-1.93 (m,4H),2.01- __ -133- This paper scale applies to Chinese national standards ( CNS) A4 size (210 X 297 mm)

k 1291951 A7 _ B7 V. INSTRUCTIONS (131 ) 2·21 (m5 5H), 2.26-2.34 (m, 1H), 3·26 (s, 2H), 3.76 (brs, 2H), 4.52-4.58 (m , lH), 4.70 (dd, 2H) 55.61 (s, lH), 6.73 (s, lH), 7.0 (t5lH), 7.14 (d, 2H), 7.27-7.43 (m5 6H), 7.49 (d, 2H) ; m/z 770.16· Example 113 jj-diketo-3,3-dibutyl-5-phenyl-7-methylthio-8-〇H (RV heart "(S)-N,-(2 -Methyl decyl-1-carboxyethyl)amine-methyl hydrazino 1 yl}amine-methyl methoxy)-2,3,4,5-tetrahydro-1,5-phenyl sulfonium sulfoxide 1,1-Diketo-3,3-dibutyl-5-phenyl-7-sulfonyl-8-(N-{(R)-heart [(S)-N,-(2- Mercapto-1-carboxyethyl)amine-methylglycolyl]-aminomethylamino)-2,3,4,5-tetrahydro-1,5-benzoquinonesulfurium heptadecene (Example 1 〇6; 15 mg, 0.02 mmol; in methanol (1.5 ml), sodium methoxide (0J04 mmol, in 0. 14 ml of methanol) and methane iodide (0.16 mmol) were added under nitrogen. ear). The reaction mixture was stirred at room temperature for 50 minutes. Add acetic acid. The solvent was evaporated under reduced pressure, and the residue was evaporated, m. The organic layer was separated, washed with EtOAc EtOAcjjjjjjjj NMR (500 MHz, CD3 OD) 0.75-8.30 (m, 6 Η), 1.03-1.57 (m, 12 Η), 2.10 (s, 3 Η), 2.17 (s, 3H), 2.83-2.30 (m, 1H), 3.0 -3.25 (m,1H),3·26 (s,2H),3.77 (brs,2H), 4.58-4.63 (m5 1H),4·72 (dd,2H),5·64 (s,1H), 6.72 (s, 1H), 7.0 (t, 1H), 7.12 (d, 2H), 7.28-7.52 (m, 8H); m/z 756.25. Example 114: fluorenyl-3,3-butyl- 5-(4-Phenylphenyl)-7-indolethio-8-[N-{(R)-(Tisino)amine-methylmercaptodecylcarbinylmethoxymethyl 1-2JA5-tetra Hydrogen-1,5-stupyl sulphur nitrogen sulphide is attached to 1,1-dione-3,3-dibutyl-5-(4-phenylphenyl)-7-methylthio-8-[N -{(R)-Heart-134- This paper scale is suitable for gg standard (CNS) A4 specification (210X 297 public) "" 1291951 A7 ___ B7 V. Invention description (132) &quot; [N·-( Tertiary-butoxycarbonylmethyl)amine-methylcarbonyl]hydrazino}amine-methylmethyloxy&gt; 2.3.4.5-tetrahydro-1,5-benzothiazepine heptarene (Method 1〇2; 129 mM, 0.164 mmol) in DCM (5 mL) in hydrazine. TFA (1.5 mL) was added under hydrazine and nitrogen. The reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and the crude product was purified by preparative HPLC using MeCN and acetic acid as a solvent (40:60 to 50:50) as a solvent to give the title compound 77 mg (63%). NMR (500 MHz, CD3 OD) 0.84 (t, 6H), 1.10.12.22 (m, 8H), 1.35-1.45 (m, 4H), 2·34 (s5 3H), 3.19-3.27 (m, 2H), 3.55 (s, 2H), 3.87 (dd, 2H), 4.67 (dd, 2H), 5.61 (s, 1H), 7.09-7.15 (m, 3H), 7.27-7.37 (m, 6H), 7.47 (d, 2H) ; m/z 748.03 (M+NH3). Example 115 i,l-dione-3,3-dipropyl-5-phenyl-7-methylthio-8-team (01)-heart []^(2-sulfonate-ethyl)aminemethylmercapto]-4-H芊yl}aminecarboxymethyl-based i-2,3,4,5-tetrahydro-1,5-benzene Strontium sulfoxide heptadecene in 1,1-diketo-3,3-dipropyl-5-phenyl-7-methylthio carboxycarboxymethoxy-2.3.4.5-tetrahydro-1,5- Add benzothiazepine heptarene (method us; 0.050 g, 〇·1 〇 5 mmol) in a solution of DMF (4 ml), add 2-{[(2R)-2-amino-2- (4-Phenyl)ethinyl]amino}ethanesulfonic acid (Method 80; 〇·〇 37 g, 0.135 mmol) with N-methylmorpholine (0.040 mL, 0.363 mmol) . The mixture was stirred for 10 minutes and then TBTU (0.044 g, 0.137 mmol) was added. The reaction mixture was stirred for two days before the solvent was removed under reduced pressure. The residue was purified by preparative EtOAc (EtOAc) elute NMR (DMSO-d6) 0.60-0.80 (m, 6H), 1.05- 1.50 (m, 8H), 2·15 (s, 3H), 2.45-2.55 (m, 2H), 3.05-3.80 (m, 6H) , 4.70 __ -135- i paper scale GS standard (CNS) eight 4 specifications (21GX297 public 6 ' ~ - 1291951 A7 -____ B7 five, invention description (133) ~ ~ --- (ABd, 1H) , 4.80 (ABd, 1H), 5.25 (d, 1H), 6.65-6.75 (m, 3H), 6.80-7.05 (m, 3H), 7.10-7.25 (m, 4H), 7_30 (s, 1H), 8.20 -8.30 (m,1Η)·8·45 (d,1H). Example 116 Keto group _3,3_dipropionylphenyl-7-methylthio-8-FN-{(R)_carboxyl decyl ) rabbit · formic acid 1 ice to methacrylate methoxyl group 1-2,3,4,5-tetrahydro-1,5-benzoquinone sulphide heptarene in U-Big 1 1-3,3 -dipropyl-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-phenylindolesulfinyl heptadecene (Method 118; 〇 〇5 gram, 〇1〇5 mmol) in a solution in DCM (4 mL), add (8) _ core (third-butoxycarbonylmethyl)amine carbaryl]:f amine (Method 86 ; 〇〇 36 g, 〇 136 mM) with N-mercapto porphyrin (0.040 ml, 〇 · 363 mmol). The mixture was stirred for 5 minutes and then TBTU (0.044 g, 0.137 mmol) was added. The reaction mixture was stirred for two days and then TFA (1.5 mL) was added. After 1.5 hours, the solution was diluted with toluene before removing the solvent under reduced pressure. The residue was purified by preparative EtOAc EtOAc (EtOAc) NMR (DMSO·d6) 0 6 (M) 80 (m, 6H), 105- 1.50 (m, 8H), 2·15 (s, 3H), 3.10-3.80 (m, 6H), 4·70 (ABd ,1H), 4.85 (ABd,1H), 5.60 (d,1H), 6.70 (s,1H), 6.80-7.05 (m,3H),7.15-7.50 (m,8H),8·35 (brs,1H ), 8.55 (d5 1H). Example 117 L-l-Diketo-3,3-dibutyl-5-phenyl-7-methoxy-8-rN] (RV...[N,-(2) - 酸 基 ) ) ) ) ) ) ) 羟 羟 羟 羟 羟 羟 羟 羟 羟 羟 羟 羟 羟 羟 羟 羟 ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ 1-Diketo-3,3-dibutyl-5-phenyl-7-methoxy-8-carboxymethoxy--136- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1291951 A7 B7 V. Description of Invention (134) 2,3,4,5-Tetrahydro-1,5-benzoquinonesulfurazoxanthine (Method 6; 0.020 g, 4·09χ 10·5 Mo a solution of 2_{[(2R)-2-amino-2-(4-hydroxyphenyl)ethinyl]amino}ethanesulfonic acid in a solution of DMF (4 ml) (Method 80; 0.014 g, 5·10χ10·5 mol) with N-methylmorpholine (0.020 ml, 1.81 X 1 (Γ4 mol). Stir the mixture for 10 minutes, then add TBTU (0.016 g, 4.98 X 10) ·5 The reaction mixture was stirred for 3 hours, then the solvent was removed under reduced pressure. The residue was purified by preparative HPLC using EtOAc EtOAc EtOAc. White solid. NMR (500 MHz, DMSO d6) 0.65-0.80 (m, 6H), 0.80-1.50 (m, 12H), 2.40-2.60 (m, 2H), 3.15-3.45 (m, 4H), 3.60 (s , 3H), 3.65 (brs, 2H), 4.60 (ABd, 1H), 4·70 (ABd, 1H), 5·25 (d, 1H), 6.50 (s5 1H), 6.70-7.25 (m5 10H), 7.35 (s, 1H), 8.20-8.30 (m5 1H)? 8.50 (d5 1H)? 9.40 (brs, 1H). Example 118 1,1-Amidino-3-butyl-3-ethyl-5- Phenyl-8-[N-{(R)- benzylideneethyl) 1-methyl hydrazino 4- fluorenyl}amine-methyl methoxy 1-2JA5-tetrahydro-1,5-pack # Nitrogen sulphate in 1,1-dione-3-butyl-3-ethyl-5-phenyl carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzene Add 2-{[(2R)-2-amino-2-(4-hydroxyl) to a solution of sulphur sulphide (Method 115; 0.020 g, 4.63 X HT5 Mo) in DMF (4 mL) Phenyl)ethinyl]amino}ethanesulfonic acid (Method 80; 0.017 g, 6.20 X 10·5 mol) with N-methyloff (0.016 ml, 1.46 X 10 · 4 mole). The mixture was stirred for 1 min, then TBTU (0.019 g, 5.92 χ 1 (Γ 5 mol) was added. The anti-deer mixture was stirred overnight. The solvent was then removed under reduced pressure. The residue was purified by preparative HPLC. 'Use MeCN / ammonium acetate buffer to obtain the title compound -137-

1291951 A7 B7 V. Description of invention (135), 0.008 g (24./〇) is a white solid. NMR (500 MHz, DMS 〇-d6) 0.65-0.80 (m, 6H), 0.80-1.60 (m, 8H), 2.40-2.55 (m, 2H), 3.20-3.40 (m, 4H)5 3.65 (brs, 2H), 4.65 (ABd, lH), 4.70 (ABd, lH), 5.25 (d, lH), 6.65-7.45 (m, 13H), 8.20-8.30 (m, 1Η)·8·60 (d, 1H) , 9.40 (brs, 1H). Example 119 1,1-dione-3,3-dibutyl-5-(4-tris-butoxycarbonylaminophenyl)-8-indole-(α- (R)-carboxyindenyl)amine fluorenylmethoxy 1-2,3,4,5-tetrahydro-1,5-benzoquinonesulfinyl heptadecene The title compound is from 1,1-dione -3,3-dibutyl-5-(4-tris-butoxycarbonylaminophenyl)-8-[N-(a-(R)-nonyloxycarbonylindenyl)amine-methylcarbonyl Base 2,3,4,5-tetrahydro-1,5-phenylindolesulfonium heptadecene (Method 45), synthesized by the procedure of Method 109. NMR (CD3 OD) 0.81 (brt, 6H), 1.03-1.3 (m, 8H), 1.32-1.59 (m, 13H), 3.24 (brs, 2H), 3.57-3.77 (m, 2H), 4.61 (brs, 2H), 5.51 (s, 1H), 6.83 (d, 1H), 7.0-7.1 (m, 3H), 7.26-7.43 (m, 7H), 7·49 (d, 1H); m/z 708.5. 120 let diketo-3,3·dibutyl-5-"4-(Nf-tris-butylureido)phenyl wRV benzyl benzyl)amine methyl methoxy 1-2,3 ,4,5-tetrahydro-1,5-phenylindolesulfinyl heptadecene gives 1,1-dione-3,3-dibutyl-5·(4-(Ν,·三-butyl) Urea-based)phenyl α-(R)-methoxycarbonylbenzyl)amine-methyl methoxy]-2,3,4,5-tetrahydro-1,5-benzoquinonesulfurium heptadecene (method) 111; 30 mg, 0.042 mmol; dissolved in THF (1.5 mL), EtOAc (EtOAc (EtOAc) By preparative purification 'using MeCN / ammonium acetate buffer gradient (5/95 to 100/0) as the eluent to give the title product 24 mg (82%). NMR (CD3 OD) 0.81 (brt, 6H), 1.05-1.26 (m,8H),1,35 (s,9H),1.38-1.57 (m,4H),3·25 (brs,2 H),3.6-3.77 (m, __ _ -138- This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm)

Binding

Line 1291951 A7 ____B7 V. Description of invention (136) &quot; '-2H), 4.61 (ABq, 2H), 5.45 (s, 1H), 6.84 (d, 1H), 7·01-7·11 (m, 3H ), 7.24 (d, 2H), 7·26_7·37 (m, 3H), 7.37-7.42 (m, 2H), 7.50 (d, 1H); m/z 707.5. Preparation of starting materials The starting materials are commercially available or can be readily prepared from known materials by standard methods. For example, the following reactions are examples of some of the starting materials used in the above reactions, and are not limiting. Method 1 1,1-Diketopoxime Butyl-3-ethyl-5-phenyl-7-bromo-8-"Γ-(ethoxycarbonyl)ethhydroindole 1 -2,3,4,5- Tetrahydro-1,5-benzoquinone-free heptaerythrene sodium carbonate (0.30 g, 2.83 mmol), ethyl 2-bromopropionate (0.145 g, 0.796 mmol) and tetrabutyl bromide Ammonium (22 g, 〇〇7 mmol) is added to 1,1-monoketo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-carbyl- 2,3,4,5-Tetrahydro-1,5-phenylindolesulfonium sulfoxide (w〇96/16051; 0·300 g, 0.663 mmol) in a solution of MeCN (10 mL). This suspension was heated under reflux overnight. The solvent was evaporated, and the crude mixture was purified (jjjjjjjjjjjjjjjjjjjjj (95%) as a white solid. NMR 0.70-0.85 (m, 6H), 1.00-1.75 (m, 8H), 1.35 (t, 3H), 1.70 (d, 3H), 3.05-3.25 (m, 2H), 3.55 - 3.90 (m, 2H) 5 4.20^4.35 (m3 2H)5 4.80 (q5 1H), 7.00-7.10 (m, 3H)5 7.15 (s5 1H), 7.25-7.35 (m, 2H), 7.45 (s, 1H). Method 2 k1: Di-brenyl-3-Tj-ethyl 5-phenyl-7-bromo-8-"Γ-carboxyethoxy 1-2,3,4,5-tetrahydro-1,5-benzoquinone sulfur N-decylene is added to sodium hydride (0.045 g, U3 mmol) to diketo-butyl _____-139- This paper scale applies to China National Standard (CNS) A4 specification (210X297 public) 1291951 A7 —— ___B7 V. DESCRIPTION OF THE INVENTION (137) -3-Ethyl-5-phenyl-7-bromo(ethoxycarbonyl)ethoxy]_2,3,4&gt;tetrahydrocentric&gt; benzoquinone nitrogen圜晞 (method 丨; 〇〇 5 gram, 〇〇 9 〇 millimolar) in Et〇H (4 ml, 95%) in a solution and heated under reflux. After 15 hours, add AcOH (0) · 2 liters), and most of the solvent was removed under reduced pressure. The crude product was extracted (dcm / H2 〇) - dehydrated (MgS 〇 4) and evaporated to give the title compound 〇·〇 31 g (65 %), as a white solid. 6H), 0.95-1.25 (m, 4H ),1.35-1.70 (m,4H), 2.65 (d,3H),3·10-3·35 (m,2H), 3.45-3.95 (m,2H), 4.70 (q,1H),6.90-7.35 (m, 6H), 7·45 (s, 1H) · Method 3 U: Diketo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-(anthracene-phenyl -1,-Ethoxycarbonyl-methyloxy-1,3,4,5-tetrahydro-1,5-stupyl#sulfuric heptaerythrene ethyl bromide acetate (0.139 g), Na2 C03 (0.200 g) and tetrabutylammonium bromide (0.034 g) were added to 1,1-dione butyl-3-ethyl-5-phenyl-7-bromo-8-hydroxy-2. 3,4,5-Tetrahydro-1,5-benzoquinonesulfurium heptadecene (w〇96/16051; 0.200 g '0.442 mmol) in MeCN (6 mL). Under reduced pressure The title compound was obtained after the solvent was removed, and the title compound was obtained (yield: EtOAc: EtOAc) 94%), as a white solid. NMR 0.65-0.85 (m, 6H), 0.95-1.65 (m, 8H), 3.00-3.15 (m, 2H), 3.50-3.80 (m, 2H), 3.70-3.80 (2s, 3H), 5.60 (s, 1H), 5·65 (d, 1H), 7.00-7.60 (m, 17H), 8.05-8.20 (2d, 1H) · Method 4 1,1-Dimercapto-3-butyl-3-ethyl- 5-phenyl-7-indolyl-8-[indolyl-phenyl-indole-yloxyl 1-2,3,4,5-tetrahydro-1,5-benzothiazepine hepene Lithium hydroxide (0.019 g) is added to 1,1-diketo-3-butyl-3-ethyl-5-benzene___-140-_ This paper scale applies to China National Standard (CNS) Α4 specification (210 X 297 mm) 1291951 A7 B7 V. INSTRUCTIONS (138) Benzyl-7-bromophenyl-1,-ethoxycarbonylmethoxy]-2,3,4,5-tetrahydro-1,5- Phenyl sulfonium heptaerythrene (Method 3; 0.244 g, 0.397 mmol) in a drop of THF/H20 (2/1, 3 liters). After 2 days, the solvent was removed under reduced pressure. NMR (CD3 OD) 0.60-0.80 (m, 6H), 0.90-1.25 (m, 4H), 1.30-1.60 (m, 4H), 3.05-3.30 (m, 2H), 3.40-3.90 (m, 2H), 5·55 (s, 1H), 6.85-7.70 (m, 12H). Method 5 jj-diketo-3,3-dibutyl-5-phenyl-7-methoxy-ethoxycarbonylcarbamate _ ϋ,4,5-tetrahydro-1,5-benzoquinone sulphide heptadecene ethyl bromoacetate (0.13 ml), Na2 C03 (0.40 g) and tetrabutylammonium bromide (〇·〇30)克) added to i,i-diketo-3,3-dibutyl-5-phenyl-7-methoxy-8-hydroxy-2,3,4,5-tetrahydro-1,5- Phenyl sulfonium sulfoxide (synthesized by means of w〇9616051, about the corresponding 3-butyl-3-ethyl analog; 0.400 g, 0 927 mmol) in MeCN (10 mL) . The suspension was heated under reflux overnight before removing most of the solvent under reduced pressure. The crude product was extracted with EtOAc (EtOAc m. NMR 0.65-0.85 (m, 6H), 0·95-1·65 (m, 8H), 3·00· 3.15 (m, 2Η), 3.50-3.80 (m, 2Η), 3.70-3.80 (s5 3Η) , 5.60 (s, 1Η), 5·65 (d, 1Η), 7.00-7.60 (m5 17H), 8.05-8.20 (d5 1H). Method 6 I: 丄-monoketone-3,3-butyl -5-Phenyl-7-methoxy-8-methyloxycarbonyl-2,3,4,5-tetrahydro-1,5-phenylindolesulfinyl heptadecene lithium hydroxide (0·062克) added to l,i-diketo-3,3-dibutyl-5-phenyl-7-methoxy-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro -^-Benzene sulphide heptaerythrene (-141 - This paper size applies to Chinese National Standard (CNS) Α4 specification (210 X 297 mm) ' &quot; — 1291951 A7 _-___B7 V. Invention description (139 ) &quot Method 5; 0.448 g, 0.865 mmoles in THF/H20 (2/1, 6 mL). After 1 hour, AcOH (0.5 mL) was added and most solvent was removed under reduced pressure. The crude product was purified by EtOAc (EtOAc) NMR (CD3OD) 0.75-0.85 (m,6H), 1.00-1.30 (m,8H),1.35-1.55 (m,4H),3·20 (s,2H), 3.65 (s,3H),3·70 (brs, 2H), 4.50 (s, 2Η), 6·50 (s, 1Η), 6·90-7·30 (m, 5Η), 7·40 (s5 1Η)· Method 7 1,1-II Ketopropyl-3-butyl-3-ethyl-5-phenyl-7-methoxy-8-ethoxycarbonylmethoxy_2,3,4,5-tetrahydro-1,5-benzo Sulfur-7-decene gives 1,1-diketo-3-butyl-3-ethyl-5-phenyl-7-methoxy-whenyl-2,3,4,5-tetrahydro-1, 5·benzothiazepines (WO 9616051; 1.0 g), bromoacetate (0.50 g), sodium carbonate (1.2 g) and tetrabutylammonium bromide (60 mg) in MeCN (15 ml) Reflux overnight. The solvent was removed under reduced pressure and the residue was extracted (DCM/H2O). The organic layer was separated and the solvent was removed under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjjj NMR (CD3 〇D) 0.75-0.85 (m5 6H)5 1.00-1.30 (m5 8H)5 1.35-1.55 (m, 4H), 3.20 (s5 2H), 3.65 (s5 3H), 3.70 (brs5 2H), 4.50 (s5 2H), 6.50 (s, 1H)? 6.90-7.30 (m5 5H), 7.40 (s, 1H) · Method 8 U-diketo-3-butyl-3-ethyl-5-phenyl- 7-Bromo-8-ethoxycarbonylmethoxy-2.3Λ5-tetrahydro-1,5-phenylindolesulfinyl heptadecene 1,1-dione-3-butyl-3-ethyl- 5-phenyl-7-bromo-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine hepene (WO 96/16051; 0.3 g), ethyl bromoacetate (0,14 g), sodium carbonate (〇·3 g), tetrabutylammonium bromide (〇·〇2 g) in MeCN (10 ml) -142- This paper scale applies Chinese National Standard (CNS) A4 specification (210X297 mm) 1291951 A7 B7 V. The mixture in the invention (14Q) was refluxed for 4 hours. The solvent was removed under reduced pressure. The residue was subjected to liquid separation between DCM/H20 and the organic layer was separated. The solvent was evaporated, and EtOAc EtOAcjjjjjjjj NMR (500 MHz) 0.7-0.9 (m, 6H), 1.0-1.8 (m, 11H), 3.2 (m, 2H), 3.6-3.8 (brs, 2H), 4·3 (q, 2H), 4· 7 (s, 2H), 7.0-7.1 (m, 3H), 7.15 (s, 1H), 7.3 (m, 2H), 7.4 (s, 1H) · Method 9 1,1-Dimercapto--3- Butyl Ethyl Ethyl-5-Streply _7_Bromo-8•Carboxymethoxy 2, 4 5_ Tetrahydro-1,5-benzoquinonesulfury-seven-decene, 1,1-dione- 3-butyl-3-ethyl-5-phenyl·7-bromo-t-ethoxyethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzoquinonethiosulphin Method 8; 34. 34 g) and sodium hydroxide (0.3 g) were dissolved in ethanol, and the mixture was heated to reflux for one hour. Acetic acid (1 liter) was added and the solvent was removed under reduced pressure. The residue was subjected to liquid separation between DCM/H2®, and the organic layer was separated and dried. The residue was triturated with n-hexanol to give the title compound 0.29 g (9??) as solid. NMR (500 MHz) 0.7-0.8 (m, 6H), 1.0-1.7 (m, 8H), 3.1-3.2 (m, 2H), 3.6 (brs, 2H), 4.6 (s, 2H), 6.9-7.1 ( m,4H),7·2 (m,2H), 7.5 (s 1H) Method 10 1,1-dione cover.:.3 dibutyl-3di^^^ 2,3,4,5-four Hydrogen-1,5-benzoquinonesulfide j. heptarene makes 1,1-dione-3-butanylethyl-5-phenyl-7-methoxy-8_ethoxycarbonylcarbonyloxy -2,3,4,5-Tetrahydro-1,5-benzoquinonesulfazepine (Method 7; 12 g) was dissolved in ethanol (20 mL). Add sodium hydroxide (〇5g) dissolved in %〇 (1 ml), and allow the reaction mixture to warm to 4 (rC for 3 minutes. Add acetic acid (1 _ -143- this paper size applies to China) National Standard (CNS) A4 specification (21〇X 297 public) &quot; ---------- 1291951 A7 B7 V. Description of invention (141) ml), and remove the solvent under reduced pressure. The residue was partitioned between EtOAc / EtOAc (EtOAc m. m,3H), 0.9 (t5 3H), 1.0-1.7 (m,8H),3·2 (q,2H),3·65 (s,3H),3.65-3.85 (m5 2H),4·7 ( s, 2H), 6.4 (s, 1H), 7.0 (t, 1H), 7·1 (d, 2H), 7·3 (t, 2H), 7·5 (s, 1H). Method 11 hi- Diketo-3,3-dibutyl-5-phenyl-7-bromo-8-ethoxycarbonyl helium gas -2.3H tetrahydro-1,5-benzoquinonesulfuryl heptadecene will be 1, 1-diketo-3,3-dibutyl-5-phenyl-7-bromo-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzoquinonesulfurium heptadecene (Synthesized by means of w〇9616〇51 for its corresponding 3_butyl·3_ethyl analogue 2.0 g, 4.16 mmol, bromoacetic acid (0.84 g, 5.03 mmol), sodium carbonate (2·g, 18.9 mmol) and tetrabutylammonium (80 mg, 〇·25) The mixture was added to a solution of EtOAc (EtOAc) (EtOAc). Purification by column chromatography, EtOAc (EtOAc: EtOAc (EtOAc) , 3 2 (brs, 2H), 3 7 (brs, 2H), 4·3 (q, 2H), 4.7 (s, 2H), 7.0-7.3 (m, 6H), 7.4 (s, 1H) · Method 12-13 The following compounds were synthesized by the procedure of Method 11 using appropriate acids and amines (in the case of commercially available, not indicated sources). ____-144- This paper scale applies to China National Standard (CNS) A4 specification (210X 297 dongdong) 1291951 A7 B7 Description of invention 12 One yang Yang~~' ^ — .ό 掌 palm isomer 1 ' ------- ........... Μ/ζ SM 1 -3⁄4 138 - Method 83 Xo %? Factory: χχχΓ ό 538 Method 84 ------- Method 14 Base - 8-carboxyindole 1-2,3,4,5·four-sham ^ 1,5-benzoquinone sulfhydryl heptarene makes U-diketo-3,3-dibutyl·5-phenyl winter bromide Ethyloxycarbonylmethoxy 2,3,4&gt; tetrahydroyi 5-benzoquinonesulfurium heptadecene (method 2; 2·2 g, 3.88 mmol) ♦ ^ ethanol (15 ml) . Na〇H (〇·8 g in 5 ml of water) was added to Zlot night, and the mixture was stirred at room temperature for 3 minutes. Add acetic acid (2 ml). The solvent was evaporated under reduced pressure, and the residue was extracted with EtOAc. The Et 〇Ac layer was separated, dried and evaporated to drynessiel职(5〇〇厅)〇义〇8 (m,6H),i 〇ι 5 (four) i2H), 1 ---- - _-]今〇· This paper scale it is the national standard of the country (CNS) A4 Specifications (2i〇x297 public) 1291951 A7 __B7 V. Invention description (143) &quot;~' 3.2 (brs, 2H), 3.7 (brs, 2H), 4.7 (s, 2H), 7.0-7.3 (m, 6H ), 7.4 (s, 1H) Method 15 Persons Diketopyl-(butyl)ethylethyl--hetero--isopropylidene-based methoxyl 2.3.4.5-four--1,5· Phenyl sulfonium sulfoxide was added to isopropanol (12 ml) and sodium (115 mg, 5 Torr) was added, and then the temperature was raised to 80 C' to form an alkoxide. After all the sodium has dissolved, add 1,1-dione-3-butyl-3-ethyl-5-phenyl-7-bromo-8-carbomethoxy-2.3.4.5 in one portion. - Tetrahydro-1,5-benzothiazepine seven oxime (Method 9; 1 〇〇 mg, 0.2 mmol). The reaction was then refluxed overnight, then cooled to room temperature and quenched with acetic acid. Then, the solvent was removed under reduced pressure, and the residue was dissolved in water and MeCN (70/30) and partially purified by HPLC. The residue was dissolved in ethylene glycol and NaOH (500 mg) was added. The reaction mixture was heated to EtOAc (EtOAc) (EtOAc) The organic layer was washed three times with acidic water to remove ethylene glycol. After the organic layer was concentrated, the residue was purified againjjjjjjj NMR (300 MHz) 0.7-1.0 (m, 6H), 1·0-1·8 (m, 15H), 3.2 (q, 2H), 3.75 (m, 2H), 4·3 (m, 1H), 4.6 (s, 2H), 6.35 (s, 1H), 6.95-7.2 (m, 3H), 7.2-7.4 (m, 2H), 7·55 (s, 1H) · Method 16 1,1-dione -3-butyl-3-ethyl-5-phenyl-7-methylthio-8-ethoxycarbonylmethyl-methane- 2.3.4.5- four-rat-1,5-benzoquinonesulfury-nitrogen 1,1-diketo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzoquinone Sulfa-nitaerythrene (Method 25; 500 mg, 1.2 mmol), MeCN (30 mL), tetrabutylammonium bromide (3 〇 mg, 0.08 mmol), -146- This paper size applies China National Standard (CNS) A4 Specification (210 X 297 mm) 1291951 A7 _____B7___ V. Description of Invention (144) Anhydrous sodium carbonate (500 mg, 4.7 mmol), ethyl bromoacetate (0.14 mL, 1.26 mmol) And cesium carbonate (2 〇 mg, 〇. 〇 6 mmol). Then, the reaction mixture was stirred at 80 ° C overnight. Next, the solvent was removed under reduced pressure, water and DCM were added, and the aqueous phase was extracted three times with DCM. The combined organic phases were dried (MgSO4). NMR (300 MHz) 0.8-1.0 (m, 6H), 1.0-1.8 (m, 11H), 2.2 (s, 3H), 3.2 (q, 2H) 3.75 (brq, 2H), 4·3 (q, 2H) ), 4·75 (s, 1H), 6·7 (s, 1H), 6.95 (t, 1H), 7·05 (d, 2H), 7·25 (t, 2H), 7.3 (s, 1H) Method 17 u-Dimercapto-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-carboxymethyl a-2,3,4,5-tetrahydro·1 , 5-cracked sulphide heptadecene in 1,1-dione butyl-3-ethyl-5-phenyl-7-methylthio-8-ethoxycarbonylmethoxy-2,3 , 4,5-tetrahydro-1,5-benzoquinonesulfazepine (Method 16; 478 mg, 〇.95 mmol), THF (15 mL), water (3 mL) and LiOH ( 34 mg, 1.4 millimoles). The reaction was then stirred for 1 hour. Next, acetic acid (0.2 ml) was added along with water (1 ml) and dcm (10 ml). The aqueous layer was then extracted three times with DCM. The combined organics were dried and concentrated to give title compound 450 mg (99%). ^0.7-0.9(111,611), 1.0-1.7 (m,8H),2·2 (s,3H),3.2 (q,2H),3.7 (m,2H),4·8 (s,2H) ), 6.65 (s, 1H), 6.95 (t, 1H), 7.05 (d, 2H), 7.25 (t, 2H), 7·35 (s, 1H), 8.4 (brs, 1H). Method 18-19 The following compounds were synthesized by the procedure of the method, using the appropriate acid and amine (in the case of commercially available sources, the source is not indicated), but using the two equivalents -147 - this paper scale applies to the Chinese National Standard (CNS). A4 size (210 X 297 public) --- 1291951 A7 B7

1291951 A7 B7 V. Inventive Note (146) Purification by flash chromatography [DCM:EtOAcEtOAcEtOAc NMR 0.7-0.8 (m, 6H), 1.0-1.65 (m, 11H), 3.2 (q, 2H), 3.3 (s, 3H), 3.7 (brs, 1H), 4·25 (q, 2H), 4.8 (s, 2H), 7.0-7.1 (m, 3H), 7.2-7.3 (m, 2H), 7.5 (s, 2H) · Method 21 1,1-dione-3-butyl-3-ethyl -5-Phenyl-7-methane-mercapto-8-benzyloxy-2,3,4,5-tetrahydro-1,5-phenylindolesulfol-7-nonylene in 1,1-dione Benzyl-3-ethyl-5-phenyl-7-methyl sulphonyl-8-ethoxy benzyl keto-2,3,4,5-tetrahydro-1,5 - Benzene sulphide sulphate (Method 2 〇; 46 mg, 0.085 mmol), THF (5 mL), water (1 mL) and LiOH (10 mg, 0.4 mmol). The reaction was stirred for 1 hour and then excess acetic acid was added to quench the reaction. Water and DCM were added and the aqueous phase was extracted three times with DCM. The combined organic phases were dried <RTI ID=0.0></RTI> and dried to give the title compound 4 s. NMR 0.7-0.85 (m, 6 Η), 1.0-1.7 (m, 8 Η), 3.2 (m, 2 Η), 3.3 (s, 3H), 3.8 (s, 2H), 4.9 (s, 2H), 5.0 (brs , 1H), 7.05-7.15 (m, 3H), 7.3-7.4 (t, 2H), 7.5 (s, 1H), 7·6 (s5 1H) · Method 22 (Preparation 1) Diketo-3,3 -Dibutyl-5-phenyl-7-methylthio-8-carboxymethoxy--2,3,4,5-tetrazol-1,5-benzoquinonesulfury-7-decene to make U-diketone 3--3,3-dibutyl-5-phenyl-7-bromo-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzoquinonesulfurium heptadecene Method 14; 5 mg, 〇, 93 mmol) was dissolved in DMF (10 mL). Sodium methanethiolate (2 mg, 2 85 mmol) was added and the mixture was stirred at 50 °C for 2 hours. Acetic acid (〇·4 ml) was added and the solvent was evaporated under reduced pressure. The residue was extracted with Et 〇Ac / water. Separation of Et〇Ac ---___-__- 149 - This paper size is used in the general ss home standard (CNS) M specification (χ 公公公) --- 1291951 A7 * ___B7 V. Description of invention (147) Layer, dehydration and drying Evaporation under reduced pressure gave the title compound 450 mg (96%). NMR (300 MHz) 0.7-0.8 (m, 6H), 1.0-1.6 (m, 12H), 2.2 (s, 2H), 3.2 (brs, 2H)? 3.7 (brs5 2H), 4.8 (s? 2H)? 6.6 (s5 1H)9 6.9-7.1 (m? 3H)5 7.2-7.4 (m5 3H). Method 22 (Preparation 2) 丄,1_二酉同基-3,3-Dibutyl-5-phenyl · 7-Methylthio-8-hydroxy methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine hepene NaOH (4.67 g, 116 mmol) in water a solution (1 ml) added to U-diketo-3,3-dibutyl-5-phenyl-7-methylthio-8-ethoxycarbonyl-2,3,4,5- Tetrahydro-1,5-phenylindolesulfonium heptadecene (Method 114; 15.45 g, 28.71 mmol) in EtOH (160 mL). This solution was stirred at room temperature for 3 minutes. The solvent was removed under reduced pressure and the residue was partitioned between Et EtOAc and EtOAc EtOAc. The aqueous layer was re-extracted twice with EtOAc (EtOAc) EtOAc (EtOAc) :^^1(500 legs 2,01^0-(16)0.65-0.80(111,611)50.90- 1.50 (m,12H),2.20 (s,3H),3.25 (s,2H),3.65 (bs , 2H), 4.80 (s, 2H), 6.70 (s, 1H), 6.80-7.30 (m, 6H), 13.20 (s, 1H) · Method 23-24 The following compounds were prepared by Method 22 (Preparation i ), using the appropriate acid and amine (in the case where commercially available, the source is not indicated), but the reaction is carried out at ambient temperature, and in Method 24, the extended reaction time is ____-150· This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1291951 A7 B7 V. Description of invention (148) Method · Compound Μ/ζ SM 23 %? Plant XOcT '6 . Take isomer 1 478 Method 18 24 〇HAVP •ο 铋 铋 2 2 478 Method 19 Method 25 U·· Diterpene butyl-3-ethyl-5-phenyl-7-methylthio-hydroxy-2,3, 4,5-tetrazine" 1,5-benzothiazepine is suspected of U_diketo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-methoxy -2,3,4,5-tetrahydro-1,5-benzoquinonesulfurium heptadecene (W0 9616051; 600 mg, 1.29 mmol) was added 1) MF (5 ml) and methanethiol (450 mg, 6.42 mmol). Then, the reaction was heated to 60 ° C for 1 hour. Then, the oil bath was heated to 120 ° C for 4 hours. To quench the reaction, the temperature was lowered to room temperature. Excess acetic acid was added rapidly. The reaction was kept under nitrogen flow through sodium hypogasate for 2 hours. Water and Et 〇Ac were added and the aqueous phase was extracted three times with EtOAc. The combined organic phases were washed with water, dried and dried. Concentrate under reduced pressure. Then, _____-151 - This paper scale applies to Chinese National Standard (CNS) A4 specification (21〇x297 mm) 1291951 A7 _ B7 V. Description of invention (149) Residues by flash chromatography Purification [DCM: EtOAc 9: 1] ield. (brq, 2H), 6.75 (s, 1H), 6.8 (t, 1H), 6.9 (d, 2H), 7.15 (t, 2H), 7.55 (s, 1H) · Method 26 丄, diketone- 3,3-Dibutyl-5-phenyl-7-sulfonylthio-8-3⁄4yl-2,3,4,5-tetrafluoro-1,5-benzoquinonesulfuric acid. N-decylene in U- Diketo-3,3-dibutyl-5-phenyl-7-bromo-8-methoxy-2,3,4,5-tetrahydro-1,5-phenylhydrazine sulfur Adds DMF (2 mL), sodium decane thiolate (60 mg, synthesized by way of w〇9616〇51 for the corresponding 3-butylethylethylamine; 40 mg, 0.08 mmol) Mg, 0.85 mmol) and sodium borohydride (60 mg '1.6 mmol). The reaction was allowed to operate at 6 ° C overnight. Additional saponin sodium hydride (60 mg, 1.6 mmol) and sodium methanethiolate (6 mg, 0.85 mmol) were added and the temperature was raised to 120 °C. The reaction was heated at this temperature for 4 hours&apos; and then cooled to room temperature. Acetic acid was then added and allowed to pass overnight under nitrogen gas from the sub-gas sulphuric acid. Water and EtOAc were added and the aqueous extracted with EtOAc EtOAc. The combined organic phases were washed with EtOAc (1 M), dried and evaporated. Then, the residue was purified by EtOAc (EtOAc) (EtOAc) 1.6 (m,12H),2.2 (s,3H),3.1 (s5 2H),3.4 (s,2H),"·7 (brs,2H),6.7 (s,1H), 6.85-7.05 (m, 2H ), 7.2-7.4 (m, 2H). Method 27 Third-butane carbonylaminophenyl phenylacetamidoamine 1 ethanesulfonic acid salt to make 2-aminoethyl ketone acid (740 mg, 5.91 mil Mohr) and (2R)-2-(Third-Ding______-152-_ This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1291951 A7 B7 V. Invention Description (15Q) Oxycarbonylamino)-2-phenylacetic acid (1.09 g, 4.34 mmol) was dissolved in DMF (20 mL). DIPEA (2.8 mL, 16.1 mmol) and TBTU (1.53 g, 4.78 m) Mohr), and the mixture was stirred at 60 ° C for 2 hours. The solvent was evaporated under reduced pressure. The residue was purified by preparative HPLC using MeCN / ammonium acetate buffer gradient (5/95 to 100/0) As a dissolving agent, the title compound was obtained 589 mg (32%). NMR (CD3 OD) 1.43 (s, 9H), 2.85-3.0 (m, 2H), 3.53- 3.68 (m, 2H), 5.1 (brs, 1H), 7.25-7.45 (m, 5H) · Method 28 2-((2fR)-2f-Amino-2^phenylethenylamino)ethanesulfonate Ammonium salt makes 2-[(2fR)-2f-(tris-butoxycarbonylamino)-2.-phenylethenylamino]ethanesulfonate ammonium salt (Method 27; 589 mg, 1.57 m Mol) was dissolved in EtOAc (20 mL), and the mixture was cooled in ice-bath. The hydrogenated gas was bubbled through the reaction, the ice bath was removed, and the reaction was allowed to stand at room temperature for 30 minutes. The solvent was evaporated under reduced pressure. The residue was evaporated from EtOAc EtOAc. It was allowed to stand at room temperature for 30 minutes. The solvent was evaporated under reduced pressure. EtOAc was evaporated. /.), which contains 1 equivalent of diisopropylethyl vaporized ammonium. NMR (D2〇) 1.35-L38 (m, 15H), 2.96-3.12 (m, 2H), 3·21 (q, 2H) , 3.50-3.80 (m, 4H), 5.11 (brs, 1H), 7.45-7.55 (m 5H). Method 29 1,1-Diketo-3,3-dibutyl-5-phenyl-7-methylthio-8-[^((11)-factor-phenyl-1'-- Oxycarbonylmethyl)amine methyl methoxy 1-2,3,4,5-tetrahydro-1,5-benzoquinone sulphide decene-153- This paper scale applies to Chinese national standards (CNS A4 size (210X 297 mm) 1291951 A7 B7 V. Description of the invention (151) 1,1_diketo-3,3-dibutyl-5-phenyl-7-ethylthio-8-carboxyl Methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine hepene (Method 22; 250 mg, 0.49 mmol), (R)-2-phenylglycine Methyl ester hydrochloride (120 mg, 0.60 mmol) and DIPEA (300 mg, 2.3 mmol) were dissolved in DCM (10 mL) and the mixture was stirred for 5 min. TBTU (210 mg, 0.65 mmol) was added and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure. EtOAcjjjjjjjjjj NMR (500 MHz) 0.7-0.8 (m, 6H)5 1.0-1.6 (m, 12H), 2.1 (s, 3H), 3·2 brs, 2H), 3.6-3.8 (m, 5H), 4.6 (ABq , 2H), 5·6 (d, 1H), 6.6 (s, 1H), 6.9-7.5 (m, 11H), 7.9 (d, 1H) · Method 30-45 The following compounds are subjected to the procedure of Method 29, The synthesis was carried out using the appropriate acid and amine (in the case where commercially available, the source did not indicate), but the reaction time for some methods was extended to 2 hours. -154- This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm) 1291951 A7 A B7 —----------------- V. Description of invention (152 ) Method J NMR or m/z 30 矣 0 (300 MHz, CD3OD) 0.8-0.9 (m, 6H), 1.1-1.6 (m, 12H), 2.2 (s, 3H), 33 (s, 2H ), 3.75 (brs, 5H), 4.7-4.8 (m, 2H), 5.45 (s, 1H), 6.7 (s, 1H), 6.8-73 (m, 9H), 7.45 (s, 1H) square F 22 31 f ”N CH3 H3C ό (300 MHz, CD3OD) 0.75-0.95 (m, 6H), 1.0-1-6 (m, 12H), 2.1 (s, 3H), 3.2 (s, 2H), 3.7 (s , 5H), 4.65 (s, 2H), 5.85 (s, 1H), 6.7 (s, 1H), 6.9-7.4 (m, 9H) ' 22 32 Η; ό (300 MHz, CD3OD) 0.75-0.9 (m , 6H), 1.0-1.6 (m, 12H), 2.2 (s, 3H), 3.2 (s, 2H), 3.75 (s, 5H), 4.7 (brs, 2H), 5.7 (s, 1H), 6.7 ( s, 1H), 6,9-7.4 (m, 6H), 7.55-7.8 (m, 4H) Method 22 and Method 71 33 /. Art V ςΡ 〇. .ό. 0.70-0.85 (m, 6H), 0.95-1.75 (m, 8H), 1.55-1.75 (2d, 3H), 3.05-3.30 (m, 2H), 3.55-3.90 (m, 2H), 3.70-3.80 (2s, 3H) 4.75-4.90 (2q, 1H), 5:60 (d, 1H), 7.00-7.55 (m, 12H), 7.80-7.95 (m, 1H) Method 2 L ___ -155- The paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1291951 A7 B7 V. Invention description (153) 34 〇ό 0.65-0.85 (m, 6H), 0.95-1.65 (m, 8H), 3.00-3.15 (m, 2H), 3.50-3.80 (m, 2H), 3.70-3.80 (2s, 3H), 5.60 (s, 1H), 5·65 (d, 1H) 7.00-7.60 (m , 17H), 8.05-8.20 (2d, 1H) Method 4 35 ό. (CD3OD) 0.75-0.85 (m, 6H), 1.00-L30 (m, 8H), L35-1.55 (m, 4H), 3.20 (s , 2H), 3.55 (s, 3H), 3.70 (s, 3H), 3.75 (brs, 2H), 4.60 (ABq, 2H), 5.55 (s, 1H), 6.50 (s, 1H), 6.95-7.40 ( m, 10H), 7.50 (s, lH) Method 6 36 〇〇C〇cC ό 707.4 Example 12 37 /3⁄4 Y . 〇C〇cC ό 0.75-0.85 (m, 6H), 1.00-1.60 (m, 12H), 3.20 (s, 2H), 3.60 (s, 3H), 3.75 (brs, 2H), 3.75 (s, 3H) , 4.55 (ABq, 2H), 5.85 (d, 1H), 6.40 (s, 1H), 6.95-7.45 (m, 9H), 7.55 (s, 1H), 8.05 (d, 1H) Method 6 -156- Ben The paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1291951 A7 B7 V. Description of invention (154) 38 /A. Y ° OCOC ό 0.75-0.85 (m, 6 Η), 1.00-1.60 (m, 12 Η), 2·20 (s, 3 Η), 3·20 (s, 2 Η), 3.75 (brs, 2 Η), 3.80 (s ,3Η), 4.60 (ABq, 2H), 5.90 (d, 1H), 6.65 (s, 1H), 6.95-7.45 (m, 10H)7 7.95 (d, 1H) Method 22 39 HO Ο ό (500 MHz) 0.7-0.8 (m, 6H), L0-L5 (m, 12H), 3.2 (m, 2H), 3.7-3.8 (m, 5H), 4.6 (ABq, 2H), 5.6 (d, 1H), 6.8- 7.4 (m, 10H), 7.5 (s, 1H) Method 14 40 ^&gt;〇e»NXC ό (300 MHz) 0.7-0.8 (m, 6H), L0-1.6 (m, 12H), 3.2 (brs, (H, 5H), 41 of them. CC〇〇C ό 766·4(Μ-(Third-Butyl)+2H Example 12 42 β^Ι^χτ 〇^JN · ό Γ° 739.3 Example 38 -157- This paper scale applies to Chinese National Standard (CNS) ) A4 size (210 X 297 mm) 1291951 A7

V. Description of the invention (155

1A-di-g-yl--7-bromo-8-rmfSM·-benzene _1L A y stem methyl) amine production.. base "^^> 2,3,4,5_tetrahydrogen -15• Stupid U-diketo-3-butyl-3·ethyl phenyl phenyl bromide|carboxy methoxyoxy 2,3,4,5-tetrahydro-1,5-benzoquinone sulphur N-decylene (Method 9; 5 mg, 〇〇98 mmol) was dissolved in DCM (2 mL). Add (2 min amino (phenyl) methyl acetate (19 mg, 〇 12 mmol) with DIPEA (0.068 mL, 〇 39 mmol) and stir the reaction for 2 min. Add TBTU (42 Mg, 〇13 mmol, and stir the mixture at room temperature for 1.5 hours. Place the mixture in pre-filled _____: 158- This paper scale applies to Chinese National Standard (CNS) Α4 size (210 X 297 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The compound is synthesized by the procedure of Method 46 (except for the overnight reaction time) using the appropriate acid and amine (in the case of commercially available sources, the source is not indicated). 0 -159 This paper scale applies to the Chinese National Standard (CNS). A4 size (210X 297 mm) 1291951 A7 B7 V. Description of invention (157 method combination # NMk or m/z SM 47 9ι ό 609.4 Method 10 48 ό 625.4 Method 17 49 9 ό 685.3 Method 14 50 ό 609.4 Method 10 51 参; χό. 637.4 Method 15 -160 - This paper scale applies to China Standard (CNS) A4 size (210 X 297 mm) 1291951 A7 B7 V. Description of invention (158) 52 judder ό 657.4 Method ~ 21 53 0 685.3 ό 14 54 0.73-0.95 (m, 6 Η), 0.98-1.78 ( m, square 8H), 3.12-3.28 (m7 2H), 3.6-4Ό (m, 9 and TV^OpcT 0 5H), 4.60 (ABq, 2H), 5.79 (d, 1H), 6.0 (brs, 1H), 6.54 (dd,1H),6·83 (t, 1H), 6.95 (dd,1H), 7.0-7.5 (m,7H), 8.43 (d, NH), 932 (brs, 1H) Method 74 55 0.75-0.9 (m, 6H), 1.0-1.78 (m, 8H), Method Ο 3.10-3.26 (m, 2H), 3, 63-3.87 (m, 10 8H), 4.56 (ABq, 2H), 5.76 ( d, 1H), 5.99 (brs, 1H), 638 (s, 1H), 6.51 (dd, 1H), 6.81 (t, 1H), 6.93 (dd, 1H), 7.0-7.15 (m, 3H), 7.23 -7.4 (m, 2H), 7.55 (s, 1H), 8.54 (d, NH), 9.45 (brs, 1H) and method 74 56 0.76-0.87 (m, 6H), 1.0-L8 (m, 8H), Ο 2.23 (s, 3H), 3.1-3.25 (m, 2H), 3.6- 17 3.95 (m, 5H), 4.61 (ABq, 2H), 5.79 (d, 1H), 6.0 (brs, 1H), 6.54 ( dd71H), 6.65 (s, 1H), 6.83 (t, 1H), 6.92-7.1 (m, 4H), 7·23-7·4 (m, 3H), 8.37 (d, NH), 9.35 (brs, 1H) and Fang 74 - ^ -161 - This paper size is applicable National Standard (CNS) A4 Specification (210 X 297 mm) 1291951 A7 B7 V. Description of Invention (159) 57 ό (CD3OD) 0.76-0.85 (m, 6H), 1.02-1.3 (m, 8H), L36-1.56 (m, 4H), 2.16 (s, 3H), 3.24 (brs, 2H), 3.66-3,80 (m, 5H), 4·71 (ABq, 2H), 5.57 (s, 1H), 6.71 (s , 1H), 6.98 (t, 1H), 7.06-7.14 (m, 4H), 7.28 (brt, 2H), 7.37-7.45 (m, 3H) Method 22 and Method 75 58 ό (CD3OD) 0.76-0.85 (m , 6H), 1.02-1.28 (m, 8H), L36-1.56 (m, 4H), 1.96 (s, 3H), 3.24 (brs, 2H), 3.6-3.8 (m, 5H), 4.73 (ABq, 2H ), 5.76 (s, 1H), 6.63 (s, 1H), 6.94-7.04 (m, 2H), 7.07-7.15 (m, 3H), 7.27 (t, 2H), 7.31 (s, 1H), 7.37 ( d, 1H), 7.42 (s, 1H), 7.56 (d, 1H) Method 22 59 矣: xi6cc ό (CD3OD) 0.80 (brt, 6H), LO-1.28 (m, 8H), 1.36-1.54 (m, 4H), 3.22 (brs, 2H), 3.61 (s, 3H), 3.69-3.8 (m, 5H), 4.62 (ABq, 2H), 5.56 (s, 1H), 6.49 (s, 1H), 6,99 (bit, 1H), 7.07-7.16 (m, 4H), 7.29 (brt, 2H), 7.37-7.43 (m, 2H), 7.52 (s, 1H) Method 6 and Method 75 60 ^bd6〇c ό (CD3OD ) 0.75-0.84 (m, 6H), L0-1.29 (m, 8H), 1.35-1.54 (m, 4H), 3.20-3.23 (m, 5H), 3.65-3.8 (m, 5H), 4.64 (ABq, 2H), 5.74 (s, 1H), 6.34 (s, 1H), 6.95-7.04 (m, 2H), 7.09-7.15 (m, 3H), 7.24- 7.31 (m, 3H), 7.37 (d, 1H), 7.50-7.54 (m, 2H) Method 6 - 162- The paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm)

1291951 A7 B7 V. INSTRUCTIONS (160) 611 〇0.74-0.83 (m, 6H), 0.98-1.7 (m, 8H), 3·18 (ABq, 2H), 3.60-3.90 (m, 5H), 4.59 ( ABq, 2H), 5.67 (d, 1H), 7.0-7.2 (m, 4H), 7.2-7.55 (m, 8H), 7.91 (d, NH) Method 9 62 1 /. Name 9: x5: 5c^ 639.4 Method 17 and: Method 76 1> The leaching agent is DCM/EtOAc, stepwise gradient from 1 〇〇/〇, 9 八, 8/2 Method 63 Ketobutyl dibutyl: ^ Base _7·methyl sulphide·8·received, · phenyl·丨,-sigh-(after _di-butoxy-methyl) ^1,1,3,4,5-tetrahydro-1,5- azathiol heptadecene gives 1,1-dione-3,3- Dibutyl-5-phenyl-7-methylthio-8-[N-((R)-l,-phenyl-1,-carboxymethyl)amine-carbenyl methoxy]-2,3 , 4,5-tetrahydro-1,5-phenylindolesulfonium sulphate (Example 1; 110 mg, 0.17 mmol), glycine acid third butyl ester (3 〇 mg, 0·23 mmol) The ear) and DIPEA (120 mg, 〇·93 mmol) were dissolved in DCM (2 mL). The mixture was stirred at room temperature for 5 minutes. TBTU (72 mg, 0, 22 mmol) was added and the mixture was stirred at room temperature for 1 hour. The title compound was obtained (yield: 94%). NMR (300 MHz) 0.7-0.8 (m3 6H), 1.0-1.6 (m? 21H), 2.2 (s, 3H) 3.2 (s, 2H)5 3.7-4.0 (m5 4H) ;4.6 (ABq, 2H), 5.6 (d, 1H), 6.4 (t, 1H), 6.6 (s, 1H), 6·9-7·5 (m, 11H), 8.1 (d, -163- This paper scale applies to Chinese national standards (CNS A4 size (210x 297 mm) 1291951 A7 B7 V. INSTRUCTIONS (161) 1H). Methods 64-69 The following compounds are prepared by the procedure of Method 63 using appropriate acids and amines (in the case of commercially available products) , source does not indicate) synthesis. -164- This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1291951

65

66

(CD30D) 0.75-0.85 (m, 6H), 1.1- Example 2 1.3 (m, 8H), 1.4 (s, 9H), 1.45-L55 (m, 4H), 2.15 (s, 3H), 3.25 (s, 2H), 3.75 (brs, 1H), 3.85 (s, 2H), 4.7 (ABq, 2H), 5.5 (s, 1H), 6.7 (s, 1H), 6.75-735 (m, 9H), 7.4 (s , 1H) 937.9 (M-HX I Example 2 67 °γ^Χ^〇

69

796.4 Example 1 Example 1 y This paper scale applies to Chinese National Standard (CNS) A4 specification (21〇x297 mm) -165- 1291951 A7 ____B7 V. Description of invention (163) Method 70 _y-diketo-3_butyl 3-ethyl-5-phenyl·7-bromo-8-(Nf(S)-l,-phenyl-indole-(di-hydroxyphosphonyl)methyl 1amine-methylhydrazine Basement-2,3,4,5-tetrahydro-1,5-benzothiazepine heptaene The title compound is from 1,1-dione-3-butyl-3-ethyl-5-benzene Benzyl-7-bromo-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-phenylindolesulfonium heptadecene (Method 9) and (5)-Amino (phenyl Diethyl methylphosphonate, synthesized by the procedure of Example 33. NMR (600 MHz) 7.77-7.72 (1H, m)5 7.47-7.42 (3H?m)? 7.36-7.27 (5H, m)5 7.14 (1H, s), 7.10-7.03 (2H, m), 5.55-5.48 (1H, m), 4.63-4.51 (2H, m), 4.14-4.02 (2H, m), 3.99-3.92 (1H, m) , 3.81-3.60 (3H, m), 3.22-3.10 (2H, m), 1.65-1.25 (8H, m), 1 · 19-0.95 (6H, m), 0.78-0.73 (6H, m). 1: trifluoromethyl-α-methoxycarbonylguanamine known as 4-difluoromethyl-... ruthenylamine (ι·4 g, ι·83 mmol) and disulfide ruthenium To a solution of MeOH (3 mL), EtOAc EtOAc.克(69.,.) NMR (300 MHz, DMSO-d6) 3.3 (s, 1H), 5.45 (s, 1H), 7.7-7.9 (m, 4H), 9·25 (brs, 3H). 72 diketo-3lX^3-ethyl-5-phenyl-7-decylthiophenyl",-oxycarbonyl JLfc amine fluorenyl 1 methyl}amine methyl sulfonyl oxime gas a gas four shame -I , 5-phenyl sulfonium sulfoxide heptarene makes U-diketo-3-butyl-3-ethyl-5-phenyl-7-fluorenyl-8-[N-((R)-lL benzene _ Γ 羧 carboxymethyl) amine mercapto methoxy] 2,3,4,5_tetrahydro]} phenyl sulfonium sulfoxide octadecene ( ___ -166 - This paper scale applies towel SS * standard (CNS A4 size (2i〇X297 public) '------1291951 A7 ____B7 V. Invention description (164 ) &quot; Example 38; 52 gram '0.082 millimoles) with ethyl glycinate hydrochloride Salt (18 mg '0.129 Amor) was dissolved in DCM (2 mL) and DIPEA (0.70 mL &lt; After stirring at ambient temperature for 5 minutes, TBTU (34 mg '0.11 mmol) was added and the mixture was stirred for 2 hours. The solvent was evaporated, and EtOAcjjjjjjjjjj NMR (500 MHz) 0.86 (m, 6H), 1.10 - 1.75 (m, 8H), 1.28 (m, 3H), 2.23 (s, 3H), 3 · 19 (q, 2H), 3.75 (m, 2H) , 3.99-4.25 (m, 4H), 4·64 (q, 2H), 5.64 (m, 1H), 6.35 (brs, 1H), 6.69 (s, 1H), 7·03 (t, 1H), 7.09 (d, 1H), 7.29-7.52 (m, 7H), 8.10 (d, 1H). Method 73 g of homo-butyl-3-ethyl-5-phenyl-7-methylthio-8-( N-{(R)-r-phenylβΚΓ-methoxycarbonylphenylmethyl)amine carbhydryl 1 methyl}amine carbaryl methoxy)·2,3,4,5-tetrahydro-I , 5-phenylindolesulfonium sulfoxide, the title compound is the procedure of Method 72, using 1,1-dione butyl-3-ethyl-5-phenyl-7-methylthio-8- [N-((R)-l,-phenyl-demethyl)aminomercaptomethoxy]-2,3,4,5-tetrahydro-1,5-benzoquinonesulfury-7-decene (example) 38) Synthesis with (2R)-amino (phenyl) acetate acetate. Method 74 1-(Γ-曱-Oxocarbonyl-indole-aminomethyl V2,3-dihydroxybenzene hydrochloride salt 1-(Γ-carboxy-oxime-aminoindenyl)-2,3-dihydroxybenzene (40 g, 0.218 mmol) was combined with methanol (230 mL). EtOAc was evaporated. The mixture was evaporated. The mixture was refluxed for 2 hr. The solvent was evaporated under reduced pressure. 35.5 g (70%) of title product. NMR (600 MHz, CD3 OD) 3.76 (s, 3H), 5.19 (s, 1H), 6.68-6-75 (m, 2H), 6.85 (dd, 1H) _ - 167- _ This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1291951 A7 B7 V. Description of invention (165 ) &quot; — Method 75 (R)-l-(l'-methoxycarbonyl- 1'-Aminomethyl)-4-indolyl hydrochloride salt (2R)-Amino (4-fluorophenyl)acetic acid (570 mg, 2.77 mmol) dissolved in methanol (5 liters) After cooling in an ice bath, sulfite (2 ml) was added dropwise and the temperature was allowed to reach room temperature. After 5 hours, the mixture was evaporated under reduced pressure. The procedure was repeated and the mixture was stirred overnight. The mixture was evaporated under reduced pressure to give the title product in quantitative yield. (500 MHz, CD3 〇D&gt; 3.84 (s, 3H), 5.26 (s, 1H), 7.26 (t, 2H), 7.53 (dd, 2H) · Method 76-77 The following compounds are by method 75 The procedure was carried out using the appropriate acid and amine (in the case where commercially available, the source is not indicated). Method Compound NMR SM 76 (S)-decylamino-pan-methoxycarbonylbenzyl (CD3 OD) 2.63 (s, 3H), 3.81 (s, 3H), 5.15 (s, 1 Η), 7·45-7.55 (m, 5 Η) (5) Let methylamino-mono-yl group 77 ι ... methoxycarbonyl-Ν-A Glycosylamine hydrochloride (D20) 2.65 (s, 3H), 3.81 (s, 3H), 5.15 (s, 1H), 7.45-7.48 (m, 2H), 7.52-7.59 (m, 3H) (methylamine Base) (phenyl)acetic acid 1 total reaction time 5 days method 78 U·-dioxime! li. each butyl-3-ethyl-5-mosyl-7-methylsulfanyl-8-{N-『 (R)-a-(Third-butoxy cold).:.4: via fluorenyl hydrazino-2,3,4,5-tetrahydro 4,5-benzoquinone sulphur (2R)·Amino (4-hydroxyphenyl)acetic acid tert-butyl ester (1〇4 mg, 0·47 mmol) and 1,1-diketo-3-butyl-3-ethyl -5-phenyl-7-methylthio-8-carboxydecyloxy-2,3,4,5-tetrahydro-1,5-benzoquinonesulfurium heptadecene (Method 17; Ι85 mg, 〇·39 mmol _____ -168- This paper size applies to Chinese National Standard (CNS) Α4 size (210X 297 mm) ' &quot; 1291951 A7 B7 V. Inventions (166) Ear) Soluble in DCM ( In 5 ml), add decylpyridine (0.09 ml, 0.77 mmol). After stirring at room temperature for 5 minutes, o-(7-azabenzotriazole small)-N,N,N',N'-tetramethylguanidine hexafluorophosphate (208 mg, 0.55 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The title compound (175 mg, 66%) was obtained. NMR (300 MHz) 0.81 (m5 6H), 1.05-1.65 (m, 8H), 1.42 (s, 9H), 2.21 (s5 3H), 3.17 (ABq, 2H), 3.74 (m, 2H), 4.60 (ABq) , 2H), 5.22 (brs, 1H), 5.49 (d, 1H), 6.67 (s, lH), 6.79 (m, 2H), 7.00 (t, 1H), 7.07 (d, 2H), 7.23-7.30 ( M5 3H), 7.40 (s, 1H), 7.82 (brd, 1H). Method 79 The following compound was synthesized by the procedure of Method 78 using the appropriate starting material: Compounds. M/z SM 79 1 d · 639.3 Method 17 and Method 77

Line Method 80 2-{f(2R)-2-Amino-2-(4-hydroxyphenyl)ethenyl 1 Amino}ethanesulfonic acid to give N-Boc oxophenylglycine (1.00 g , 3.21 mmoles, dissolved in DMF (5 mL) and added tetrabutylammonium taurate (2.36 g, 6.42 mmol) with an additional 5 mL of DMF. The resulting suspension was cooled on ice and TBTU (1.24 g, 3.85 mmol) was added. Remove the ice bath after 30 minutes and apply the Chinese National Standard (CNS) A4 size (210 X 297 mm) at -169 - this paper size 1291951 • A7 ___B7 V. Invention description (167) — &quot; Filter it The mixture was stirred for 2 hours before concentration. TFA (20 〇 /., 20 mL) in DCM was added and the mixture was stirred overnight. Ethyl alcohol (20 mL) was added and the solvent was evaporated. The crude product was refluxed for 1 hour in ethanol (1 mL). Filtration gave the pure title compound as a white solid 626 mg (71%). NMR (DMSO-d6) 2.4-2.6 (m, 2H), 3.2-3.4 (m, 2H), 4.79 (s, 1H), 6.78 (d, 2H), 7.23 (d, 2H), 8.22 (t , 1H), 8·4 (brs, 3H), 9·7 (s, 1H)· Method 81

Lk, di W-methyl-3-butyl-3-ethyl-5-phenyl-7-carboxymethylthio-8-methoxy-g, 3,4,5-tetrahydro-1,5- Benzopyrene and heptadecene make U-diketo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-methoxy-2,3,4,5-tetrahydro -1,5-benzoquinonesulfurium heptadecene (113 mg, 〇24 mmol), cs2CO3 (170 mg, 0. 52 mmol) and ethyl thioglycolate (〇〇6〇 ml, 〇 • 54 millimoles) Microwave irradiation was carried out in DMF (4.0 ml) in a Smith synthesizer at 8 ° C for 3 minutes and then at 9 ° C for 8 minutes. The reaction mixture was diluted with water (250 mL) and EtOAc (EtOAc (EtOAc)EtOAc. &gt; 2 : 1) Purification. The product formed was dissolved in THF (2 mL) and water (2 mL), and EtOAc (aq. The reaction was quenched with EtOAc (1 M). Purification by preparative HPLC gave the title compound (58 mg, 59%). NMR (300 MHz, CD3 OD) 0.81 (m, 6H), 1.00-1.70 (m? 8H), 3.21 (m? 2H)5 3.42 (m, 2H), 3.71 (m, 2H), 3.92 (s, 3H) ), 6.88 (m, 2H), 7.02 (m, 2H), 7.23 (t, 2H), 7.40 (s, 1H). ___ -170-____ This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1291951

Method 82 1,1-Diketo-3-butyl-3-ethyl, male glucosyl-oxycarbonylmethylthio-carboxy-methyl---- 2,3,4, mutually: hydrazine-1, 5-Benzene to 1,1-monoketo-3-butylsethyl j-phenylglycolylmethyloxy-2,3,4,5-tetrahydro-1,5-benzosulfur N-decylene (Method 9; % mg, 〇〇98 mmol) and Cs2C〇3 (51^: g, 〇15 mmol) were added to DMp (2 mL) and thioethanol was added. Ethyl acetate (0. 02 ml, 〇 15 mmol). The reaction mixture was subjected to microwave irradiation for 5 minutes at 15 Torr in an Smkh synthesizer. The reaction mixture was diluted with water (100 liters), made acidic with HCl (1 M), extracted with DCM (3×10 mL), and the dried organic layer was dried (MgS 〇 4) The title compound was crude (54 mg). 55〇·2· Method 83 and Method 84 — ketone, quinone di 3-butyl-3-ethyl-5-methyl-7-bromo-8-hydroxy-2,3,4,5-tetrahydro- 1,5-benzoquinonesulfurium heptadecene (#堂isomer 丨); 舆1,1-一酉1|capped di-3-butyl-3-ethyl-5-phenyl-7-bromo -8-light base-2,3,4,5-tetrahydro-1,5-

Benzoquinone sulphide heptadecene (pair, 1,, 1,, 二, butyl, butyl, acetoyl, _5, phenyl, 7-bromo, hydroxy, 2, 3, 4, 孓Two pairs of palmo-isomers of hydrogen 1,1 - benzoquinone sulphide heptadecene (W0 96/16051) were obtained by preparative HPLC and separated by the corresponding racemic mixture. The column is Chiralpak AD (20 x 250 mm id, l 〇 [Hm), and the mobile phase is G:: IPA mixture, in a ratio of 1 。. The injected racemate (17.3 mg, in IPA (1 ml)) Medium), dissolved at a flow rate of 1 〇 ml/min, and traced the chromatogram by UV-detection at 285 nm. Separation of a total of 260 mg of the racemate to produce 121 mg of the first dissolution pair Palm isomer (for palm 171 - this paper scale applies Chinese National Standard (CNS) A4 specification (210X297 mm) 1291951 A7 ___B7__ 1, invention description (169) ~ ~ isomer 1) and 115 mg second dissolution The total yield was 91%. The two palm isomers were each obtained at 99.4% ee. Method 85 (Εϋ芊-oxycarbonyl-heart [Ν'-(第Tris-butoxycarbamoylamine (R)-N-; oxycarbonyl-cyclylbenzylamine (10 g, 35 〇 mmol) and tris-butylglycine hydrochloride (6.3 g, 37.4 mmol) dissolved in DCM ( 200 ml) with 2,6-monodecyl p-precipitate (8.2 ml, 70.4 mmol). After 5 minutes of dropping at 〇°c, add TBTU (12.4 g, 38·6 mmol), And the mixture was continuously stirred for 1 hour and 30 minutes at TC, and at room temperature for 3 hours and 45 minutes. The reaction mixture was washed with water (2 X 100 ml), dehydrated and dried (MgS04), and purified by flash chromatography ( DCM: EtOAc 7 : 1 - 5 : 1), ield ( s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, , 5.10 (m, 2H), 5·28 (brs, 1H), 6.13 (brs, 1H), 6.23 (brs, 1H), 7.30-7.44 (m, 10H). Method 86 迅) [N-(third Butyroxycarbonylmethyl)amine-mercaptoheptamine gives (R)-N-aryloxycarbonyl-heart [Nf-(tris-butoxycarbonylmethyl)aminecarbamyl]henamine (Method 85; 12· 8 g, 32·2 mmol) dissolved in EtOH (99%, 200 ml) and toluene (50 ml). Add Pd/C (10%, 0.65 g) and in the atmosphere Force and at room temperature for 5 hours 30 minutes hydrogenation. The reaction mixture was filtered with EtOAc EtOAcjEtOAc NMR (600 MHz) 1.45 (s, 9H), 3.93 (m, 2H), 4.54 (s, 1H), 7.31-7.42 (m, 5H), 7·51 (brs, 1H). Method 87 1,1- Diketo-3,3-dibutyl-5-phenyl-7-methylthio-84N-(SW...methoxycarbonyl 芊__-172-______ This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1291951 A7 ________Β7 V. Description of the invention (170) Covering methoxy on tetrahydro 4,5-benzothiazepine heptarene makes U·diketo-3,3-dibutyl- 5-phenyl-7-indolethio-carboxymethyloxy-2,3,4,5-tetrahydro-1,5-benzoquinonesulfury-seven-decene (Method 22; 5 mg, 〇〇99 m Mol) was dissolved in DCM (2 mL). Add (s)-phenylglycine methyl ester hydrochloride (24.8 mg, 〇·ΐ 23 mmol) and diisopropylethylamine (7 mL). 〇4〇1亳莫耳). The mixture was stirred for 15 minutes, then TBTU (38 mg, 0.118 Torr) was added. After 5 hours, the reaction was completed (LC/MS). For purification, use gas imitation / κ〇Α (: (8/2) as the dissolving agent (88 6 〇 / . ; 55.2 mg, 0.064 mmol). μ / ζ 653 Method 88 dibutyl methionyl _8 - ((5)·心呢(A s Shengji as a base 甲 甲 甲 Α Α Α Α Α Α Α Α Α Α Α Α Α ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! Methylthio group | and (8) _ (...carboxybenzyl)amine ketone methoxy]-2,3,4,5-tetrahydro-i,5-benzoquinone sulphide heptadecene (Example 88 ' 25 grams, 〇·〇39 Amol) and methyl glycinate (7.5 mg, 〇〇59亳莫) dissolved in DCM (2 ml). Continuous addition of diisopropylethylamine (27 </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; /2) as a dissolving agent. 79% yield (22 mg). Addition method 89 bromo-8-(2-carboxyethyl U^ benzoquinone sulphide heptadecene to make sodium hydroxide (38 mg, 0.95 mmol) Ear) is contained in ethanol (2.5 ml)

1291951 A7 ____ B7 V. INSTRUCTIONS (171) Then 1,1-dione-3-butyl-3-ethyl-5-phenyl-7-bromo-8-hydroxy-2.3.4.5- Hydrogen-1,5-benzoquinonesulfurium heptasulfoxide (w〇96/1605i; 2〇〇mg, 〇443 mmol). After stirring for 5 minutes at room temperature, 3-bromopropionic acid (68 mg, 443·443 mmol) was added, and the reaction mixture was refluxed for 2 hr. Add acetic acid. The solvent was evaporated under reduced pressure and the residue was purified eluting with Et. The organic layer was separated, washed with water, dried and dried under reduced pressure. The crude product was purified by EtOAc EtOAc EtOAc EtOAc EtOAc NMR (CD3OD) 0.75-0.83 (m, 6H), 1.0-1.25 (m, 4H), 1.38-1.65 (m, 4H), 2·82 (m, 2H), 3.26 (s, 2H), 3.50-3.90 (m, 2H), 4·33 (t, 2H), 6.99 (t, 1H), 7.07-7.13 (m, 3H), 7·28 (t, 2H), 7.53 (s, 1H). Di-g-yl-3-butyl-3-ethyl-5-phenyl-7-indiyl (Third-Dinghui j carbon-based) aryl group]aminomethyl hydrazide} ethoxy)-2,3 ,4,5-tetrahydro-1,5-benzoquinonesulfazin-7-nonylene in 1,1-dione-3-but-3-yl-5-phenyl-7-bromo-8- (2-carboxyethoxy)_2.3.4.5-tetrahydro-1,5-benzoquinonesulfurium heptasulfoxide (method 89; 70 mg, 0.134 mmol) and (R)-heart (third-but Oxycarbonyl) amide (J Amer Chem. Soc.; EN; 117, 44, 1995; 10879-10888; 35 mg, 0.169 mmol) in DCM (2.5 mL), 2,6-di Mercaptopyridine (29 mg, 0.268 mmol) with D-BTU (56 Aike '0.174 mmol). The reaction mixture was stirred at room temperature for 2.5 hours and then diluted with DCM. This solution was washed with NaHC 3 (saturated aqueous), water, dried over water and evaporated. The residue was suspended in ether / petroleum ether, crystals crystals crystals crystals crystals crystals crystalsssssssssssssssssssssssssssssssssssssssssssssss · 56 (m, 11H), 1.60-1.77 (m, 2H), 2.82 (t5 2H), 3.13 - 3.25 (m, 2H), 3.72 (brs, a ___ - 174-_ This paper scale is used towel@ g home standard (CNS) A4ft grid (21GX 297 public) one -- 1291951 A7 B7 five, invention description (172) 2H), 4.35-4.44 (m, 2H), 5 · 54 (d, 1H), 6 · 95 (d,1H),7.04 (t,1H),7.08 (d,2H), 7.15 (s,1H), 7.29-7.43 (m,6H),7.52 (s,1H)·Methods 91-94 The synthesis was carried out by the procedure of Example 104 using the appropriate starting material (in the case where it is not commercially available, indicating the source of the amine). Method i NMR (S00MHz) and m/z SM 91 5〇〇0·77-0·86 (m,6H), 1.03-1.62 (m, 21H), 2.21 (s,3H), 2.32 (dd,1H),2,54 (dd, 1H), 3.14 ( s, 2H), 3.74 (brs, 2H), 4.48-4.53 (m, 1H), 4.60 (dd, 2H), 5.57 (d, 1H), 6.33 (d, 1H), 6.67 (s, 1H), 7.01 (t, 1H), 7.09 (d, 2 H), 7.17-7.40 (m, 21H), 7.50 (d, 2H), 8.10 (d , 1H); m/z 1040.83 Example l; 1 92 Winter ό 0.78-0.86 (m, 6H), L05-1.27 (m, 8H), L36-1.58 (m, 13H), 1.78 (s, 3H), 2.23 (s, 3H), 2.77-2.92 (m? 2H), 3.19 (s, 2H), 7.75 (brs, 2H), 4.64 (dd, 2H), 4.72-4.77 (m, 1H), 6.68 (s, 1H ), 6.81 (d, 1H), 7.01 (t, 1H), 7.09 (d, 2H), 7.27-7.42 (m, 6H), 7.50 (d, 2H), 8.16 (d, 1H); m/z 812.23 Example 1; 2 93 0.74-0.81 (m, 6H), 1.0-1.22 (m, 8H), 1.29-1.62 (m, 13H), 2.13 (s, 3H), 2.50-2.64 (m, 2H), 3.14 ( s, 2H), 3.69 (brs, 2H), 4.42-4.48 (m, 1H), 4.58 (dd, 2H), 5.45 (d, 1H), 6.13 (d, 1H), 6.62 (s, 1H), 6.96 (t, 1H), 7.04 (d, 2H), 7·17 knives · 21 (m, 3H), 7.23-7.37 (m, 18H), 7.41 (d, 2H), 8.0 (d, 1H) Example 1; Method 113 -175- This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 public)

Binding

Line A7 B7 1291951 V. Description of invention (173) 94 Q 0.81-0.87 (m, 6Η), 1.06-1.29 (m, 8H), Example 1 1.39-1.61 (m, 4H), 1.78 (brs, 2H), 1.94 (s, 3H), 2Ό7-2.17 (m, 1H), 2.20- ' ό 2.27 (m, 4H), 3.31 (s, 2H), 3.77 (brs, 2H), 3.80 (s, 3H), 4.65 (dd , 2H), 4.76-4.82 (m, 1H), 5.65-5.70 (m, 1H), 6.69 (s, lH), 7.04(t, lH), 7.12(d, 2H), 7.29-7.44 (m, 7H) ), 7.52 (d, 2H), 8.16 (d, 1H) 1 L-(S-trityl) cysteine tri-butyl ester hydrochloride: 〇rg· pre· proced· Int· ; 1999 , 31 : 571-572 2S-methyl-1-cysteine third-butyl ester: Pestic.Sci. ; ΕΝ ; 45 ; 4 ; 1995 ;357-362 Method 95 3,3-dibutyl ketone a 5-(4-phenylphenyl)-7-bromo-8-methoxy-2,3,4,5-tetrahydro-1 phenyl sulfonium sulfonate 4-keto-7-bromo-8-decyloxy-2,3,4,5-tetrahydro-1,5-benzothiazepine heptarene (W0 95/04534; 1.0 g, 2.5 Mixture of millimolar, 4-bromobenzene (4.78 g, 24.98 mmol), copper bromide (36 mg, 0·25 mmol) and potassium carbonate (0.35 g, 2.5 mmol) 20 hours. The reaction mixture was loaded onto a column and the product was dissolved in EtOAc EtOAc (EtOAc) &gt;^11(500 legs2)0_86-0.92 (111,611),1.16-1.35(111,811),1.45-1.65 (m, 4H), 3.16 (s? 2H), 3.96 (s, 3H), 7.06-7.10 (m5 2H), 7.19 (s, 1H), 7.29 (s, 1H), 7.33-7.38 (m, 2H). M/z 511. Legislation 96 ____-176-___ This paper scale applies to Chinese national standards (CNS) A4 size (210 x 297 mm)

Remaining order

Line 1291951 A7 Β·7 V. Description of invention (174) -

Lki—_ I with the same base _5·(4·qiqiji)·7_bromo _8•methylhydrogen·IMA-tetrahydronitridinium in 3,3-dibutyl-4, basal ice (4_chlorophenyl group) 7_Alkyl-8 methoxy-2,3,4,5-tetrahydro-1,5-benzoquinonesulfury-seven-decene (method %; 0·67 g, 1.3 〇4 mM), DCM (34 liters), water (34 ml), and potassium carbonate (〇 554 g, * 〇 mmol) in the mouth of the mouth, under 〇C, with a portion of the addition - Gas-peroxybenzoic acid (0.78 g, 3.2 moles). The reaction mixture was stirred for 1 hour under hydrazine: then at room temperature for 14 hours. Add DCM (100 mL) and NaHC03 (saturated aqueous solution, 150 The title compound 〇68 0.92 (m5 6H), 1.0-1.60 (m3 10H), L70-1.92 (m5 2H), was obtained, eluted with EtOAc. 2.300.7 (m, 2H)? 3.99 (s5 3H)5 7.16-7.20 (m, 2H)5 7.24 (s3 1H)? 7.34-737 (m, 2H)5 7.44 (s5 1H) ; m/z 543. Method 97 Dimercapto-3,3:tri-X-ylketoyl-5-(4-chlorophenyl)-7-methylthio-8-decyloxy-, _4,5-tetrahydro-1 , 5- stupid # sulfur nitrogen hepene olefins sodium thiolate (0. 43 g, 6.08 m The ear is added to U-dioxamethyl-3,3-dibutyl ketone ketone under nitrogen. 5_(Winter phenyl odor; methoxy 3,4,5, hydrogen-1,5- Phenylsulfonium sulfoxide heptadecene (method 96; 0.66 g, 1.22 mmol) in dry DMF (11 mL). The reaction mixture was taken at room temperature for 72 hours. And the residue is extracted with tri-methane / water. The organic layer is separated, washed with brine, washed with brine, dried and evaporated under reduced pressure. The crude product is purified by column chromatography using DCM as solvent. 〇·6 g (96%). NMR (500 ΜΗζ) 〇·8〇_1·〇(m,6Η),1·10-1·6 ___ -177- This paper scale applies to China National Standard (CNS) A4 Specification (210X297 mm) 1291951 A7 B7 V. Description of invention (175) (m, 10H), 1.70-2.0 (m, 2H), 2.28 (s, 3H), 3.37-3.70 (m, 2H), 4.04 (s , 3H), 6.65 (s5 1H), 7·25-7·30 (m5 2H), 7.35-7.42 (m, 3H); m/z 510·4· Method 98 1,1-dione-3 3-Dibutyl-5-(4-phenylphenyl)-7-methylthiomethoxy-2,3,4,5-tetrahydro-1,5-benzoquinone nitrogen-filled hepeneene in 1 1-dione -3,3-dibutyl-4-keto-5-(4-chlorophenyl)-7-methylthiomethyloxy-2,3,4,5-tetrahydro-1,5-benzene幷 幷 氮 圜晞 (Method 97; 41. 41 g, 〇. 79 mmol) in a solution of anhydrous ether (15 mL), Uaih4 (0·15 g ' 3.97 耄 Mo) was added under nitrogen. . The reaction mixture was stirred at room temperature for 2.5 hours. The reaction flask was cooled to 0&lt;0&gt;&gt; and excess <RTI ID=0.0># </ RTI> </ RTI> </ RTI> <RTIgt; The mixture was filtered, and the filtrate was dried and evaporated and evaporated. The crude product was purified by column chromatography eluting with EtOAc (EtOAc) NMR (300 MHz) 0.8-0.90 (m,6Η),1·(Μ·47 (m,12Η), 2.33 (s5 3Η), 3.17 (s, 2H), 3.70 (s,2H),3·93 ( s, 3H), 7.03-7.08 (m, 3H), 7.23-7.32 (m, 3H); m/z 496. Method 99 L1 · Diterpene dibutyl-5-(4-phenylphenyl)- 7-Methylthio-8-hydroxy-2.3A5-tetraqi-1,5-benzoquinonesulfurium heptadecene in 1,1-monoketo-3,3-dibutyl-5·(4-gas Phenyl)-7-methylthio-8-decyloxy-2,3,4,5-tetrahydro-1,5-benzothiazepine sulphate (Method 98; 0,26 g, 〇·52 In a solution of anhydrous DCM (10 liters), boron tribromide (2.63 g, 10.48 mmol) was added under nitrogen. The reaction mixture was stirred at room temperature for 2.5 hours. The reaction flask was cooled to 〇. (:, water (2 〇 ml) and hydrazine monohydrate-178-)

1291951 A7 ______ B7 V. Description of invention (176) (〇·5 ml). The organic layer was separated, dried under reduced pressure and evaporated under reduced pressure. The crude product was purified by EtOAc EtOAc EtOAc (EtOAc) NMR (500 MHz) 0.85 (t, 6H), 1.03-1.28 (m, 8H), L35-1.46 (m, 4H), 2.39 (s, 3H), 3.21 (s, 2H), 3.73 (s, 2H), 7.04 (d, 2H), 7.29-7.34 (m5 3H), 7.44 (s5 1H); m/z 482 · Method 100

Ll. Dimercapto-3,3-dibutyl-5-(4-phenylphenyl)-7-indolethio-8-ethoxycarbonylindoleyl-2,3,4,5-tetrahydro- 1,5- stupid #thio-nitrodecene is added to vinegar (0.101 g, 0.604 mmol) to 1,1_2 g of the same group _3,3-butyl-5-(4- Phenyl)-7-methylthio-8-hydroxy-2,3,4,5-tetrahydro-1,5-phenylindolesulfinyl heptadecene (method 99; 0.194 g, 0.402 mmol), Anhydrous Na2C〇3 (〇.192 g, 1.81 mmol) and a mixture of tetrabutylammonium bromide in MeCN (5 mL). The reaction mixture was refluxed for 3.5 hours. The solvent was evaporated under reduced pressure, and the residue was evaporated, m. The organic layer was separated, dried and dried under reduced pressure. The crude product was purified by column chromatography eluting with EtOAc EtOAc (EtOAc: EtOAc NMR (300 MHz) 0.80-0.89 (m, 6H), 1.0-1.45 (m, 15H), 2.34 (s, 3H), 3.16 (s, 2H), 3.68 (s, 2H), 4.30 (q, 2H) , 4.71 (s, 2H), 7.05-7.11 (m, 3H), 7.19 (s, 1H), 7.29-7.35 (m, 2H). Method 101

Uf M-based-3,3-dibutyl-5-(4)-gas phenyl V7-methylthio-8-carboxymethyl- 2,3,4,5-tetrahydro-1,5-benzoquinone sulphur Heptadecene in 1,1-monoketo-3,3-butyl-5-(4-phenylphenyl)-7-methylthio-8-ethoxyxylmethoxy-2,3, 4,5-tetrahydro-1,5-benzoquinonesulfurium heptasulfoxide (method 1 〇〇; 〇 195 g, -179- This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 DON) - -- 1291951 A7 B7 V. INSTRUCTIONS (177 ) 0.343 mmoles) In a solution of ethanol (8 ml), Na〇H (1〇3 mmol, in 0.5 mL water) was added. The reaction mixture was shaken at room temperature for 7 Torr, then quenched by the addition of acetic acid (0.3 mL). The solvent was evaporated under reduced pressure, and the residue was evaporated, m. The organic layer was separated, dried with EtOAc EtOAcjjjjjjj NMR (500 MHz, CD3 OD) 0·86 (t, 6H), 1.11-1.28 (m, 8H), 1.37-1.44 (m, 4H), 2.33 (s, 3H), 3.25 (s, 2H) , 3.55 (s, 2H), 4.73 (s, 2H), 7.10-7.15 (m, 3H), 7, 26 (s, 1H), 7.28-7.32 (m, 2H). Method 102

Ll.diketo-dibutyl-5.(4-Phenylphenyl-V7-sulfonylthio) (di-hair:butoxycarbonylmethyl)amine-methyl hydrazide-based guanamine-methyl hydrazide-based hydrazine 1_2, 3,4,5·tetrahydro-1,5-benzoquinonesulfinium heptarene in 1,1-dione-3,3-dibutyl-5-(4-phenylphenyl)-7-A Thioyl-8-methyloxy-2,3,4,5-tetrahydro-1,5-phenylindolesulfinyl heptadecene (Method 1〇1; 1〇〇 mg, 〇185 耄mol) With a solution of (R)w-[N-(2nd-butoxymethylmethyl)amine-based arylamine (Method 86; 56 mg, 0.213 mmol) in DCM (4 mL) Add 2,6-monomethyl 1 : bite (40 g, 〇 · 37 mmol) with TBTU (89 mg, 0.28 mmol). The reaction mixture was stirred at room temperature for 2 h then EtOAc And the liquid was washed with water. The organic layer was dehydrated and dried under reduced pressure. The crude product was purified by column chromatography using DCM/Me〇H (100·3); The title compound 〇129 g (89%). (600 MHz) 0.78-82 (m5 6H), 1.0M.23 (m, 8H)5 1.30-1.42 (m5 13H)5 2.32 (s, 3HX 3.10 -3.16 (m, 2H)5 3.62-3.68 (m5 2H)5 3.81-3.87 (m5 1H)5 3 .95-4.03 (m, 1H), 4.52 (dd, 2H), 5.57 (d, 1H), 6.27 (t, 1H), 7.01-7.07 (m, 3H), 7.20-7.43 _______-180- This paper The scale applies to China National Standard (CNS) A4 specification (210 x 297 public love ^ &quot; -- 1291951 A7 ______B7 V. Invention description (178 ) (m? 8H) 5 8.02 (d5 1H). 31^103 base ice Homo-indole 4·nitrophenyl on 8-methoxy-2-,3,4,5_tetra-gM·5· laughing and sulfur-nitroseptene in 3,3-dibutyl ketone-based methoxy Base 2,3,4,5-tetrahydro-1,5-benzothiazepine heptarene (synthesized by the procedure of WO 9616051 for the corresponding 3-butyl-3-ethyl analog; 2.9 g, 9.0 In millimolar, add brominated p-nitrobenzene (24 g, 119 mmol), K:2 C〇3 (1.6 g, 12 mmol) and CuI (180 mg, 〇95 mmol) The reaction mixture was heated to 2 ° C overnight, then allowed to cool to room temperature 'and the solid formed was purified by chromatography using DC]y [as a dissolving agent. Concentrate under reduced pressure and add Et 〇H (95 °)) and then filter out insoluble brominated p-nitrobenzene. The residue was again purified by flash chromatography using DCM as a solvent. The product was still impure, so the residue was purified by flash chromatography eluting with EtOAc EtOAc EtOAc (EtOAc) (6〇〇MHz) 0.77-0.87 (m,6H), U2-1.31 (m,8H),1.4-1.6 (m,4H),3.09 (brs,2H), 3.79 (s,3H),6.72-6.83 (m, 2H), 7.18-7.27 (m, 3H), 8.3 (d, 2H). Method 104 M; diketo-3,3-dibutyl ketone-5-(4-nitrophenyl) V8-Methoxy-2,3,4,5-tetraindole-1,5-phenylindolesulfonyl heptadecene in 3,3-dibutyl-4-keto-5-(4-nitrobenzene Addyl DC) (8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine heptarene (Method 103; 2.57 g, 5·8 mmol) 130 ml), water (130 ml) and k2C03 (2.44 g, 17.6 mmol). Allow the reaction mixture to cool to 〇 ° C, and add a medium-gas peroxybenzophenone-181 - this paper scale SS home standard (CNS) A4 specification (210 X 297 ^ 1 - 1291951 - A7 ___ Β 7 5, invention description (179) acid (3.42 g '13·9 mmol). The reaction was completed overnight, the temperature was slow The groundwater was allowed to rise to room temperature. Then, an aqueous solution of NaHC〇3 (saturated) was added, and the two liquid layers were separated. Then, the aqueous layer was extracted three times with DCM. The combined organic layers were dried and dried, filtered and evaporated under reduced pressure. Production Purification by flash chromatography <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Base &gt;8-helium a certain 2,3,4,5-tetrahydro-1,5-benzoquinone sulfonium sulphate was added to THF (200 ml) in LiAlH4 (5.76 g, 151 mmol). The reaction mixture was cooled to 〇C and h2S04 (4.06 mL &lt;&lt;&gt;&gt;&lt; l,l-diketo-3,3-dibutyl-4-mercapto-5-(4-nitrophenyl)-8-methoxy-2,3,4,5 in THF (50 ml) - tetrahydro-1,5-benzoquinonesulfurium heptadecene (method 104; 2.57 g, 5.06 mmol). After 1 hour of vigorous stirring, 'removing the cooling bath' and heating the reaction to 4 °C Overnight. Next, add Na2 S04 ·10Η2 Ο (3-4 teaspoons), water (8 ml), Na〇H (15% in water) (8 ml), water (25 ml) and MeOH (30) (ml). Remove the precipitate by hydrazine and rinse with DCM/MeOH. Dehydrate the solvent, filter and under reduced pressure Shrink. The residue was purified by flash chromatography eluting elut elut elut elut elut elut elut elut elut Μ/ζ431.3· Method 106 Dimethyl-3,3-dibutyl-5-(4-aminophenyl)diamine-2,3,4,5-g^hydro],5- Benzene _ _ · 182- ^ paper scale applicable to China National Standard (CNS) A4 specification (210 X 297 mm) ' — 1291951 A7 _____ B7 V. Description of invention (180) Terpene makes U-diketo-3 3-dibutyl-5-(4-aminophenyl) methoxy-2,3,4,5•tetrahydro-1,5-benzothiazepine hepene (Method 105; 918 mg, 2.13 mmol is dissolved in DMF (anhydrous, 20 mL). Sodium thiomethoxide (81 mg, ιι 6 m) was added. The reaction mixture was treated at 10 〇〇 12 ° C for four hours and then at room temperature overnight. Acetic acid (3 ml) was added, and the mixture was flushed with nitrogen (gas) and the gas system was introduced through a flask containing sodium hypochlorite to destroy the formed mercaptan. Water was added and the aqueous layer was extracted in two portions (: extracted twice. The combined organic layers were washed with brine, dried and dried, filtered and evaporated under reduced pressure. The mixture contained DMF, thus adding toluene and brine (each The aqueous layer was extracted twice with toluene. The combined organic layers were washed once with brine. The separatory funnel was washed with Et EtOAc to dissolve each material. Filtration and evaporation under reduced pressure. EtOAc EtOAc EtOAc. Diketo-3,3-dibutyl-5-(4-tris-butoxycarbonylaminobenzene benzene a·hydroxy-^^,4,5-tetrahydro-1,5-alum sulphur nitrogen seven Terpene makes 1,1-diketo-3,3-dibutyl (4-aminophenyl)yl each via a '3,4,5-tetrahydro-1,5-phenylindolesulfonate圜 ( (method 106; 6 〇〇 mg, 丨. 44 mmol) dissolved in THF (10 ml). Add di-tert-butyl phthalate (314 mg, 丨 44 mmol) and The mixture was stirred at 60 ° C for two hours, and 3 days at room temperature. The solvent was evaporated under reduced pressure. EtOAc was added and the organic layer was washed once with a solution of EtOAc (3·3 Μ, aqueous solution) and once with brine, dried and dried. The scale applies to the Chinese National Standard (CNS) Α4 specification (210X 297 mm) ' ' ----- 1291951 A7 B7 V. Description of the invention (181 reduction and evaporation under reduced pressure. Purification of the residue by flash chromatography) Using brain: job 9: 1 as the eluent to obtain the title compound reading gram (8 〇%) 〇M/z 517.3. Method 108 上, upper bis-indenyl-3,3·dibutyldiamine Stupid 氪漶If oxy-2,3,4,5-tetra is 1,1-dione-3,3-dibutyl·5_(4_third-butoxyaminophenyl) Pin-(10)-tetrahydro--p-benzoquinone-sulfur-nitrogen sulphate---------------------------------------------------------------------------------------- Tetrabutylammonium bromide (54 mg, 0.17 mmol), and ethyl bromoacetate (16 μl, 1.5 mmol) was added. The mixture was heated to 6 (r (: overnight, under reduced pressure) Solvent solvent. Add EtOAc and water and extract the aqueous layer twice with Et EtOAc. The combined organic layers were washed once with brine, dried over EtOAc EtOAc EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Carbonylamine, anthraceneoxy-2,3,4,5-tetrahydro-1,5-phenylindolesulfonium sulfoxide, U-diketo-3,3-dibutyl-5-(4- Third-butoxycarbonylaminophenyl)-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzoquinonesulfon% hepene (Method 1〇8; 6 〇7 mg, 1·〇 mmol was dissolved in THF (6 mL), %0 (6 mL), and LiOH (127 mg, 3.02 mmol, monohydrate) was added. The mixture was stirred for ι hours. The mixture was poured into water and the solution was acidified using an HCl solution (aqueous solution, im). The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed once with brine, dried, dried and evaporated and evaporated, and evaporated. M/z 575.4. Method 110 1,1-Diketo-3,3-dibutyl-5-(4-aminophenyl)-8-[N-( g^(R)-methoxyl-yl辛某)1Methyl methoxy 1-2,3,4,5-tetrahydro-1&gt; phenyl sulfonium sulfoxide heptarene makes 1,1-dione-3,3-dibutyl-5 -(4-Terti-butoxycarbonylaminophenyl) groups ((KR)-methoxycarbonyl decyl)amine carbhydryl methoxy]_2,3,4,5-tetrahydro], 5- Benzoquinone sulphide heptadecene (Method 45; 562 mg, 〇78 mmol) was dissolved in DCM (18 mL). TFA (4 mL) was added and the mixture was stirred for 3 h. The solvent was evaporated under reduced pressure. The residue was partitioned between EtOAc and EtOAc (1 EtOAc). The aqueous phase was extracted once more with EtOAc. The combined organic layers were filtered with EtOAc EtOAc EtOAc. M/z 622.5· Method 111

LkS keto-3,3-dibutyl-5-PKN'-tri-butyl-anthracene (...(R)_ 1 oxycarbonyl fluorenyl)amine-methyl methoxyl 1- 2,3A5-tetrahydro-1,5-loaded f-sulphide sulphate gives 1,1-dione-3,3-dibutyl-5-(4-aminophenyl) each [N as - (R)-oxime oxycarbonylbenzyl)amine carbhydryl methoxy]-2,3,4,5-tetrahydro-1,5-benzoquinone sulphide sulphate (Method 110; 40 mg, 0.064 m Mole) was dissolved in DMF (1 mL). A second-butyl isocyanate (8. 3 microliters, 0.071 millimolar) was added. The reaction mixture was stirred at 6 〇 8 〇 c overnight. Add a third-butyl isocyanate (2 〇 microliter, 〇i7i millimolar). The reaction mixture was stirred at 60-80 ° C for 2 days and then at room temperature for several days. The solvent was evaporated under reduced pressure. The product was purified by preparative HpLC using MeCN/ammonium acetate buffer gradient (5/95 to 1 〇〇/〇) as the eliminator to obtain -185 - the paper size is applicable to the Chinese National Standard (CNS) A4 specification ( 210 X 297 公爱Γ----- 1291951 A7 B7

The title product was 30 mg (65%). M/z 721.6. Method 112 LL-Tridecyl-3-X^Ethylethyl-5-phenyl-7-methylthiocarbamate) Aminomethyl 1-2,3,4 ,5-tetrahydro-1,5-benzoquinone sulphur atmosphere seven resignation&gt; The title compound is composed of 1,1-dione-based butyl-3-ethyl-5-phenyl-7-methylthio group 8-Butylmethoxy-2,3,4,5-tetrahydro-1,5-phenylindolesulfonium heptadecene (Method 17) and 3-amino-methyl phenylpropionate (Helv. Chim Acta ; EN ; 83 ; 6 ; 2000 · 1256 1267), synthesized by the procedure of Example 56. M/z 639.4. Method 113 D-(S-trityl)cysteine third-butyl ester hydrochloride in S-di-butylmethyl-semi-deaminic acid (2.0 g '5.5 Amor) Add %% hciq4 (1.6 ml) dropwise to the vigorously suspended suspension in the second acetic acid (35 liters). The reaction mixture was stirred at room temperature for 7 min. EtOAc (50 mL)EtOAcEtOAc The precipitate was filtered out as unreacted S-trityl-D-cysteine. The organic layer was separated, washed with EtOAc EtOAcjjjjjjjjjj ^ ^ 111 (5001 ^ 2): 1.43 (5, 911), 2.83 - 2.95 (m, 2 Η), 3.41-3.48 (m, 1 Η), 7.21-7.37 (m, 9 Η), 7.46 (d, 6 Η) · Method 114 1,1-diketo-3,3-dibutyl-5-phenyl-7-sulfonylthioethoxycarbonyl-2,3,4,5-tetrahydro-1,5-benzoquinonesulfide N-decylene in 1,1-dione-3,3-dibutyl-5-phenyl-7-sulfonyl-8-hydroxy-2,3,4,5-tetrahydro, 1,5 - Benzene sulphide heptadecene (Method 26; 12.85 g, 28.71 mmol) in a suspension in MeCN (150 mL), ethyl bromoacetate (3.85 mL, -186- Standard (CNS) A4 size (210 X 297 mm) m binding

1291951 A7 B7 V. Description of the invention (184) 34.6 millimolar), tetrabutylammonium bromide (0.925 g, 2.869 mmol) and carbonic acid steel (12.85 g '121.2 Amore). The mixture was heated under reflux for 5 hours. The solvent was removed under reduced pressure and the residue was partitioned between DCM and &lt The organic layer was washed with brine, dried (MgSO4) and concentrated. Chromatography using DCM /EtOAc (9:1) elute NMR 0.70-0.85 (m, 6H), 1.00-1.55 (m, 15H), 2.15 (s, 3H), 3.10 (s, 2H), 3.70 (bs, 2H), 4·25 (q, 2H), 4.70 (s, 2H), 6·65 (s, 1H), 6.90-7.30 (m, 6H). Method 115 from -diketo-3-butyl-3-ethyl-5-strato-8-carboxyl Methoxy-2,3,4,5-tetramethylene-L5-benzoquinonesulfurium heptadecene makes U-diketo-3-butyl-3-ethyl-5-phenyl-8-ethoxy Carbonyl decyloxy-2,3,4,5-tetrahydro-1,5-phenylindolesulfonium heptadecene (Method H6; 0.48 g, 1.04 mmol) was dissolved in ethanol (10 mL). NaOH (0.30 g, 7.5 mmol) was added and the mixture was refluxed for 30 min. Add acetic acid (1 ml). The solvent was evaporated under reduced pressure and the residue was purified eluting eluting The DCM layer was separated, dried and evaporated. 0.44 g (97%) of the title compound was obtained. NMR (300 MHz) 0.7-0.8 (m, 6H), 1.0-1.6 (m, 8H), 3.1-3.3 (m, 2H), 3.5-3.8 (m, 2H), 4.6 (s, 3H), 6.8- 7.3 (m, 7H), 7·5 (s, 1H)· Method 116 ill: diketo-3-butyl-3-ethyl-5-phenyl-8-ethoxycarbonylmethoxy-2, 3,4,5-tetra straight-1,5-alum sulphur nitrogen sulphate U-diketo group = 3-butyl-3-ethyl-5-phenyl-8-hydroxy-2,3, 4,5-tetrahydro-1,5-benzoquinonesulfurium heptadecene (WO 9616051; 0.40 g, 1.07 mmol), bromoacetic acid B_______-187-______ This paper scale applies to the Chinese National Standard (CNS) A4 size (210X 297 mm) 1291951 A7 ___ B7_. V. Description of invention (185) Ester (0.23 g, 1.38 mmol), sodium carbonate (〇·5 g, 4.7 mmol) and tetrabutyl bromide Ammonium (30 mg, 0.093 mmol) was added to MeCN (10 mL). The mixture was refluxed for 18 hours and then evaporated under reduced pressure. The residue was extracted with DCM / water. The DCM layer was separated and evaporated under reduced pressure. The residue was purified by column chromatography. The product was dissolved in DCM / EtOAc (90: 10). 0.480 g (97%) of the title compound was obtained. NMR (300 MHz) 0.7-0.85 (m, 6H), 1.0-1.7 (m, 11H), 3.1-3.3 (m, 2H), 3.6-3.8 (m, 2H), 4·3 (q, 2H), 4.6 (s, 2H), 6·9·7.3 (m, 7H), 7.5 (d, lH)· Method 117 1,1-dione-3,3-dipropyl-5-phenyl-7- Methylthio-8-hydroxy-2,3,4,5-tetrahydro-n benzothiazepine hepeneene in a S-synthesis-3,3-dipropyl-5-phenyl-7-formyl -8-Methoxy-2,3,4,5-tetrahydro-1'5-open sulphur-nitrogen-7 (according to WO 96/16051, using the same synthetic procedure, but starting materials are selected To obtain a dipropyl compound instead of a butyl/ethyl compound; 0.756 g, L62 mmol; in a suspension in DMF (40 ml), add NaSMe (0.605 g, 8,20 mmol, 95%) ) and the mixture was dispensed overnight at 120 °C. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc andEtOAc. The aqueous layer was extracted twice more with EtOAc and EtOAc EtOAc m. The title compound was obtained in 0.665 g (98%). NMR (500 MHz, DMSO-d6) 0.60-0.80 (m, 6H), 1.05-1.50 (m, 8H), 2.15 (s, 3H), 3.20 (s, 2H), 3.65 (brs, 2H), 6.65 ( s, 1H), 6.75-6.95 (m, 3H), 7·10-7·25 (m, 2H), 7.30 (s, 1H), 10.5 (s, 1Η) · Method 118 1,1-dione -3,3-dipropyl-5-phenyl-7-methylthio-8-#ylmethoxy-2,3,4,5-tetra-188- This paper scale applies to Chinese National Standard (CNS) A4 size (210X297 mm) 1291951 A7 B7 V. Description of invention (186) Hydrogen-1,5-benzothiazepine hepene on 1,1-dione-3,3-dipropyl-5-benzene Base-7-methylthio-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine hepene (Method 117; 0.665 g, 1.58 mmol) at MeCN (10 Ethyl bromoacetate (0.262 ml, 2.35 mmol), tetrabutylammonium bromide (0.051 g, 0.158 mmol) and sodium carbonate (0.870 g, 8.21 mmol) were added to the suspension in ML). . The mixture was stirred at 80 ° C overnight. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc and 0.5 M EtOAc. The organic layer was washed with brine, dried (MgSO4) and concentrated. The residue was filtered through a pad of EtOAc (EtOAc:EtOAc) A solution of NaOH (0.25 g, 6.25 mmol) in water (1 mL) was added and the solution was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc and EtOAc. The aqueous layer was extracted twice more with EtOAc. The crude product was purified by preparative EtOAc (EtOAc) NMR (DMSO-d6) 0.55-0.75 (m5 6H), 1.05-1.50 (m, 8H), 2.15 (s, 3H), 3·20 (s, 2Η), 3.65 (brs, 2Η), 4.50 (s, 2Η), 6.65 (s, 1Η), 6.80-7.00 (ffi, 3Η), 7.15 (s, 1H), 7.15-7.25 (m, 2H). Example 121. The following series are representative of human therapeutic or prophylactic uses. A pharmaceutical dosage form comprising a compound of the formula (1) or a pharmaceutically acceptable salt, solvate thereof, a solvate of such a salt, or a prodrug thereof (hereinafter referred to as a compound X) ·· -189- Zhang scale applies Chinese National Standard (CNS) A4 specification (210X 297 mm)

1291951 A7 B7

V. Description of the invention (W (4): Tablet I mg/tablet compound X 100 Lactose Ph. Eur 182.75 Cross-linked carboxymethyl cellulose sodium 12.0 Corn starch paste (5% w/v paste) 2.25 Magnesium stearate 3.0 (b): Tablets II mg/tablet compound X 50 Lactose Ph. Eur 223.75 Croscarmellose sodium 6.0 Corn starch 15.0 Polyethylidene tetrahydropyrrolidone (5% w/v paste) 2.25 Magnesium Stearate 3.0 (c): Tablet III mg/tablet Compound X 1.0 Lactose Ph.Eur 93.25 Cross-linked Carboxymethyl Cellulose Sodium 4.0 Corn Starch Paste (5Q/.w/v Paste) 0.75 Magnesium Stearate 1.0 (d): Capsules mg/capsules Compound X 10 Lactose Ph.Eur 488.5 Magnesium stearate 1.5 (e): Injection I (50 mg/ml) Compound X 5.0% w/v 1 M sodium hydroxide Solution 15.0% v/v 0.1M hydrochloric acid (to adjust pH to 7.6) Polyethylene glycol 400 4.5% w/v Water for injection to 100〇/〇-190 - This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) 1291951 A7 B7 V. INSTRUCTIONS (188 (7): Injection II 10 mg/ml Compound X 1.0% w/v Squamo Steel BP 3.6% w/v 0.1 M sodium hydroxide solution 15.0% v/v Water for injection to 100% (g): Injection III (1 mg/ml, buffered to pH 6) Compound X 0.1% w/v Tantalum steel BP 2.26% w/v citric acid 0.38% w/v Polyethylene glycol 400 3.5% w/v Water for injection to 100% The above formula can be obtained by customary procedures known in the art of medicine. Tablets (a)-(c) can be used in the form of enteric substances. Coating, for example, provides a cellulose acetate phthalate coating.

_- 191 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) i?1291951 Application deadline 90.12.20 ---- Case number 090131712 Category j (The above columns are 4 notes by this Council) Public AL C4

4 &amp; Ming - ^ type patent specification Chinese benzothiazepine heptarene derivative, its preparation method, and including the pharmaceutical composition of the first one, the name of the new English BENZUIHIAZINE derivatives, preparation process THEREOF, AND PHARMACEUTICAL COMPOSITIONS COMPRISING THE SAME Name 1 · Inge Mosdak INGEMAR STARKE 2 · McKeldas East MIKAEL DAHLSTROM Nationality 3. David Bubroberg DAVID BLOMBERG - Inventor I creator 1 · Sweden 2. Finland 3. Sweden live , residence 1 · Sweden Mondal S-43183 2 Sweden Mondal S-43183 3 Sweden Mondal S-43183 Name Swedish business Asteritlikon company (name) ASTRAZENECA AB Nationality Sweden III, applicant living, residence Sweden赛得特来 S-15185 (office) Joanne Margaret Marshall representative name JOANNE MARGARET MARSHALL -1 - bound paper size applicable to China National Standard (CNS) A4 specification (210 χ 297 public fund)

Claims (1)

129 View Patent Application No. 131712 Chinese Patent Application Substitution (September 95) A B c D 4 1 9. 5. :9 Patent Application Range 1. A compound of formula (I) or a pharmaceutically acceptable salt thereof Wherein: Rv and Rw are hydrogen; R1 and R2 are independently selected from (: 6 alkyl; Rx and Ry are hydrogen; Rz is selected from halo, amine, (6: alkoxycarbonyl. And N'-(q_6 alkyl)urea; v is 0 or 1; one of R4 and R5 is a group of formula (IA): Θ. V· 0A) R3 and R6, and R4 and R5 The other is independently selected from hydrogen and halogen 75289-950914.DOC. This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1291951 Ch alkoxy and Ch alkyl S(0)a (where 3 is 0 or y; wherein R3 and R6, and the other of R4 and R5 may be optionally substituted on the carbon by one or more R16; D is 0- or -S(0)b-; wherein b is 0, · Ring A is phenyl, porphinyl or fluorenyl; wherein ring a is optionally substituted by one or more substituents selected from R1 7 R is a wind, a base or a carbocyclic group; R8 is hydrogen or (: 4 alkyl; R9 is hydrogen or (: 4 alkyl; R1G is hydrogen; R11 is carboxyl or -P(0)(0H) ( 0Rc), wherein Rc is selected from the group consisting of q_6 alkyl; or R11 is a group of formula (IB): Wherein: X is -N(Rq)- or _N(Rq)C(0)_; wherein Rq is hydrogen; wherein Rq is hydrogen; R12 is hydrogen or CV4 alkyl; R13 and R14 are independently selected from hydrogen, C !-4 alkyl, phenyl or caliper 23; wherein the C! j alkyl group may be optionally substituted by one or more substituents selected from R 2 fluorene; R 1 5 is a thiol, a repeating acid group, a phosphonic acid group , _p(〇)(〇Re )(〇Rf), a P(0)(0H)(0Re), -P(〇)(〇H)(Re) or -P(〇)(〇Re)(Rf ), where ^ and Rf -2- 75289-950914.DOC This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) A8 B8 1291951, · R, the scope of patent application is independently selected from Cl_6 alkyl; or Rl5 is a group of formula (IC): Wherein: R24 is selected from hydrogen; R25 is selected from hydrogen; R26 is selected from carboxyl; P is 1-3; wherein R1 3 may be the same or different; q is 0-1; r is 0-2; The meaning of Ri 4 may be the same or different; m is 0 or 1; η is 1 or 2; wherein the meaning of R7 may be the same or different; ζ is 1; R16 and R17 are independently selected from halo, hydroxy, carboxy, a 4-alkyl, Ch alkoxy and N,N-(Cb4 alkyl) 2 amine group; wherein Ri 6 and R 1 7 may be independently substituted on the carbon by one or more R 2 1 ; R20 and R23 Independently selected from the group consisting of hydroxyl, amine, carboxyl, sulfhydryl, oxime 4 alkoxy, Ch alkyl S(0)a (where a is ruthenium or osmium), phenyl and imidazolyl; wherein R 2 〇 and R 2 3 may Independently, it is substituted on the carbon by one or more R 2 2 ; R21 and R22 are independently selected from a halogen group and a hydroxyl group. 2. The compound of formula (1) according to the scope of claim 1 or its pharmaceutically acceptable 75289-950914.DOC 1291951 Text &lt; Salt, where R1 and R2# 猸上 3 sister Cheng a, your only child is selected from ethyl, propyl or butyl.化合物 A compound of formula 1 or an unacceptable salt according to any one of claims 1 or 2 and //, wherein R3 is hydrogen. The second medicine can be attached to the salt of the salt, which is not the formula (ia) or the r5 is selected from ^ c-^-^^^c1M^^S(O)a(^ta^0^2): / , R4 or R5 can be replaced by one or more r16 on carbon; the R series is selected from the group! The base, the carboxyl group, and the alkyl group and the amine group. • The compound of the formula (1) or the eight drug according to any one of the claims of the first aspect of the patent application is a forkable salt, wherein R5 is a formula group (as depicted in the first item of the patent application) iR4 is Methylthio group. 6. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 or 2 wherein R6 is hydrogen. 7. The compound of formula 1 or a pharmaceutically acceptable salt thereof according to any one of claims 1 or 2, wherein in the group of formula (IA): D is -〇- or -S-; Is phenyl, porphinyl or P?|fluorenyl; wherein ring a is optionally substituted by one or more substituents selected from decyl, hydroxy, methoxy or trifluoromethyl; R7 is hydrogen, A Or phenyl; R8 is hydrogen or methyl; R9 is hydrazine or methyl; R1 G is hydrogen; m is 0-2, wherein R1 0 can be the same or different; and 75289-950914.DOC Applicable to China National Standard (CNS) Α4 specification (210X 297 mm) η 1291951 A8 B8 C8 VI. Patent application i: ~ R 1 is 竣 base, -P(〇)(〇H)(OEt) or formula ( IB) group (as depicted in item 1 of the patent application). The compound of the formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 or 2, wherein in the group of the formula (IB): R12 is hydrogen or methyl; R13 is Hydrogen, methyl, ethyl, butyl or phenyl or 23; wherein Rl3 is optionally substituted by one or more substituents selected from R20; R20 is hydroxy, methylthio, methoxy, amine, Imidazolyl or fluorenyl; wherein r2 is independently substituted on the carbon by one or more hydroxyl groups; R23 is a carboxyl group; X is -NH- or; R14 is selected from hydrogen, methyl or phenyl; The phenyl or phenyl group may be substituted by one or more substituents selected from the radicals in the case of October; R 15 is a carboxyl group, a sulfonic acid group, a phosphonic acid group ... p (〇) (〇Re) (〇Rf), _ P ( 0) (0H) (0Re), _p(〇)(〇H)(Re) or -p(〇)(〇Re)(Rf), wherein Re^ Rf is independently selected from methyl or ethyl, or Rl 5 is a group of formula (IC) (as depicted in item 1 of the patent application); p is 1-3, wherein the meaning of R13 may be the same or different; q is (M; and r is 0-3) , the meaning of which may be the same or different. 9. According to any one of the claims 1 or 2 of the patent application scope A compound of formula 1, or a pharmaceutically acceptable salt thereof, wherein in the group of formula (Ic): R24 is hydrogen; R25 is hydrogen; 75289-950914.DOC This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297)兼) 1291951 A8 B8 C8 R2 6 is a carboxyl group; and z is 1 0 10. According to the scope of the patent application! A compound of the formula 1 or a pharmaceutically acceptable salt thereof, wherein: both R and R 2 are independently selected from the group consisting of c 4 alkyl; R x and Ry are both hydrogen; Rz is selected from the group consisting of an amine and an amine. a group, a Ci_6^ group, a Ci 6 alkoxylated amino group or an N'-(Cb6 alkyl)ureido group; v is 0 or 1; R3 and R6 are hydrogen; one of R and R is a formula (IA) a group (as described in claim 1), and the other is selected from the group consisting of hydrogen, dentate, Ciy alkoxy or C 4 s(0)a ' where a is 〇 to 2; Wherein R4 or R5 may be optionally substituted on the carbon with one or more Ri6; wherein Ri6 is independently selected from the group consisting of hydroxy, carboxy and hydrazine, Ν-((ν4 alkyl) 2 amine; D is -0- or - S-; R7 is hydrogen, methyl or phenyl; R8 is hydrogen or methyl; ring oxime is phenyl, porphinyl or fluorenyl; wherein ring a is optionally selected from one or more selected from R1 7 Substituted by a substituent; wherein ri 7 is selected from the group consisting of a base group, a per group, a C. Fe group or a C alkoxy group; wherein r1 7 may optionally be substituted on the carbon by one or more R 2 1; wherein R 2 1 is selected From the base; R9 is hydrogen or methyl; 75289-950914.DOC This paper scale applies to the Chinese national standard (CNS) A4 size (210X 297 mm) AB c D 1291951 VI. Patent application range u1 G is hydrogen; is carboxyl group, -P(〇)(〇H)(ORc), where rc is selected from Ci 4 alkyl Or a group of formula (IB) (as depicted in claim 1); R12 is hydrogen or methyl; X is -NH- or -NHC (〇&gt;; R1 3 is hydrogen, Ci·4 alkane Or phenyl or R 2 3 ; wherein R 3 is optionally substituted by one or more substituents selected from R 2 fluorene; wherein R 2 〇 is hydroxy, C 1 M alkyl S(0) a, wherein a is 〇, c 1 - Alkoxy, amino, phenyl, milano or fluorenyl; wherein r 2 〇 may be independently substituted on the carbon by one or more R 22 ; R 22 is selected from a hydroxyl group; and 23 is a carboxyl group; Or a phenyl group; wherein the ClM alkyl group or phenyl group is optionally substituted with one or more substituents selected from the group consisting of r 2 fluorene; and R 2 () is a hydroxyl group; R 15 is a carboxyl group, a sulfonic acid group, Phosphonic acid group, 孑(〇)(〇1^)(01^), -P(0)(0H)(0Re), -P(〇)(〇H)(Re) or -P(〇)(〇 Re)(Rf), wherein ... and Rf are independently selected from C _4 alkyl, or Ri5 is a group of formula (ic) (as depicted in item 1 of the patent application) R2 4 is hydrogen; R2 5 is hydrogen; R2 6 is carboxyl; p is 1-3; wherein the meaning of R13 may be the same or different; q is 0-1; r is 0-3; wherein R1 4 can be Same or different; m is 0-2; where R1 0 can be the same or different; 75289-950914.DOC _7. This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 public) 1291951 A8 B8 C8 -;---------- D8 VI. Applying for patents ^ 'η is l·2; where R7 can be the same or different; z is (M '·where R25 can be Same or different. 11. A compound of the formula (1) or a pharmaceutically acceptable salt thereof according to the scope of claiming patent i, which is selected from the group consisting of: U-diketo-3,3,dibutyl ice phenyl-7-methylthio 8_Team {(8)-Goldylphenyl·Methyl)Aminemethyl]Methyl}Aminomethyl methoxy)_2,3,4,5-tetrahydro-1,5-benzothiazepine Daughter-in-law; 1,1-diketo- 3,3-dibutyl-5-phenyl-7-methylthio-(carboxymethyl)amine fluorenyl] glacial benzyl}amine-methyl thiol Oxygen&gt;2,3,4,5-tetrahydro-1,5-benzothiazepine seven daughters; 1,1-monoketo-3-3-butyl-5-phenyl-7_ Methylthio each ^^(R)-1L phenyl·Γ-[Ν'-(2-sulfoethylethyl)aminomethane]methyl}amine methyl methoxy)_ 2.3.4.5- Tetrahydro-l,5-benzothiazepine seven daughters; U-dipropionyl-3-butyl-3·ethyl-5·phenyl-7-methylthio-8-(N-{(R )-l, _phenyl-indole-[Ν'-(2-supply acid ethyl)aminomethane]methylguanamine-methyl methoxy)_ 2.3.4.5-tetrahydro-1,5 -benzothiazepine heptarene; 1,1-diketo-3,3-dibutyl ice phenyl; sulfonylthio sulfonate ethyl)amine methyl hydroxybenzyl) amide Methoxy)-2,3,4,5_tetrahydro-1,5·benzene Sulfur nitrogen sulfonium; l1-dimercapto; butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-〇s [N'-(2- Continuation acid ethyl)amine methyl hydrazide]_4_hydroxydecyl decyl carbazyl methoxy) _ 2.3.4.5- tetrahydro-1,5-benzothiazepine quinone; 1,1-two Ketopropyl-3-butyl-3.ethyl phenyl phenylmethanethione winter defeat 丨(8)-heart [N'-(2-carboxyethyl)amine-carbamyl]-aminomethyl methoxy )_2,3,4,5_Four 75289-950914.DOC 0 This paper scale applies to China National Standard (CNS) A4 specification (2i〇X297 public) 1291951 A8 B8 C8 -------- --- ----D8 _ Six, apply for patent Fanyuan hydrogen-1,5-benzothiazepine hepene; 1'1 -keto-3,3-butyl-5-phenyl-7-methyl sulfide -8-(N-{(R)-α-[Ν'-(2·hexaethyl)amine-carbamoyl]_4•hydroxyindole}amine-methylmercaptomethoxy)_2,3,4, 5_tetrahydro-1,5-benzothiazepine seven daughters; 丨上二S同基Ibutyl-3-ethyl-5-phenyl-7-fluorenyl-8-(N-{( R)-a-[N'-(5-Resylpentyl)amine-carbamoyl]fluorenyl}amine-methylmethyloxy)_2,3,4,5-tetrahydro-1,5-benzosulfur N-decylene; 1,1-dione-3,3-dibutyl-5-phenyl-7.methylthio each (N-{(R)-a -[N,-(2-ethylethyl)amine-carbamoyl}aminomethyl methoxy) 2,3,4,5-tetrahydrobenzothiazepine; 1,1-two Keto-3,3-dibutyl-5-phenyl-7,methylthio-8-(Ν-{ α-[Ν'-(2-sulfoethyl)amine fluorenyl]-2 -Fluoromethyl fluorenyl}amine carbaryl methoxy)-2,3,4,5-tetrahydro-1,5 «·benzothiazepine heptarene; 1,1-dione butyl each Ethyl-5_phenyl_7·methylthio group {team^_[N'-(R)-(2)-based small carboxyethyl)amine-methyl sulfhydryl] Base&gt;2.3.4.5-tetrahydro-1,5-benzothiazepine; 1,1-dione-3,3-dibutyl-5-phenyl-7-methylthio-8 -(N-{(R)-α-[Ν,·(R)-(2-hydroxy-1-carboxyethyl)aminemethanyl]indolyl}amine-methylcarbonyl]&gt; 2.3.4.5 - tetrahydro-1,5-benzothiazepine seven daughters; 1,1-dione-3,3-dibutyl-5-phenyl-7-methylthio-8-{N-[( R)-α-(Ν'-{(R)-l-[N"-(R)-(2-light-based small carboxyethyl)amine-carbamoyl]-2-ethyl}aminocarboxamide Benzyl]amine-methylmercaptomethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine hepene; 1,1-dione-3-butene-3 -ethyl-5-phenyl-7-methylthio-8-(Ν-{ α-[Ν'- 75289-950914.DOC -9- This paper scale applies to Chinese National Standard (CNS) Α4 specification (210 X 297 mm) ABCD 1291951 VI. Patent application range (methyl) Aminomethyl hydrazino} Aminomethyl amide Methoxy)-253,4,5-tetrahydro-1,5-benzothiazepine hepene; U-diketo-3-butyl-3-ethylphenyl-7-methylthio -8-(Ν-{α-[Ν,_((ethoxy)(methyl)phosphonium-methyl)amine carbamoyl]mercaptocarbazylmethoxy>&gt; 3,4,5-tetrahydro-1,5-benzothiazepine heptarene; U-di-yl-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- {N-[(R)-α·(Ν'-{2-[(light))(methyl)phosphonium]ethylguanidinyl)-ylamino)-aminomethyl methoxy}- 2,3,455-tetrahydro-1,5-benzothiazepine; U-dimercapto-3,3-dibutyl-5-phenyl^methylthio each (N-{(R)- A-[N,-(2-Indolyl-1-monoethyl)amine-methylcarbonyl]amine-methylmethyloxy&gt;2,3,4&gt; tetradec-1,5-benzo Sulfur nitrogen sulphide; U--keto-3,3·dibutyl-5-phenyl-7·methylthio-8-{N-[(R)-α-(N,-{2- [(Methyl)(ethyl)phosphonium]ethyl}aminecarbamyl]4-hydroxyindenyl]aminecarboxymethylmethoxy }-2,3,4,5-tetrahydro-l,5-benzothiazepine heptarene; 1,1-monodecyl-3,3-dibutyl-5-phenylmethylthio {N-[(R)-a-(N,-{2-[(methyl)(3⁄4yl))phosphonyl]ethyl decylamine), thiol]aminomethyl methoxy 2,3,4,5-tetrahydro-1,5·benzothiazepine seven daughters; 1,1-oneketo-3,3-dibutyl-5-phenyl-7-methylthio winter (N-{(R)-a-[(R)_N-(2-methylindolyl)-carbamoyl)-carbamyl]-ylaminomethylamino)-2, 3,4,5-tetrahydro-l,5-benzothiazepine hepene; and 1,1-monoketo-3,3-dibutyl-5-phenylj methoxysulfonate Aminomethyl hydrazino]-4 fluorenyl}amine carbaryl methoxy>2,3,4,5-tetrahydro-1,5-benzothiazepine hepene. 12·- Preparation of the formula 1 according to any of the scope of the patent application, i. 1 75289-950914.DOC 5 9 91 12 8 8 8 8 ABCD Patent Application The method of the compound, which comprises: - Method 7; · · Oxidation of the benzothiazepine heptaquinone of formula (II): (Π); Method 2J. For a compound of the formula (1) wherein D is -0-, -NRa or each; a compound of the formula (Ilia) or (Illb): HD 4 (Rz)v (nia) &gt;rr^Rx Reaction with a compound of formula (IV): -11 - 75289-950914.DOC This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) 1291951 8 8 8 8 A BCD ~, apply for patent garden where L is a replaceable group; Method 3) · (Va) or (Vb) acid: Or an activated derivative thereof; reacted with an amine of formula (VI): (VI); Method 4: For a compound of formula (I) wherein R11 is a group of formula (IB); a compound of formula (I) wherein R11 is a carboxy group, which is reacted with an amine of formula (VII): 75289-950914.DOC -12- This paper scale is applicable to China National Standard (CNS) A4 specification (210X297 mm) 8 8 8 8 ABCD 1291951 ~, application for patent garden method~ For compound of formula (I), where R11 is carboxyl group; ): Or (Vlllb) compound removal protection: Wherein RP is a Cp4 alkyl group; a method for a compound of formula (1) wherein R11 is a group of formula (IB) and 75289-950914.DOC - 3 - the paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210X) 297 mm) 59 Ίχ92 8 8 8 8 ABCD The patent application scope R15 is the carboxyl group; the system (IXa): 〇 R]0 R« n7 1 R9| ^ •Ν' N R1 R2 Ry Rx mv (IXa) or (IXb) compound removal protection: , R], R2 wherein RP is C1M alkyl; Method 7" · For compounds of formula (I), wherein R4 and R5 are independently selected from q _4 -14- 75289-950914.DOC This paper scale applies to Chinese national standards ( CNS) A4 size (210x 297 mm) 1291951 8 8 8 8 A BCD Patent application range Alkylthio, optionally substituted with one or more R16 on carbon; system (Xa) or (Xb) Compound: Wherein L is a displaceable group; reacted with a thiol of formula (XI): Ry-H(XI) wherein Ry is a q_4 alkylthio group, optionally substituted on the carbon by one or more r1 6; For a compound of formula (I) wherein R1 5 is a group of formula (1C), a compound of formula (IXa) or (IXb) wherein RP is hydrogen is reacted with a compound of formula (XII): 25 (XII) NH i R24 75289-950914.DOC -15- This paper scale applies to China National Standard (CNS) A4 specification (210 297 297 mm) 1291951 VI. Patent application garden 8 8 8 8 ABCD Method ρ) · For a compound of the formula (1), wherein R1 R15A ® ^ 96 is a group of the formula (ΙΒ), and R is a group of the formula (1C), and R26 is a group of the formula (Xllla) : (Xiria) (R2)v or (Xlllb) compound removal protection · R10 R8 ^24 RH R13 CRz)v (Xinb) wherein RP is Ci-4 fluorenyl; method for the compound of formula (I) wherein χ is -N(Rq)C(〇> is the formula (XlVa) ): • 16- 75289-9509l4.DOC This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 1291951 Patent application scope 8 8 8 8 A BCD Or (XlVb) compound: .R1, R2 react with compound of formula (XV)-17- 75289-950914.DOC This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1291951 VI. Patent application A BCD Rx (XV) Then, if necessary or desired, 0: a compound of formula (1) is converted to another compound of formula (1); II) any protecting group is removed; III) a pharmaceutically acceptable salt is formed. 13. The compound of formula (I) or the pharmaceutically acceptable sulfonium salt of any of the above-mentioned items of claim 1 or 2, which is used for the prophylactic or therapeutic treatment of warm-blooded animals such as humans. . M. According to the scope of the patent application, the alpha or the medicinal and ... the salt of the compound (the compound of formula 1 or the sub-injectable salt) is used for the manufacture of a medicament for the treatment of a warm-blooded animal such as a human. For use in the production of IBAT inhibition. 15. A pharmaceutical composition for the production of sputum inhibition in a warm-blooded animal, comprising a compound of the bismuth (I) according to the scope of the patent application! Acceptable to the 'Stele', ^Music, and accompanied by a pharmaceutically acceptable diluent or carrier. 16. A formula (vma), (VIIIb), _, (xmb) (such as the scope of patent application) (2) a compound of the formula (IXb), wherein the compound of the formula (IXb) is a compound of the formula (IXb), or a pharmaceutically acceptable salt thereof. -18· 75289-950914.DOC This paper scale is applicable to China National Standard (CNS) A4 specification (21〇χ297 mm). VI. Patent scope '基-5Ί7-methylthio-8-(N-{(R) ", phenyl], [N, (tris-butoxycarbonylmethyl) amine methyl hydrazide] methyl decyl carbaryl methoxy) - 2, 3, 4, 5- Hydrogen 1-5 benzothiazepine decene. 18. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 2, which is for use in a medicament Manufactured, the agent is used for the treatment of a hyperlipidemia symptom in a warm-blooded animal such as a human. 19. The compound of the formula (1) according to any one of claims 2 to 2, or a pharmaceutically acceptable salt thereof, is used. In the manufacture of pharmaceuticals, the medicament is used for treating adverse symptoms and diseases of lipemia in warm-blooded animals such as humans, such as hyperlipidemia, hypertriglyceridemia, high rock lipidemia (high LDL), high pre- § lipoproteinemia (^VLDL), excessive chylomicrons in the blood, hypolipoproteinemia, hypercholesterolemia, hyperlipoproteinemia, and low alpha lipoproteinemia (low HDL). 20. According to the scope of the patent application The compound of the formula (1) or a pharmaceutically acceptable salt thereof according to any one of the above 2, which is used for the manufacture of a medicament for treating different clinical symptoms of a warm-blooded animal such as a human, such as an atheroma Tumor sclerosis, arteriosclerosis, irregular rhythm, high thrombosis symptoms, vascular dysfunction , endothelial dysfunction, heart failure, coronary heart disease, heart and vascular disease, myocardial infarction, palpitations, peripheral vascular disease, inflammation of heart and blood vessels, such as heart, valve, blood vessel distribution, arteries and veins, aneurysms, Stenosis, restenosis, vascular plaque, vascular fat streaks, leukocyte, single cell and/or giant smear cell infiltration, intimal thickening, thinning of the middle vascular layer, infection and surgical trauma and vascular thrombosis, stroke and temporary hemorrhage 75289-950914.DOC . ί9. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) one -- 1291951 8 8 8 8 AB c D 々, patent application scope 21. According to the patent application The compound of the formula (I), or a pharmaceutically acceptable salt thereof, according to any one of the items 1 to 2, which is for use in the manufacture of a medicament for the treatment of atherosclerosis of a warm-blooded animal such as a human, Coronary heart disease, myocardial infarction, palpitations, peripheral vascular disease, stroke and temporary episodes of seizures. 75289-950914.DOC -20- This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm)