TWI313601B - Benzamide compounds, process for preparation thereof, and pharmaceutical compositions for treating or prevevting a disease or medical condition mediated through glucokinaswe (glk) comprising same - Google Patents

Description

1313601 A7 B7 V. INSTRUCTIONS (1) The present invention relates to the use of a group of benzoguanamine compounds for the preparation of a medicament for the treatment or prevention of a disease or medical condition modulated by glucokinase (GLK), resulting in a decrease in insulin secretion. Glucose threshold. In addition, it is inferred that the compound will lower blood sugar by increasing the intake of hepatic glucose. These compounds may have utility in the treatment of type 2 diabetes and obesity. The present invention also relates to a pharmaceutical composition containing the benzoguanamine compound, a subgroup of novel compounds of the benzoguanamine compound, and the use of these compounds in the above symptoms. In the callus-cell and hepatocytes of the knee, the main plasma membrane glucose transport system GLUT2. At physiological glucose concentrations, the rate at which glucose is delivered to the membrane by GLUT2 is not limited to the rate of total glucose uptake in these cells. The rate of glucose uptake is limited by the rate of phosphorylation of glucose-6-phosphate (G-6-P) catalyzed by glucokinase (GLK) [1]. GLK has a high Km (6-10 mg molecular weight) for glucose and is not inhibited by the physiological concentration of G-6-P[l]. GLK performance is set in a few tissues and cell types, most notably the stone-cell and liver cells (hepatocytes) of the pancreas [1]. In these cells, GLK activity limits the rate of glucose utilization and thus the degree of insulin secretion and hepatic glycogen synthesis by glucose embolization. These processes are key to maintaining systemic glucose homeostasis, and both are dysfunctional in diabetes [2]. In the Diabetes Paratype of Type 2 mature onset diabetes (MODY-2), 'diabetes is caused by loss of functional GLK [3,4]. Hyperglycemia in MOO Y-2 patients is caused by the use of glucose in the pancreas and liver [5]. Defective glucose utilization in the pancreas of patients with MODY-2 causes a glucose-stimulated insulin secretion. -6 - This paper scale is suitable for 8 (CNS) M specifications (21QX297 public)~-

Binding t 1313601 A7 B7 V. Description of invention (2) 槛 rises. Conversely, rare GLK activating mutations reduce this threshold for familial hyperinsulinism [6,7]. In addition to the reduced GLK activity found in M〇DY 2 diabetes, hepatic glucokinase is also reduced in type 2 diabetes [8]. It is important to prevent or reverse the development of diabetic phenotypes in both dietary and genetic diseases by comprehensive or hepatic selective overexpression [9_12]. Moreover, type 2 diabetes with fructose emergency treatment Improves glucose tolerance by stimulating hepatic glucokinase utilization [13] ^ This effect is regulated by glial GLK activity in hepatocytes induced by fructose induced by the following mechanism [13] The association of (GLKRP) inhibits liver GLK activity. Stabilizing GLK/GLKRP complex with fructose-6-phosphate (F6P) in combination with GLKRP and replacing the sugar phosphate with fructose _i_phosphate (F1P) The way it is unstable. Phosphorylation of dietary glucose controlled by glucokinase produces F1P. Therefore, glk/GLKRP complex integrity and hepatic GLK activity are regulated in a nutrient-dependent manner because the F6P system rises after absorption. On the contrary, F1P has an advantage in the post-meal condition. Compared with hepatocytes, 'pancreatic call-cells show GLK in the absence of GLKRP. Therefore, it is limited to the regulation of its matrix (glucose) utilization. cell GLK activity. Small molecules can activate GLK either directly or via a method that renders the GLK/GLKRP complex unstable. It is inferred that the former compound class stimulates glucose utilization in both the liver and the viscera, whereas the latter is inferred to be limited to In the liver, however, it is concluded that compounds with any distribution have therapeutic benefit in the treatment of type 2 diabetes because the disease is characterized by glucose utilization that is defective in the two tissues. This paper scale is suitable for A4 specifications (21QX) 297 A7 B7 I 1313601 V. INSTRUCTIONS (3) GLK and the pipeline system are expressed in hippocampal neurons, which regulate energy balance and control the important brain regions of blood intake [[4_18]. These neurons have been proven Neuropeptides that promote appetite and loss of appetite [15,19, 20], and have been hypothesized to be glucose-sensing neurons that change or inhibit or stimulate glucose at room temperature in the hippocampus [17, i9, 2i, 22] These neuronal abilities that sense changes in glucose values are deficient in a variety of genetically and experimentally induced <obese patterns [23-28]. Glucose analogs (which are glucokinase-like) Intraventricular injection (icv) infusion of competitive inhibitors stimulates food intake in squirrels [29,30]. In contrast, icv infusion of glucose suppresses feeding [31]. Therefore, GLK small molecule activators can be used. Food intake and weight gain are reduced via the central effect of glk. Thus, GLK activators can have therapeutic use in the treatment of eating disorders other than diabetes, including obesity. The hippocampal effect will add or synergize the same compound in the liver. And/or the effect of normalizing the glucose homeostasis in the pancreas to treat type 2 diabetes. Therefore, the GLK/GLKRP system can be interpreted as a potential "diabetes obesity" (both beneficial to diabetes and obesity). In W00058293 and WO01/44216 (Roche), a series of thiolamines Thiol-based compounds are interpreted as glucokinase activators. The direct effects in the assays in which these compounds link GLK activity to NADH production are measured and the mechanism by which these compounds are activated by GLK is assessed in optical measurements - reference is given in Example A. Description of the details of the in vitro assay. The compounds of the invention can directly activate GLK or inhibit the interaction of GLKRP with GLK to activate GLK. The latter mechanism provides a more important advantage than the direct activator of GLK, in that it does not directly Severe stimuli cause severe -8- paper quality standard 逋 Chinese National Standard (CNS) A4 specification (210X297 mm) 1313601 A7 B7 V. Description of invention (4) Inferred hypoglycemia plot. Many compounds of the invention It can exhibit more favorable selectivity than known GLK activators. W09622282, W09622293, W09622294, W09622295, WO9749707 and WO9749708 are disclosed Intermediates used in the preparation of compounds useful as vasopressin agents, which have structural similarities to those disclosed herein. In W09641795 and JP8143565 (vasopressin antagonism), Structurally similar compounds are also disclosed in JP 8301760 (prevention of skin damage) and in EP 619116 (osteopathy). WO 01/12621 describes the preparation of related compounds as isoxazolyl pyrimidines and as inhibitors of cJUN N-terminal kinases. Role, and pharmaceutical compositions containing these compounds. Cushman et al [Bioorg Med Chem Lett (1991) 1 (4), 211-4] illustrates the synthesis and action of pyridine-containing guanidine and guanamine As an evaluation of protein-tyrosine kinase inhibitors, Rogers et al. [J Med Chem (1981) 24(11) 1284-7] described as inhibitors of the ring-AMP phosphodiesterase The intermediate ion ketone analogs. WO00/26202 describes the preparation of 2-amino-»------------------- 6/36619 describes the preparation of an amine-based tetraazole derivative as an agent for the improvement of digestive tract excretion. US Pat. No. 5,466,715 and US Pat. No. 5,258,407 disclose the preparation of a 3,4-disubstituted phenol immunostimulating agent. JP 58069812 describes a hypoglycemic agent containing a benzoguanamine derivative ^ US 395035 1 describes 2-benzoguanamine-5-nitropyrazole and Cavier et al [Eur J Med Chem-1313601 A7 B7 V. Description of invention (5)

Chim Ther (1978) 13(6), 539-43] is the biological importance of owj cavitation. Dropping Compounds or Prodrugs In the preparation of & or medically symptomatic agents, we have proposed that the use of a compound of formula (I) or a salt thereof for the treatment or prevention of modulation via GLK is a property of the present invention:

Wherein m is 0, 1 or 2; η is 〇, 1, 2, 3 or 4; and n+m>0; each R1 is independently selected from OH ' - (CH2h.4〇H, - CH3. aFa, -(CH2h.4CH3.aFa, -0CH3.aFa, halo, (^-6 Slope, C2.6, C2.6 alkynyl, NH2, -NH-C丨.4 alkyl, - N-di-(<^.4 alkyl), CN, methionyl, phenyl or, if desired, substituted with a Cu alkyl group (heterocyclic group; each R2 is a YX- group, each of which is independently selected From: -0-Z- ' -0-Ζ-0-Ζ- ' -C(〇)〇-Z- ' -0C(0)-Z- ' -Sz- ' -SO-Z- ' -S02- Z- ' -N(R6)-Z- ' -N(R6)S〇2-Z- -10* This paper scale applies to the national standard of ten countries (CNS) A4 specification (210X297 male dragon) 1313601 A7 B7 DESCRIPTION OF THE INVENTION (6, -S02N(R6)-Z-, -CH=CH-Z-, -C=CZ-, -N(R6) CO-Z-, -CON(R6)-Z-, -C( 0)N(R6)S(0)2-Z-, -S(0)2N(R6)C(0)-Z- ' -C(0)-Z- ' -Z- ' -C(0) -Z-0-z-, -N(R6)-C(0)-Z-0-Z-,-0-ZN(R6)-Z-, -〇-c(o)-zoz- or straight bond Bonding bond; each Z series is independently a straight bond, a c2_6 excimer or a formula -(CH2)pC(R6a)2-(CH2)q-; each Y is independently selected from an aryl-Z1-, Heterocyclyl-Z1-, c3.7 cycloalkyl-z1-, CN6 alkane a group, c2.6 alkenyl, C2.6 alkynyl, -(CHJm CH3-aFa or -CH(0H)CH3-aFa; wherein each Y is independently substituted with up to 3 R4 groups as needed; each R4 Is independently selected from halo, -CH3.aFa, CN, NH2, C, .6 alkyl, deuterium (:, .6 alkyl, -C00H, -(:(0)0(:,-6 alkyl, OH or phenyl substituted with CU6 alkyl or -0(0)0(:^alkyl, or R5-X 1 - as required, where X1 is independently as defined in X above and R5 is selected from hydrogen, CU6 An alkyl group, -CH3-aFa, phenyl, phenyl, heterocyclic or C3.7 cycloalkyl; and R5, if desired, independently selected from halo, Cu6 alkyl, -oc, .6 alkyl, -CHhaFa, CN ' OH, NH2, C00H or -0(0)0 (^-6 alkyl substituents are substituted, each Z1 is independently a direct bond, a C2.6 extension or a formula -(CH2)pC(R6a)2-(CH2)q-; R3 is selected from phenyl or heterocyclic group, and R3 is optionally substituted with one or more R7 groups; R6 is independently selected from hydrogen, ^.6 alkyl or -C2_4 alkyl-fluorene-Cu alkyl; -11 - Common paper size of China National Standard (CNS) A4 specification (210X 297 mm) 1313601 A7 B7 V. Description of invention (7) Han "The system is independently selected from hydrogen, south, cN6 alkyl or - C2-4 alkyl; each R7 is independently selected from:

Cu alkyl, C2-6 alkenyl, C2.6 alkynyl, (CH2) 〇.3 aryl, (ch2) 〇.3 heterocyclic, (CH2)0.3C3.7 cycloalkyl, OH, CU6 -OH, halo, Cu alkyl-halo, OCw alkyl, (CH2)0.3S(O)0.2R8, SH, S03, thio, NH2, CN, (CH2) 〇.3NHS02R8, (CH2) 〇.3COOH ' (CH2)〇.3-0-(CH2)0.3R8 ' (CH2)〇.3 C(0)(CH2)〇.3R8 ' (CH2)〇.3C(0)OR8 ^ (CH2) 〇.3C(0) nh2 , (CH2)〇.3C(0)NH(CH2)〇.3R8, (CH2)〇, 3 nh(ch2)〇-3r8, (ch2)0.3nhc(o)(ch2) 0-3r8, (ch2)〇-3 c(o)nhso2-r8 and (ch2)〇_3so2nhc(o)-r8, wherein the alkyl chain, cycloalkyl ring or heterocyclic group in r7 is optionally One or more substituents independently selected from the group consisting of: (^.4 alkyl, OH, halo, CN, NH2, ii-Cw hexylamino, NN-di- 〇ι·4 sylamino and OCi_4 alkyl) Substituted; R8 is selected from the group consisting of argon, C!-6 alkyl, aryl, heterocyclic, C3.7 cycloalkyl, OH 'Cu alkyl-OH, COOH, C(0)0C!.6 ^ & Alkyl, OCu alkyl, C〇.6 alkyl 0(:(0)(:,.6 alkyl, 0(011)((:,.6 alkyl)Cualkyl; wherein the alkene in R8 Base chain or aryl, heterocyclic or cycloalkyl ring To be substituted with one or more substituents independently selected from the group consisting of C 4 alkyl, 0H, halo, CN, NH 2 , —NH-Cid alkyl, —N-di-(Cw alkyl) and OCm alkyl Each a is independent of 1, 2 or 3; 1313601 A7 B7 5. Inventive Note (8) p is an integer between 0 and 3; q is an integer between 0 and 3; and p+ q<4 0 is based on R3-series 2-pyridyl and X is not -Z-, -C(0)-Z-0-Z-, -N(R6)-C(0)-Z-0- When Z- or -0-ZN(R6)-Z-, then R3 is unlikely to be monosubstituted at the 5-position with a R7 group selected from COOH or (:(0)0(:^alkyl). For the avoidance of doubt, Therefore, the numbers in the above book are related to the indole bond attached to the pyridine ring, so the R3 in the book is a group with respect to the following structure:

One of them represents the point of attachment to the guanamine group in formula (I). According to a further feature of the invention, there is provided the use of a compound of formula (la) or a salt thereof for the manufacture of a medicament for the treatment or prevention of a disease or medical condition mediated by GLK:

Formula (la) where the paper size applies to China's i^CNS) A4 size (210X297 mm) 1313601 A7 B7 V. Description of invention (9) m series 0, 1 or 2; η series 0, 1, 2, 3 or 4 ; and n+m>0 ; each R1 is independently selected from OH, (CHAjOH, CH3.aFa, (CHOw CH3.aFa, 〇CH3_aFa, halo, leuco, C2.6 gynecyl, C2-6 alkyne) a group, NH2, N(Cn6 alkyl) CU6 alkyl, CN, phenyl or, optionally, a heterocyclic group substituted with C丨-6 alkyl; each R2 is a YX-group, wherein each X is independently selected from : -0(CH2)〇.3- ' -(CH2)〇.3〇- ' -C(0)0(CH2)〇.3- ' -S(CH2)〇.3- ' -SO(CH2) 〇.3- ' -S02(CH2)〇.3- ' -nhso2-, _S02NH-, -N(CH2)〇-3-, -N(CH2)0-3O(CH2)0-3-, -( CH2),.4- '-CH=CH(CH2)〇.2- '-C= C(CH2)〇.2- '-NHCO-, -CONH- bonding bond; each Y line is independently selected from benzene (CH2) Q.2, fluorenyl (CH2) 〇.2 'Heterocyclyl (CH2) 〇.2 'C3.7 cycloalkyl (0112). 2, C!_6 alkyl, 0C 丨.6 Alkyl, c2_6 alkenyl, C2.6 alkynyl or CH(OH)CH3-aFa; each Y is independently substituted with one or more R4 groups as desired; each R4 is independently selected from halo, CH3. aFa ' 0CH3.aFa, CN, NH2, Cu alkyl, OCu alkyl, COOH, (CH2) 〇.3 COOH, O(CH2)0-3COOH, C(0)0C丨·6 alkyl, C丨. 6 alkyl hydrazine: (0) 0 (^.6 alkyl, CO-phenyl, CONH2, CONH-phenyl, S02NH2, SC^Cu alkyl, OH or, if desired, one or more R5 groups or R6b- X-substituted phenyl; -14- This paper is the standard Chinese National Standard (CNS) A4 specification (210X297 public)

Install 1336061 A7 B7 V. Description of the invention (1〇) R5 is selected from hydrogen, Cw alkyl or 0(0)0 (:, -6 alkyl 'R6b is selected from hydrogen, C丨·6 alkyl, CH3. aFa, phenyl, fluorenyl, heterocyclic or C3.7 cycloalkyl; and 61) as desired, halo, C, sylvain, CH3.aFa, CN, NH2, COOH and C00C Substituent 'each a is independently 1, 2 or 3; R3 is selected from phenyl or heterocyclic, and R3 is optionally substituted with one or more R7 groups; each R7 is independently selected from:

Cu alkyl, C2.6 alkenyl, C2-6 block, heterocyclyl '(CH2)〇.3C3-7 cycloalkyl, OH, Cw alkyl-0H, halo, Cm alkyl halo, OCu alkane Base, SCu alkyl, SH, S03, NH2, CN, NHCHO, NS02C丨.6 alkyl, (CH2)0-3COOH, (CH2)〇.3 C(0)0CU6 alkyl, (CH2)〇.3CONH2 , (CH2)〇.3CON (ch2)〇_3r8, (CH2)o.3NH(CH2)0-3R8, (CH2)〇-3NHCO (o)(ch2)〇-3r8 ; R8 is selected from hydrogen, Ct .6 alkyl, (: 3.7 cycloalkyl, OH, Cw alkyl-OH, COOH, (:(0)0(^.6 alkyl, N(C0_6 alkyl)):: 6 alkyl, 0 ( (:, .6 alkyl) ¢::.6 alkyl, C〇.6 alkyl 〇C(0)Ci.6 alkyl, (:(0!!)((:!.6 alkyl)Cu Alkyl; a prerequisite for the R3 pyridine, then R7 is not C00H or COOCu alkyl. According to a further feature of the invention, it provides a compound of formula (lb) or a salt, solvate or prodrug thereof: -15- This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1313601 A7

V. Description of invention (11)

Rm is 0, 1 or 2; η is 1, 2 or 3; and n+m is 2 or 3; each R1 is independently selected from 〇H, -(CH2)i-4〇H, _CH3.aFa, - (CHdwCHs.aFa, -〇CH3.aFa, aryl, 〇CH3 C2H50, CH3C(〇)0., Ci 6 alkyl, c2.6 alkenyl, C2-6 block, -NH-C丨.4 alkane a group, -N_:_(Cl.4 alkyl), CN, anthracenyl, phenyl or a heterocyclic group optionally substituted with a cu6 alkyl group; each R2 is a YX- group, the prerequisite of which is γ_Χ_ It may be CH3〇, c2h5o or ch3c(o)〇_; wherein each X is independently selected from: -0-Z- ' -0-Ζ-0-Ζ- ' -C(0)0-Z- > -OC(〇)-Z- ' -s' Z-, -SO-Z-, -S02-Z-, -N(R6)-Z- ' -N(R6)S〇2-z-, -S02N (R6)-Z-, -CH=CH-Z-, -C=cZ-, -N(R6) CO-Z- ' -C0N(R6)-Z- ' -C(0)N(R6)S (0)2-z* ' -S(0)2N(R6)C(0)-Z-, -C(0)-Z-, -Z-, -C(0)-Z-0-Z- '-N(R6)-C(0)-2-0-Z- ' -0-ZN(R6)-Z- ' -〇-C(0)-Z-0-Z- or the bond of the direct bond Except in this ZSC, "Alkyl-16- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm)

Cold Order & 1313601 A7 B7 V. Inventive Note (12); Each Z series is a direct bond, c2.6 extension base or formula -(CH2)pC(R6a)2-(CH2)q- Each Y group is independently selected from the group consisting of an aryl group _Z1_, a heterocyclic group 2:1·, a C37 cycloalkyl group-z1- ' (: 丨.6 alkyl 'c2-6, a C2 6 alkynyl group, - (cn, CH3.aFa or -CH(OH)CH3-aFa; wherein each Y is independently substituted with up to 3 R4 groups as needed; each R4 is an independent dentate, ·CHhFa, CN, NH2, Cw Alkyl, -OC^.e alkyl, ·<:〇〇Ι·ί, _C(0)0Cu6 炫, 〇H or selected from (:丨.6 alkyl or -c(〇) 〇Ci.6 alkyl substituted phenyl, or RS-X1- 'wherein X1 is independently as defined above for X and R5 is selected from hydrogen, Cu alkyl, -CH3.aFa, phenyl, phenyl, hetero a cyclic group or a C3.7 cycloalkyl group; and R5 is independently selected from one or more selected from the group consisting of: halo, Cl_6 alkyl, -OCualkyl, CN, OH, hydrazine 2, C00H or -(:(0) Substituted by a substituent of 0 (1-6), each Z1 is independently a straight bond, a c2-6 extended alkenyl group or a formula of -(CH2)pC(R6a)2-(CH2)q-; R3 heterocyclic group Wherein attached to the R3 group relative to the guanamine A hetero atom of the atomic system at the 2-position of the heterocyclic ring, and when it is in the atomic system nitrogen at the 2-position of the heterocyclic ring of the hydrazino group, it is a nitrogen of the Sp2 hybrid and R3 is required Substituted with up to 2 R7 groups; R6 is independently selected from hydrogen, Cm alkyl or -c2.4 alkyl-O-Cm alkyl; 1169 is independently selected from hydrogen, functional, Cu alkyl or -C2. 4 alkyl-O-Cw-alkane-17- This paper pump scale is applicable to China National Green (CNS) A4 specification (210 X 297 mm)

Binding

1313601 A7 B7 V. Description of invention (13 bases; each R7 series is independently selected from:

Cu6 alkyl, C2.6 alkenyl, C2.6 alkynyl, (CH2) 〇.3 aryl, (CH2) 〇.3 heterocyclic, (CH2)0.3C3.7 cycloalkyl, OH, C! -6-alkyl-OH, halo' CU6 alkyl-halo, OCu alkyl, (CH2)〇.3S(0)〇_2Rs, SH, S03, thio, NH2, CN, (CH2)〇. 3NHS02R8, (CH2)〇.3COOH, (CH2)〇.3-0-(CH2)〇.3R8, (ch2)〇_3 c(o)(ch2)〇.3r8 ' (ch2)〇_3c(o )or8, (CH2)0-3C(O)

NH2, (CH2)〇.3C(0)NH(CH2)〇.3R8, (CH2)〇.3NH (CH2)〇-3R8, (CH2)〇.3NHC(0)(CH2)〇.3R8 > ( CH2) 〇, 3 c(o)nhso2-r8 and (CH2)0-3SO2NHC(O)-R8, wherein the alkyl chain, cycloalkyl ring or heterocyclic group in R7 is optionally selected by one or more From: 〇1.4 burning base, 01'1, halogen group, €1|4, 1^112, with >-匸1-4 burning amine group, liji-di-c 1 ·4 burning amine group and oc!· 4 Hyun> Substituent substituent; R8 is selected from the group consisting of argon, C i. 6 phenyl, aryl, heterocyclic, C 3-7 cycloalkyl, OH, Cm alkyl-OH, COOH, C (0 ) 0CU6 alkyl, alkyl, OCu alkyl, C0-6 alkyl 0 (: (0) (^-6 alkyl, (: (〇 only) ((: 1-6 alkyl) 0: 1_6 alkyl : wherein the alkyl chain or aryl group, the heterocyclic group or the ring-based ring in the ulmen 8 is optionally selected from one or more of: Ct. 4 alkyl, 0H 'halo, CN, NH2, -NH- Substituents for CbvJ^, -N-di-(C1·4 alkyl) and OC1·4 alkyl; each a is independently 1, 2 or 3; p is an integer between 0 and 3. ; -18- This paper scale applies to China National Standard (CNS) A4 specification (210 X 29·7 mm) A7 B7 1313601 V. Explain that (14) q is an integer between 〇 and 3; and p+ q< 4 0 is a prerequisite (i) when R3 is 2-pyridyl and X is not -Z-, -C(0)- When Z-0-Z-, -N(R6)-C(0)-Z-0-Z- or -0-ZN(R6)-Z-, then R3 is unlikely to be selected from COOH at the 5-position. Or a monosubstituted R7 group of C(0)0CN6 alkyl; (ii) substituted at position 3,5 (attached to R1 and R2) on the phenyl ring of the guanamine bond, and at least one of which is at position 3 and The base R2 group on 5; (iii) the unbranched unsubstituted CN6 alkyl chain does not exceed the length of the 6 alkyl group; (iv) when the η system is 2 or 3, then only one X group may be -NHC(O)-; (v) When R3 is a pyridyl group and an r7-based halo group or a methyl group, the phenyl ring to which R2 is attached may not be substituted with an R2 group at the 2-position relative to the guanamine bond. Wherein X-C(0)NH- and Y are optionally substituted phenyl, optionally substituted fluorenyl or optionally substituted pyridyl; (vi) when n+m is 2, m 0 or m is 1 and R1 is OH, η is 1 and X is -NHC ( Ο )- or η is 2 and X is independently selected from -C ( Ο ) Ν Η -, -NHC(O)-, -〇 -, -S(0)2NH- or a direct bond, one of which is X-based -NHC (O)-, Y is selected from the group consisting of phenyl and cyclohexyl; 4,5-diargon-5-oxypyrazolyl, fluorenyl, 1,3-dihydro-1,3·dioxyisoindole Indanyl, 2-oxy-1-benzopyran or pyridyl, and Y is optionally substituted with R4, then R3 may not be an unsubstituted carbazole, substituted with a triphenyl group 4,5 -Di-argon-5-oxypyrazolyl, ethoxycarbonyl-substituted ____ This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1313601 A7 B7 V. Description of invention (15) 4,5,6,7-tetrahydrobenzo[b] porphin or, optionally, a mono- or di-substituted pyridyl group with a methyl, ethoxy or propylamino group; or (vii) n+m is 3, m is 0 or 2, R1 is independently selected from methyl, methoxy or hydroxy, η is 1, 2 or 3, and X is independently selected from _〇·, _s(〇2)NH- , -C( Ο) -, - S( 〇2) -, - CH2- or a direct bond, γ is selected from? R3 may not be unsubstituted if the γ is optionally substituted with R4 and the R4 is selected from the group consisting of dihydroxymethoxy or Cl_4 alkyl, if it is substituted with R, morpholino, phenyl, tetrazolyl or propyl. Substituted tetrazolyl, unsubstituted pyrazolyl or thiazolyl substituted with ethoxycarbonylmethyl, for the avoidance of doubt, is a 6 alkyl group _ch2-CH2-CH2-CH2-CH2-CH. For the avoidance of doubt, an example of R3 wherein the r3 is a heterocyclic group and a nitrogen which is sp2 hybridized with respect to the atomic system at the 2-position of the R3 heterocyclic ring of the amidino group attached to R3 includes:

This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public) 1313601 A7 B7 V. Invention description (16)

Wherein m is 0, 1 or 2; η is 0, 1, 2, 3 or 4; and n+m >0; each R5 is independently OH, (CH2) i-4〇H, CH3. aFa, (CH2) U4 CH:, aFa, 〇CH3_aFa, halo, Cu alkyl, C2-6 alkenyl, C2-6 alkynyl, NH2, thio) C2-6 alkyl, CN, phenyl or selected Self-respecting heterocyclic groups which are substituted with an alkyl group; each is a YX-group, wherein each X-series is independently selected from: -0(CH2)〇.3- '-(CH2)〇.3〇- '-C (0)0(CH2)〇.3- ' -S(CH2)〇.3- ' -SO(CH2)〇.3- ' -〇2(CH2)〇.3- ' -nhso2-' -S02NH- '-N(CH2)o-3- '-N(CH2)〇.3〇(CH2)〇-3- ' -(CH2),.4- > -CH=CH(CH2)〇.2- ' - 〇Ξ C(CH2) 〇. 2--NHCO-, -CONH- bonding bond; each Y is independently selected from phenyl (CH2) 〇.2-, fluorenyl (ch2) 0_2-, heterocyclic group (CH2)G.2_, C3-7 ring pit base (CH2) 0-2_, 〇2-6 burnt base, C2-6 bond-21 - This paper scale applies to China's two standards (CNS) A4 specification (210 X297 1313601 A7 ______ B7 V. INSTRUCTIONS (17) Base, C2.6 alkynyl or CH(OH)CH; .EFa ; Each Y is independently substituted with one or more r4 groups as needed; each R4 Independently selected from A halogen group 'CHhaFa, OCH:.-aFa, CN, NH2, Cu alkyl, 〇CN<5 alkyl, COOH, <CH2)0-3COOH substituted with one or more V groups or r6, x_, O(CH2)0-3 COOH ' C(0)0C!.6>tl: ' 0-..6^1.0(0)00,.6^3⁄4 ' CO-phenyl, C0NH2, CONH-fluorenyl, S02NH2, SC^Cw alkyl, OH or phenyl; R5 is selected from the group consisting of hydrazine, Ci.6^I4C(0)0Ci. (S^S, R6b is selected from hydrogen, Cy alkyl, CH:..aFa, Phenyl, fluorenyl, heterocyclic or C3_7 cycloalkyl: and 1 枧 need to be substituted with halo, c 丨.6 alkyl, CH3.aFa, CN, NH2, C00H殳COOCw alkyl, each a system Independently 1, 2 or 3; R3 is a heterocyclic group, and R3 is optionally substituted with one or more: U R7 groups; each R7 is independently selected from:

Ci.6 alkyl, C2.6, 〇2-6 anthracene, heterocyclic, (〇Η2)〇-3〇3-7 cyclohexanyl, OH, Ci.6 tiger-OH, halogen Base, Ci.6 alkyl-halo, OCm alkyl, SCU6 pit, SH, S03 'NH2, CN, NHCH0, NSC^Cus pit, (, CH2) 〇.3COOH, (CH2)0.3 CWOCm alkyl , (CH soil jCONHz, (CH2) 〇.3CON (CH2) 〇.3R8 ' (CH2) 〇.3NH(CH; i〇.3R8 ' (CH2) 〇.3NHC(0) (CH2) 〇.3R8 ; R8 Is selected from the group consisting of argon, Cu alkyl 'C_:.-cycloalkyl' OH, CN6 alkyl-OH, COOH, (:(0)0(:,-6-daki, N(C〇-6 alkyl) Cu alkane paper scale applies to Chinese National Standard (CMS) A4 specification (210 297 s S: binding

1313601 A7 ... ___B7 V. Description of the invention (18), 0 (CN6 alkyl) Ci.6 alkyl, CQ.6 alkyl 0 (: (0) (:, .6 alkyl, alkyl) Cm Alkyl; the prerequisites are (i) when the R3 system is 11 thiophene and the R7 nitro group, then at least one r2 group is not -〇_ propylene; (ii) when R3 is densely occluded or ρ is more And r 1 is not 〇H; (iii) when R3 is pyridine, then R7 is not CO〇H or C00Ci 6 alkyl. Further characteristics of the invention are a compound of formula (Id) or a salt, solvate or prodrug thereof;

Wherein R3 is a phenyl group optionally substituted with one or more R7 groups; nWHx, ^^,. , "'. And the heart as above is used for the definition of the compound of formula (I). The compounds of the formula (I), (la) '(lb), (IC) or (Id) may form salts within the scope of the invention which are pharmaceutically acceptable, although other salts may be useful, for example, for isolation. Or purify the compound. When the claws are 2, each of the R1 groups may be the same or not, and the same two R1 groups are preferred. When "2, 3 or 4, then - pure 2 bases may be the same or different from any other R2 groups" and at least two base 2 bases are not preferred. -twenty three-

1313601 A7 I-------__ - B7 V. INSTRUCTIONS (19) The R and/or R2 groups may be attached to the -2, -3, -4, -5 or -6 positions. The term "aryl" refers to phenyl, fluorenyl or contains from 8 to 12 carbon atoms = partially saturated bicyclic carbocyclic ring, preferably from 8 to 10 carbon atoms. Examples of the 6-saturated bicyclic carbocyclic ring include: 1,2,3,4-tetrahydroindenyl, indanyl, fluorenyl, 1,2,4a, 5,8,8a-hexahydroindenyl or Hydropentene. The term "halo" includes chloro, bromo, fluoro and iodo groups, preferably a gas group, a bromine group and a fluorine group, and the fluorine group is most preferred. In the case where a is an integer between 丨 and 3, the term _CH3_aFa" denotes a methyl group in which 1, 2 or all 3 hydrogens are replaced by a gas atom. Examples include trifluoromethyl, monofluoromethyl and fluorine. Methyl. A similar note is used for the -(CHd^CH^Fa) system, examples include: 2,2-difluoroethyl and 3,3,3•trifluoropropyl. In the specification of the present application, " The term "alkyl" includes both straight and branched chain radicals. For example, "Ci-4 alkyl" includes propyl, isopropyl and tert-butyl. For the avoidance of doubt, the alkyl chain can be The remaining molecules at the end of the alkyl chain or in the middle of the alkyl chain are joined, ie the definition of "alkyl" includes the following structure: ( /CH2 pHrCH3

i~CH2-CHrCH2-CH3 4-CH2-CH CH3, CH3 where + represents the attachment point to the remaining molecules. "Heterocyclyl" is a saturated, partially saturated or unsaturated, monocyclic or fused bicyclic-24-containing 3-12 atoms of at least one atom selected from nitrogen, sulfur or oxygen. National Green Standard (CNS) A4 Specification (210X297 public) 1313601 A7 __________ B7 V. Invention Description (2〇) The ring can be replaced by _c(〇)- or can be used in _CH2_ The sulphur in the ring system is oxidized to 3 (〇) or $(〇)2. Unless otherwise specified, the heterocyclyl ring may be attached as carbon or nitrogen, and a charged quaternary nitrogen may be formed if not connected via nitrogen. "Heterocyclyl" is a saturated, partially saturated or unsaturated 'monocyclic or fused bicyclic ring containing 5 or 6 atoms (1 to 3 of which are nitrogen, sulfur or oxygen). Preferably, unless otherwise specified, it may be attached as carbon or nitrogen 'wherein the _CH2- group may be replaced by _c(〇)- or the sulfur atom in the heterocyclic ring may be oxidized to S(0) or s(〇) 2 base. Examples of "heterocyclyl" and suitable meanings are oxazolidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidone' 2,5-dioxypyrrolidinyl, 2-benzoxazolidine Keto group, 1,1 -dioxytetrahydrotetrazole, 2,4-dioxyimidazolidinyl, 2-lacyl-l,3,4-(4-trivalent alkyl), 2-σ Olfactory oxime, 5,6-dihydrouracilyl, 1,3-benzodioxanyl 1,2,4-oxadiazolyl, 2-azabicyclo[2.2 · 1 ]heptyl, 4- 塞 ° 炫 酮 酮 、 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , Hydropyranyl, piperidinyl, 1 _oxy-1,3-diarisoisodecyl 'hexahydropyridyl> thiomorpholino, 1,1-dioxythiomorpholine Generation 'tetrahydropyranyl, 1,3-didecylalkyl', hexahydropyrrole, thiophene, iso- 17 thiol, imipenyl, ρ-mercapto, thiophene, 〃 Serotonin, iso-septidyl, 1,2,4-trisole, 1,2,3-trisyl, ρ-pyranyl, phenyl, hydrazine, '• oxazolyl , pyroline, argon, pyridyl, 4-pyridone, &l t;» quinolyl and 1-isoquinolinyl. "Heterocyclyl•• terminology to indicate a monocyclic heterocyclic ring with a 5- or 6-member system-25- This paper scale applies to Chinese national standards ( CNS) Α4 specifications (210X297 public)

Binding

1313601 A7 B7 V. Description of the invention (21) Preferably, such as isoxazolyl, pyrrolidinyl, 2-pyrrolidone, 2,5·dioxy 17 ratio slightly, entertainment, base, β-lin, tetranitrogen P-vector, squaring, six gas p than sputum, thiomorpholino, tetrahydropyranyl, "shim-based, imidazolyl, 1,2,4-tri- thio" 1,3 , 4-trisyl, thiol, oxime, ρ syphonyl, fluorenyl, fluorenyl and pyridyl. Preferred examples of the 5/6 and 6/6 bicyclic tether systems include benzofuranyl, benzimidazolyl, benzindolyl, benzo, pyrazolyl' benzisopyrazolyl benzo Azolyl, benzisoxazolyl 'pyridoimidazolyl, pyrimidazolidinyl, '•quininyl, isoquinoline, linyl, oxazolidine, kui, lyophilized 酞 酞 、, porphyrin And acridinyl. The term 'cycloalkyl" is used to mean a saturated phosphorus ring ring containing between 3 and 12 carbon atoms, preferably between 3 and 7 carbon atoms. Examples of the c3-7 cycloalkyl group include a cycloheptyl group, a cyclohexyl group, a cyclopentyl group, a cyclobutyl group or a cyclopropyl group. Preferably, it is a cyclopropyl group, a cyclopentyl group or a cyclohexyl group.

Examples of the Cm alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a second butyl group, a tert-butyl group, and a 2-ethylbutyl group; examples of the Cu-slope-OH include a methyl group and a hydroxyethylene group. Examples of the C. 6 alkyl-halo group include gas methylene, fluoromethylene, styrene, and ethylene. Examples of the Cz. beta alkenyl group include ethionyl group, 2-propyl group, and 2- Butyl or 2-methyl-2-butanyl; examples of C2.6 alkynyl include ethynyl, 2-propynyl, 2-butynyl or 2-methyl-2-butynyl; -OCm Examples of the group include a methoxy group, an ethoxy group, a propoxy group, and a tert-butoxy group; - (3) of the alkyl group includes an methoxycarbonyl group, an ethoxycarbonyl group, and a tert-butoxy group. Examples of carbonyl;-NH-C,.4 alkyl include: -26- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1313601 A7 B7 V. Invention description (22 Yan 3 -N-CH3 卞C3H7 -N-CH2-<p-CHrCH3 λ Η Η Η Η : and -Ν-di-(Ci-4 alkyl) Examples: ch3 -N-CH3 _y-C3H7 -N-CH ?(j;-CHrCH3

CH3 C2H5 CH3 H For the avoidance of doubt, in the definition of the bond 'X' base, the right hand side of the base is attached to the phenyl ring and the left hand side is bonded to the Υ. The same orientation applies to the bond 'X1·base, so the right hand side of 'X' is attached to the Υ and the left hand side is conjugated to 'Ri. It will be appreciated that a particular compound of formula (I), (la), (lb), (Ic) and (Id) as defined above or formula (II) as defined below may be derived from one or more asymmetric carbon atoms. (Ilk) compounds exist in optically active or racemic forms, and the invention includes any optically active or racemic forms within their definition that have direct stimuli to GLK or inhibit GLK/GLKRP interactions. The synthesis of the optically active form can be carried out by standard techniques of organic chemistry well known in the art, for example, by the synthesis of an optically active starting material or by the decomposition of a racemic form. It will also be appreciated that a particular compound may exist in tautomeric form, and that the invention is also directed to any or all tautomeric forms of the compounds of the invention that will activate Glk. Preferred compounds of the above formula (I), (la), (lb), (Ic) and (id) or compounds of the following formulae (II) to (Ilk) are those in which one or more are suitable for the following Compound: -27- This paper wave scale applies _ @固家标准(CNS) A4 specification (210X297 mm) 1313601 A7 B7 V. Description of invention (23) (1) m series 0 or 1; η series 1 or 2; η 2 is preferred; m is 0 and η is 2 is optimal. (2) attaching the R1 and/or R2 groups to the 2· position and/or the 3-position and/or the 5-position; when n+m is 3, the group is at 2-′ 3- and 5- Preferably, when n+m is 2, the group is preferably at the 2- and 5- or 3- and 5-positions; for a total of two substitutions at the 3- and 5-positions The best group. (3) Each R1 is independently selected from the group consisting of OH, formazan, CH3.aFa (preferably CF3), 〇CH3.aFa, halo, <:丨. 6 alkyl, NH2, CN, (CHzhdOH or heterocyclic; R1 is selected from the group consisting of: OH, methionyl 'CH3-aFa (preferably CF3), 〇CH3-aFa (preferably OCF3), halo, C丨-4 alkyl (preferably methyl), NH2, CN and (CHzhdOH are preferred; R1 is selected from the group consisting of: OH, formazan, NH2, halo (preferably as a chloro group) or (CH2) oxime · 4ΟΗ Best; (4) Each R2 system Υ-Χ-based, each of which is independently selected from: Ζ- ' -CH=CH-Z- ' -0-Z- ' -C(0)-Z - ' -C(0)0-Z- ' -0C(0)-Z- ' -C(0)-Z-0-Z- ' -0-C(0)-Z-0-Z- ' - sZ-, -S0-Z-, -S02-Z-, -N(R6)-Z-, -N(R6)C0-Z· ' -CON(R6)-Z- ' -N(R6)-C (0)-Z-0-Z- ' -S02N(R6)- -28- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 public love > 1313601 A7 B7 V. Invention description (24 ) Z -, -N(R6)S〇2-Z- or -〇-ZN(R6)-Z, each X is selected from: -Z- ' -CH = CH-Z- ' -O'Z- ' -C(0)-Z- ' -C(〇)〇_2_ , -C(0)-Z-0-Z-,-0-C(0)-Z-0-Z- ' -N(R6 )_Z-, -N(R6) C0-Z-, -N(R6)-C(0)-Z-0-Z- or -0-ZN(R6)·z- is preferred; each X is selected from: • Z_, -CH=CH -Z_, -0_Z-, -C(0)_Z-, _C(0)0.Z·, -c(o)-zoz-, -N(R6)-Z- or -N(R6)C0-Z - more preferably; each X is selected from the group consisting of: -CH=CH-Z-, -0-Z- or -C(0)-Z-optimal; each z-series is independently selected from: direct bond, -(CHJw Or a group of the formula -(CH2)pC(R6a)2-(CH2)q-, wherein R6a| is independently selected from hydrogen and q.4 alkyl: a straight bond, -(CH2)丨2- or formula-( Preferably, the group of CHdp-CiRhhVCHOq- is independently selected from the group consisting of argon and (^.4 alkyl, and p and q are independently 0 or 1; with a direct bond, -CH2- or -C(CH3)2- Better; and each Y series is independently selected from:

Ch6 alkyl, c2_6, aryl-Z1-, heterocyclyl-Z1·, (:3_7 cycloalkyl(CH2)0.2, -(CH2h.4CH3.aFa; each Y is selected from:

Ci.6 tiger base (with a bond cz_6 Hyun "base is preferred, such as isopropyl, isobutyl, etc.), C2. 6 alkenyl, phenyl-Z1- or heterocyclic group -Z1- is preferred; -29 - The paper music scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) " 1313601 A7 ______ B7___ V. Description of invention (25) Each γ is selected from the group consisting of: -CH3, -C2H5, prop-2- Base, isopropyl, methyl-propyl, 2-methyl-propyl, allyl, phenyl, 2-ethyl-butyl, phenyl-Z1-, cyclopropyl-Z1-, cyclodecyl -Z1-, morpholino-Z1-, piperidinyl-Z1-, hexahydropyrryl-Z1-, pyrrolidinyl-Z1-, tetrahydro-2H-pyranyl-Z1-, isotope - Z1-, 嗓 base - Z1-, p than decyl - Z1- ' >» keto-Z1-, thiol-Z1- or isopyrrolidine-Z1- best; each Z1 system Independently selected from the group consisting of: a straight bond, -(CH2)U2 or a group of the formula -(CH2)pC(R6a)2-(CH2)q-, wherein R6a is independently selected from hydrogen and hydrazine "alkyl; - (CHJ^- or a formula of -(CH2)pC(R6a)2-(CH2)q- is preferably selected from argon and Cw alkyl independently, and p and q are independently 0 or 1; Key, -CH2-, -CH2-CH(CH3)- or -(CH2)2- is preferred; with a direct bond, -CH 2- or -(CH2)2- is optimal; wherein each of the above γ is independently substituted by R4. (5) Each R2 is a γ_χ_ group, a z-type direct bond within the definition range of X and Ζ 1 in the definition of Υ - (CH2) pC(R6a)2-(CH2)q- (6) Each R4 is independently selected from halo groups substituted with one or more R5 groups as needed , CH3.aFa (theory is CF3), 〇CH3-aFa (theoretical 〇CF3), CN, (:丨.6 alkyl, OCu alkyl, COOH, qcoocu alkyl, (CH2)0-3 COOH , 〇 (CH2) 0.3COOH, CO-phenyl, conh2, -30- This paper scale is used in the National Standard (CNS) A4 specification (210X297 public) 1313601 A7 ____ B7 __ V. Invention description (26 ) CONH -phenyl, s〇2NH2, S02Ci_6 alkyl, OH or phenyl, wherein R5 is selected from hydrogen, CN6 alkyl or CCCOOCu alkyl; each R4 is selected from halo, CN, CK6 alkyl, OCu Preferably, the base or COOH (7) each R5 is selected from the group consisting of: (^•6 alkyl, phenyl, heterocyclic or c3.7 cycloalkyl; each R5 is selected from:

Ct-6 pit base, tetrahydrofuranyl group, imyl ketone group, isoindole olfactyl group, ρ specific thiol group, Yu dian group, thiophene group, 1,3-benzo benzoic acid, cyclopropyl, cyclobutyl , cyclopentyl or cyclohexyl is preferred; each R 5 is selected from the group consisting of: CH 3 , C 2 H 5 , propan-2-yl, tetra arbitrage, sulphide, sulphate, sigma, p, thiol, *> dense bite group, p-mercapto, 1,3-benzodioxanyl or cyclopentyl is best; (8) each X1 is independently selected from: direct bond, -2-,-0-<;:(0)-2-,-<:(0)-0-2-,-(:(0)-2- ' -N(R6)-C(0)-Z- ' -C(0 )-N(R6)-Z- ' -S(02)-Z- ' -n(r6)so2-z- or -so2n(r6)-z-; Each X1 is independently selected from: direct bond, - Z-, -0-C(0)-Z-, -c(o)-z-, n(r6)-c(o)-z- or -s(o2)-z. preferably; each X1 Independently selected from: straight key, -ch2-, -oc(o)-, -c(o)- '-n(ch3)-c(o)-ch2- or -s(o2)-best: __ -31 -__ This paper size applies to China National Standard (CNS) A4 specification (210X297 public) 1313601 A7 B7

V. INSTRUCTIONS (27) (9) The substituents on R5 are optionally selected from the group consisting of: OH, CN, NH2, Cufe, OCu, or halo; the substituents on R5 are independently selected. From: OH, alkyl, OCm alkyl or halo; preferably, the substituents on R5 are independently selected from the group consisting of: OH 'CH3, tert-butyl, OCH3, chloro or fluoro;

(10) R3 is preferably a heterocyclic group substituted with one or more R7 groups (preferably a nitrogen-containing heterocyclic group); and R3 is preferably a heterocyclic group selected from the group consisting of:

Ν'

-N 0

ρ比呼Ν

Apyrimidine binding pyrazole furan imidazole carbazole isoxazole co < , 吐 〇 密 · 密 bite

〇〇〇〇 'Bow I benzofuran benzophenan benzimidazole DO Benzazaki - 32- This paper scale applies to China National Standard (CMS) A4 specification (210 X 297 public) 1313601 A7 B7 V. DESCRIPTION OF THE INVENTION (28) R3 is selected from the group consisting of: I» plug bite, p-plug bismuth, p-bite bit, B-bike, health p well, p 啥 啥, shout bite, isotazole, furan, benzopyrazole , benzimidazole and benzo. R3 is better; R3 is selected from the group consisting of: P stopper, benzo-11 spit, p-plugin, p-precipitate, 峨11 well, vio-p well, I» 吐吐, 咪 sniff, shout bite, 11 It is preferred to sniff "?丨<»; R3 is selected from the group consisting of: leaf bite, p-sniffing or p-plugging. In a further embodiment of the invention, R3 is selected from the group consisting of: benzene And P plug, "Serma," <» stopper two sniffing, p than this, P than "well, seam 0 well, P than spit, P · dense bite, different" and spit and sputum; (11) R3 is unsubstituted or substituted with one R7 group; (12) Each R7 is independently selected from the group consisting of: OH, CN, NH2, S03, hydration, halo' Cu-based, (:b 6-kilo-OH, O -Ci.6 alkyl, C|.6 cyclyl, halo, (CH2) 〇-3 COOH ' (CH2) 〇.3C(0)OR8 ' (CH2)〇.3NH(CH2)〇.3R8 ' ( CH2)〇.3NHC(0)(CH2)〇.3R8 ' (CH2)〇.3C(0)NH(CH2)〇.3 R8 ' -(CH2)〇.3S(0)〇.2R8 ' -(CH2 〇.3N(R6)S02R8 ' (CHJwCXCONUqsCOhR8 or ((:112)..3 heterocyclic group; R7 is selected from: OH, CN, NH2, S03, thio, halo, C 4 alkyl, Ci_4 Tiger-OH, OC丨.4 alkyl, Cw alkyl-halo, (CHj COOH '(CH2)〇., C(0)〇R8 ' (CH2)〇.iNH(CH2)〇.2R8 ' (CH2)〇.1NHC(0)(CH2)〇.2R8 ' (CH2)〇.1C(0)NH(CH2)〇.2 -33- Paper Zhang scale applies to China National Standard (CNS) A4 specification (210X 297 public love:) 1313601 A7 __B7___ V. Invention description (29 ) R8 ' -(CH2)〇.2S(0)〇.2R8 ' -(CH2)〇 .,N(R6)S02R8 ^ (CHJo.iCCCON (R6)S(0)2R8 or (CHdo-iheterocyclyl (heterocyclyl selected from furanyl, morpholino, 5-oxo-oxadiazole) Preferably, the base or tetrazolyl group is preferred; R7 is selected from the group consisting of: COOH 'C(0)0C, .6^1: '(CH2)〇.1C(0)NH(CH2)〇.2 R8, (ch2 〇_3c(o)nhso2-r8 or (CH2)0_3SO2NHC(O)-Rs is more preferable; R7 is selected from: COOH '0(0)00^6^&il(CH2)〇.1C(0) NH(CH2)〇.2R8 is the best; (13) R8 is selected from the group consisting of: nitrogen, OH, COOH, 0b6, OC^, _C(0)_0_Cu alkyl, CG.6 alkyl 0 (: (0) (^.6 alkyl, alkyl, aryl, heterocyclic or c3.7 cycloalkyl; R8 is selected from: hydrogen '0H, C00H, CH3, isopropyl, 2-A -butyl, pent-3-yl, -C^CH3, -C(0)-0C2H5, -CH2-0-C(0)-CH3, -CH2-0-C(0)-C2H5, -C (CH3)2-0-C(0)-CH3, NH-isopropyl, NH-tert-butyl, N(CH3)-CH3, phenyl, iso Preferably, the carbazolyl, pyrazolyl, pyridyl, fluorenyl, cyclopropyl or cyclobutyl; (14) preferred substituents on H8 are independently selected from the group consisting of: OH, CN, NH2. Halogen or Cu pit base; ____-34-_____ This paper scale is applicable to China National Standard (CNS) A4 specification (210X 297 mm) A7 B7 1313601 V. Invention description (3〇) Better view on R8 Desirable substituents are independently selected from the group consisting of: OH, halo or yl; the more preferred substituents on R8 are independently selected from the group consisting of: OH, chloro, fluoro and CH3. For example, particularly preferred compounds of the invention are those in which: m-system 0 and η-system 2, two R2-based systems are attached at the 2- and 5- or 3- and 5-positions (theoretically 3- and 5-positions). ), and X-〇((:112)..2-(theoretical 〇(:η2-); or m-system 0 and η-system 2, two R2-based systems attached to 2- and 5- or 3- and 5-positions (theoretically 3- and 5-positions), X-system-〇(CH2)〇-2-(theoretically or -OCH-)- and Y-systems are required to have a halogen group ( For example, a fluoro group or a gas group, in theory, a fluoro group or a heart alkyl group substituted benzyl group; or m system 0 and η system 2 * two R 2 groups attached to 2- and 5- or 3- and 5- Position (theoretically 3- and 5-positions), X-form-0(CH2)〇.2-(theoretically -〇- or -OCH2-), and R3 are heterocyclic groups which are optionally substituted with R7 Or m system 0 and η system 2, two R2 groups attached to the 2- and 5- or 3- and 5-positions (theoretically 3- and 5-positions), X-series -0 or -0 (CH2)〇_2- (theoretical is -0- or -OCH2-), Y is a phenyl group which is substituted with a functional group (such as a fluorine group or a chlorine group, theoretically a fluorine group) SCu alkyl group, and R3 is a heterocyclic group which is substituted with R7; or m system 1 and η system 1, R1 and R2 are attached At the 2- and 5- or 3- and 5-positions (theoretically 3 - and 5 - positions), R1 is a halo group (such as a fluoro group, a gas group)' and an X-form - 0 (CH2) 〇.2 - (theoretically - 〇- or -OCHr). According to a further feature of the invention, it provides the following compounds of the invention __-35-____ This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1313601 A7 B7

V. DESCRIPTION OF THE INVENTION (31) Preferred groups: (I) a compound of the formula (I) or a salt, solvate or prodrug thereof

Wherein: X, Z1, R3 and R4 are as defined above in the compound of formula (1); (II) a compound of formula (Ila) or a salt, solvate or prodrug thereof

among them:

Het is preferably a monocyclic heterocyclic group substituted with up to 3 groups selected from R4, and X, Z1, R3 and R4 are as defined above in the compound of formula (1); Lib) a compound or a salt, solvate or prodrug thereof - 36 -

1313601 A7 B7 Description (32)

Wherein: a C1-6 alkyl group is optionally substituted with up to 3 groups selected from R4, preferably substituted; Μ:-6 alkyl optionally includes a double bond 'Ci6 alkyl group to exclude double bonds. , Z丨, R3 and R4 are as defined above in the compound of formula (1); (IV) a compound of formula (lie) or a salt, solvate or prodrug thereof

(Formula 11 c) wherein: a C3,7 cycloalkyl group is optionally substituted with up to 3 groups selected from R4, and X, Z1, R3 and R4 are as defined above in the compound of formula (1); V) a compound of the formula (lid) or a salt, solvate or prodrug thereof - 37- This paper size is applicable to the Chinese Standard (CNS) A4 specification (210 X 29 mm) 1313601 V. Invention Description A7

Alkyl-X, (Formula) wherein: The cU6 alkyl group is independently 7 丄 and is substituted with up to 3 groups selected from R4, and one of the Ci·6 alkyl groups is preferably not substituted.

The Cl.6 environment depends on the need to independently include a double bond group including a double bond, and only one of the 0.6 alkane X, R3 and R4 systems are as defined above in the compound of formula (1) (VI) formula (IIe) a compound or a salt, solvate or prodrug thereof

Wherein: the C3·? ring alkyl group and the Cu alkyl group are independently substituted according to the need, and the C!-6 alkyl group is not substituted. Preferably, up to 3 are selected from R4.

Ci.6 alkyl group needs to include double bond, C!·6 fluorenyl group is not included, and double bond is more than -38 - This paper size is applicable to a @家标准(CNS) A4 specification (210X 297 mm)

1313601 A7 B7 V. INSTRUCTIONS (34) ~- X, Z1, R3 and R4 are as defined above in the compound of formula (1): (VII) a compound of formula (Ilf) or a salt, solvate or prodrug thereof

(Formula Ilf) where:

The Het is a monocyclic heterocyclic group, and it is preferred that only the alkyl group and the alkyl group are independently substituted with up to three groups selected from R4, and the C丨·6 alkyl group is not substituted;

The Cm alkyl group optionally includes a double bond, and the Ci_6 alkyl group preferably does not include a double bond; and X, Z1, R3 and R4 are as defined above in the compound of the formula (1), and the (VII) group compound is more preferable. The group comprises a compound of the formula (IIf), wherein: Het is a saturated monocyclic heterocyclic group; X is -Z-, preferably -CH2-; R4 is a R5-X1- group; and X1 is used in the formula (I) Definition of compound; R5 system 〇: _β alkyl, phenyl, heterocyclic group, each of which is optionally substituted as defined for the compound of formula (I); (VIII) a compound of formula (Ilg) or a salt thereof , Solvate or Prodrug-39- This paper size is suitable for the Chinese Standard (CNS) A4 specification (210 X 297 public) 1313601 A7 B7 I V. Invention description (35)

R3 where:

Het is a monocyclic heterocyclic group; Het and C3.7 cycloalkyl groups are independently substituted as needed, and up to 3 groups selected from the group X, R3 and R4 are as described above in the compound of formula (1) Definition of (IX) a compound of the formula (Ilh) or a salt, solvate or prodrug thereof'

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Wherein: Y is an aryl-Z1- group, wherein the aryl group is partially saturated with a bicyclic carbocyclic ring as desired; and the Y and Cu alkyl groups are independently substituted with up to 3 groups selected from R4 as (:丨.6 alkyl is not substituted; (^.6 alkyl optionally includes double bond, CU6 alkyl does not include double bond than -40-^ paper scale applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) 〉 1313601 A7 B7 5. Inventive Note (36) Good; and X, Z1, R3 and R4 are as defined above in the compound of formula (I); (X) a compound of formula (Ilj) or a salt, solvate or former thereof medicine

Wherein: X is selected from the group consisting of -S02N(R6)-Z- or -N(R6)S〇2-Z-, X is preferably -S02N(R6)-Z-; Z is as described above, Z is It is preferred to extend the propyl group, the ethyl group or the methylene group, and the Z system is preferably a methylene group;

Za is selected from a straight bond or a group of the formula -(CH2)rC(R6a)2_(CH2)q·, and za is preferably selected from a C 2 alkyl group or a straight bond, and is preferably a straight bond; R 6a It is selected from: C丨·4 alkyl or hydrogen, preferably methyl or argon; lanthanide is selected from aryl-Ζ1- or heterocyclic ΖΙ_ΖΙ_; 丫 and ^·6 alkyl are independently required as many as 3 base substitutions selected from R4:

The Cm alkyl group optionally includes a double bond, the Ci.6 alkyl group preferably does not include a double bond, and the Z1, R3 and R4 systems are as defined above in the compound of the formula (1); (XI) a compound of the formula (Ilk) or Its salt, solvate or prodrug-41 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public) 1313601 A7 B7 V. Invention description (37

Wherein: the C3·7 cycloalkyl group is independently substituted with up to 3 groups selected from r4; and X, R3 and R4 are as defined above in the compound of formula (I); in (I) above A more preferred group of the compounds of the invention in any one of the groups of (XI) wherein: X is independently selected from the group consisting of: -0-Z-, S02N(R6)-Z- or ·N(R6)-Z_; Z-type direct bond or -CH2-, Z1 is selected from a straight bond, -CH2-, -(CH2)2- or ch3, (CH2); S, and R3 are as defined above in the compound of formula (I); a compound or a salt, solvate or prodrug thereof. More preferred groups of the compounds of the invention in any of the above groups (I) - (XI) are: wherein R3 is substituted with at least one R7 group (preferably as an R7 group); -42- paper Zhang scale applies to China National Standard (CNS) A4 specification (210X 297 mm) ------

Install a 1313601 A7 -_____ B7 V. Inventive Note (38) R7 System (CH2)0-3NH(CH2)0.3R8, (ch2)0.3n(r6)s(o)2r8 or (CH2)〇-3 a heterocyclic group (based on a 5-methoxy-l, 2,4-tf-di-n-tris- or 4-tetra--5-yl) group; R3, R6 and R8 are as defined above in the compound of formula (I) Definitions; a compound or a salt, solvate or prodrug thereof. The compounds of the invention may be administered in the form of a prodrug. The prodrug may be degraded in vivo to produce a biological precursor of the compound of the invention or a pharmaceutically acceptable compound (such as an ester or guanamine of a compound of the invention, especially Hydrolyzable ester in vivo). Various prodrug forms are known in the art. For examples of these prodrug derivatives, reference is made to: a) Design of Prodrugs (Elsevier, 1985), edited by Bundgaard, and Methods in Enzvmologv, edited by K. Widder et al. 42 pp. 309-396 (Academic Press, 1985); b) A Textbook of Drug Design and Development > edited by Krogsgaard-Larsen c) H. Boudgard "Design and Application of Prodrugs" Chapter 5, pp. 113-191 (1991); d) Advanced·Budgard's "Advanced Drug .Delivery Reviews, and, 1-38 (1992); e) H Boudgard et al., Journai 0f Pharmaceutical Sciences, II, 285 (1988): and f) Ν· Kakeya et al., Chem Pharm Bull, 32., 692 (1984). -43- Paper scale 逋The Chinese National Standard (CMS) A4 is used (210X297 mm> 1313601 A7 - _B7 V. Inventive Note (39) The contents of the above cited documents are incorporated herein by reference. Examples of prodrugs are as follows. Containing carboxyl or hydroxyl groups The ester of the compound of the present invention which is hydrolyzable in vivo Such as a pharmaceutically acceptable ester which is hydrolyzed to produce a parent acid or an alcohol in the human or animal body. Pharmaceutically acceptable esters suitable for the carboxyl group include (^ to <:6 alkoxymethyl ester) Classes (eg, decyloxymethyl), (^ to decane decyloxy decyl esters (eg, pentyloxymethyl), base-branched, c3 to Cs cycloalkoxycarbonyloxy (^ to (6 alkyl esters (for example, cyclohexylcarbonyloxyethyl), 1,3-dioxen-2-one methyl esters (eg ' 5-methyl-i, 3 - Dioxanthene-2-ketomethyl) and (:, .6 alkoxycarbonyloxyethyl esters. The hydrated vinegars containing the compounds of the present invention which are hydrolyzed in the aliquot include inorganic brewings ( For example, phthalic acid esters, including serotonin ring esters and related compounds, which are broken due to ester hydrolysis in vivo, Examples of the oxime: oxime oxyalkyl ethers include ethoxycarbonyl methoxy and 2,2-dimethylpropoxy methoxy. The ester which is hydrolyzable in vivo by the base The choice of forming base includes alkyl sulfonyl and benzene. Styrene, phenylethylhydrazine and substituted phenylhydrazine with phenylethylhydrazine, oxycarbonyl (to give alkyl carbonate), dialkylamine sulfhydryl and hydrazine-(dialkylamine Alkyl)-fluorenyl-alkylaminecarbamyl (to give urethanes), dialkylaminoethyl fluorenyl and carboxyethyl fluorenyl. Suitable pharmaceutically acceptable salts of the compounds according to the invention are, for example, the acid addition salts of the compounds according to the invention, which are of sufficient nature, for example, to have, for example, inorganic or organic acids (for example, sulphuric acid, argon bromate, sulphuric acid) An acid addition salt of phosphoric acid, trifluoroacetic acid, citric acid or maleic acid. Further, the benzo is the present invention. No. -44 - t paper size 4 using Chinese national standard (CNS^A4 specification (210 X 297 mm) ~ ' 1313601 A7

Suitable pharmaceutically acceptable salts of phase derivatives have a sufficiently acidic metal salt (for example, sodium or salt), a soil metal salt (for example, about or a slow salt), a salt or a physiologically acceptable salt. An organic residue salt of an acceptable cation (e.g., a salt having a methylamine, dimethylamine, trimethylamine, piperidine, morpholine or cis-(2.hydroxyethyl)amine). Further features of the present invention comprise a pharmaceutical combination of a compound of formula (1) to (10) or (II) to (Ilk) as defined above, or a salt, solvate or prodrug thereof, together with a pharmaceutically acceptable diluent or carrier. Object,

According to another aspect of the present invention, there is provided the use of a compound of the formula (Ib) to (Id) or (II) to (nk) as defined above as a medicament, the prerequisite being the R-based 2-pyridyl group and the X- When not, -C(0)-Z-0-Z-, C(0)-Z-0-Z· or -0-ZN(R6)-Z-, it is impossible to select from c〇〇H or C(0)〇Ci_6炫; a radical R7 group at the 4 position to monosubstituted r3 β further according to the invention, which provides a compound of formula (Ib) to (Id) or (ΙΙ) to (IIk) for use in preparation Use of a medicament for treating a disease modulated by GLK, particularly type 2 diabetes. It is suitable to formulate the compound into a pharmaceutical composition for use in this manner. According to another aspect of the present invention, there is provided a method of treating a disease (especially diabetes) modulated by GLK, in an effective amount of a compound of formula (lb) to (Id) or (II) to (Ilk) or Salt 'solvates or prodrugs are administered to mammals that require such treatment. Specific diseases that can be treated with the compounds or compositions of the invention include: decreased blood glucose (and efficacy of type 1), dyslipidemea, obesity, islets - in type 2 diabetes without a risk of severe hypoglycemia - 45- The paper size is the common Chinese national standard (CNS) A4 specification (210 X 297 mm) 1313601 A7 Γ_______Β7______ V. Description of invention (41) Impedance, X metabolism syndrome, glucose tolerance. As discussed above, the GLK/GLKRP system can therefore be interpreted as a potential '>diabetic obesity" target (both beneficial to diabetes and obesity). Thus, according to another aspect of the present invention, there is provided a compound of formula (lb) to (Id) or (II) to (Ilk) or a salt, solvate or prodrug thereof for use in the combined treatment or prevention of diabetes and obesity The use of the agent. According to another aspect of the present invention, there is provided a use of a compound of the formula (Ib) to (Id) or (to (Ilk) or a salt, solvate or prodrug thereof for the preparation of a medicament for treating or preventing obesity. A further aspect of the present invention provides a method for the combined treatment of diabetes and obesity in an effective amount of a compound of formula (Ib) to (Id) or (π) to (Ilk) or a salt, solvate or prodrug thereof Administration of Mammals in Need of Such Treatment According to a further aspect of the present invention, there is provided a method of treating obesity by administering an effective dose of a compound of the formula (Ib) to (Id) or (11) to (nk) Or a salt, solvate or prodrug thereof is administered to a mammal in need of such treatment. The composition of the invention may be suitable for oral use (for example, as a tablet, an elixir, a hard or soft capsule, an aqueous or oily suspension, an emulsion) , dispersible powders or granules, syrups or elixirs), topical use (for example, as a cream, ointment, gel or aqueous or oily solution or suspension), inhalation (for example, as a fine powder or liquid spray) Agent To be administered by insufflation (for example, as a finely divided powder) or parenterally (for example, as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular administration or as a suppository for rectal administration). -46-

1313601

V. INSTRUCTION DESCRIPTION (42) The compositions of the present invention can be obtained in a conventional manner using conventional pharmaceutical excipients well known in the art. Compositions intended for oral use may include, for example, - or a plurality of coloring agents, sweeteners, flavoring agents, and/or preservatives. Pharmaceutically acceptable excipients suitable for tableting include, for example, inert diluents (such as lactose, carbonated, calcium phosphate or carbonated), granulating or disintegrating agents (such as corn starch or alginic acid), binding agents ( Such as starch), lubricants (such as stearic acid money, hard acid or talc), preservatives (such as _ (tetra) benzoic acid or vinegar) and antioxidants (such as ascorbic acid). The tablet formulation may be uncoated or coated, or may be modified for its disintegration in the gastrointestinal tract and subsequent absorption of the active ingredient, or to improve its stability and/or appearance, in either case, Known coatings and procedures are well known in the art. The composition for oral use may have a hard capsule form in which the active ingredient is mixed with an inert solid diluent (for example, calcium carbonate, potassium phosphate or kaolin) or becomes a soft capsule type in which the active ingredient is combined with water or oil ( Such as peanut oil, liquid stone or olive oil. Aqueous suspension & usually consists of fine powder type #"active ingredient with one or more suspending agents (eg, methyl cellulose, methyl cellulose, propyl methyl cellulose, sodium alginate, polyethylene cyclopyridine) Ketones, tragacanth and gum arabic), dispersing or wetting agents (such as squamose or concentrated products of deuterated oxygen and lipids (iv) (for example, polyoxyethylene stearate), or ethylene oxide and long a concentrated product of a chain fatty alcohol (for example, heptahexadecyloxyhexadecanol) or a concentrated product of ethylene oxide and a part derived from a ruthenium acid-proof and hexitol (eg, polyoxyethylene yam Alcohol monoethyl ester), or an aqueous suspension of ethylene oxide with a partial ester product derived from fatty acid and hexitol anhydride (such as poly-ethyl sorbitan monooleate) a-47-

1313601 A7 B7 V. INSTRUCTIONS (43) may include one or more preservatives (such as ethyl p-hydroxybenzoate or propyl), hydrazine oxidizing agents (such as ascorbic acid), coloring agents, flavoring agents and/or sweeteners ( Such as sucrose, saccharin or aspartame). An oily suspension can be formulated by suspending the active ingredient in a vegetable oil (such as peanut oil, olive oil, sesame oil or coconut oil) or a mineral oil (such as liquid stone). The oily suspensions may also include thickening agents (e.g., beeswax, hard paraffin or cetyl alcohol). Sweetening agents (such as those listed above) and flavoring agents can be added to provide an oral preparation. These compositions can be preserved by the addition of an anti-oxidant such as ascorbic acid. Dispersible powders and granules suitable for the preparation of aqueous suspensions by the addition of water usually together comprise the active ingredient together with dispersing or wetting agents, suspending agents and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are illustrated by way of example of the above-mentioned reagents. Additional excipients such as sweetening, flavoring, and coloring agents may also be present. The pharmaceutical compositions of the present invention may also be in the form of an oil-in-water emulsion, and the oil phase may be a vegetable oil such as olive oil or peanut oil or a mineral oil such as, for example, liquid paraffin or a mixture of any of these. Suitable emulsifiers may be, for example, naturally occurring gums such as acacia or tragacanth, naturally occurring scales such as soy beans, lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides (for example, A sorbitan monooleate and a concentrated product of the partial ester and ethylene oxide (eg, polyoxyethylene sorbitan monooleate). The emulsifier may also include a sweetener, a flavoring agent, and a preservative. It can also be used as a sweetener (such as glycerin, propylene glycol, sorbitol, aspartame or sucrose) to prepare syrups and tinctures, and can also include sedatives and preservatives. Seasoning-48-1 This paper scale applies to Chinese national standards. (CNS) A4 specification (210 X 297 public) 1313601 A7 __B7 V. Invention description ("""^4~) " - agent and / or colorant. Pharmaceutical composition can also be sterile injectable The aqueous or oily suspension form may be formulated according to the known use of one or more of the appropriate dispersing agents or wetting agents and suspending agents mentioned above. Sterile injectable preparations may also be in non-toxic parenteral Acceptable diluent or solvent An injectable solution or suspension of bacteria, for example, a solution in 1,3-butanediol. The composition for administration by inhalation may have a conventionally formulated pressurized spray form to dispense a spray containing finely divided solids or The active ingredient of the drip. A conventional spray propellant (such as a volatile fluorinated hydrocarbon or hydrocarbon) and a convenient spray device can be used to dispense the metered active ingredient. See pergain〇n publishing

Comprehensive Medicinal Chemistry, Volume 5, Chapter 25.2 (1990) (Corwin Hansch; chairman of Editorial Board). The amount of active ingredient to be combined with one or more excipients will necessarily vary depending on the host to be treated and the particular route of administration to produce a single dosage form. For example, a formulation that is intended to be administered orally to an animal will generally comprise an appropriate and expedient amount of excipient (which may vary from about 5% by weight to about 98 Å per gram of total composition), for example from 〇. 5 mg. Up to 2 grams of active agent. Unit dosage forms typically comprise from about 1 mg to about 500 mg of active ingredient. For more information on the route of administration and dose intake, the reader is referred to Chapter 25.3 (1990) of Pergamon Press, Comprehensive Medicinal Chemistry, Volume 5 (Calvin Hansha; Editorial Board). According to well-known medical principles, for the purpose of treatment or prevention (〗), -49- This paper scale applies to the Chinese Standard (CNS) A4 specification (210 X 297 mm) 1313601 A7 B7 V. Description of the invention ( The dose size of the (la), (lb), (ic) or (Id) compound will naturally vary depending on the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration. For use in therapy or prevention In the case of a compound of formula (I), (la), (lb), (Ic) or (Id), it is usually administered in a daily dose ranging from 5 mg to 75 gram per kilogram of body weight, if necessary The drug is administered in multiple doses. When the parenteral route is used, it is usually administered in a lower dose. Therefore, for example, a dose of, for example, 5 mg to 3 mg per kg body weight is usually used. It is administered intravenously. For example, a dose ranging from 0.5 mg to 25 mg per kg of body weight is used for administration by inhalation. However, it is preferred to administer the drug by oral administration. The GLK activity as described herein can be used as the sole therapeutic method. Or One or more other substances and/or treatments other than the subject matter of the present invention may be achieved by administering the individual therapeutic components simultaneously, sequentially or separately. The treatment may be a single tablet or a separate tablet. For example, in the treatment of diabetes, chemotherapy can include the following major therapeutic categories: 1) insulin and insulin homologs; 2) insulin secretagogues, including sulfonyl ureas (eg, glibenclamide) , glitizide (gUpizide) and dietary glucose tincture (for example, repagHnide 'nateglinide); 3) insulin sensitizers, including ppARg agonists (eg pioglitazone (pioglitazone) ) and vistaglitazone (r〇sigijtaz〇ne): -50- This paper scale is suitable for @g家标准(CNS) ΜSpecifications (_ χ 297 public)

Packing % 1313601 A7 _____ B7 V. INSTRUCTIONS (46) 4) Reagents for suppressing hepatic glucose output (for example, metfom (minf〇rmin)); 5) reagents designed to reduce glucose absorption in the intestine (for example, Acarbose): 6) Reagents designed to treat complications of long-term hyperglycemia; 7) Anti-obesity agents (eg, sibutramine and orlistat); 8) anti-dyslipidaemia agents, such as HMG_c〇A reductase inhibitors (statins), for example, pravastatin (pravastatin), ppARa agonists (fibrates), for example, Gemmibrozil) 'Bile acid extract (cholestyramine), cholesterol absorption inhibitor (phytosterol, synthetic inhibitor), bile acid absorption inhibitor (IB ATi) and niacin and homologous (nicotinic acid and sustained-release formulations); 9) antihypertensive agents, such as cold blockers (eg, amine 〇1〇1, inderal), ACE inhibitors ( For example, lisinopril, calcium antagonists (for example, nifedipi (nifedipi) Ne)) ' Blood stimulators (eg, candesartan), alpha antagonists, and diuretics (eg, furosemide 'benzthiazide'); 10 Hemostasis regulators (such as antithrombotics, activators of antifibrinolytic agents and antiplatelet agents), thrombin antagonists, factor Xa inhibitors, factor Vila inhibitors, antiplatelet agents (eg, aspirin) (aspirin), clopido (cl〇pid〇grel), anticoagulant (heparin and low molecular weight homologue, hirudin) and warfarin (warfarin): and -51 - this paper scale common Chinese country Standard (CNS) A4 size (210 X 297 mm) ~~~

装 1313601 A7 _____________B7 V. INSTRUCTIONS (47) Agents such as non-steroidal anti-inflammatory drugs (eg, aspirin) and 'alcohol anti-inflammatory agents (eg, cortisone). Another aspect of the invention is provided by the following examples - the individual compounds produced for the cockroach and their salts, solvates and pre-a can be any known to be suitable for the preparation of these compounds or structurally related Method of Compounds The compounds of the present invention or salts thereof are prepared. These methods are exemplified by the following representative equations (paths 18), where no (iv) basis has any meaning of definition (1) unless otherwise stated. The functional group can be protected by a conventional method. For examples of M protecting groups (such as amine groups and carboxylic acid protecting groups) and methods of formation and final deprotection, refer to T. W, Greene, and p GM Uz (John Wiley & Sons, New York City). Wuts) Second Edition of "protective Gr〇ups in 〇rganic Synthesis" (1991). Concentration of the acid with a heterocyclic amine (path 丨) β in the preparation of the compound of the invention and the intermediate to be the final product. Then one or more reactions can be carried out on these intermediates (eg ester hydrolysis, path 2 &; and 2b). Preferably, the indoleamine forming reaction is carried out via mercapto chloride, which is often prepared using grasshopper gas (path 1). However, it is also possible to use an alternative method to form mercapto chloride (e.g., triphenylphosphine combined with tetra-carbonated carbon and dioxane). In addition, alternative methods can be used to form a guanamine bond (e.g., a peptide coupler (e.g., EDC or HATU) with or without an additive such as DIPEA or DMAP). The remaining preparative routes (paths 2-18) contain further processing of compounds having a guanamine bond in place. More preparation paths are summarized in the path 19--52- This paper scale is used in the national standard (CNS) A4 specification (210 X 297 mm) 1313601 V. Invention description (48) A7 B7

29. An example of a path is provided in the examples below. The reagents and conditions provided are for illustrative purposes only and alternative methods can generally be used. Path 1

1 (C〇ci) 2 -- H CHjjCIj (i) Other indole forming reactions include: la: grassy chlorine in the presence of a suitable solvent or base; lb: coupling agent in the presence of a suitable solvent or base , such as haTU or EDAC; and lc: POCl; / pyridine, according to Dirk T. s. Rijkers, Hans P. Η. 阿 Adams, Η Coenraad Hemker, Godefridus I. Tesser Tedrahedron, 1995, 51 (41) 1 1235-11250.

Path 2a and 2h NaOH

THF/H20

This paper is suitable for China National Standard (CNS) A4 specification (210 x 297 mm) 1313601 A7

This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1313601 A7 B7

装

1313601

This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1313601 A7 B7

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

1313601 A7 B7 V. Description of invention (53 path 15 〇

N N NH2 Η

A1 path 16

Ml

^CN—Path 17

CN

n-OH

Path lg 〇

Path 19:

O

o x0 < , s, /0

O \〇

-58-This paper wave scale applies to China National Standard (CNS) A4 specification (210 x 297 mm) 1313601 A7 B7

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

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I 1313601 A7 B7

1313601 A7

V. Description of the invention (56) Path 28:

The synthesis of the compound of formula (I) provides the improved properties of the present invention. Thus, in accordance with a further aspect of the present invention, there is provided a process for the preparation of a compound of formula (I) which comprises: (a) reacting a compound of formula (Ilia) with a compound of (Illb) (R, L (called a compound) Mb): or where X1 is abandoning the base; -61 -

1313601 A7 B7 V. INSTRUCTIONS (57) (b) Deprotection of a compound of formula (IIIc) in which compound r (_ChCh)0.3COOH is substituted

Wherein the P1 is a protecting group; (c) a compound of the formula (I) wherein the η system 1, 2, 3 or 4 is reacted with a compound of the formula (Hid) and a compound of the formula (Ille)

R3 compound (me) Y—X" Compound (md) wherein X· and X" contain groups which form a sulfhydryl group when reacted together; (d) where η is 1 ' 2, 3 or 4 and X or X1 A compound of the formula (I), which is a compound of the formula (I), wherein the X or X1 system is -SZ-; Reaction with (Illg) compound -62-

1313601 A7 B7 V. Description of invention (58)

(R,)m mn x-r3 compound (IHf) compound (EUg); or wherein X2 is a leaving group; and, if necessary, i) converting a compound of formula (I) to another compound of formula (I); Remove any protecting groups; iii) form salts, prodrugs or solvates thereof. The specific reaction conditions for the above reaction are as follows: Method a) - as explained in Route 1) above; Method b) - as explained in Route 2) above; Method c) - Examples of the method are as follows: (0 Formation base 'When X -0-Z-, X'-based HO-Z-based and X" when leaving the base (or X'-based L2-Z-based 'where L2 is a leaving group and X" is a hydroxyl group), then The compound of the formula (Illd) and (Ille) is reacted in a suitable solvent (such as DMF or THF) with a base (such as sodium hydride or tert-butanol) at a temperature ranging from 〇 to 1 〇〇. Use a metal catalyst (such as palladium or cuprous iodide on carbon) as needed; (ii) form a base 'when X is N(R6)-Z-, X' is a group of H-(R6)NZ- And X" is the basis for the abandonment of the base (or the base of the X' series L2-Z-, where the L2 is the abandonment base and the X"--the base of the formula -N(R6)-H), then the formula (Illd) and (nie )合合-63- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm)

Binding

Line 1336061 A7 !_______B7 V. Description of the invention (59) Use a reducing agent (such as sodium cyanoborohydride or sodium triethoxysulfonate) in a suitable solvent (such as THF, alcohol or acetonitrile) at room temperature Reacting together; ((1)) forming a base 'when X system _S02N(R6)-Z-, X, a group of formula HN(R6)-Z- (wherein L2 is a leaving group) and X" activated sulfonyl group (as in the case of the formula _s〇2_a), then the compound of the formula (Illd) and (Ille) in a suitable solvent (such as dichlorosilane, THF or pyridine) in the presence of a base (such as triethylamine or Pyridine) reacts together at room temperature; (iv) forms a group, when ^f, -N(R6)s〇2_z_, a sulfonyl group activated by a ruthenium system (such as a group of formula C1-S02-Z-) and X&quot Where the formula -N(R6)-L2- is a group (wherein the l2 is a leaving group), the compound of the formula (Illd) and (Ille) is in a suitable solvent (such as dichlorosilane, THF or pyridine). In the presence of a base (such as triethylamine or pyridine), react together at room temperature; (V) form a group, when X is _c(o)N(R6)-z-, X, is a formula HN(R6)- Z-based (where L2 is a leaving group) and X" is an activated carbonyl group (eg, In the presence of a compound of the formula (Illd) and (Ille) in a suitable solvent (such as THF or a mortar) in the presence of an assay (such as triethylamine or p-precipitate) in the chamber Reacting together at a temperature; (vi) forming a group, when X-N(R6)C(0)-Z-, X, an activated condensate (such as a group of formula C1-C(0)-Z-) and X"---(N6)-L2_ (wherein L is a leaving group), then formulating (nid) and (Ille) compounds in a suitable solvent (such as THF or dichloromethane) in an alkali In the presence of (such as triethylamine or pyridine) react together at room temperature; (vii) form a group, in the X system - CH=CH-Z-, then you can use the Zhang Taige-64- paper scale for China Standard (CNS) A4 size (210X 297 mm)

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1313601 A7 B7 V. Inventive Note (6〇) (Wlttag) reaction or Wadsworth-Emmans Horner reaction. For example, 'the aldehyde group and the γ·χ" phosphine derivative of the formula YC Η-Ρ+ΡΗ3 can be used in a strong base (such as sodium hydride or potassium butoxide) and in a suitable solvent ( For example, THF) is reacted together at a temperature between room temperature and 100 °C. Process d) - It is well known in the art that the oxidation of a compound of formula (j) wherein χ or χ, _ s — z ·, for example, the reaction with m-hydroxyperbenzoic acid (MCpBA) is at room temperature In the presence of a suitable solvent (e.g., dichloromethane), if an excess of MCPBA is used, a compound of formula (1) wherein lanthanide s(〇2)_ is obtained is obtained. Method e) - The compound of formula (Inf) and formula (nig) can be carried out in a polar solvent (such as DMF) or a non-polar solvent (such as THF) and at a temperature between 0 and 1 °C. For the reaction of a strong base such as sodium hydride or potassium t-butoxide, a metal catalyst (such as a hardened or molybdenum) is used as needed. During the preparation process, it is preferred to use a protecting group that protects the functional groups in R2. The protecting groups can be removed in a convenient manner, as described by the literature or by methods known to the skilled chemist, suitably removing the protecting groups in question, which are selected to have the least number of bases in order to accomplish removal. The protection base of the obstacles. For the sake of convenience, a specific example of a protecting group is provided below, wherein, "low carbon" means that the base thereof is applied to have 1 to 4 carbon atoms. "It should be understood that these examples are not unique" Specific examples of methods for protecting groups 'These are also not unique. The use and deprotection of protecting groups not specifically mentioned are of course within the scope of the invention. Carboxyl protecting groups may be ester-forming aliphatic or araliphatic groups Alcohol or ester forming bite-65- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1313601 A7 Γ_______ Β7 V. Description of invention (61) Alkanol residue (the alcohol or stanol It is preferred to include 20 carbon atoms. Examples of the carboxy protecting group include a linear or branched (1 - 12C) alkyl group (for example, isopropyl 'tert-butyl), a lower alkoxy a lower alkyl group. (eg, methoxymethyl, ethoxylated, isobutoxymethyl), lower aliphatic decyloxy lower alkyl (eg 'ethyloxymethyl, propyloxymethyl) , butyl oxymethyl, pentyloxymethyl), lower alkoxy Olelow lower alkyl (for example, methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl), aryl lower alkyl (for example, p-nonyloxy fluorenyl) Sulfhydryl, p-nonindolyl, diphenylmethyl and fluorenyl), tris(lower alkyl)carboxyalkyl (for example, trimethylmethanyl and tert-butyldimethylformamidin), three (lower alkyl)carbenyl lower alkyl (for example, trimethylcarbamidoethyl) and (2- 6C)alkenyl (for example, decyl and vinyl ethyl). Particularly suitable for removal The method of protecting the carboxy group includes, for example, acid-, metal- or enzyme-catalyzed hydrolysis. Examples of the base protecting group include a low-alkenyl group (e.g., propyl) 'low-decane fluorenyl group (e.g., acetamidine) a lower alkoxycarbonyl group (for example, a tetrabutoxycarbonyl group), a lower carboxycarbonyl group (for example, a fluorenyloxycarbonyl group), an aryl lower alkoxycarbonyl group (for example, a benzoquinoneoxy group) Carbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nonanoyloxycarbonyl), tripocarboalkyl/arylcarbenyl (for example, tridecyl)矽alkyl, tert-butyldimethylformamidinyl, tert-butyldiphenylmethanealkyl), aryl lower alkyl (for example, benzyl) and triaryl low carbon (for example, triphenyl Examples of the amine protecting group include a aryl group and an aryl group (for example, a aryl group and a substituted group, for example, a p-nonoxyl group, a nitrite group, and a 2,4-dimethoxy group). -66 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1313601 A7 B7 V. Description of invention (62) Benzyl and triphenylmethyl) 'di-p-anion Methyl and fluorenylmethyl 'lower alkoxycarbonyl (eg, tert-butoxycarbonyl), lower carboxyoxycarbonyl (eg, allyloxycarbonyl), aryl lower alkoxycarbonyl ( For example, a decyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group, an o-nitroxyloxycarbonyl group, a p-nitrobenzyloxycarbonyl group, a trialkylcarbenyl group (for example, a trimethylcarbinyl group and Tert-butyl dimethyl mercaptoalkyl), alkane (eg, methylidene), benzylidene, and substituted gems. Suitable methods for removing hydroxyl and amine protecting groups include, for example, acid-, base, metal- or enzyme-catalyzed hydrolysis, or photolysis of groups such as o-nitrobenzyloxycarbonyl or Fluoride ion for formamyl. Examples of the protecting group of the indenyl group include an aralkoxymethyl group (for example, a decyloxymethyl group and a substituted decyloxymethyl group), an alkoxymethyl group (for example, a methoxymethyl group and a trimethyl group). Methyl decyl ethoxymethyl), trialkyl / aryl carboxyalkyl (for example, trimethyl methoxyalkyl 'tert-butyl dimethyl decyl, tert-butyl diphenyl carboxyalkyl) , a trialkyl/arylmethyl alkoxymethyl group (for example, tert-butyldimethylmercaptooxymethyl, tert-butyldiphenylcarbamoyloxymethyl), 4·alkoxyphenyl (eg, 4-methoxyphenyl), 2,4-di(alkoxy)phenyl (eg '2,4-bis(methoxy)phenyl), 4-alkoxythio (eg eg , 4-methoxyindenyl), 2,4-di(alkoxy)indenyl (for example, 2,4-di(methoxy))) and indol-1-yl (for example, allyl) , D- 1 - anthracenyl and substituted ethyl fluorenyl, for example, 2-phenylvinyl). An aralkoxymethyl group can be introduced on the guanamine group by reacting the guanamine group with a suitable saponin methyl gas and removing it by catalytic nitridation. Can be cited -67- This paper scale applies to Chinese National Standard (CNS) Α4 specification (210 X 297 mm) 1313601 A7 _____ B7 V. Description of invention (63) Alkoxymethyl, dialkyl/aryl decane And a trialkyl/carbomethoxymethyl group which is reacted with a suitable chloride and removed with an acid, or in the case of a f-alkyl group, with a vapor ion. It is suitable to introduce an alkoxyphenyl group and an alkoxybenzyl group which are removed by arylation or alkylation of a suitable dentate and oxidation by ceric ammonium nitrate. Finally, a cation-based group can be introduced which is reacted with an appropriate chain and removed with an acid. The following examples are for illustrative purposes and are not intended to limit the scope of the application. Each of the compounds illustrated by way of example represents a particular and independent point of view of the invention, in the following non-limiting examples, unless otherwise stated: (1) evaporation by rotary evaporation in the true 2, and Performing the finishing step after removing residual solids (such as desiccant) by hydrazine; (Π) operating at room temperature (ie, in the 18 rc range) and under an inert gas (such as ammonia or nitrogen); (III) The proposed yield is only exemplified and &, and it is not necessary to obtain the maximum amount; (IV) to confirm the structure of the final product of (1) I by means of magnetic resonance (NMr) and mass spectrometry techniques; The proton magnetic resonance chemical drift value is measured on a scale of 5, and the peak number of the peak is expressed as follows: s, singlet peak; d, doublet; t, triplet; m, multiple $; br, broad peak; q, four Qun; quin, quintuple; (v) hangs incompletely describes the characteristics of the intermediate and is characterized by thin layer chromatography (TLC), high performance liquid chromatography (HpLc) 'infrared (IR) or NMR Analyze its purity: -68-

1313601 A7 B7 V. INSTRUCTIONS (64) (vi) Chromatography on silica gel (Merck 60, 0.040-0.063 mm, 230-400 mesh); and (vii) Biotage匣 represents the UK Pre-filled cerium oxide (from 40 grams up to 400 grams) from Biotage UK, Hertford, Herts, was dissolved using a biotage dish and fraction collector system. Abbreviation ADDP azodicarbonyldipiperidine; DCM dichloromethane; DEAD diazodicarboxylate; DIAD diazo azodicarboxylate; DIPEA diisopropylethylamine; DMSO dimethyl hydrazine DMF dimethylformamide; DtAD di-tert-butyl azodicarboxylate; EDAC/EDC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; HATU 0-(7-azabenzotriazol-1-yl)-N,N,N,,N'-tetramethylhexafluorophosphate pulse; LCMS liquid chromatography/mass spectrometry; MPLC Medium pressure liquid chromatography; RT room temperature: and THF tetrahydrofuran. General procedure for alkylation of mono- and di-hydroxy benzoate: The following general alkylation process is illustrated in the following examples. -69- This scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1313601 A7 B7

Synthetic effect of general method A-symmetric dynamite mi = R2)

Oc〇 compound (a). Dissolve methyl 3,5-dihydroxybenzoate (74.1 g, 0.44 mol) in dimethylformamide (400 ml) and add potassium carbonate (152 g, 1.1 〇 mo The ear was stirred for 15 minutes, then 2-chlorobenzyl chloride (117 mL, 0.92 mol) was added and heated at 1 °C under argon. After 3 hours, the reaction mixture was cooled to EtOAc EtOAc EtOAc. The organic extract was washed with brine (3 mL), dried (MgSO4), filtered, and concentrated in vacuo to give a color oil, which was triturated with diethyl ether/isohexane to give a white solid. Compound (a) (195 g, 1 〇〇〇/0); nmr (d6-DMS 〇5 value): 3.81 (3H, s); 5.18 (4H, s); 6.98 (1H, m); 7.16 (1H) d); 7.36(4H, m); 7.50(2H, m); 7.58(2H, m) < ' jlJ method B - synthesis of asymmetric diterpenoids (R1 = /R2) -70- paper Zhang scale applies Chinese National Standard (CNS) A4 specification (210X297 mm) 1313601 A7 B7 V. Invention description (66)

OMe

Compound (b) Methyl 3,5-di-perbenzoic acid (16.8 g, 0.1 mol) was dissolved in dimethylformamide (180 ml), and powdered potassium carbonate (27.6 g, 0.2 mol) was added. Then, 2-iodopropane (1 mL, 〇.1 mol) was added, and the resulting suspension was stirred overnight at room temperature under argon. The reaction mixture was diluted with water (1 liter) and EtOAc (EtOAc) The organic extract was washed successively with water and brine, dried (MgSOO, filtered and concentrated in vacuo to give a pale gold oil) which was then wet-milled with toluene and filtered to remove unreacted hydrazine starting material. Concentrate in vacuo and the residue was chromatographed (2 x 90 g of Biotage EtOAc, eluted with ethyl acetate in isohexane (1% by volume/volume to 15% vol/vol)) to give a colorless solid. 3-Hydroxy-5-isopropoxyphenyl decanoate (5.3 g, 25%); 4 nmr (d6-DMSO, 5): 1.2 (6H, d); 3.8 (3H, s); 4.6 ( 1H, hept); 6.55 (1H, m); 6.85 (1H, m); 6.95 (1H, m); 9.8 (1H, s). Methyl 3-hydroxy-5-isopropoxybenzoate (1.5 G, 7.2 mmol) dissolved in dimethylmethamine (10 ml) 'added potassium carbonate (25 g, is redundant)' followed by 2 - xidinidine (1.2 ml, 11 mmol) And the resulting suspension was stirred at 80 ° C under argon for 7 hours. The reaction mixture was cooled to room temperature 'diluted with hexane / ethyl acetate (1:1 volume / volume), and continuously -71 - the paper scale With China National Standard (CNS) A4 size (210X 297 mm)

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V. INSTRUCTIONS (67) Washing water and brine, drying (MgS04), filtering and concentrating in vacuum to produce a colorless oil, which is separated by chromatography (flash column on silica gel (2 gram) 'Dissolved in isohexane (5% by volume/volume) containing ethyl acetate) to obtain 3, (2-butoxy)-5-isopropoxybenzoic acid methyl ester (1·06 g) as a colorless oil; 'H nmr (d6-DMSO, d value)·· 0.9(3H,t); 1.2(3H, d+6H, d); 1.6(2H, m); 3.85(3H, s); 4.4(1H, hept 4.55(1H, hept); 6.7(1H,m); 7.0(2H,m); m/z 267(M+H)+. Synthesis of i〇l_method C_-asymmetric diethers (R1 = /R2):

Compound (c) Methyl 3-hydroxy-5-isopropoxybenzoate (0.5 g, 2.4 mmol) was dissolved in dichloromethane (10 mL) and cooled to EtOAc. (:, while stirring under argon) The solution was continuously fed with triphenylphosphine (supported by polymer, 1.19 g '3.6 mM) sterol (0.23 ml, 2.7 mmol) and dihalo methane added dropwise ( Treatment with di-tert-butyl azodicarboxylate (DtAD, 0.082 g, 3.5 mmol) in 4 mL), and stir the resulting solution for 1.5 hours. Monitor the reaction with hplc and add more reagents until the starting phenol is consumed. The total reagents added were triphenylphosphine (supported by polymer, 2.38 grams, 3 equivalents), decyl alcohol (0.53 ml '2:5 equivalents) and DtAD (1.64 grams, 3 equivalents). The reaction mixture was placed in vacuum paper. Scale applicable @国标准(CMS) A4 specification (210 X 297 mm) 1313601 A7 B7

In the middle concentration and chromatographic separation method (flash column on silica gel, dissolved in isopropyl acetate (5% by volume/volume)) to obtain 3-(poly) Methyl 2-furylmethoxy)-5-isopropoxybenzoate (〇22^g); iHnmr^-DMSOJ value factory [25(6^d); 3.85(3h,s)A. 4.65(1H , hept); 5.1 (2H, s); 6, 45 (1H, m); 6 6 (ih, two ' 6.85 (1H, m); 7.05 (1H, m); 7.15 (1H, m); 75(ih m). General method D-Asymmetric diether synthesis:

Compound (d) Diisopropyl azodicarboxylate (DIAD, 0.74 ml, 3.7 mmol) was added to hexane (3 eq.) in DCM (40 mL). -methanol) methyl benzoate (0.56 g, 2.5 mmol), triphenylphosphine (〇 98 g, 3,7 mmol) and 2-fluorophenol (〇.24 ml, 27 mmol) . After 1 min, it was concentrated and purified on EtOAc (EtOAc EtOAc (EtOAc). 90%); A NMR <5 (d6-DMSO): 1.26 (d, 6H), 3.82 (s, 3H); 4.64 (m, 1H); 5.21 (s, 2H); 6.92 (m, 1H); 7.09(m, 1H); 7.16-7.26(m, 3H); 7.35(s, 1H); 7.58(s, 1H) · The above general method is only used as an example. It should be confirmed that this paper scale is applicable to China. National Standard (CNS) A4 Specification (210 X 297 mm) 1313601 A7 B7 Five Invention Notes (69) Alternative conditions used include: use of alternative solvents (such as acetone or tetrahydrofuran), alternative reagent stoichiometry, alternative reaction temperatures and Alternative purification methods β All analytical data (NRM and/or MS) are consistent with the proposed structure. Road_Disc 1: 2·-[3,5-di-(2-1 benzyl benzyl sulfoxide) phenyl hydrazine 1 肱摹 嗾 carbazole

Diisopropylethylamine (DIPEA, 0.34 mL, 2.0 mmol) followed by Ν, Ν-dimethylamino p-bite (DMAP '12 mg, 〇.1 mmol) in argon 2-A-based p-plug (〇, 1〇g, 1.0 mmol) and 3,5-di-(2-carbylmethoxy)benzene added to a lactine (10 ml) under Jaa A solution of formic acid gasification (0.42 g, 1.0 mmol). After 8 minutes, the reaction mixture was filtered <~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (4H, s); 6.93 (1H, d); 7.26 (1H, d); 7.36- 7.43 (6H, m); 7.50 (2H, m); 7.55 (1H, d); 7.61 (2H, m); 12.60 (IH, br s). Alternative conditions that may be used as needed include: use of an alternative solvent (such as tetrahydrofuran), use of 唉 as a solvent, with or without the addition of DMAP or DIPEA, with the base gas component dissolved in the selected solvent and the addition of the amine component. -74- The paper size is suitable for the family (CNS) A4 specification (2iGX297 public) 1313601 A7 B7 V. Invention description (7〇) Prepare the necessary 3,5_二_(2_chloro group) as follows芊oxy)benzoic acid gasification raw material, compound (c):

Oc〇 compound (a ) Methyl 3,5-dihydroxybenzoate (741 g, 〇44 mol) was dissolved in dimethylformamide (400 ml), and potassium bromate (in g, 11 〇) was added. Moer) 'mixed for 15 minutes' followed by 2-chloro-based gas (117 ml, 0.92 mol) and heated at 1 Torr under the wind. After 3 hours, the reaction mixture was cooled to rt EtOAc (EtOAc m. The mixture was dried (MgS 4), filtered, and concentrated in vacuo to give a brown oil which was triturated with diethyl ether/hexanes to give compound (a) (195 g. 〇〇/0) ; 4 nnir (d6-DMSO, 5 values): 3.81(3H, s); 5.18(4H, s); 6.98(1H, m); 7.16(1H, d); 7.36(4H,m ); 7.50 (2H, m); 7.58 (2H, m).

-75- This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) 1313601 A7 B7 V. Description of invention (71) Add 2 g of molecular weight sodium hydroxide (700 ml, 1.40 mol) to methanol ( 600 ml) / tetrahydrofuran (150 ml) of compound (a), 3,5-bis(2-carbyl-oxy) oleic acid (195 g, 0.45 m) in a liquid solution and at 55 Stir at ° C for 6 hours. The organics were then removed in vacuo, acidified to pH 3-4 with concentrated hydrochloric acid, and filtered, washed with water and dried under high vacuum of 6 Torr. Obtained as a colorless solid compound (b) (.2/3NaCl) (199 g '100%); 4 nmr (d6-DMSO, 6 value): 5.18 (4H, s); 6.93 (1H, m); 7.15 ( 1H, d); 7.37(4H, m); 7.49(2H, m); 7.58 (2H, m).

Compound (c) oxalic acid chloride (7.91 ml, 91 mmol) was added to dioxane (5 mL) containing dimethylformamide (4 drops) under argon and room temperature. Compound (b), 3,5-bis(2-carbylmethoxy)benzoic acid. 2/3 NaCl (18.3 g, 45.4 mmol) in suspension. After a period of 16 hours, the reaction mixture was filtered with EtOAc EtOAc EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj - DMSO, 5 values): 5.18 (4H, s); 6.94 (1H, m); 7·16 (1Η, d); 7·35 (4Η, m); 7.50 (2Η, m); 7·58 ( 2Η, m). This paper is applicable to the gl interpreter standard (CNS) A4 specification (210X297 mm) 1313601 A7 B7 V. Invention description (72) ^fe2a : base, sulfhydryl 1 amine 1

2-[3,5-Di-(2-chlorobenzyloxy)phenylhydrazinyl]amino-Sev-5-carboxylic acid ethyl ester (158 mg, 〇2 8 mM) in THF (2 mL) The solution of mohr was treated with sodium hydroxide solution (2 g of molecular weight 0.57 ml, 14 mmol) and the reaction was stirred at 40-50 C until complete hydrolysis was achieved (monitoring with tic, about 2 hours of reaction) time). The resulting solution was cooled, diluted with water (5 mL) and acidified to pH 1 using concentrated EtOAc. The precipitate thus formed is filtered, washed (water) and dried to give the title compound as a colorless solid, 13 mg, iH NMR5 (d6-DMSO): 5.25 (4H, s); 7.0 (1H, s); 7.4 (6Η,m); 7.5(2H,m); 7.6(2H,m); 8·2(1Η,d). The necessary starting materials were prepared in a similar manner to that provided in Example A.

Example C Path 2b: Two-(2·氪氪芊, a stupid 1 neck benzoic acid _

-77- This paper size is applicable to National Standard (CNS) A4 specification (210X297 mm) 1313601 A7 B7 V. Inventive Note (73) [3,5-Di-(2-Chlorobenzyloxy) in THF A suspension of methyl phenyl hydrazino]amino benzene·3_ succinate (455 mg, 1.04 mmol) was treated with sodium hydroxide solution (2 g molecular weight 0.85 mL, 1.7 mmol) and the reaction Stir at room temperature and monitor with tic. Methanol (3 drops) and more sodium hydroxide solution (2 g of molecular weight 2 x 0.85 mL, 3.4 mmol) were added until complete hydrolysis was achieved. The resulting solution was diluted with water (30 ml) and acidified to EtOAc (2 g, NMR). </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; D6-DMSO): 5.25 (4H, s); 7.0 (1H, s); 7.4 (6H, m); 7.5 (2H, m); 7·6 (2Η, m); 8.2 (1H, d). The necessary methyl ester starting materials were prepared in a manner similar to that provided in Example A.

Example D Path 3: 2-Π.5-two "2-gas 竽氲 苽醯 苽醯 苽醯 1 1 1 1 1 1 1 1 1 -4- -4- -4- -4-

Dissolving 2-[3,5-di-(2-carbyloxy)phenyl]amino]-4-methylmethylpyrazole (56 mg, 〇·1 〇 mmol) in methanol 33% methylamine in alcohol (4 ml) was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo, EtOAc mjjjjjjjjjjjjjjjjj橾 ( (CNS) A4 size (210 X 297 mm) 1313601 A7 B7 V. Description of invention (74) DMSO, &lt;5 value): 2.63 (3H, m), 4.16 (2H, m); 5.24 (4H, s); 6.99 (1H, s); 7.38-7.44 (7H, m); 7.52 (2H, m); 7.62 (2H, m); 9.06 (1H, br s); 12.75 (1H, br s). From 3,5-di-(2-nitrobenzyloxy)benzoquinone chloride (prepared according to the procedure described in Example A) and 2-amino-4-methylmethyl-carbazole (JACS, 1946, 68, 2155; prepared according to the route 1 described in Example A) 2-[3,5-di-(2. chlorophenyloxy)phenyl]amino]-4-methylmethyl π was also prepared.

Example E Path 4: 2-"3,5-di-(2-gaso-gas-based) benzene-brewing a certain amine-amine carbazole

2-[3,5-Di-(2-carbylbenzyloxy)phenylhydrazinyl]aminopyridyl 6-nitrobenzoquinone»serazole (235 mg, 0.40 mmol) was dissolved in ethyl acetate ( 40 ml), ethanol (20 ml) and dimethylformamide (5 ml) were added 5% palladium on carbon (46 mg) under argon, then the reaction mixture was stirred under argon for 16 h. . The reaction mixture was filtered with EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj (2H, br s), 5.23 (4H, s); 6.72 (lH, dd); 6.93 (lH, m); 7.03 (lH, m); 7.35-7.44 (7H, m); 7.51 (2H, m) ; 7.61 (2H, m); 12.46 (1H, br s). -79- This scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1313601 A7 _____B7 V. Description of invention (75) From 3,5-di(2-chlorobenzyloxy)benzoquinone chloride Preparation of 2-[3,5-di-(2-) by 2-amino-6-nitrobenzoxazole (prepared by path 1 as illustrated in Example a) (prepared according to the procedure described in Example a) Gas-based benzyloxy)phenylhydrazinyl]aminopyridyl 6-nitrobenzo-serazole. 4 nmr (d6-DMSO, &lt;5 value): 5·27 (4Η, s), 7.03 (1Η, s); 7.38-7.46(4H, m); 7.49-7.55( 4H, m); 7.65(2H , m); 7'93 (1H, d); 8.30 (1H, dd); 9.09 (1H, m); 13.28 (1H, br s).

Example F signing fe 5 : 5-gas-based oxy-oxygen) 某 i i i yl u 13 4 Bu «Sebutadiazole-2-decanoic acid

Suspension of 5-[3,5-di-(2·chloroindolyl)phenylhydrazinyl]aminopyrazine-2-sulfonate (200 mg, 〇·38 mmol) in 2 g molecular weight In NaOH (5 ml), cool (ice bath) and add 30% aqueous argon peroxide (〇. 16 ml '1.54 mmol), then allow to warm to room temperature. After 4 hrs, react The mixture was filtered with EtOAc (EtOAc) EtOAc (EtOAcjjjjjjjjjjjjjj , s), 6.68 (1H, m); 7.37 (4H, m); 7.45 (2H, m); 7.50 (2H, m); 7.62 (2H, m). MS (M-H+)·564, 566. From 3,5-di-(2-carbyl decyloxy)benzene and 5·amine-based di-80- This 尺度-scale is applicable to China National Standard (CNS) A4 specification (210X297 mm) 1313601 A7 B7 V. INSTRUCTIONS INSTRUCTIONS (76) Disodium-2-sulfur (May bridge) Preparation of 5-[3,5-di-(2-chloromethoxy)oxy group by the route 1 illustrated in Example A Benzoyl]amino]-[1,3,4]&lt;1 sputum_2_ sulphur. 4 nmr (d6-DMSO, 5 values): 5_21 (4 hearts 3), 6.98 (1!^111)· 7.34-7.40 (6H, m), 7.50 (2H, m); 7.59 (2H, m). MS (M-H+).

516, 518 » Example G Signed Deer 6: 2-K3-isopropyl hydrazine-5-"2-cooking a guanylamine" jasmine jade-5-·»salmonazole#acid

2-Chlorobenzaldehyde (0.012 ml, 0.11 mmol) was added to 2-[(3-isopropoxy-5-aminophenylindenyl)amine in methanol under inert atmosphere at room temperature. _ 5-carbazole carboxylic acid (29 mg, 〇. 〇 9 mmol) and 4 angstrom molecular sieve (9 〇 mg). After 1 hour, sodium cyanoborohydride (7 mg, 〇 11 mmol) was then taken and the mixture was stirred for 16 hours. The reaction mixture was filtered, dried with EtOAc EtOAc. The organic extract was washed with EtOAc (2 mL) (EtOAc) DMSO, 5 values): 1.22 (6H'd), 4.36 (2H, m); 4·58 (1Η, m); 6·24(1Η, s); 6.47(1H, m); 6.84(2H, m 7.26(3H, m); 7.37(2H, m); -81 - This paper scale applies to China National Standard (CNS) A4 specification (210 x 297 mm) 1313601 A7 B7 V. Description of invention (77) 7 · 45 (1Η, ni); 7·76 (1Η, br s). MS [M-C02H]_ 400, 402. Preparation of 2-[(3-isopropoxy-5-aminophenylhydrazino)amino]-5-pyrazolic acid as follows:

Compound (d) 3-Nitro-5-hydroxybenzoic acid (6.1 g, 33.3 mmol) was dissolved in methanol (150 ml), concentrated sulfuric acid (2.0 ml) was added, and the solution was applied at room temperature. 5夭. The reaction mixture was concentrated in EtOAc (EtOAc) (EtOAc m. (MgS04), EtOAc (EtOAc) (EtOAc) (jjjjjjjjjjjjjjj 7·67(1Η,m); 7.75(1H,m); 8.05(1H,m); 10.88(1H,br s).

Compound (e) 2-Nitro-5-hydroxybenzoic acid in dimethylformamide (15 ml) was added to 2-iodopropane (0.54 ml, 5.4 mmol) 4 argon at room temperature. Methyl ester (1.06 g, 5.4 mmol) and potassium carbonate (1.12 g, 8.1 mmol) -82- This paper scale applies to China National Standard (CNS) VIII 4 specifications (210X297 mm) 1313601 A7 B7

5. Description of the invention (78) in solution. The reaction mixture was heated at 60 ° C for 1 hour, then additional 2-iodopropane (0.32 mL, 3.2 mmol) was added and heating was continued for an additional hour. The reaction mixture was concentrated in vacuo. EtOAc (EtOAc) (EtOAc) Concentration in vacuo to give the title compound (e) as a coloured oil; 4 nmr (d6-DMSO, ά): 1.30 (6H, s); 3.90 (3H, s); 4.84 (1H, m ); 7.76(1H, m); 7.89(1H, m); 8·16(1Η, m) »

Compound (f) 2 g of molecular weight sodium hydroxide (12.3 ml, 24.7 mmol) was added to the fluorenyl (3-nitro-5-isopropoxy)benzoic acid (1.18 g) in methanol (60 ml). 4.9 millimoles) and stirred at room temperature for 5 hours. The reaction mixture was then concentrated in vacuo, acidified with 2 g of molecular weight hydrogen acid to pH 1 - 2 '. The compound (f) (1.04 g, 94%) was obtained as an off-white solid; 1H nmr (d6-DMSO, 5): 1.30 (6H, s); 4.81 (1H, m); 7.74 (1H, m); (1H, m); 8.14 (1H, m). MS (M-H+)·224. -83- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm)

Binding 1313601 A7 B7 V. Description of invention (79)

Compound (g) 3 g of nitroxane (0.75 ml, 8.6 mmol) was added to dioxane (50 ml) containing dimethylformamide (2 drops) under argon and room temperature. Base _ 5-isopropoxy benzoic acid (ι·03 g, 4.3 mmol). After 3 hours, the reaction mixture was concentrated in vacuo and aq. to toluness to afford to afford orange oil, which was dissolved in dichloromethane (40 ml). 2-Aminothiazole 5-carboxylate (0.89 g, 5.1 mmol), diisopropylethylamine (1.77 g ' 10.3 mmol) and N,N-dimethylaminopyrene Symptoms (50 mg, 0.43 mmol) and stirred under argon for 1 hour. The reaction mixture was then concentrated in vacuo then a brown brown residue was purified on EtOAc EtOAc EtOAc Obtained as a pale yellow solid (g) (1.56 g, 92%); 4 nmr (d6-DMSO, &lt;5 value): 1.32 (6H, d); 4.88 (1H, m); 7.87 (1H, s 8.05(1H, s); 8.14(1H, s); 8.45( 1H, s).

Compound (h) 10% palladium on carbon (20 mg) was added to ethyl acetate under argon (35 -84- This paper scale applies Chinese National Standard (CNS) A4 size (210X 297 mm) 1313601 A7 B7 V. Ethyl 2-((3-isopropoxy-5-nitro)phenylhydrazinoamino]-5-indazolecarboxylic acid ethyl ester (209 mg, 0.53 mmol) in ml) In the solution of the ear). Hydrogen gas was introduced, and the reaction mixture was stirred vigorously for 18 hours, then filtered through EtOAc EtOAc EtOAc EtOAc (EtOAc) 5 值): i 25(6H,d); i 29(3H, t); 4.28(2H, q); 4.58(1H, m); 5.3l(2H, br s); 6.33(1H, m); 6.81 (1H, m); 6.87 (1H, s); 8.17 (ih, s).

Compound (k) 2 g of molecular weight sodium hydroxide (0.3 ml, 0.57 mmol) was added to 2-[(3-isopropoxy-5-amino) in tetrahydrofuran (1.2 ml) / methanol (0.5 ml) The phenyl arylamino group was also a solution of the acid (40 mg, o. ii millimolar) and was heated at 50 ° C for 5 hours and at room temperature overnight. The reaction mixture is then concentrated in vacuo to acidify to pH 4-5 with 2 g of molecular weight hydrogen acid. The precipitate is filtered, washed with water and dried over silica gel under high vacuum. Obtained as a red-brown solid compound (k) (35 mg, 1 〇〇./0); nmr (d6-DMSO, 5 value): 1.27 (6H, d); 4.63 (1H, m); 6.58 (1H , s); 7.05 (1H, s); 7.16 (1H, s); 8.14 (1H, s).

Example H Path 7 : 2-17 3.5-Dioxy oxane a certain amine face + 4 a ___ -85- This paper scale applies to China National Standard (CNS) A4 size (210 X 297 mm) 1313601 A7 B7

A solution of zinc powder (1300 mg) and gasified iron hexahydrate (1700 mg) in water (6 ml) was added to 2_[(3 5•dioxybenzoquinone) in DMF (6 ml) A stirred solution of the amine]-5-nitropyridine (910 mg). The resulting mixture was stirred at 120 ° C for 3 hours. Allow to cool to room temperature and extract the mixture with ethyl acetate. The extract was washed with water (50 ml) and brine (5 mL), dried over MgSO4, and then evaporated to remove the solids, leaving the solids at a high vacuum of 100 ° C for 24 hours. Drying to give the title compound as a solid ( 518 mg), &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&&&&12H);7.71(s,1H);7.78(d,1H); 10.28(br s,1H) » MS ES. 426.52(M+H)+ e is similar to the method provided in Example A (path 1), Starting from 2-amino-5-nitrosoguanidin, the necessary 6-[(3,5·dioxaphenyl)amino]-3]nitropyridine starting material was prepared. 1H NMR 6 (d6-DMSO): 5.18 (s, 4H); 6.90 (s, 1H); 7.29-7.50 (m, 12H); 8.42 (d, 1H); 8.64 (d, 1H); 9.23 (s, 1H); 11.46 (brs, 1H). MS ES+ 456.12 (M+H)+.

Example I Path 8 : Ν-(6-Γ(3.5·二芊氲基茉醯) Aminopyridin-3- Something Ethyl S-Oxo-2-methyl-propane S-amine-86- This paper Wave scale using China National Standard (CNS) A4 specification (210 X 297 mm)

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Line 1313601 A7 B7 V. Description of invention (82

A solution of 2- ethoxylated isobutyl sulfonium chloride (98 mg) in THF (1 mL) was added to 2-[(3,5-dioxane) in THF (2 mL) and pyridine (2 mL) The stirred solution of the phenyl hydrazino)amino]-5-aminopyridine (2 mg) was stirred at room temperature for 16 hours to remove the volatiles by evaporation. The residue was dissolved in ethyl acetate (50 ml), washed with water (25 ml) and brine (25 ml), dried over EtOAc EtOAc EtOAc To give the title compound as a solid (2 mg), *H NMR &lt;5 (d6-DMSO): 1.55 (s, 6H); 2.08 (s, 3H); 5.18 (s, 4H); 6.85 ( s,1H); 7.29 to 7.50 (m,12H); 7.98(dd,1H); 8·13 (d,1H); 8.61(s,1H); 9.70(s,1H); 10.72(s, 1H) . MS ES· 552.22(MH)* * Example J Path 9: N-J6_f(3,5-二芊g华醯醯一醯amine pyridine·]-^^^ Hydroxy-2-methyl-propionate amine

This paper scale applies to Chinese National Standard (CfS) A4 specification (210x 297 mm) 1313601 A7 B7 V. Description of invention (83) LiOH.H2O (30 mg) in water (1 ml) and THF (3 ml) The solution was added to [^-{6-[(3,5-dioxaphenyl)amino]pyridin-3-yl}-2-ethenyloxy in methanol (1 mL). -2·Methylpropanamide (158 mg) in a stirred suspension. The mixture was stirred at room temperature for 2 hours. The volatiles were removed by evaporation. Water (10 ml) was added to the residue. It is made acidic with 2 grams of molecular weight hydrochloric acid. The precipitate was filtered, washed with ethyl acetate and dried <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; , 4H); 6.88 (s, 1H); 7.28 to 7.48 (m, 12H); 8.08 (d, 1H); 8.22 (d, 1H); 8.82 (s, 1H); 9.90 (s, 1H); .96(s,1H) » MS ES+ 512.16(M+H)+.

Example K whole! Think 10: 3,5-di-yloxy-yi (5-{"((Special amine a certain 1 some 1 pulse even g) bite -_2_r base) stupid S-amine

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A solution of tert-butyl isocyanate (51 mg) in THF (5 mL) with 2_[(3,5-dimethoxyphenylphenyl)amino]5-aminopyridine (212 mg) ) Treatment and stirring at room temperature for 24 hours. More tert-butyl isocyanate (〇 34 ml) was added and stirring was continued for another 4 days at room temperature. The volatiles were removed by evaporation, EtOAc mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 88 - This paper scale applies to China National Standard (CNS) A4 specification (210X297 public) 1313601 A7 B7 V. Invention description (84) 祀); 6.09 (3,111); 6.85 (3,111), 7.32 to 7.50 ( 111,1211); 7.78

(dd, 1H); 8.04(d, 1H); 8.38(s, 1H); 8.44(s, 1H); 10.65(s, 1H). MS ES+ 525.61 (M+H)+. Example L Path 11: 3.5-bis(2-cyanoindole)-yi {5-172-methyl argon) [|^ base 1 pyridin-2-one guanamine

Adding trifluoroacetic acid (3 ml) to 6-({3,5-bis(2-cyanobenzyloxy)phenyl)}amino)pyridine-3-yl (in 3 m methane (1 mL) A stirred solution of tert-butyl 2-methoxyethyl)carbamate (237 mg). The solution was stirred at room temperature for 3 days. The volatiles were removed by evaporation. The residue was diluted with DCM (1 mL) and washed with 2 g of molecular weight sodium hydroxide (50 ml) and brine (5 liters) and dried over MgSO. The volatiles were evaporated to give the title compound ( 190 mg), NMR &lt;5&gt; (d6-DMSO): 3.22 (t, 2H); 3.28 (2, 3H); 3.50 (t, 2H); (s, 4H); 6.92(s, 1H), 7.12(dd, 1H); 7.34(s, 2H); 7.57(m, 2H); 7.75(m, 5H); 7.82(d, 1H); 7.91( d, 2H); l〇.49(br s, 1H). MS ES + 534.41 (M+H)+. Prepare the necessary raw materials as follows: 2-Nitropyridin-5-yl (2-methoxyethyl)amine a formic acid # Butyrate 劁 Storage as the paper size 中国 China National Standard (CNS) A4 specification (210 X 297 mm)

Line * 1313601 A7 B7 V. Description of invention (85)

2-Nitro-5-bromopyridine (406 mg), Pd(Ac) 2 (44 mg), 1,1-bis(diphenylphosphino)ferrocene (322 mg) and 2-methoxy Ethylamine (0.26 mL) was added to a suspension of Cs2C03 (1430 mg) in toluene. The mixture was stirred at 85 ° C for 16 hours under nitrogen to allow cooling to room temperature. Diluted with ethyl acetate (100 mL) and filtered through a pad of Celite. The volatiles were removed by evaporation and the residue was purified eluting eluting eluting eluting eluting eluting In a solution of di-tert-butyl dicarbonate (436 mg) and N-dimethylaminopyridine (catalyzed). The solution was stirred at 75 ° C for 14 hours. Allow to cool to room temperature and then remove the volatiles by evaporation. The residue was dissolved in ethyl acetate (100 ml), washed with water (50 ml) and brine (5 ml) and dried over EtOAc. The volatiles were removed by evaporation. EtOAc EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 1 η NMR 5 (CDCL3) · 1.49 (s, 9H), 3.33 (s, 6H), 3.62 (t, 2H), 3.86 (t, 2H), 8.06 (dd, 1H), 8.21 (d, 1H), 8.65(s, 1H) « MS ES+ 298.35(M+H)+. Amino p is more than a -5-yl(2-methyloxyethyl)amine prepared for the age of 3_-90- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) )

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1313601 A7 B7 V. Description of invention (86

Add 10% palladium on carbon (100 mg) to 2-(6-nitro-p--3-yl)-4-methoxy in ethanol (20 ml) and ethyl acetate (20 ml) In a solution of tert-butyl butyrate (350 mg). The suspension was stirred at room temperature under hydrogen for 6 hours. Filtration through EtOAc, EtOAc (EtOAc) (EtOAc) (jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj , 2H), 3.56 (t, 2H), 5.84 (s, 2H), 6.37 (d, 1H), 7.17 (dd, 1H), 7.70 (d, 1H). MS ES+ 268.34 (M+H)+.

Example M Path 12: N: 〇-amine 棊咐 · 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- s s s s s s s s s s s s 氨 氨 氨

Using a method similar to that described in Scheme 7, from ^^_(5-nitropyridine-2-yl-poly-3-[(2-carbylindenyl)oxy]-5-[(2-cyano;yl)oxy Preparation of the title compound β by the benzoguanamine The following materials were prepared in the following manner: -91 -

Line 1313601 A7 B7 V. Invention, Sun and Moon (87) 3-(Κ5-nitropyridin-2-yl)amine Tomb 1 Carbonyl 1-5-ΙΎ2-Amino 竽) Gas Group 1 Preparation of Acetyl Acetate

Add a solution of 3-ethoxycarbonyl, 5-(2-cyanobenzyloxy)benzoic acid (8760 mg) in THF (100 mL) in THF (3 mL) in. The mixture was stirred at room temperature for 3 hours. The volatiles were removed by evaporation. The residue was dissolved in a mixture of THF (60 ml) and pyridine (40 ml). 2-Amino-5-nitropyridine (3919 mg) was added. The stirred mixture was heated to 55 ° C for 16 hours. The volatiles were removed by evaporation to give crystals eluted eluted eluted eluted elut elut elut elut , *H NMR 5 (d6-DMSO): 2.29 (s, 3H), 5.37 (s, 2H), 7.17 (s, 1H), 7.45 (s, 1H), 7.58 (m, 1H), 7.70 (s, 1H), 7.76 (m, 2H), 7.92 (d, 1H), 8.40 (d, 1H), 8.65 (dm, 1H), 9.21 (m, 1H), 11.57 (s, 1H). MS ES+ 433.48 (M+H)+. Preparation of EH.Nitropyridine-2-Ammonia, a argon, argon, 5-quinone, benzoquinone

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This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1313601 A7 ____B7 V. Description of invention (88) 3-{[(5-nitropyridine-2-) in THF (35 ml) A suspension of the amino]carbonyl]-5-[(2-cyanobenzyl)oxy]phenyl acetate (5710 mg) was treated with 25% NaOMe in methanol (6 mL). Stir at room temperature for 30 minutes. It was acidified with 2 g of molecular weight hydrogen acid (25 ml), and then ethyl acetate (100 ml). The extract was washed with water (50 ml) and brine (50 ml) and dried over EtOAc. The volatiles were evaporated to give a crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal ES+ 391.45 (M+H)+. N-(5-nitroindole. in the dioxin, a certain 1-5-K2. ammonia thiol) argon 1 benzoguanamine

A solution of N-(5-nitropyridin-2-yl)-3-[(2-cyanoindolyl)oxy]-5-hydroxybenzoguanamine (195 mg) in DMF (3 mL) Treated with Ag2C03 (1 65 mg) and 2·glycolyl bromide (0.073 ml), heated to 85 ° C and stirred under nitrogen for 17 hours. Allow to cool to room temperature. After adding water (25 ml), it was extracted with ethyl acetate (50 ml), washed with brine (25 ml), and dried over EtOAc. The volatiles were removed by evaporation to give a solid crystals crystals eluted eluted eluted eluted Mg), ιΗ NMR 5 (d6-DMSO): 5.20(s, 2H), 5.33(s, 2H), 6.96(s, 1H), -93- This paper scale applies to China National Standard (CNS) A4 specification ( 210x 297 mm) I313601 A7 B7___ V. Description of invention (89) 7.40(m, 5H), 7.57(m, 2H), 7.72(m, 2H), 7.90(d, 1H), 8.40(d,1H), 8.64 (dd, 1H), 9.22 (s, 1H), 11.5 〇 (s, 1H) » LCMS rt = 3.27 min (97.4%). ES+ 515.50 (M+H)+.

Responsibility N Signing 13:6]1~35-two-(竿Argolium&gt;) phenylhydrazinyl 1^yl}-&gt;1-"2-(dimethyl-1_ 狴)ethyl] in the age of gii neck

Diisopropylethylamine (DIPEA, 0.23 mL, 1.3 mmol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC, 126 mg, 0.66) Add 2-dimethylaminoethylamine (0.57 ml, 0.53 mmol) and 6-{[3,5- in dichloromethane (1 mL) under argon at room temperature. - (Yo) phenyl aryl] amine group in a solution of acid (0.20 g, 0.44 mmol). After 16 hours, the reaction mixture was evaporated in vacuo and then chromatographed on EtOAc (EtOAc) eluting with gradients of 10 to 25% methanol in dioxane. The product-containing fraction was evaporated to give a creamy solid (0.052 g, 25%); NMR5 (d6-DMSO): 2.67 (6H, s); 3.11 (2H, m); 3.62 (2H, m); (4H, s); 6.88 (1H, s); 7.27-7.52 (12H, br m); 8.18-8.36 ( 2H, m); 8.90 (1H, s); 10.20 (1H, br s).

Example O Integral 14 : 2-J丄5 -B-(2-Air-based gas-based) amine A certain sea methyl-94- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1313601 A7 B7 V. Inventions? Month (9〇)

Add 4-methylmorpholine (80 μL, 1 eq.) and isobutyl chloroformate (76 μL, 1.02 eq.) to 2-[3,5 in dimethoxyethane (5 mL) • A cold (-15 ° C) solution of bis(2-chlorobenzyloxy)phenylindenyl]amino]•pyridinecarboxylic acid (305 mg, 0.59 mmol). The reaction mixture was stirred for 15 min. Cool the filtrate and wash to -15. (: and treated with a suspension of sodium hydride (22 mg, 1 eq.) in water (1 ml). After quenching, add water (50 ml) and ethyl acetate (30 ml). The mixture was evaporated to dryness and the residue was taken on EtOAc (methanol). (97 mg), 1H NMR (5 (d6-DMSO): 4.5 (1H, d); 5.25 (s, 4H); 6.9 (s, 1H); 7.40 (m, 6H); 7.5 (m, 2H); (m, 2H), 7.75(dd, 1H), 8.1〇(d, 1H); 8.3(s, 1H), l〇.8(br s, 1H), LCMS rt=3.25 minutes (loo%) es+ 509 (M+H)+.

Example P is carried out to 1 5 : N- { 6-J~ 3 J ( 2- gas benzyl oxychloride 莘 醯 ) ) 眩 卜 a a a a a a a a a a a a a a a a a a a a a 本 本 本 本 本 本 本中 a S 家搮准 (CNS) A4 specification (210X 297 mm) 1313601 A7 B7 V. Description of invention (91

Add pyridine (43 mg, 0. 54 mmol) and acetonitrile (42 mg, 0.54 mmol) to 2-[3,5·di-(2-chlorobenzyl) in tetrahydrofuran (4 mL) A solution of oxyphenylhydrazino)amino]-6-aminopyridine (220 mg, 0.45 mmol) was stirred at room temperature for 16 h. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. The title compound (75 mg) was obtained by EtOAc (EtOAc: EtOAc: EtOAc (EtOAc: EtOAc) m, 4H); 7.5 (m, 2H), 7.6 (m, 2H), 7.7 (m, 1H); 7.8 (m, 2H), 10.14 (br s, 1H), 10.36 (br s, 1H); 536/538 (M+H)+. The 2-[3,5-di-(2-chlorobenzyloxyphenyl)amino]-6-amino ratio bite starting material is illustrated herein by way of example, as in Example No. 1 〇6. Example Ο Road _|16 : 3,5-bis (芊oxy 1-Ν-Γ5-ΠΗ-tetra---) 咄忒-2- 1 benzoamide

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This paper is suitable for China National Standard (CNS) A4 specification (210 X 297 mm) 1313601 A7 B7 V. Invention _ Ming (92) Add tributyl azide (156 μl, 0.57 mmol) a suspension of 3,5-bis(decyloxy)-N-(5-cyano n-predative-yl)phenylamine (180 mg, 0.41 mmol) in toluene (3 mL) . The mixture was heated under reflux for 16 hours. The suspension was cooled and dissolved between ethyl acetate and hydrochloric acid (1 gram molecular weight). The organic layer was concentrated in vacuo and residue was purified on EtOAc (EtOAc) eluting with MPLC (1% methanol / DCM to 15% methanol / DCM). Obtained as a colorless solid tetrazole (113 mg, 57%), NMR δ (de-DMSO): 5.19 (4H, s); 6.88 (1H, s); 7.26-7.48 (12H, m); 8.40 (1H, d); 8.46 (1H, dd); 9.04 (1H, s); 11.13 (1H, br s); m/z (LCMS; ESI+) 479 (MH)+. Prepare the necessary raw materials as follows: Preparation of 3·5-series (decyloxy)-N-(5-aminopyridine-2-) jasmonamine

The title compound was prepared starting from 2-amino-5-cyanopyridine and 3,5-bis(benzyloxy)benzoquinone as described in Example A (path 1), lHNMR (J (d6-DMSO): 5.19 (4H, s); 6.89(1H, m); 7.26-7.46( 12H, m); 8.27 (1H, dd); 8.33(1H, d); 8.84(1H, s), 11.23(1H, br s) m/z (LCMS; ESI+) 436 (MH)+. The necessary 2-amino-5 5-cyanopyridine-97 can be purchased (Bionet Research and other suppliers) or can be prepared according to the method provided by W095/06034 - This paper size is applicable to China's household standard (CNS) A4 specification (210X 297 mm) 1313601 A7 B7 V. Invention description (93)

material. Example R good diameter _ Π : 3,5-bis(芊 aryl)-N-"5-(5U-4.5-disindol-114-coxadiazol-3-yl)pyridine-2-one guanamine

Ethyl decanoic acid ethyl ester (32 μL, 0.33 mmol) was added to 3,5-bis(benzyloxy)-N-{5-[(hydroxylamino)(imido) in pyridine (5 mL) a solution of methyl]pyridine·2-yl}benzamide (140 mg, 0.30 mmol). The solution was heated under reflux overnight. The mixture was cooled and concentrated under reduced pressure. The residue was dissolved using DCM and methanol, and the solution was washed with water. The organic solution was concentrated under reduced pressure and the residue was purified mjjjjjjjjjjj The title compound (103 mg, 70%) was obtained as a colorless solid, 1H NMR δ (d6-DMSO): 5.19 (4H, s); 6.87 (1H, s); 7.28-7.46 (12H, m); 8.21 (1H, dd 8.38 (1H, d); 8.79 (1H, s); 11.14 (1H, br s); m/z (LCMS; ESI+) 495 (MH)+. Prepare the necessary raw materials as follows: 3,5-bis(benzyl group-yl)-:^-"5-"(hydroxylamine a certain "leamine") a certain 1 pyridin-2-one 1 guanamine Preparation -98 - The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

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1313601 A7 B7 V. Description of invention (94

α 3,5-bis(decyloxy)-oxime (5-cyanopyridin-2-yl)phenylamine (212 mg, 0.49 mmol), triethylamine in ethanol (5 mL) A mixture of (170 μl, 1.22 mmol) and hydroxylamine hydrochloride (85 mg, 1.22 mmol) was heated under reflux overnight. The mixture was cooled and concentrated under reduced pressure. The residue was purified by MPLC on EtOAc EtOAc (EtOAc) The title compound (171 mg &apos; 75%) was obtained as a colorless solid. 4 NMR &lt;5 (d6-DMSO): 5.19 (4H, s), 5.92 (2 Η, s), 6.87 (1H, s), 7.28-7.48 (12H, m), 8.06 (1H, dd), 8.17 (1H) , d), 8.65 (1H, s), 9.68 (1H, s), 10.85 (1H, br s); m/z (LCMS; ESI+) 469 (MH)+. The necessary 3,5-bis(decyloxy)_N_(5-enyl p-p-but-2-yl)benzamine was prepared as described in Example P (path 15).

Example S Road. Trail 18:. "(2.-丨丨3,5-double (benzyloxyquinone) benzoquinone 1 neck a certain babidine-5_ a certain makeup U 氲) acetic acid

This paper size applies to the Chinese Painter Standard (CNS) A4 specification (210X 297 mm) 1313601 A7 B7 Description of the invention Add methyl oxadiazepine (37 μL, 0.4 mmol) to N in |DCM (5 mL) a mixture of -(5-aminopyridin-2-yl)-3,5-bis(benzyloxy)phenylamine (15 mg, 0.36 mmol) and triethylamine. The mixture was stirred under nitrogen for 1 hour. The solution was diluted with DCM and washed with water. The organics were concentrated under reduced pressure, and the residue was purified eluted eluted eluted eluting eluting This material was dissolved in THF (2 mL). Water (3 ml) and sodium argon (0.5 ml, 2 g molecular weight, i millimolar) were added. The mixture was stirred for a few hours, then acidified with hydrogen acid (2 g molecular weight) and diluted with water. The resulting precipitate was separated by EtOAc (EtOAc m. 6.88(1H, s); 7.30-7.50( 12H, m); 8.17(2H, s); 8.79(1H, s); 10.79(1H} s); 10.93(1H, br s); m/z(LCMS ; ESI+) 498 (MH)+.

Preparation of the necessary starting materials e according to Example H (path 7) Example T The compounds of the following example numbers D1 to D2 can also be obtained in a manner similar to those described above. The compound Τ '9 was prepared in the following manner by the route lb (for multi-parallel synthesis). One drop of dimethylformamide was added to dichloromethane (25 ml) in aq. Grass chloroform (0.867 ml) was added to the acid and stirred at room temperature for 2 hours. The solvent was removed in Genevac DD4 and the residue obtained was azeotroped with dichloromethane (3 EtOAc) and then dried under high vacuum over 2 s. Then dissolve the obtained mercapto chloride -100- This paper size is used in the National Standard (CNS) Α4 specification (210 X 297 mm) 1313601

In THF (30 iS liter), 5 ml of the solution was added to one of the group of 6 amines (53⁄4 liters) in THF/pyridine. The resulting mixture was stirred at room temperature and diluted with EtOAc (5 mL). Transfer the resulting solution to an Allex automated extractor' and wash with water (2 χ 5 ml), sodium bicarbonate (10 liters), 1 gram of molecular weight citric acid (5 ml) and saline (5 ml), and dry ( Magnesium sulfate) and evaporated in Genevac DD4. The obtained gum was wet-milled with methanol (12 ml) and the resulting solid was dried, washed with methanol and dried with air. 1 2 example painting structure

1H NMR d (d6-DMSO): 5·26 (4Η, s); 6.96 (1H, m); 7.38-7.45 (6H, m); 7.53 (2H, m); 7.62 (2H, m); 8.43 (1H, d); 8.49 (1H, m); 9.42 (1H, m); 11.13 (1H, s). 1HNMRd (d6-DMSO): 5_25 (4H, s); 6.97 (1 H, m); - 7.45 (6H, m); 7.53 (2H, m); 7.63 (2H, m); 8.64 (1H, d); 9.26 (1H, d); 11.33 (1H, s). 1HNMRd (d6-DMSO): 5.24 (4H, s); 6.95 (1H, s); 7.35-7.40 (6H, m); 7.50 (2H, m); 7.60 (2H, m); 8.61 (1H, s); 9.22 (1H, s) 11.25 (1H, br s). This paper scale adopts Chinese National Standard (CNS) A4 specification (210 X 297 mm) -101 - 1313601 A7 B7 V. Invention description (97) Example dynamic structure; 1 ι Ά- · HUB / C 4 1 1H NMR d (d6-DMSO): 5.36 (4H, s); 7.00 (1H, m); 7.44 (2H, d); 7.55-7.64 (2H, m); 7.77 (4H, m 7.93 (2H, d); 8.43 (1H, d); 8.49 (1H, m); 9.43 (1H, s); 11.17 (1H, s). °xp« 1 1H NMR d (d6-DMSO): 3.90 (3H, S); 5.24 (4H, s); 6.97 (1H, m); 7.39 (6H, m); 7.50 (2H, m); 7.60 (2H, m); 9.02 (1H, s); 9.52 (1H, s); 11.54 (1H, brs). 6 0tW^ &amp; 2 1H NMR d (d6-DMSO): 5.24 (4H, s); 6.96 (1H, m); 7.39 (6H, m); .51 (2H, m); 7.62 (2H, m); 8.98 (1H, s); 9.48 (1H, s); 11.44(1 H, brs). 7 °X^rV^J. Less 2 * 1H NMR d (d6-DMSO): 5.34 (4H, s); 7.00 (1 H, s); 7,57 (2H, m); 7.75 (4H, m); 7.91 (2H, d); 9.00 (1H, s 9.52 (1H, s); 11.53 (1H, s); 13.43, (1H br s). 8 ο^χ^Λ again] ϊτ 1 1HNMRd(d6-DMSO): 2.29 (3H, s); 2.33 ( (3H, s); 3.24 (m, 2H); , m); 8.39 (1H, m); 8.45 (1H, m); 8.82 (1H, s); 9.38 (1H, s); 11.06 (1H, br s). -102- The paper music scale applies to Chinese national standards (CNS) A4 size (210X297 mm) 1313601 A7 B7 V. Invention description (98): Example &lt; i structure 丨 path] «r-ar»·»-»--· 9 Vv° 0r 1b 'HNMRiKd^- DMSO): 1.25 (d, 12H), 4.7 (hept, 2H), 6.6 (d, 1H), 7.2 (d, 2H), 8.4 (d, 1H), 8.45 (t, 1H), 9.4 (s, 1H) ), 11.0 (brs, 1H). 10 1 1HNMR5(d6-DMSO): 2.37 (s, 3H), 3.24 (t, 2H), 4.23 (t, 2H), 4.65 (d, 2H), 5.28 (d, 1H), 5.42 (d, 1H), 6.05 (m, 1H), 6.75 (s, 1H), 7.23 (s, 2H), 8.43 (s, 1H), 8.84 (s, 1H), 9.40 (s, IH ), 11.07(brs, 1H). 11 1 4 NMR δ (di-DMSO): 2.32 (s, 3H), 2.35 (s, 3H), 3.21 (t, 2H), 4.21 (t, 2H), 5.13 (s, 2H), 6.81 (s, 1H), 7.14-7.26 (m, 4H), 7.32 (1H, s), 7.41 (lH,d), 8.51 (s, 1H), 8.81 (s, 1H), 9.39 (s , 1H), 11.34 (brs, 1H). 12 1 364 *H NMR δ (d^-DMSO): 2.12 (s, 6H), 3.81 (s, 3H), 5.05 (s, 2H), 6.95 (s, lH), 7.05 (s, 2H), 7.1 (s, 1H), 7·72 (d, 1H), 7.78 (s, 1H), 8.36 (d, 1H), 8·43 (s, 1H), 9 · 4 (st 1H), 10.92 (brs, 1H) 13 lb 412 410 14 A#] lb 330 15 lb 288 -103- This paper scale is common Chinese national standard (CMS) A4 size (210 X 297 mm) 1313601 A7 B7 V. INSTRUCTIONS (99) EXAMPLE i ΡΐWm 16 0 lb 312 17 ^°όγ°-4 ό° lb 452 18 Λ lb 400 19 fr^° 2a, lc 428 1 426 δΗ (500MHz, DMSO-dtf) 1.28 (6H,d), 3·07 (2H,t), 4.26 (2H, t), 4.70 (lH,m), 6.71 (lH,m),7_12(lH,m), 7.24 (2H, m), 7.30 (lH,m), 7.46 (1H,m), 8.98 (lH,d), 9.48 (lH,d), 11.33 (1H. s), 13.24 (lH,brs). 20 la 382 ! 1 ! *About Example 7, Preparation of Ester in Path 1 Inter were:

-104- This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1313601 A7 B7 V. Description of invention (100) *H NMR&lt;5 (d6-DMSO): 3.90(3H, s); 5.34 (4H, s); 7.〇KlHs s); 7.43(2H,s); 7.58(2H,m); 7.74(4H,m); 7.91(2H, d); 9.02(1H,s); 9.52( 1H, s); 11.57 (1H, br s).

Example U 2-Γ3-(2-(4-A certain carbazole-5-an-1 ethyl sulfonyl-5-dimethylamine) 1 pen cleavage A amine certain 1-Π.3.41-oxadiazole (path 19)

Formaldehyde (37% in water) (0.033 ml, 0.44 mmol) in inert gas at room temperature in methanol (4 mL) / acetonitrile (3 mL) / g. AcOH (2 drops) 2- [3·{2-(4-Methyloxazol-5-yl)ethoxy}-5-amino]benzoylamino]-[1,3,4]-pyrimidine (27 mg, 0.074 millimoles). After 15 minutes, cyanoguanidine (7 mg, 0.12 mmol) was added and the mixture was stirred 40 hr. The reaction mixture was filtered, concentrated in vacuo and EtOAc EtOAc m. The title compound (25 mg, 85%) was obtained eluted eluted eluted eluted eluted eluted eluted (m, 2H), 4.19 (m, 2H), 6.41 (m, 1H), 6-98 (m, 1H), 7.06 (m, 1H), 8.80 (s, 1H), 9.17 (s, 1H). Prepare the necessary 2-[3-{2-(4,methylindole-5-yl)ethoxy}-5-amino]-mercaptoamino]-[1,3,4 as follows ]-&gt;»Second two to eat raw materials. -105- This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm) 1313601 A7 B7 V. Invention description (101)

/) 10% palladium on carbon (80 mg) was added to 2-[3-{2-(4-methyloxazol-5-yl) in ethyl acetate (4 mL) under argon. Ethoxy-5-nitro]benzoinylamino]-[l,3,4]-u stoppered diazole (0.38 g, 0-99 mmol) solution. Hydrogen gas was introduced and the reaction mixture was stirred vigorously for 18 hours, then filtered through Celite, concentrated in vacuo and solvent (80 mg). The final catalyst exchange was carried out after 18 hours of mixing under hydrogen. The crude aniline was then purified on silica gel (1% to 4% MeOH/DCM) to afford 2-[3-{2-(4-methylcarbazol-5-yl)ethoxy as a colorless solid. -5-Amino]benzoylamino]-[1,3,4]-, cediazole (0.1 g, 28%); MS (M-H+)· 360.

Add grasshopper gas (0.20 ml, 2,35 mmol) to 3-{2-(4-methyl) in argon (SO2) containing DMF (2 drops) under argon and room temperature. p tombazole-5-yl)ethoxy}-5-nitrobenzoic acid (0.72 g, 2 mmol). The reaction mixture was concentrated in vacuo <RTI ID=0.0> The hydrazine-based gas and 2-amino-Secondone (0.19 gram '1.9 mM) were dissolved in DCM (20 mL) followed by DIPEA (0.96 mL '5.6 mM) and dmAP (0.04 gram, 0 3 millimeters of paper size applicable + National Solid State Standard (CNS) A4 specification (210 X 297 mm) 1313601 A7 B7 V. Invention Description (102) Ear). After stirring under argon overnight <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI></RTI></RTI> - [ 3- { 2-(4-Methylthiazol-5-yl)ethoxy}-5-nitro]phenylhydrazinyl]-[H4]-oxobisazole (0.30 g, 48%) ; 4 NMR &lt;5 (d6-DMSO): 2.37 (s, 3H), 3.26 (t, 2H), 4.35 (t, 2H), 7.89 (m, 1H), 8.09 (s, 1H), 8.47 (s, 1H), 8.81 (s, 1H), 9.24 (s, 1H).

Add DIAD (3.16 ml, 16.1 mmol) to 3-nitro-5-carbamic acid methyl ester (2.11 g, 10.7 mmol) in THF (50 mL) under argon and room temperature. 4-(2-Hydroxyethyl)-5-methylcarbazole (1.55 mL, 12.8 mmol) and triphenylphosphine (4.21 g [ 16.1 mmol) in a stirred solution. After 1 hour, the reaction mixture was concentrated in vacuo and the residue was crystallised eluted with diethyl ether to afford a colorless solid (triphenylphosphine oxide). The dark brown gum was obtained by concentrating diethyl ether and purified on silica gel (50% to 75% EtOAc/isohexane) to afford reduced product of DIAD and triphenylphosphonium oxide (6.8 g). The crude product was dissolved/suspended in MeOH (80 mL), and 2 g of molecular weight NaOH (20 ml, 40 m.m.) was added and heated at 65 ° C for 4 hours, followed by cooling and concentration. The residue was diluted with water (140 ml) / 2 g of molecular weight NaOH (40 ml), and the precipitated triphenylphosphine oxide was filtered, then acidified to pH 1.25 with concentrated HCl. The sacred material will be smashed, washed with water, and dried under high vacuum to obtain -107- This paper scale applies to Chinese National Standard (CMS) A4 specification (210 X 297 mm) 1313601 A7

V. INSTRUCTION DESCRIPTION (103) B7 to 3-{2-(4-methyloxazol-5-yl)ethoxy}-5-nitrobenzoic acid as a colorless solid (3.12 g, obtained in 2 steps 79 %HNMR&lt;5(d6-DMSO): 2.39(s, 3H), 3.23(t, 2H), 4.35(t, 2H), 7.78(s, 1H), 7.9〇(m,1H), 8.22( s, 1H), 8_93 (s, 1H). (4-methyl 嗥 -5 - yl) ethane 丨 · 5 _ hydroxy 苽醯 苽醯 胺 胺 L L L1, 3.4~| - » Helmet arsenic (Road

2-[3- {2-(4-Methyloxazol-5-yl)ethoxy}-5-allyloxy]phenylhydrazinyl]-[i] in tetrahydrofuran (40 ml) , 3,4] oxadiazole (1.1 g '2.7 mmol) solution was stirred under argon and with Meldrum's acid (0.79 g, 5.4 mmol) and 肆 (three Phenylphosphine)palladium(0) (825 mg, 0.7 mmol, 0.25 eq.) was taken and the resulting yellow solution was stirred at room temperature for 2 hr. Continuous wet milling with di-methane and hot tetrahydrofuran to give 2-[3-{2-(4-methyl-α-azol-5-yl)ethoxy}-5-yl]benzene as a colorless solid Amino group]_[1,3,4]-!» stopper II also (〇.59 g, 59%); *H NMR (5 (d6-DMSO): 2.35(s, 3H), 3.2(t, 2H), 4.2(t, 2H), 6.55(m, 1H), 7.05(s, 1H), 7.2(s, 1H), 8.81(s, 1H), 9.2(s, 1H), 9.8(br s, 1H); m/z 363 (M+H) + , 361 (MH)-. This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 public) 1313601 A7 B7 104) V. Description of invention (

The necessary 2_[3丨2_(4-methylthiazolyl)ethoxy] is prepared according to the appropriate general alkylation method and coupling of the obtained benzene f acid according to path 1 with 1,3,4·pyrimidine. -5-Allyloxy]phenylhydrazinoamino]_[ υ〆]-β soxadiazole starting material. The analytical data for all intermediates is consistent with the proposed structure.

Example W Κ.3-isopropyl oxy-screen-5-; mercaptomethyl) 茇醢 眩 眩 4 4 (Path 2 Π

VnI&gt;

Y a solution of 2-(3-isopropoxy-5-mercapto)phenylhydrazinoyl-serazole (0·11 g, 0·39 mmol) in dichloromethane as dimethyl The amine (about 5.6 grams of a molecular weight solution of 0.074 milliliters in ethanol, 〇 4 ΐ millimolar, 1 丨 equivalent) was treated and stirred under argon for 10 minutes. Sodium triethoxy borohydride (〇 11 g '0.53 mmol, 1.4 eq.) was added to the solution, and the resulting mixture was stirred overnight at room temperature. More reagents were then added (same amount as above) and the mixture was stirred at room temperature overnight. The solution was treated with a saturated solution of sodium bicarbonate (10 mL) and stirred for 20 min, then extracted twice with dichloromethane. The organic extracts were dried over magnesium sulfate and evaporated in vacuo. National Standard (CNS) Α4 Specification (210X 297 mm) A7 B7 1313601 V. Description of Invention (105) Obtained as a product of colorless oil. It is dissolved in ethyl acetate, and the solution is treated with an ether solution of HC1 (more than 1 gram of molecular weight), and the thus formed sediment is filtered under the atmosphere and washed with diethyl ether to obtain a colorless solid. (3-isopropoxy-5-dimethylaminomethyl)phenylhydrazinyl carbazole hydrochloride (0.1 g, 72%); A NMR &lt;5 (d6-DMSO): ^(d, 6H), 2.71(s, 6H), 4.26(m, 2H), 4.76(m, 1H), 7.29(d, 1H), 7.42(m, 1H), 7.55(d, 1H), 7.70(s, 1H ), l〇.66 (bs, 1H). Prepare the necessary raw materials as follows:

Example X 3-Isopropanyl-5-methylindenyl) 茇醯一领甚_地 (Path 22)

A solution of 2-(3-isopropoxy-5-hydroxymethyl)phenylhydrazinyl "serazole" (0.115 g, 0.39 mmol) in tetrahydrofuran (8 mL) with manganese dioxide (0.27) Treated in grams, 3.1 mmol, 8 eq.), and the resulting suspension was stirred overnight at room temperature and additional oxidant (1 gram portion) was added until all the starting material was consumed (tic). The residue was completely washed with ethyl acetate, and the combined filtrate and washings were evaporated in vacuo to give the product as a pale yellow solid, iH NMR d (d6-DMSO &gt;: 1.31 (d, 6H), 4.82(m,1H), 7.26(d,1H), 7.56(d,1H), 7.59(s, 1H), 7.94(d, 1H), 8.15(s, 1H), 10.00(s, 1H), 12.77 (bs, I------110- This paper size applies to the S country standard (CNS) A4 specification (210 X 297 mm) 13136〇1 A7 B7 V. Description of invention (1Q6 1H). Ways to prepare the necessary raw materials:

Fantasy Y 1 propoxy-5-hydroxymethyl) alum amide a 4 azole Α Α ^ 23 Ι

An ester of 2-(3-isopropoxy-5-ethyloxymethyl)phenylhydrazinyl thiazole (0.15 g, 0.46 trometh) was used for 2 hours using 2 g of molecular weight NaOH/THF/MeOH. Cleavage to give 2-(3-isopropoxy-5-hydroxymethyl)phenylhydrazinyl carbazole (〇.149 g, 100%) as a colorless solid; β NMR &lt;5 (d6-DMSO) ): 1.28(d, 6H), 4.51(s, 2H), 4.71(m, 1H), 7.05(s, 1H), 7.25(d, 1H), 7.50(s, 1H), 7.53(d, 1H) , 7.58 (s, 1H), 12.50 (bs, 1H).

Prepare the necessary 2-(3-isopropoxy _ 5 according to the standard coupling between 3-isopropoxy-5-ethoxymethyl benzoquinone chloride and 2-amino 11 odor according to path 1 ' - ethoxylated methyl phenyl phenyl aryl ketone s s s s ' to give the title compound as a pale yellow oil, (5 (d6-DMSO): 1.3 (d, 6H), 2.1 (s, 3H), 4.75 111 - This paper scale applies to Chinese National Standard (CNS) A4 specification (21〇x 297 mm) 1313601 A7 B7 V. Invention description (107) (hept, 1H), 5.1(s, 2H), 7.15(s, 1H ), 7.25(d, 1H), 7.65(d, 1H), 7.6(m, 2H), 12.6(bs, 1H). The necessary 3·isopropoxy-5-ethyloxy group was prepared as follows. Methyl benzoic acid raw materials:

A solution of 3-isopropyliso-5-hydroxymethylbenzoic acid (0.77 g, 3.7 mmol) in a gas-fired (20 ml) was cooled (ice bath) and stirred under argon. The bite (1.18 ml, 14.6 mmol, 4 equivalents) was then added, followed by dropwise addition of acetonitrile (0.55 mL '7.7 mmol, 2_1 equivalent). The mixture was stirred for 5 minutes' then allowed to warm to room temperature for 90 minutes, water (2 mL) was added and the mixture was stirred for 2 s then allowed to stand overnight. The organic layer was separated and the water portion was taken from dichloromethane. Wash and combine the two gas methane fractions and evaporate. The obtained pale yellow oil was taken up in ethyl acetate, and the solution was washed with 0.05 g of molecular weight aqueous HCl (20 ml), the organic layer was separated, dried over magnesium sulfate and evaporated in vacuo to give a pale yellow The product of the solid, 1H NMR5 (d6-DMSO): 1.25 (d, 6H), 2.06 (s, 3H), 4.65 (hept, 1H), 5.05 (s, 2H), 7.12 (s, 1H), 7.31 (d, 1H), 7.46(s,1H) e Prepare the necessary 3-isopropoxy-5-methyl hydrobenzoic acid as follows: -112- This paper is again passed the S 8 standard ( CNS) A4 size (210X297 mm) 1313601 A7 B7 V. Description of invention (1 (38

Cleavage of 3-isopropoxy-5-hydroxymethylbenzoate (1.12 g, 5.0 mmol) in a standard 2 g molecular weight NaOH/THF/MeOH to give the title compound as a colorless solid (0-98 g, 94 %)1HNMR&lt;5(d6-DMSO): 1.25(d, 6H), 4.47(s, 2H), 4.60(m, 1H), 5.23(bs, 1H), 7.06(s, lii), 7.24(s , 1H), 7.45 (s, 1H). The necessary 3-isopropoxy-5-hydroxymethylbenzoic acid methyl ester starting material was prepared as follows:

Dissolve 5-isopropoxyisodecanoic acid monomethyl ester (5.15 g, 21.6 mmol) in THF (180 mL), cool to and add borane: THF complex dropwise over 15 min. 72 ml of 1, 5 g of molecular weight solution in THF, 0.11 mmol) maintained the internal temperature of &lt; 5 °C. After 15 minutes, the reaction mixture was warmed to room temperature and stirred for 3 hours, then cooled (ice bath) and quenched with crushed ice. When no further reaction was found, saline (15 Torr) / diethyl ether (150 mL) was added. The organic layer was removed and the aqueous layer was extracted with diethyl ether (1×100 mL). The combined organics were washed with brine (1·1 mL) and dried (MgS 〇 4) filtered and concentrated. Purified on silica gel (2〇_ 25% EtO Ac/isoprecipitate) · The title compound is obtained as a colorless solid (3 57 泜 尺度 适用 适用 适用 适用 规格 规格 规格 规格 规格 规格 规格 规格 规格 规格 规格 规格 210 210 210 210 210 210 210 210 210 210 210 210 210 210 210 210 210 210 210 210 210 &quot;·* 1313601 A7 B7 V. Description of invention (1Q9) grams, 74%); 4 NMR&lt;5 (d6-DMSO): 1.26 (d, 6H), 3.82 (s' 3H), 4.50 (d, 2H) , 4.63(m, 1H), 5.26(t, 1H(-0H)), 7.1〇(s, 1H), 7.25(s, 1H), 7.47(s, 1H) » Prepare the necessary 5-- Isopropoxy-isophthalic acid monomethyl ester raw material:

2 g of molecular weight NaOH (1.03 g, 25.9 mmol) in a drunk (9 ml) was added to 5-isopropoxy-isodecanoic acid dimethyl ester (5.68 g) in acetone (45 ml). , 22.5 mmol), and stirred at room temperature overnight. The reaction mixture was concentrated and acidified to pH 1-2 (2 g molecular weight HCl), filtered, washed with water and dried under vacuum to give 14279/66/1 (5.25 g, 98%) as colorless solids (including 15- 20% diacid); MS (M-H+). 237 . Prepare the necessary dimethyl 5-isopropoxy-isophthalate as follows: Binding

line

5-hydroxy-isodecanoic acid dinonyl ester (5.2 g, 24'6 mmol), potassium carbonate (4·07 g, 29.5 mmol), potassium iodide (0.82 g) in DMF (50 ml) 4.9 millimoles) and 2-bromopropane (2.4 ml, 25.8 mmol) -114- This paper scale applies to China S standard (CNS) Α4 size (210X 297 mm) 1313601 A7 B7 V. Description of invention ( 11Q) Heating at 90 ° C for 3 hours' then adding additional 2-bromopropane (2.4 ml) and potassium carbonate (2.2 g), heating for an additional 4 hours, then cooling to room temperature and concentrating EtOAc (150 ml) Then, it was washed with water and brine, dried (MgSCU) 'filtered and concentrated' to give a pale yellow oil, which was solidified (6.0 g, 97%); MS (MH+) 253.

Example Z 2-(3-isopropoxy-5-methyl 醯 curtain) awkward a certain neck tapping -5-decanoic acid (path 24)

A solution of 2-(3-isopropoxy-5.hydroxymethyl)benzoylaminocarbazole-5-carboxylic acid (0.42 g, 1.25 mmol) in tetrahydrofuran (50 mL). - Martin periodinane (DMP, 58 kg, 1.37 mmol, 1 '1 equivalent) was treated and stirred at room temperature for 90 minutes. The repellent was removed under vacuum and the residue was taken up in dichloromethane and filtered. The residue was dissolved in ethyl acetate and a saturated solution of sodium hydrogencarbonate containing sodium thiosulfate solution (approximately 7 a quantity '2.1 gram of meta-mole) and the resulting 2-phase mixture was vigorously mixed' and then acidified to about pH 6. The title compound (0.145 g, 35%) was obtained as a colorless solid. &lt;5&gt;5 (d6-DMSO): 1.32 (d6H), 4.79 (m, 1H), 7.62 (m, 1H), 7.92 (m,1H), 8.13(s' 1H) 8.18(s, 1H), 10.03(s,1H) » ' Prepared according to the procedure provided in path 2a and illustrated by example (eg example Π8ΐ) -115 This paper scale applies China National Standard (CNS) Α4 Specification (210X 297 mm) 1313601 A7 B7 V. Description of Invention (111) Necessary 2-(3-Isopropoxy-5-hydroxymethyl)phenylhydrazinyl pyrimidazole _ 5-carboxylic acid starting material.

Example AA 7-{2-|~3-isopropoxy-5-(,3-carbo-butyr-1-propyl) molybdenum an amine 4崦_ 5-鼗acid fly f path 25)

A solution of isobutyltriphenyl bromide (45 g [1·13 mmol] 3.1 equivalent) in tetrahydrofuran (20 ml) was added with potassium t-butoxide (1.1 ml in 1 g of molecular weight tetrahydrofuran). 1.13 mmol, 3.1 eq.) was treated and stirred at 0 ° C under argon. 2-(3-Isopropoxy-5-methylindenyl)phenylhydrazinoyl «serazole-5-carboxylic acid (0.122 g '0.36 mmol) was added thereto, and the resulting solution was stirred for 100 minutes. Allow to warm to room temperature. Water was added and the solvent was removed in vacuo. The residue was partitioned between water and ethyl acetate and the layers were separated. The water was partially neutralized (2 g molecular weight HC1) and extracted twice with ethyl acetate. The organic extract was dried (MgSCU), filtered and concentrated, and the residue was chromatographed on a silica gel (10 g) Bondelut(R), which was purified by dissolving with methane (10% v/v) in the presence of MeOH to give the title compound as a colorless solid (0.012 g. 9%), NMR5 (d6-DMSO): l. d, 6H), 1.29(d, 6H), 2.81(m, 1H), 4.72(m, 1H) 6.53(dd, 1H), 6.29(d, 1H), 6.97(s, 1H), 7.50(s, 1H), 7.53(s -116- This paper size applies to Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1313601 A7 B7

V. INSTRUCTIONS (112) 1H), 8.11 (s, 1H), 8.18 (s, 1H).

The necessary 2_(3_isopropoxy-5-methyl)phenyl stearylamino" plug was prepared according to the procedure provided in Example Z (path 24). Sit-5 - a few acids, refer to the example ιι89. Example BB _2-"3-Isopropanyl-5-(4-methyl-1-|7-biting and cleavage of a argon _) 1 stupid _ Aminocarbazole (path 26)

Prepared starting from 2-(3-isopropoxy-5-carboxymethyloxy)phenylhydrazinyl pyrimidazole using standard sulfhydryl agglutination (Example A, Path 1) to give the title compound , lH NMR &lt;5 (d6-DMSO): 1.28 (d, 6H), 2.18 (s, 3H), 2.24 (m, 2H), 2.32 (m, 2H), 3.44 (ap t, 4H), 4.65 (m) , 1H), 4.85(s, 2H), 6.68(ap t, 1H), 7.19(m, 1H), 7.24(ap d, 2H), 7.55(ap d, 1H), 12.45(bs, 1H); m /z 419 (M+H) + , 417 (MH)·.

Preparation of the necessary 2-(3-isopropyl) from 2-(3-isopropoxy-5-methoxycarbonylmethyloxy)phenylhydrazinyl carbazole by standard ester hydrolysis (path 2a) Oxygen paper size is applicable to China National Standard (CNS) Α4 specification (210X 297 mm) 1313601 A7 B7 V. Description of invention (113) yl-5-carboxymethyloxy)phenylhydrazinyl hydrazone i' hNMRSd-DMSO): 1.28 (d, 6H), 4.69 (m, 1H), 4.73 (s, 2H), 6.66 (ap, 1H), 7.22 (s, 1H), 7.27 (ap d, 2H), 7.53 (ap d, 1H); m/z 337.3 1 (M+H) + , 335.27 (MH)-.

Prepare the necessary 2-(3-iso) from 3-isopropoxy-5-(methoxycarbonyl)methoxybenzoic acid and 2-aminopyrazole using standard sulfhydryl agglutination (path 1) Propoxy-5-methoxycarbonylmethyloxy)phenylhydrazinyl pyrimide starting material (48% winter isolated yield); NMR 5 (d6-DMSO): 1.27 (d, 6H), 3.70 (s, 3H) ), 4.71(m, 1H), 4.86(s, 2H), 6.99(t, 1H), 7.23(t, 1H), 7.26-7.27(m, 2H), 12.53(s, 1H); m/z 351.31 (M+H) + , 349.28 (MH)· 〇

c ΜθΟ^Ο Use the conditions of Ram and Charles (Tetrahedron 1997, 53 (21) pp. 7335-7340) to 3-isopropoxy-5·(carboxymethyloxy) Monoesterification of benzoic acid to prepare the necessary 3-isopropoxy-5-(methoxycarbonylmethyloxy)benzoic acid starting material (78% yield); iH NMR δ (d6-DMS0): 1.25 (d, 6H), 3.69(s, 3H), 4.65(m, 1H), the paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1313601 A7 B7 V. Description of invention (114) 4.83 (s, 2H), 6.71(ap t, 1H), 6.98(s, 1H), 7.0l(s>1H), 12.97(bs, 1H); m/z 554.27 (2M+NH4) + , 267.26 (M -Η)· » 3 -Isopropoxy-5-(carboxymethoxy)benzoic acid

The title compound (56 〇/〇 isolated yield) was obtained from (3-isopropoxy-5-(t-butoxy) methoxy) benzoic acid methyl ester using standard hydrolysis method 2a. 4 NMR5 (d6-DMSO) ·· 1.25 (d,6H), 4.62 (m,1H), 4.69 (s, 2H), 6.67 (ap t, 1H), 6.96 (s, 1H), 7.02 (s, 1H) ), 12.95 (bs, 1H); m/z 253.27 (MH)·.

The necessary methyl (3-isopropoxy-5-(t-butoxycarbonyl)methoxy)benzoate was prepared according to the general alkylation procedure B. The analytical data for all intermediates is consistent with the structure &quot;

Example CC Isoprote a certain -5-isopropyl hydrazine, a certain pyridine, neck pyridine (path 7b) This paper scale is applicable to China National Standard (CNS) A4 specification (21〇x 297 mm) A7 B7 1313601 V. Invention Description (115)

Adding 10% Pd/C to 2-(3·isopropoxy-5-isopropoxyphenyl)amino-5-nitron ratio in ethanol (2 mL) under inert gas (1.74 g, 4.66 mmol) solution. The reaction mixture was placed under hydrogen and vigorously stirred for 16 hours. Inert gas was poured into the reaction mixture, which was then diluted with water (2 mL) and acidified with 2 g of molecular weight HCl (5 mL). The residue was taken up in EtOAc (EtOAc) (EtOAc) The MgS〇4 is dried. The title compound (1.30 g, 81%) was obtained as a brown solid. *H NMR5 (d6-DMSO): 0.97 (d, 6H), 1.26 (d, 6H), 2. 〇〇 (m, 1H), 3.78 (d, 2H), 4.69 (m, 1H), 5.12 (s) , 2H), 6.58 (t, 1H), 6.99 (dd, 1H), 7.1 (ap d, 2H), 7.73-7.78 (m, 2H), 10.24 (bs, 1H); m/z 344.41 (M+H )+.

The necessary 2·(3·isobutoxy-5-isopropoxy)benzoylamino-5-nitropyridine was prepared according to path 1 (refer to Example 10 in the pyridine table). 1H NMR 5 -120- This paper size is applicable to China National Standard (CNS) Α4 specification (210 X 297 mm) 1313601 A7 B7 V. Description of invention (116) (d6-DMSO): 0.98(d, 6H), 1.27( d, 6H), 2.01(m, 1H), 3.60(d, 2H), 4.71(m, 1H), 6.67(ap t, 1H), 7.17(ap d, 2H), 8.39(d, 1H), 8.63 (dd, 1H), 9.20(d, 1H), 11.43(bs, 1H); m/z 374 (M+H) + , 372 (MH)· »

Example DD 2-1~(3-Isobutyl Lacyl..-5-Isopropoxy) Stuffed 1 Amino-5"]^-Methyl" Brewed a) Amidinopyridine (path 27)

2-[(3-Isobutoxy-5-isopropoxy)benzoinyl]aminopyridine-5-carboxylic acid (95 mg, 0.255 mmol) with EDC in DCM (3 mL) (59 mg '0.306 mmol), DMAP (37 mg, 0.306 mmol) and methanesulfonamide (36 mg '0.378 mmol) were stirred under inert atmosphere for 16 hours. The reaction mixture was diluted with more DCM (10 mL) andEtOAcEtOAc. One gram of molecular weight citric acid (5 ml) and saline (5 ml) were added. The title compound (90 mg &apos;790/o) was obtained as a colorless crystalline solid. 1HN^lRό(d6-DMSO) : 0.97(d, 6H), 1.26(d, 6H), 2.03(m, 1H), 3.01(s, 3H), 3.79(d, 2H), 4.70(m, 1H) , 6.63(ap t, 1H), 7.l4(ap d, 2H), 7.70(dd, 1H), 8.12(d, 1H), 8.34(ap d, 1H), 9.83(s, 1H), this Zhang scale applies to China National Standard (CNS) A4 specification (210x 297 mm) 1313601 A7 B7

V. Description of invention (117) ‘ 十ϋ) +, 420.30 (M-Η)-. Color 2a), from 2_[(3_isobutoxy-5 isopropyl-methyl acid) to prepare the necessary 2-[(3-isobutyl l〇-81(bs, 1H); m/z 422.37 (M +H) + by standard hydrolysis (path 2a), from oxy) phenyl aryl] amine acetophenone - 5 焱醢 methoxy-5-isopropoxy) phenyl hydrazino] pyridine _ 5-carboxylic acid starting material.

Prepare the necessary 2_(3_isobutoxy-5-isopropoxy)phenylhydrazinyl pyridine carboxylic acid methyl ester by standard 四 (4) based gas coupling (path υ). Example EE

. 乙气, a certain 醯 醯 丨 4 4 4 ( ( ( (path 28)

Hydrolysis of 2_ { 3-isopropoxy-5-[1-methyl-1-(5-ethoxycarbonyloxazol-2-ylaminocarbonyl)] B by standard method according to the route 2a of the example Ethyl phenyl hydrazino}amino oxazole-5-carboxylate to give 2-{3-isopropoxy-5-[l-methyl-1-(5-carboxythiazol-2-ylamine) Alkyl carbonyl)] ethoxyphenyl hydrazino amide, thiazole-5-carboxylic acid, NMR &lt; 5 (d6-DMSO): 1.22 (d, 6H), 1.61 (s, 6H), 4.58-4.64 ( m, 1H), 6.62(s, 1H), 7.19(s, 1H), 7.40(s, 1H), 8.05(s, 1H), 8.12(s, 1H), m/z 533 (MH)'-

Paper size suitable for material (CNS) A4 size (210 X 297 mm) 1313601 A7 B7 V. Description of invention (118) According to path 1 of example A, using standard sulphur-based gas method, from 3-isopropoxy -Methyl-1-yl)ethoxy]benzoic acid to start the necessary 2-{3-isopropoxy-5-[1-methyl-1-(5-ethoxycarbonyl-serazole-2 -ylaminocarbonyl)]ethoxyphenyl hydrazino}aminocarbazole 3-5-carboxylic acid ethyl ester raw material

0 human OH Prepare the necessary 3-isopropoxy group starting from methyl 3-isopropoxy-5-hydroxybenzoate according to the procedure described by Corey et al., JACS 21, page 4782 (1969). -5-[(1-Methyl-1-carboxy)ethoxy]benzoic acid starting material. The methyl group is hydrolyzed under the reaction conditions, and extracted into an aqueous solution of sodium hydrogencarbonate, followed by liquefaction and annual extraction into ethyl vinegar. The organic extract is dried (MgSOd, filtered and concentrated in vacuo). The title compound is obtained as a colorless solid: iH NMR5 (d6-DMSO): 1.15 (d, 6H), 1.5 (s, 6H), 4.55 (hept) , 1H), 6.55 (dd, 1H), 6.95 (m, 1H), 7.05 (m, 1H), 13.0 (br s, 283 (M+H)+. Example FF: similar to those described above The following example numbered alfalfa compounds can be made. _ Example;: Structure:: suitable: 3⁄4π', I path &gt; mH) + (MH) 5 1 &amp; 1 1HNMRd (d6-DMSO): 3.95 (3H, s); 5.25 (4H, s); 6.95 (1H, s); 7.4 (6H, m); 7.5 (2H, m); 7.65 (2H, m); 8.25 (1H, d); 8.6 (1H, d ); 11.85 (1H, br s). -123- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1313601 V. Invention description (119) A7 B7 Real-Example 1 2~ Γ4 Trail ; (scared mmmaBm..妒V 2 524/52 6 522 1HNMRd(d6-DMSO):' 2.0 (1H, s); 5.25 (4H, s); 6.95 (1H, s); 7.4 (6H, m); 7.5 (2H, m); 7.6 (2H, m); 8.25 (1H, d); 8.55 (1H, d); 1H, brs). MS and NMR contain a signal due to the acid starting material (~20 mol%); NMR contains a signal due to ethyl acetate | (~33 mol %) 3 1 1H NMR d (d6-DMSO): 5.24 (4H, s); 6.93 (1 Η, m); 7.37 (6Η, m); 7.50 (2H, m); 7.61 (2H, m); 7.71 (1H, dd); 8.36 (1H, d); 9.00 (1 H,d). 4 2* 524/526 522/5 24 1H NMR 6 (d6-DMSO): 5.2 (4H, s); 6.95 (1H, m); 7.15 (1H, s); 7.3 (1H , d); 7.4 (4H, m); 7.5 (2H, m); 7.6 (2H, m); 9.1 (2H, s); 11.35 (1H, brs); the spectrum also contains the letter due to the acid material' / -40 莫开', 5 丫0 ° 妒Χ&quot;.Ν fjr^° 2a, lc (c) 428 δΗ (300MHz, DMSO-di) 1.29 (6H, d), 3.08 (2H, t), 4.30 (2H , t), 4.74 (1H, m), 6.73 (1H, s), 7.13 (lH,m), 7.24 (1H, s), 7.27 (lH,s), 7.34 (lH,m), 7.52 (1H, m), 8.25 (1H, d), 8.56 (1H, d), 11.75 (1H, s), 13.66 (lH, brs). * For Example 15 5, the ester intermediate is prepared by Route 1, and is Illustrated in Example 1 2 : -124- This paper scale applies to China National Standard (CNS) A4 specification (21 x 297 mm) 1313601 A7 B7 V. invention is described (12Q)

Example GG: The following compounds of Examples 001 to 007 were also prepared in a manner similar to those described above. Examples | Climbing _ 丨ρι_ 1 if 2* 1H NMRd (d6-DMSO): 5.22 (4H, s); 6.54 (1 H, d); 6.93 (1H, d); 7.27 (1H, d); 7.32-7.44 ( 6H, m); 7.53 (2H, m); 7.63 (2H, s); 11.85 (1H, s); 12.86 (1H, br s). 2 1HNMRd (d6-DMSO): 3.75 (3H, s); 5.21 (4H, s); 6.55 (1H, d); 6.86 (1H, m); 7.31 (1H, m); 7.38 (4H, m); 7.38 (2H, m); 7.56 (1H, m); 7.59 (2H, m); 10.80(1 H, hr s). 3 0r la 331 4 〇Ν -Ν la 332.53 330.51 1 1 . i δΗ (300MHz, CDClj) 1.02 (6H, d), 1.36 (6H, d) , 2.08 (lH,m), 2.30 (3H, s), 3.75 (d, 2H), 4.60 (1H, hept), 6.66 (2H, m), 7.08 (2H, m), 9.85 (1H, br s) 5 I Τ^ΝΧ&gt;-&lt;_ X la 376.47 374.45 δΗ (300MHz, DMSO-d^) 0,98 (6H, d), 1.27 (6H, d)t 2.02 (1H, m), 3.80 (2H (d), 3.84 (1H, pt) Applicable to China National Standard (CNS) A4 specification (210X297 mm) -125 -

Binding

Line 1336061 A7 B7 V. Description of invention (121) 1 Example _ \ 丨 structure - 6 vp- lb (HA TU) 386.47 δΗ (300MHz, CDC13) 1.35 (6H,d), 3.13 (2H, 0,3.72 (3H, s), 4.16 (2H, t), 4.53 (lH, hept), 6.60 (1H, s), 6.83 (1H, s), 7.00 (4H, m) 7.28 (2H, m), 8.98 (lH, brs) 7 &gt;&gt; 1 la 384 j *About GGt, prepare the ester intermediate with path 1:

;7.33-7.43 (7H, lH NMR 5 (di-DMSO): 3.80 (3H, s); 5.23 (1H, m); 6.61 (1H, d); 6.95 (1H, s) m); 7.50-7.55 ( 2H, m); 7.60-7.63 (2H, m); 11.90 (1H, br s). Example HH: The following example numbered compounds can also be prepared in a manner similar to those described above. HH^I surface m 赖1 I 1 I 484 1H NMR d (d6-DMSO): 5.26 (4H, s); 7.02 (1H, s); 7.40 (4H, m); 7.46 (2H, m); 7.54 ( 2H,m); 7.63 (2H, m); 9.24(1 H, s); 13.08 (1H, brs). -126- This scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1313601 V. INSTRUCTIONS (122) A7 B7 Γίϋ _ _ 2 1 1H NMR d (d6-DMSO): 2.63 (3H, s); 5.24 (4H, s); 6.96 (1H, s); 7.35-7.45 (6H , m); 7.51 (2H, m); 7.61 (2H, m); 12.84 (1H, brs). 3 Sr 1 1HNMRd (d6-DMSO): 1.38 (3H, t), 3.25 (2H, q); (4H, s); 6.97 (1H, s); 7.41 (6H, m); 7.54 (2H, m); 7.64 (2H, m); 13.13 (1H, br s). 4 °v^ °ir 1 1HNMRd (d6-DMSO): 1.32 (3H, t), 4.32 (2H, q); 5.20 (4H, s); 6.78 (1H, s); 7.39 (4H, m); 7.46 (2H, m); 7.53 ( 2H, m); 7.64 (2H, m). 5 1 1H NMR d (d6-DMSO): 4.20 (3H, s); 5.28 (4H, s); 6.98 (1H, s); 7.42 (6H, m) 7.53 (2H, m); 7.62 (2H, m); 12.78 (1H, br s). 6 °ir 2 530, 532 1HNMRd (d6-DMSO): 5.24 (4H, s); 6.96 (1H, s) 7.37 (4H, m); 7.33 (2H, m); 7.53 (2H, m); 7.62 (2H, m). 7 ΪΤ 1 1H NMR d (d6-DMSO): 5.2 5 (4H, s); 6.74 (1H, m); 6.99 (1H, s); 7.23 (1H, m); 7.41 (4H, m); 7.49 (2H, m); 7.53 (2H, m); (2H, m); 7.97 (1H, s); 13.20 (1H, br s)_ -127- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1313601 A7 B7 V. Description of invention (123) _Example A. Y Crystal:::Mono f police', 1 path i Talk: (H)+ (Mi H)- 8 1 1H NMR d (d6-DMSO): 5.34 (4H, s); 7.03 (1H, s); 7.49 (2H, m); 7.57 (2H, m); 7.75 (4H, m); 7.91 (2H, d); 9.22 (1H, s); 13.06 (1H, br s). 9 19 564, 566 1H NMR d (d6-DMSO): 5.20 (4H, s); 6.68 (1H, m); 7.37 (4H, m); 7.45 (2H, m); 7.50 (2H, m); (2H, m). 10 1 566 564, 566 1H NMR d (d6-DMSO): 5.22 (4H, s); 6.99 (1H, m); 7.39 (4H, m); 7.45 (2H, m); (2H, m); 7.60 (2H, m); 13.34 (1H, brs). 11 °ir 1 1HNMRd(d6-DMSO): 2.33 (3H, s), 2.37 (3H, s); 3.25 (2H, m 4.21 (2H, t); 5.14 (2H, s); 6.84 (1H, m); 7.22 (3H, m); 7.31 (1H, s); 7.40 (2H, m); 8.83 (1H, s) 9.21 (1H, s); 12.99 (1H, br s). 12 ΪΤ 1 1HNMRd(d6-DMSO): 1.33 (3H, t); 2.32 (3H, s), 2.35 (3H, s); 3.22 (2H, m); 4.21 (2H, t); 4.40 (2H, q); 5.13 (2H, s); 6.87 (1H, m); 7.22 (3H, m); 7.33 (1 H, m); 7.41 (2H, m); 8.82 (1H, s); 13.46 (1H, brs). -128- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1313601 A7 B7 V. Description of invention (124) ._example; ί V'?·· . 13 ' Μξ % 516, 518 1H NMR d (d6-DMSO): 5.21 (4H, s); 6.98 (1 H, m); 7.34-7,40 (6H, m); 7.50 (2H, m); 7.59 (2H, m). I 14 398 NMR NMR 5 (d^^DMSO): 1.0 (d, 6H), 2.0 (hept, 1H), 2.35 (s , 3H), 3.8 (d, 2H), 5.2 (s, 2H), 6.85 (d, 1H), 7.15-7.25 (m, 3H), 7.30 (d, 1H), 7.4 (2H, m), 9.2 ( s, 1H), 11.6 (brs, 1H). 15 402 lH NMR δ (cU-DMSO): 1.0 (d, 6H), 2.0 (hept, 1H), 3.8 (d, 2H), 5.2 (s, 2H) , 6.85 (s, 1H), 7.2-7.3 (m, 2H), 7.35 (s, 1H), 7.4 (m, 2H), 7.6 (t, 1H), 9.2 (s, 1H), 13.0 (brs, 1H) 16 350 17 °r 322 *H NMR 6 (d^-DMSO): 1.3 (d, 12H), 4.7 (hept, 2H), 6.65 (s, 1H), 7.25 (s, 2H), 9.2 (s , 1H), 12.95 (br s, 1H). 18 v^> 'H NMR δ (d6-DMSO): 2.34 (s, 3H), 3.23 (t, 2H), 4.21 (t, 2H), 4.62 (d, 2H), 5.26 (d, 1H), 5.40 (d, 1H), 6.05 (m, 1H), 6.75 (s, 1H), 7.31 (s, 2H), 8.83 (s, 1H), 9.20 (s, 1H), 12.48 (br s, 1H)_ -129- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1313601 A7 B7 V. Description of invention (125) Γ Path 丨 I Xinjiang H)-?' 19 Sr 'H NMR δ (d6-DMSO): 2.31 (s, 3H), 2.34 (s, 3H), 3.22 (t, 2H), 4.21 (t, 2H), 5.13 (s, 2H), 6.84 (s, 1H), 7.15-7.25 (m, 3H), 7.26 (1H, m), 7.39 (2H, m), 8.81 (s, 1H). 20 ir 'H NMR 6 (d6-DMSO ): 2.37 (s, 3H), 2.42 (s, 3H), 3.29 (t, 2H), 4.29 (t, 2H), 5.21 (s, 2H), 5.58 (s, 2H); 6.92 (s, 1H) , 7.22-7.31 (m, 3H), 7.40 (1H, bs), 7.47 (2H, m), 8.90 (s, 1H). MS ES+ 547.2, 549.1 (M+H)' 21 19 lH NMR 5 (d&lt; I-DMSO): 2.35 (s, 3H), 2.93 (s, 6H), 3.22 (m, 2H), 4.19 (m, 2H), 6.41 (m, 1H), 6.98 (m, 1H), 7.06 (m , 1H), 8.80 (s, 1H), 9.17 (s, 1H). 22 0 N H5r 19 lHNMRS(d6-DMSO): 2.58 (m, 6H), 3.43 (t, 2H), 4.37 (t, 2H) , 4.50 (d, 2H), 6.41 (m, 1H), 6.61 (m, lH), 7.16 (m, 2H), 7.34-7.45 (m, 3H), 7.50 (m, 1H), 9.05 (s, 1H) ), 9.42 (s, 1H). 23 1 358 *H NMR δ (d&lt;i-DMSO): 3.81 (s, 3H), 5.15 (s, 2H), 7.18 (t, 1H), 7.2-7.3 (m, 3H) ), 7.38 (d, 1H), 7.39-7.43 (m, 1H), 7.55 (t, 1H), 12.27 (br s, 1H) 24 H〇t^^ 20 363 361 lH NMR δ (d&lt;5-DMSO) ): 2.35 (s, 3H), 3.2 (t, 2H), 4.2 (t, 2H), 6.55 (m, 1H), 7.05 (s, 1H), 7.2 (s, 1H), 8.81 (s, 1H) , 9.2 (s, 1H), 9.8 (br s, 1H). -130- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1313601 A7 B7 V. Description of invention (126) Example -丨 Path “ _ H)^ 25 〇V- 〇Μ SJ lb 336 26 Κϋ. , 0 Ν V lb 405 27 2a, lc (b) 388 386 δΗ (500MHz, DMSOO 1.27 (6H,d), 4.73 (lH,m), 5.21 (2H, s), 6.82 (1H? s), 7.20- 7.31 (3H, br m), 7.36-7.47 (2H, brm), 7.58 (1H, t), 9.23 (1H, s), 12.97 (1H, br s). 28 Νγ^ Ο Ύχ^:^ cr^ 2a , lc (b) 389 δΗ (500MHz, DMSO-cW 1.28 (6H, d), 3.06 (2H, t), 4.27 (2H, t), 4.72 (1H, m), 6.72 (1H, s), 7.12 ( 1H, d), 7.26 (1H, s), 7.31 (2H, m), 7.48 (lH, m), 9.20 (lH, s). 29 ατ-° 2a, la (d) 434 δΗ (300MHz, DMSO- Dtf) 1.26(6H,d),3.07(2H,t), 4.15 (2H, t), 4.70 (1H, m), 6.68 (1H, s), 7.11 (1H, d), 7.22-7.34 (3H, Br m), 7.47 30 V彳lb (HA TU) 402 .42 400 •39 δΗ (300MHz, DMSO-dtf) 1.27 (6H, d), 2.63 (3H, s), 4,70 (lH,hept), 5.20 (2H, s), 6.82 (lH, s), 7.24 (3H, m), 7.39 (2H, m), 7.56 (1H, t), 12.80 (1H, br s). 31 f/ lb (HA TU ) 404 .40 402 .37 δΗ (300MHz, DMSO-dtf) 1.27 (6H,d), 2.63 (3H,s), 3.06 (2H, t), 4.25 (2H, t), 4.70 (1H, hept), 6.72 (1H, s), 7.12 (lH, d), 7.28 (3H, m), 7.47 (lH, m), 12_77 (lH, br s). 32 lb (HA TU) 468 .39 466 .37 δΗ (300MHz, DMSO-φ) 2.63 (3H, s), 5.23 (4H, s), 6.97 (lH, s), 7.24 (4H, m), 7.43 (4H, m), 7.57 (2Hf t ), 12.84 (1H, br s).

Binding-131 - This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1313601 A7 B7 V. Invention description (127) 1' tM L 13⁄43⁄4 m Η)- 33 AV Η la 336 .44 334 .40 Example II: The following compounds of Examples Nos. 11 through 11166 can also be prepared in a manner similar to those described above. Part of the compound (multi-parallel synthesis) was prepared by path lb as illustrated in Example T. With respect to the compound prepared by the route 2a (hydrolysis of the ester), the necessary starting materials can be prepared in the route 1 or 1b. Example 丨wmm: job Ί m _ 1 °ir 1 485, 487 1H NMRd (d6-DMSO): 5.24 (4H, s); 6.93 (1H, s); 7.26 (1 H, d); 7.36-7.43 (6H , m); 7.50 (2H, m); 7.55 (1 H, d); 7.61 (2H, m); 12.60 (1H, brs). 2 6&quot; 2a ★★★* 1H NMRd (d6-DMSO): 5.25 (4H, s); 7.0 (1 H, s); 7.4 (6H, m); 7.5 (2H, m); 7.6 (2H, m); 8.2 (1H, d). 3 °v^— 1 1HNMRd( D6-DMSO): 3.62 (3H, s); 3.76 (2H, s); 5.24 (4H, s); 6.94 (1H, m); 7.06 (1 H, s); 7.38-7.47 (6H, m); 7.54 (2H, m); 7.63 (2H, m); 12.69 (1H, brs). -132- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1313601 V. Description of invention (128 A7 B7 Example - Road planting. wm m (exposure 4 Vr ϊτ 1 531 1H NMRd (d6-DMSO): 4.77 (2H, s); 5.25 (4H, s); 6.94 (1H, m); 7.31 (1H, s 7.36-7.48 (6H, m); 7.53 (2H, m); 7.63 (2H, m); 12.83 (1H, br s) (+ 0.4 eq. iPr2NEt). 5 3 528, 530 1HNMRd (d6-DMSO) ): 2.63 (3H, m); 4.16 (2H, m); 5.24 (4H, s); 6.99 (1H, s); 7.38-7.44 (7H, m); 7.52 (2H, m); 7.62 (2H, m); 9.06 (1 H, br s); 12.75 (1H, brs). 6 ϊτ, 3 1H NMRd (d6-DMSO): 2. 57 (3H, m); 3.48 (2H, m); 5.25 (4H, s); 6.95 (2H, m); 7.36-7.44 (6H, m); 7.53 (2H, m); 7.62 (2H, m) ; 7.83 (1H, m); 12.60 (1H, br s). 7 °VAfi 2a irkirk 497, 499 (· C02 ) 1HNMRd (d6-DMSO): 3.64 (2H, s); 5.26 (4H, s); 6.95 (1H, s); 7.37 (1H, s); 7.37-7.46 (6H, m); 7.54 (2H, m); 7.63 (2H, m); 12.40 (1 H, br s); 12.68 (1H, brs (•HCI). 8 6 2a acre 459, 415 (C02) 1H NMR d (d6-DMSO): 5.15 (4H, S); 6.9 (1 H, s); 7.2-7.5 (12H, m); (1H, s). 9 1 1H NMR d (d6-DMSO): (iPr2NEt salt) 1.24 (15H, m); 3.12 (2H, m); 3.80 (2H, m); 5.24 (4H, s); (1H, m); 7.36-7.45 (7H, m); 7.51 (2H, m); 7.61 (2H, m); 12.56 (1H, brs). -133- This paper scale applies to the Chinese National Standard (CNS) A4 size (210X 297 mm) 1313601 V. Description of invention (129) A7 B7 Spare m §) 志 m H)^v mwmmmmsami 10 3 1H NMR d (d6-DMSO): 2.45 (4H, m); 3.55 ( 2H, s); 3.61 (4H, m); 5.29 (4H, s); 7.00 (1 H, m); 7.11 (1H, s); 7.43-7.51 (6H, m); 7.58 (2H, m); 7.67 (2H, m); 12.66 (1H, brs). 11 ° Ir 4 550, 552 1H NMR d (d6-DMSO): 5.19 (2H, brs); .23 (4H, s); 6.72 (1H, dd); 6.93 (1H, m); 7.03 (1H, m); 7.35-7.44 (7H, m); 7.51 (2H, m); 7.61 (2H, m 12.46 (1H, brs). 12 3 558, 560 1H NMRd (d6-DMSO): 2.60 (2H, t); 3.45 (2H, t); 3.72 (2H, s); 5.22 (4H, s); (1H, m); 6.96 (1H, s); 7.35-7.30 (7H, m); 7.50 (2H, m); 7.60 (2H, m). 13 ir 3 586, 588 1H NMR d (d6-DMSO) : 3.11 (2H, q); 3.37 (2H, q); 3.50 (2H, s); 3.61 (1H, t); 5.22 (4H, s); 6.92 (2H, m); 7.34-7.42 (6H, m 7.49 (2H, m); 7.60 (2H, m); 7.88 (1H, brs). 14 V, 2r 3 554, 556 1H NMR d (d6-DMSO): 0.29 (2H, m); 0.40 (2H , m); 2.16 (1H, m); 3.79 (2H, s); 5.27 (4H, s); 6.98 (2H, m); 7.40-7.48 (7H, m); 7.56 (2H, m); 7.66 ( 2H, m). 15 2b 麦 麦 366 364 1H NMR d (d6-DMSO): 7.05 (1H, d); 7.35 (1H, t); 7.45 (1H, dd); 7.6-7.75 (2H, m 7.85 (1H, m); 7.9 - 8.0 (2H, m); 8.15 (1H, s); 13.1 (2H, br s). -134- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1313601 A7 B7 V. INSTRUCTIONS (130) EXAMPLES - CHECK ΒΒ &amp; ήβΒΙ 1 _ i 16 6 1H NMR d (d6-DMSO) : 2.68 (3H, s); 3.81 (1H, s); 5.15 (2H, s); 6.38 (1H, s); 6.87 (1 H, s); 7.00 (1H, s); 7.37 (2H, m) ;7.49 (1H, m); 1 H, m); 7.87 (1H, s); 8.05 (1H, s); 8.14 (1H, s); 8.45 (1H, s). 18 Y 6 400, 402 (- C02 ) 1H NMR d (d6- DMSO): 1.22 (6H, d); 4.36 (2H, m); 4.58 (1H, m); 6.24 (1H, s); 6.47 (1 H, m); 6.84 (2H, m); 7.26 (3H, m); 7.37 (2H, m); 7.45 (1H, m); 7.76 (1H, br s). 19 Υ 6 1HNMRd (d6-DMSO): 1.21 (6H, d); 4.28 (2H, m); 4.55 (1H, m); 6.26 (1H, s); 6.43 (1H, m); 6.83 (1H, s); 6.89 (1 H, s); 7.20 (1H, m); 7.26-7,37 (4H, m); 7.74 (1 H, brs). 20 Υ 6 367 (- C02 ) 1H NMR d (d6-DMSO): 1.23 (6H, d); 4.38 (2H, s); 4.60 (1H, m); (1H, m); 6.89 (2H, m); 7.47 (1H, dd); 7.89 (1H, d); 8.10 (1H, s); 8.51 (1H, dd); 8.63 (1H, d). 21 Ύ 6 396 (- C02 ) 1H NMR d (d6-DMSO): 1.21 (6H, d); 3.81 (3H, s); 4.24 (2H, m); 4.55 (1H, m); 6.26 (2H, m); 6.84 (3H,m); 6.97(1 H, m); 7.20 (2H, m). -135- This paper scale applies to Chinese national standard (CNS) A4 size (210 X 297 mm) 1313601 A7 B7 V. Description of invention (131) ^ i ϋβΗνβΒΒ s diameter ϋ m 22 Tr 6 464, 420 (- C02 ) 23 Y 6 1HNMRd(d6-DMSO): 0.28 (2H, m); 0.52 (2H, m); 1.09 (1H, m); 1.32 (6H, d); 3.02 (2H, d); 4.69 (1H, m); 6.50 (1H, s); 6.99 ( </ RTI> <RTIgt; , m); 6.37 (1H, m); 6.85 (1H, s); 6.90 (1H, s); 7.26 (2H, m); 7.13 (3H, m); 8.10 (1H, s). Y 6 348 1H NMRd (d6-DMSO): 1.27 (6H, d); 2.96 (6H, s); 4.69 (1H, m); 6.39 (1H, m); 6.97 (1 H, s); 7.04 (1H, s); 8.13 (1H, s); 12.89 (1H, brs). 26 °V〇H σχ^Λ person, 〇y 2a ★★★★ 389, 391 1H NMR d (d6-DMSO): 5.21 (2H, s); 7.29-7.49 (6H, m); 7.74 (2H, s); 8.13 (1H, s); 13.1 (1H, brs). 27 5r 1 1HNMRd (d6-DMSO): 2.31 (3H, s); 2.35 (3H, s); 3.22 (2H, t); 4.21 (2H, t); 5.12 (2H) s); 6.79 (1H, m); 7.18-7.28 (4H, m); 7.30 (1 H, m ); 7.54 (1H, d); 8.82 (1H, s); 12.48 (1H, br s). -136- This paper scale applies to the Chinese National Standard (CNS) A 4 specifications (210X297 mm) 1313601 A7 B7 V. Description of invention (132) Dirty 1: Following path 96Ι*·| ·Γ M Π) 十; (M'fc _ 28 °ir 1 1H NMR d (d6-DMSO) : 2.32 (3H, s); 2.37 (3H, s); 3.24 (2H, t); 4.22 (2H, t); 5.13 (2H, s); 6.80 (1H, m); 7.19 (3H, m); 7.29 (1H, s); 7.37-7.45 (3H, m); 9.06 (1H, s); 12.48 (1H, brs). 29 1 1H NMR d (d6-DMSO): 1.28 (3H, t); 2.32 ( (3H, s); (1H, s); 7.38 (2H, m); 8.20 (1H, s); 8.81 (1H, s). 30 0 V〇H 6 2a (1) Ή NMR d (de-DMSO): 1.26 (d, 6H), 4.69 (m, 1H), 5.14 (s, 2H), 6.75 (s, 1H), 7.26-7.48 (m, 7H), 8.01 (s, 1H). 31 2a (1b) 391 Ή NMR d ( Di-DMSO): 1.0 (d, 12H), 2.0 (m, 2H), 3.8 (d, 4H), 6.75 (s, 1H), 7.25 (d, 2H), 8.15(s, 1H). 32 °v ^ Ύ 1 W NMR δ (d«-DMSO): 1.26 (d, 6H), 4.69 (m, lH), 5.16 (s, 2H), 6.74 (s, 1H), 7.26 (d, 1H), 7.31- 7.47 (m, 7H), 8.54 (d, 1H), 12.47 (bs, 1H). 33 °r 2a (1) *H NMR δ (d^-DMSO): 1.26 (d, 6H), 2.38 (s, 3H), 4.69 (m, lH), 5.18 (s, 2H ), 6.31 (s, 1H), 6.76 (s, 1H), 7.30 (s, 1H), 7.35 (s, 1H), 8.00 (s, 1H). -137- This paper is again applicable to the Chinese National Standard (CNS) A4 size (210 X 297 mm) 1313601 A7 B7 V. Description of invention (133) t example ~~ ^3 m mmn path _ m HP 34 υ 2a (1) • HNMRaid^-DMSO): 1.26 (d, 6H ), 2.39 (s, 3H), 4.70 (m, 1H), 5.20 (s, 2H), 6.31 (s, 1H), 6.79 (s, 1H), 7.27 (s, 1H), 7.32 (s, 1H) , 8.12 (s, 1H). 35 d·. 1b 397 36 1b 401 37 Y 1 ^NMRaid^-DMSO): 1.27 (d, 6H), 2.39 (s, 3H), 4.69 (m, 1H), 5.18 (s, 2H), 6.31 (s, 1H), 6.76 (s, 1H), 7.26 (m, 2H), 7.32 (s, 1H), 8.53 (d, 1H). 36 2a (1) 379 377 ^NMRaidi-DMSO): 12.98 (bs, 1H), 8.12 ( s, 1H), 7.24(s, 1H), 6.66(s, 1H), 4.70( m, 1H), 3.79 (d, 2H), 2.01 (m, 1H), 1.28 (d, 6H), 0.98 (d , 6H). 37 〇V〇HY 2a (1b) 365 NMR NMR d (c^-DMSO): 1.25 (d, 12H), 4.7 (hept, 2H), 6.65 (s, 1H), 7.2 (s, 2H) ), 8.15(s, 1H). 38 . 0 2a (1) *H NMR δ (d&lt;i-DMSO): 2.64 (s, 3H), 5.16 (s, 4H), 6.90 (s, 1H), 7.29-7.47 (m, 7H), 7.53 (s , 1H), 8.03 (m, 1H), 12.90 (bs, 1H). 1 -138- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1313601 A7 B7 V. Description of invention (134 Path surface m 39 °ό 2a(1) lH NMR 5 (d^-DMSO): 2.64 (s, 3H), 5.17 (s, 4H), 6.93 (s, 1H), 7.29-7.45 (m, 7H), 7.53 ( s, 1H), 8.13 (m, 1H). 40 shv ” 1 'H NMR δ (d&lt;i-DMSO): 2.64 (s, 3H), 5.14 (s, 4H), 6.90 (s, 1H), 7.26 (d, IK), 7.31-7.47 (m, 7H), 7.49 (m, 1H), 7.55 (d, 1H), 12.56 (bs, 1H). 41 °&gt; 1b 349 42 °v^ 2a(1) 'H NMR 5 (d^-DMSO): 5.22 (s, 4H), 6.96 (s, 1H), 7.20-7.29 (m, 4H), 7.37-7.44 (m, 4H), 7.55 (m, 2H), 8.12 (s , 1H). 43 2a(1) 'H NMR δ (cU-DMSO): 5.21 (s, 4H), 6.93 (s, 1H), 7.19-7.29 (m, 4H), 7.38-7.46 (m, 4H), 7.56 ( m, 2H), 8.03 (s, 1H). 44 2a (1) 'H NMR 5 (c^-DMSO): 2.38 (s, 3H), 3.25 (t, 2H), 4.24 (t, 2H), 4.65 (d, 2H), 5.27 (d, 1H), 5.42 (d, 1H), 6.05 (m, 1H), 6.78 (s, 1H), 7.32 (s, 2H), 8.15 ( s, 1H), 8.90 (s, 1H), 12.94 (br s, 1H). 45 2r -1 2a(1) 39- 'HNMRaCdi-DMSO): 2.32 (s, 3H), 2.34 (s, 3H), 3.22 (t , 2H), 4.21 (t, 2H), 5.13 (s, 2H), 6.82 (s, 1H), 7.16-7.25 (m, 3H), 7.30 (1H, s), 7.39 (lH, m), 7.98 ( s, 1H), 8.81 (s, 1H). This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1313601 A7 B7 V. Invention description (135) Example im-m ^mwwM Path V· · ·...' -- m H 芦 (MS Η}-: m^m\ 46 2a * 419 417 NMR δ (d6-DMSO): 3.8 (s, 3H), 5.3 (s, 2H), 7.15 ( Dd, IH), 7.2-7.4 (m, 4H), 7.5 (d, lH), 7.6 (dt 1H), 8.0 (st IH). 47 2a * 427 425 'HNMR5(d6-DMSO): 1.1 (d, 6H), 2.85 (hept, IH), 3.75 (s, 3H), 5.2 (s, 2H), 7.0-7.3 (m, 6H), 7.4 (d, IH), 8.0 (st IH). 48 ^°χρΛ ^°Η νη2 2a ** 405 403 XK NMR 6 (d6-DMSO): 2.34 (s, 3H), 3.20 4.13 (t, 2H), 6.43 (s, IH), 6.92 (s, IH), 6.97 (s , 1H), 8.09 (s, 1H), 8.83 (s, IH), 12.75 (bs, IH) 49 ore. χ?γΎ 2a * *H NMR δ (d6-DMSO): 2.33 (s, 3H), 2.36 (2.36, 3H), 3.23 (t, 2H), 4.22 (t, 2H), 5.15 (s, 2H), 7.21 (s, IH), 7.02-7.44 (m, 6H), 8.13 (s, 1H), 8.85 (s, lH), 12.92 (bs, IH) 50 {jC°rX^ 6 ** 'HNMR5(d6- DMSO): 2.32 (s, 3H), 2.34 (s, 3H), 3.19 (t, 2H), 4.12 (t, 2H), 4.25 (s, 2H), 6.37 (s, IH), 6.92 (d, 2H) ), 7.08-7.21 (m,3H), 7.25 (dd, IH), 8.10 (s, 1H), 8.85 (s, IH), 12.76 (bs, IH) 51 HX 6 ** 52 1 lH NMR δ (d6 - DMSO): 1.28 (t, 3H), 2.35 (s, 3H), 3.22 (t, 2H), 4.11 (t, 2H), 4.27 (q, 2H), 4.63 (d, 2H), 5.26 (dd, (I, IH) (bs, IH) 53 lb 261 259 'ΗΝΜΚδ(€〇α3): 4.58((1, 2H), 5.31 (dd, IH), 5.45 (dd, lH), 6.04(m, 1H)(6.95 (d, IH) 7.11(d, iH), 7.18(m,lH), 7,41 (t,IH),7.55 (m,2H), 12.09 (brs, IH). -140- This paper scale applies to Chinese national standards (CNS) A4 size (210X 297 mm) 1313601 A7 B7 V. Description of invention (136) ^ tn -4 mm 'IS, _ (M戎Η)-.ΐ 斋录缘,卜4愚^. 54 Ay〆2a 445 *H NMR 5 (d6-DMSO): 0.98 (d, 6H), 1.98-2.05 (τη. 1H), 3.81 (d, 2H), 5.20 (s, 2H), 6.81 ( s, 1H), 7.0-7.1 (m, 2H), 7.35 (s, 1H), 7.38-7.45 (mt 2H), 7.58 (t, 1H), 8·03 (s, 1H), 12.90 (br s, 1H). 55 6r 2a 441 lH NMR δ (d6-DMSO): 0.98 (d, 6H), 1.98-2.05 (m, 1H), 2.36 (s, 3H), 3.81 (d, 2H), 5.17 (s, 2H), 6.81 7.17-7.23 (m,3H), 7.32 (s,1H), 7.40 (ap d, 2H), 8.01 (s, 1H) 56 丫χ/θ: ό° 2a lH NMR 5 (d6-DMSO ): 1.27 (d, 6H), 4.71 (sept, 1H), 5.16 (d, 2H), 6.78 (d, 1H), 7.25-7.51 (m, 7H), U2(s, 1H), 12.98 (bs, 1H) 57 2a 434 432 *H NMR δ (d6-DMSO): 0.98 (d, 6H), 1.98-2.05 (m, 1H), 3.81 (d, 2H), 5.26 (s, 2H), 6.83 (apt, 1H), 7.30 (s, lH), 7.39 (s, 1H), 7.79 (s, 1H), 8.12 (s, 1H), 9.1 (s, 1H). 58 0 Η « ~{ lb 335 59 0 ) lb 293 60 Ύχ/Ρ 6f 1 lHNMR5(d6-DMSO): 1.29 (d. 6H), 4.74 (sept, 1H), 5.22 (s, 2H), 6.79 (t, 1H), 7.19-7.32 (m, 4H) , 7.37 (t, 1H), 7.43 (m, 1H), 7.56 (m, 2H), 12.61 (bs, 1H) 61 V only 2a lH NMR δ (d6-DMSO) 1.26 (d, 6H), 4.64-4.76 (m, 1H), 5.20 (s, 2H), 6.78 (s, 1H), 7.18-7.34 (m, 3H), 7.36-7.46 (m, 2H), 7.50-7.60 (m, 1H), 7.98 (s, 1H) -141 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1313601 V. Invention description (137) A7 B7 Example ~丨':._响1 Path ra- coupon-:#· _ 曙62 2a lH NMR δ (d6-DMSO):): 1.27 (d,6H), 4.71 (m,lH), 5.20 (s, 2H), 6.78-6.84 (m, lH), 7.18-7'31 (m, 3H), 7.34-7.49 (m, 2H), 7.52-7.61 (m, 1H), 8.12 (s, 1H), 12.98 ( Bsf 1H) 63 &lt;V-OH 丄. 2a 377 lH NMR δ (c^-DMSO): 0.0-0.2 (m, 2H), 0.22-0.3 (m, 2H), 0.98 (d, 6H), 3.59 (d, 2H), 4.35-4.42 (m, 1H), 6.4 (s, 1H), 6·93 (s, 2H), 7.82 (s, 1H). 64 V〆4. 2a 403 *H NMR δ (d6-DMSO): 1.29 (d,6H), 4.78 (m, 1H), 4.86 (q, 2H), 6.89 (ap t, 1H), 7.36 (ap t, 2H),8_ 17 (s, 1H), 13.05 (bs) 65 0rF 1氺氺氺lH NMR δ (d6-DMSO): L29 (d, 6H), 4.72 (m, 1H), 5.19 (s, 2H), 6.88-6.97 (m, 1H), 7.09 (m, 1H), 7.16-7.26 (m, 4H), 7.54 (d, iH), 7.6i (s, lH), 7.70 (s, 1H), 12_05 (bs, 1H) 66 0rF 2a *** lHNMRS(d6-DMSO): 1.29 (d,6H), 4.74 (m,1H), 5.18 (s, 2H), 6.87-6.97 (m, 1H), 7.11 (m,1H) , 7.16-7.26 (m,3H), 7.63 (s, lH)t7.71(st 1H), 8.11 (s, 1H). 67 0rF 2a *** ^NMRdidi-DMSO): 1.29 (d, 6H), 4.74 (m, 1H), 5.18 (s, 2H)f 6.89-6.97 (m, 1H), 7.09 (m, 1H), 7.17-7.26 (m, 3H), 7.66 (s, 1H), 7.74 (s· 1H), 7.99 (s, 1H). 68 HN^O , lb 457 69 N lb 404 70 ^〇H -1 23 42- 'HNMR8(d6-DMSO): 1.28 (d, 6H), 4.5 l(s, 2H), 4.71 (mt 1H), 7.05 (s, 1H), 7.25 (d, 1H), 7.50 (s, 1H), 7.53 (d, 1H), 7.58 (s, 1H), 12.50 (bs, 1H) The paper size is based on the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1313601 A7 B7 V. Description of the invention (138) mm H )-f 71 2a 405 403 ^NMRSCde-DMSO): 1.L4 (d, 6H), 1.3-1.4 (m, 2H), 1.42-1.62 (m, 4H), 1.65-1.82 (m, 2H), 3.9 (d, 2H), 4.62-4.78 (m, 1H), 6.68 (s, lH)t 7.22 (s, 2H), 8.12 (s, 1H). 72. Corpse 2a 381 379 'HNMReidi-DMSO): 1.25 (d, 6H), 3.3 (s, 3H), 3.7 (t, 2H), 4.15 (t, 2H), 4.6-4.8 (hept, 1H), 6.75 (t , lH)t 7.25 (d, 2H), 8.15 (sflH), 13.0 (bs, 2H). 73 .十二2a 379 377^NMRSCdi-DMSO): 3.85 (s,3H), 5,25 (s,2H) 6,9 (m, 1H) 7.2-7.35 (m, 3H), 7.4-7.5 (m, 2H) , 7.6-7.7 (t of d, 1H), 8.15 (s, 1H), 13.0 (bs, 2H). 74 2a 401 'H NMR δ (d6-DMS0): 0.9 (t, 3H), 1.2-1.3 ( d,3H + d,6H) 1.5-1.75 (m, 2H) 4.45 (hex, 1H), 4.75 (hept,lH), 6.7 (t, 1H), 7.2 (d,2H), 8.15 (s, iH) , 13.0 (bs, 2H). 75 H^0 22 lHNMR5(d6-DMSO): 131 (dt 6H), 4.82 (m, 1H), 7.26 (dt 1H), 7.56 (d, 1H), 7.59 (s, 1H), 7.94 (d, lH), 8.15 (s, lH), 10*00 (s, 1H) ( 12.77 (bs, 1H). 76 2a lH NMR δ (d6-DMSO): 0.97 (d, 3H) , 1.26(s,6H), 1.72(t,2H), 3.85-4.20 (m, 2H), 4.56-4.83 6.69 (s,lH), 7.00 (s, 1H), 7.26 (s,lH), 8.11 ( s,lH) 77 S-OH 0 S 乂ΥχρΛ, 2a 359 NMR δ (d6-DMSO): 1.30 (d, 6H), 3·30 (s, 1H), 4.74 (m, 1H), 4.88 (s, 2H), 6.80 (s, lH), 7.31 app d, 2H), 8.15 (s, 1H), 10.01 (bs, IH) 78 丫ιρ^ square 2a 407 405 'H NMR δ (d6-DMSO): 0.91 ( t,6H), 1.29(d,6H),1.37-1.53 (m,4H), 1.56-1.70 3.30 (d,2H), 4.73 (m, 1H) 6.72 (s, iH), 7.26 (app d, 2H )f 8.14 (s, 1 H), 13.00 (bs, IH) -143 - This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) 1313601 A7 B7 V. Invention description (139), knot C:.:/record, Hua. :Signal path _ Η)® (μ η)- f诵丨79 °V〇- 丫_ 1 378 lH NMR δ (d6-DMSO): 0.98 (d, 6H)?1.28 (dt6H), 2.02 (m. 1H ), 3.80 (d, 2H), 4.65 (m, 1H), 6.75 (ap t, 1H), 7.25 (apd, 2H), 8.68 (s, 1H) 80 〇J~OH 28 533 *H NMR δ (d6 - DMSO): 1.22 (d, 6H), 1.61 (s, 6H), 4.58-4.64 (m, lH), 6.62 (s, lH), 7.19 (s, 1H), 7.40 (s, lH), 8.05 ( s,lH), 8,12 (s,lH). 81 γΜ^: HO" 2a ^HNMRS^-DMSO): 1.29 (d,6H), 4.50 (m,2H), 4.71 (m, 1H), 5.26 (bs,iH), 7.08 (s, 1H), 7,53 (s,1H),7,60 (s, 1H), 8.01 (s, 1H), 13.00 (bs, 1H). 82 I, 21 lHNMRS (d6-DMSO) 1.32 (d, 6Η), 2.80 (s, 3H), 3.37-3.63 (m, 4H), 3.95-4.10 (m, 4H), 4.39 (m, 2H), 4_76 (m, 1H) , 7.29 (d,lH), 7.53 (m,3H), 7.68 (s* 1H), 7.79 (sf 1H), 12.77 (bs,1H)· 83 Ν\ 21 ^NMRS^-DMSO): 1.31 (d? 6H)f 2.7 l(s, 6H), 4.26 (m, 2H), 4.76 (m, 1H), 7.2 9 (d, 1H), 7.42 (m, 1H), 7.55 (d, 1H), 7*70 (s, 1H), 10.66 (bs, 1H). 84 丫妒Ή οτ 21 !HNMR5(d6-DMSO) : 1.31 (d, 6H), 3.03-3.16 (m, 4H), 3.71-3·95 (πν4Η), 4.34 (m, 2H), 4.77 (m, IH), 7.47 (m, lH), 7.72 (m) , 2H), 8.13 (s, 1H). 85 y^P ΗΝ〆21 lHNMRS(d6-DMSO): 0.41 (m, 2H), 0.60 (m, 2H), 1.14 (m, 1H), 1.35 (d, 6H), 2.85 (m, 2H), 4.19 (m, 2H), 4.81 (m, 1H), 7.32 (d, 1H), 7.46 (s, 1H), 7.60 (d, iH), 7.72 (s, 1H) ), 7.80 (s, lH), 9.35 (bs, 2H)· 86 yWP 21 'H NMR δ (d6-DMSO): 1.27 (m, 12H), 3.26 (m, 2H), 4.14 (m, 2H), 4.76 (m, 1H), 7.26(d, IH), 7.45 (s,lH), 7.55 (d,1H),7,68 (s,1H),7·76 (s, lH), 9.18 (bs, 2H). -144-

Binding

This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) 1313601 A7 B7 V. Invention description (14Q) * . -, example &amp;mm.n path (_ spray (fiber H)-:t painting 87 丫N ^ A 21 lHNMR5(d6-DMSO): 0.72 (m, 2H), 0_89 (m, 2H), l_32 (d, 6H), 2.66 (m, 1H), 4.2I (m, 2H), 4.75 (m, 1H), 7.26 (d, lH), 7.42 (s, lH), 7_55 (d, lH), 7.68 (s, 1H), 7.76 (s, 1H), 9.53 (bs, 2H). 88 VP &lt; 1 (See Ex 26) 351 349 IHNMR5 (d6^DMSO): 1.27 (d, 6H), 3.70 (s, 3H), 4.71 (m, 1H), 4.86 (s, 2H), 6.99 (t , 1H), 7.23 (t, 1H), 7.26-7.27 (m, 2H), 12, 53 (s, 1H) 89 Υ^ΛΉη 24 ^NMRaidi-DMSO); 1.32 (d,6H), 4.79 (m, 1H), 7.62 (m, lH), 7.92 (m, IH), 8, 13 (s, 1H), 8.i8(s,lH), 10.03 (s,lH). 90 26 419 417 ^NMRSi^- DMSO); 1.28 (d, 6H), 2.18 (s, 3H), 2.24 (m, 2H), 2.32 (mt 2H), 3.44 (ap t, 4H), 4.65 (m, lH), 4.85 (s, 2H) ), 6.68 (apt, lH)t7.19 (m, 1H) ( 7.24 (ap d, 2H), 7.55 (ap d, 1H), 12.45 (bs, 1H) 91 yn ZFORM 25 'HNMRSC^-DMSO): 1.01 (d, 6H), 1.29 (d, 6H), 2.81 (mf IH), 4.72 ( m, 1H), 6.53 (dd, iH), 6.29 (d,1H), 6.97 (s,1H), 7.50 (s,lH),7.53 (s,lH),8.11 (s,lH),8.18(s , 1H)· 92 HO" 1 ^NMRSC^-DMSO): 1.29 (df 9H), 4*28 (q, 2H), 4.53 (d, 2H), 4.71 (m, lH), 5.26 (t, lH ( -OH)), 7.10 (s, 1H), 7.53 (s, 1H), 7.60 (s, IH), 8.20 (s, 1H), 13.01 (bs, IH). 93 〇』h 1 'HNMRS^-DMSO ): 1.34 (cUH), 1.39 (m,6H), 4.30 (q, 2H), 4.84 (m,1H), 7.58 (s, 1H), 7.97(s, 1H), 8.17(s,1H),8_26 (s( 1H), 10.09 (s, IH). 94 0 la 307 Binding

-145-This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1313601 A7 B7 V. Description of invention (141) Example: Path (_ (Mi H) - Fine drawing 95 r° la 307 96 &lt ; 0 0 2a, lc 389 387 δΗ (300MHz, DMSOO -0.04-0.06 (4H, m); 0.22-0.35 (4H, m); 0.854.05 (2H, m); 3.54-4.64 (4H, d); 6.44(iH, m); 6.93 (6.93-6.97 (2H, m); 7.84 (1H, s) 97 f/ lb (HA TU) 389 .38 387 .34 δΗ (300MHz, DMSO-dtf) 1.30 (6H, d), 3.08 (2H, t), 4.25 (2H, t), 4.73 (lH, hept), 6.70 (1H, s)f7.14(lH, d), 7.3 (4H, m), 7.48 (lH, m), 7.57 (1H, d). 12.55 (1H, brs). 98 0r la 349 99 lb (HA TU) 374 •43 372 .39 δΗ (300MHz, DMSO-d0) 0.98 (6H,d), 1.27 ( 6H,d),2,00 (1H,m), 3.80 (2H,d), 4.24 (2H, s), 4.70 (lH,hept), 6.66 7.23 (2H,d), 7.46 (lH,s), 12.59 (1H, brs). 100 la 401 101 D; °'iprw〇or la 415 102 V々s- 3(e) (CM la) 395 .19 393 .19 δΗ (300MHz, CDC13) 1.02 (6H,d ), 1.35 (6H, d), 2.08 (4H, m), 3.74 (4H, m), 4.60 (1H, hept), 6.64 (lH, m), 6/78 (lH, s), 7.00 (lH, m). Binding

-146-This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1313601 A7 B7 V. Invention description (142) Ball:: :::woman 1 life _ Hp am. tl\ :Vr (7) A 103 3(8) (CM la) 393 • 22 391 .21 δΗ (300MHz, CDC13) 1.02 (6H, d), 1.26 (3H, t), 1.35 (6Ht d), 2.08 (1H, m), 3.60 ( 2H,q), 3.74 (d,2H), 4.47 (2H, s), 4.58 (1H, hept), 6.64 (1H, m), 6.88 (1H, s), 7.02 (lH, m). 104 411 . 42 409 .38 δΗ (300MHz, DMSO-dtf) 0.98 (6H,d), 1.27 (6H,d), 2.02 (1H, m), 2.55 (3H,s), 3.80 (2H,d),4.14(2H ,s), 4.70 (1H, hept), 6.66 (lH,s), 7.23 (3H, m), 12.62 (iH, brs). 105 jC la 427 •39 425 .38 δΗ (300MHz, CDCI3) 1.02 (6H , d), 1.36 (6Htd), 2.08 3.75 (2H,d), 4.60 (1H,hept), 6.68 (lH,m), 7.00 (2H,m),7_69(lH,s). 106 V# x° Lb (HA TU) 349 .45 347 .43 δΗ (300MHz, CDCI3) 0.95 (6H,d), 1.25(6H,d),1.95-2.05 (lH,m),2.2 (3H,s), 3.65 (2H , d), 6.7 (lH, m), 6.98 (lH, m), 7_02 (lH.m). 107 lb (HA TU) 403 .39 401 .37 δΗ (300MHz, DMSO-d6) 1.25 (6H, d ), 2.38 (3H, s), 3·05 (2H, t), 4. 6-4.8 (1H, m), 7.05 (lH, d), 7.10-7.12 (3H, m), 7.15, (1H, m), 7.42-7.45 (lHtm) 108 lb (HA TU) 401 .42 399 . 39 δΗ (300MHz, CDCI3) 1.25 (6H, d) 2.3 (3H, s). 4.4-4.6 (1H, m)5.〇5 (2H, s), 6.65 (1H, m)t 6.85 (1H, s ), 7.0-7.15 (4H, m) 7.2-7.3 (IH, m).7.38-7.42 (1H, m). 109 lb (HA TU) 467 .38 465 .37 δΗ (300MHz, DMSO-d6) 2.35 ( 3H, s), 5.2 (4H, s), 6.95 (1H, s), 7.2-7.3 (5H, m), 7.4-7.45 (4H, m), 7.5-7.6 (2H, m). 110 • ^ lb (HA TU) 467 .37 465 .38 δΗ (300MHz, CDClj) 1.9 (3H, s), 4.95 (4H, s), 6.4 (1H, S), 6.9-7.1 (6H, m), 7.15-7.25 ( 2H, m), 7.3-7.4 (2H, m). -147- The paper music scale applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 1313601 A7 B7 V. Description of invention (143) 丨 Path _ m 111 2a, la 433 431 δΗ (500MHz, DMSO-dtf) 1.27 (6H, d), 3.06 (2H, t), 4.25 (2H, t), 4.72 6.71 (1H, s), 7.12 (1H, ¢1), 7.23-7.32 (3H,brm), 7.46 (lH,m), 8.10 (1H, s). 112 rr^ 2a, la 433 431 δΗ (500MHz, DMSO-dtf) 1.28 (6H, d)t 3.06 (2H, t), 4.24 (2H,t), 4.72 (iH,m), 6.69 (1H,s) 7.12 (lH,d), 7.27 (1H, s), 7.31 (2H, s), 7.47 (1H(m), 8.02 (1H, s). 113 21 439 .44 437 .39 δΗ (300MHz, DMSOO 1.25 ( 6H,d),3.0-3_2(2H,m),3.3-3.55 (4H, m), 4.3-4·5 (4H,m), 4.75-4.85 7.25 (1H, d), 7.55-7.6 (2H, m), 7.65 (lH, s), 7.75 (lH, s), 7.95 (1H, s), 8.1 (1H, s), 8.4 (1H, s). 114 v〆3 430 .40 428 .38 δΗ ( 300MHz, CDC13) 1.25 (6H, d), 2.42 (3H, s), 3.82 (2H, s), 4.45-4.6 (lH, m), 5.05 (2Ht s), 6.6 (1H, s), 6.95-7.15 (3H, m), 7.2-7.25 (2H, m), 7.35-7.45 (1H, m). 115 v0H ^&gt;NM ά 3 474 •42 472 •40 116 ,. ~ο 21 419 .47 417 .44 δΗ (300MHz, DMSO-d6) 1.25 (6H, d), 3.25 (3H, s), 3.3-3.75 (12H, m), 4.3-4.45 (2H, m), 4.75 -4.8 (1H.m), 7.25 (lH, d), 7.5-7.6 (2H, m), 7·7 (1H, s), 7.8 (lH, s). 117 〇ν〇Τ *«-»- »» r 0 21 453 .39 451 .37 118 r^~ 3 458 •39 456 .42 This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -148- 1313601 A7 B7 V. Invention Explanation (144) 丨 Example > Suspension wr mm obtained 嗔 119 &lt;: χχοτ 21 495 •43 δΗ (300MHz, DMSO*d6) 1.25 (6H, d), 3.3-3.65(8H, m), 4.2- 4.5 (2H,m), 4/7-4.8 (iH, m), 6.05 (2H, s)t6.95(lH, d), 7.05 (lH,d), 7.25 (2H,m), 7.55 (2H, m),7_7(lH,s),7.8 (lH,s). 120 ά 3 490 .43 488 .42 121 ά 3 470 .48 468 .47 122 ά 3 488 .49 486 •47 123 Ύψχ^ ά 3 486 .51 484 .51 124 cc° 21 467 .50 465 .49 125 F^r° 21 455 .48 453 •46 126 21 467 .50 465 .48 Mounting

-149-This paper scale applies to national standard (CNS) of national standard (CNS) A4 specification (210 X 297 mm) 1313601 A7 B7 V. Description of invention (145) mm 酽m 127 j〇r° 21 453 .49 451 .47 128 〇 S° 21 459 .49 457 .47 129 21 390 .51 388 .47 130 21 446 •51 444 .49 131 21 431 .55 429 .51 132 Λ lb (HA TU) 401 .37 399 33 δΗ (300MHz, DMSO -dtf) 2.08 (3H, s), 5.12 (2H, s), 5.24 (2H, s), 7.23 (4H, m), 7·42 (lH, m), 7.56 (2H, m), 7.68 (iH , s), 7.76 (lH, s), 12.64 (lH, brs). 133 2a (0 359 .43 357 •39 δΗ (300MHz, DMSO-de) 4.55 (2H, d), 5.23 (2H, s), 7.23 (4H,m), 7.42 (lH,m), 7.56 (2H, m), 7.68 (2H, m), 12.56 (1H, brs). 134 〇- if 3 474 .48 472 .47 135 v〆Λ 3 ;r~ λ 460 .46 458 .43 ——-:- -150- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1313601 A7 B7 V. Invention description (146) Example &gt ; ....····.- 'ΧΓ. 雠. Path; t 参: dirty (M, u: Η)-&quot; 136 V〆3 458 .48 456 •47 137 rJ~ y-NH V , Plant 3 472 • 51 470 .49 138 / Plant 3 488 .51 486 .52 139 3 486 .49 484 .47 140 V, 3 486 •50 484 .49 141 3 444 .45 442 •41 142 21 441 .43 439 •42 δΗ (300MHz, DMSO-dtf) 2.82 (3H,s), 3.49 (8H,m), 4.54 (1H, d), 5.24 (3H,m), 7.30 (3H, m),7_45 (2H, m), 7.59 (2H, m), 7.81 (2H,m), 12.65 ( lH,brs)· 143 ¢.° 21 505 .45 503 .38 δΗ (300MHz, DMSO-dtf) 3.15 (2H, m), 3.45 (2H, m), 4.25 (4H,m), 4.52 (lH,d ), 5.25 (3H, m), 7.27 (3H, m), 7.45 (1H, m), 7.62 (3H, m), 7.90 (3H, m), 8.16 (lH, s), 8.42 (lH, s) , 12.70 (lH, brs). -151 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1313601 A7 B7 V. Invention description (147) "Path" m ϊ _ 144 21 521 . 43 δΗ (300MHz, DMSO-dtf) 3·33 (8H, m), 4_52 (lH, d), 5.27 (3H, m), 7.03 (5H, m), 7.28 (3H, m), 7.45 7,65 (3Hf m), 7.89 (lH, m), 9.20 (lH, brs), 12.69 (lH, brs) · 145 〇 21 361 .50 359 .46 δΗ (300MHz, CDCl3) 1.36 (6H, d), 2.56 ( 4H. m), 3.04 (4H, m), 3.53 (2H, s), 4.61 (lH, hept), 6.95 (lH, d), 7.07 (lH, m), 7.24 (lH, m) 7.44 (2H, m). 14 6 f9 21 382 .12 380 .13 lHNMR5(CDCl3): 1.37 (d, 6H), 2.3 (m, 2H), 2·7 (m, 2H), 2.7 (m, 2H), 2.85 (m, 2H) , 4.6 (m, 1H), 6.95 (m, iH), 7.1 (m, lH), 7.2 (nUH), 7.4 (m, 2H) 147 F 21 396 .45 394 .4 *H NMR δ (CDC13): 1.37 (d, 6H), 1.95 (m, 4H, 2.5 (m, 4H), 3.55 (s, 2H), 4.6 (m, 1H), 7.0 (d, 1Η), 7·1 (m, lH), 7.6(m, 1H) 148 f/ lb (HAT U) 382 .12 380 .13 {KNMR6(COChy. 1.37 (d, 6H), 2·3 (m, 2H), 2.7 (m, 2H), 2.7 ( m, 2H) ( 2.85 (m, 2H), 4,6 (m, 1H), 6.95 (m, lH), 7, l (m, lH), 7.2 (m, lH), 7.4 (m, 2H) 149 Λ 0 lb (HAT U) 403 •39 401 .36 δΗ (300MHz, DMSO_dtf) 2.09(3H,s), 3.26(2H,t), 4.30 (2H,t), 5.08 (2H,s), 6.98( 2H,m),7.17(lH,s), 7.26 (iH,d),7.35 (lH,m), 7.54 (lHt d)t 7.64 (2H, br s), 12.62 (lH,brs). 150 H0J 2a (g) 361 .41 359 .38 151 v,, f/ 3 432 , 40 430 .37 binding

-152-This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1313601 A7 B7 V. Description of invention (148) t 13⁄43⁄4 face (Mi H)^S mm m 152 f/ 3 476 . 48 474 .47 153 r/° 3 472 •48 470 .45 154 r/ H 3 462 •45 460 .43 155 °X^rV, CP 21 462 •41 460 .38 156 •X 21 521 .42 519 •40 157 ·? {7rj H 2Ϊ 507 •48 158 rxf:^ iTV^ N ^ 21 453 .52 451 •49 *HNMR6(CDC13): 1.35 (df 6H), 2.5 ((m, 2H), 3.65 (m, 4H ), 4.65 (m, 1H), 6.3 (d, 1H), 6.95 (d, lH), 7.1 (m, 1H), 7.35 (d, 1H), 7.5 (m, lH), 7.58 (s, 1H) , 8.1 (d, 1H) 159 °rO 21 461 .49 459 .48 -153- This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 public) 1313601 A7 B7 V. Description of invention (149) Example · Structure!~., Path (M+ H)+ (Μ Η)- NMR '--- 160 ib (HAT U) (h) 453 .44 45 i .40 161 lb (HAT U) (h) 406 •40 162 丫21 (1) 467 •50 465 .49 163 -Λ OW 21 (0 506 *47 504 •46 164 〇5〇☆ \ 21 (i) 505 •46 503 .43 165 〇§0 a 21 (i) 541 . 39 539 .35 166 21 429 .54 427 .5 1 Notes: * The final product prepared by hydrolysis method 2a; according to the general alkylation method and -154- this scale is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1313601

The necessary starting material β is then prepared by coupling (path i): the final product prepared by reciprocating method 6, according to the general alkylation formula = by coupling (pathway and hydrolysis (path 2 &amp;)) It is necessary to prepare the necessary starting materials for the 瑕μ product prepared by hydrolysis (path 2a) Qianki chloro coupling (path) according to the general alkylation method and then by coupling (path 1). About Examples 112, 117 , Π8, ΙΙΐ5&amp; π interstitial: 26, prepared by ester 1

t); 7.4 (6H,m); 7.5 〇: ^ ^ (^); ?*° 〇H,

As illustrated by example ΙΙ3 as an example

'Η NMR(5 (d6-DMSO) : 1.3(3H, t); -155- This paper size applies to Chinese National Standard (CNS) A4 size (210 X 297 mm) 1313601 A7 B7 V. Description of invention (151) 4.3(2H, q); 5.2(4H, s); 6.95(1H, t); 7.2-7.5(12H, m); 8.2(1H,s); 13.05(1H,br s); The signal of the 2-amino-based porter.

Uncharacterized

MH+ = 389, 391 M-H = 387, 389 Example JJ: The following compounded examples are also prepared in a manner similar to those described above. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) A7 B7 1313601 V. Invention description (152) 1 Example i Structure ί ..... Path (Μ+Η)+ (Μ-Η )- NMR :, 1 7 426.19 424.25 1Η NMR d (d6-DMSO): 5.17 (m, 6H) , 6.80 (s, 1 Η), 7.00 (d, 1H), 7.26 to 7.46 (m, 12H), 7.71 (s, 1H), 7.78 (d, 1H), 10.28 (br s, 1H) 2 6 8 552.22 1H NMR d (d6-DMS0): 1.55 (s, 6H), 2.08 (s, 3H), 5.18 (s , 4H), 6.85 (s, 1H), 7.29 to 7.50 (m, 12H), 7.98 (del, 1H), 8.1 C(d, 1H), 8.61 (s, 1H), 9.70 (s, 1H), 10.72 (s, 1H) 3 6 9 512.16 510.22 1HNMRd(d6-DMS0): 1.35 (s, 6H)t 5.18 (s,4H), 6.88 (s,1H), 7.28 to 7.48 (m, 12H), 8.08 (d , 1H), 8.22 (d, 1H), 8.82 (s, 1H), 9.90 (s, 1H), 10.96 (s, 1H) 4 8 502.49 1HNMRd(d6-DMS〇): 3.02 (s, 3H), 5.17 (s, 4H), 6.86 (s, 1H), 7.29 to 7.58 (m, 12H), 7.70 (d, 1H), 8.13 (d, 1H), 8.24 (s, 1H), 9.83 (s, 1H), 10.83 (s, 1H) 5 V skill 6 8 526.41 524.45 1HNMRd(d6-DMS0): 2.13 (s, 3H), 4.65 (s, 2H), 5.18 (s, 4H), 6.84 (s, 1H), 7.27 to 7.48 (m, 12H), 7.96 (d, 1H), 8.13 (d, 1H), 8.61 (S, 1H), 10.24 (s, 1H), 10.73 (s, 1H) -157- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1313601 A7 B7 V. Description of invention (153) Example structure 1 path (M+H)+ (MH)- (SJMR V ,- 6 8 498.55 496.55 1H NMRd (d6-DMSO): 3.39 (s,3H), 4.01 (s, 1H), 5.18, (s, 4H) , 6.85 (s, 1H), 7.28 to 7.50 (m, 12H), 8.07 (m, 2H), 8.67 (s, 1H), 9.95 (s, 1H), 10.71 (s, 1H) 7 6 Η 8 540.58 538.63 1H NMRd (d6-DMS〇): 1.20 (t,3H), 3.47 (s,2H), 4.11 (q, 2H), 5.17 (s, 4H), 6.83 (s, 1H), 7.28 to 7.48 (m, 12H), 7.95 (d, 1H), 8.13 (d, 1H), 8.60 (s, 1H), 10.35 (s, 1H), 10.73 (s, 1H) 8 6 8 526.53 524.61 1H NMR d (d6-DMSO) : 1.30 (t, 3H), 4.30 (q, 2H)t 5.17 (s, 4H), 6.86 (s, 1H), 7.28 to 7.50 (m, 12H), 8.14 (s, 2H), 8.74 (s, 1H ), 10.78 (s, 1H), 10.97 (s, 1H) 9 10 525.61 523.66 1H NMR d (d6-DMS0): 1.30 (s, 9H), 5.18 (s, 4H), 6.09 (s, 1H), 6.85 (s, 1H), 7.32-7.50 (m, 12H), 7.78 (dd, 1H), 8.04 (d, 1H), 8.38 (s, 1H), 8.44(s, 1H), 10.65 (s, 1H) 10 ^^xrrr 6 9 512.4 1H NMR d (d6-DMS0): 3-41 (s, 2H), 5.17 (s 4H), 6.90 (S, 1H), 7.29 to 7.54 (m, 12H), 8.03 (d, 1H), 8.13 (d, 1H), 8.70 (s, 1H), 10.50 (s, 1H), 10.85 (s , 1H) 11 %V^广..6 9 484.4 1HNMRd(d6-DMSO): 4.04 (s, 2H), 5.20 (s, 4H), 6.89 (s, 1H), 7.30 to 7.51 (m, 12 H) , 8.12 (d, 1H), 8.22 (d, 1H), 8.81 (s, 1H), 10.05 (s, 1H), 11.00 (s, 1H) Binding - 158 - This paper size applies to the Chinese National Standard (CNS) Α4 size (210 X 297 mm) 1313601 A7 B7 V. Description of invention (154) Example _ Structure path (M+H)+ (MH)- NMR H.... 12 7 476.36 1HNMRd(d6-DMSO): 5.14 (s , 2H), 5.32 (s, 4H), 6.90 (s, 1 Η), 7.01 (dd, 1 Η), 7.35 (s, 2H), 7.59 (m, 2H), 7.80 (m, 6H), 7.90 ( d, 2H), 10.30 (s, 1H) + 0.1 EtOAc 13 8 604.29 602.3 1H NMR d (d6-DMS0): 1.55 (s, 6H), 2.07 (s, 3H), 5.33 (s, 4H), 6.95 ( s, 1H), 7.40 (s, 2H), 7.56 (m, 2H), 7.73 (m, 4H), 7.90 (d, 2H), 7.98 (dd, 1H), 8.13 (d, 1H), 8.63 (s , 1H), 9.71 (s, 1H), 10.82 (s, 1H) 14 9 562.28 560.27 1HNMRd(d6-DMS0): 1.34 (s, 6H), 5.32 (s, 4H), 6.97 (s, 1H), 7.40 (s, 2H), 7.57 (m, 2H), 7.75 (m, 4H), 7.90 (d, 2H), 8.09 (d , 1H), 8.21 (dd, 1H), 8.82 (s, 1H), 9.90 (S, 1H), 10.99 (S, 1H) 15 11 534.41 1H NMR d (d6-DMS0): 3.22 (t, 2H), 3.28 (2, 3H), 3.50 (t, 2H), 5.31 (s, 4H), 6.92 (s, 1H), 7.12 (dd, 1H), 7.34 (s, 2H), 7.57 (m, 2H), 7.75 (m, 5H), 7.82 (d·1H), 7.91 (d, 2H), 10.49 (brs, 1H) 16 N 11 547.86 1H NMR d (d6-DMSO): 2.20 (s, 6H), 3.12 (m, 2H), 5.32 (s, 4H), 5.51 (br s, 1H), 6.89 (s, 1H), 7.06 (dd, 1H), 7.37 (s, 2H), 7.57 (m, 2H), 7.74 (m, 5H), 7.83 (d, 1H), 7.92 (d, 2H), 10.41 (s, 1H), and · 2H under DMSO or water -159 This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1313601 A7 B7 V. INSTRUCTIONS (155 ί EXAMPLES) STRUCTURE, PATH (Μ+Η)+ (Μ-Η)- NMR — 17 11 504.54 1Η NMR d (d6-DM.SO): 1.15 (t, 3H) , 3.06 (quartet, 2H), 5.32 (s, 4H), 6.90 (s, 1H), 7.00 (dd, 1H), 7.35 (s, 2H), 7.57 (m, 2H), 7.73 (m, 5H), 7.85 (d, 1H), 7.92 (d, 2H), 10.41 (s, 1H) 18 12 485.5 483.5 1H NMR d (d6*DMSO): 5.13 (s, 2H), 5.18 (s, 2H), 5.31 (s , 1H), 6.88 (s, 1H), 7.00 (dd, 1H), 7.32 (s, 2H), 7. 40 (m, 3H), 7.50 (s, 1H), 7.58 (m, 1H), 7.74 (m, 3H), 7.80 (d, 1H), 7.90 (d, 1H), 10.33 (S, 1H) 19 1 493, 495 1H NMR d (d6-DMSO): 2.35 (3H, s); 5.31 (4H, s); 6.98 (1H, t); 7.43-7.48 (6H, m); 7.58-7.61 (2H, m) 7.65-7.71 (3H, m); 8.14 (1H,d); 8.29 (1H, s); 10.84 (1H, s) 20 οα Μ 13 525 1HNMRd(d6-DMSO): 3.10 (2H, m); 3.30 (6H, s); 3.60 (2Ht m); 5.19 (4H, s); 6.89 (1H, s); 7.31-7.48 (12H, m); 8.29 (2H, m); 8.92 (1H, s); (1H, s) 21 14 509 Ή NMR d (de*DMSO): 4.5 (1H, d), 5.25 (s, 4H), 6.9 (s, 1H), 7.40 (m, 6H), 7.5 (m, 2H) ), 7.6 (m, 2H), 7.75 (dd, 1H), 8.10(d, 1H), 8.3 {s, 1H), 10.8 (br s,1H); 22 1 494/49 6 1H NMR d (d6- DMSO): 5.25 (4H, s); 5.65 (2H, s); 6.23 (1H, d); 6.85 (1H, s); 7.05-7.15 (3H, m); 7.18-7.22 (5H, m); -7.55 (2H, m); 7.58-7.62 (2H, m); 10.16 (1H, br s). -160- This paper size applies to Chinese National Standard (CMS) A4 specification (21〇x 297 mm) 1313601 A7 B7 V. INSTRUCTIONS (156) 1 EXAMPLE&gt; Structure path (M+H)+ (MH)- mr ·一*: 23 & 1 476 1HNMRd(d6-DMS0): 5.25 (4H, s); 5.75 (2H, s); 6.22 (1H, d); 6.90 (1H, s); 7.25-7.41 (4H, m); 7.50-7.60 (2H, m); 7.70-7.80 (4H , m); 7.90 (2H, d); 10.19 (1H, br s). 24 15 536/53 8 1HNMRd(d6-DMS0): 3.25 (3H, s); 5.20 (4H, s); 6.9 (1H, t); 7.25 (2H, d); 7.35-7.40 (4H, m); 7.4-7.55 (2H, m); 7.58-7.63 (2H, m); 7.68-7.72 (1H, m); 7.75-7.80 ( 2H, d); 10.14 (1H, brs); 10.36 (1H, brs). 25 OJ 16 479 477 1HNMRd (d6-DMSO): 5.19 (4H, s); 6.88 (1H, s); 7.26-7.48 (12H , m); 8.40 (1H, d); 8.46 (1H, dd); 9.04 (1H, s); 11.13 (1H, br s). 26 ca 17 495 493 1H NMRd (d6-DMSO): 5.19 (4H, s); 6.87 (1H, s); 7.28-7.46 (12H, mj; 8.21 (1H, dd); 8.38 (1H, d); 8.79 (1H, s); 11.14 (1H, brs). 27 18 498 1H NMR d (d6-DMSO): 5.18 (4H, s); 6.88 (1H, s); 7.30-7.50 (12H, m); 8.17 (2H, s); 8.79 (1H, s); 10.79 (1H, s 10.93 (1H, br s). 28 〇ό^ 1 460 lH NMR δ (d6-DMSO): 2;32 (s. 3H), 2.36 (s. 3H). 3.23 (t, 2H), 4.22 ( t,2H), 5.13(s,2H)· 6.78 (m· ΙΗ), 7.Π-7.24 (brm. 5H).7.30 (m, lH)f7.41(d, 1H), 7.83 (m. 1H ), 8.14 (d. 1H), 8.37 (m, 1H). 82 (s, 1H), 10.74 (brs, 1H) 29 〇 "&lt;^. N °^r 7 475 'H NMR δ (d6-DMSO): 2.32 (s. 3H). 2.36 (s, 3H). 3.22 (t, 2H), 4.20 (t, 2H) ( 5.11 (s, 4H) ), 6.72 (m, 1H), 7.00 (m. 1H), 7.15-7.28 (brm, 5H), 7·41 (d·1H), 7.73 (m. 2H), 8.82 (s, 1H), 10.29 ( Brs, IH). -161 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1313601 Δ7 Α7 Β7 V. Invention description (157) ! Example ί Structure, path (M+H)+ (MH)-NMR 30. 0 1 丨H NMR δ (d6-DMS0): 2.66 (s, 3H). 5.15 (s, 4H), 6.88 (m. 1H), 7.14 (m, 1H), 7.39-7.47 (brmf 7H), 7_52(s·lH), 7.83(m, 1H), 8.15 (d. 1H), 8.38 (m, 1H), 10.72 (brs. 1H). 31.&gt;· lb 395 32 〇' N 0r 1 'H NMR δ (d6-DMSO): 1.28 (d, 6H), 2.39 (s, 3H), 4.72 (m, 1H), 5.20 (s, 2H), 6.33 (s, lH), 6.72 ( s, lH).7.14(m, 1H), 7.20 (s, IH), 7.27 (s, 1H). 7.82 (m, 1H), 8.13 (d, 1H), 8.36 (d. 1H), 10.72 (brs , 1H). 33 丫1 'H NMR δ (d6-DMSO): 1.27 (d, 6H), 4.71 (m.lH)· 5.21 (s,2H)· 6.73 (t, 1H), 7.12-7.29 (brmf 5H), 7.22(m, lH), 7_56(m, 1H), 7.83 (m, 1H)· 8.14 (d, 1H), 8.35 (m, 1 H). 10.72 (brs. 1H). 34 .\ lb 311 35 ύα lb 451 36 Λ ζγ^ο-Ο^ lb 398 37 γ Lu 1 374 372 NMR δ (d6-DMSO): 0_98 (d, 6H), 1.27 (d.6H), 2.01 (m, 1H). 3.60(d,2H), 4.71(m,丨.H), 6.67 (apt, 1H), 7.17 (apd,2H), 8.39 (d, 1H) , 8.63 (d, 1H). 9.20 (d, 1H). 11.43 (bs, 1H) 38 z 7b 344 'H NMR δ (d6-DMSO): 0.97 (d, 6H). 1.26 (d,6H), 2.00 (m, 1H), 3.78 (d, 2H), 4.69 (m, 1H), 5.12 (s, 2H), 6.58 (t. 1H). 6*99 (dd, 1H), 7.1 (ap d, 2H) 7.73-7.78 (m, 2H), 10.24 (bs, 1H) -162 This paper is again applicable to China National Standard (CNS) A4 specification (210 X 297 public) 1313601 A7 B7 V. Invention description (158) 1 Example 5 structure? p path (Μ+Η)+ (Μ-Η)- NMR 39 丫严 V 15 386 'Η NMR δ (d6-DMSO): 0.98 (d, 6Η), 1.26 (d,6Η), 2.01 (m,1Η) ), 2.05 (s, 3H), 3.79 (d, 2H), 4.70 (m, 1H), 6.61 (ap tt 1H), 7.14 (ap d, 2H), 7.95 (dd, 1H), 8_08 (d, 1H) ), 7.59 (ap d, 1H), 10.07 (bs* 1H) 40 v^. 15 422 420 *H NMR δ (d6-DMSO): 0.97 (d, 6H), 1.26 (d, 6H), 2.03 (m. 1H). 3.01 (s, 3H), 3.79 (d, 2H), 4.70 ( m, 1H), 6.63 (apt, IH), 7.14 (ap d, 2H), 7.70 (dd, lH), 8.12 (d, 1H), 8.34 (ap d, 1H), (9.83, s, 1H), 10.81 (bs,1H) 41 9 Μ+Η 430 Μ·Η 428 lH NMR δ (d6-DMSO): 0.98 (d, 6H), 1.27 (d,6H), 1.35 (s,6H), 2.01 (m, lH), 3.79 (d, 2H), 4.70 (m, 1H), 5.71 (s, iH), 6.61 (s, 1H). 7.15 (s, 2H), 8.06-8.15 (mt 2H), 8.76 (apd, lH), 9.78(s, 1H), 10.65 (bs, 1H) 42 V〆15 412 (M+HCO ΟΗ)+ 456 'H NMR δ (d6-DMSO): 0.79-0.82 (m, 4H), 0.98 ( d,6H), 1.26 (d, 6H)f 1.77 (m, lH), 2.0i (m.lH), 4.70 (h, 1H), 6.11 (ap ί, 1H), 7.14 (ap d, 2H), 7.95 (dd, 1H), 8.08 (d, lH)f 8.62 (apdt 1H). 10.33 (bs, 1H), 10.64 (bs. 1H) 43 V gentleman 27 Μ+Η 450 Μ-Η448 *H NMR δ ( D6-DMSO): 0.98 (d. 6H), l_27 (d, 6H), 2.01 (m_, 1H), 3.37 (s, 3H), 3.80 (d, 2H), 4.71 (mt 1H), 6.65 (ap t , IH), 7.17 (s. 2H)( 8.27-8.35 (m, 2H)t 8.91 (m. 1H), lU3(bs, 1H) 44 lc 352 δΗ (300MHz, DMSO-d6) 0.94-1.02 (6H, d); 1.24-1.34 (6H,d); 1095- 2.10 (lH,m); 3.76-3.84 (2H.d); 4.64-4.77 (lH,m); 6.64-6.70 (IH.m); 7.14-7.17 (2H,m); 8.25-8.36 (2H.m 8.85 (lH,m); 11.21 (!H,s) 45 &lt;ι M3 Η Ν-^ Ν 0 8(a) 7c δΗ (300MHz, DMSO-dd) 0.94-1.03 (6H,d); 1.26 -1.30 (6H,d); L95-2.08(lH,m); 2.90 (3H.s); 3.75-3.84 (2H.d); 4.04-4.26 (2H,d + H20); 4.65-4.77 (lH( m); 6.64 (lH.m); 7.15 (2H, m); 7.50-7.62 (IH^road t); 7.80-7.90 (lH, d of m); 8.08-8.16 (lH, app d); 8.35 ( 1H. m); 10.84 (lHfm) -163- This paper scale adopts Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1313601 A7 B7 I V. Invention description (^9) Example: Structure · 'Path (M+H)+(MH)-NMR 46 Η 0 8(a) 7c δ„ (300MHz, DMSO-d0) 0.94-1.02 (6H, d); 1.24-1.30 (6H.d); 1.84 (3H, s); 1.95-2.07 (IH.m); 3.750.83 (2Htd)t 4.18-4.27 (2H,d); 4.64-4.76 (lH.m); 6.62 (lH,m); 7.15 (2H,m) 7.63-7.73(lH, appd ofm); 8.05-8,13(lH,app d); 8.27 (lH.s); 8.30-8.38 (1H, app broad t); 10.69 (IH, s) 46a &lt; /la 408 406 δΗ (300MHz, DMSO-dtf) 1.26 (d, 6H), 3.05 (t, 2H)t4.25 (t. 2H), 4.72 (sept, 1H), 6.68 (s, 1H), 7.12 (d, 1H), 7.16 (s, IH).7.19(st 1H). 7.33 (s. 1H)· 7.47 (dd,lH), 8.30 (m, 2H), 8.83 (s, 1H) , 11.23 (bs, 1H) 47 V〆, 27 504 δΗ (300MHz, DMSO-dtf) i.27 (d,6H)· 3.06 3.38 (s, 3H). 4.25 (t, 2H)(4.71 (sept, 1H) ), 6.68 (t, 1H), 7.11 (dd, 1H), 7.12 (s, 1H), 7.17 (st 1H), 7.31 (d.lH)· 7.46 (dd, lH), 8_29(d, lH), 8.34(dd, 1H). 8.92(d, 1H), H.14(bs. IH) 48 27 584 582 δ,, (300MHz, DMSO-dtf) 1.25 (d,6H), 3.04 (t,2H), 4.23 (t, 2H)· 4.69 (sept, IH), 6.67 (s, lH&gt;, 7.11(d, lH), 7.15(s, lH), 7, 20(s, iH), 7.31(d, IH) , 7.46 (m, 3H)· 8.07 (dd, 2H), 8.26 (s, 2H), 8.86 (s. lH), lU3(bs, 1H) 49 r^^Tr r/ 27 556 δΗ (300MHz, -DMSO -dtf) 1.27 (dt 6H)t3.04 (t, 2H), 4.23 (t, 2H), 4.71 (sept, IH), 6.64 (s, 1H), 7.1 l(d,iH)· 7.18 (s, 1H&gt;· 7.22 (s,lH), 7.32 (s, IH)t 7.46 (dd, 1H), 8.19 (m% 2H). 8.82 (d, 1H), 10.93 (bs, 1H) 50 r/ 27 567 δ „(300MHz, DMSO-dtf) 1.26 (d,6H), 3.04 (t,2H), 4.24(t, 2H), 4.70 (sept, IH), 6.64 (t, 1H), 7.11 (dd, IH), 7.16 (s, IH), 7.21 (s, IH), 7 .30 (m, 1H), 7.46 (m, lH)f 8.16 (m, 3H), 8.62 (d, 1H), 8.83 (s, 1H), 8.98 (s, 1H), 10.90 (bs, IH) - 164 - This 尺度 尺度 applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

1313601 A7 B7 V. INSTRUCTIONS (16(5) EXAMPLE: STRUCTURE. Path (M+H)+ (MH)- NMR ' 51 f/ 27 585 583 Know (300MHz, DMSO-cW 1.27 (d. 6H), 2.39 (s, 3H), 2.68 (s, 3H), 3.06 (t, 2H)· 4.26 (t, 2H), 4.73 (sept, 1H), 6.69 (t, 1H), 7.12 (df lH) (7.17(s) , 1H). 7.22 (s, 1H), 7.33 (m, lH)t 7.49 (m, 1H), 8.28 (m, 2H), 8.89 (s, 1H), 11.10 (bs. 1H) 52 f/ 27 618 /62 0 (IxCl) 616/618 (IxCl) δΗ (300MHz, DMSO-dtf) 1.28 (d,6H), 2.40 (s, 3H), 3.08 (t, 2H), 3.79 (s, 3H), 4.25 ( t,2H), 4.71 (sept, 1H), 6.68 (s, 1H), 7.12 (d,lH), 7.18 (s,lH), 7.22(s, lH).7.34(m,lH)· 7.39 (st 1H), 7.48 (dd, 1H), 8.30 (m, 2H), 8.92 (s, 1H), 11.15(bs, 1H) 53 r/ 27 584 δΗ (300MHz( DMSO-d6) 1.26 (d, 6H), 3.04 (t, 2H), 4.24 (t. 2H)· 4.70 (sept, iH), 6.66 (t, 1H), 7.12 (dd, lH)· 7.18 (s, 1H), 7.22 (s, 1H), 7.30 (m. 1H), 7.37 (m, 1H), 7.45 (dd, 1H), 7.67 (m, 1H)· 7.78 (dt. 1H), 7.96 (dt, 1H). 8.822 (s. 2H).8.86 ( Sf 1H). 11.08 (bs, 1H) 54 f/ 27 606 ^04 δΗ (300MHz, DMSO-dtf) 1.2C (d,6H), 3.04 (t,2H), 4.25 (t, 2H) , 4.71 (sepUH), 6.64 (t, IH), 7.00 (d. 1H), 7.12 (dd. 1H), 7.16 (s, IH), 7.22 (s, 1H), 7.32 (m, 2H). 7.46 ( Dd, lH), 8.14(d, 1H), 8.22 (dd, 1H). 8.83 (t, 1H). 10.87 (bs. 1H) 55 N f/ 16 451 449 δΗ (300MHzf DMSO-dtf) 1.28 (d, 6H)· 3.06 4.26 (t, 2H), 4.72 (sept, 1H), 6.65 (s, lH).7.12(d, lH), 7.18(s, 1H), 7.23 (s, 1H), 7.32 (s. 1H), 7.47 (m, 1H), 8.23 (d, 1H). 8.32 (dd, 1H), 8.95 (s, IH), 10,81 (bs.lH) 56 la 329.48 327.46 -165- This is a scale Applicable to China National Standard (CNS) A4 specification (210X 297 mm) A7 B7 1313601 彡, invention description (161) H ji~~~~ 1 path (M+m+liM-HVl NMR 57 ----- λΥ Η la 354.46 352.43 Notes: * Final product prepared by hydrolysis method 2a; the necessary starting materials are prepared according to the general alkylation method followed by coupling (path 丨). ** The final product prepared by reductive amination 6; the necessary starting materials are prepared according to the general alkylation method' followed by coupling (path 丨) and hydrolysis (path 2a). * * * The final product prepared by hydrolysis (path 2a) or mercapto chloride coupling (path 1); the necessary starting materials are prepared according to the general alkylation method followed by coupling (path 1). EXAMPLE KK: The following example can be made with the example number ΚΚ·ι to KK7 by the method similar to those described above. Path (M+H)+(MH)-NMR 1 2b* 522 520 lHNMRd(d6-DMSO): 5.20 (4H, s); 6.95 (1H, s); 7.25 (2H, s); 7.30-7.5 (4H , m); 7.5 (2H, m); 7.6 (2H, m); 7.8 - 8.0 (4H, s). 2 r α °ν«Η .^ 1 494 No data -166- This paper scale applies to China Standard (CNS) Α4 size (210 X 297 mm) 1313601 A7 B7 V. Description of invention (162) 1 Example ί Structure! ϋ' Path (M+H)+(MH)-NMR . . 'W ... 3 ^ . 1 556/55 8 NMR not right 4 2b 522 1H NMR d (d6-DMSO): 5.25 (4H, s); 6.95 (1H, s); 7.25 (2H, s); 7.35-7.55 (7H, m); 7.6 - 7.7 (3H, m); 8.05 (lH, d); 8.4 (1H, s); 10.3 (1H, brs 12.9 (1H, br s). 5 2b* 536 534 lHNMRd(d6-DMSO): 3.4 (2H, s); 5.2 (4H, s); 6.95 (1H, s); 7.2 (4H, m); 7.4 (4H, m); 7.5 (2H, m); 7.6 -7.7 (4H, m); 10.1 (1H, br s). 6 1 519 1H NMR d (d6-DMSO): 5.2 (4H, s); 6.95 (1H, m); 7.25 (2H, m); 7.4 (5H, m); 7.5 (2H, m); 7.55 - 7.65 (4H, m); 7.9 (2H, m); 8.2 (1H, s) 10.3 (1H, br s). 7 6&quot; 1 577 V. poor spectrum For example KK, and ΚΚ5, prepare ester intermediates with path 1: -167- This paper scale applies to Chinese National Standard (CNS) Α4 specifications ( 210X 297 mm) 1313601 A7 B7 V. Description of invention (163)

χΛ [H NMR 5 (d^-DMSO): 3.8 (3Η, s); 5.25 (4H, s); 6.95 (1H, t); 7.25 (2H, d); 7.4 (4H, m); 7.5 (2H , m); 7.6 (2H, m); 8.0 (4H, q); 10.6 (1H, br s).

Cl

'H NMR δ (dc-DMSO): 1.2 (3H, t); 3.6 (2H, s); 4.1 (2H, q); 5.25 (4H, s); 6.95 (1H, t); 7.2 (4H, m 7.4 (4H, m); 7.5 (2H, m); 7.6 (2H, m); 7.7 (2H, m); 10.15 (1H, br s). f Example LL: in a manner similar to those described above The following compounds of the example numbers 1^1 to 1^3 can also be obtained. Example 1. Structure path (M+H)+ (Μ Η)- NMR 1 V la 360 2 la 382 3 0 ^ la 412 -168-This paper scale applies to Chinese National Standard (CNS) A4 specification (21〇x 297 Love) 1313601 A7 B7 V. INSTRUCTIONS (164) EXAMPLE MM: The following compounds with the example numbers MM1 to MM2 can also be prepared in a manner similar to those described above. Example Structure Path (M+H)+ (MH) NMR 1 la 385 2 Ο 〇F la 371 Biological Test: The biological effects of the compound of formula (I) or (IA) or (IB) can be tested in the following manner: 1) GLK, ATP and glucose can be measured to measure the enzyme activity of GLK β to determine the coupling with G-6-P dearoxidase, NADP/NADPH system and to measure the optical density at 340 nm (Maskins) Kay (Matschinsky et al., 1993) can determine the rate of product formation. (2) GKL·/GLICRP binding assay to measure the binding interaction between GLK and GLKRP. Confirmation with this method to adjust for GI^K and GLKRP Inter-binding interactions modulate GLK compounds. GLKRP and GLK are incubated at an inhibitory concentration of F-6-P, optionally in the presence of test compounds, and the degree of interaction between GLK and GLKRP is measured. - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) A7 B7 1313601 V. Description of invention (165) Low GLK/GLKRP complex formation amount detection or replacement F-6-P or some Other ways to reduce the GLK/GLKRP interaction Detection of compounds that promote F-6-P binding or enhance GLK/GLKRP interaction in some other way with increased GLK/GLKRP complex formation. Specific examples of such binding assays are described below. GLK/GLKRP scintillation proximity The compounds were found to have at least 40% activity at 10 microns when tested in the GLK/GLKRP scintillation proximity assay described below for compounds A to S (illustrated by Examples A through S) and 1 to 118 (illustrated by Examples T to Y). Activity. The use of recombinant human GLK and GLKRP was developed as described in WOO 1/20327 (incorporating the contents herein for reference) &quot;mixing and measuring · 96 well SPA (scintillation method). GLK (biotinylation) and GLKRP were incubated with chain antibiotic-linked SPA beads (Anson) in the presence of inhibitory concentration of 3H]F-6-P (Amersham Custom Synthesis TRQ8689) to obtain a signal. -6-P or a compound that cleaves the GLK/GLKRP binding interaction in some other way causes the signal to disappear. A 2 hour binding assay is performed at room temperature. The reaction mixture includes 50 mg of molecular weight Tris-HCl (pH 7.5), 2 Millimeter molecular weight ATP, 5 Gram molecular weight MgCl2, 0.5 mg molecular weight DTT, recombinant biotinylated GLK (0.1 mg), recombinant GLKRP (0.1 mg), 〇.〇5mCi[3H]F-6-P (Anson) to obtain a final volume of 100 ml . After the incubation, the degree of formation of the GLK/GLKRP complex was determined by scintillation counting with SPA beads (Anson) joined with albendin in 〇·1 mg/well and on a Packard TopCount NXT. (3) Measurement of the binding interaction between GLKRP and F-6-P F-6--170- This paper scale applies to China National Standard (CNS) A4 specification (21〇x 297 mm> 1313601 A7 B7 V. GLKRP binding assay. This method can be used to provide information on the mechanism of action of more compounds. Compounds identified by GLK/GLKRP binding assay are either substituted or replaced by F-6-P or in some other way. Modifying the GLK/GLKRP interaction can modulate the interaction between GLK and GLKRP. For example, it is generally known that protein-protein interactions can occur via interactions between multiple binding positions. It is therefore possible to modify the interaction between GLK and GLKRP. Compounds can bind to one or more of a number of different binding sites. The F-6-P/GLKRP binding assay only confirms that F-6-P, which modulates its binding position on GLKRP, regulates the interaction of GLK with GLKRP. GLKRP was incubated with test compound and inhibitory concentration of F-6-P in the absence of GLK and the extent of interaction between F-6-P and GKLPP was measured. GLKRP/F·6-P complex Change in formation amount can detect displacement Compounds in which F-6-P binds to GLKRP. A specific example of this binding assay is described below. 0 F-6-P/GLKRP scintillation proximity method using recombinant human GLKRP development as in W001/20327 (incorporating the contents) For reference, the "mixing and measuring" 96 well SPA (scintillation method) is a SPA beads coated with protein A in the presence of a concentration of radiolabeled [3H]F-6-P (Anson) And the anti-FLAG antibody incubated with the FLAG GLKRP 〇 to generate a signal. Substitution of the ρ_ό_Ρ compound will cause the signal to disappear. The combination of this assay and the GLK/GLKRP binding assay allows the observer to confirm the split GLK by replacing F-6-P. /GLKRP combines interaction compounds. Binding assay at room temperature for 2 hours. Reaction mixture includes 50 mg-171 - This paper scale applies to Chinese National Standard (CNS) A4 size (210 X 297 mm) 1313601 A7 B7 , invention description (167) molecular weight Tris-HCl (pH 7.5), 2 mg molecular weight ATP, 5 mg molecular weight MgCl2, 5. 5 mg molecular weight DTT, GLKRP (0.1 mg) with additional recombinant FLAG, anti-Flag M2 antibody (0.2 Mg) (IBI Kodak) Kodak)), 0.05 mCi [3H]F-6-P (Anson)' to obtain a final volume of 100 ml. After incubation, add 0.1 mg/well of protein A-linked SPA beads (Anson) and at Packard TopCount NXT The degree of formation of F-6·P/GLKRP complex was determined by scintillation counting. The production of GLKRP was as follows: the preparation of mRNA was carried out in 4 g of molecular weight isothiocyanate, 2.5 mg of molecular weight citrate, 0.5. Polytron homogenization in % 12 sarcosine sarcosine steel (Sarkosyl), 100 mg molecular weight b-spy. ethanol, followed by centrifugation (maximum) at 135 g molecular weight CsCl, 25 mg molecular weight sodium acetate at 135,000 g, To prepare human liver total mRNA, such as the description of Sambrook J, Fritsch EF & Maniatis T (1989). Poly A+ mRNA was prepared directly using the FastTrackTM mRNA isolation kit (Invitrogen). PCR amplification of GLK and GLKRP cDNA sequences Human GLK and GLKRP cDNAs were obtained by PCR of human liver mRNA using the established technique described by Shanbrook, Frych & Maniatis (1989). According to LGK and GLKRP presented by Tanizawa et al. (1991) and Bonthron DT et al. (1994) (subsequently corrected by Warner J. (1995)) The cDNA sequence was designed as a PCR primer. -172- The paper size is applicable to China National Standards (CNS) A4 size (210X297 mm) 1313601 A7 B7 V. Description of invention (168) Selection of GLK and GLKRP cDNA in Blue script II vector Plan II (Short et al., 1998) was cloned in E. coli, similar to the recombinant used by Yanisch-Perron C et al. (1985). A selection vector system comprising a multi-linker DNA fragment containing multiple singular restriction regions and a colEI-based replicator flanked by phage T3 and T7 promoter sequences, a fibrillar phage replica origin and an anti-amine oxime The tyromycin drug marker gene. Transformation The transformation of E. coli is usually carried out by electroporation. The 400 h liter DH5a or BL21 (DE3) culture strain was grown in L-broth to an OD 600 of 0.5 and centrifuged at 2,000 g. The cells were washed twice with ice-cold water, resuspended in 1 ml of 10% glycerol and stored in whole portions at -70 °C. The joint mixture was desalted using a Millipore V SeriesTM film (0.0025 mm pore size). 40 ml of cells were incubated on ice for 1 min in 1 ml of the ligation mixture or plasmid DNA in a 0.2 cm electroporation tank and then delivered using a Gene PulserTM device (BioRad) at 0.5 volt volts ", 250 mF, 250 Å. Selective transformation was carried out on L-agar supplemented with 10 mg/ml tetracycline or 100 mg/ml Panlinix. The vector pTB375NBSE expressed in E. coli BL21 cells exhibited GLK, which produced a direct contiguous N-terminal methionine. Recombinant protein of 6-His add-on. Or another suitable vector is pET21 (+) DNA, Novagen catalog number 697703. Use 6-His appendage to allow reconstitution -173- This paper scale applies China National Standard (CNS) A4 Specification (21〇x 297 mm) 1313601 A7 B7 V. Description of Invention (169) Body Protein in Nickel-Nitrogen Triacetate Sepharose purchased from Qiagen (Catalog No. 30250) Purified on column. The vector pFLAG CTC (IBI Kodak) from E. coli BL21 cells expresses GLKRP, producing a recombinant protein containing a C-terminal FLAG appendage. First with DEAE agarose gel Sepharose) ion exchange and subsequent purification of the protein, GLK, using the FLAG addendum as final purification on the M2 anti-FLAG immunoaffinity column (catalog number A1205) purchased from Sigma-Aldrich Bio-disposal: Reaction with biotin arginine hexanoate N-hydroxysuccinimide (Biotin-NHS) (Catalog No. B2643) from Sigma-Adesch to make GLK Biotin In short, the free amine group of the target protein (GLK) is reacted with biotin-NHS to form a stable guanamine bond to form a product containing a covalently bonded biotin. The action removes excess non-conjugated biotin-NHS from the product. In particular, 7.5 mg of GLK is added to 4 ml of 25 mg molecular weight HEPES pH 7.3, 0.15 g molecular weight KC1, 1 mg molecular weight dithiothreitol, 1 mg molecular weight EDTA 0.31 mg of biotin-NHS in 1 mg of molecular weight MgCl2 (buffer A). The reaction mixture was dialyzed against 100 ml of buffer A containing 22 mg more biotin-NHS. After 4 hours, Extensive dialysis against buffer A Excess Biotin-NHS. Pharmaceutical Compositions The following is a representative pharmaceutical dosage form of the invention as defined herein for the therapeutic or prophylactic use in humans (referred to as active compound &quot;compound X&quot;): -174- The paper scale applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) A7 B7 1313601 V. Description of the invention (17(3) (a) Tablet I Tablet/Pill Compound X... .................................... 100 Lactose Ph· Eur......... ................................ 182.75 croscarmellose sodium......... ....................12.0 cornstarch paste (5% weight/volume paste 2.25 magnesium stearate........... ............................3.0 (b) Tablet II 亳克/Pill Compound X... ......................................... 50 Lactose Ph. Eur.... ..................................... 223.75 croscarmellose sodium.... .........................6.0 Corn Starch...................... .......................15.0 Polyvinylcyclopyridone (5% by weight/volume paste).. 2.25 Magnesium stearate... ......... ...........................3.0 (c) Tablet III Tablet/Pill Compound X..... ........................................ 1.0 Lactose Ph. Eur..... .................................... 93.25 croscarmellose sodium..... ........................4.0 Cornstarch paste (5% by weight/volume of paste).........0.75 Hard Magnesium sulphate..........................................1.0 ( d) 台 克 / / 胶 匕 4 X X..................................... ........ 10 Lactose Ph. Eur..................................... .... 488.5 l............................................ ........... 1.5 -175- The paper size is the common Chinese national standard (CNS) A4 specification (210 X 297 mm) 1313601 Description 1 ~~) Α7 Β7

• 5.0% w/v 15.0% v/v 4.5% w/v

(e) Injection I Compound X.............................. 1 gram molecular weight sodium hydroxide Solution................ 0.1 g molecular weight hydrochloric acid (adjust pH to 7.6) Polyethylene glycol 400 Make injection 100% water (f) SitRIl (l〇 _£_AZ_£iL) Compound X....................................1.0% w/v sodium phosphate BP 3.6% weight / volume 0.1 g molecular weight sodium hydroxide solution.............. 15.0% volume / volume makes the injection into 100% water

(g) Injection III Compound X....................

Sodium phosphate BP citric acid Polyethylene glycol 400 makes the injection 100% water

(h) Tanning agent I compound X.................... sorbitan trioleate....... trichlorofluoromethane.... ............ Dihydrodifluoromethane.............

(i) Tincture II Compound X................... (1 mg / liter, embroidered to DH6) ........ 0.1% Weight / volume 2.26% weight / volume 0.38% weight / volume 3.5% weight / volume Taiwan. / bright rise ................ 10.0 ......... ........13.5 .................910.0 .................490.0 Taiwan / ml. ...............0.2 -176- This paper scale adopts Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1313601 A7 B7 V. Invention description (172) Sorbene trioleate..........................0.27 trichlorofluoromethane... ....................................70.0 Dichlorodifluoromethane........ ...............................280.0 Dioxotetrafluoroethane............ ...........................1094.0 (j) Tanning agent III Taiwan./Taiwan compound X........ ..................................... 2.5 sorbitan trioleate.... ...........................3.38 Tri-gas fluoromethane.................. ........................67.5 Dichlorodifluoromethane........................ ...................1086.0 Dioxetane tetrafluoroethane........................ ...............19 1.6 (k) Tincture IV mg/ml Compound X...................................... ....... 2.5 Soy lecithin.......................................... ...2.7 Trichlorofluoromethane.......................................... 67.5 Dichlorodifluoromethane.................................1086.0 Dioxetane Ethane....................................191.6 (l) Ointment ML compound X. ...................................... 40 mg ethanol... ........................................300 microliters of water. .................................................. .300 μl of 1-dodecylazepane-2-one......................50 microliters of propylene glycol.... .........................................to 1 ml Note familiar with medical skills The above formulation can be obtained by a conventional procedure.可-177- This paper size applies to Chinese National Standard (CNS) A4 size (210 X 297 mm) 1313601 A7 B7 V. Description of invention (173) Pills (a)-(c) are covered with casings using conventional equipment For example, a cellulose acetate phthalate coating is provided. Spray formulations (h) - (k) can be combined with standard metered spray dispensers and can be substituted for suspending agents (eg sorbitan monooleate, sorbitan sesquioleate, poly Sorbic acid 80, polyglycerol oleate or oleic acid) replaces sorbitan trioleate and soy lecithin suspension. -178- The paper size is 中 China National Standard (CNS) A4 size (210X 297 mm) A7 B7 1313601 V. Description of invention (174 No document 1 Printz, RL, Magnuson, MA and Granner, DK (1993) Annual Review of Nutrition 13,463-96 2 DeFronzo, RA (1988) Diabetes 37, 667-87 3 Froguel, P., Zouali, H., Vionnet, N., Velho, G., Vaxillaire, M., Sun, F. , Lesage, S., Stoffel, M., Takeda, J. and Passa, P. (1993) New England Journal of Medicine 328, 697-702 4 Bell, GI, Pilkis, SJ, Weber, IT and Polonsky, KS ( 1996) Annual Review of Physiology 58, 171-86 5 Velho, G., Petersen, KF, Perseghin, G., Hwang, JH, Rothman, DL, Pueyo, Μ. E., Cline, GW, Froguel, P. and Shulman, GI (1996) Journal of Clinical Investigation 98, 1755-61 6 Christesen, Η. Bt Jacobsen, BB, Odili, SM Buettger, CM Cuesta-Munoz, A., Hansen, T., Bnisgaard, K., Massa, 0., Magnuson, MA, Shiota, C., Matschinsky, FM and Barbetti, F. (2002) Diabetes 51, 1240-6 7 Glaser, B., Kesavan, P., Heyman, M., Davis, E Cuesta, A., Buchs, A., Stanley, CA, Thornton, P. SM Permutt, MA, Matschinsky, FM and Herold, KC (1998) New England Journal of Medicine 338, 226-30 8 Caro, JF, Triester, S., Patel, VK, Tapscott, EB, Frazier, NL and Dohm, GL (1995) Hormone &amp; Metabolic Research 27, 19-22 9 Desai, U. J„ Slosberg, ED, Boettcher, BR, Caplan, SL, Fanelli, B., Stephan, Z., Gunther, VJ, Kaleko, M. and Connelly, S. (2001) Diabetes 50, 2287-95 10 Shiota, M., Postic, C., Fujimoto, Y., Jetton, TL, Dixon, K., Pan, D., Grimsby, J., Grippo, JF, Magnuson, MA and Cherrington, AD (2001) Diabetes 50, 622-9 -179- This paper scale applies to Chinese painter standards ( CNS) A4 size (210X 297 mm) 1313601 A7 B7 V. Description of invention (175) 11 Ferre, T., Pujol, A., Riu, E., Bosch, F. and Valera, A. (1996) Proceedings of The National Academy of Sciences of the United States of America 93, 7225-30 12 Seoane, J., Barbera, A., Telemaque-Potts, S., Newgard, CB and Guinovart, JJ (19 99) Journal of Biological Chemistry 274, 31833-8 13 Moore, MC, Davis, SN, Mann, SL and Cherrington, AD (2001) Diabetes Care 24, 1882-7 14 Alvarez, E., Roncero, I., Chowen, JA, Vazquez, P. and Blazquez, E. (2002) Journal of Neurochemistry 80, 45-53 15 Lynch, RM, Tompkins, LS, Brooks, HL, Dunn-Meynell, AA and Levin, BE (2000) Diabetes 49, 693-700 16 Roncero, I., Alvarez, E., Vazquez, P. and Blazquez, E. (2000) Journal of Neurochemistry 74, 1848-57 17 Yang, XJ, Kow, LM, Funabashi, T. and Mobbs, CV (1999) Diabetes 48, 1763-1772 18 Schuit, FC, Huypens, P., Heimberg, H. and Pipeleers, DG (2001) Diabetes 50, 1-11 19 Levin, BE (2001) International Journal of Obesity 25 20 Alvarez, E., Roncero, I., Chowen, JA, Thorens, B. and Blazquez, E. (1996) Journal of Neurochemistry 66, 920-7 21 Mobbs, CV, Kow, LM and Yang, XJ (2001) American Journal of Physiology - Endocrinology &amp; Metabolism 281, E649-54 22 Levin, BE, Dunn-Meynell, AA and Ro Uth, VH (1999) American Journal of Physiology 276, R1223-31 23 Spanswick, D., Smith, MA, Groppi, VE, Logan, SD and Ashford, ML (1997) Nature 390, 521-5 24 Spanswick, D” Smith, M. A” Mirshamsi, S” Routh, VH and Ashford, ML (2000) Nature Neuroscience 3, 757-8 -180- This paper scale applies to China's sleepy home (CNS) A4 specification (210X 297 mm) 1313601 Δ7 Α7 Β7 V. Inventions (176) 25 Levin, BE and Dunn-Meynell, AA (1997) Brain Research 776, 146-53 26 Levin, BE, Govek, EK and Dunn-Meynell, AA (1998) Brain Research 808, 317 -9 27 Levin, BE, Brown, KL and Dunn-Meynell, AA (1996) Brain Research 739, 293-300 28 Rowe, IC, Boden, PR and Ashford, ML (1996) Journal of Physiology 497, 365-77 29 Fujimoto, K., Sakata, T., Arase, K., Kurata, K., Okabe, Y. and Shiraishi, T. (1985) Life Sciences 37, 2475-82 30 Kurata, K., Fujimoto, K. and Sakata, T. (1989) Metabolism: Clinical &amp; Experimental 38, 46-51 31 Kurata, K., Fujimoto, K., Sakata, T., Eto u, H. and Fukagawa, K. (1986) Physiology & Behavior 37, 615-20 -181 - 1313601 I* evening application period &lt;fi, 8, and case number 091118550 (the above columns are filled by this Council) A4 C4 fVru./ ^ '7/fx Chinese manual replacement page (93 years 3_河1 f|patent specification« name Chinese and English benzoguanamine compounds, their preparation methods, and their use for treatment or Pharmaceutical composition for preventing diseases or medical symptoms regulated by glucokinase (GLK)

BENZAMIDE COMPOUNDS, PROCESS FOR PREPARATION THEREOF, AND PHARMACEUTICAL COMPOSITIONS FOR TREATING OR PREVENTING A DISEASE OR MEDICAL CONDITION MEDIATED THROUGH GLUCOKINASE (GLK) COMPRISING SAME Name Nationality Invention Creation #人住,居所

1. Scott Bald SCOTT BOYD 2. Peter William Roycott CATERKETT 3. RONINEY RODNEY BRIAN HARGREAVES 1.2.3. UNITED KINGDOM 1.2.3. Alleyley Park, MACCLESFIELD, CHESHIRE, SK10 4TG, UK, Maldives City, Czech Republic. Name of the applicant (name) Nationality residence, residence (office) Representative name

Swedish company AstraZeneca ASTRAZENECA AB

Sweden SWEDEN

Sweden Sudeto S-15185 S-151 85 SODERTALJE, SWEDEN. Margaret Lindrose MARGARETA LINDEROTH This paper scale applies to the Chinese national standard deduction 1^8) A4 size (210 X 297 mm) 1313601 (above The column is filled by this Council)

Application for the late case number category 1336061 Application for the case number of the later period (the above columns are filled by this Council) A4 C4 Cloud also patent specification invention 揸 new name * Chinese English -, inventor a creator name nationality residence, residence 7 CLIFFORD DAVID JONES 8. DARREN MCKERRECHER 9. MICHAEL HOWARD BLOCK 7.8.9. UNITED KINGDOM 7.8. Both are located in Malesfield, Czech Republic Alderley Park ALDERLEY PARK, MACCLESFIELD, CHESHIRE, SK10 4TG, UK 9. 35 GATEHOUSE DRIVE, WALTHAM, ΜΑ 02451, WALTHAM, ΜΑ, USA, Watson, MA, USA 3, Applicant's Name (Name Nationality residence, residence (office) Representative name -3- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm)

Claims (1)

13 13 Qin Qi 118550 Patent Application A8 | Chinese patent application scope replaced September, C8! A compound of the formula (lib) or a salt thereof: Wherein the 匸丨·6 alkyl group is optionally substituted with up to 3 groups selected from R 4 and optionally includes a double bond; each X system is independently selected from the following bonding bonds: -0-Z- ' -0 -Ζ-0-Ζ- ' -C(0)0-Z- ' -0C(0)-2-, -SZ-, -SO-Z-, -S02-Z_, -N(R6)_Z_, - N(R6)S02-Z-, _S02N(R6)-Z-, -CH=CH-Z-, -c Ξ c_z-, -n(r6)co-z-, -con(r6)-z-, -C(0)N(R6)S(0)2-Z- ' -S(0)2N(R6)C(0)-Z-' -C(0)-Z- ' -Z- ' -C (0)-Z-0-Z- ' -N(R6)- C(0)-Z-0-Z-, -〇-ZN(R6)-Z-,-0-C(0)-Z- 0-Z- , each Z series is independently a straight bond, a c2_6 extended alkenyl group or a group of the formula -(CH2)pC(R6a)2-(CH2)q-; each R4 is independently selected from a halogen group, -CH3_aFa , CN, NH2, Cu alkyl, -OCu alkyl, -C00H, -(:(0)0(:!.6 alkyl, OH or phenyl substituted with Cb6 alkyl or -CCCOOCu alkyl, if desired, This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1313601, the patent application scope AB c D or R^-X1-, where X1 is independent of the definition of X above, and R5 is selected from hydrogen. , Ci-6 alkyl, -CH3.aFa, phenyl, naphthyl, heterocyclic or C3-7 cycloalkyl, and R5 is optionally selected from halo, Cu alkyl, or OC&quot;alkyl, _CH3_aFa, CN, OH, NH2, COOH or -(:(0)0 (^.6 alkyl substituent substitution, each Z1 is independently a direct bond, c2.6 an alkenyl group or a formula - (CH2)pC(R6a)2-(CH2)q-; R3 is a heterocyclic group in which the atomic system sp2 at the 2-position of the sulfhydryl group attached to R3 Mixed nitrogen, and R3 is substituted with up to 2 R7 as needed; R6 is independently selected from hydrogen, Cw alkyl or -c2.4 alkyl-o-Cw alkyl; The ruler &amp; is independently selected from hydrogen, halogen a group, a Cu alkyl group or a -C2.4 alkyl-O-Cj.4 alkyl group; each R7 group is independently selected from the group consisting of: Cj.6 alkyl, C2.6 alkenyl, C2.6 alkynyl, (CH2) 〇_3 aryl, (CH2)Q_3 heterocyclic group, (CH2)G.3C3.7 cycloalkyl, OH, Cu alkyl-OH, halo, Ch alkyl-halo, OCu alkyl, (CH2)0_3S(O)0_2R8, SH, S03H, thio, NH2, CN, (CH2)〇.3NHS02R8 ' (CH2)〇.3COOH ' (CH2)〇.3-〇. (ch2)〇.3r8, (ch2)〇.3c(o)(ch2)〇.3r8, (ch2)〇_3 C(0)0R8 ' (CH2)〇.3C(0)NH2 ' (CH2)〇.3C(0)NH ( Ch2)0.3r8, (CH2)〇.3NH(CH2)〇.3R8 ' (CH2)〇.3NH C(0)(CH2)〇.3R8, (CH2)〇.3C(0)NHS02-R8 and _ 2 - The paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) ABCD 1313601 VI. Patent application scope (CH2) 0_3S〇2NHC(O)-R8, wherein the alkyl chain and cycloalkyl ring in R7 Or a heterocyclyl ring is optionally selected from one or more selected from the group consisting of Cw alkyl, hydrazine H, halo, CN, NH2, iV-Cj.4 alkylamine, and ##二_&lt;^.4 Substituted with an amine group and a substituent of OC丨.4 alkyl; R8 is selected from the group consisting of hydrogen, (^-6 alkyl, aryl, heterocyclic, c3-7 cycloalkyl, hydrazine H, Cu alkyl 〇h, COOH, C(0)0CV6 alkyl, alkyl, 0Cl-6 alkyl, C〇_6 alkyl 0C(9)Cl6 alkyl, qOHKCw alkyl)Cualkyl; wherein alkyl or aryl, heterocyclyl or ring in R8 The alkyl ring system is optionally selected from one or more selected from the group consisting of Cu alkyl, OH, Substituted by substituents of CN, NH2, -NH-Cm alkyl, -N-:_(CN4 alkyl) and OCm alkyl; each a is independently 1, 2 or 3; P is 0 to An integer between 3; q is an integer between 0 and 3; and p+q&lt;4, with the constraint that (i) when R3 is 2-pyridyl and X is not -Z-, -C(0 When -Z-0-Z-, -N(R6)-C(0)-Z-0-Z- or -0-ZN(R6)-Z-, then R3 cannot be selected from the 5-position ROH monosubstituted by COOH or C(0)0CN6 alkyl; (ii) Unbranched unsubstituted alkyl chain may not exceed the length of C6 alkyl; (iii) Only one X group may be _^^(: (〇)-; This paper scale applies to China National Standard (CNS) A4 specification (210X297 public) ABCD 1313601 VI. Application for patent garden (iv) When X is independently selected from _c(〇)NH-, -NHC(O ) -, - 0-, -S(0)2NH- or a straight bond, and one of the X groups - NHC(O)-, then R3 may not be an unsubstituted 4 azo group, a triphenyl group Substituted 4,5-dihydro-5-oxypyrazolyl, 4,5,6,7-tetrahydrobenzo[b]sulfonyl substituted with ethoxycarbonyl or, optionally, methyl, Ethoxy or propylcarbonylamino mono- or di-substituted pyridyl (v) When R3 is 2-pyridyl, X is z or -C(0)-Z-0-Z-, and Z is selected such that X thus becomes a direct bond, -, -CH = CH-Z- Or -C(0)0-Z-, then R3 cannot be monosubstituted at the 5-position with R7 selected from C00H or (:(0)0(:!_6 alkyl). 2. A compound according to claim 1 or a salt thereof, wherein R3 is selected from the group consisting of: thiazole, benzoxazole, thiadiazole, pyridine, piperene, pyridin, piperazole, imidazole, pyrimidine, oxazole and 〇?丨哚. 3. A compound according to claim 1 or 2 or a salt thereof, wherein z is a straight bond, -CH2- or -c(ch3)2-. 4. A compound according to item 3 of the patent application or a salt thereof, wherein z is a straight bond. 5. According to the scope of the patent application! Or a compound of 2 or a salt thereof, wherein z is selected from the group consisting of a straight bond, _(CH2)1.2, and a group of the formula _(CH2)p_C(R6a)2_(CH2V, wherein 1163 is independently selected from hydrogen and Ci 4 The compound according to item 5 of the patent application, or a salt thereof, wherein z is a straight bond, -CH2- or -(ch2)2. 7. A compound according to claim 丨 or 2 or Salt of each -4- ABCD 1313601 VI. Application for the patent garden X series are independently selected from: -Z-, -CH=CH-Z-, -0-Z-, -C(0)-Z-, -c(0)0-z -, -0-C(0)-Z-, -C(0)-Z-0-Z-, -0-C(0)-Z-0-Z-, -SZ- ' -SO-Z- ' -S02-Z- ' -N(R6)-Z- ' -N(R6)CO-Z- , -con(r6)-z., -n(r6)-c(o)-z-〇- Z-, _so2n(r6)-z-, -N(R6)S02-Z-, and -ozn(r6)-z-. 8. A compound according to claim 7 or a salt thereof, wherein x is selected from the group consisting of -Z-, -CH=CH-Z-, -0-Z-, -C(〇)-Z-, -C (0) 0-Z-, -C(0)-Z-0-Z-, -N(R6)-Z- and -N(R6)CO-Z-. 9. A compound according to claim 8 or a salt thereof, wherein the oxime is selected from the group consisting of -CH=CH-Z-, -0-Z- and -C(0)-Z-. 10. A compound according to claim 9 or a salt thereof, wherein the oxime is _〇_Z. 11. A compound according to claim i or 2 or a salt thereof, wherein each R4 is independently selected from the group consisting of halo, CH%aFa, 0CH3 aFa, CN, Cw alkyl, ocu alkyl, COOH, c ( 0) 0Cl 6 alkyl, (CH 2 ) 〇 3 COOH, hydrazine (CH 2 ) 0.3 COOH, CO-phenyl, CONH 2 , CONH-phenyl, S 02 NH 2 , SOAu alkyl, OH or, if desired, one or more R 5 Substituted phenyl' wherein R5 is selected from hydrogen, Cl-6 alkyl or C(O)OCl.6 alkyl. 12. The compound according to claim 1 or 2, or a salt thereof, wherein R3 is unsubstituted or substituted with one R7 group. 13. A compound according to claim 1 or 2 or a salt thereof, wherein each R7 is independently selected from the group consisting of 〇H, CN, NH2, S03H, thio, halo, and the paper size applies to the Chinese National Standard (CNS). A4 size (21〇x 297 mm) 1313601 A8 B8 C8 D8 VI. Patent application scope C, .4 炫基, C!.4 alkyl-OH, 0-(^-4 alkyl, (:,-4 Alkyl-halo, (CH2)〇.1COOH ' (CH2)〇.iC(0)OR8 &gt; (CH2)〇.1NH(CH2)〇.2 R8, (CH2)〇.1NHC(0)(CH2 )〇2R8, (CH2)〇-iC(0)NH(CH2)〇.2 R8 ' -(CH2)〇.2S(0)〇.2R8 ' -(CH2)〇.,NHS02R8 ' (CH2)〇 .C(o)nhs(o)2r8 or (CH2)〇.4 ring group. 14. A compound of the formula (11b) according to the scope of claim 1 or a salt thereof, wherein the compound is selected from the group consisting of: -6- This paper scale applies to China National Standard (CNS) A4 specification (21〇 X 297 mm) 1313601 - C8 D8 VI. Patent application scope 0. YYyV^&gt; F F 丫雄〇 F r^^0H F x^j F 丫欢r F F lr end f. :s: - - ,, 丫' F 九. · 'φ^ΙτΌ .. · - y^〇v5n F 丫 τίΛ^ ιίς) F F CO, H person. ΊρΛ 乂$ °^JyH people. X&gt;Vf ιίς) F CO〆丫〇^^ji 丫^yV^c°aH F 丫^^乂) °^Jy) F This paper scale applies to China National Standard (CNS) A4 specification (210X 297 dongdong) A8 B8 C8 D8 1313601 VI. Apply for a patent ' ----·~--- 丫. F 〇---^ 丫' f 丫乂}c°, H f F -- 丫 常 — F Ytj1^ F ------ F 丫XrW FF 丫XrW 乂χ^&gt; F 丫t/«乂X^) FFF Bu·~—F 0 /C〇2H 丫. Hn〇rV〇HN^aa 〇〇- &quot; - °^Jy) F p F 15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 1 or a salt thereof, And a pharmaceutically acceptable diluent or carrier. 16. Use of a compound of the formula (lib) according to the scope of claim 1 or a salt thereof for the preparation of a medicament for the combined treatment or prevention of diabetes and obesity. This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 1313601 17. A compound of the formula (lib) or a salt thereof according to the patent application scope 1 + j: / 1 , which is used as a medicament. 18, according to the patent application HI 窜, c. 1 guilty of the use of the formula (11 b) of the formula (11 b) or its salt 'is used for preparation · A. W for treatment or prevention via GLK regulation A drug for a disease or medical condition. The 19' pharmaceutical composition' contains a formula (lib) according to the patent application amount (lib) or a salt thereof, and a pharmaceutically acceptable diluent or carrier. The system is for the preparation of a medicament for the treatment or prevention of a disease or medical condition via modulation. 20. A method of preparing a compound of the formula (nb) or a salt thereof according to the scope of the patent application, comprising: (a) reacting a compound of the formula (Ilia) with a compound of (Inb) Formula (IIIa) Formula (mb) wherein X1 is a leaving group; (b) a compound of formula (lib) wherein R3 is substituted by -(CH2)0.3c〇〇H, which is deprotected by a compound of formula (IIIc) - 9- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1313601 Patent application scope 8 8 8 8 A BCD Wherein the P1 is a protecting group; (c) reacting a compound of the formula (Hid) with a compound of the formula (nie) (〇η3Λ. (RV0^.X&quot; Formula (Ille) Formula (Illd) wherein X' and X&quot; contain a group which forms a sulfhydryl group when reacted together; (d) Formula (where X or χΐ_8〇_B or _8〇2_2_ ( Nb) The compound ' is oxidized by a compound of the formula (jjb) wherein χ or χΐ are each -s_ z; (e) reacting a compound of the formula (Illf) with a compound of (IIIg) -10- Common Chinese National Standard for Paper Size (CNS) A4 specification (210X297 mm) 1313601 A8 B8 C8 D8 VI. Patent application scope Formula (nif) wherein n2 is a leaving group; and then, if necessary: i) converting a compound of formula (lib) to another compound of formula (lib); ii) removing any protecting groups; iii) forming it salt. -11 - This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm)