TW200906395A - New amide derivative - Google Patents

Abstract

The present invention concerns amide derivatives or the pharmaceutically acceptable salts thereof which have an excellent SCD (stearoyl CoA desaturase) inhibiting action. The present invention provides amide derivatives of the following formula (I): [wherein, R1 represents a hydroxyl group, C1-C6 alkoxy group, a hydroxylC1-C6 alkoxy group etc. ; R2 represents a hydroxyl group, C1-C6 alkoxy group, a hydroxylC1-C6 alkoxy group etc. ; R3 represents a hydrogen atom etc. ; R4 represents a C6-C10 aryl group which may be independently substituted with 1 to 5 groups selected from substituents A etc. ; V represents a group of the formula -NH- or a single bond; W represents a group of the formula -NH- or a single bond; T represents a group of the formula = C (R5) - or a nitrogen atom; Q represents a group of the formula = C (R5) - or a nitrogen atom], or the pharmaceutically acceptable salts thereof.

Description

200906395 IX. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to the inhibition of the function of a hard acetoin-based c〇A desaturase (Desaturase) for diabetes, arteriosclerosis, obesity, non-alcoholic steatohepatitis, and high A guanamine derivative or a pharmacologically acceptable salt thereof having a specific chemical structure which is effective for the treatment and prevention of various human diseases associated with stearyl sulfhydryl-based CoA desaturase such as lipemia or hypertension. [Prior Art] The thiol-CoA desaturase is a catalyst for the formation of a double bond in a fatty acid produced by inhalation or synthesis in a cell. The animal has a type 4 thiol-CoA desaturase in which a double bond is introduced at a position of δ-9, δ-6, δ-5, δ-4 of each fatty chain. The sterol oxime-based CoA desaturase (hereinafter also referred to as SCD) is an enzyme which introduces a double bond at the δ-9 position of a saturated fatty acid, and converts the soft ester sulfhydryl group CoA and the stearyl sulfhydryl group CoA into each soft ester in vivo. The oil-based CoA and the oil-based CoA are used as a main component of phospholipids, triglycerides, and cholesterol esters. The ratio of stearic acid to oleic acid affects the fluidity of the cell membrane, and participates in diabetes, 'obesity, arteriosclerosis, hypertension, neurological diseases, heart disease, cancer, and aging (Non-Patent Document 1). The mouse liver SCD is highly expressed in the appetite suppressor Leptin deficiency ob/ob mice, and its expression is suppressed to a normal level due to the administration of the Leptin. SCD-deficient mice showed lower liver triglycerides, lower hepatic cholesterol esters, and lower adipose tissue weight than normal mice. Under high-fat diets, they inhibited weight gain compared with normal animals, and were resistant to sugar and hypersensitivity to insulin. It was mated with 0 b / 〇 b mice by 200906395 to reduce body weight, hypermetabolism, and normalize fatty liver (Non-Patent Documents 2 and 3). When antisense nucleotides of SCD are administered to mice to inhibit SCD expression and activity, body weight gain rate, body fat percentage, plasma insulin sputum, blood glucose sputum decrease, and fatty acid synthesis and fat droplet accumulation in liver sputum decrease ( Non-Patent Document 4) 推 Inferred from these experimental results, due to the extensive influence of SCD inhibitors on the lipid metabolism system, it contributes to the improvement of insulin resistance, improvement of hyperglycemia, anti-obesity, improvement of liver function, improvement of arteriosclerosis, and treatment The standard of medicine. Although some compounds have been known to have SCD inhibition in the past, they are all structurally different from the compounds of the present invention. For example, a compound containing a piperidine ring is disclosed in Patent Document 1, and a compound containing a piperene ring is known from Patent Documents 2 to 5. [Patent Document 1] International Publication No. 2006/03433 No. 8 [Patent Document 2] International Publication No. 20〇5/0 1 1 65 No. 3 Booklet [Patent Document 3] International Publication No. 2005/50 1 1 654 Booklet [Patent Document 4] US 2005/0 1 1 92 5 1 [Patent Document 5] International Publication No. 2006/0S6447 Booklet [Non-Patent Document 1] Prog Lipid Res·, 1 995; 34(2) :1 3 9-150. [Non-Patent Document 2] Science., 2002; 297(5579): 240-243. [Non-Patent Document 3] Proceedings of the National Academy of Sciences of the United States of America, 2002; (17): 11482-11486. [Non-Patent Document 4] The Journal of Clinical 200906395

Investigation, 200 5 ; 1 15 (4): 1030-1038. [Disclosure of the Invention] The inventors of the present invention have found a specific chemical structure of indoleamine in view of the results of research on the SCD inhibitory compound. The compound has excellent S CD inhibition. Further, the present inventors have found such a guanamine compound as obesity, obesity, hyperlipidemia, hypertriglyceridemia, abnormal lipid metabolism, insulin resistance syndrome, abnormal glucose tolerance, diabetes, diabetes mellitus, Prevention and/or treatment of diseases selected from the group consisting of cataracts, gestational diabetes, polycystic ovary syndrome, atherosclerosis, atherosclerosis, diabetic atherosclerosis, fatty liver, and nonalcoholic steatohepatitis The active ingredients of medicine, or the following diseases caused by obesity: hyperlipidemia, hypertriglyceridemia, abnormal lipid metabolism, insulin resistance syndrome, abnormal glucose tolerance, diabetes, diabetes mellitus, cataract, pregnancy Diabetes, polycystic ovary syndrome, atherosclerosis, atherosclerosis, diabetic atherosclerosis, hypertension, cerebrovascular disease, coronary artery disease, respiratory abnormalities, low back pain, deformed knee joint disease, gout, and gallbladder Useful ingredients for the treatment and/or prevention of diseases selected by the group of stone diseasesThe present invention has been completed based on the above findings. (Means for Solving the Problem) The present invention relates to: (1) A guanamine derivative or a pharmacologically acceptable salt thereof of the following formula (I), 200906395 R4

S 丫V, R2 Q- 〇R1 (I) [wherein R1 is hydroxy, ci_c6 alkoxy, C2-C6 hydroxyalkoxy, (CrG alkoxy MCrCe alkoxy) group, bis-(Ct-C) ^Alkylamino-(CrC^alkoxy) group, substituted with 4-morpholinyl 1 (^-(^ alkoxy, (C^-Ce alkylthio)-(Κ6 alkoxy) Base, (<^-(:6 alkylsulfinylalkyloxy) group, (Ci-Q alkylsulfonyl alkoxy) group, amine group 'mono-Ci-Q alkylamino group, two-( CrC6 alkyl)amino, mono-C2-C7 alkylcarbonylamino or 4-morpholinyl, R2 is hydroxy, Ci-C6 alkoxy, c2-C6 hydroxyalkoxy, (C^Ce alkoxyalkane Oxy) or bis-(C^Ce alkyl)amino-(Cl-C6 alkoxy) group, R1 and R2 are not simultaneously a trans group or a Ci-Ce methoxy group, and R 3 is a hydrogen atom or a halogen Atom, C^-CU, or a radical, R4 is a C6_C1() aryl group which may have 1 to 5 substituents independently selected from the group selected by substituent group A or may have a group independently selected from substituent group a to 3 substituted heterocyclic groups, V is a group of the formula -NH - or a single bond, W is a group of the formula -NH- or a single bond, and V and W are not simultaneously a group of the formula -NH_ or a single bond, τ is Formula = C(R5)- or a nitrogen atom, R5 is a hydrogen atom, a halogen atom or Cl- C6 alkyl, -9- 200906395 Q is a group of the formula =C(R6)- or a nitrogen atom, R6 is a hydrogen atom, a halogen atom or an alkyl group, and the substituent group A is a halogen atom, a C^-CU alkyl group, CVC6 halogenated alkyl, G-C6 hydroxyalkyl, (H6 alkoxy)-(C丨-C6 alkyl) group, c!-c6 alkoxy group, Ci-Ce halogenated alkoxy group, Ci-C6 alkyl sulfide Base, carboxyl group, c2-c7 alkylcarbonyl group, C2-C7 alkoxycarbonyl group, nitro group, amine group, mono-C2-C7 alkylcarbonylamino group, mono-CrQ alkylamino group, bis-(Q-C6 alkyl)amine In the present invention, the guanamine derivative or the pharmacologically acceptable salt thereof, wherein (I) is a Ci-Ce alkoxy group, is preferably a group of the guanamine group or a pharmacologically acceptable salt thereof. And a mono-CVC6 alkylamino group, a di-(CrCe alkyl)amino group or a 4-morpholinyl group. (3) The indoleamine derivative or a pharmacologically acceptable salt thereof, wherein R1 is a methoxy group, An acetamide derivative or a pharmacologically acceptable salt thereof, wherein R1 is an ethylamine group, or a pharmaceutically acceptable salt thereof, wherein R1 is an ethylamine group, or a 4-hydroxyl group, or a pharmaceutically acceptable salt thereof. A guanamine derivative or a pharmacologically acceptable salt thereof according to any one of (1) to (4), which is a dimethylamine group, a diethylamino group or a 4-morpholinyl group. 112 is a Ci-Ce alkoxy group or a C2-C6 hydroxyalkoxy group. (6) The guanamine derivative or a pharmacologically acceptable salt thereof according to any one of (1) to (4) wherein R2 is 2-hydroxyethyl (A) A guanamine derivative or a pharmacologically acceptable salt thereof according to any one of (1) to (6), wherein R3 is a hydrogen atom. (8) The indoleamine derivative or a pharmacologically acceptable salt thereof according to any one of (1) to (7), wherein R4 is halogenated by (halogen atom, C丨-C6 alkyl group, halogenated alkyl group, and C〗-C6) The base of the choice is independently 1 to 3 substituted phenyl groups. (9) The indoleamine derivative or a pharmacologically acceptable salt thereof according to any one of (1) to (7), wherein R4 is independently selected from (fluorine atom, chlorine atom and trifluoromethyl group) or 2 Substituted phenyl. (10) The indoleamine derivative or a pharmacologically acceptable salt thereof, wherein R4 is 3-fluorophenyl, 3-chlorophenyl, 3-trifluoromethylphenyl , 3,4-difluorophenyl, 3,5-difluorophenyl, 3-chloro-4-fluorophenyl, 4-oxo-3-trifluoromethylphenyl, 3,5-dichlorophenyl Or 3,5-di-trifluoromethylphenyl. (1) The indoleamine derivative or a pharmacologically acceptable salt thereof according to any one of (1) to (10), wherein V is a group of the formula -NH-, and W is a single bond. (1) The indoleamine derivative or a pharmacologically acceptable salt thereof according to any one of (1) to (1), wherein T is a nitrogen atom, and Q is a group of the formula = CH-. (13) A guanamine derivative or a pharmacologically acceptable salt thereof, wherein R1 is a Ci-C6-homoyloxy group, a mono-Ci-C6-hotrienyl group, a di-(C丨-C6-group) amine group or 4-morpholinyl 'R2 is a C1-C6 alkoxy group or a C2_C6 hydroxyalkoxy group, R3-11-200906395 is a hydrogen atom, and R4 is a halogen atom (G-C6 alkyl group, C^-C:6 halogenated). The alkyl group and the C^-Ce halogenated alkoxy group are independently selected from 1 to 3 substituted phenyl 'V is a group of the formula -NH-, W is a single bond, and T is a nitrogen atom 'Q is a formula =CH- The basis. (1) A guanamine derivative or a pharmacologically acceptable salt thereof, wherein R1 is a methoxy group, an ethoxy group, an ethylamino group, a dimethylamino group, a diethylamino group or a 4-morpholinyl group, R 2 is 2-hydroxyethoxy, R 3 is a hydrogen atom ' R 4 is (fluorine atom, chlorine atom and trifluoromethyl group), the selected group is independently 1 or 2 substituted phenyl groups, and V is a group of the formula -NH-, W is a single bond, T is a nitrogen atom, and Q is a group of the formula =CH-. (15) The indoleamine derivative of (1) or a pharmacologically acceptable salt thereof, wherein R1 is ethylamino, dimethylamino, diethylamino or 4-morpholinyl, and R2 is 2-hydroxyethoxy. R3 is a hydrogen atom, and R4 is 3-fluorophenyl, 3-chlorophenyl, trifluoromethylphenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3-chloro- 4-fluorophenyl, 4-fluoro-3-trifluoromethylphenyl, 3,5-dichlorophenyl or 3,5-di-trifluoromethylphenyl, V is a group of the formula -NH-, W is a single bond, T is a nitrogen atom, and Q is a group of formula = -. (16) The guanamine derivative or a pharmacologically acceptable salt thereof according to (1), wherein the compound of the formula (1) is 4-dimethylamino 4-[5-(3-fluorobenzyl)-thiazole-2- 3-(2-hydroxy-ethoxy)-benzylguanamine, N-[5-(3-chloro-benzyl)-thiazol-2-yl]-4-ethylamino-3-(2 -hydroxy-ethoxy)-benzylguanamine, N-[5-(3-chlorobenzyl)-shrazol-2-yl]-4-dimethylamino-3-(2-hydroxyethoxy) -12- 200906395 )-benzylamine, 1[5-(3-chloro-benzyl)-thiazol-2-yl]-4-diethylamino-3-(2-hydroxy-ethoxy)-benzyl Indoleamine, 4-ethylamino-3-(2-hydroxy-ethoxy)-N-[5-(3-trifluoromethyl-benzyl)-thiazol-2-yl]-benzamide, 4 -dimethylamino-3-(2-hydroxy-ethoxy)-N-[5-(3-trifluoromethylbenzyl)thiazol-2-yl]-benzylamine, 4-diethylamine 3-(2-hydroxyethyloxy)-N-[5-(3-trifluoromethylbenzyl)-thiazol-2-yl]-benzylamine, 3-(2-hydroxy-ethoxy -4-morpholin-4-yl-N-[5-(3-trifluoromethylbenzyl)-thiazol-2-yl]-benzylamine, N-[5-(3,5-di Fluoro-benzyl)-thiazol-2-yl]-4-ethylamino-3-(2-hydroxy-ethoxy)-benzamide, 4-diethylamino-N-[5-(3, 5-difluorobenzyl)-thiazole-2- 3-(2-hydroxy-ethoxy)-benzylamine, N-[5-(3,5-dichloro-benzyl)-thiazol-2-yl]-4-ethylamino-3 -(2-hydroxy-ethoxy)-benzylamine, or N-[5-(3,5-dichlorobenzyl)-thiazol-2-yl]-4-dimethylamino-3-(2 -Hydroxy-ethoxy)-benzylamine. (17) A guanamine derivative or a pharmacologically acceptable salt thereof, wherein the compound of the formula (I) is: N-[5-(3-chloro-benzyl)-thiazol-2-yl]-4-B Amino 3-(2-hydroxy-ethoxy)-benzamide, N-[5-(3-chloro-benzyl)-thiazol-2-yl]-4-diethylamino-3-( 2-hydroxy-ethoxy-13 - 200906395 benzyl)-benzylamine, 4-ethylamino-3-(2- benzyl-ethyl)-N-[5-(3-dimethylmethyl-oxime) , oxazol-2-yl]-benzylamine, 4-diethylamino-3-(2-hydroxy-ethoxy)-N-[5-(3-trifluoromethylbenzyl)- Thiazol-2-yl]-benzylamine, N-[5-(3,5-difluoro-benzyl)-thiazol-2-yl]-4-ethylamino-3-(2-hydroxy-ethoxy Benzylamine, 4-diethylamino-N-[5-(3,5-difluorobenzyl)-thiazol-2-yl]-3-(2-hydroxy-ethoxy)-benzyl Indoleamine, or N-[5-(3,5-dichloro-benzyl)-thiazol-2-yl]-4-ethylamino-3-(2-hydroxy-ethoxy)-benzamide. (18) A guanamine derivative or a pharmacologically acceptable salt thereof according to any one of (1) to (4), wherein the compound of the formula (I) is: 4-dimethylamino-N-[5-(3-fluoro Benzyl)-thiazol-2-yl]-3-(2-hydroxy-ethoxy)-benzylguanamine, N-[5-(3-chloro-benzyl)-thiazol-2-yl]-4- Ethyl 3-(2-hydroxy-ethoxy)-benzylamine, N_[5_(3-dichlorobenzyl)-thiazol-2-yl]-4-dimethylamino-3-(2- Hydroxy-ethoxy)-benzylamine, N-[5-(3-chloro-benzyl)-thiazol-2-yl]-4-diethylamino-3-(2-hydroxy-ethoxy) - decylamine, 4-ethylamino-3-(2-hydroxy-ethoxy)-N-[5-(3-trifluoromethyl-benzyl)-thiazol-2-yl]-benzylguanamine , 4-dimethylamino 3-(2-hydroxy-ethoxy)-N-[5-(3-trifluoromethylbenzyl)-thia-14- 200906395 oxazol-2-yl]-benzidine Amine, 4-diethylamino-3-(2-hydroxy-ethoxy)-N-[5-(3-trifluoromethylbenzyl)-thiazol-2-yl]-benzylguanamine, 3- (2-Hydroxy-ethoxy)-4-morpholin-4-yl-N-[5-(3-trifluoromethylbenzyl)-thiazol-2-yl]-benzamide, N-[5 -(3,5-difluoro-benzyl)-thiazol-2-yl]-4-ethylamino-3-(2-hydroxy-ethoxy)-benzamide, 4-diethylamino-N -[5-(3,5-difluorobenzyl -thiazol-2-yl]-3-(2-hydroxy-ethoxy)-benzamide, 1[5-(3,5-dichloro-benzyl)-thiazol-2-yl]-4-B Amino-3-(2-hydroxy-ethoxy)-benzamide, or N-[5-(3,5-dichlorobenzyl)-thiazol-2-yl]-4-dimethylamino- 3-(2-Hydroxy-ethoxy)-benzamide. (19) A guanamine derivative or a pharmacologically acceptable salt thereof, wherein the compound of the formula (I) is N-[5-(3-chloro-benzyl)-thiazol-2-yl]-4-ethylamine 3-(2-hydroxy-ethoxy)-benzamide, N-[5-(3-chloro-benzyl)-thiazol-2-yl]-4-diethylamino-3-(2 -hydroxy-ethoxy)-benzylamine, 4-ethylamino-3-(2-hydroxy-ethoxy)-N-[5-(3-trifluoromethyl-benzyl)-thiazole-2 -yl]-benzylamine, 4-diethylamino-3-(2-hydroxy-ethoxy)-N-[5-(3-trifluoromethylbenzyl)-thiazole-2-yl]- Benzylamine, N-[5-(3,5-difluoro-benzyl)-thiazol-2-yl]-4-ethylamino-3-(2-hydroxy-ethyl-15- 200906395 oxy)- Benzylamine, 4-diethylamino-\-[5-(3,5-difluorobenzyl)-thiazol-2-yl]-3-(2-hydroxy-ethoxy)-benzamide, Or N-[5-(3,5-Dichloro-benzyl)-thiazol-2-yl]-4-ethylamino-3-(2-hydroxy-ethoxy)-benzamide. (20) A sterol oxime-based CoA desaturase inhibitor containing the guanamine derivative or the pharmacologically acceptable salt thereof according to any one of (1) to (19) as an active ingredient. (2) A medicinal composition containing the guanamine derivative or the pharmacologically acceptable salt thereof according to any one of (1) to (19) as an active ingredient. (22) A pharmaceutical composition according to (21) for inhibiting the stearin-based CoA desaturation enzyme. (23) A pharmaceutical composition according to (21) for use in the treatment and/or prevention of a disease in which a hard ester sulfhydryl-based CoA desaturase activity is implicated. (24) A pharmaceutical composition such as (21) for the treatment and/or prevention of obesity, obesity, hyperlipidemia, hypertriglyceridemia, abnormal lipid metabolism, insulin resistance syndrome, abnormal glucose tolerance, Diabetes, Diabetes Mellitus, Cataract, Gestational Diabetes, Polycystic Ovary Syndrome, Atherosclerosis, Atherosclerosis, Diabetic Atherosclerosis, Fatty Liver or Nonalcoholic Steatohepatitis. (25) The medical composition of (2 1) for treating and/or preventing the following causes of obesity: hyperlipidemia, hypertriglyceridemia, abnormal lipid metabolism, insulin resistance syndrome, sugar tolerance Abnormal ability, diabetes, diabetes mellitus, cataract, gestational diabetes, 'multiple cell ovarian syndrome, atherosclerosis, atherosclerosis, diabetic atherosclerosis, -16- 200906395 Hypertension, cerebrovascular disease, coronary Arterial disease, fatty liver, respiratory abnormalities, low back pain, deformed knee joint disease, gout or cholelithiasis. (26) A pharmaceutical composition according to (21) for the treatment and/or prevention of hyperlipidemia, hypertriglyceridemia, diabetes, hypertension or arteriosclerosis caused by obesity, obesity or obesity. (27) A pharmaceutical composition according to (21) for the treatment and/or prevention of obesity or obesity. (2) A pharmaceutical composition according to (2 1) for the treatment and/or prevention of diabetes. (29) A pharmaceutical composition according to (21) for the treatment and/or prevention of fatty liver or non-alcoholic steatohepatitis. (30) A pharmaceutical composition according to (2 1) for the treatment and/or prevention of hyperlipidemia or hypertriglyceridemia. (31) A pharmaceutical composition which is produced by using the guanamine derivative or the pharmacologically acceptable salt thereof according to any one of (1) to (19). (3 2) The use of (31), wherein the pharmaceutical composition is a composition for inhibiting a hard ester sulfhydryl-based Co A desaturase. (3 3) The use of (3 1), wherein the pharmaceutical composition is for treating and/or preventing obesity, obesity, hyperlipidemia, hypertriglyceridemia, abnormal lipid metabolism, insulin resistance syndrome, and sugar tolerance Composition of abnormal ability, diabetes, diabetes mellitus, cataract, gestational diabetes, multi-cytoplasmic ovarian syndrome, atherosclerosis, atherosclerosis, diabetic atherosclerosis, fatty liver or non-alcoholic steatohepatitis . (3 4) The use of (3 1), wherein the pharmaceutical composition is the following diseases for treating and/or preventing the cause of obesity: hyperlipidemia, hypertriglyceridemia, lipid -17-200906395 Disease, insulin resistance syndrome, abnormal glucose tolerance, diabetes, diabetes mellitus, cataract, gestational diabetes, polycystic ovary syndrome, atherosclerosis, atherosclerosis, diabetic atherosclerosis, hypertension, brain Vascular disorders, coronary artery disease, fatty liver, respiratory abnormalities, low back pain, deformed knee joint disease, gout or cholelithiasis. (3 5) The use of a pharmaceutical composition for the treatment and/or prevention of obesity, obesity or obesity, hyperlipidemia, hypertriglyceridemia, diabetes, hypertension or arteriosclerosis, as used in (3) disease. (3) The use of (3), wherein the pharmaceutical composition is for the treatment and/or prevention of obesity or obesity. (3 7) The use of (3), wherein the pharmaceutical composition is a component for the treatment and/or prevention of diabetes. (38) The use of (31), wherein the pharmaceutical composition is a composition for the treatment and/or prevention of fatty liver or non-alcoholic steatohepatitis. (39) The use of (31), wherein the pharmaceutical composition is a composition for treating and/or preventing hyperlipidemia or hypertriglyceridemia. (40) A method for inhibiting a sterol oxime-based CoA desaturase, which comprises administering a pharmacologically effective amount of the guanamine derivative or a pharmacologically acceptable salt thereof according to any one of (1) to (19) to warm blood animal. (4) A method for the treatment and/or prevention of a disease, which comprises administering a pharmacologically effective amount of the indoleamine derivative or a pharmacologically acceptable salt thereof according to any one of (1) to (19) to a warm-blooded animal. (4) The method according to (41), wherein the disease is obesity, obesity, hyperlipidemia, hypertriglyceridemia, abnormal lipid metabolism, insulin resistance -18-200906395 syndrome, abnormal glucose tolerance, diabetes 'diabetes mellitus, cataract, gestational diabetes, multi-cell ovarian syndrome, atherosclerosis, atherosclerosis, diabetic atherosclerosis, fatty liver or non-alcoholic steatohepatitis. (43) The method according to (41), wherein the disease is caused by obesity: hyperlipidemia, hypertriglyceridemia, abnormal lipid metabolism, insulin resistance syndrome, abnormal glucose tolerance, diabetes, diabetes Symptoms, cataracts, gestational diabetes, multi-cytoplasmic ovarian syndrome, atherosclerosis ' atherosclerosis, diabetic atherosclerosis, hypertension, cerebrovascular disease, coronary artery disease, fatty liver, respiratory abnormalities, low back pain, Deformable knee joint disease, gout or cholelithiasis. (44) The method according to (41), wherein the disease is hyperlipidemia, hypertriglyceridemia, diabetes, hypertension or arteriosclerosis which is caused by obesity, obesity or obesity. (4) The method according to (41), wherein the disease is obesity or obesity. (46) The method of (41), wherein the disease is diabetes. (4) The method according to (41), wherein the disease is fatty liver or non-alcoholic fatty liver inflammation. (48) The method according to (41), wherein the disease is hyperlipidemia or hypertriglyceridemia. (49) The method of any one of (40) to (48) wherein the warm-blooded animal is a human. In the present invention, the rCl-C6 alkyl group is a linear or branched alkyl group having 1 to 6 carbon atoms. For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, new -19-200906395 Pentyl, 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylmethylbutyl, 1, 1-dimethylbutyl, 1,2-dimethylbutylbutyl, 2,3-dimethylbutyl, 1-ethylbutyl or 2-ethyl: 1 to 4 linear or Branched chain alkyl (CrC alkyl) ethyl 'propyl or isopropyl (Ci-Cs alkyl), more preferably methyl alkyl), particularly preferably methyl. In the present invention, 'Cl_c6 alkoxy group' is a straight chain or a branch having a carbon number of 1 to 6 such as a methoxy group, an ethoxy group, a propoxy group or an isopropoxy group. , butyl, first butoxy, second butoxy, pentyloxy, isobutoxy, 1-ethylpropoxy, 2-ethylpropoxy, decyl dimethyloxy, A straight chain of 1 to 4 carbon atoms or a (C1-C4 alkoxy group) 'especially methoxy' ethoxy, propoxy (Ci-C3 alkoxy), more preferably methoxy or ethoxy (Ci-C: methoxy group. In the present invention, "Cl_C6 hydroxyalkyl group" is a group in which a hydroxyl group is bonded to a linear or branched alkyl group, for example, hydroxymethylpropyl group, hydroxybutyl group, or hydroxy group. The pentyl or hydroxyhexyl group is preferably a 4-hydroxyl straight or branched alkyl group, particularly preferably 2-propyl. In the present invention, "C 2 - C 6 hydroxyalkoxy" is 1 a linear or branched alkoxy group bonded to a hydroxyl group, such as a hydroxyoxy group, a hydroxybutoxy group, a pentyloxy group or a hydroxyhexyloxy group, preferably a pentyl group, a 3-methylbutyl group, and a 2,2 group. - 1,3-dimethyl butyl, preferably carbon, especially methyl, or ethyl (q-Cz: 6 alkyl) in oxyalkane An example of an oxy group, an isobutoxypentyloxy group, a 2-methylhexyloxy group or a 2,3-branched alkoxy group or an isopropoxy acetoxy group, and a specific carbon number of 1 to 6, Hydroxyethyl, hydroxy at 2 to ethyl or 3-hydroxy to 2 to 6 ethoxy, hydroxypropyl 1 hydroxy to carbon-20- 200906395 2 to 4 linear or branched chains The alkoxy group is bonded, in particular: an oxy group. In the present invention, the "alkoxyalkyl" group "f" refers to "C丨-<:6 alkoxy" in the above-mentioned "C丨-C6 alkyl group". Methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, tert-butoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-yl, 2- (Ternth butoxy)ethyl, 1-methoxyethyl or 3-isopropyl is preferably one of the aforementioned "Ci-C# alkoxy groups" in the aforementioned alkyl group ((G-C4 alkoxy)-(( ^-(24alkyl) group), particularly preferably 2-methoxyethoxyethyl, 2-propoxyethyl or 3-methoxypropyl. In the present invention, "(C丨-C6 alkoxy)- (C丨-C6 alkoxy) group "C^-Ce alkoxy" as described above in the above "(^-(:6 alkoxy) group such as methoxymethoxy, ethoxymethoxy, propyloxy) Oxygen, iso-yl, butoxy Oxyl, isobutoxymethoxy, second butoxymethoxybutoxymethoxy, 2-methoxyethoxy '2-ethoxyethoxy, 2-oxy' 2- (third butoxide) Ethyloxy, 1-methoxyethoxy, oxy, 1-(t-butoxy)ethoxy or 3-isopropoxypropoxy, the aforementioned "C丨-C4 alkoxy" in the foregoing "Ci-C4 alkoxy" ((匸1-(:4alkoxy)-((:1-(:4 alkoxy)))), preferably 1 prealkoxy) is the above "(^ -(:3 alkoxy) bonded group ((Cr MCi-Cs alkoxy) group), more preferably 2-methoxyethoxy, 2-ethyl, 2-propoxyethoxy, 3-methoxy Propyloxy or 3-ethoxypropoxy Group In the present invention, "mono-(^-(alkylamino)" is one of the above-mentioned "("" groups bonded to an amine group. For example, methylamino, ethylamino and propylamine are preferably 2-hydroxyethyl. For example, butoxymethyl isopropyloxypropyl propyl, "the combined ethyl group, 2-" is a combined group. Propoxymethoxy, third isopropoxyethyl 1-ethoxyethyl' should be combined as one of the "Ci-Cs C3 alkoxy oxyethoxy hydrazone - 1 - C 6 yards: base, isopropyl -21 - 200906395 Amino, butylamino, agmatine 't-butylamino, tert-butylamino, pentylamino, isoamylamino, 2-methylbutylamino, neopentylamino, 1-ethylpropylamino, hexylamino or isohexylamino, preferably one of the above-mentioned "Cl-C4 alkyl" groups bonded to an amine group (mono-alkylamino group), particularly preferably a methylamino group or an ethylamino group ( single-

Ci-C2 compound amine) is more preferably ethylamine. In the present invention, the "dialkyl)amino group is a group in which two or more "c i - C6 alkyl groups" which are the same or different are an amine group. For example, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, diamylamino, diisoamylamine, dipentylamino, dihexyl Amino, N-ethyl-N-methylamino, methyl-N-propylamino, N-isopropyl-N-methylamino, N-butyl-N-methylamino, N-isopentyl -N-methylamino, N-ethyl-N-propylamino or N-ethyl-N-isopropylamino, preferably the same or different two of the above "c!-C4 alkyl" are bonded to the amine group Base (di-(Cl_C4 alkyl)amino), especially dimethylamino, diethylamino or N-ethyl-N-methylamino (di-(Ci-Cz alkyl)amino) It is preferably dimethylamino or diethylamino. In the present invention, the "di-(CrQ alkyl)amino-(CpQ alkoxy) group" is one of the above-mentioned "di-(CPC6 alkyl)amino group" bonded to the aforementioned "Ci-Q alkoxy group". base. For example, dimethylaminomethoxy, diethylaminomethoxy, dipropylaminomethoxy, N-ethyl-N-methylaminomethoxy, 2-(dimethylamino)ethoxy, 2-(diethylamino)ethoxy, 2-(dipropylamino)ethoxy or 2-(N-ethyl-N,methylamino)ethoxy, preferably one of the aforementioned "di-(Cl) -C4 alkyl)amino" in the above-mentioned "CrC4 alkoxy" bonded group (di-(CrC^alkyl)amino-(C^-C:4 alkoxy) group), particularly preferably dimethylamine Methoxy, diethylaminomethoxy, 2-(dimethylamino)ethoxy or 2-(diethylamino)ethoxy. -22- 200906395 In the present invention, the "Ct-Ce alkoxy group substituted with 4-morpholinyl group" is a group in which one 4-morpholine is bonded based on the above-mentioned "Ci-Ce alkoxy group". For example, 4-morpholinylmethoxy, 2-(4-morpholinyl)ethoxy or 3-(4-morpholinyl)propoxy, preferably one 4-morpholine is based on the aforementioned "CrG alkoxy" The combination is particularly preferably a 2-(4-morpholinyl)ethoxy group. In the present invention, the "C?Cs alkylthio group" is a straight-chain or branched alkylthio group having 1 to 6 carbon atoms of the above-mentioned "Ci-Cs alkyl group" bonded to a sulfur atom. Methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, pentylthio, isopentylthio, neopentylthio or hexylthio^ It is preferably a linear or branched alkanethio group (CMC4 alkylthio group) having 1 to 4 carbon atoms, particularly preferably a methylthio group or an ethylthio group (CrCz alkylthio group), more preferably a methylthio group. In the present invention, the "alkylthioalkoxy" group is one of the above-mentioned "CrQ alkylthio groups" in the above-mentioned "(^-(:6 alkoxy)" group. For example, methylthiomethoxy group, ethyl sulfide Methoxy, propylthiomethoxy, isopropylthiomethoxy, methylthioethoxy, ethylthioethoxy or methylthiopropoxy, preferably one of the aforementioned "Ci-C4 alkylthio" is as described above "Ci-CU alkoxy group"-bonding group ((C!·c4 alkylthioalkoxy) group), particularly preferably 2-(methylthio)ethoxy group. In the present invention, "((^-( : 6-alkylsulfinyl)-((:!-C6 alkoxy) group" is a sulfur atom of the above "(Ci-Ce alkylthio)-((^-06 alkoxy))" a group bonded to an oxygen atom, such as sulfinylmethoxy, sulfinylmethoxy, propylsulfinylmethoxy, sulfinylethoxy, ethanesulfinyl ethoxy or kea Sulfhydryloxy, preferably 2-(methylsulfinyl)ethoxy. In the present invention, "(Ci-Ce Institute)-(Ci_C6 Instituteoxy) group is in the above "(CrC^ The sulfur atom of the alkylthio-MCrQ alkoxy) group has two groups of •23-200906395 oxygen atom-bonded groups. For example, methylsulfonyl methoxy, B Mercaptomethoxy, propanesulfonylmethoxy, methanesulfonylethoxy, ethylsulfonylethoxy or methanesulfonyloxy, preferably 2-(methylsulfonyl)ethoxy. The "C2-C7 alkylcarbonyl group" is a group in which the above-mentioned "Cl_c6 alkyl group" is bonded to a carbonyl group. For example, an ethyl group, a propyl group, a butyl group, an isobutyl group or a pentyl group is preferably a "Ci-C* alkyl group". a carbonyl-bonding group (C2-C5 alkylcarbonyl), particularly preferably an ethyl hydrazino group or a propyl fluorenyl group (C2-C3 alkylcarbonyl group), more preferably an ethyl hydrazine group. In the present invention, the "C2-C7 alkoxycarbonyl group" is as described above. "Ci-Ce alkoxy" to a carbonyl group (for example, methoxycarbonyl), ethoxycarbonyl), propoxycarbonyl), isopropoxycarbonyl), butoxycarbonyl, or a third butoxycarbonyl group, preferably as described above. In the present invention, the C^-c4 alkoxy group is a carbonyl-bonding group (c2-c5 alkoxycarbonyl group), particularly preferably a methoxycarbonyl group or an ethoxycarbonyl group (c2-c3 alkoxycarbonyl group), more preferably a methoxycarbonyl group. The "mono-c2-c7 alkylcarbonylamino group" is a group of a carbonyl-based amine group bonded to one of the aforementioned "Cl-c6 alkyl groups", for example, an acetamide, an ethoxycarbonyl group, a propylcarbonyl group, an amine group, or a different group. Propyl carbonyl)amine Base, butancarbonyl)amino, tert-butylcarbonyl)amino or pentylcarbonyl)amine, preferably having one of the aforementioned "Ci-Q" groups combined with an amine-based group (single-ca-C5 Amidoxime), especially acetamido or acetamino group (single-C2_C3 amidoxime), more preferably an amine. In the present invention, the "halogen atom" is a fluorine atom, a chlorine atom, a bromine atom or a w atom, preferably a fluorine atom, a chlorine atom or a bromine atom, particularly preferably a fluorine atom or a chlorine atom. In the present invention, "Ci-C6 halogenated alkyl group" It is a group in which 1S5 of the above-mentioned "halogen atoms" which are the same or different are bonded to the above-mentioned "CrC6 alkyl group". For example, -24-200906395 trifluoromethyl, trichloromethyl, difluoromethyl, dibromomethyl, methoxymethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl 2, fluoroethyl or penta-ethyl' should have the same or different 1 to 5 of the above-mentioned "halogen atom" in the group of "C ^ < 34 alkyl" (Κ4 halogenated alkyl), It is preferable to have the same or different 1 to 5 of the above-mentioned "halogen atom" in the above-mentioned "Ci-C2 hospital group" (Ci-C^halogenated alkyl group), and more preferably a trifluoromethyl group. In the present invention, the "C^-Cs halogenated alkoxy group" is a group having the same or different 1 to 5 "halogen atoms" in the "Ci-C6 alkoxy group". For example, trifluoromethoxy, trichloromethoxy 'difluoromethoxy, dibromomethoxy, fluoromethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloro The ethoxy group, the 2 fluoroethoxy group or the pentafluoroethoxy group preferably have the same or different 1 to 5 of the above-mentioned "halogen atoms" in the above-mentioned "<^-(:4 alkoxy group)-bonding group ( C1-C4 halogenated oxy), it is preferred to have the same or different 1 to 5 of the above "halogen atoms" in the above "Ci-C; ! alkoxy" bonded group (Ci-C2 halogenated alkoxy) More preferably, the "C6-C1G aryl group" is an aromatic hydrocarbon group having 6 to 10 carbon atoms. For example, a phenyl group or a naphthyl group is preferably a phenyl group. In the present invention, "heterocyclic ring" The base is a 4- to 7-membered heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms or/and nitrogen atoms, and more preferably 1 or 2 nitrogen atoms, and the sulfur atom may have 2 oxygen atoms. For example, furan Base, thienyl, pyrrolyl, azepine, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, triazolyl , tetrazolyl, thiadiazolyl, pyranyl, pyridyl, argon, pyrimidine "Aromatic heterocyclic group" such as a pyridyl group, or a tetrahydropyranyl group, a tetrahydrothiophenyl group, a morpholine-25 - 200906395 group, a thiomorpholinyl group, a pyrrolidinyl group, a pyrrolinyl group, an imidazolidinyl group Partial or complete reduction of pyrazolidine, piperidinyl, piperidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, oxaridinyl, didecylalkyl or dialkyl a saturated heterocyclic group of the type", the above heterocyclic group may be fused to other ring groups such as a benzene ring ("fused bicyclic spiro group"), for example, benzothienyl, benzothiazolyl, benzoxazole , isobenzofuranyl, I,3-dihydroisobenzofuranyl, quinolyl, 1,3-benzodioxanyl, j,4-benzodioxanyl, fluorenyl , isodecyl or porphyrin group, preferably aromatic heterocyclic group, particularly preferably pyridyl group, more preferably 3-pyridyl group. In the present invention, "the group selected by the substituent group A may be independently 1 to 5 The substituted C6-C1G aryl group is the aforementioned "C6-C1() aryl group) which may have 1 to 5 substituents independently selected from the substituent group A, preferably (halogen atom, Ci-Ce alkyl group, Ci). -Cs halogenated alkyl and halogenated alkoxy The selected group is independently one to three substituted phenyl groups, and particularly preferably one or two substituted phenyl groups selected from (fluorine atom, chlorine atom and trifluoromethyl group), more preferably 3-fluorophenyl group, 3 -Chlorophenyl, 3-trifluoromethylphenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3-chloro-4-fluorophenyl, 4-fluoro-3-trifluoro Methylphenyl, 3,5-dichlorophenyl or 3,5-di-trifluoromethylphenyl. In the present invention, "the substituents selected from the substituent group A may be independently substituted with 1 to 3 substituents. The "cycloalkyl group" is the aforementioned "heterocyclic group" which may have 1 to 3 substituents independently selected from the substituent group A, and is preferably composed of (a crypto atom, a Ci-C6 alkyl group, a C>-c6 halogenated alkyl group, and a Ci-). The C6 halogenated alkoxy group is independently selected from the group consisting of 1 to 3 substituted pyridyl groups, which are preferably substituted by a group selected from (fluorine atom, chlorine atom, methyl group, trifluoromethyl group and trifluoromethoxy group). 3_pyridyl. -26- 200906395 In the present invention, "V is a group of the formula -NH - and W is a single bond" means "the base of the formula - VC( = 0)-W-" is "form-NH-C( = 〇) - the basis." In the present invention, a suitable R1 is a CrQ alkoxy group, a mono-CrQ compound amine group, a bis-((:,-(:6 alkyl)amino group or a 4-morpholinyl group, and a suitable R1 is a methoxy group. Ethyloxy, ethylamino, dimethylamino, diethylamino or 4-morpholinyl, more preferably R1 is ethylamino, dimethylamino, diethylamino or 4-morpholinyl. In the present invention, a suitable one is a Cl-C6 alkoxy group or a <:2-06 hydroxyalkoxy group, and more preferably R2 is a 2-hydroxyethoxy group. In the present invention, a suitable R3 is a hydrogen atom. In the invention, a suitable R4 is (halogen atom, CrG alkyl group, Κ6-alkyl group and Ci-Cs halogenated alkoxy group), and the selected group is independently one to three substituted phenyl groups, and more preferably R4 is (fluorine atom). a chlorine atom and a trifluoromethyl group are selected independently of one or two substituted phenyl groups, and more preferably R4 is 3-fluorophenyl, 3-chlorophenyl, 3-trifluoromethylphenyl, 3, 4-difluorophenyl, 3,5-difluorophenyl, 3-chloro-4-fluorophenyl, 4-fluoro-3-trifluoromethylphenyl, 3,5-dichlorophenyl or 3, 5-di-trifluoromethylphenyl. In the present invention, a suitable V is a group of the formula -NH-. In the present invention, a suitable W is a single bond. In the present invention, a suitable τ In the present invention, a suitable R5 is a hydrogen atom. In the present invention, a suitable Q is a group of the formula. The indoleamine derivative of the formula (I) or a pharmacologically acceptable salt thereof has an asymmetric carbon in its molecule. Since the atom exists, there are various isomers. Among the compounds of the present invention, these isomers and mixtures of these isomers are represented by a single formula, that is, by the formula -27-200906395 (I). An isomer and a mixture of these isomers in any ratio. The above stereoisomers are synthesized using a stereospecific starting material compound or by asymmetric synthesis or asymmetric induction to synthesize a compound of the invention or a compound of the invention to be synthesized. It is obtained by the usual optical division method or separation method as it is. "The pharmacologically acceptable salt" means a salt which can be used as a medicine without significant toxicity. The indoleamine derivative of the formula (I) of the present invention has an amine. When a basic group such as a group is reacted with an acid, and if it has an acidic group such as a carboxyl group, it can be used as a salt by reacting with a base. The salt based on a basic group may be, for example, a hydrofluoric acid salt, a hydrochloride salt or a hydrobromine salt. Acid salt, hydroiodic acid Mineral acid salts such as salts such as hydrohalides, nitrates, perchlorates, sulfates, phosphates; alkane sulfonates such as methanesulfonate, trifluoromethanesulfonate, and ethanesulfonate; Salts, p-toluenesulfonates and the like, arylsulfonates, acetates, malates, fumarates, succinates, citrates, ascorbates, tartrates, oxalates, maleates, etc. An acid salt; and an amine acid salt such as a glycinate, an amidate, a arginine, an alanate, a glutamate or an aspartate. In other aspects, a salt of an acidic group is, for example, sodium. Metal salts such as alkali metal salts such as salts, potassium salts and lithium salts, alkaline earth metal salts such as calcium salts and magnesium salts, aluminum salts and iron salts; inorganic salts such as ammonium salts, tertiary octylamine salts and dibenzylamine salts, a porphyrin salt, a glucosamine salt, an alkyl phenylglycine salt, an ethylenediamine salt, an N-methylglucamine salt, a phosphonium salt, a diethylamine salt, a triethylamine salt, a dicyclohexylamine salt, a hydrazine, Ν'-Dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, bismuth-benzyl-28-200906395 phenylethylamine salt, piperazine salt tetramethylammonium salt, ginseng Hydroxymethyl)amine Methane salts and organic amine salts and other salts; and glycine salts, lysine salts, arginine salts, ornithine salts, glutamic acid salts, aspartic acid salts and other salts of amino acids. The hydrazine derivative of the formula (I) of the present invention or a pharmacologically acceptable salt thereof, which is allowed to stand in the atmosphere or recrystallize, absorbs water to adsorb water or forms a hydrate, and thus the hydrate is also contained in the salt of the present invention. The hydrazine derivative of the formula (I) of the present invention or a pharmacologically acceptable salt thereof can absorb other solvents to form a solvate, and such a solvate is also included in the present invention. Specific examples of the guanamine derivative of the formula (I) of the present invention may be, for example, the compounds described in the following Tables 1 to 11, but the present invention is not limited by these compounds. In the following Tables 1 to 11, the abbreviations have the following meanings. That is, Me is a methyl group,

Et is ethyl,

Pr is n-propyl, CH2OMe is methoxymethyl, CH2CH2SMe is 2-methylthioethyl, CH2CH2S02Me is 2-methanesulfonylethyl,

Ph is phenyl, 3- OCF3-Ph is 3-trifluoromethoxyphenyl, 3.4-F2-Ph is 3,4-difluorophenyl, 3.5-(€?3)2-卩11 is 3, 5-di-trifluoromethylphenyl, 4-F-3-CF3-Ph is 4-fluoro-3-trifluoromethylphenyl,

Het (A) is 2-(4-morpholinyl)ethyl,

Het (B) is 4-morpholinyl. -29- 200906395 (Table i)

OR8

OR 7 Compound Number R4 R8 R7

1-1 3-F-Ph Me CH2CH2OH 1-2 3-F-Ph Me CH2CH2CH2OH 1-3 3-F-Ph Me CftCH2〇Me 1-4 3-F-Ph Me CH2CH2〇Et 1-5 3-F -Ph Me CH2CH2〇Pr 1-6 3-F-Ph Me CHCHCBOMe 1-7 3-F-Ph Me CH2CBCH2〇Et 1-8 3-F-Ph Me Het(A) 1-9 3-F-Ph Et CH2CH2OH 1-10 3-F-Ph Et CH2CH2CH2OH 1-11 3-F-Ph Et CHaCHzOMe 1-12 3-F-Ph Et CHiCHiOEt 1-13 3-F-Ph Et CHzCHiOPr 1-14 3-F-Ph Et CH2CH2CH2〇Me 1-15 3-F-Ph Et CH2CH2CH2〇Et 1-16 3-F-Ph CH2CH2OH Me 1-17 3-F-Ph CH2CH2OH Et 1-18 3-F-Ph CH2CH2OH Pr 1-19 3- F-Ph CH2CH2OH CH2CH2OH 1-20 3-F-Ph CH2CH2OH CftOLOMe 1-21 3-F-Ph CH2CH2OH CHzCHiOEt 1-22 3-F-Ph CH2CH2OH CH2CBOPr 1-23 3-F-Ph CH2CH2OH CH2CftCH2〇Me 1-24 3-F-Ph CH2CH2OH CHiCHiCHzOEt 1-25 3-Cl-Ph Me CH2CH2OH 1-26 3-Cl-Ph Me CH2CH2CH2OH 1-27 3-Cl-Ph Me CH2CH2〇Me 1-28 3-Cl-Ph Me CHaCBOEt 1 -29 3-Cl-Ph Me CHffiOPr 1-30 3-Cl-Ph Me CHCHiCHiOMe 1-31 3-Cl-Ph Me CH2CH2CH2〇Et 1-32 3-Cl-Ph Me Het(A) 1-33 3-Cl -Ph Et CH2CH2OH 30- 200906395 1-34 3-Cl-Ph Et CH2CH2CH2OH 1-35 3-Cl-Ph Et CHiCHiOMe 1-36 3-Cl-Ph Et CHiCHiOEt 1-37 3-Cl-Ph Et CHzCBOPr 1-38 3-CI-Ph Et CHiCHzCHiOMe 1-39 3-Cl-Ph Et CH2CH2CH2〇Et 1-40 3-Cl-Ph CH2CH2OH Me 1-41 3-Cl -Ph CH2CH2OH Et 1-42 3-Cl-Ph CH2CH2OH Pr 1-43 3-Cl-Ph CH2CH2OH CH2CH2OH 1-44 3-Cl-Ph CH2CH2OH CH2CH£)Me 1-45 3-Cl-Ph CH2CH2OH CHaCBOEt 1-46 3-Cl-Ph CH2CH2OH CmCHOPr 1-47 3-Cl-Ph CH2CH2OH CH2CH2CH2〇Me 1-48 3-Cl-Ph CH2CH2OH CH2CH2CH2〇Et 1-49 3-CF3-Ph Me CH2CH2OH 1-50 3-CF3-Ph Me CH2CH2CH2OH 1-51 3-CF3-Ph Me CHzCHiOMe 1-52 3-CB-Ph Me CHzCHaOEt 1-53 3-CF3-Ph Me CHiCHiOPr 1-54 3-CFs-Ph Me CftCHCBOMe 1-55 3-CF3-Ph Me CHiCHzCHiOEt 1-56 3-CR-Ph Me Het(A) 1-57 3-CR-Ph Et CH2CH2OH 1-58 3-CF3-Ph Et CH2CH2CH2OH 1-59 3-CR-Ph Et CH2CH2〇Me 1-60 3 -CR-Ph Et CHaCHiOEt 1-61 3-CR-Ph Et CH2CH2〇Pr 1-62 3-CR-Ph Et CHiCHiCHzOMe 1-63 3-CF3-Ph Et CHaCHiCHzOEt 1-64 3-CFs-Ph CH2CH2OH Me 1- 65 3-CR-Ph CH2CH2OH Et 1-66 3-CF3-Ph CH2CH2OH Pr 1-67 3-CR-Ph CH2CH2OH CH2CH2OH 1-68 3-CR-Ph CHCHzOH CHzCHiOMe 1-69 3-CFs-Ph CH£H2〇 H CHaCHaOEt 1-70 3-C F3-Ph ch2ch2〇h CHfflOPr 1-71 3-CB-Ph CH2CH2OH CH2CH2CH2〇Me 1-72 3-CIVPh CH2CH2OH CHiCHaCHaOEt 1-73 3-CF3-Ph Me CHiCHaSMe 1-74 3-CF3-Ph Me CHaCHiSOMe 1-75 3-CB-Ph Me CmCHiSChMe 1-76 3-CF3-Ph Et CftCBSMe 1-77 3-CF3-Ph Et CHaCHiSOMe 1-78 3-CF3-Ph Et CftCKSCbMe -31 - 200906395 1-79 3-CF3-Ph CH2CH2OH CHffiSMe 1-80 3-CR-Ph CH2CH2OH CHiCHiSOMe 1-81 3-CF3-Ph CH2CH2OH CHzCHiSOiMe 1-82 3-OCF3-Ph Me CH2CH2OH 1-83 3-OCF3-Ph Me CH2CH2CH2OH 1-84 3-OCF3-Ph Me CH2CH2〇Me 1-85 3-OCF3-Ph Me CH2CH2〇Et 1-86 3-OCFs-Ph Me CH2CH2〇Pr 1-87 3-OCR-Ph Me OLCftCHOMe 1-88 3-OCF3-Ph Me CHiCHiCHiOEt 1-89 3-OCR-Ph Me Het(A) 1-90 3-OCF3-Ph Et CH2CH2OH 1-91 3-〇CF3-Ph Et CH2CH2CH2OH 1-92 3-OCF3-Ph Et CftCHOMe 1-93 3-OCF3-Ph Et CH2CH2〇Et 1-94 3-OCF3-Ph Et CftCHzOPr 1-95 3-OCF3-Ph Et CHCHCHOMe 1-96 3-OCFs-Ph Et CHiCHxCHiOEt 1-97 3-OCF3-Ph CH2CH2OH Me 1-98 3-OCR- Ph CH2CH2OH Et 1-99 3-OCF3-Ph CH2CH2OH Pr 1-100 3-OCF3-Ph CH2CH2OH CH2CH2OH 1-101 3-〇CF3-Ph CH2CH2OH CH2CH2〇Me 1-102 3-OCB-Ph CH2CH2OH CHiCHaOEt 1-103 3-OCF3-Ph CH2CH2OH CHzCftOPr 1-104 3-OCR-Ph CH2CH2OH CHCHCHOMe 1-105 3-OCF3-Ph CH2CH2OH CH2CH2CH2〇Et 1-106 3,4-F2-Ph Me CH2CH2OH 1-107 3,4-Fa-Ph Me CH2CH2CH2OH 1-108 3,4-F2-Ph Me CHiCHaOMe 1-109 3,4-F2-Ph Me CHzCHiOEt 1-110 3,4-F2-Ph Me CBCHiOPr 1 -111 3,4-F2-Ph Me CftCHCMMe 1-112 3,4-R-Ph Me CHmCIMM 1-113 3,4-Fa-Ph Me Het(A) 1-114 3,4-R-Ph Et CH2CH2OH 1-115 3,4-R-Ph Et CH2CH2CH2OH 1-116 3,4-Fa-Ph Et CH2CH2〇Me 1-117 3,4-Fz-Ph Et OLCHOEt 1-118 3,4-F2-Ph Et CHiCHiOPr 1-119 3,4-F2-Ph Et CH2CH2CH2〇Me 1-120 3,4-F2-Ph Et CH2CH2CH2〇Et 1-121 3,4-F2-Ph CH2CH2OH Me 1-122 3,4-F2-Ph CH2CH2OH Et 1-123 3,4-F2-Ph CH2CH2OH Pr 32 200906395 1-124 3,4-B-Ph CH2CH2OH CH2CH2OH 1-125 3,4-F2-Ph CH2CH2OH CHmOMe 1-126 3,4-F2-Ph CH2CH2OH CHfflOEt 1-127 3,4-F2-Ph CH2CH2OH CBCHOPr 1-128 3,4-F2-Ph CH2CH2OH CHCHCHOMe 1-129 3,4-B-Ph CH2CH2〇H CH2CH2CH2〇Et 1-130 3-Cl-4 -F-Ph Me CH2CH2OH 1-131 3-Cl-4-F-Ph Me CH2CH2CH2OH 1-132 3-Cl-4-F-Ph Me CftCH2 〇Me 1-133 3-Cl-4-F-Ph Me CHzCHiOEt 1-134 3-Cl-4-F-Ph Me cmcaopr 1-135 3-Cl-4-F-Ph Me CHiCHiCHaOMe 1-136 3-Cl -4-F-Ph Me CHCftCftOEt 1-137 3-Cl-4-F-Ph Me Het(A) 1-138 3-Cl-4-F-Ph Et CH2CH2OH 1-139 3-Cl-4-F- Ph Et CH2CH2CH2〇H 1-140 3-Cl-4-F-Ph Et CHaCHOMe 1-141 3-Cl-4-F-Ph Et CftCPKM 1-142 3-Cl-4-F-Ph Et CftCiLOPr 1-143 3-Cl-4-F-Ph Et OLCHffiOMe 1-144 3-Cl-4-F-Ph Et CftCHCBOEt 1-145 3-Cl-4-F-Ph CH2CH2OH Me 1-146 3-Cl-4-F- Ph CH2CH2OH Et 1-147 3-Cl-4-F-Ph CH2CH2OH Pr 1-148 3-Cl-4-F-Ph CH2CH2OH CH2CH2OH 1-149 3-Cl-4-F-Ph CH2CH2OH CHiCHiOMe 1-150 3- Cl-4-F-Ph CH2CH2OH CHmOEt 1-151 3-Cl-4-F-Ph CH2CH2OH CH2CH2〇Pr 1-152 3-Cl-4-F-Ph CH2CH2OH CHfflCHOMe 1-153 3-Cl-4-F- Ph CH2CH2OH CH2CH2CH2〇Et 1-154 3-F-4-Me-Ph Me CH2CH2OH 1-155 3_F-4-Me-Ph Me CH2CH2〇Me 1-156 3-F-4-Me-Ph Me CHmOEt 1-157 3-F-4-Me-Ph Et CH2CH2OH 1-158 3-F-4-Me-Ph Et CHaCHiOMe 1-159 3-F-4-Me-Ph Et CH2CH2〇Et 1-160 3-F-4- Me-Ph CH2CH2OH Me 1-161 3-F-4-Me-Ph CH2CH2OH Et 1-162 4-F-3-CF3-Ph Me CH2CH2O H 1-163 4-F-3-CF3-Ph Me CH2CH2CH2〇H 1-164 4-F-3-CF3-Ph Me CHiCHaOMe 1-165 4-F-3-CF3-Ph Me CftOLOa 1-166 4- F-3-CF3-Ph Me CftCBOPr 1-167 4-F-3-CF3-Ph Me CHaCHiCHiOMe 1-168 4-F-3-CF3-Ph Me CHaCHiCHiOEt -33 - 200906395

1-169 4-F-3-CR-Ph Me Het(A) 1-170 4-F-3-CF3-Ph Et CH2CH2OH 1-171 4-F-3-CF3-Ph Et CH2CH2CH2OH 1-172 4- F-3-CF3-Ph Et CHCftOMe 1-173 4-F-3-CF3-Ph Et CHiCHiOEt 1-174 4-F-3-CF3-Ph Et CH2CH2〇Pr 1-175 4-F-3-CF3- Ph Et CftCHmOMe 1-176 4-F-3-CR-Ph Et CftCHCftOEt 1-177 4-F-3-CF3-Ph CH2CH2OH Me 1-178 4-F-3-CR-Ph CH2CH2OH Et 1-179 4- F-3-CF3-Ph CH2CH2OH Pr 1-180 4-F-3-CR-Ph CH2CH2OH CH2CH2OH 1-181 4-F-3-CF3-Ph CH2CH2OH CHfflOMe 1-182 4-F-3-CFs-Ph CH2CH2OH CHbCftOEt 1-183 4-F-3-CF3-Ph CH2CH2OH CHiCHaOPr 1-184 4-F-3-CFs-Ph CH2CH2OH CHCftCftOMe 1-185 4-F-3-CF3-Ph CH2CH2OH CH2CH2CH2〇Et 1-186 3, 4-Cl2-Ph Me CH2CH2OH 1-187 3,4-Ck-Ph Me CH2CH2CH2OH 1-188 3,4-Cl2-Ph Me CH2CH2〇Me 1-189 3,4-Cb-Ph Me CHzCHaOEt 1-190 3, 4-Cl2-Ph Me CHCftOPr 1-191 3,4-Cl2-Ph Me CBCHzCftOMe 1-192 3,4-CU-Ph Me CH2CH2CH2〇Et 1-193 3,4-Ck-Ph Me Het(A) 1- 194 3,4-Cl2-Ph Et CH2CH2OH 1-195 3,4-Cl2-Ph Et CH2CH2CH2OH 1-196 3,4-Cl2-Ph Et CH2CH2〇Me 1-197 3,4-Cl2-Ph Et CHiCHaOEt 1- 198 3,4-Ch-Ph Et CH2CH2 Pr 1-199 3,4-Cb-Ph Et CH2CH2CH2〇Me 1-200 3,4-Ch-Ph Et CHzCHiCHzOEt 1-201 3,4-Cl2-Ph CH2CH2OH Me 1-202 3,4-Cl2-Ph CH2CH2OH Et 1-203 3,4-Ck-Ph CH2CH2OH Pr 1-204 3,4-Cl2-Ph CH2CH2OH CH2CH2OH 1-205 3,4-Cb-Ph CH2CH2OH CH2CH2〇Me 1-206 3,4-Cb-Ph CH2CH2OH CHiCHiOEt 1-207 3,4-Cb-Ph CH2CH2OH CHffiOPr 1-208 3,4-Cl2-Ph CH2CH2OH CH2CHCH2〇Me 1-209 3,4-Cb-Ph CH2CH2OH CH2CBCH2〇Et 1-210 4-Cl-3- CF3-Ph Me CH2CH2OH 1-211 4-Cl-3-CF3-Ph Me CHzCBOMe 1-212 4-Cl-3-CF3-Ph Me CHiCHiOEt 1-213 4-Cl-3-CF3-Ph Et CH2CH2OH -34- 200906395

1-214 4-Cl-3-CF3-Ph Et CHfflOMe 1-215 4-Cl-3-CR-Ph Et CH2CH2〇Et 1-216 4-Cl-3-CF3-Ph CH2CH2OH Me 1-217 4-Cl -3-CF3-Ph CH2CH2OH Et 1-218 3,5-R-Ph Me CH2CH2OH 1-219 3,5-F2-Ph Me CH2CH2CH2OH 1-220 3,5-F2-Ph Me CHiCHaOMe 1-221 3,5 -R-Ph Me CHiCHiOEt 1-222 3,5-F2-Ph Me CHCftOPr 1-223 3,5-F2-Ph Me CH2CH2CH2〇Me 1-224 3,5-F2-Ph Me CHCmCBOEt 1-225 3,5 -R-Ph Me Het(A) 1-226 3,5-Fa-Ph Et CH2CH2OH 1-227 3,5-F2-Ph Et CH2CH2CH2OH 1-228 3,5-F2-Ph Et CH2CH2〇Me 1-229 3,5-F2-Ph Et CHCftCM 1-230 3,5-F2-Ph Et CHCHOPr 1-231 3,5-F2-Ph Et CHCH2CH£)Me 1-232 3'5-R-Ph Et CHiCHiCHzOEt 1- 233 3,5-R-Ph CH2CH2OH Me 1-234 3,5-F2-Ph CH2CH2OH Et 1-235 3,5-B-Ph CH2CH2OH Pr 1-236 3,5-F2-Ph CH2CH2OH CH2CH2OH 1-237 3 ,5-Fi-Ph CH2CH2OH CHiCHiOMe 1-238 3,5-F2-Ph CH2CH2OH CHzCHiOEt 1-239 3,5-F2-Ph CH2CH2OH CHzCHaOPr 1-240 3,5-F2-Ph CH2CH2OH CHiCHzCHiOMe 1-241 3,5 -F2-Ph CH2CH2OH CH2CH2CH2〇Et 1-242 3-F-5-Cl-Ph Me CH2CH2OH 1-243 3-F-5-Cl-Ph Me CHiCHiOMe 1-244 3-F-5-Cl-Ph Me CH2CH2 〇Et 1-245 3-F-5-Cl-Ph Et CH2CH2OH 1-246 3-F-5-Cl-Ph Et CHfflOMe 1-247 3-F-5-Cl-Ph Et CHfflOEt 1-248 3-F-5-Cl- Ph CH2CH2OH Me 1-249 3-F-5-Cl-Ph CH2CH2OH Et 1-250 3-F-5-CF3-Ph Me CH2CH2OH 1-251 3-F-5-CF3-Ph Me CH2CH2〇Me 1-252 3-F-5-CF3-Ph Me CHaCHiOEt 1-253 3-F-5-CF3-Ph Et CH2CH2OH 1-254 3-F-5-CF3-Ph Et CHfflOMe 1-255 3-F-5-CF3- Ph Et CHiCHzOEt 1-256 3-F-5-CF3-Ph CH2CH2OH Me 1-257 3-F-5-CF3-Ph CH2CH2OH Et 1-258 3,5-Cl2-Ph Me CH2CH2OH -35- 200906395 1-259 3,5-Cl2-Ph Me CH2CH2CH2OH 1-260 3,5-CL-Ph Me CH2CH2〇Me 1-261 3,5-Cb-Ph Me CH2CH2〇Et 1-262 3,5-Cl2-Ph Me CH2CH2〇 Pr 1-263 3,5-CL-Ph Me CH2CH2CH2〇Me 1-264 3,5-Cl2-Ph Me CHfflCHOEt 1-265 3,5-Cl2-Ph Me Het(A) 1-266 3,5-Cb -Ph Et CH2CH2OH 1-267 3,5-Cl2-Ph Et CH2CH2CH2OH 1-268 3,5-Cl2-Ph Et CH2CH2〇Me 1-269 3,5-Cl2-Ph Et CH2CH2〇Et 1-270 3,5 -Ck-Ph Et CH2CH2〇Pr 1-271 3,5-Cl2-Ph Et CHCHfflOMe 1-272 3,5-Cb-Ph Et CftCHCHCEt 1-273 3,5-Cl2-Ph CH2CH2OH Me 1-274 3,5 -Cl2-Ph CH2CH2OH Et 1-275 3,5-Cb-Ph CH2CH2OH Pr 1-276 3,5 -Cl2-Ph CH2CH2OH CH2CH2OH 1-277 3,5-Cb-Ph CH2CH2OH CHCHOMe 1-278 3,5-Cl2-Ph CH2CH2OH CHzCHiOEt 1-279 3,5-Cb-Ph CH2CH2OH CHfflOPr 1-280 3,5-Cl2 -Ph CH2CH2OH CHiCHaCHiOMe 1-281 3,5-Cb-Ph CH2CH2OH CH2CH2CH2〇Et 1-282 3-Cl-5-CR-Ph Me CH2CH2OH 1-283 3-Cl-5-CF3-Ph Me CHaCHiOMe 1-284 3 -Cl-5-CF3-Ph Me CH2CH2〇Et 1-285 3-Cl-5-CF3-Ph Et CH2CH2OH 1-286 3-Cl-5-CF3-Ph Et CHaCHiOMe 1-287 3-Cl-5-CF3 -Ph Et CH2CH2〇Et 1-288 3-Cl-5-CF3-Ph CH2CH2OH Me 1-289 3-Cl-5-CR-Ph CH2CH2OH Et 1-290 3,5-(CF3)2-Ph Me CH2CH2OH 1 -291 3,5-(CF3)2-Ph Me CH2CH2CH2OH 1-292 3,5-(CF3)2-Ph Me CH2CH2〇Me 1-293 3,5-(CF3)2-Ph Me CHiCHzOEt 1-294 3 ,5-(CF3)2-Ph Me CH2CH2〇Pr 1-295 3,5-(CF3)2-Ph Me CH2CH2CH2〇Me 1-296 3,5-(CF3)2-Ph Me CHzCHaCHiOEt 1-297 3, 5-(CF3)2-Ph Me Het(A) 1-298 3,5-(CF3)2-Ph Et CH2CH2OH 1-299 3,5-(CF3)2-Ph Et CH2CH2CH2OH 1-300 3,5- (CF3)2-Ph Et CH2CH2〇Me 1-301 3,5-(CF3)2-Ph Et CHaCHiOEt 1-302 3,5-(CF3)2-Ph Et CHiCHiOPr 1-303 3,5-(CF3) 2-Ph Et CHiCHiCHzOMe -36- 200906395 1-304 3,5- (CF3)2-Ph Et CHCHCHOEt 1-305 3,5-(CF3)2-Ph CH2CH2OH Me 1-306 3,5-(CF3)2-Ph CH2CH2OH Et 1-307 3,5-(CF3)2- Ph CH2CH2OH Pr 1-308 3,5-(CR)2-Ph CH2CH2OH CH2CH2OH 1-309 3,5-(CF3)2-Ph CH2CH2OH CftCHOMe 1-310 3,5-(CF3)2-Ph CH2CH2OH CHfflOEt 1- 311 3,5-(CF3)2-Ph CH2CH2OH CBCHOPr 1-312 3,5-(CF3)2-Ph CH2CH2OH CH2CH2CH2〇Me 1-313 3,5-(CF3)2-Ph CH2CH2OH CH2CH2CH2〇Et 1-314 2,5-Cl2-Ph Me CH2CH2OH 1-315 2,5-Cli-Ph Me CH2CH2〇Me 1-316 2,5-Cb-Ph Me CHiCHaOEt 1-317 2,5-Cl2-Ph Et CH2CH2OH 1-318 2,5-Cl2-Ph Et ChhClhOMe 1-319 2,5-Ck-Ph Et CftCHOEt 1-320 2,5-Cb-Ph CH2CH2OH Me 1-321 2,5-Cb-Ph CH2CH2OH Et (Table 2)

2-1 3-CF3-Ph Me CH2CH2OH 2-2 3-CF3-Ph Me CftCILOMe 2-3 3-CF3-Ph Me CH2CH2〇Et 2-4 3-CFs-Ph Et CH2CH2OH 2-5 3-CF3-Ph Et CHzCftOMe 2-6 3-CF3-Ph Et CH2CH2〇Et 2-7 3-CF3-Ph CH2CH2OH Me 2-8 3-CF3-Ph CH2CH2OH Et 2-9 3-Cl-4-F-Ph Me CH2CH2OH 2- 10 3-Cl-4-F-Ph Me CHaCHiOMe 2-11 3-Cl-4-F-Ph Me CH2CH2〇Et 2-12 3-Cl-4-F-Ph Et CH2CH2OH 2-13 3-Cl-4 -F-Ph Et CBCBOMe 2-14 3-Cl-4-F-Ph Et CH2CBOEt 2-15 3-Cl-4-F-Ph CH2CH2OH Me -37- 200906395

2-16 3-Cl-4-F-Ph CH2CH2OH Et 2-17 4-F-3-CF3-Ph Me CH2CH2OH 2-18 4-F-3-CF3-Ph Me CH£H2〇Me 2-19 4 -F-3-CF3-Ph Me CHiCHiOEt 2-20 4-F-3-CF3-Ph Et CH2CH2OH 2-21 4-F-3-CF3-Ph Et CBCHOMe 2-22 4-F-3-CF3-Ph Et CHiCHiOEt 2-23 4-F-3-CF3-Ph CH2CH2OH Me 2-24 4-F-3-CF3-Ph CH2CH2OH Et 2-25 3,5-F2-Ph Me CH2CH2OH 2-26 3'5-R -Ph Me CHiCHaOMe 2-27 3,5-R-Ph Me CHfflOEt 2-28 3,5-F2-Ph Et CH2CH2OH 2-29 3,5-F2-Ph Et CHiCHaOMe 2-30 3,5-F2-Ph Et CHiCHaOEt 2-31 3,5-F2-Ph CH2CH2OH Me 2-32 3,5-F2-Ph CH2CH2OH Et 2-33 3,5-Cl2-Ph Me CH2CH2OH 2-34 3,5-Cl2-Ph Me CHCftOMe 2-35 3,5-Cb-Ph Me CH2CH2〇Et 2-36 3,5-Cli-Ph Et CH2CH2OH 2-37 3,5-Cl2-Ph Et CHzCHiOMe 2-38 3,5-Cb-Ph Et CHaCHzOEt 2-39 3,5-Cl2-Ph CH2CH2OH Me 2-40 3,5-Cl2-Ph CH2CH2OH Et 2-41 3,5-(CF3)2-Ph Me CH2CH2OH 2-42 3,5-(CF3)2 -Ph Me CHzCHiOMe 2-43 3,5-(CF3)2-Ph Me CHzCHiOEt 2-44 3,5-(CF3)2-Ph Et CH2CH2OH 2-45 3,5-(CF3)2-Ph Et CH2CH2〇 Me 2-46 3,5-(CF3)2-Ph Et CBCH2〇Et 2-47 3,5-(CF3)2-Ph CH2CH2OH Me 2-48 3,5-(CF3)2-Ph CH2CH2 OH Et (Table 3) (iv) Compound No. R4 R8 R7 -38- 200906395

3-1 3-CF3-Ph Me CH2CH2OH 3-2 3-CF3-Ph Me CH2CH2〇Me 3-3 3-CF3-Ph Me CHCftOEt 3-4 3-CR-Ph Et CH2CH2OH 3-5 3-CF3-Ph Et CHCILOMe 3-6 3-CR-Ph Et CHiCHiOEt 3-7 3-CF3-Ph CH2CH2OH Me 3-8 3-CR-Ph CH2CH2OH Et 3-9 3-Cl-4-F-Ph Me CH2CH2OH 3-10 3 -Cl-4-F-Ph Me CttCHOMe 3-11 3-Cl-4-F-Ph Me CH2CH2〇Et 3-12 3-Cl-4-F-Ph Et CH2CH2OH 3-13 3-Cl-4-F -Ph Et CHfflOMe 3-14 3-Cl-4-F-Ph Et CHiCHiOEt 3-15 3-Cl-4-F-Ph CH2CH2OH Me 3-16 3-Cl-4-F-Ph CH2CH2OH Et 3-17 4 -F-3-CF3-Ph Me CH2CH2OH 3-18 4-F-3-CF3-Ph Me CH2CH2〇Me 3-19 4-F-3-CF3-Ph Me CHiCHiOEt 3-20 4-F-3-CR -Ph Et CH2CH2OH 3-21 4-F-3-CF3-Ph Et CHaCHiOMe 3-22 4-F-3-CF3-Ph Et CH2CH2〇Et 3-23 4-F-3-CF3-Ph CH2CH2OH Me 3- 24 4-F-3-CF3-Ph CH2CH2OH Et 3-25 3,5-R-Ph Me CH2CH2OH 3-26 3,5-F2-Ph Me CH2CH2〇Me 3-27 3,5-F2-Ph Me CHiCHiOEt 3-28 3,5-F2-Ph Et CH2CH2OH 3-29 3,5-F2-Ph Et CH2CH2〇Me 3-30 3,5-F2-Ph Et CH2CH2〇Et 3-31 3,5-Fz-Ph CH2CH2OH Me 3-32 3,5-F2-Ph CH2CH2OH Et 3-33 3,5-Ck-Ph Me CH2CH2OH 3-34 3,5-Cb-Ph Me CH2CH2〇Me 3 -35 3,5-Cl2-Ph Me CHCftOEt 3-36 3,5-Cl2-Ph Et CH2CH2OH 3-37 3,5-Cl2-Ph Et CHCBOMe 3-38 3,5-Cb-Ph Et CHiCHaOEt 3-39 3,5-Ch-Ph CH2CH2OH Me 3-40 3,5-Cl2-Ph CH2CH2OH Et 3-41 3,5-(CR)2-Ph Me CH2CH2OH 3-42 3,5-(CF3)2-Ph Me CBCILOMe 3-43 3,5-(CF3)2-Ph Me CHiCHiOEt 3-44 3,5-(CF3)2-Ph Et CH2CH2OH -39- 200906395 3-45 3,5-(CF3)2-Ph Et CBCftOMe 3-46 3,5-(CR)2-Ph Et CH2CH2〇Et 3-47 3,5-(CF3)2-Ph CH2CH2OH Me 3-48 3,5-(CF3)2-Ph CH2CH2OH Et (Table 4 ) 〇Η R4 (V) Compound No. R4 R8 R7 4-1 3-CR-Ph Me CH2CH2OH 4-2 3-CF3-Ph Me CHCftOMe 4-3 3-CF3-Ph Me CHiCHzOEt 4-4 3-CF3-Ph Et CH2CH2OH 4-5 3-CF3-Ph Et CHCIKMe 4-6 3-CF3-Ph Et CHzCHaOEt 4-7 3-CF3-Ph CH2CH2OH Me 4-8 3-CFs-Ph CH2CH2OH Et 4-9 3-Cl-4 -F-Ph Me CH2CH2OH 4-10 3,Cl-4-F-Ph Me CHiCHiOMe 4-11 3.Cl-4-F-Ph Me CHCftOEt 4-12 3-Cl-4-F-Ph Et CH2CH2OH 4- 13 3.Cl-4-F-Ph Et CHOtOMe 4-14 3-Cl-4-F-Ph Et CHiCHaOEt 4-15 3-Cl-4-F-Ph CH2CH2OH Me 4-16 3-Cl-4-F -Ph CH2CH2OH Et 4-17 4-F-3-CB-Ph Me CH2CH2OH 4-18 4-F-3-CF3-Ph M e CH2CH2〇Me 4-19 4-F-3-CR-Ph Me CH2CH2〇Et 4-20 4-F-3-CF3-Ph Et CH2CH2OH 4-21 4-F-3-CF3-Ph Et CH2CH2〇Me 4-22 4-F-3-CF3-Ph Et CBCHOEt 4-23 4-F-3-CF3-Ph CH2CH2OH Me 4-24 4-F-3-CF3-Ph CH2CH2OH Et 4-25 3,5-F2 -Ph Me CH2CH2OH 4-26 3,5-F2-Ph Me CHiCHiOMe 4-27 3,5-F2-Ph Me CHaCHiOEt 4-28 3,5-F2-Ph Et CH2CH2OH 4-29 3,5-F2-Ph Et CHCHOMe -40- 200906395 4-30 3,5-R-Ph Et CH2CH2〇Et 4-31 3,5-F2-Ph CH2CH2OH Me 4-32 3,5-F2-Ph CH2CH2OH Et 4-33 3,5 -Ck-Ph Me CH2CH2OH 4-34 3,5-Cl2-Ph Me CHaCHiOMe 4-35 3,5-Cl2-Ph Me CH2CH2〇Et 4-36 3,5-Cb-Ph Et CH2CH2OH 4-37 3,5 -Cb-Ph Et CH2CH2〇Me 4-38 3,5-Cl2-Ph Et CH2CH2〇Et 4-39 3,5-Cl2-Ph CH2CH2OH Me 4-40 3,5-Ch-Ph CH2CH2OH Et 4-41 3 ,5-(CF3)2-Ph Me CH2CH2OH 4-42 3,5-(CF3)2-Ph Me CHiCHaOMe 4-43 3,5-(CF3)2-Ph Me CHaCHiOEt 4-44 3,5-(CF3 2-Ph Et CH2CH2OH 4-45 3,5-(CF3)2-Ph Et CHCILOMe 4-46 3,5-(CF3)2-Ph Et CHzCHzOEt 4-47 3,5-(CF3)2-Ph CH2CH2OH Me 4-48 3,5-(CF3)2-Ph CH2CH2OH Et (Table 5) 7

OR8

OR Compound No. R4 R8 R7 5-1 3-CF3-Ph Me CH2CH2OH 5-2 3-CF3-Ph Me CHiCHiOMe 5-3 3-CFs-Ph Me CHaCHiOEt 5-4 3-CR-Ph Et CH2CH2OH 5-5 3 -CR-Ph Et CHiCHaOMe 5-6 3-CR-Ph Et CH2CH2〇Et 5-7 3-CFs-Ph CH2CH2OH Me 5-8 3-CB-Ph CH2CH2OH Et 5-9 3-Cl-4-F-Ph Me CH2CH2OH 5-10 3-Cl-4-F-Ph Me CH2CH2〇Me 5-11 3-Cl-4-F-Ph Me CH2CH2〇Et 5-12 3-Cl-4-F-Ph Et CH2CH2OH 5- 13 3-Cl-4-F-Ph Et CHiCHiOMe 5-14 3-Cl-4-F-Ph Et CHaCHaOEt -41 - 200906395 5-15 3-Cl-4-F-Ph CH2CH2OH Me 5-16 3-Cl -4-F-Ph CH2CH2OH Et 5-17 4-F-3-CF3-Ph Me CH2CH2OH 5-18 4-F-3-CFs-Ph Me CH2CH2〇Me 5-19 4-F-3-CF3-Ph Me CHaCHaOEt 5-20 4-F-3-CF3-Ph Et CH2CH2OH 5-21 4-F-3-CF3-Ph Et CH2CH2〇Me 5-22 4-F-3-CF3-Ph Et CH2CH2〇Et 5- 23 4-F-3-CF3-Ph CH2CH2OH Me 5-24 4-F-3-CF3-Ph CH2CH2OH Et 5-25 3,5-Fz-Ph Me CH2CH2OH 5-26 3,5-F2-Ph Me CH2CH2 〇Me 5-27 3,5-F2-Ph Me CHiCHiOEt 5-28 3,5-F2-Ph Et CH2CH2OH 5-29 3,5-F2-Ph Et CH2CH2〇Me 5-30 3,5-F2-Ph Et CHiCHzOEt 5-31 3,5-F2-Ph CH2CH2OH Me 5-32 3,5-F2-Ph CH2CH2OH Et 5-33 3,5- Cl2-Ph Me CH2CH2OH 5-34 3,5-Cl2-Ph Me CH2CH2〇Me 5-35 3,5-Ch-Ph Me CH2CH2〇Et 5-36 3,5-Cl2-Ph Et CH2CH2OH 5-37 3, 5-Cb-Ph Et CHzCHiOMe 5-38 3,5-Cb-Ph Et CHCHOEt 5-39 3,5-Ch-Ph CH2CH2OH Me 5-40 3,5-Cl2-Ph CH2CH2OH Et 5-41 3,5- (CR)2-Ph Me CH2CH2OH 5-42 3,5-(CF3)2-Ph Me CHiCHiOMe 5-43 3,5-(CF3)2-Ph Me CHaCHiOEt 5-44 3,5-(CF3)2- Ph Et CH2CH2OH 5-45 3,5-(CF3)2-Ph Et CftCH2〇Me 5-46 3,5-(CF3)2-Ph Et CH2CH2〇Et 5-47 3,5-(CF3)2-Ph CH2CH2OH Me 5-48 3,5-(CF3)2-Ph CH2CH2OH Et 5-49 Ph Me CH2CH2OH 5-50 Ph Me CHCftOMe 5-51 Ph Me CH2CH2〇Et 5-52 Ph Et CH2CH2OH 5-53 Ph Et CHffiOMe 5 -54 Ph Et CH2CH2〇Et 5-55 Ph CH2CH2OH Me 5-56 Ph CH2CH2OH Et (Table 6) -42- 200906395

Compound No. R4 R8 R7 6-1 3-CB-Ph Me CH2CH2OH 6-2 3-CF3-Ph Me CHzCHzOMe 6-3 3-CR-Ph Me CH2CH2〇Et 6-4 3-CF3-Ph Et CH2CH2OH 6-5 3-CF3-Ph Et CHiCHiOMe 6-6 3-CFs-Ph Et CH2CH2〇Et 6-7 3-CR-Ph CH2CH2OH Me 6-8 3-CF3-Ph CH2CH2OH Et 6-9 3-Cl-4-F- Ph Me CH2CH2OH 6-10 3-Cl-4-F-Ph Me CHzCHaOMe 6-11 3-Cl-4-F-Ph Me CHzCHaOEt 6-12 3-Cl-4-F-Ph Et CH2CH2OH 6-13 3- Cl-4-F-Ph Et CH2CH2〇Me 6-14 3-Cl-4-F-Ph Et CH2CH2〇Et 6-15 3-Cl-4-F-Ph CH2CH2OH Me 6-16 3-Cl-4- F-Ph CH2CH2OH Et 6-17 4-F-3-CF3-Ph Me CH2CH2OH 6-18 4-F-3-CF3-Ph Me CHiCHzOMe 6-19 4-F-3-CF3-Ph Me CH2CH2〇Et 6 -20 4-F-3-CF3-Ph Et CH2CH2OH 6-21 4-F-3-CB-Ph Et CHzCHzOMe 6-22 4-F-3-CR-Ph Et CH2CH2〇Et 6-23 4-F- 3-CF3-Ph CH2CH2OH Me 6-24 4-F-3-CF3-Ph CH2CH2OH Et 6-25 3,5-Fi-Ph Me CH2CH2OH 6-26 3,5-Fa-Ph Me CHzCHaOMe 6-27 3, 5-F2-Ph Me CILCBOEt 6-28 3,5-Fi-Ph Et CH2CH2OH 6-29 3,5-F2-Ph Et CHaCHzOMe 6-30 3,5-F2-Ph Et CHaCHaOEt 6-31 3,5- Fz-Ph CH2CH2OH Me 6-32 3,5-F2-Ph CH2CH2OH Et 6-33 3,5-Cl2-Ph Me CH2CH2OH 6-34 3,5-Cl2-Ph Me CHzCBOMe 6-35 3,5-Cl2-Ph Me CHsCHiOEt -43 - 200906395

(VIII) 6-36 3,5-Cl2-Ph Et CH2CH2OH 6-37 3,5-Cl2-Ph Et OLCHOMe 6-38 3,5-Cb-Ph Et CH2CH£)Et 6-39 3,5-Cl2 -Ph CH2CH2OH Me 6-40 3,5-Ck-Ph CH2CH2OH Et 6-41 3,5-(CF3)2-Ph Me CH2CH2OH 6-42 3,5-(CF3)2-Ph Me CH2CH2〇Me 6- 43 3,5-(CF3)2-Ph Me CHfflOK 6-44 3,5-(CF3)2-Ph Et CH2CH2OH 6-45 3,5-(CF3)2-Ph Et CH2CH2〇Me 6-46 3, 5-(CF3)2-Ph Et CH2CH2〇Et 6-47 3,5-(CF3)2-Ph CH2CH2OH Me 6-48 3,5-(CF3)2-Ph CH2CH2OH Et (Table 7) Compound No. R4 R8 R7

7-1 3-CF3-Ph Me CH2CH2〇H. 7-2 3-CFs-Ph Me CHmOMe 7-3 3-CF3-Ph Me CH2CH2〇Et 7-4 3-CFs-Ph Et CH2CH2OH 7-5 3- CFs-Ph Et CHiCHaOMe 7-6 3-CIVPh Et CH2CH2〇Et 7-7 3-CFs-Ph CH2CH2OH Me 7-8 3-CFj-Ph CH2CH2OH Et 7-9 3_Cl-4-F-Ph Me CH2CH2OH 7-10 3_Cl-4-F-Ph Me CHCftOMe 7-11 3-Cl-4-F-Ph Me CH2CH2〇Et 7-12 3-Cl-4-F-Ph Et CH2CH2OH 7-13 3-Cl-4-F- Ph Et CHaCHiOMe 7-14 3-Cl-4-F-Ph Et CH2CH2〇Et 7-15 3-Cl-4-F-Ph CH2CH2OH Me 7-16 3_Cl-4-F-Ph CH2CH2OH Et 7-17 4- F-3-CF3-Ph Me CH2CH2OH 7-18 4-F-3-CF3-Ph Me CHOMMe 7-19 4-F-3-CF3-Ph Me CHaCHaOEt 7-20 4-F-3-CFs-Ph Et CH2CH2OH -44- 200906395 7-21 4-F-3-CF3-Ph Et CHiCHzOMe 7-22 4-F-3-CF3-Ph Et CH2CH2〇Et 7-23 4-F-3-CF3-Ph CH2CH2OH Me 7 -24 4-F-3-CF3-Ph CH2CH2OH Et 7-25 3,5-Fz-Ph Me CH2CH2OH 7-26 3,5-F2-Ph Me CftCHOMe 7-27 3,5-F2-Ph Me CH2CH2〇 Et 7-28 3,5-F2-Ph Et CH2CH2OH 7-29 3,5-R-Ph Et CHzCHaOMe 7-30 3,5-F2-Ph Et CH2CH2〇Et 7-31 3,5-F2-Ph CH2CH2OH Me 7-32 3,5-F2-Ph CH2CH2OH Et 7-33 3,5-Cl2-Ph Me CH2CH2OH 7-34 3,5-Ch-Ph Me CILCBOMe 7-35 3,5-Ch-Ph Me CHzCHzOEt 7-36 3'5-CU-Ph Et CH2CH2OH 7-37 3,5-Cl2-Ph Et CftOLOMe 7-38 3,5-Ch-Ph Et CHzCBOEt 7-39 3,5-Cl2-Ph CH2CH2〇H Me 7-40 3,5-Ch-Ph CH2CH20H Et 7-41 3,5-(CF3)2-Ph Me CH2CH2OH 7-42 3,5-(CF3 )2-Ph Me CHzCHiOMe 7-43 3,5-(CF3)2-Ph Me CHaCHaOEt 7-44 3,5-(CF3)2-Ph Et CH2CH2OH 7-45 3,5-(CF3)2-Ph Et CH2CH2〇Me 7-46 3,5-(CF3)2-Ph Et CH2CH2〇Et 7-47 3,5-(CF3)2-Ph CH2CH2OH Me 7-48 3,5-(CF3)2-Ph CH2CH2OH Et (Table 8) 〇厂TH R4 \J (IX) Compound No. R4 R8 R7 8-1 3-CR-Ph Me CH2CH2OH 8-2 3-CF3-Ph Me CHCHOMe 8-3 3-CR-Ph Me CHiCHiOEt 8- 4 3-CB-Ph Et CH2CH2OH 8-5 3-CF3-Ph Et CHiCHiOMe 45- 200906395 8-6 3-CFs-Ph Et CHaCHzOEt 8-7 3-CF3-Ph CH2CH2OH Me 8-8 3-CF3-Ph CH2CH2OH Et 8-9 3-Cl-4-F-Ph Me CH2CH2OH 8-10 3-Cl-4-F-Ph Me CHiCHiOMe 8-11 3-Cl-4-F-Ph Me CHfflOEt 8-12 3-Cl- 4-F-Ph Et CH2CH2OH 8-13 3_Cl-4-F-Ph Et OLCILOMe 8-14 3-Cl-4-F-Ph Et CHCHOEt 8-15 3-Cl-4-F-Ph CH2CH2OH Me 8-16 3-Cl-4-F-Ph CH2CH2OH Et 8-17 4-F-3-CF3-Ph Me CH2CH2OH 8-18 4-F-3-CF3-Ph Me CHaCHzOMe 8-19 4-F-3-CF3-Ph Me CHiCHiOEt 8-20 4-F-3-CF3-Ph Et CH2CH2OH 8-21 4-F -3-CF3-Ph Et CHiCHzOMe 8-22 4-F-3-CF3-Ph Et CHiCHiOEt 8-23 4-F-3-CF3-Ph CH2CH2OH Me 8-24 4-F-3-CF3-Ph CH2CH2OH Et 8-25 3,5-F2-Ph Me CH2CH2OH 8-26 3,5-F2-Ph Me CHiCHzOMe 8-27 3,5-F2-Ph Me CHiCHiOEt 8-28 3,5-F2-Ph Et CH2CH2OH 8- 29 3,5-F2-Ph Et CHCBOMe 8-30 3,5-F2-Ph Et CHiCHiOEt 8-31 3,5-R-Ph CH2CH2OH Me 8-32 3,5-F2-Ph CH2CH2OH Et 8-33 3 ,5-Cl2-Ph Me CH2CH2OH 8-34 3,5-Cl2-Ph Me CHiCHzOMe 8-35 3,5-Cl2-Ph Me CftCftOEt 8-36 3,5-Cl2-Ph Et CH2CH2OH 8-37 3,5 -Cl2-Ph Et CHzCHzOMe 8-38 3'5-Cl2-Ph Et CHiCHiOEt 8-39 3,5-Cl2-Ph CH2CH2OH Me 8-40 3,5-Cl2-Ph CH2CH2OH Et 8-41 3,5-( CF3)2-Ph Me CH2CH2OH 8-42 3,5-(CF3)2-Ph Me CH2CH£)Me 8-43 3,5-(CF3)2-Ph Me CHiCHiOEt 8-44 3,5-(CF3) 2-Ph Et CH2CH2OH 8-45 3,5-(CF3)2-Ph Et CH2CH2〇Me 8-46 3,5-(CF3)2-Ph Et CftOLOEt 8-47 3,5-(CF3)2-Ph CH2CH2OH Me 8-48 3,5-(CF3)2-Ph CH2CH2OH Et (Table 9) -46- 200906395

R6

OR8 OR7 (X)

Compound number R4 R3 R丨. R8 R7 9-1 3-CFs-Ph H Me Me CH2CH2OH 9-2 3-CF3-Ph H Me Me CHiCHzOMe 9-3 3-CFs-Ph H Me Et CH2CH2OH 9-4 3-CF3-Ph H Me Et CHaCHaOMe 9-5 3-CR-Ph H Me CH2CH2OH Me 9-6 3-CF3-Ph H Me CH2CH2OH Et 9-7 3-CFs-Ph H Cl Me CH2CH2OH 9-8 3-CR-Ph H Cl Me CHiCHiOMe 9- 9 3-CFs-Ph H Cl Et CH2CH2OH 9-10 3-CF3-Ph H Cl Et CHiCHiOMe 9-11 3-CB-Ph H Cl CH2CH2OH Me 9-12 3-CF3-Ph H Cl CH2CH2OH Et 9-13 3 -CFs-Ph OH H Me CH2CH2OH 9-14 3-CR-Ph OH H Me CHaCHiOMe 9-15 3-CB-Ph OH H Et CH2CH2OH 9-16 3-CB-Ph OH H Et CH2CH2〇Me 9-17 3 -CF3-Ph OH H CH2CH2OH Me 9-18 3-CF3-Ph OH H CH2CH2OH Et 9-19 3-Cl-4-F-Ph H Me Me CH2CH2OH 9-20 3-Cl-4-F-Ph H Me Me CHzCILOMe 9-21 3-Cl-4-F-Ph H Me Et CH2CH2OH 9-22 3-Cl-4-F-Ph H Me Et CH2CH2〇Me 9-23 3-Cl-4-F-Ph H Me CH2CH2OH Me 9-24 3-Cl-4-F-Ph H Me CH2CH2OH Et 9-25 3-Cl-4-F-Ph H Cl Me CH2CH2OH 9-26 3_Cl-4-F-Ph H Cl Me CHiCHzOMe 9- 27 3-Cl-4-F-Ph H Cl Et CH2CH2OH 9-28 3-Cl-4-F-Ph H Cl Et CBCHOMe 9-29 3_Cl-4-F-Ph H Cl CH2CH2OH Me 9-30 3-Cl -4-F-Ph H Cl CH2CH2OH Et 9-31 3-Cl-4-F-Ph OH H Me CH2CH2OH 9-32 3-Cl-4-F-Ph OH H Me CH2CH2〇Me 9-33 3-Cl-4-F-Ph OH H Et CH2CH2OH -47- 200906395 9-34 3-Cl-4-F-Ph OH H Et CHiCHaOMe 9-35 3-Cl-4-F-Ph OH H CH2CH2OH Me 9-36 3-Cl-4-F-Ph OH H CH2CH2OH Et 9-37 4-F-3-CF3-Ph H Me Me CH2CH2OH 9-38 4-F-3-CF3-Ph H Me Me CH2CH2〇Me 9-39 4-F-3-CF3-Ph H Me Et CH2CH2OH 9-40 4-F-3-CF3-Ph H . Me Et CBCftOMe 9-41 4-F-3-CF3-Ph H Me CH2CH2OH Me 9-42 4-F-3-CF3-Ph H Me CH2CH2OH Et 9-43 4-F-3-CF3-Ph H Cl Me CH2CH2OH 9-44 4-F-3-CF3-Ph H Cl Me CH2CH2〇Me 9-45 4-F-3-CF3-Ph H Cl Et CH2CH2OH 9-46 4-F-3-CF3-Ph H Cl Et CHiCHaOMe 9-47 4-F-3-CF3-Ph H Cl CH2CH2OH Me 9-48 4-F-3-CF3-Ph H Cl CH2CH2OH Et 9 -49 4-F-3-CF3-Ph OH H Me CH2CH2OH 9-50 4-F-3-CF3-Ph OH H Me CHCHOMe 9-51 4-F-3-CF3-Ph OH H Et CH2CH2OH 9-52 4-F-3-CF3-Ph OH H Et CH2CH2〇Me 9-53 4-F-3-CF3-Ph OH H CH2CH2OH Me 9-54 4-F-3-CF3-Ph OH H CH2CH2OH Et 9-55 3,5-F2-Ph H Me Me CH2CH2OH 9-56 3,5-F2-Ph H Me Me CHiCHiOMe 9-57 3,5-F2-Ph H Me Et CH2CH2OH 9-58 3,5-F2-P h H Me Et CFbCHOMe 9-59 3,5-F2-Ph H Me CH2CH2OH Me 9-60 3,5-F2-Ph H Me CH2CH2OH Et 9-61 3,5-F2-Ph H Cl Me CH2CH2OH 9-62 3,5-F2-Ph H Cl Me CH2CH2〇Me 9-63 3,5-F2-Ph H Cl Et CH2CH2OH 9-64 3,5-F2-Ph H Cl Et CHzCHiOMe 9-65 3,5-F2- Ph H Cl CH2CH2OH Me 9-66 3,5-Fz-Ph H Cl CH2CH2OH Et 9-67 3,5-F2-Ph OH H Me CH2CH2OH 9-68 3,5-F2-Ph OH H Me CHiCHiOMe 9-69 3,5-F2-Ph OH H Et CH2CH2OH 9-70 3,5-F2-Ph OH H Et CH2CH2〇Me 9-71 3,5-F2-Ph OH H CH2CH2OH Me 9-72 3,5-F2- Ph OH H CH2CH2OH Et 9-73 3,5-Ch-Ph H Me Me CH2CH2OH 9-74 3,5-Cl2-Ph H Me Me CH2CH2〇Me 9-75 3,5-Cb-Ph H Me Et CH2CH2OH 9 -76 3,5-Cl2-Ph H Me Et CHiCHiOMe 9-77 3,5-Cl2-Ph H Me CH2CH2OH Me 9-78 3,5-Cl2-Ph H Me CH2CH2OH Et -48- 200906395

OR 8 R1 9-79 3,5-Cl2-Ph H Cl Me CH2CH2OH 9-80 3,5-Cl2-Ph H Cl Me CHiCHzOMe 9-81 3,5-Cl2-Ph H Cl Et CH2CH2OH 9-82 3, 5-Cb-Ph H Cl Et CH2CH2〇Me 9-83 3,5-Cb-Ph H Cl CH2CH2OH Me 9-84 3,5-Cl2-Ph H Cl CH2CH2OH Et 9-85 3,5-Cl2-Ph OH H Me CH2CH2OH 9-86 3,5-Ch-Ph OH H Me CHaCBOMe 9-87 3,5-CU-Ph OH H Et CH2CH2OH 9-88 3,5-Ck-Ph OH H Et CBCHiOMe 9-89 3, 5-Cl2-Ph OH H CH2CH2OH Me 9-90 3,5-Cl2-Ph OH H CH2CH2OH Et 9-91 3,5-(CF3)2-Ph H Me Me CH2CH2OH 9-92 3,5-(CF3) 2-Ph H Me Me CH2CH2〇Me 9-93 3,5-(CF3)2-Ph H Me Et CH2CH2OH 9-94 3,5-(CF3)2-Ph H Me Et CHfflOMe 9-95 3,5- (CF3)2-Ph H Me CH2CH2OH Me 9-96 3,5-(CF3)2-Ph H Me CH2CH2OH Et 9-97 3,5-(CF3)2-Ph H Cl Me CH2CH2OH 9-98 3,5 -(CF3)2-Ph H Cl Me CftCILOMe 9-99 3,5-(CF3)2-Ph H Cl Et CH2CH2OH 9-100 3,5-(CF3)2-Ph H Cl Et CftOLOMe 9-101 3, 5-(CF3)2-Ph H Cl CH2CH2OH Me 9-102 3,5-(CF3)2-Ph H Cl CH2CH2OH Et 9-103 3,5-(CF3)2-Ph OH H Me CH2CH2OH 9-104 3 ,5-(CF3)2-Ph OH H Me CHfflOMe 9-105 3,5-(CF3)2-Ph OH H Et CH2CH2OH 9-106 3,5-(CF3)2-Ph OH H Et CHiCHzOMe 9-107 3,5-(CF3)2-Ph OH H CH2CH2OH Me 9-108 3,5-(CF3)2-Ph OH H CH2CH2OH Et (Table 10) (XI) Compound No. R4 R8 R1 10-1 3-F-Ph Me NHz -49- 200906395 10-2 3-F-Ph Me NHMe 10-3 3-F-Ph Me NHEt 10-4 3-F-Ph Me NHPr 10-5 3-F -Ph Me NMea 10-6 3-F-Ph Me NEt2 10-7 3-F-Ph Me N(Me)Et 10-8 3-F-Ph Me NHCOMe 10-9 3-F-Ph Me NHCOEt 10- 10 3-F-Ph Me Het(B) 10-11 3-F-Ph Et NH2 10-12 3-F-Ph Et NHMe 10-13 3-F-Ph Et NHEt 10-14 3-F-Ph Et NHPr 10-15 3-F-Ph Et NMe2 10-16 3-F-Ph Et NEt2 10-17 3-F-Ph Et N(Me)Et 10-18 3-F-Ph Et NHCOMe 10-19 3- F-Ph Et NHCOEt 10-20 3-F-Ph Et Het(B) 10-21 3-F-Ph CH2CH2OH NH2 10-22 3-F-Ph CH2CH2OH NHMe 10-23 3-F-Ph CH2CH2OH NHEt 10- 24 3-F-Ph CH2CH2OH NHPr 10-25 3-F-Ph CH2CH2OH NMe2 10-26 3-F-Ph CH2CH2OH NEta 10-27 3-F-Ph CH2CH2OH N(Me)Et 10-28 3-F-Ph CH2CH2OH NHCOMe 10-29 3-F-Ph CH2CH2OH NHCOEt 10-30 3-F-Ph CH2CH2OH Het(B) 10-31 3-Cl-Ph Me NH2 10-32 3-Cl-Ph Me NHMe 10-33 3- Cl-Ph Me NHEt 10-34 3-Cl-Ph Me NHPr 10-35 3-Cl-Ph Me NMei 10-3 6 3-Cl-Ph Me NEt2 10-37 3-Cl-Ph Me N(Me)Et 10-38 3-Cl-Ph Me NHCOMe 10-39 3-Cl-Ph Me NHCOEt 10-40 3-Cl-Ph Me Het(B) 10-41 3-Cl-Ph Et NH2 10-42 3-Cl-Ph Et NHMe 10-43 3-Cl-Ph Et NHEt 10-44 3-Cl-Ph Et NHPr 10-45 3- Cl-Ph Et NMez 10-46 3-Cl-Ph Et NEti -50- 200906395 10-47 3-Cl-Ph Et N(Me)Et 10-48 3-Cl-Ph Et NHCOMe 10-49 3-Cl- Ph Et NHCOEt 10-50 3-Cl-Ph Et Het(B) 10-51 3-Cl-Ph CH2CH2OH NH2 10-52 3-Cl-Ph CH2CH2OH NHMe 10-53 3-Cl-Ph CH2CH2OH NHEt 10-54 3 -Cl-Ph CH2CH2OH NHPr 10-55 3-Cl-Ph CH2CH2OH NMe2 10-56 3-Cl-Ph CH2CH2OH NEt2 10-57 3-Cl-Ph CH2CH2OH N(Me)Et 10-58 3-Cl-Ph CH2CH2OH NHCOMe 10-59 3-Cl-Ph CH2CH2OH NHCOEt 10-60 3-Cl-Ph CH2CH2OH Het(B) 10-61 3-CR-Ph Me NH2 10-62 3-CF3-Ph Me NHMe 10-63 3-CB- Ph Me NHEt 10-64 3-CR-Ph Me NHPr 10-65 3-CF3-Ph Me NMe2 10-66 3-CF3-Ph Me NEt2 10-67 3-CF3-Ph Me N(Me)Et 10-68 3-CR-Ph Me NHCOMe 10-69 3-CF3-Ph Me NHCOEt 10-70 3-CF3-Ph Me Het(B) 10-71 3-CF3-Ph Et NH2 10-72 3-CF3-Ph Et NHMe 10-73 3-CB-Ph Et NHEt 10-74 3-CF3-Ph E t NHPr 10-75 3-CF3-Ph Et NMe: 10-76 3-CF3-Ph Et NEt2 10-77 3-CF3-Ph Et N(Me)Et 10-78 3-CF3-Ph Et NHCOMe 10-79 3-CF3-Ph Et NHCOEt 10-80 3-CF3-Ph Et Het(B) 10-81 3-CF3-Ph CH2CH2OH NH2 10-82 3-CF3-Ph CH2CH2OH NHMe 10-83 3-CR-Ph CH2CH2OH NHEt 10-84 3-CR-Ph CH2CH2OH NHPr 10-85 3-CFs-Ph CH2CH2OH NMe: 10-86 3-CF3-Ph CH2CH2OH NEta 10-87 3-CF3-Ph CH2CH2OH N(Me)Et 10-88 3- CF3-Ph CH2CH2OH NHCOMe 10-89 3-CF3-Ph CH2CH2OH NHCOEt 10-90 3-CF3-Ph CH2CH2OH Het(B) 10-91 3,5-Fa-Ph Me NH2 -51 - 200906395 10-92 3,5 -B-Ph Me NHMe 10-93 3,5-Fa-Ph Me NHEt 10-94 3,5-F2-Ph Me NHPr 10-95 3,5-F2-Ph Me NMe: 10-96 3,5- F2-Ph Me NEt2 10-97 3,5-F2-Ph Me N(Me)Et 10-98 3,5-F2-Ph Me NHCOMe 10-99 3,5-F2-Ph Me NHCOEt 10-100 3, 5-F2-Ph Me Het(B) 10-101 3,5-F2-Ph Et NH2 10-102 3,5-Fa-Ph Et NHMe 10-103 3,5-F2-Ph Et NHEt 10-104 3 ,5-F2-Ph Et NHPr 10-105 3,5-F2-Ph Et NMez 10-106 3,5-F2-Ph Et NEt2 10-107 3,5-F2-Ph Et N(Me)Et 10- 108 3,5-F2-Ph Et NHCOMe 10-109 3,5-Fa-Ph Et NHCOEt 10-110 3,5-F2- Ph Et Het(B) 10-111 3,5-R-Ph CH2CH2OH NH2 10-112 3,5-F2-Ph CH2CH2OH NHMe 10-113 3,5-F2-Ph CH2CH2OH NHEt 10-114 3,5-F2 -Ph CH2CH2OH NHPr 10-115 3,5-F2-Ph CH2CH2OH NMei 10-116 3,5-F2-Ph CH2CH2OH NEt2 10-117 3,5-Fa-Ph CH2CH2OH N(Me)Et 10-118 3,5 -F2-Ph CH2CH2OH NHCOMe 10-119 3,5-F2-Ph CH2CH2OH NHCOEt 10-120 3,5-F2-Ph CH2CH2OH Het(B) 10-121 3,5-Cl2-Ph Me NH2 10-122 3, 5-Cb-Ph Me NHMe 10-123 3,5-Cl2-Ph Me NHEt 10-124 3,5-Cb-Ph Me NHPr 10-125 3,5-Cl2-Ph Me NMe2 10-126 3,5- Ck-Ph Me NEt2 10-127 3,5-Cl2-Ph Me N(Me)Et 10-128 3,5-Cl2-Ph Me NHCOMe 10-129 3,5-Cb-Ph Me NHCOEt 10-130 3, 5-Ch-Ph Me Het(B) 10-131 3,5-Cl2-Ph Et NH2 10-132 3,5-Cl2-Ph Et NHMe 10-133 3,5-Cl2-Ph Et NHEt 10-134 3 ,5-Cb-Ph Et NHPr 10-135 3,5-Cl2-Ph Et NMe2 10-136 3,5-Cl2-Ph Et NEt2 52- 200906395

OR8 R1 10-137 3,5-Ch-Ph Et N(Me)Et 10-138 3,5-Cb-Ph Et NHCOMe 10-139 3,5-Cb-Ph Et NHCOEt 10-140 3,5-Cl2 -Ph Et Het(B) 10-141 3,5-Cl2-Ph CH2CH2OH NH2 10-142 3,5-Cl2-Ph CH2CH2OH NHMe 10-143 3,5-Cb-Ph CH2CH2OH NHEt 10-144 3,5- Cl2-Ph CH2CH2OH NHPr 10-145 3,5-Ck-Ph CH2CH2OH NMe2 10-146 3,5-Cl2-Ph CH2CH2OH NEt2 10-147 3,5-Ck-Ph CH2CH2OH N(Me)Et 10-148 3, 5-Cl2-Ph CH2CH2OH NHCOMe 10-149 3,5-Cl2-Ph CH2CH2OH NHCOEt 10-150 3,5-Ch-Ph CH2CH2OH Het(B) (Table 11) (XII) Compound No. R4 R8 R1 11-1 3 -F-Ph Me NHz 11-2 3-F-Ph Me NHMe 11-3 3-F-Ph Me NHEt 11-4 3-F-Ph Me NHPr 11-5 3-F-Ph Me NMea 11-6 3 -F-Ph Me NEt2 11-7 3-F-Ph Me N(Me)Et 11-8 3-F-Ph Me NHCOMe 11-9 3-F-Ph Me NHCOEt 11-10 3-F-Ph Me Het (B) 11-11 3-F-Ph Et NH2 11-12 3-F-Ph Et NHMe 11-13 3-F-Ph Et NHEt 11-14 3-F-Ph Et NHPr 11-15 3-F- Ph Et NMe2 11-16 3-F-Ph Et NEt2 11-17 3-F-Ph Et N(Me)Et -53- 200906395 11-18 3-F-Ph Et NHCOMe 11-19 3-F-Ph Et NHCOEt 11-20 3-F-Ph Et Het(B) 11-21 3-F-Ph CH2CH2OH NH2 11-22 3-F-Ph CH2C H2OH NHMe 11-23 3-F-Ph CH2CH2OH NHEt 11-24 3-F-Ph CH2CH2OH NHPr 11-25 3-F-Ph CH2CH2OH NMea 11-26 3-F-Ph CH2CH2OH NEt2 11-27 3-F-Ph CH2CH2OH N(Me)Et 11-28 3-F-Ph CH2CH2OH NHCOMe 11-29 3-F-Ph CH2CH2OH NHCOEt 11-30 3-F-Ph CH2CH2OH Het(B) 11-31 3-Cl-Ph Me NH2 11 -32 3-Cl-Ph Me NHMe 11-33 3-Cl-Ph Me NHEt 11-34 3-Cl-Ph Me NHPr 11-35 3-Cl-Ph Me NMe: 11-36 3-Cl-Ph Me NEb 11-37 3-Cl-Ph Me N(Me)Et 11-38 3-Cl-Ph Me NHCOMe 11-39 3-Cl-Ph Me NHCOEt 11-40 3-Cl-Ph Me Het(B) 11-41 3-Cl-Ph Et NH2 11-42 3-Cl-Ph Et NHMe 11-43 3-Cl-Ph Et NHEt 11-44 3-Cl-Ph Et NHPr 11-45 3-Cl-Ph Et NMe: 11- 46 3-Cl-Ph Et NEta 11-47 3-Cl-Ph Et N(Me)Et 11-48 3-Cl-Ph Et NHCOMe 11-49 3-Cl-Ph Et NHCOEt 11-50 3-Cl-Ph Et Het(B) 11-51 3-Cl-Ph CH2CH2OH NH2 11-52 3-Cl-Ph CH2CH2OH NHMe 11-53 3-Cl-Ph CH2CH2OH NHEt 11-54 3-Cl-Ph CH2CH2OH NHPr 11-55 3- Cl-Ph CH2CH2OH NMe2 11-56 3-Cl-Ph CH2CH2OH NEtz 11-57 3-Cl-Ph CH2CH2OH N(Me)Et 11-58 3-Cl-Ph CH2CH2OH NHCOMe 11-59 3-Cl-Ph CH2CH2OH NHCOEt 11 -60 3-Cl -Ph CH2CH2OH Het(B) 11-61 3-CF3-Ph Me NH2 11-62 3-CF3-Ph Me NHMe -54- 200906395 11-63 3-CF3-Ph Me NHEt 11-64 3-CFs-Ph Me NHPr 11-65 3-CFs-Ph Me NM& 11-66 3-CFs-Ph Me NEt2 11-67 3-CR-Ph Me N(Me)Et 11-68 3-CFs-Ph Me NHCOMe 11-69 3 -CF3-Ph Me NHCOEt 11-70 3-CF3-Ph Me Het(B) 11-71 3-CB-Ph Et NH2 11-72 3-CF3-Ph Et NHMe 11-73 3-CFs-Ph Et NHEt 11 -74 3-CR-Ph Et NHPr 11-75 3-CF3-Ph Et NMe2 11-76 3-CF3-Ph Et NEta 11-77 3-CR-Ph Et N(Me)Et 11-78 3-CF3- Ph Et NHCOMe 11-79 3-CF3-Ph Et NHCOEt 11-80 3-CR-Ph Et Het(B) 11-81 3-CF3-Ph CH2CH2OH NH2 11-82 3-CFs-Ph CH2CH2OH NHMe 11-83 3 -CF3-Ph CH2CH2OH NHEt 11-84 3-CF3-Ph CH2CH2OH NHPr 11-85 3-CF3-Ph CH2CH2OH NMe2 11-86 3-CB-Ph CH2CH2OH NEt2 11-87 3-CF3-Ph CH2CH2OH N(Me)Et 11-88 3-CR-Ph CH2CH2OH NHCOMe 11-89 3-CFj-Ph CH2CH2OH NHCOEt 11-90 3-CF3-Ph CH2CH2OH Het(B) 11-91 3,5-R-Ph Me NH2 11-92 3, 5-R-Ph Me NHMe 11-93 3,5-Fz-Ph Me NHEt 11-94 3,5-F2-Ph Me NHPr 11-95 3,5-R-Ph Me NMei 11-96 3,5- R-Ph Me NEt2 11-97 3,5-F2-Ph Me N (Me)Et 11-98 3,5-F2-Ph Me NHCOMe 11-99 3,5-F2-Ph Me NHCOEt 11-100 3,5-F2-Ph Me Het(B) 11-101 3,5- F2-Ph Et NH2 11-102 3,5-R-Ph Et NHMe 11-103 3,5-F2-Ph Et NHEt 11-104 3,5-F2-Ph Et NHPr 11-105 3,5-F2- Ph Et NMe2 11-106 3,5-R-Ph Et NEtz 11-107 3,5-F2-Ph Et N(Me)Et -55- 200906395 11-108 3,5-R-Ph Et NHCOMe 11-109 3,5-F2-Ph Et NHCOEt 11-110 3,5-F2-Ph Et Het(B) 11-111 3,5-F2-Ph CH2CH2OH NH2 11-112 3,5-F2-Ph CH2CH2OH NHMe 11- 113 3,5-Mi CH2CH2OH NHEt 11-114 3,5-F2-Ph CH2CH2OH NHPr 11-115 3,5-F2-Ph CH2CH2OH NMez 11-116 3,5-Fi-Ph CH2CH2OH NEt2 11-117 3,5 -F2-Ph CH2CH2OH N(Me)Et 11-118 3,5-F2-Ph CH2CH2OH NHCOMe 11-119 3,5-R-Ph CH2CH2OH NHCOEt 11-120 3,5-F2-Ph CH2CH2OH Het(B) 11 -121 3,5-Ch-Ph Me NH2 11-122 3,5-Cl2-Ph Me NHMe 11-123 3,5-Cl2-Ph Me NHEt 11-124 3,5-Cb-Ph Me NHPr 11-125 3,5-Cl2-Ph Me NMe2 11-126 3'5-Ch-Ph Me NEt2 11-127 3,5-Cl2-Ph Me N(Me)Et 11-128 3,5-CL-Ph Me NHCOMe 11 -129 3,5-Cb-Ph Me NHCOEt 11-130 3,5-Ch-Ph Me Het(B) 11-131 3,5-Cl2-Ph Et NH2 11-132 3,5-Cl2-Ph Et NHMe 11-133 3,5-Cl2-Ph Et NHEt 11-134 3,5-Cl2-Ph Et NHPr 11-135 3,5-Cl2-Ph Et NMei 11-136 3, 5-Ch-Ph Et NEt2 11-137 3,5-Cl2-Ph Et N(Me)Et 11-138 3,5-Cb-Ph Et NHCOMe 11-139 3,5-Cl2-Ph Et NHCOEt 11-140 3,5-Ch-Ph Et Het(B) 11-141 3,5-Ck-Ph CH2CH2OH NH2 11-142 3,5-Cl2-Ph CH2CH2OH NHMe 11-143 3,5-Cl2-Ph CH2CH2OH NHEt 11- 144 3,5-Cl2-Ph CH2CH2OH NHPr 11-145 3,5-Cl2-Ph CH2CH2OH NMe2 11-146 3,5-Cl2-Ph CH2CH2OH NEt2 11-147 3,5-Cb-Ph CH2CH2OH N(Me)Et 11-148 3,5-Cl2-Ph CH2CH2OH NHCOMe 11-149 3,5-Cl2-Ph CH2CH2〇H NHCOEt 11-150 3,5-Cb-Ph CH2CH2OH Het(B) In Tables 1 to 11, suitable The compound is compound number 1 -1 6 , -56- 200906395 1-17 ' 1-40 ' 1-41 ' 1-64 ' 1-65 ' 1-121 ' 1-122 ' 1-145 ' 1-177, 178, 1 -23 3, 1-234, 1-273, 1-305, 10-25, 10-53, 10-55, 10-56, 10-83, 10-85, 10-86, 10-90 , 10-113, 10-116, 10-143 or 10-145. A preferred compound is 4-dimethylamino-AM5-(3-fluorobenzyl)-thiazol-2-yl]-3-(2-hydroxy-ethoxy)-benzylguanamine (Compound No. 10-25) , AM5-(3-chloro-benzyl)-thiazol-2-yl]-4-ethylamino-3-(2-hydroxy-ethoxy)-benzamide (Compound No. 10-53), AM5 -(3-chlorobenzyl)-thiazol-2-yl]-4-dimethylamino-3-(2-hydroxy-ethoxy)-benzamide (Compound No. 10-55), TV-[5 -(3-chloro-benzyl)-thiazol-2-yl]-4-diethylamino-3-(2-hydroxy-ethoxy)-benzamide (Compound No. 10-56), 4-B Amino 3-(2-hydroxy-ethoxy)-7V-[5-(3-trifluoromethyl-benzyl)-thiazol-2-yl]-benzylguanamine (Compound No. 10-83), 4-Dimethylamino-3-(2-hydroxy-ethoxy)-[5-(3-trifluoromethylbenzyl)-thiazol-2-yl]-benzamide (Compound No. 10-85 , 4-diethylamino-3-(2-hydroxy-ethoxy)-, [5-(3-trifluoromethylbenzyl)-thiazol-2-yl]-benzylguanamine (Compound No. 10) -86), 3-(2-hydroxy-ethoxy)-4-morpholin-4-yl-,[5-(3-trifluoromethylbenzyl)-thiazol-2-yl]-benzylguanamine (Compound No. 10-90), TV-[5-(3,5-Difluoro-benzyl)-thiazole-2- 4-ethylamino-3-(2-hydroxy-ethoxy)-benzamide (Compound No. 10-113), 4-Diethylamino-AM5-(3,5-difluorobenzyl )-thiazol-2-yl]-3-(2-hydroxy-57-200906395-ethoxy)-benzylguanamine (Compound No. 10-116), iV-[5-(3,5-dichloro- Benzyl)-thiazol-2-yl]-4-ethylamino-3-(2-hydroxy-ethoxy)-benzamide (Compound No. 10-143), or, [5-(3,5- Dichlorobenzyl)-thiazol-2-yl]-4-dimethylamino-3-(2-hydroxy-ethoxy)-benzamide (Compound No. 10-145) 〇 More suitable compound is: yV -[5-(3-chloro-benzyl)-thiazol-2-yl]-4-ethylamino-3-(2-hydroxy-ethoxy)-benzamide (Compound No. 10-53), 7V -[5-(3-chloro-benzyl)-thiazol-2-yl]-4-diethylamino-3-(2-hydroxy-ethoxy)-benzamide (Compound No. 10-56), 4-Ethylamino-3-(2-hydroxy-ethoxy)-7V-[5-(3-trifluoromethyl-benzyl)-shrazol-2-yl]-benzylguanamine (Compound No. 10 -83), 4-diethylamino-3-(2-hydroxy-ethoxy)-indole 5-(3-trifluoromethylbenzyl)-thiazol-2-yl]-benzylguanamine (Compound No. 10 -86), ΑΜ5·(3,5-difluoro-benzyl)-thiazol-2-yl]- 4-ethylamino-3-(2-hydroxy-ethoxy)-benzamide (Compound No. 10-113), 4-diethylamino-AM5-(3,5-difluorobenzyl)-thiazole -2-yl]-3-(2-trans-ethoxy-benzyl)-benzylamine (Compound No. 10-116), or AM5-(3,5-dichloro-benzyl)-thiazol-2-yl ]-4-Ethylamino-3-(2-hydroxy-ethoxy)-tuberamine (Compound No. 1〇-143). (Effect of the Invention) The indoleamine derivative of the present invention or a pharmacologically acceptable salt thereof has an excellent SCD inhibitory action, and is used as a disease in a warm-blooded animal (suitable mammals, including humans) as -58-200906395: obesity, Obesity, hyperlipidemia, hypertriglyceridemia, abnormal lipid metabolism, insulin resistance syndrome, abnormal glucose tolerance, diabetes, diabetes mellitus, cataract, gestational diabetes, polycystic ovary syndrome, arteriosclerosis, A disease selected from the group consisting of atherosclerosis, diabetic atherosclerosis, fatty liver, and nonalcoholic steatohepatitis, or the following diseases caused by obesity: hyperlipidemia, hypertriglyceridemia , abnormal lipid metabolism, insulin resistance syndrome, abnormal glucose tolerance, diabetes, diabetes mellitus, cataract, gestational diabetes, r cytopathic ovarian syndrome, atherosclerosis, atherosclerosis, diabetic atherosclerosis, Hypertension, cerebrovascular disease, coronary artery disease, fatty liver, respiratory abnormalities, low back pain, deformation It is useful for the prevention and/or treatment of diseases selected from the group consisting of knee joint disease, gout, and cholelithiasis. Further, the guanamine derivative of the formula (I) or the pharmacologically acceptable salt thereof provided by the present invention has an excellent SCD inhibitory action, and is useful as a medicine for the prevention and/or treatment of the above-mentioned diseases in a warm-blooded animal (suitable mammals, including humans). The active ingredients are useful. Suitable diseases are diseases selected from the group consisting of obesity, obesity, hyperlipidemia, hypertriglyceridemia, abnormal lipid metabolism, diabetes, atherosclerosis, fatty liver, and nonalcoholic steatohepatitis, or The following diseases caused by obesity: diseases selected from the group consisting of hyperlipidemia, hypertriglyceridemia, abnormal lipid metabolism, diabetes, arteriosclerosis, hypertension, cerebrovascular disease, and coronary artery disease, Especially suitable for obesity, obesity, hyperlipidemia, hypertriglyceridemia, diabetes, fatty liver or non-alcoholic steatohepatitis. It should be used as a medicine for the treatment of the above diseases. [Embodiment] -59-200906395 (Best Mode for Carrying Out the Invention) The compound of the formula (I) of the present invention can be produced by the following method A to p. The solvent used in the reaction of each of the following A to P methods is not limited as long as it does not inhibit the reaction, and the starting material is not limited, and may be selected, for example, from the following solvent group. The solvent group is a hydrocarbon such as pentane, hexane, octane, petroleum ether, petroleum, cyclohexane or the like; formamide, N,N-dimethylformamide, N,N-dimethylacetamide , N-methyl-2-pyrrolidone, N-methyl-2-pyrrolidinone, decylamine such as trimethylamine hexamethylphosphate; diethyl ether, diisopropyl ether, tetrahydrofuran, monodecane Ethers such as monomethoxyethane and diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, 2-methyl-1-propanol Alcohols such as butanol, isoamyl alcohol, __ethylene glycol, glycerol, octanol, cyclohexanol, methyl glycol ethyl ether; hydrazines such as dimethyl sulfoxide; hydrazines such as cyclobutyl hydrazine; acetonitrile, Nitriles such as propionitrile, butyronitrile, isobutyronitrile; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate; acetone, methyl ethyl ketone, 4-methyl-2-pentyl Ketones such as ketone, methylpentanone, isophorone, cyclohexanone; nitro compounds such as nitroethane and nitrobenzene; dichloromethane, ~ 1,2-dichloroethane, chlorobenzene, Halogenated hydrocarbons such as dichlorobenzene and chloroform, such as carbon tetrachloride; benzene, toluene, xylene, etc. Aromatic hydrocarbons; carboxylic acids such as acetic acid, formic acid, propionic acid, butyric acid, trifluoroacetic acid; N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexyl Amine, N-methylpiperidine, pyridine, 2,6-lutidine, 4-pyrrolidinopyridine, picolin, 4-(1^,1^dimethylamino)pyridine, 2,6-di (Third butyl)-4-methylpyridine 'quinoline, hydrazine, hydrazine-dimethylaniline, hydrazine, hydrazine-diethylaniline, 1,5-dioxabicyclo[4.3.0] 壬-5- Alkene (06 > 〇, 1,4-dioxinbicyclo[2.2.2] octane (〇8:6(:〇)'1,8-二吖双-60- 200906395 ring [5.4.0]-7- An amine-based solvent such as undecene (DBU) or piperidine. Alkali metal sodium hydroxide such as sodium, potassium carbonate, lithium carbonate or cesium carbonate is used in the reaction of each of the following methods A to P. An alkali metal hydride such as potassium hydrogencarbonate or lithium hydrogencarbonate; an alkali metal hydride such as sodium hydride or potassium hydride; or an alkali metal fluoride such as potassium hydroxide, cesium hydroxide or lithium hydroxide; Alkali; sodium tributoxide, potassium methoxide, potassium ethoxide, tert-butanol metal alkoxide; trimethyl decane Alkali metal trialkyl decane oxides such as sodium, trimethylsulfonium oxychloride; thiol alkali metals such as sodium alkoxide; N-methylmorpholine, triethylbutylamine, diisopropylethylamine, bicyclo Hexylamine, N-methyl dimethylpyrrolidine, 4-pyrrolidinopyridine, picolin, pyridine, 2,6-di(t-butyl)-4-methylpyridine quinidine, N, N-diethylaniline, iota, 5-dioxabicyclo[4.3.0] 壬·dioxabicyclo[2.2.2]octane (DABCO) '1,8-dioxadiene (DBU) and other organic bases An organic metal base such as butyl lithium or diisopropyl sulfonyl lithium amide; or a guanamine which is priced as a ruthenium (triphenylphosphine) palladium or palladium in the reaction of each of the following A to P processes. Activated carbon, palladium acetate (11), palladium rhodium, palladium (II) bromide, palladium chloride (11), iodide, palladium (II) nitrate, palladium oxide (ruthenium), palladium sulfate (11), (II , dichlorobis(benzonitrile)palladium(11), dichloro(1,5-cyclohexane:water; and these mixed bases are, for example, carbon carbonates; hydrogencarbonates; lithium hydride, sodium hydroxide Substance; sodium alkoxide, sodium alkoxide, sodium ethoxide, potassium, lithium methoxide, etc. Sodium thiolate, ethionamide, tripropylamine, tri-I-pyridine, pyridine, 2,6-4-(N,N-dimethylamino:, N,N-dimethylaniline 5-ene (DBN), M- : Ring [5.4.0]-7-~]--- Lithium amine, bis(trimethyl) and other amino acids. Palladium catalyst for use as an example, palladium (II) trifluoroacetate (Π), palladium cyanide (π) dichlorobis(acetonitrile) palladium diene) palladium (II), B-61 - 200906395 Palladium (II), palladium (II) sulfide, dichloro [U'-bis(diphenylphosphino)ferrocene] palladium (II), ginseng (dibenzylideneacetone) dipalladium (ruthenium), tetrafluoroboric acid A divalent palladium catalyst such as ruthenium (acetonitrile) palladium (II) or an aryl palladium chloride dimer or an iridium palladium catalyst. The condensing agent used in the reaction of each of the following A to p processes is, for example, 0-(7-fluorenylbenzotriazol-1-yl)tetramethyluronium hexafluorophosphate (HATU), 1-propene. Sulfonic acid cyclic anhydride (T3P), dicyclohexylcarbodiimide (DCCD), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), chloroformic acid Butyl ester (IBCF), 1,1'-carbonyl bis-1H-imidazole (CDI), diethyl cyanophosphate (DEPC), diphenylphosphonium azide (DPPA), N-hydroxybutanediimide, 1 - Hydroxybenzotriazine, N-hydroxy-5-nordecene-2,3-dicarboxylimenide or dipyridyldisulfide. In the reaction of each of the following A to P processes, the reaction temperature varies depending on the solvent, starting materials, reagents, and the like, and the reaction time varies depending on the solvent, starting materials, reagents, reaction temperature, and the like. In the reaction of each of the following A to P processes, after completion of the reaction, the compound of each compound can be recovered by the usual reaction mixture. For example, the reaction mixture is appropriately neutralized, and if it is insoluble, it is filtered, and an organic solvent such as water or ethyl acetate is added, and the organic layer containing the objective compound is separated, washed with water, and then anhydrous magnesium sulfate and anhydrous. Sodium sulfate, anhydrous sodium hydrogencarbonate or the like is dried, filtered, and the solvent is distilled off. The desired compound obtained is suitably combined, if necessary, by a usual method such as recrystallization or reprecipitation, and is usually subjected to separation and purification by an organic compound, and subjected to column chromatography to be separated and purified by a suitable dissolving agent. The compound which is insoluble in the solvent can be obtained by washing and refining the crude product of the obtained solid. Furthermore, the compound of each project may not be purified by -62-200906395 in the next reaction. The A method is a method for producing a compound of the formula (I_A).

(XIV)

In the present invention, R1, R2, R3, R4, T and Q have the same meanings as defined above, and Rla, R2a, R3a and R4a are an amine group, a hydroxyl group and/or a substituent which is a substituent at the groups of R1, R2, R3 and R4. The carboxyl group is a group which is protected by an amine group, a hydroxyl group and/or a carboxyl group, and is a group similar to the group defined by the radicals of Ri, R2, R3 and R4. Project A 1 This project is a project for the manufacture of a compound of formula (I-A). This is a compound of the formula (XIII) which is easily prepared by a known compound or a known compound as a starting material in an inert solvent in the presence of a condensing agent and a base, and a known compound or a known compound. The reaction of the compound of the formula (XIV) which can be easily obtained by a known method is carried out by removing the protective groups of the amine group, the hydroxyl group and/or the carboxyl group in Rla, R2a, R3a and R4a as desired. The inert solvent used in this project is preferably an amine, especially N,N-dimethylacetamide. The condensing agent used in this project is preferably _ (7-indole benzotriazole-diyl)-hydrazine, hydrazine, hydrazine, and N'-tetramethyluronium hexafluorophosphate (HATU). -63 - 200906395 The alkali used in this project is preferably an organic base, especially triethylamine. The reaction temperature in this project is usually -40 ° C to 2 ° ° C, preferably (^ to i〇〇〇c 〇 the reaction time in this project is usually 0.5 hours to 96 hours, preferably 1 hour to 24 hours. B method A method for producing a compound of the formula (I-B).

In the present invention, R1, R2, R3, R4, Rla, R2a, R3a, R", τ and Q have the same meaning as described above. The first project is a project for producing a compound of the formula (1). In the presence of a condensing agent and a base in an inert solvent, a known compound or a compound of the formula (XV) which can be easily obtained by a known method can be obtained by a known method, or a known compound or a known compound can be used as a starting material. The reaction of the compound of the formula (XVI) which is easily prepared by the method is carried out, and after the same procedure as in the above-mentioned A1 process, the protective groups of the amine group, the hydroxyl group and/or the carboxyl group in the R, R2a, R3a and R4a are removed as desired. Implementation. The C method is a method for producing a compound of the formula (I-B). -64- 200906395 C Law

(XVI)

In the present invention, R1, R2, R3, R4, Rla, R2a, r3», R", T and Q have the same meaning as the above - Z is a hydrogen atom 'chlorine atom' bromine atom or a spider atom. The production process of the compound of the formula (XVII). When Z is a chlorine atom, a bromine atom or an iodine atom, the present invention is a method in which a known compound or a known compound can be used as a starting material in an inert solvent, which is easily produced by a known method ( XIII) A compound, in the presence of a copper salt, reacted with sodium nitrite or tributyl nitrite, as described, for example, in Org Chem. 1996, 61, 4623. or BMCL 2001, 11, 641-646, etc. When Z is a hydrogen atom, the present invention is a compound of the formula (XIII) which can be easily obtained by a known compound or a known compound as a starting material in an inert solvent in the presence of a phosphonic acid. The reaction of sodium nitrite or tert-butyl nitrite may be carried out by the method described in, for example, Med. Chem. 1977, 20, 572, etc., and the inert solvent used in the present process is preferably nitrile, especially acetonitrile. , -65- 200906395 can be mixed with water The solvent (mixing ratio is 1:100~100:1, preferably 10:1~1:10). The copper salt used in the present project is, for example, zero-valent copper or a complex thereof; copper chloride (I), a monovalent copper salt such as copper (I) bromide, copper (I) iodide or copper (I) triflate; or copper (II) chloride, copper (II) bromide or copper (II) acetate Copper salt of copper (II) sulfate or copper iodide (bismuth), preferably a copper salt of one price or a copper salt of two, preferably copper (II) bromide. The reaction temperature in this project is usually - 10 ° C to 60 ° C, preferably 0 ° C to 30 T: The reaction time in this project is usually 0.1 hour to 24 hours, preferably 〇 5 hours to 2 hours. The C2 project is the formula (I-B) The manufacturing process of the compound is carried out by (1) to (1). (i) This work is carried out by reacting a compound of the formula (XVII) with a Schiff base in an inert solvent. The inert solvent used in this project is preferably ether, especially tetrahydrofuran. The organometallic bases used in this work are, for example, butyl lithium, = lithium amide, lithium bis(trimethyldecyl) guanamine, and butyl lithium. The reaction temperature in this project is usually -l 〇〇 ° C to 30 ° C '--78 ° CM 2 (rc 〇 反应 反应 〇 〇 〇 〇 〇 〇 〇 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 (ii) The process is carried out by reacting a compound of formula (XVI) with a wheel and phosgene in an inert solvent. The inert solvent used in this project is a halogenated hydrocarbon suitable for the class 'Using = Chloroformine-66 - 200906395 The alkali used in the project is a suitable organic base, especially triethylamine. The phosgene used in this project is, for example, phosgene, diphosgene, triphosgene, and suitable phosgene. The reaction temperature in this project is usually -20. °C to 60 ° C '0 ° C to 30 ° C. The reaction time in this project is usually 0.1 hours to 24 hours, preferably 0.5 hours to 2 hours. (iii) This project is in an inert solvent, the above (1) After reacting the obtained compound with the compound obtained in the above (ii), the protective group of the amine group, the hydroxyl group and/or the carboxyl group in Rla, R2a, R3a and R4a is removed as desired. The inert solvent used in the present process is preferably an ether. Especially suitable for tetrahydrofuran. The reaction temperature in this project is usually -1〇〇 °C to 100 °C, preferably -78t to 3 0 .. This project reaction time is usually from 0.1 to 24 hours, should the method for producing 0.5 to 2 hours. Method D is of formula (I-C) of the compound.

-67- 200906395 In the present invention, R1, R2, R4, Rla, R2a, Ι^, τ and Q have the same meanings as described above. D1 Project This project is a manufacturing process for a compound of formula (XIX). The present invention is a compound of the formula (XVIII) which can be easily obtained by a known compound or a known compound as a starting material in the presence of a condensing agent and a known compound, and a known compound or a known compound can be used as a starting material. The reaction of the compound of the formula (XIV) which is easily produced by a known method is carried out in the same manner as in the above-mentioned A1 process of the A method, and the protective group of the amine group, the hydroxyl group and/or the carboxyl group in R2a and R4a is removed as desired. . D2 Project This project is a manufacturing process for a compound of formula (I-C). This work is carried out by reacting a compound of the formula (XIX) with a reducing agent in an inert solvent. The inert solvent used in this project is preferably an ether or an alcohol, particularly preferably tetrahydrofuran or methanol, more preferably a mixed solvent of tetrahydrofuran and methanol. If necessary, it can be a mixed solvent with water (mixing ratio 1:100 to 100:1). The reducing agent used in the present project may be, for example, an alkali metal borohydride such as sodium borohydride, lithium borohydride or sodium cyanoborohydride; an aluminum hydride compound such as lithium dihydrogen hydride aluminum hydride or lithium aluminum hydride; Hydrogenation reagent for hydrogenated organoaluminum reducing agent such as sodium dihydrogen hydride, diisobutylaluminum hydride or sodium methoxyethoxyaluminum hydride; or alkali metal such as sodium or lithium, preferably alkali metal borohydride Sodium borohydride. The reaction temperature in this project is usually from 0 ° C to 80 ° C, preferably from 10 ° C to 30 ° C. -68- 200906395 The reaction time in this project is usually 0.1 hour to 24 hours, preferably 0.5 hours to 2 hours. The E method is the production of a compound of the formula (XXIV) wherein T is a nitrogen atom and Q is a group of the formula: C(R6)- among the compounds of the formula (AIII) used in the above-mentioned method A and the compound (XIII) used in the above-mentioned method C1. method.

E 2 Project R3a R6

R4a v , , 〇 (XXII ) E method E 1 project R4a—I —* (XX) R6 (XXI)

In the present invention, 'R3a, R4a and R6 have the same meanings as defined above, and X is a chlorine atom, a bromine atom or an iodine atom. E E Project This project is a manufacturing process for a compound of formula (XXII). The present invention is a compound of the formula (XX) which is easily prepared by a known compound or a known compound as a starting material in an inert solvent in the presence of a base, a phase shifting catalyst and a palladium catalyst, and a known compound or It is known that the compound is a starting material which can be easily produced by a known method (} (1) The reaction of the compound reaction can be carried out, for example, by the method described in J. Org. Chem. 1996, 61, 2604-2605, etc. The solvent used in the project is Yishenamine, especially N,N-dimethylformamide. If necessary, cocoa is a mixed solvent with water. -69- 200906395 The base used in this project is alkali. Metal hydrogencarbonate, especially sodium bicarbonate. The phase-shifting catalyst used in this project is, for example, tetrabutylammonium chloride (TBAC1), tetrabutylammonium bromide, or tetrabutylammonium iodide, preferably TBAC1. The palladium catalyst used in this project is palladium acetate (Π).

The reaction temperature in this project is usually from 0 ° C to 160 ° C, preferably from 20 ° C to 60 ° C. The reaction time in this project is usually from 0.1 to 96 hours, preferably from 0.5 to 12 hours. E2 Project This project is a manufacturing process for a compound of formula (XXIII). This project is a reaction of a compound of the formula (XXII) with a halogenating agent in an inert solvent in the presence or absence of a base (in the presence of a base), for example, J. Am. Chem. Soc. 2004, 1 26 , 4790-479 1 and other methods are described. The inert solvent used in this project is preferably a halogenated hydrocarbon, especially dichloromethane. The base used in this project is an amino acid, especially lysine. The halogenating agent used in this project is a chlorinating agent, a brominating agent or an iodinating agent such as hydrochloric acid, chlorine, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, grass chloroform, sulfinium chloride, toluene. Sulfonyl chloride, sulfonium chloride, N-chlorobutanediimide, trimethyldecyl chloride, bromic acid, bromine, phosphorus tribromide, phosphorus pentabromide, phosphorus oxybromide, oxalate bromide, sulfin醯Bromo, toluene sulfonium chloride, sulfonium chloride, N-bromosuccinimide, or trimethyldecyl bromo, preferably N-chlorobutanediamine, trimethyldecyl chloride, N-bromobutyl Diimine or trimethyldecyl bromide.

The reaction temperature in this project is usually -20 ° C to 140 ° C, preferably ° ° C to 60 ° C -70 - 200906395 The reaction time in this project is usually 0.1 hour to 96 hours, preferably 0.5 hours to 6 hours. E3 Project This project is a manufacturing process for a compound of formula (XXIV). This work is a process in which a compound of the formula (XXIII) is reacted with thiourea in an inert solvent, and can be carried out, for example, by the method described in Russian J. Org. Chem. 2004, 40, 3 8 3-3 89 or the like. The inert solvent used in this project is preferably an alcohol, especially ethanol.

The reaction temperature in this project is usually 0 ° C to 160 ° C, preferably 2 (TC to 100 ° C 〇 The reaction time in the project is usually 0.1 hour to 96 hours, preferably 0.5 hours to 6 hours. F method is the aforementioned A Among the compounds of formula (XIII) used in the method of formula A1 and the above-mentioned method C1, the method for producing a compound of the formula (XXVIII) wherein T is a group of formula = C(R5)-, and Q is a nitrogen atom, F method R3a

In the present invention, R3a, R4a and R5 have the same meanings as described above. F1 Project This project is a manufacturing process for a compound of formula (XXVII). The present invention is a compound of the formula (XXV) which is easily prepared by a known method in the presence of a condensing agent and a base in an inert solvent, or a known compound or a known compound, and a known compound or The compound of the formula (XXVI) which can be easily produced by a known method can be known as a starting material. The inert solvent used in this project is preferably an amine, especially N,N-dimethylacetamide. The condensing agent used in this project is preferably 1-propanesulfonic acid cyclic anhydride (T3p). The alkali used in this project is preferably an organic base, especially triethylamine.

The reaction temperature in this project is usually - 20 ° C to 160 ° C, preferably 0 ° C to 60 ° C. The reaction time in this project is usually 0 · 5 hours to 96 hours, preferably 1 hour to 24 hours. F2 Project This project is a manufacturing process for a compound of formula (XXVIII). This work is carried out by reacting a compound of the formula (XXVII) with an acid in an inert solvent. The inert solvent used in this project is preferably aromatic hydrocarbons, especially toluene. The acid used in this project is a hydrogen halide such as hydrogen chloride or hydrogen bromide; a mineral acid such as sulfuric acid, methyl sulfate, hydrobromic acid or hydrochloric acid; methanesulfonic acid, p-toluenesulfonic acid, sulfonic acid or trifluoromethyl. An organic sulfonic acid such as sulfonic acid; a carboxylic acid such as acetic acid, formic acid or trifluoroacetic acid; a Lewis acid such as aluminum chloride, zinc chloride, tin tetrachloride, titanium trichloride, boron trifluoride or boron tribromide; Or acidic ion exchange resin, suitable for mineral acids 'especially sulfuric acid. The reaction temperature in this project is usually 〇 °C to 200 °C, preferably 2 (TC to i2 (rc -72- 200906395) The reaction time in this project is usually 〇. 1 hour to 96 hours, Yihao. 5 hours to 1 2 hours. The G method is a method for producing a compound of the formula (X) in which the 'T is a nitrogen atom' and the Q is a nitrogen atom among the compounds of the formula (AIII) used in the above-mentioned A method and the above-mentioned c-method C1. R3a

G2 project

In the present invention, R3a and R4a have the same meanings as described above. G1 Project This project is a manufacturing process for a compound of formula (XXIX). The present invention is a compound of the formula (XXV) which can be easily obtained by a known compound or a known compound as a starting material in an inert solvent in the presence of a condensing agent and a base, and reacts with sulfur sulfonium. The F1 project of the F method is also implemented. G2 Project This project is a manufacturing process for a compound of formula (XXX). This project is to react a compound of the formula (XXIX) with an acid in an inert solvent, and the same can be carried out in the same manner as the F2 project of the above F method. The method is a method for producing a compound of the formula (XXXVI) wherein R3a is a hydrogen atom among the compounds of the formula (IIII) used in the above-mentioned method A1 and the above-mentioned method C1. -73 - 200906395 Η法

(XXXI) HI Project

(XXXill)

H 3 Project (XXXIV) νη2 R4a—CHO (XXXII)

Dijon 4 Project (XXXV)

(XXXVI) In the present invention, R4a, T, Q and ζ are in the same meaning as described above.第 第 1 Project This project is a manufacturing process for a compound of formula (XXXIII). The present invention is a compound of the formula (XXXI) which can be easily obtained by a known compound or a known compound as a starting material in an inert solvent in the presence of an organometallic reagent, and a known compound or a known compound can be used as a starting material. The process of the reaction of the compound of the formula (XXXII) which can be easily produced by a known method can be carried out, for example, by the method described in LM Ed. Chem. 2000, 43, 72 1 - 735, etc., and the inert solvent used in the present process is preferably used. Suitable for tetrahydrofuran. The organometallic reagents used in this project are, for example, butyl lithium, sodium hexamethyldisodium hydride, potassium hexamethyldisodium hydride, lithium hexamethyldiazepine, diisopropyl hydrazine. Lithium amine, lithium bis(trimethyldecyl) decylamine, ethyl magnesium bromide or isopropyl magnesium bromide, preferably butyl lithium. The reaction temperature in this project is usually -100 ° C to 40 ° C, preferably -78 ° C to 20. (: The reaction time in this project is usually 0.1 hours to 24 hours, preferably 0.5 hours to 2 hours. -74- 200906395 The H2 project This project is a manufacturing process for the compound of formula (XXXIV). This project is in an inert solvent. The reaction of reacting a compound of the formula (XXXIII) with a quinone alkylating agent and a halogenating agent can be carried out, for example, as described in Tetrahedron 1995, 5 1, 1 1 043- 1 1062, etc., and the inert solvent used in the present process is preferably a nitrile. Preferably, the hydrazine alkylating agent used in the present invention may be, for example, trimethylsulfonyl chloride, triethylsulfonyl chloride, or tert-butyldimethylsilyl chloride, preferably trimethylsulfonyl chloride. The halogenating agent used in the project is a chlorinating agent, a brominating agent or an iodinating agent, such as hydrochloric acid, chlorine, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, grass chloroform, sulfinium chloride, toluene Antimony chloride, sulfonium chloride, N-chlorobutanediamine, trimethylsulfonium chloride, bromic acid, bromine, phosphorus tribromide, phosphorus pentabromide, phosphorus oxybromide, grassy desert, sulfin Bromine, toluene, sulfonium chloride, sulfonium chloride, N-bromobutanediamine, trimethyldecyl bromide, sodium bromide, Sodium iodide, sodium iodide. The reaction temperature in this project is usually 0 °C to 160 °C, preferably 60 °C to 90T: The reaction time in the project is usually 〇·1 hour to 96 hours, Yihao 5 hours to 12 hours. Section 3 Engineering This project is a manufacturing process for a compound of formula (XXXV). This project is a compound of @ (XXXIV) with a nitro group in an inert solvent or in the absence of a solvent or acid. For the chemical reaction, the inert solvent used in the present process may be, for example, a method described in Chem. Heterocycle compound (Engl. Translation) 1981, 17, 67 3 -67 5 -75- 200906395, etc., preferably acetic acid. If necessary, it can be a mixed solvent with water (mixing ratio is 1:1 0 0 ~ 1 0 0 : 1, preferably 10:1-1:10). The acid used in this project is, for example, sulfuric acid, methyl sulfate , hydrobromic acid, hydrochloric acid, methanesulfonic acid, p-toluenesulfonic acid, sulfonic acid, trifluoromethanesulfonic acid, acetic acid, formic acid, trifluoroacetic acid or acetic anhydride, preferably acetic anhydride. Nitrifying agent used in this project For example, nitric acid, copper (II) nitrate or potassium nitrate, copper (II) nitrate is preferred. The reaction temperature in this project is usually 0 ° C to loot, preferably 20 ° C to 60 ° c 反应 The reaction time in the project is usually 0.1 hour to 96 hours, preferably 0.5 hours to 24 hours. The H4 project This project is a manufacturing process of the compound of formula (XXXVI). This project is carried out in an inert solvent or without solvent, and in the presence of acid, the compound of formula (XXXV) is reacted with zinc. The inert solvent used in this project is preferably alcohol, especially isopropyl alcohol. It is a mixed solvent with water (mixing ratio is 1:100~丨00:1, preferably 10:1~1:10). The acid used in the project is, for example, sulfuric acid, methyl sulfate, hydrobromic acid, hydrochloric acid, methanesulfonic acid, p-toluenesulfonic acid, sulfonic acid, trifluoromethanesulfonic acid, acetic acid, formic acid, trifluoroacetic acid or acetic anhydride. Suitable for hydrochloric acid.

The reaction temperature in this project is usually 〇 ° C to 100 ° C, preferably 20 ° C to 60 ° C -76 - 200906395 The reaction time in this project is usually from 12 hours to 12 hours. 0.1 hour to 96 hours, preferably 0.5 small I method is the formula (χν) compound used in the B method of the B method, τ is the formula of the formula = C(R5)-, and Q is the formula of the nitrogen atom (IL) Compound manufacturing method

In the present invention, R3a, R4a, R and X have the same meaning as described above, and R9 is

Ci-C6 alkyl (preferably methyl or ethyl). II Project This project is a manufacturing process for a compound of formula (XXXIX). In the present invention, a known compound or a known compound or a known compound can be obtained as a starting material, and a compound of the formula (χχχνπ) can be easily obtained by a known compound or a known compound can be obtained by a known method. The reaction of the compound of formula (XXXVIII), such as

Eur.JT.Med.Chem. 1 993, 28, 3 87, etc. The inert solvent used in this project is preferably aromatic hydrocarbons, especially toluene. -77- 200906395

The reaction temperature in this project is usually from 0 ° C to 200 ° C, preferably from 20 ° C to 120 ° C. The reaction time in this project is usually from 0.1 to 96 hours, preferably from 0.5 to 24 hours. 12th Project This project is a manufacturing process for a compound of the formula (IL). This work is carried out by reacting a compound of the formula (X X XIX) with a base in an inert solvent. The inert solvent used in this project should be ether, especially dioxane. If necessary, it can be mixed with a solvent (mixing ratio: 1:100-100:1, preferably 1:10 to 10:1). The alkali metal hydroxide used in this project is especially suitable for sodium hydroxide 0

The reaction temperature in this project is usually from 0 ° C to 160 ° C, preferably from 20 ° C to 100 ° C. The reaction time in this project is usually from 0.1 to 96 hours, preferably from 0.5 to 24 hours. The J method is a method for producing the compound of the formula (XVIII) used in the above D method of the D method.

J 2 Project - J 1 Project R4a-CHO (XXXII)

-78- 200906395 In the present invention, R4a, T, Q and Z have the same meanings as described above. Dijon Engineering This project is a manufacturing process for a compound of the formula (ILII). The present invention is a compound of the formula (ILI) which can be easily obtained by a known compound or a known compound as a starting material in an inert solvent in the presence of an organometallic reagent, and a known compound or a known compound can be used as a starting material. The reaction of the compound of the formula (XXXII) which is easily produced by a known method can be carried out in the same manner as the first item of the above-mentioned method. J2 Project This project is a manufacturing process for a compound of the formula (ILIII). This work is carried out by reacting a compound of the formula (ILII) with an oxidizing agent in an inert solvent. The inert solvent used in this project should be halogenated hydrocarbons, especially the dichlorocarbazone. The oxidizing agent used in this project may be, for example, Jones reagent, Collins test; drug, PDC, PCC, cerium oxide, Dess-Martin reagent, TPAP reagent, and Dess-Martin reagent.

The reaction temperature in this project is usually from 0 ° C to 100 ° C, preferably from 20 ° C to 60 ° C. The reaction time in this project is usually from 0.1 to 96 hours, preferably from 5 hours to 6 hours. No. 3 Engineering This project is a manufacturing process for a compound of formula (XVIII). This work is carried out by reacting a compound of the formula (ILIII) with an acid in an inert solvent. -79- 200906395 The inert solvent used in this project is a halogenated hydrocarbon, especially dichloromethane. If necessary, it can be mixed with a solvent (mixing ratio of 1:1 to 00:1, preferably 1:10 to 10:1). The acid used in this project is hydrogen halide such as hydrogen chloride or hydrogen bromide; mineral acid such as sulfuric acid, hydrobromic acid or hydrochloric acid; organic acid such as methanesulfonic acid, p-toluenesulfonic acid, sulfonic acid or trifluoromethanesulfonic acid. Sulfonic acid; carboxylic acid such as acetic acid, formic acid or trifluoroacetic acid; Lewis acid such as zinc chloride, tin tetrachloride, boron trifluoride or boron tribromide; or acidic ion exchange resin, preferably carboxylic acid, especially suitable for three Fluoroacetic acid.

The reaction temperature in this project is usually 〇 ° C to 100 ° C, preferably 2 (TC to 40 ° C 〇 The reaction time in this project is usually 0.1 hour to 96 hours, preferably 0.5 hours to 6 hours. K method is the aforementioned A Method for producing a compound of formula (XIII) used in the first A1 project and the C method in the above C method.

Boc (XV) (ILIV) (XIII) Project K2

R3 gas R4a/ In the present invention, 'R3a, R4a, Τ and q have the same meanings as described above. K 1 Project This project is a manufacturing process for a compound of the formula (ILIV). The present invention is a compound of the formula (χν) -80-200906395 which is easily prepared by a known compound or a known compound as a starting material in the presence of a base in the second butanol, and is reacted with an azide agent. ° The base used in this project is a suitable organic base type, especially triethylamine. The azide agent used in this project is, for example, diphenylphosphonium azide (DPPA) or sodium azide, preferably DPPA.

The reaction temperature in this project is usually from 10 ° C to 100 ° c '2 ° ° C to 80 ° C 〇 The reaction time in this project is usually from 〇 5 hours to 144 hours' is preferably from 2 hours to 24 hours. Section 2 Project This project is a manufacturing process for a compound of formula (XIII). This work is carried out in the same manner as in the above-mentioned I method, the J3 project, in which an 'ILIV compound is reacted with an acid' in an inert solvent. The L method is a method for producing the compound of the formula (XIV) used in the above-mentioned Α method Α 1 project and the aforementioned D method D1 project. L method

Project L 1 This project is a manufacturing process for a compound of formula (XIV). This project is carried out in an inert solvent, and the reaction of the compound of the formula (ILV) with a base can be carried out in the same manner as the twelfth project of the above I method. The method is a method for producing the compound of the formula -81 - 200906395 (XVI) used in the above B method B1 project and the aforementioned C method C2 project. Μ法 »1a

R2a nr 02N^^^R2a (ILVI) , R1a No. 1 Engineering In the present invention, Rla and R2a have the same meaning as described above. No. 1 Engineering This project is a manufacturing process of a compound of the formula (XVI). This project is carried out by reducing the compound of the formula (ILVI) in a hydrogen atmosphere in the presence of a palladium catalyst in an inert solvent. The inert solvent used in this project is a suitable alcohol, especially ethanol. If necessary, it can be mixed with a solvent (mixing ratio: 1:100~100:1, preferably 10:1~1:10). The palladium catalyst used in this project is preferably palladium-activated carbon.

The reaction temperature in this project is usually up to 12 (TC, preferably 20 ° C to 90 ° C. The reaction time in this project is usually 0.5 hours to 96 hours, preferably 1 hour to 12 hours. The N method is the A1 project of the aforementioned A method. And a method for producing a compound of the formula (XIIX) wherein Rla is a group of the formula -N(CH2RI())R13 and R2a is a group of the formula 〇R8b, and a compound of the formula (XIV) used in the D method of the D method. - 200906395

R12 J, R10

N 5th Engineering R12-Y (LVI)

In the present invention, R9 has the same meaning as defined above, R115 and R11 are a hydrogen atom or a Ch C5 alkyl group, R12 is a Ci-Cs alkyl group, R13 is a hydrogen atom, a group of the formula -CH2RM, a group of the formula -CH^R11 or R12 "(Ci-Ce alkoxy MCi-C% alkyl or bis-(Ct-Ce alkyl))) Amino-(Ci-Ci alkyl, Y is a halogen atom, a Ci-Ce alkane sulfonate group or a Cs-C!. aryl sulfonate group (preferably a halogen atom, particularly preferably a chlorine atom, a bromine atom or a ruthenium atom, More preferably a bromine atom or an iodine atom.) Item N 1 Engineering This is a manufacturing process for a compound of the formula (ILIX). -83 - 200906395 This work is a known compound or a known compound in the presence of a base in an inert solvent. The compound of the formula (ILVII) which is easily prepared by a known method, which is easily prepared by a known method, or a compound of the formula (ILVIII) which can be easily produced by a known compound or a known compound can be used as a starting material to carry out the inertness of the present invention. The solvent is preferably an amine, especially N,N-dimethylacetamide. The alkali used in the project is alkali metal carbonate, especially potassium carbonate.

The reaction temperature in this project is usually from 0 ° C to 200. (:, 6 (TC to 80 °C) The reaction time in this project is usually 0 · 1 hour to 72 hours, preferably 2 hours to 24 hours. The N 2 project is the manufacturing process of the compound of formula (L) This project is carried out in an inert solvent in the presence of a palladium catalyst, and the compound of the formula (ILIX) is reduced under a hydrogen atmosphere. The inert solvent used in this project is preferably an ester, especially ethyl acetate. The palladium catalyst used in the process is preferably palladium-activated carbon. The reaction temperature in the project is usually 0 ° c to 100 ° C '20 ° C to 60 ° C 〇 The reaction time in the project is usually 0.5 hours to 72 hours ' 2 hours to 24 hours. N3 Project This project is a manufacturing process for a compound of formula (LII) and a compound of formula (LIII) -84- 200906395 This project is in the presence of an acid and a borane-based reducing agent in an inert solvent. The compound of the formula (L) is reacted with a compound of the formula (LI) to carry out the reaction. The inert solvent used in the present project is preferably an ether, particularly tetrahydrofuran. The acid used in the project may be, for example, hydrogen chloride or hydrogen bromide. Hydrogen halides; sulfuric acid, methyl sulfate, hydrobromic acid or hydrochloric acid Mineral acids; organic sulfonic acids such as methanesulfonic acid, p-toluenesulfonic acid, sulfonic acid or trifluoromethanesulfonic acid; carboxylic acids such as acetic acid, formic acid or trifluoroacetic acid; aluminum chloride, zinc chloride, tin tetrachloride, a Lewis acid such as titanium trichloride, boron trifluoride or boron tribromide; or an acidic ion exchange resin, preferably a carboxylic acid, particularly preferably acetic acid. The borane-based reducing agent used in the present project may be, for example, sodium borohydride, Lithium borohydride or sodium cyanoborohydride, preferably sodium cyanoborohydride. The reaction temperature in this project is usually CTC to 60 ° C, preferably 20 ° C to 40 ° C. The reaction time in this project is usually 0.5 hour to 144 Hour, preferably 2 hours to 7 2 hours. N4 Project This project is a manufacturing process of a compound of the formula (LV). This project is in the presence of an acid and a borane-based reducing agent in an inert solvent, and the formula (LII) The compound is reacted with a known compound of the formula (LIV), and can be similarly carried out in the same manner as the above N3 project. The N5 project is a manufacturing process of the compound of the formula (LVII). The work is carried out in an inert solvent in the presence of a base. a compound of the formula (Ln), and a known compound or a known compound The starting material is reacted by a compound of the formula (LVI) which is easily prepared by a known method. -85- 200906395 The inert solvent used in the project is preferably anthraquinone, especially hydrazine, hydrazine-dimethylformamide. The base used in the alkali metal hydrides, especially sodium hydride. The reaction temperature in this project is usually -20 ° C to 160 ° C, preferably 0 ° C to 40 t: the reaction time in this project is usually 0.5 hour to 96 Hour, preferably from 2 hours to 24 hours. N6 Project This project is a manufacturing process for a compound of the formula (LVIX). This project is to react a compound of the formula (LVIII) with a base in an inert solvent. The 12 works are also implemented. The method is the compound of the formula (ILV) when the compound of the formula (LXI) used in the above L method and the compound (LXI) used in the above M1 project (R14 is a group of the formula -C〇2R9, and the group of the formula -R8b is R2»). And R14 is a nitro group, and the formula of the formula _〇R8b is a method for producing a compound of the formula (ILVI). Law

Item 1 R8b-γ (ILVIII) R14 J〇C (LXI) R1a OR8b In the present invention, Rla, R8b and Y have the same meaning as defined above, and R "is a group of formula _c〇2R;> R9 is synonymous with the above.) The first project is a manufacturing process of a compound of the formula (LXI). This project is known in the presence of a base in an inert solvent, and a known compound or a known compound can be used as a starting material. The method can easily produce a compound of the formula -86-200906395 (LX), which is reacted with a known compound or a compound of the formula (IL VIII) which can be easily produced by a known compound as a starting material, and can be, for example, US Patent No. 2686. In the method described in No. 98, etc., the inert solvent used in this project is preferably nitrile, especially acetonitrile. The alkali used in this project is alkali metal carbonate, especially potassium carbonate.

The reaction temperature in this project is usually from 〇 ° C to 160 ° C, preferably from 60 ° C to 90 ° C. The reaction time in this project is usually from 0.5 to 96 hours, preferably from 1 hour to 24 hours. The P method is the L1 project of the above L method and the compound of the formula (LXI) used in the above M1 project (wherein R14 is a group of the formula -CChR9, when the hydroxyl group is R2a), the compound of the formula (ILV), and the ring of R14 are a nitro group and a fluorine atom. When it is Rla, it is a manufacturing method of the compound of the formula (ILVI).

In the present invention, R2a and R14 have the same meanings as defined above, and R7b is a fluorene-terpenyl group, a C2-C6 hydroxyalkyl group, a protected C2-C6 hydroxyalkyl group, (Ci-C6 alkoxy MCi-Ce alkyl group, Dialkyl)amino-(Ci-Cs alkyl, 4-morpholinyl 1 substituted C丨-C6 alkyl, (C丨-Ca alkylthio MC^-Cs alkyl), (C|- C6 Institute of sulfinyl fluorenyl-fluorenyl) or (Ci-C% alkanesulfonyl MG-Ce) based on the first P 1 project This project is a manufacturing process of a compound of formula (LXI). -87- 200906395 This is a compound of the formula (LXII) which can be easily obtained by a known compound or a known compound as a starting material in an inert solvent in the presence of a base, and a known compound or a known compound can be used as a starting material. The known method is easily prepared by reacting a compound of the formula (LXIII). The inert solvent used in the project is preferably an alcohol, particularly a compound of the formula (LV). The alkali metal alkoxide used in the project is particularly suitable. Sodium ethoxide.

The reaction temperature in this project is usually 0 ° C to 160 ° C, preferably 2 (TC to 100 ° C 〇 The reaction time in this project is usually 0 · 5 hours to 96 hours, preferably 6 hours to 24 hours. XIII), (XIV), (XV), (χνΐ), (XVII), (XX), (XXI), (XXII), (XXV), (XXVI), (XXXI), (XXXII), (χχχιν) , (XXXVII), (XXXVIII), (ILI), (ILV), (ILVI) '(ILVII), (ILVIII), (LI), (LIV), (LVI), (LX), (LXII) and The raw material compound of LXIII) is a known compound, or a known compound can be used as a starting material by a known method or the like. The compound of the formula (XXXVIII) can be produced, for example, by the method described in Heterocycles, 1991, 32, 693. In the definitions of Rla, R2a, R3a and R4a, "protected amine group", "protectable hydroxyl group" and "protectable carboxyl group" and R7b and ruler" are defined as "protected C2- The protective group of C6 hydroxyalkyl group refers to a protective group which can be cracked by chemical methods such as hydrogenolysis, hydrolysis, electrolysis, photolysis, etc., and is generally used in organic synthetic chemistry. Base (see, for example, TW Greene et al. Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, Inc. (1999)) -88-200906395 The above definitions of Rla, R2a, 1132, and R "may be "protected hydroxy" and the definition of "protected C2-C6 hydroxyalkyl group" in the definition of R7b and R8b are not limited to the protecting group of the hydroxy group used in the field of organic synthetic chemistry, for example, "hydroxyl ester" A related general protecting group", a halogenated alkylcarbonyl group such as a "C2-C-alkylcarbonyl group", a chloroethane group, a dichloroethane group, a trichloroethylene group or a trifluoroethenyl group, Alkoxyalkylcarbonyl such as methoxyethyl, propylene fluorenyl, propynyl fluorenyl, methacryl fluorenyl, butenyl, isobutylene, (E)-2-methyl-2-butene "Alkylcarbonyl group" such as an ethylenically unsaturated alkylcarbonyl group: an arylcarbonyl group such as a benzhydryl group, a naphthylmethyl group or a /3-naphthylmethyl group; a halogenated arylcarbonyl group such as a 2-bromobenzyl group or a 4-chlorobenzyl group; Ci-Cs alkoxylated arylcarbonyl group such as 2,4,6-trimethylbenzylhydrazone, 4-toluylcarbenyl, etc., 匕-匕alkylated arylcarbonyl, 4-methoxybenzylidene, etc., 4 a C2-C7 alkoxycarbonylated arylcarbonyl group such as a nitrobenzyl group or a 2-nitrobenzyl fluorenyl group, a carbonylcarbonyl group such as a 2-(methoxycarbonyl)benzyl fluorenyl group, a 4-phenylbenzyl fluorenyl group, etc. "Aromatic carbonyl group" such as an aryl arylcarbonyl group: the above "C2-C7 compound oxygen ore group", 2,2,2-trichloroethoxycarbonyl group, 2-trimethyldecyl ethoxycarbonyl group, etc. have a halogen or "Alkoxycarbonyl" such as C-C7 alkoxycarbonyl substituted by tris-(CMC6 alkyl)decylalkyl: tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl, 4-methoxy "tetrahydropyranyl or tetrahydrothiopyranyl" such as tetrahydropyran-4-yl, tetrahydrothiopyran-2-yl, 4-methoxytetrahydrothiopyran-4-yl; tetrahydrofuran "tetrahydrofuranyl or tetrahydrothiofuranyl" such as 2-yl, tetrahydrofuran-2-yl, etc.; trimethyldecyl, triethyldecyl, isopropyldimethylmethyl, tert-butyl Tri-(dG alkyl)decyl, etc., dimethyl decyl, methyl diisopropyl decyl, methyl di-tert-butyl fluorenyl, triisopropyl decyl, etc. , diphenylbutyl decyl, bis-89- 200906395 phenylisopropyl fluorenyl, phenyl diisopropyl hydrazine a "decylalkyl group" such as an alkyl group or the like (c-C6 alkyl) diarylalkylene group or a bis(c,-c6 alkyl)arylalkylene group; methoxymethyl group, 1,1-dimethyl-1 -Methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, tert-butoxymethyl, etc. (C1_C6 alkoxy) methyl, 2-methoxyethoxy (ChCe alkoxy MC^-Ce alkoxy)methyl, 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, etc. "Alkyloxymethyl" such as methyl); 1-ethoxyethyl, 1-(isopropoxy).ethyl (Ci-Ce alkoxy)ethyl, 2,2,2-trichloro "Substituted ethyl" such as a halogenated ethyl group; benzyl, α-naphthylmethyl, /3-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenyl a group of 9-fluorenylmethyl and the like having 1 to 3 aryl groups substituted by -(:6 alkyl, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5- Trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl Base, 4-cyanobenzyl, etc. have Ci-C% alkyl, Ci-G alkoxy, nitro'halide "Cyano-alkyl" substituted by an aromatic ring, having an alkyl group substituted with i to 3 aryl groups, such as an "aralkyl group" such as an ethylene oxycarbonyl group or an allyloxycarbonyl group; a benzyloxycarbonyl group; -methoxybenzyloxycarbonyl, 3,4-dimethoxyoxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, etc. with 1 or 2 Ci-G alkoxylates The "arylalkyloxycarbonyl" group may be substituted with a nitro group or a nitro group, and is preferably an alkylcarbonyl group, a decyl group or an aralkyl group. The "protecting group" of the "protectable carboxyl group" in the definition of 'R4a' is not limited to the protecting group of the carboxyl group used in the field of organic synthetic chemistry, for example, "the general protecting group related to the ester of a carboxyl group", The above-mentioned "hospital base"; "C2-C6 alkenyl" such as vinyl, 1-propenyl or 2-propenyl; -90-200906395 ethynyl, 1·propynyl, 2-propynyl, etc. "C2- C6 alkynyl group: the above-mentioned "Ci-halogenated alkyl group"; the above "ChCe hydroxyalkyl group"; an ethyl ethyl group or the like (C2-C7 alkylcarbonyl MC^-Ce alkyl group); the aforementioned "aralkyl group"; The above "nonylalkyl group" is particularly preferably a Ci-Ce alkyl group or an aralkyl group. In the above, the "protecting group" of the "protectable amine group" in the definition of R4a2 is not limited as long as it is a protecting group for the amine group used in the field of organic synthetic chemistry, for example, the above-mentioned "the general protecting group related to the ester of a hydroxyl group" , "alkylcarbonyl J; "arylcarbonyl"; "alkoxycarbonyl"; "decylalkyl"; "aralkyl"; "alkenyloxy": or the same radical or hydrazine as "aralkyloxycarbonyl", Ν-dimethylaminomethylene, benzylidene, 4·methoxybenzylidene, 4-nitrobenzylidene, arylene, 5-chlorolinalylene, diphenylmethylene, 5-Chloro-2-hydroxyphenyl)phenylmethylene and the like "Substituted methylene group forming a Schiff base", preferably an alkylcarbonyl group, an arylcarbonyl group or an alkoxycarbonyl group, particularly preferably an alkoxycarbonyl group. The process requiring protection and deprotection can be carried out according to known methods (for example, the method described in Protective Groups in Organic Synthesis &quot; (Theodora W. Greene, published by Peter GMWuts, 1999, A Wiley-Interscience Publication)) When the guanamine derivative of the above formula (I) or a pharmacologically acceptable salt thereof is used as a medicine, it may be mixed by itself or with a suitable pharmacologically acceptable excipient, diluent or the like, for example, a tablet, a capsule, a granule or a powder. Or a syrup or the like is administered orally or by injection or a sitting agent. These preparations are excipients (for example, sugar derivatives such as lactose, white sugar, glucose, mannose, sorbose; starch derivatives such as corn starch, potato starch, alpha starch, dextrin; cellulose derivatives such as crystalline cellulose; Glue-91 - 200906395; polydextrose; polytrimose and other organic excipients; light phthalic anhydride, synthetic sulphuric acid, sand acid 15, magnesium sulphate and other soda derivatives; calcium sulphate, etc. Phosphate; carbonates such as calcium carbonate; and inorganic excipients such as sulfates such as calcium sulfate; and slip agents (such as stearic acid, calcium stearate, magnesium stearate, etc.; talc; Wax; propolis, cetyl wax and other waxes; boric acid; adipic acid; sodium sulfate and other sulfates; ethylene glycol; fumaric acid; sodium benzoate; DL leucine; fatty acid sodium salt; Dodecyl sulfate such as dodecyl magnesium sulfate; tannic acid such as phthalic anhydride or citric acid hydrate; or the above-mentioned starch derivative), a binding agent (for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyethylene) Pyrrolidone, polyethylene glycol or the above excipient derivatives), Disintegrating agent (for example, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, internal croscarmellose sodium and other cellulose derivatives; @ methyl starch, sodium carboxymethyl starch , chemical modification of cross-linked polyvinylpyrrolidone; starch and cellulose), stabilizer (parabens such as methyl paraben, propyl paraben; chlorobutanol, benzyl Alcohols such as alcohols and phenylethyl alcohol; benzyl chloride ammonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; or sorbic acid)' flavoring deodorant (for example, commonly used sweeteners, sour materials, spices, etc.) Additives such as diluents are produced by known methods. The amount of use varies depending on the symptoms, age, etc. of the patient (warm-blooded animal, especially human). When oral, the lower limit of 0_0015 mg/kg body weight (equivalent to 0.008 mg/kg body weight) is 0.1 times per day for adults, and the upper limit is 70 mg/kg. Body weight (preferably 7mg/kg body weight), when administered intravenously, the daily limit is 〇.〇〇〇15mg/kg body weight (preferably 0.0008mg/kg body weight), the upper limit is 8.5mg/kg body weight (preferably 5mg) /kg body weight) Adults, 1 to 6 times depending on the symptoms. -92-200906395 (Examples) Hereinafter, the present invention will be described in more detail by way of Examples and Test Examples, but the scope of the invention is not limited thereto. The dissolution in the column chromatography of the examples was carried out under the observation of TLC (Thin Layer Chromatography). In the TLC observation, the TLC plate was made of silicone resin 60F254 manufactured by Merck Co., Ltd., and the solvent was used for column chromatography as a solvent for the dissolution solvent, and the UV detector was used for the detection method. For the column, the silicone is also made of silicone-based SK-85 (230-400 mesh) or Fuji Syrian chemical Chromatorex NH (200-350 mesh). In addition to the usual column chromatography, Biotage's automated chromatography unit (SP-1) is suitable. The abbreviations used in the examples have the following meanings. Mgmg: milligrams, g: gram, mL: milliliters, MHz: microhertz. In the following examples, a nuclear magnetic resonance (hereinafter referred to as 1H NMR) spectrum was prepared using tetramethyl decane as a standard material and a chemical shift enthalpy of 5 Å (ppm). The split graph is formed by one line with s, two lines with d, three lines with t, and four lines with q. Mass analysis (hereinafter referred to as MS) is performed by FAB (Fast Atom Bombardment) method, EI (Electron Ionization) method, or ESI (Electron Spray I ο nizati η η) method (Example 1) 3-(2-hydroxy-B Oxy)-4-methoxy-,[5-(3-trifluoromethyl-benzyl)-thiazol-2-yl]-benzylguanamine (Compound No. 丨-64) (13) 3-(3 -Trifluoromethyl-phenyl)-propanal in 3-iodobenzotrifluoride (10.8 g) in dimethylformamide (15 mL), allyl alcohol (4.1 mL), tetrabutyl chloride Ammonium (16.6 g), sodium hydrogencarbonate (8.34 g), and palladium acetate (485 mg) were added at 0 °C. The reaction mixture was warmed to room temperature, -93 - 200906395 was heated at 50 °C for 2 hrs, and diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated. The residue was purified by column chromatography eluting eluting elut elut elut elut elut elut NMR NMR (400MHz, CDCl3): (5 (ppm) = 9.84 (lH, s), 7.49-7.39 (4H, m), 3.02 (2H, t, J = 7.4 Hz), 2.83 (2H, t, J = 7.6 Hz). (lb) 5-(3-Trifluoromethyl-benzyl)-thiazol-2-ylamine 3-(3-trifluoromethyl-phenyl)-propanal obtained in Example (la) (7.17 g) dichloromethane (80 mL) was added L-proline (808 mg) and N-chlorobutaneimine (6.09 g) at 0 ° C. The reaction mixture was allowed to warm to room temperature for 1 hour. After stirring, hexane (100 mL) was added, and the mixture was stirred for 1 hour, and the white solid was filtered. The filtrate was washed with saturated aqueous sodium hydrogen carbonate and brine and dried over sodium sulfate. The acetaldehyde was 8.98 g of a pale yellow oil. A solution of 7.62 g of this chloroacetaldehyde and thiourea (2.45 g) in ethanol (100 mL) was heated and refluxed for 7 hours and concentrated. The residue was diluted with ethyl acetate. The residue was purified by chromatography (mjjjjjjjjjjjjj Ή NMR (400MHz, CDCh): &lt;5 (ppm) = 7.48-7.46(2H, m), 7.43- 7.38(2H, m), 6.81(1H, s), 4.87(2H, brs), 4.01(2H, s) MS(ES) m /z:259 (M + H) + . (lc) methyl 3-(2-hydroxyethoxy)-4-methoxybenzoate methyl 3-hydroxy-4-methoxybenzoate (27.8 g), a suspension of 2-bromoethanol (27 mL), and potassium carbonate (42.3 g) in dimethylacetamide (280 mL) -94-200906395 was heated at 80-100 °C for 8 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated. The residue was purified by column chromatography (hexane/ethyl acetate 7:1 to 1:4). The obtained solid was washed with hexane/diisopropyl ether (5:1). MS(ES) m/z: 227 (Μ + H) + . (ld) 4-methoxy-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy)-benzoic acid Methyl 3-(2-hydroxyethoxy)-4-methoxybenzoate (14.8 g), 3,4-dihydro-2H-pyran (18 mL), A solution of PPTS (1.64 g) in dichloromethane (150 mL) was stirred at room temperature for 32 hr. Triethylamine (1.8 mL) was added and the reaction mixture was concentrated. The residue was diluted with ethyl acetate and washed with water, saturated aqueous sodium hydrogen sulfate and brine, and dried over sodium sulfate. The residue was purified by column chromatography (hexane /EtOAc) MS(FAB + ) m/z: 3 3 3 (Μ + Na) + . (le) 4-methoxy-3-(2-(tetrahydro-pyran-2-yloxy)·ethoxy) -benzoic acid 1N of 4-methoxy-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy)-benzoic acid methyl ester (14.4 g) obtained in Example (1 d) A mixture of aqueous sodium hydroxide (51 mL) and dioxane (140 mL) was heated at 70 ° C for 2.5 hours. After cooling to room temperature, the organic solvent was removed under reduced pressure. The aqueous solution was acidified with a 10% aqueous citric acid solution and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and evaporated. The residue was purified by column chromatography (dichloromethane / methanol 1: </ RTI> 10:1). The resulting solid was dried with EtOAc EtOAcjjjjjjjj MS(FAB + ) m/z: 319 (Μ + Na) + , (lf) 4-methoxy-3-(2-ethoxy)-7V-[5-(3-trifluoromethyl-benzyl) 5-(thiazol-2-yl)-benzylamine The 5-(3-trifluoromethyl-benzyl)-thiazol-2-ylamine (4.35 g) obtained in Example (lb), EXAMPLE (1 e The resulting 4-methoxy-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy)-benzoic acid (5.49 g), HATU (7.03 g), and triethylamine (4.7) A solution of dimethyl acetamide (90 mL) was stirred at room temperature for 4 days and heated at 70 ° C for 3 hours. The reaction mixture was diluted with EtOAc. The residue was purified by column chromatography (dichloromethane/methanol) to give the title compound (9.26 g). A solution of this guanamine (9.26 g) in 1N hydrochloric acid (17 mL) and methanol (90 mL) was evaporated. The reaction mixture was neutralized with a 2N aqueous sodium hydroxide solution and the organic solvent was evaporated. The aqueous solution was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen sulfate and brine and dried over sodium sulfate. The residue was purified by column chromatography (chloroform / methanol: EtOAc: 30:1). The obtained solid was washed with methylene chloride (methanol) !H NMR (400MHz, DMSO-d6): (5 (ppm) = 12.4 (lH, brs), 7.73-7.7K3H, m), 7.64-7.57 (3H, m), 7.38 (1H, s), 7.10 ( 1H, d, J = 9.0Hz), 4.88(1H, brs), 4.25(2H, s), 4.08(2H, t, J = 5.2Hz), 3.85(3H, s), 3.76(2H, t, J = 4.9 Hz) MS (ES) m/z: 45 3 (M + H) +. Melting: 1 5 7 -1 5 9 °C. -96-200906395 (Example 2) 4-(2-Hydroxy-ethoxy)-3-methoxy-N-[5-(3-trifluoromethyl-benzyl)-thiazol-2-yl] -benzylamine (Compound No. 1-49) (2a) 4-(2-Hydroxy-ethoxy)-3-methoxy-benzoic acid 4-Hydroxy-3-methoxybenzoic acid (10.0 g) A solution of 2-bromoethanol (4.6 mL) and potassium hydroxide (8.35 g) in ethanol/water (2:1, 100 mL) was stirred at 90 ° C for 4 hours and concentrated. The residue was diluted with water and acidified with 2N hydrochloric acid (60 mL). The precipitate was filtered, washed with water and EtOAc. MS(ES) m/z: 213 (Μ + H) + . (2b) 4-(2-hydroxy-ethoxy)-3-methoxy-N-[5-(3-trifluoromethyl· 5-(3-trifluoromethyl-benzyl)-thiazol-2-ylamine obtained by the method of Example (1), benzyl)-thiazol-2-yl]-benzylamine (100 mg), 4-(2-hydroxy-ethoxy)-l-methoxy-benzoic acid (89.3 mg). NMR (500MHz, DMSO-d6): (5 (ppm) = 12.4 (lH, brs), 7.69-7.55 (6H, m), 7.35 (1H, s), 7.08 (1H, d, J = 9.3 Hz) , 4.88(1H, t, J = 5.1Hz), 4.23(2H, s), 4.05(2H, t, J = 5.2Hz), 3.83(3H, s), 3.72(2H, q, J = 5.9Hz) MS (ES) m/z: 45 3 (M + H) +. mp: 199 - 20 1 ° C. (Example 3) 4-(2-hydroxy-ethoxy)-3-methoxy-N -[4-Methyl-5-(3-trifluoromethyl-benzyl)-thiazol-2-yl]-benzylguanamine (Compound No. 9-1) (3a) 4-(3-Trifluoromethyl -Phenyl)-butan-2-one-97- 200906395 The same procedure as in Example (la), from 3-iodobenzotrifluoride (5.59 g) and (±)-3-but-2-ol (2.7 mL) The title compound 3.8 6 g (87%) of yellow oil. MS (FAB + ) m/z: 217 (Μ + H) + . (3b) 4-methyl-5-(3-trifluoromethyl) -benzyl)-thiazol-2-ylamine. The method of Example (lb), 4-(3-trifluoromethyl-phenyl)-butan-2-one (2.86 g) obtained from Example (3a) The title compound l. 〇 5g (29%) of brown oil. MS(ES) m/z: 273 (Μ + H) + . (3c) 4-(2-hydroxy-ethoxy)-3-methoxy The method of the example (If) of the radical N-[4-methyl-5-(3-trifluoromethyl-benzyl)-thiazol-2-yl]-benzamide; 4-(4-trifluoro-5-(3-trifluoromethyl-benzyl)-thiazol-2-ylamine (100 mg) obtained in Example (3b), 4-(2-hydroxy-ethoxy) obtained in Example (2a) Benzyl-3-methoxy-benzoic acid (77.9 mg), mp. , brs), 7.68(1Η, s), 7.66(1Η, d, J=1.9Hz), 7.60-7.5 3 (4H, m), 7.07(1H, d, J = 8.2Hz), 4.86(1H, t , J = 5.3Hz), 4.16(2H, s), 4.04(2H, t, J = 4.9Hz), 3.82(3H, s), 3.72(2H, q, J = 5.3Hz), 2.27(3H, s MS (ES) m/z: 466 (M + H) +. Melting: 2 1 5 - 2 1 7 ° C. (Example 4) N-(5-benzyl-1,3,4-thiadiazol-2-yl)-4-(2-hydroxy-ethoxy)-3-methoxy-benzylguanamine ( Compound No. 5 - 4 9) Method of imitation Example (If) ' 4-(2-hydroxy-ethoxy) obtained from 5-benzyl-thiadiazol-2-ylamine (100 mg), Example (2a) Benzyl-3-methoxy-benzoic acid (122 mg) gave the title compound 22.2 mg (11%). -98- 200906395 NMR (500MHz, DMSO-d6): (5 (ppm) = 12.8 (lH, br 7.7K2H, m), 7.36-7.27 (5H, m), 7.10 (1H, d, 4.88 (1H, t, J = 5.4 Hz), 4.37(2H, s), 4.06(2H, t, 3.84(3H, s), 3.73(2H, q, J = 5.3Hz) MS(ES) m/z:3 86 ( M + H) + . Melting point: 202-204 ° C. (Example 5) 3-(2-hydroxy-ethoxy)-4-methoxy-N-[5-(3-J benzyl) -1,3,4-thiadiazol-2-yl]-benzylguanamine (Compound No. 5-7: (53) 5-(3-Trifluoromethyl-benzyl)-thiadiazol-2-yl Amine (α,α,α-trifluoro-m-tolyl)acetic acid (1 · 25 g), sulfur half, BOP reagent (3.24 g), triethylamine (1.7 mL) anhydrous t (20 mL) The mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc) The toluene (20 mL) of the sulfonic acid (0.48 mL) was heated and suspended for 4 hours. The reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous solution (2 s) and brine, and the residue was dried with sodium sulfate. Methyl chloride/methanol 30:1~10:1) refined compound 760mg (48%) Color solid MS (ES) m/z: 260 (Μ + H) + . (5b) 3-(2-hydroxy-ethoxy)-4-methoxy-N-[5-(3-trifluoro Methyl 1,3,4-thiadiazol-2-yl]-benzamide amide Example (If), 5-(3-benzyl)-thiadiazol-2- obtained from Example (5a) Base amine (100 mg) and s) from example (le), 7.72-J = 9.2 Hz), J = 4.9 Hz), trifluoromethyl-) hydrazine (1.15 g) Concentrated with 3H-hydrofuran, sodium bicarbonate The obtained white float liquid was refluxed and concentrated with sodium carbonate to give the titled-benzyl-trifluoromethyl-4-methoxy--99-200906395 3-[2-(tetrahydro-pyran-2- <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; Ή NMR (400MHz, DMSO-d6): &lt;5 (ppm) = 1 2.8 (1 Η, brs), 7.76 (3Η, d, J = 9.8 Hz), 7.68 (2H, dd, J = 8.1 and 8.1 Hz), 7.61 (1H, dd, J = 7.8 and 7.8 Hz), 7.62 (1H, d, J = 7.9 Hz), 4.88 (1H, t, J = 5.2 Hz), 4.52 (2H, s), 4.07 (2H, t, J = 4.9 Hz), 3.85 (3H, s), 3.76 (2H, dt, J = 4.8 and 4.9 Hz) MS (ES) m/z: 454 (M + H) + melting point: 1 98-200 °C. (Example 6) 3-methoxy-4-(2-morpholin-4-yl-ethoxy)-N-[5-(3-trifluoromethyl-benzyl)-thiazol-2-yl ]-benzylamine (Compound No. 1-56) (6 a) 4-(2-Methanesulfonyloxy-ethoxy)-3-methoxy-benzoic acid methyl ester 4-(2-hydroxy- A suspension of methyl ethoxy)-3-methoxy-benzoate (US 2686 1 98) (1.01 g), methanesulfonium chloride (0.41 mL), triethylamine (1.3 mL) in anhydrous tetrahydrofuran (30 mL) Stir at room temperature for 30 minutes. The reaction mixture was diluted with EtOAc EtOAc. The residue was stirred vigorously in hexane, filtered and dried to give the title compound 1. NMR NMR (400MHz, CDCb): 5 (ppm) = 7.67 (lH, dd, J = 8.〇 and 1.7Hz), 7.58(1H, d, J = 2.0Hz), 6.90(1H, d, J = 8.3 Hz), 4.65(2H, t, J = 4.5Hz), 4.34(2H, t, J = 4.5Hz), 3.91(3H, s), 3.90(3H, s), 3.16(3H, s). (6b 3-methoxy-4-(2-morpholin-4-yl-ethoxy)-benzoic acid methyl ester 4-(2-methanesulfonyloxy-ethoxy) obtained in Example (6a) 3-methoxy-benzene-100-200906395 A suspension of methyl formate (304 mg), morpholine (0.11 mL), potassium carbonate (276 mg) in acetonitrile (10 mL). The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. The residue was purified by EtOAc EtOAcjjjjjjjjj NMR NMR (400MHz, CDCh): (5 (ppm) = 7.67 (lH, dd, J = 8.4 and 2.2Hz), 7.56 (1H, d, J = 2.0Hz), 6.91 (1H, d, J = 8.6Hz ), 4.22(2H, t, J = 5.9Hz), 3.9K3H, s), 3.90(3H, s), 3.74(4H, t, J = 4.7Hz), 2.87(2H, t, J = 6.0Hz) , 2.60 (4H, t, J = 4.7 Hz). (6c) 3-methoxy-4-(2-morpholin-4-yl-ethoxy)-benzoic acid imitation method (le), 3-methoxy-4-(2-morpholin-4-yl-ethoxy)-benzoic acid methyl ester (185 mg), m. NMR (400 MHz, DMSO-d6): 5 (ppm) = 7.52 (1H, d, J: 7.8 Hz), 7.43 (1H, s), 7.05 (1H, d, J = 8.2 Hz), 4.12 (2H, t, J = 5.7Hz), 3.7 8(3H, s), 3.55(4H, brs), 3.30(4H, brs), 2.69(2H, t, J = 5.5Hz). (6(1)3-A Example of oxy-4-(2-morpholin-4-yl-ethoxy)-1^[5-(3-trifluoromethyl-benzyl)-thiazol-2-yl]-benzamide (If), 3-methoxy-4-(2-morpholin-4-yl-ethoxy)-benzoic acid (1 6 1 mg) obtained from Example (6c) and Example (1b) The obtained 5-(3-trifluoromethyl-phenyl)-thiazino-2-ylamine (148 mg) gave 84 mg of the decylamine. 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 12.4(lH, brs), 1.12-7.68(3H, m), 7.64 - 7.5 8 (3 H, m), 7.37(1H, s), 7.12(1H, d, -101 - 200906395 J = 9.0Hz), 4.25(2H, s), 4.16(2H, t, J = 5.9Hz), 3.84(3H, s), 3.58(4H, t, J = 4.7Hz), 2.71(2H, t, J = 5.9Hz), 2.48 (4H, t, J = 4.7 Hz) MS (ES) m/z: 522 (M + H) + (Example 7) 3,4-bis-(2-hydroxy-ethoxy)-N- [5-(3-Trifluoromethyl-benzyl)-thiazol-2-yl]-benzylguanamine (Compound No. 1-67) (7a) 3,4-bis-[2-(tetrahydro-pyran) Ethyl -2-yloxy)-ethoxy]-benzoate Example (lc) Method '3. (58%) yellow oil. MS (FAB + ) m/z: 461 (Μ + Na) + . (7b) 3,4-bis-[2-(tetrahydro-pyran-2-yloxy)-B Oxy]-benzoic acid imitation of the method of Example (le), 3,4-bis-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzene obtained from Example (7a) Ethyl formate (2.04 g) gave the title compound (yield: ield. Method for the hydroxy-ethoxy)-hydrazine-[5-(3-trifluoromethyl-benzyl)-thiazol-2-yl]-benzamide compound (If), obtained from the example (7b) 3,4-bis-[2-(tetrahydro-pyran-2-yloxy)·ethoxy]-benzoic acid (173 mg) and the resulting 5-(3-trifluoromethyl- Benzyl)-thiazol-2-ylamine (100 mg) gave 267 mg of the title compound. This melamine 165 mg was deprotected with 1N hydrochloric acid to give the title compound 45.2 mg (39%) of white amorphous. NMR NMR (500MHz, DMSO-d6): (5 (ppm) = 1 2.4 (1 Η, brs), 7.71 (1Η, -102- 200906395 d, J = 2.4Hz), 7.68-7.66(2H, m), 7.6 2 - 7.5 5 (3 H, m), 7.35(1H, s), 7.09(1H, d, J = 8.8Hz), 4.89(1H, t, J = 6.9Hz), 4.87(1H, t, J = 6.6Hz), 4.23(2H, s), 4.08(2H, t, 1 = 5.1Hz), 4.07(2H, t, J = 5.0Hz), 3.74(2H, q, J = 6.1Hz), 3.73( 2H, q, J = 6.1 Hz) MS (ES) m/z: 48 3 (M + H) + (Example 8) 5-(3-trifluoromethyl-benzyl)-thiazole-2-carboxylate Acid [3-(2-hydroxy-ethoxy)-4-methoxy-phenyl]-decylamine (Compound No. 2-7) (8 3) 2-(2-methoxy-5-nitro -Phenoxy)-ethanol 2-methoxy-5-nitro-phenol (5.02 g), 2-bromoethanol (4.3 mL), potassium carbonate (8.22 g) in dimethylacetamide (50 mL) The suspension (50 mL) was stirred at EtOAc (EtOAc) (EtOAc). 400MHz, CDCl3): (5 (ppm) = 7.96 (lH, d, J = 2.4Hz), 7.87 (1H, dd, J = 58.5 and 2.5Hz), 6.94 (1H, d, J = 9.0Hz), 4.53 (1H, s), 4.2K2H, t, J = 4.5Hz), 4.03(2H, t, J = 4.5Hz), 3.9 7(3H, s). (8b) tert-butyl-[2-(2-methoxy-5-nitro-phenoxy)-ethoxy)-dimethyldecane. Example (8a) 2-(2-Methoxy-5-nitro-phenoxy)-ethanol (4.99 g), tert-butyldimethylammonium chloride (5. g), imidazole (2.42 g) A solution of dimethylformamide (5 OmL) was stirred at room temperature for 24 hours. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. MS(ES) m/z: 328 (Μ + H) + . -103- 200906395 (8c) 3-[2-(T-butyl-dimethyl-decyloxy)-ethoxy]_4_A Oxyphenylamine The third butyl-[2-(2-methoxy-5-nitro-phenoxy)-ethoxy]-dimethyldecane (8.34 g) obtained in Example (8b) A suspension of palladium on carbon (10%, 1.6 g) in tetrahydrofuran (100 mL) was stirred at room temperature for 48 hr. The reaction mixture was filtered and concentrated. The residue was purified by EtOAcjjjjjjjli MS (ES) m / z: 297 ( Μ + H) + . (8d) 2-bromo-5-(3-trifluoromethyl-benzyl)-thiazole obtained in Example (lb) 5·(3- a suspension of trifluoromethyl-benzyl)-thiazol-2-ylamine (2.85 g), copper sulfate (5.27 g), sodium bromide (4.53 g) in sulfuric acid (9 mol/L, 24 mL), sodium nitrite (911 mg) aqueous solution (10 mL) was added to (TC). The reaction mixture was stirred at 0 ° C for 1 hour, then warmed to room temperature, stirred for 3.5 hours, diluted with water and extracted with ethyl acetate. The organic layer was washed with EtOAc EtOAc (EtOAc m. m/z: 322 (Μ + H) + . (8e) 5-(3-trifluoromethyl-benzyl)-thiazole-2-carboxylic acid 3-(2-hydroxy-ethoxy)-4-methyl 3-[2-(t-butyl-dimethyl-decane) obtained by the method (8c) was added dropwise to a solution of triphosgene (44 mg) in dichloromethane (1 mL). A solution of oxy)·ethoxy]-4-methoxyphenylamine (111 mg) in dichloromethane (2 mL) and triethylamine (1 14 // L). The reaction mixture was stirred at room temperature for 20 minutes, diluted with EtOAc EtOAc EtOAc EtOAc EtOAc. A solution of 2-bromo-5-(3-trifluoromethyl-benzyl)-thiazole (93 mg) in anhydrous tetrahydrofuran (1 mL) obtained in Example (8d): n-butyl lithium (1.6M, hexanes, 218 y L) was added at -7 8 °C. After 1 hour, a solution of the isocyanate obtained in the above process in anhydrous tetrahydrofuran (1 mL) was added at -78 °C. The reaction mixture was slowly warmed to room temperature, diluted with EtOAc EtOAc. The residue was purified by column chromatography (hexane / ethyl acetate) to afford succinamine 89 mg brown syrup. The title compound was obtained (37.0 mg (22% Ή NMR (500MHz, DMSO-d6): &lt;5 (ppm) = 10.5 (lH, brs), 7.93 (1H, s), 7.72 (1H, s), 7.66-7.58 (3H, m), 7.53 (1H, d, J = 2.4 Hz), 7.40 (1H, dd, J = 8.8 and 2.4Hz), 6.92(1H, d, J = 8.8Hz), 4.85(1H, brs), 4.42(2H, s), 3.93(2H, t, J = 5.2Hz) , 3.74 (3H, s), 3.74-3.72 (2H, m). MS (ESI) m/z: 45 3 (M + H) + . (Example 9) 3-(2-hydroxy-ethoxy)-N-{5-[hydroxy-(3-trifluoromethyl-phenyl)-methyl]-thiazol-2-yl b-4- Oxy-benzylamine (Compound No. 9-17) (9 a) {5-[Hydroxy-(3-trifluoromethylphenyl)-methyl]-thiazol-2-yl)-carbamic acid tert-butyl A solution of (5-bromo-thiazol-2-yl)-aminecarboxylic acid tert-butyl ester (1. 7 g) in anhydrous tetrahydrofuran (10 mL), n-butyllithium (2.7 mol/L hexane solution, 3.6 mL) At -7 8. (: slowly dripping. After 1 hour, a solution of 3-trifluoromethylbenzaldehyde-105 - 200906395 (1.00 g) in anhydrous tetrahydrofuran (5 mL) was slowly added. The reaction mixture was slowly warmed to -5 ° C to sat. The aqueous solution of ammonium chloride was diluted with EtOAc. EtOAc (EtOAc m. (6 8%) yellow solid. MS (ES) m/z: 375 ( Μ + H) + . (9b) [5-(3-trifluoromethyl-benzyl)-thiazol-2-yl]- Tert-butyl carbamic acid tert-butyl {5-[hydroxy-(3-trifluoromethylphenyl)-methyl]-thiazol-2-yl}-aminecarboxylic acid obtained in Example (9a) (473 mg) Dichloromethane (10 mL) was added to a solution of EtOAc (3 mL), EtOAc (EtOAc). The aqueous solution was washed with EtOAc EtOAc (EtOAc m. 371 (Μ-Η) + . (9c)(2-Amino-thiazol-5-yl)-(3-trifluoromethyl-phenyl)-methanone obtained in Example (9b) [5-(3- A suspension of tributylmethyl-benzylidene)-thiazol-2-yl]-carbamic acid tert-butyl ester (234 mg) in dichloromethane (5 mL) was added trifluoroacetic acid (1.7 mL) at room temperature. The mixture was stirred for 2 hours, and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated. Chromatography (dichloromethane/methanol) (mdHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH -transyl-ethoxy)-4-methoxy-N-[5-(3-trifluoromethyl-throkily)-thiazol-2-yl]-benzamide compound (If) Method, 4-methoxy-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoic acid (175 mg) obtained in Example (3) and obtained in Example (9c) (2-Amino-thiazol-5-yl)-(3-trifluoromethyl-phenyl)-methanone (I46 mg) gave decylamine. The guanamine was deprotected with 1N hydrochloric acid. The title compound is 136 mg (54%) (m.). 3-trifluoromethyl-phenyl)-methyl]-thiazol-2-yl}-4-methoxy-benzylamine (3-(2-hydroxy-ethoxy)-) obtained in Example (9d) Methanol/tetrahydrofuran (1:1, 6 mL) suspended in 4-methoxy-N-[5-(3-trifluoromethyl-benzyl)-thiazol-2-yl]-benzylguanamine (3 lmg) Sodium borohydride (5 mg) was added at 0 °C. The reaction mixture was allowed to rise to room temperature, sodium borohydride was added until the end of the reaction, which was concentrated and diluted with 1N hydrochloric acid and ethyl acetate. The organic layer was washed with sodium hydrogen carbonate and brine and dried over sodium sulfate. The residue was purified by EtOAcjjjjjjjjj NMR NMR (400MHz, CDCh): (5 (ppm) = 7.72 (lH, s), 7.6 6 - 7.6 1 (2H, m), 7.57 (1H, d, J = 7.8 Hz), 7.50 (1H, d, J = 7.8 Hz), 7.47 (1H, s), 7.13 (1H, s), 6.95 (1H, d, J = 8.2 Hz), 6.09 (1H, s), 4.05- 3.97 (4H, m), 3.92 ( 3H, s) MS (ES) m/z: 469 (M + H) + . melting point: 1 1 9 -1 2 1 ° C. (Example 10) 7V-[5-(3-fluoro-benzyl) -thiazol-2-yl]-3-(2-hydroxy-ethoxy-107-200906395-based)-4-methoxy-benzylguanamine (Compound No. 1-16) (10a) 3-(3-Fluoro- Phenyl)-propanal imitation of the method of Example (1), from 3-fluoroiodobenzene (10.0 g) and allyl alcohol (4.64 mL) afforded the title compound 6.24 g (91%) of brown oil. NMR (500 MHz , CDCh): 5 (ppm) = 9.82 (lH, s), 7.27-7.23 (1 Η, m), 6.98-6.96 (lH, m), 6.92-6.89 (2H, m), 2.96 (2H, t, J = 7.4 Hz), 2.79 (2H, t, J = 7.4 Hz). (10b) 5-(3-Fluoro-benzyl)-thiazol-2-ylamine. The method of Example (lb), by example (10a) 3-(3-Fluoro-phenyl)-propanal (6.24 g) and thiourea (3.19 g). (Μ + H) + . (10c) AM5-(3-Fluoro-benzyl)-thiazol-2-yl]-3-(2-hydroxy-ethoxy)-4- The method of the oxy-benzylamine compound (If), 4-methoxy-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy] obtained from the example (le) - benzoic acid (161 mg), 5-(3-fluoro-benzyl)-thiazol-2-ylamine (103 mg) obtained in Example (10b), afforded phthalamide 132 mg (55%). Deprotection with 1N EtOAc afforded EtOAc (EtOAc: EtOAc (EtOAc): ), 7.4 1-7.3 3 (2H, m), 7.1 5 - 7.0 5 (4H, m), 4.88 (1H, t, J = 5.4Hz), 4.14(2H, s), 4.07(2H, t, J = 5.2Hz), 3.84(3H, s), 3.75(2H, dt, J = 5.4, 5.2Hz) MS(ES) m/z: 403 (M + H) + . -108- 200906395 Melting point: 1 60- 1 62 °C. (Example 1 1) 7V-[5-(2,5-Dichloro-benzyl)-thiazol-2-yl]-3-(2-hydroxy-ethoxy)-4-methoxy-benzylhydrazine Amine (Compound No. 320) (lla) 3-(2,5-Dichloro-phenyl)-propanal im of the method of Example (la), from 2,5-dichloroiodobenzene (10.Og) and Allyl alcohol (3.77 mL) gave the title compound 7.64 g (yield of yield) as a brown oil. MS (EI) m/z: 202 M + . (1 lb) 5-(2,5-dichloro-benzyl)-thiazole-2, amide. The obtained 3-(2,5-dichloro-phenyl)-propanal (7.64 g) and thiourea (2.92 g) gave the title compound 3.21. MS (EI) m/z: 25 8 M + . (1 1c)jV-[5-(2,5-dichloro-benzyl)-thiazol-2-yl]-3-(2-hydroxy-ethoxy 4-methoxy-benzamide-impurified Example (10), 4-methoxy-3-[2-(tetraki-p-pyran-2-yloxy) obtained from Example (le) )-ethoxy]-benzoic acid (I35 mg), Example (lib) v 5-(2,5-mono-indolyl)·thiazol-2-ylamine (10 mg) obtained as decylamine 161 mg (72%) of EtOAc EtOAc (EtOAc: EtOAc) Brs), 7.71 (1Η, d, J = 8.9Hz), 7.71(1H, s), 7.57(1H, d, J = 2.7Hz), 7.52(1H, d, J = 8.6Hz), 7.39(1H, Dd, J = 8.6 and 2.7 Hz), 7.34 (1H, s), 7.10 (1H, d, J = 8.9 Hz), 4.89 (1H, t, J = 5.2 Hz), 4.22 (2H, s), 4.07 ( 2H, t, J = 5.0Hz), 3.84(3H, s), 3.75(2H, dt, J = 5.2, -109- 200906395 5.0Hz) MS(ES) m/z:45 3 (M + H) + Melting point: 2 1 0 - 2 1 1 ° C. (Example 12) 7V-[5-(3-chloro-benzyl)-thiazol-2-yl]-3-(2-hydroxy-ethoxy) 4-methoxy-benzamide (Compound No. 1-40) (12a) 3-(3-Chloro-phenyl)-propanal imitation Example (la) By 3-chloroiodobenzene (10 g) and allyl alcohol (4.33 mL), the title compound 7.36 g (quant. yield) of brown oil was obtained. MS (EI) m/z: 168 M+. 12b) 5-(3-Chloro-benzyl)-thiazol-2-ylamine. The method of Example (lb), 3-(3-chloro-phenyl)-propanal obtained from Example (12a) (7.36) g) and thiourea (3.39 g) gave the title compound 4.70 g (50%) as a pale yellow solid. MS (ES) m/z: 225 ( Μ + H) + . (12c) AM5-(3-chloro-benzyl 4-)-thiazol-2-yl]-3-(2-hydroxy-ethoxy)-4-methoxy-benzylamine as the method of Example (If), 4-A obtained from Example (le) Oxy-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoic acid (144 mg), 5-O-chlorobenzyl)-thiazole obtained in Example (12b) -2-ylamine (99.3 mg) gave 133 mg (60%) of decylamine. The guanamine was deprotected with 1N HCl to give the title compound 90.0 mg (81%) of white solid. NMR NMR (400MHz, DMSO-d6): δ (pp m) = 1 2.4 (1 Η, brs), 7.72 (1Η, s), 7.71 (1Η, d, J = 7.1Hz), 7.3 8 - 7.3 5 ( 2Η, m), 7.3 1-7.26(3Η, m), 7.07(1Η, d, J = 8.9Hz), 4.88(1H, t, J = 5.3Hz), 4.12(2H, s), -110- 200906395 4.06(2H, t, J = 5.3Hz), 3.84(3H, s), 3.75(2H, dt, J = 5.3, 5_3Hz) MS(ES) m/z: 419 (M + H) + . Melting point: 169 -171 °C. (Example 13) 4-ethoxy-3-(2-hydroxy-ethoxy)-N-[5-(3-trifluoromethyl-benzyl)-thiazol-2-yl]-benzylguanamine (Compound No. 1-65) (13a) 4-Fluoro-3-hydroxy-benzoic acid ethyl ester 4-Fluoro-3-hydroxy-benzoic acid (5.0 g) t Concentrated sulfuric acid (2.5 mL) in ethanol (50 mL) The solution was heated under reflux for 23 hours. The reaction mixture was concentrated, dried with EtOAc EtOAcjjjjjjjjjjj NMR NMR (400MHz, CDC13): 5 (ppm) = 7.73 (lH, dd, J = 8.4 and 2.1 Hz), 7.63 -7.59 (lH, m), 7.12 (1H, dd, J = 9.8 and 8.6 Hz), 5.60(1H, d, J = 3.5Hz), 4.37(2H, q, J = 7.2Hz), 1.39(3H, t, J = 7.0Hz). (13b)4-Fluorine 3-[2-(four Hydrogen·pyran-2-yloxy)-ethoxy)-benzoic acid ethyl ester 4-fluoro-3-hydroxy-benzoic acid ethyl ester (5.67 g) obtained in Example (13a), 2-(2-bromo A suspension of ethoxy)tetrahydro-2H-pyran (7.75 g) and potassium carbonate (8.52 g) in acetonitrile (50 mL) was heated at reflux for 3 days. The reaction mixture was diluted with ethyl acetate. EtOAc (EtOAc m. iHNMRHOOMHz'CDClOJippnOdjSCHdc^Jr^.Sand 2·0Ηζ), 7.67·7·63 (1Η, m), 7·11 (1Η, dd, J 20.8 and 8.5Hz), -Ill - 200906395 4.73(1H, t, J = 3.5Hz), 4.37(2H, q, J = 7.3Hz), 4.3 2-4.26 (2H, m), 4.12-4.07(1H, m), 3.9 4 - 3.8 3 (2H, m), 3.5 6 - 3.5 0 ( 1 H, m), 1.89- 1.69 (2H, m), 1.67- 1.50 (4H, m), 1.39 (3H, t, J = 7.2 Hz). (13c) 4-ethoxy-3 -[2-(tetrahydro-pyran-2-yloxy)-ethoxy)-benzoic acid ethyl ester The 4-fluoro-3-[2-(tetrahydro-pyran-2) obtained in Example (13b) A solution of ethyl oxy)-ethoxy]benzoate (10.6 g) and sodium ethoxide (21% by weight in ethanol, 14.5 mL) in ethanol (100 mL) was heated under reflux for 20 hr. The reaction mixture was concentrated, diluted with water and ethyl acetate (2). The organic layer was washed with EtOAc (EtOAc m. MS(ES) m/z: 339 (Μ + H) + . (13d) 4-ethoxy-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy)-benzoic acid 4-Ethoxy-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoic acid ethyl ester obtained by the method of Example (13). 8.96 g) gave the title compound 4.28 g (45%). NMR NMR (400MHz, DMSO-d6): ό (ppm) = 1 2.6 (1 Η, brs), 7.53 (1Η, d, J = 7.8Hz), 7.47(1H, s), 7.02(1H, d, J = 9.0Hz), 4.67(1H, s), 4.14(1H, s), 4.08(2H, q, J = 6.9Hz), 3.9 1 - 3.8 7 (1 H, m), 3.82-3.77(1H, m ), 3.7 3 - 3.7 0 ( 1 H, m), 3.4 2 - 3.3 8 (2 H, m), 1.75- 1.66 (1H, m), 1.64- 1.55 ( 1H, m), 1.5 2- 1. 3 8 (4H, m), 1.32(3H, t, J = 6.6Hz). MS(EI) m/z: 310 M + . (13e) 4-ethoxy-3-(2-hydroxy-ethoxy) - 7V-[5-(3-trifluoromethyl-benzyl)--112- 200906395 thiazol-2-yl)-benzamide compound method (If), obtained from Example (13d) 4 -ethoxy-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoic acid (203 mg) and 5-(3-trifluoromethyl-) obtained in Example (lb) Benzyl)-thiazol-2-ylamine (17611^) gives the guanamine. The guanamine was deprotected with 1N hydrochloric acid to give the title compound i </ RTI> (4%) as a pale yellow solid. NMR (400MHz, DMSO-d6): 5 (ppm) = 1 1.7 (1H, s), 7.73- 7.66 (3H, m), 7.64 - 7.5 7 (3 H, m), 7.37 (1H, s), 7.08(1H, d, J=10.2Hz), 4.86(1H, t, J = 6.0Hz), 4.25(2H, s), 4.12(2H, q, J = 7.3Hz), 4.08(1H, t, J = 5.8Hz), 3.84 - 3.7 3 (3 H, m), 1.36(3H, t, J = 6.9Hz) MS(ES) m/z:467 (M + H)+. Melting point: 1 3 0 - 1 3 3 °C. (Example 14) 3-(2-Hydroxy-ethoxy)-4-methoxy-TV-[5-(3-trifluoromethyl-benzyl)-thiophen-2-yl]-benzylguanamine (Compound No. 7_7) (14a) Siniphen-2-yl-(3-trifluoromethyl-phenyl)-methanol. The method of Example (9a), from thiophene (1.8 mL) and 3-trifluoromethyl Benzaldehyde (2.7 mL) gave the title compound 5.05 g (98%) MS (EI) m/z: 25 8 M + . (14b) 2-(3-trifluoromethyl-benzyl)-thiophene in sodium iodide (5.37 g) in acetonitrile (9 mL) Trimethyl decane (4.5 mL). After 15 minutes, a solution of the thiophen-2-yl-(3-trifluoromethyl-phenyl)-methanol (1.99 g) obtained in Example (14a. After stirring for 15 minutes at 0 ° C, a solution of 2N sodium hydroxide water -113 - 200906395 (13.5 mL) was applied. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, sodium sulfate, and brine, and dried over sodium sulfate. The residue was purified by EtOAcjjjjjjjli MS (EI) m/z: 242 M + . (14c) 2-nitro- 5-(3-trifluoromethyl-benzyl)-thiophene 2-(3-trifluoromethyl) obtained in Example (14b) A solution of acetic acid anhydride (9 mL) of benzyl-benzyl)-thiophene (702 mg), a solution of copper nitrate (yttrium), trihydrate (700 mg), and acetic anhydride (9 mL) was added at 0 °C. After 1.5 hours, the reaction mixture was poured into ice and stirred for 1 hour to remove the supernatant. The oily residue was extracted with ethyl acetate and water. The organic layer was washed with saturated aqueous sodium hydrogen sulfate and brine and dried over sodium sulfate. The residue was purified by EtOAcjjjjj elut elut MS(ES) m/z: 286 (Μ - Η) + . (14d) 3-(2-hydroxy-ethoxy)-4-methoxy-indole 5-(3-trifluoromethyl-benzyl) -Thiophen-2-yl]-benzylguanamine. 2-Nitro-5-(3-trifluoromethyl-benzyl)-thiophene (152 mg) obtained in Example (14c) isopropyl alcohol (10 mL) and 1N A mixed solution of hydrochloric acid (5 mL) was added to a zinc powder (692 mg) at room temperature. After 30 minutes, a saturated aqueous solution of sodium hydrogencarbonate was added to the mixture. The resulting mixture was stirred for 10 minutes and filtered through celite. The filtrate was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated. The residue was dissolved in dimethylacetamide (2 mL), and 4-methoxy-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxylated as obtained in Example (3) Benzoic acid (157 mg), HATU (201 mg), and triethylamine-114-200906395 (0.15 mL) were mixed. The reaction mixture was stirred at room temperature for one night, diluted with ethyl acetate, washed with saturated sodium hydrogen sulfate, water, and brine, and evaporated. The residue was purified by column chromatography (dichloromethane / ethyl acetate) to afford 46 mg of amide. The guanamine was deprotected with 1N hydrochloric acid to give the title compound 19 mg (8%) as a yellow solid. NMR NMR (500MHz, DMSO-d6): 5 (ppm) = l 1.2 (1H, brs), 7.63-7.53 (6Η, m), 7.09 (1Η, d, J = 8.7Hz), 6.72(1H, d, J = 3.9 Hz), 6.70 (1H, d, J = 3.9 Hz), 4.89 (1H, t, J = 5.4 Hz), 4.18 (2H, s), 4.05 (2H, t, J = 5.1 Hz), 3.84 (3H, s), 3.75 (2H, q, J = 5.1 Hz) MS (EI) m/z: 45 2 (M + H) +. Melting: 17 4 - 17 6 °C. (Example 15) AM5-(3·Trifluoromethoxy-benzyl)-thiazol-2-yl]-3-(2-hydroxy-ethoxy)-4-methoxy-indole (compound) No. 1-97) (15 a) 3-(3-Trifluoromethoxy-phenyl)-propanal imitation Example (la) from 3-(trifluoromethoxy)iodobenzene (5.04 g And allyl alcohol (1.80 mL) gave the title compound 3_61 g (95%) of yellow oil. MS (EI) m/z: 218 M + . (15b) 5-(3-trifluoromethoxy-benzyl)-thiazol-2-ylamine imitation Example (lb), by Example (15a) The obtained 3-(3-trifluoromethoxy-phenyl)-propanal (3.61 g) and thiouret (1.29 g) MS(ES) m/z: 275 (Μ + H) + . (15c)7V-[5-(3-trifluoromethoxy-benzyl)-thiazol-2-yl]-3-(2-hydroxyl -ethoxy)-4-methoxy-benzylamine-115-200906395 By the method of the example (If), 4-methoxy-3-[2-(tetrahydro- Pyr-2-yloxy)-ethoxy]-benzoic acid (133 mg), 5-(3-trifluoromethoxy-benzyl)-thiazol-2-ylamine obtained in Example (15b) (11 2 mg) gave 112 mg (50%) of hydrazine. The guanamine was deprotected with 1N aqueous EtOAc (EtOAc:EtOAc) NMR NMR (500MHz, DMSO-d6): 5 (pp m) = 1 2.4 (1 Η, brs), 7.70(1H, s), 7.69 (1H, d, J = 8.3Hz), 7.46(1H, t, J = 8.0 Hz), 7.32 (1H, d, J = 7.8 Hz), 7.27-7.22 (3H, m), 7.04 (1H, d, J = 8.3 Hz), 4.87 (1H, t, J = 5.6 Hz) , 4.15(2H, s), 4.05(2H, t, J = 5.1Hz), 3.82(3H, s), 3.75(2H, dt, J = 5.6, 5.1Hz) MS(ES) m/z:469 ( M + H) + . Melting point: 1 5 8 - 1 5 9 °C. (Example 16); V-[5-(4-fluoro-3-trifluoromethyl-benzyl)-thiazol-2-yl]·3-(2-hydroxy-ethoxy)-4-methoxy Base-benzylamine (Compound No. 1-177) (16&amp;) 3-(4-Fluoro-3-trifluoromethyl-phenyl)-propanal imitation Example (la), from 2-fluoro- 5-iodobenzotrifluoride (4.91 g) and allyl alcohol (1.74 ml) gave the title compound 2.9 4 g (79. MS (EI) m/z: 220 M + . (16b) 5-(4-fluoro-3-trifluoromethyl-benzyl)-thiazol-2-ylamine imitation Example (lb) The title compound (1.63 g (44%), m. MS(ES) m/z: 277 (Μ + H) + . (16c) AM5-(4-fluoro-3-trifluoromethyl-benzyl)-thiazol-2-yl)-3-(2-hydroxyl -B-116-200906395 oxy)-4-methoxy-benzylamine as the method of Example (If), 4-methoxy-3-[2-(tetrahydro-) obtained from Example (le) Pyran-2-yloxy)-ethoxy]-benzoic acid (136 mg), 5-(4-fluoro-3-trifluoromethyl-benzyl)-thiazol-2-yl obtained from Example (16b) The amine (115 mg) gave melamine 134 mg (5 8%). The guanamine was deprotected with 1N hydrochloric acid to give the title compound 91.0 mg (81%) as a white solid. NMR (500MHz, DMSO-d6): 5 (ppm) = 12.4 (lH, brs), 7.74-7.66 (4H, m), 7.48 (1H, t, J = 9.8 Hz), 7.35 (1H, s), 7.09(1H, d, J = 8.7Hz), 4.88(1H, t, J = 5.4Hz), 4.22(2H, s), 4.07(2H, t, J = 5.4Hz), 3.84(3H, s), 3.75 (2H, dt, J = 5.4, 5.4 Hz) MS (ESI) m/z: 471 (M + H) +. Melting: 1 5 6 - 1 5 7 ° C. (Example 17) #-[5-(3,5-Dichloro-benzyl)-thiazol-2-yl]-3-(2-hydroxy-ethoxy)-4-methoxy-benzylguanamine (Compound No. 1 - 273) (17a) 3-(3,5-Dichloro-phenyl)-propanal imitation Example (la), from 3,5-dichloroiodobenzene (5.23 g) and alkene Propanol (1.97 mL) gave the title compound 2.16 g (55%). MS (EI) m / z: 202 M + . (17b) 5-(3,5-dichloro-benzyl)-thiazol-2-ylamine. The method of Example (lb), from Example (17a) The obtained 3-(3,5-dichloro-phenyl)-propanal (2.16 g) and EtOAc (EtOAc) MS(ES) m/z: 25 9 (Μ + H) + . (17c) jV-[5-(3,5-dichloro-benzyl)-thiazol-2-yl]-3-(2-hydroxyl - ethoxy)--117- 200906395 4-methoxy-benzylamine imitation of the method of Example (If), 4-methoxy-3-[2-(tetrahydro- Pyran-2-yloxy)-ethoxy]-benzoic acid (221 mg), 5-(3,5-dichloro-benzyl)-thiazol-2-ylamine (193 mg) obtained in Example (17b)醯 232 mg (43%). The guanamine was deprotected with 1N EtOAc to afford 155 mg (79%) NMR NMR (400MHz, CDCls): 5 (ppm) = 1 0.3 ( 1 H, brs), 7.51 (1Η, dd, J = 8.4, 1.0Hz), 7.50(1H, s), 7.24(1H, d, J = 1.0Hz), 7.13(2H, d, J = 6.7Hz), 7.13(1H, s), 6.92(1H, d, J = 8.4Hz), 4.17(2H, t, J = 4.5Hz), 4.05( 2H, s), 4.01(2H, brs), 3.90(3H, s), 2.66(1H, brs) MS(ES) m/z: 453 (M + H) + . Melting point: 1 74- 1 75 t: . (Example 18) W-[5-(3,5-bis-trifluoromethyl-benzyl)-thiazol-2-yl]-3-(2-hydroxy-ethoxy)-4-methoxy -benzylamine (Compound No. 1 - 305 ) (18 a) 3-(3,5-bis-trifluoromethyl-phenyl)·propanal im of the method of Example (la), from 3,5-double (Trifluoromethyl)iodobenzene (5.07 g) and allyl alcohol (1.55 mL) afforded 671 mg (17%) MS (EI) m/z: 270 M + . (18b) 5-(3,5-bis-trifluoromethyl-benzyl)-thiazole·2-ylamine. The method of Example (lb) was carried out by 3-(3,5-bis-trifluoromethyl-phenyl)-propanal (672 mg) and thiourea (193 mg), m. MS(ES) m/z: 327 (Μ + H) + . 200906395 (18c)AM5-(3,5-bis-trifluoromethyl-benzyl)-thiazol-2-yl)-3-(2- Hydroxy-ethoxy)-4.methoxy-benzamide amide The method of Example (If), 4-methoxy-3-[2-(tetrahydro-pyran-) obtained from Example (le) 2-(2-oxo)-ethoxy]-benzoic acid (10 mg), 5-(3,5-bis-trifluoromethyl-benzyl)-thiazol-2-ylamine obtained in Example (18b) (116 mg) gave 88.6 mg (41%) of amide. The guanamine was deprotected with 1N hydrochloric acid to give the title compound (yield: 75.6 mg (99%) of white solid. NMR NMR (400MHz, CDCh): 5 (ppm) = 1 0.3 (1 Η, brs), 7.79 (1Η, s), 7.7K2H, s), 7.5 3-7.48(2H, m), 7.17(1H, s ), 6.91(1H, d, J = 8.6Hz), 4.24(2H, s), 4.17(2H, t, J = 4.4Hz), 4.02(2H, brs), 3.89(3H, s), 2.76(1H , brs) MS (ES) m/z: 521 (M + H) +. Melting: 1 72 - 1 73 °C. (Example 19) TV-[5-(3,5·Difluoro-benzyl)-thiazol-2-yl]-3-(2-hydroxy-ethoxy)-4-methoxy-benzylamine (Compound No. 1 - 233) (19a) 3-(3,5-Difluoro-phenyl)-propanal imformation Example (la), from 3,5-difluoroiodobenzene (5.10 g) and alkene Propanol (2.1 2 m L) gave the title compound 2·3 3 g (81%) as pale yellow oil. MS (EI) m/z: 170 M+. (19b) 5-(3,5-difluoro-benzyl)-thiazol-2-ylamine. The method of Example (lb), obtained from Example (19a) 3-(3,5-Difluoro-phenyl)-propanal (2.83 g) and thiourea (1.29 g). MS (ES) m/z: 227 (Μ + H) + . -119- 200906395 (19c) iV-[5-(3,5-difluoro-benzyl)-thiazol-2-yl]-3-( 2-Hydroxy-ethoxy)-4-methoxy-thymidine imitation of the method of Example (If), 4-methoxy-3-[2-(tetrahydro-pyridyl) obtained from Example (le) M--2-yloxy)-ethoxy]-benzoic acid (I38 mg), 5-(3,5-difluoro-benzyl)-s- oxazol-2-ylamine (106 mg) obtained in Example (19b)醯 7 7 75.4mg (32%). The guanamine was deprotected with 1N HCl to afford 50.2 mg (yiel. Ή NMR (400MHz, DMSO-d6): &lt;5 (ppm) = 1 2.4 (1 Η, brs), 7.73-7.71 (2Η, m), 7.35(1H, s), 7.1 3-7.04 (4H, m), 4.89(1H, t, J = 5.5Hz), 4.15(2H, s), 4.07(2H, t, J = 5.2Hz), 3.84(3H, s), 3.76(2H, dt, J = 5.5, 5.2Hz) MS(ES) m/z : 421 (M + H) + . Melting point: 1 75- 1 76 °C. (Example 20) 沁[5-(3-chloro-4-fluoro-benzyl)-thiazol-2-yl]-3-(2-hydroxy-ethoxy)-4-methoxy-benzylguanamine (Compound No. 1-145) (20a) 3-(3·Chloro-4-fluoro-phenyl)-propanal imformation Example (la) from 3-chloro-4-fluoroiodobenzene (5.04 g) And allyl alcohol (1.98 mL) gave the title compound 2. 2. MS (EI) m/z: 186 M + . (20b) 5-(3-chloro-4-fluoro-benzyl)-thiazol-2-ylamine. The method of Example (lb), by the example ( 20a) </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; MS (ES) m/z: 243 (Μ + H) + . -120- 200906395 (20c) iV-[5-(3-chloro-4-fluoro-benzyl)-thiazol-2-yl]-3- (2-Hydroxy-ethoxy)-4-methoxy-benzylamine as the method of Example (If), 4-methoxy-3-[2-(tetrahydro-) obtained from Example (le) Pyr-2-yloxy)-ethoxy]-benzoic acid (140 mg), 5-(3-chloro-4-fluoro-benzyl)-thiazol-2-ylamine obtained in Example (20b) (115 mg ), 173 mg (70%) of hydrazine was obtained. The guanamine was deprotected with 1N EtOAc to afford titled compound (EtOAc) Ή NMR (400MHz, CDCl3): &lt;5 (ppm) = 10.9 (lH, brs), 7.52 (1H, dd, J = 8.6, 2.0 Hz), 7.46 (1H, d, J = 2.0 Hz), 7.47-7.4 6 ( 1 H, m) , 7.13-7.05(2H, m), 7.01(1H, s), 6.88(1H, d, J = 8.6Hz), 4.14(2H, t, J = 4.7Hz), 4.04(2H, s), 4.02( 2H, t, J = 4.7Hz), 3.87(3H, s), 2.95(1H, brs) MS(ES) m/z: 437 (M + H) + . Melting point: 1 5 2 - 1 5 3 °C . (Example 21) 7V-[5-(3,4-Difluoro-benzyl)-thiazol-2-yl]-3-(2-hydroxy-ethoxy)-4-methoxy-benzylguanamine (Compound No. 1-121) (21a) 3-(3,4-Difluoro-phenyl)-propanal imformation Example (la), from 3,4-difluoroiodobenzene (3.71 g) and alkene Propanol (1.591111 〇, title compound 2.19 £ (83%) pale yellow oil. MS (EI) m/z: 170 M+. (21b) 5-(3,4-difluoro-benzyl)-thiazole-2 -Based to the method of Example (lb), the title of 3-(3,4-difluoro-phenyl)-propanal (2.19 g) and thiourea (1.0 g) obtained from Example (21a) Compound 1.61 g (55%) White solid. -121 - 200906395 MS (ES) m/z: 227 (M + H) + . (21c) A^-[5-(3,4·difluoro-benzyl) -thiazol-2-yl]-3-(2-hydroxy-ethoxy)-4-methoxy-benzylamine as the method of Example (If), 4-methoxyl obtained from example (le) -3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoic acid (154 mg), 5-(3,4-difluoro-benzyl) obtained as an example (2 lb) </RTI> </RTI> </RTI> </RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; 400MHz, CDCl3) (5 (ppm) = 10.5 (lH, brs), 7.53-7.49 (2H, m), 7.1 3-7.02 (3H, m), 6.98-6.96 (lH, m), 6.90 (1H, d, J = 8.6 Hz), 4.15(2H, t, J = 4.5Hz), 4.05(2H, s), 4.01(2H, brs), 3.90(3H, s), 2.72(1H, brs) MS(ES) m/z: 421 (M + H) + . Melting point: 1 6 3 - 1 6 4 ° C. (Example 22) 3-(2-hydroxy-ethoxy)-4-(2-methoxy-ethoxy) -vV-[5-(3-trifluoromethyl-benzyl)-thiazol-2-yl]-benzylguanamine (Compound No. 1-68) (22a) 4-fluoro-3-hydroxy-benzoic acid methyl ester The title compound 1 0.8 g (9 9 %) pale peach solid was obtained from the title compound (13). Μ + H) + . (22b ) 4-fluoro-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoic acid methyl ester imitation of the method of the embodiment (13b), The 4-fluoro-3-hydroxy-benzoic acid methyl ester (10.8 g) obtained in Example (22a) gave the title compound. -122- 200906395 NMR (400MHz, CDC13): δ (ppm) = 7.73 (lH, dd, J = 8.2, 1.9 Hz), 7.66-7.63 (lH, m), 7.11 (1H, dd, J = l〇 .6, 8.6 Hz), 4.73 (1H, t, J = 3.5 Hz), 4.3 1-4.27 (2H, m), 4.1 2 - 4.07 (1 H, m), 3.92-3.83 (2H, m), 3.91 (3H, s), 3.56-3.5 1 (1 H, m), 1.84-1.82 (1H, m), 1.77-1.7 1(1H, m), 1.6 5 -1 . 5 1 (4H, m). ( 22c) 4-(2-methoxy-ethoxy)-3-[2-(tetraki-p-pyran-2-yloxy)-ethoxy]-benzoic acid imitation method (13c) , 4-fluoro·3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoic acid methyl ester (l.98 g) obtained from Example (22b), mp. Color oil. The title compound (284 mg (13%, 2%)) was obtained as a beige solid. MS(ES) m/z: 3 39 (Μ - Η) + . (22d) 3-(2-hydroxy-ethoxy)-4-(2-methoxy-ethoxy)-7V-[5 -(3-Trifluoromethyl-benzyl)-thiazol-2-yl]-benzamide compound (If), 4-(2-methoxy-ethoxylated) obtained from Example (22c) 3-(2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoic acid (154 mg), 5-(3-trifluoromethyl-benzyl) obtained in Example (lb) )-thiazol-2-ylamine (117 mg) to give the guanamine. The guanamine was deprotected with 1N HCl to give title compound 106 mg (47%) of white solid. NMR NMR (400 MHz, DMSO-d6): (5 (ppm) = 1 2.4 (1 Η, brs), 7.74 (1 Η, d, J = 2.0 Hz), 7.70 (1H, d, J = 2.0 Hz), 7.68 (1H, d, J-2.3Hz), 7.68 - 7.68(3H, m), 7.38(1H, s), 7.1 1(1H, d, J = 8.6Hz), 5.14(1H, brs), 4.25(2H , s), 4.20-4.18(2H, m), 4.09(2H, t, J = 5.3Hz), 3.75(2H, t, J = 5.2Hz), 3.70-3.68(2H, m), 3.32(3H, -123 - 200906395 s). MS(ES) m/z: 497 (M + H) + . Melting point: 1 3 6 - 1 3 8 ° C. (Example 2 3 ) TV- [5-(3,4 - _Chloro-indenyl)-salben-2-yl]-3-(2-propionyl-ethoxy)-4.methoxy-benzylguanamine (Compound No. 1-201) (23 a) 3 -(3,4-Dichloro-phenyl)-propanal im of the method of Example (la) from 3,4-dichloroiodobenzene (5.00 g) and allyl alcohol (1.89 mL) g (68%) light yellow oil. MS (EI) m/z: 202 M + . (23b) 5-(3,4-dichloro-benzyl)-thiazol-2-ylamine imitation Example (lb) The title compound, 1.41 g (44%), m. MS(ES) m/z: 25 9 (Μ + H)+. (23c)AM5-(3,4-dichloro-benzyl)-thiazol-2-yl]-3-(2-hydroxy-ethoxy 4-methoxy-benzylamine imine by the method of Example (If), 4-methoxy-3-[2-(tetrahydro-pyran-2-yloxy) obtained from the example (le) -Ethoxy]-benzoic acid (121 mg), 5-(3,4-dichloro-benzyl)-thiazol-2-ylamine (106 mg) obtained in Example (23b), mp 134 mg (61%) The guanamine was deprotected with 1N EtOAc (EtOAc:EtOAc) &lt;5 (ppm) = 1 2.4 (1 Η, brs), 7.72 (1 Η, s), 7.71 (1Η, d, J = 7.8 Hz), 7.59 (1H, d, J = 8.8 Hz), 7.58 (1H , s), 7.35(1H, s), 7.30(1H, dd, J = 7.8, 2.0Hz), 7.09(1H, d, -124- 200906395 J = 8.8Hz), 4.88(1H, t, J = 5.4 Hz), 4.14(2H, s), 4.07(2H, t, J = 5.1Hz), 3.84(3H, s), 3.75(2H, dt, J = 5.4, 5.1Hz) MS(ES) m/z: 45 3 (M + H) + . Melting point: 1 65 - 1 66 °C. (Example 24) 7V-[5-(3-Fluoro-4-methyl-benzyl)-thiazol-2-yl]-3-(2-hydroxy-ethoxy)-4-methoxy-benzyl Indoleamine (Compound No. 1-160) (24a) 3-(3-Fluoro-4-methyl-phenyl)-propanal imitation Example (la), from 2-fluoro-4-iodotoluene (5.16) g) and allyl alcohol (2.23 mL) gave the title compound 2. MS (EI) m/z: 166 M + . (24b) 5-(3-fluoro-4-methyl-benzyl)-thiazol-2-ylamine. </RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; MS(ES) m/z: 223 (Μ + H) + . (24c) 7V-[5-(3-Fluoro-4·methyl-benzyl)-thiazol-2-yl)-3-(2- Hydroxy-ethoxy)-4.methoxy-benzamide amide The method of Example (If), 4-methoxy-3-[2-(tetrahydro-pyran-) obtained from Example (le) 2-(2-oxo)-ethoxy]-benzoic acid (137 mg), 5-(3-fluoro-4-methyl-benzyl)-thiazol-2-ylamine obtained in Example (24b) (103 mg ), obtained lysamine 154 mg (67%). The guanamine was deprotected with 1N EtOAc (EtOAc) (EtOAc) NMR NMR (400MHz, DMSO-d6): 5 (ppm) = 1 2.4 (1 Η, brs), 7.72 (1Η, s), 7.71 (1Η, d, J = 7.5Hz), 7.28(1H, s), 7.23(1H, t, J = 8.0Hz), -125- 200906395 7.09-7.0K3H, m), 4.87(1H, t, J = 5.4Hz), 4.08(2H, s), 4.06(2H, t, J = 5.1Hz), 3.84(3H, s), 3.75(2H, dt, J = 5.4, 5.1Hz), 2.20(3H, s) MS(ES) m/z: 417 (M + H) + . 1 8 1 -1 8 2 °C. (Example 25) 2-(3,5-bis-trifluoromethyl-benzyl)-thiazole-5-carboxylic acid [3-(2-hydroxy-ethoxy)-4-methoxy-phenyl ]-decylamine (Compound No. 4-47) (25a) 2-(3,5-Bis-Trifluoromethyl-benzyl)-thiazole-5-carboxylic acid ethyl ester in sodium ethoxide (20% ethanol solution, 18.5) A solution of anhydrous ethyl ether (40 mL) in EtOAc EtOAc (EtOAc) The reaction mixture was warmed to room temperature, stirred overnight and filtered. The filtrate was dissolved in water, carefully made acidic with 2N hydrochloric acid and extracted with diethyl ether. The organic layer was washed with brine, dried over sodium sulfate and evaporated This oil (860 mg) was added to a solution of 2-[3,5-bis(trifluoromethyl)phenyl]ethanethioindole (410 mg) in toluene (4 mL). After refluxing for 5 hours, the reaction mixture was crystallised eluted eluted elut elut elut elut elut elut elut MS (ES) m / z: 384 ( Μ + H) + . (25b) 2-(3,5-bis-trifluoromethyl-benzyl)-thiazole-5-carboxylic acid obtained from Example (25a) 1-(3,5-Bis-trifluoromethyl-benzyl)-thiazole-5-carboxylic acid ethyl vinegar (260 mg) in 1N aqueous sodium hydroxide (1 mL) and 1, 4 - 2 (3 mL) The mixed solution was heated at 60 ° C for 30 minutes. The reaction mixture was made acidic with a 1% aqueous solution of citric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated. The residue was washed with isopropyl ether / hexane - 126 - 2009063 95 (2:1). MS(ES) m/z: 354 (Μ - Η) + . (25c) 2-(3,5-bis-trifluoromethyl-benzyl)-thiazole-5-carboxylic acid [3-(2-hydroxyl) -Ethoxy)-4-methoxy-phenyl)-nonylamine 2-(3,5-bis-trifluoromethyl-benzyl)-thiazole-5-carboxylic acid obtained in Example (25b) 5 3 mg) and 3-[2-(t-butyl-dimethyl-decyloxy)-ethoxy]-4-methoxyphenylamine (49 mg) obtained in Example (8c), HATU ( A solution of 62 mg) and triethylamine (40 &quot; L) in dimethylacetamide (1 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. The residue was dissolved in 1 N hydrochloric acid (0.2 mL) and methanol (2 mL), and then warmed at 50 ° C for 30 minutes. The reaction mixture was diluted with EtOAc (EtOAc m. The residue was washed with EtOAc (EtOAc)EtOAc. NMR NMR (400MHz, DMSO-d6): 5 (ppm) = l〇.2(lH, brs), 8.47(1H, \s), 8.16(2H, s), 8.07(1H, s), 7.34(1H , d, J = 2.4Hz), 7.23(1H, dd, J = 8.6 and 2.4Hz), 6.95(1H, d, J = 8.6Hz), 4.86(1H, t, J = 5.5Hz), 4.66(2H , s), 3.94 (2H, t, J = 5.3 Hz), 3.75 (3H, s), 3.73 (2H, q, J = 5.1 Hz) MS (ES) m/z: 521 (M + H) + . Melting point: 1 4 8 - 1 5 0 °C. (Example 26); V-[5-(3-chloro-benzyl)-salrazolyl]ethoxy-3-(2-hydroxyethyloxy)-benzylguanamine (Compound No. I-41) - 127-200906395 By the method of Example (If), 4-ethoxy-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoic acid obtained from Example (13d) (158 mg), and 5-(3-chloro-benzyl)-thiazol-2-ylamine (114 mg) obtained from Example (12b). The title compound was obtained (35.0 mg (49% Ή NMR (400MHz, DMSO-d6): &lt;5 (ppm) = 1 2.4 (1 Η, brs), 7.73 (1Η, d, J = 1.9 Hz), 7.69 (1H, dd, J = 8.2, 1.9 Hz), 7.39-7.27 (5H, m) , 7.08(1H, d, J = 8.6Hz), 4.86(1H, t, J = 5.1Hz), 4.1 5-4. 1 1 (4H, m), 4.08(2H, t, J = 5.0Hz), 3.75(2H, dt, J = 5.1, 5.0Hz), 1.35(3H, t, J = 7.0Hz) MS(ES) m/z:43 3 (M + H) + . Melting point: 1 5 1 -1 5 3 °C. (Example 27) 4-Ethoxy-N-[5-(4-fluoro-3-trifluoromethyl-benzyl)-thiazol-2-yl]-3-(2-hydroxy-ethoxy) -benzylguanamine (Compound No. 1-178) 4-ethoxy-3-[2-(tetrahydro-pyran-2-yloxy) obtained from Example (13d) by the method of Example (If) -ethoxy]-benzoic acid (130 mg), and 5-(4-fluoro-3-trifluoromethyl-benzyl)-thiazol-2-ylamine (116 mg) obtained in Example (16b) Body 120 mg (51%). The title compound (42.6 mg (42%)) NMR (400 MHz, DMSO-d6): 5 (ppm) = 12.4 (1H, brs), 7.75-7.67 (4H, m), 7.48 (1H, dd, J = 10.6, 8.6 Hz), 7.35 (1H, s), 7.08(1H, d, J = 8.6Hz), 4.86(1H, t, J = 5.5Hz), 4.22(2H, s), 4.12(2H, q, J=7.0Hz), 4.08(2H, t, J = 5.2 Hz), 3.75 (2H, dt, J = 5.5, 5.2 Hz), 1.35 (3H, t, J = 7.0 Hz) -128- 200906395 MS(ES) m/z: 485 (M + H ) +. Melting point: 1 60-162 °C. (Example 28) TV-[5-(3-Chloro-benzyl)-thiazol-2-yl]-3-(2-hydroxy-ethoxy)-4-(2-methoxy-ethoxy group - benzinamide (Compound No. 1-44) 4-(2-methoxy-ethoxy)-3-[2-(tetrahydrogen) obtained by the method of Example (If) -pyran-2-yloxy)-ethoxy]-benzoic acid (63 mg), and 5-(3-chloro-benzyl)-thiazol-2-ylamine (42 mg) obtained in Example (12b) Amidoxime. The title compound (22 mg (26%)) NMR NMR (400MHz, DMSO-d6): 5 (ppm) = 1 2.4 ( 1 H, brs), 7.72 (1 Η, d, J = 1,9 Hz), 7.66 (1H, dd, J = 8.4, 2.1 Hz) , 7.35(1H, t, J = 7.8Hz), 7.33(1H, s), 7.3 0 - 7.2 2 (3 H, m), 7.04(1H, d, J = 8.6Hz), 4.84(1H, brs) , 4.17(2H, t, J = 4.5Hz), 4.08(2H, s), 4.07(2H, t, J = 6.0Hz), 3.74(2H, q, J = 5.1Hz), 3.68(2H, t, J = 4.5 Hz), 3.32 (3H, s). MS (ESI) m. (Example 29) jV-[5-(4-Fluoro-3-trifluoromethyl-benzyl)-thiazol-2-yl]-3-(2-hydroxy-ethoxy)-4-(2- Methoxy-ethoxy)-benzylguanamine (Compound No. 1-181) 4-(2-methoxy-ethoxy)-3 obtained by the method of Example (If) -[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoic acid (60 mg), and 5-(4-fluoro-3-trifluoromethyl-benzyl) obtained in Example (16b) Base)-thiazol-2-ylamine (49 mg) gave the guanamine. The guanamine was deprotected with 1N hydrochloric acid to give a compound (yield: 129-2009063) (24% (26%) of white solid. 1Η N M R (4 0 0 Μ H z, D M S 0 - d 6): &lt;5 (ppm) = 1 2 · 4 (1 Η, brs), 7 · 7 4 (1 Η, dd, J = 6.3, 2.0 Hz), 7.73 (1H, s), 7.7 0-7.67 (2H, m), 7.49(1H, t, J = 5.3Hz), 7.36(1H, s), 7.12(1H, s), 4.85(1H, t, J = 5.3Hz), 4.22(2H, s), 4.19( 2H, t, J = 4.7Hz), 4.09(2H, t, J = 5.2Hz), 3.75(2H, q, J = 5.5Hz), 3.68(2H, t, J = 4.5Hz), 3.32(3H, MS (ESI) m/z: 515 (M + H) + . (Example 30) ΛΜ 5-(3-Fluoro-benzyl)-thiazol-2-yl]-3-(2-hydroxy-ethoxy)-4-(2-methoxy-ethoxy)- Benzalamine (Compound No. 1-20) 4-(2-methoxy-ethoxy)-3-[2-(tetrahydro-pyridyl) obtained by the method of Example (If) M--2-yloxy)-ethoxy]-benzoic acid (166 mg), and 5-(3-fluoro-benzyl)-thiazol-2-ylamine (10 mg) obtained in Example (10 g) Amidoxime. The title compound was obtained as a white solid. Ή NMR (400MHz, DMSO-d6): &lt;5 (ppm) = 1 2.4 (1 Η, brs), 7.73 (1Η, d, J = 2.0 Hz), 7.69 (1H, dd, J = 8.4, 2.2 Hz), 7.4 1-7.3 5 (1H, m), 7.33(1H, s), 7.16-7.05(4H, m), 4.85(1H, t, J = 5.1Hz), 4.19(2H, t, J = 4.7Hz), 4.14(2H, s), 4.09(2H, t, J = 5.2Hz), 3.75(2H, q, J = 5.3Hz), 3.69(2H, t, J = 4.6Hz), 3.32(3H, s). MS(ESI) m/z : 447 (M + H) + . Melting point: 1 3 7 - 1 3 8 °C. (Example 31): ¥-[5-(3,4-difluoro-benzyl)-shrazol-2-yl]-3-(2-hydroxy-ethoxy) 4-(2-methoxy) -ethoxy)-benzylguanamine (Compound No. 1-125) -130-200906395 The method of the example (If), 4-(2-methoxy-ethoxy)- obtained from the example (22c) 3-[2-(tetrahydro-pyran-2-yloxy)·ethoxy]-benzoic acid (159 mg), and 5-(3,4-difluoro-benzyl)- obtained from Example (21b) Thiazol-2-ylamine (106 mg) 'deacetylamine. The guanamine was deprotected with 1N hydrochloric acid to give the title compound 124 mg (57%) of white solid. NMR (400MHz, DMSO-d6): 5 (ppm) = 1 2.4 ( 1 H, brs), 7.73 (1 Η, d, J = 2.0 Hz), 7.68 (1H, dd, J = 8.4, 2.1 Hz), 7.4 0 - 7.3 4 (2H, m), 7.28(1H, s), 7.16-7.13(1H, m), 7.08(1H, d, J = 8.6Hz), 4.85(1H, t, J = 5.0Hz) , 4.18(2H, t, J = 4.7Hz), 4.10(2H, s), 4.08(2H, t, J = 5.5Hz), 3.75(2H, q, J = 5.3Hz), 3.69(2H, t, J = 4.5 Hz), 3.33 (3H, s). MS (ESI) m/z: 465 (M + H) + . (Example 32); V-[5-(3,5-Difluoro-benzyl)-thiazol-2-yl]-3-(2-hydroxyethoxy)-4-(2-methoxy- Ethoxy)-benzylamine (Compound No. 1-237) 4-(2-methoxy-ethoxy)-3-[2- obtained from the compound of Example (22c). (tetrahydro-pyran-2-yloxy)-ethoxy]-benzoic acid (157 mg), and 5-(3,5-difluoro-benzyl)-thiazol-2-yl obtained in Example (19b) Amine (104 mg) gave the guanamine. The guanamine was deprotected with 1N HCl to afford titled compound (l. NMR (400MHz, DMSO-d6): (5 (ppm) = 1 2.4 (1H, brs), 7.73 (1 Η, d, J = 2.0 Hz), 7.69 (1H, dd, 1-8.4, 2.2 Hz), 7.37(1H, s), 7.13-7.04(4H, m), 4.19(2H, t, J = 4.7Hz), 4.16(2H, s), 4.09(2H, t, J = 5.2Hz), 3.75(2H , t, J = 5.1Hz), 3.69(2H, t, J = 4.5Hz), -131 - 200906395 3.32(3H, s). MS(ESI) m/z:465 (M + H) + . 140-143 ° C. (Example 33) 7V-[5-(3-chloro-4-fluoro-benzyl)-thiazol-2-yl]-3-(2-hydroxy-ethoxy)-4- (2-Methoxy-ethoxy)-benzylguanamine (Compound No. 1-149) 4-(2-methoxyethoxy) obtained by the method of Example (If). -3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoic acid (15111^), and 5-(3-chloro-4-fluoro-) obtained in Example (20b) Benzyl)-thiazol-2-ylamine (107 mg) gave decylamine. EtOAc (EtOAc: EtOAc) : 5 (ppm) = 1 2.4(1 Η, brs), 7.73(1H, d, J = 1.9Hz), 7.68(1H, dd, J = 8.4, 2·2Ηζ), 7.51(1H, dd, J = 7.1, 2.0 Hz), 7.37 (1H, t, J = 9.0 Hz), 7.3 2 - 7.2 8 ( 1 H, m), 7.28 (1H, s), 7.0 8(1H, d, J = 8.6Hz), 4.85(1H, t, J = 5.0Hz), 4.18(2H, t, J = 4.7Hz), 4.10(2H, s), 4.08(2H, t, J = 5.2 Hz), 3.75 (2H, q, J = 5.0 Hz), 3.68 (2H, t, J = 4.5 Hz), 3.32 (3H, s). MS (ESI) m/z: 481 (M + H) +. Melting point: 1 59- 1 60 ° C. (Example 34) 7V-[5-(3,5-Dichloro-benzyl)-thiazol-2-yl]-3-(2-hydroxy·B Oxy)-4-(2-methoxy-ethoxy)-benzamide (Compound No. 1-277) 4-(2-A) obtained by the method of Example (If) Oxy-ethoxy)-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoic acid (142 mg), and 5-(3,5) obtained in Example (17b) -Dichloro-benzyl)-thiazol-2-ylamine (108 mg) gave the decylamine. The guanamine was deprotected with 1N HCl to afford titled </ RTI> </ RTI> </ RTI> <RTIgt; NMR NMR (400MHz, DMSO-d6): (5 (ppm) = 1 2.4 (1 Η, brs), 7.73 (1H, d, J = 2.0 Hz), 7.69 (1H, d, J = 8.6 Hz), 7.49 (1H, s), 7.37(3H, d, J = 10.2Hz), 7.11(1H, d, J = 8.6Hz), 4.86(1H, t, J = 5.5Hz), 4.19(2H, t, J = 4.5Hz), 4.15(2H, s), 4.09(2H, t, J = 5.2Hz), 3.75(2H, q, J = 5.1Hz), 3.69(2H, t, J = 4.5Hz), 3.32(3H MS (ESI) m/z: 495 (M + H) +. mp.: 1-5 s. - thiazol-2-yl]-3-(2-hydroxy-ethoxy)-4-(2-methoxy-ethoxy)-benzamide (Compound No. 1-205) The method of If), 4-(2-methoxy-ethoxy)-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzene obtained from the compound (22c) Formic acid (143 mg), and 5-(3,4-dichloro-benzyl)-thiazol-2-ylamine (109 mg) obtained in Example (23b) gave decylamine. The title compound was obtained as a white solid: EtOAc (EtOAc: EtOAc: EtOAc) (1H, dd, J = 8.4, 2.2Hz), 7.59(1H, d, J = 8.2Hz), 7.57(1H, s), 7.30(1H, s), 7.29(1H, d d, J = 8.2, 2.3 Hz), 7.08 (1H, d, J = 8.2 Hz), 4.86 (1H, t, J = 5.3 Hz), 4.18 (2H, t, J = 4.5 Hz), 4.12 (2H, s), 4.08(2H, t, J = 5.0Hz), 3.75(2H, q, J = 5.4Hz), 3.68(2H, t, J = 4.5Hz), 3.33(3H, s). MS(ESI) m/z: 497 (M + H) + . m.p.: 140 - 142 C. (Example 36) 3-(2-hydroxy-ethoxy)-4-(2-methoxy-ethoxy) -ΛΜ5--133- 200906395 (3-Trifluoromethoxybenzyl)-thiazol-2-yl]-benzamide (Compound No. 1-101) The method of the example (If), by the example ( 22c) 4-(2-methoxy-ethoxy)-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoic acid (Mlmg), and ( 15b) The obtained 5-(3-trifluoromethoxy-benzyl)-thiazol-2-ylamine (114 mg) gave the title compound. The guanamine was deprotected with 1N aqueous hydrochloric acid to give the title compound 87 mg (41%) of white solid. NMR NMR (400MHz, DMSO-d6): (5 (ppm) = 1 2.4 (1 Η, brs), 7.72 (1H, d, J = 2.0 Hz), 7.67 (1H, dd, J = 8.4, 2.1 Hz) , 7.47(1H, dd, J = 8.1, 8.0Hz), 7.33(1H, d, J = 7.8Hz), 7.28(2H, s), 7.23(1H, d, J = 7.8Hz), 7.07(1H, d, J = 8.6 Hz), 4.85 (1H, t, J = 5.5 Hz), 4.17 (2H, t, J = 5.4 Hz), 4.16 (2H, s), 4.08 (2H, t, J = 5.3 Hz) , 3.75 (2H, q, J = 5.1 Hz), 3.68 (2H, t, J = 4.7 Hz), 3.33 (3H, s). MS (ESI) m/z: 513 (M + H) + . 1 3 3 - 1 3 4 ° C. (Example 37) AM5-(3,5-difluoro-benzyl)-thiazol-2-yl]-4-ethoxy-3-(2-hydroxy-B Oxy)-benzylamine (Compound No. 234) 4-ethoxy-3-[2-(tetrahydro-pyran-2-yl) obtained by the method of Example (13d). Oxy)-ethoxy]-benzoic acid (148 mg), and 5-(3,5-difluoro-benzyl)-thiazol-2-ylamine (108 mg) obtained in Example (19b) gave decylamine. The guanamine was deprotected with 1N aqueous HCl to give the title compound: 65 mg (37%) as a white solid. NMR (400 MHz, DMSO-d6): &lt;5 (pp m) = 1 2.4 (1 Η, brs), 7.73 (1H, d, J = 2.0 Hz), 7.70 (1H, d, J = 8.6 Hz), 7.36 (1H, s), 7.14- -134- 200906395 7.04(4H, m), 4.86(1H, t, J = 5.5Hz), 4.16(2H, s), 4.14(2H, q, J = 7.0Hz), 4.08(2H, t, J = 5.1 Hz), 3 · 7 6 (2 H, q, J = 5.1 Hz), 1.35 (3H, t, J = 7.0 Hz). MS (ESI) m/z: 435 (M + H) + . 1 8 2 -1 8 4 °C. (Example 38) AM5-(3-Fluoro-benzyl)-thiazol-2-yl]-4-ethoxy-3-(2-hydroxy-ethoxy)-benzamide (Compound No. 1-17 4-Ethoxy-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoic acid (162 m) obtained by the method of Example (13). g), and 5-(3-fluoro-benzyl)-thiazol-2-ylamine (109 mg) obtained in Example (10 g) gave decylamine. The title compound was obtained as a white solid (yield: 46%). Ή NMR (500MHz, DMSO-d6): &lt;5 (ppm) = 1 2.4 ( 1 H, brs), 7.71 (1 Η, s), 7.69 (1Η, d, J = 8.7 Hz), 7.37 (1H, q, J = 7.8 Hz), 7.34 (1H , s), 7.15-7.12(2H, m), 7.08-7.05(2H, m), 4.85(1H, t, J = 5.4Hz), 4.14(2H, s), 4.12(2H, q, J = 6.8 Hz), 4.08(2H, t, J = 5.1Hz), 3.75(2H, q, J = 5.4Hz), 1.35(3H, t, J = 6.8Hz). MS(ESI) m/z:417 (M + H) + . Melting point: 1 7 6 - 1 7 8 °C. (Example 39) iV-[5-(3,4-difluoro-benzyl)-thiazole·2-yl]-4-ethoxy-3-(2-hydroxy-ethoxy)-benzamide ( Compound No. 122) 4-Ethoxy-34 kappa; tetrahydro-pyran-2-yloxy)-ethoxy]-benzoic acid (149 mg obtained by the method of Example (13d). And 5-(3,4-difluoro-benzyl)-thiazol-2-ylamine (109 mg) obtained in Example (21b) afforded the amine-135 - 200906395. The title compound was obtained as a white solid. NMR NMR (400 MHz, DMSO-d6): 5 (ppm) = 1 2.4 (1 Η, brs), 7.72 (1 Η, d, J = 2.4 Hz), 7.69 (1H, dd, J = 8.4 and 2.2 Hz), 7.40-7.36(2H, m), 7.33(1H, s), 7.1 7-7.1 5 (1 H, m), 7.08(1H, d, J = 8.6Hz), 4.87(1H, t, J = 5.3Hz ), 4.1 5-4.1 1 (4H, m), 4.08(2H, t, J = 5.0Hz), 3.75(2H, q, J = 5.5Hz), 1.35(3H, t, J = 7.1Hz). MS (ESI) m/z: 435 (M + H) +. Melting point: 1 8 3 - 1 8 5 °C. (Example 40) 7V-[2-(3,5-bis-trifluoromethyl-benzyl)-s-piperazol-5-yl]-3-(2-hydroxy-ethoxy)-4-methoxy Base-benzylamine (Compound No. 3-47) (40a) 2-(3,5-Bis-Trifluoromethyl-benzyl)-thiazole-5-carboxylic acid ethyl ester in 2-[3,5-double A solution of (trifluoromethyl)phenyl]ethionamide (410 mg) in toluene (4 mL) at room temperature with 2-chloro-3-oxo-propionic acid ethyl acetate (Heterocycles, 1991, 32, 699) (430 mg) ). The reaction mixture was heated to reflux for 4 hours to concentrate. The residue was purified by chromatography EtOAcjjjjjjjj MS (ES) m / z: 3 84 ( Μ + H) + . (40b) 2-(3,5-bis-trifluoromethyl-benzyl)-thiazole-5-carboxylic acid Example (40a) a mixture of the obtained ethyl 2-(3,5-bis-trifluoromethyl-benzyl)-thiazole·5-carboxylate (238 mg) and 1N aqueous sodium hydroxide (1 mL) and dioxane (3 mL) Heat at 60 ° C for 30 minutes. The reaction mixture was diluted with a 10% aqueous citric acid solution and extracted with ethyl acetate. The organic layer was washed with EtOAc EtOAc m. -136- 200906395 MS(ES) m/z: 354 (M - H) + . (4 0c) [2-(3,5-bis-trifluoromethyl-benzyl)-thiazol-5-yl]- A solution of the third butanol (5 mL) of 2-(3,5-bis-trifluoromethyl-benzyl)-thiazole-5-carboxylic acid (206 mg) obtained in Example (40b) Triethylamine (90 // L) and DPPA (0.13 mL) were added sequentially at room temperature. The reaction mixture was heated at 80 ° C for 22 hours. Triethylamine and DPPA were added and stirred until the end of the reaction. The reaction mixture was cooled to 0 ° C and diluted with ethyl acetate. The resulting water-soluble mixture was stirred at room temperature for 1 hour and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated. The residue was purified by chromatography (yield: EtOAc) MS (ES) m/z: 427 ( Μ + H) + . (40d) 2-(3,5-bis-trifluoromethyl-benzyl)-thiazol-5-ylamine obtained in Example (40c) a solution of [2-(3,5-bis-trifluoromethyl-benzyl)-thiazol-5-yl.]-aminocarboxylic acid tert-butyl ester (79 mg) in dichloromethane (2 mL) (1 mL). The reaction mixture was stirred at room temperature for 1 hour and concentrated. The residue was made basic with a saturated aqueous solution of hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate and concentrated to give a crude oil (yield: 63 mg). MS(ES) m/z: 327 (Μ + H) + . (40e) AM2-(3,5-bis-trifluoromethyl-benzyl)-thiazol-5-yl]-3-(2-hydroxyl _Ethoxy)-4-methoxy-benzylamine. The method of Example (If), 4-methoxy-137-200906395 tetrahydro-pyran-2-yloxy obtained from Example (le) )-ethoxy)-benzoic acid (60 mg), and 2-(3,5-bis-trifluoromethyl-benzyl)-thiazol-5-ylamine (63 mg) obtained in Example (40d). Amines. The guanamine was deprotected with 1N hydrochloric acid to give 6 mg (yiel. NMR NMR (500MHz, DMSO-d6): δ (ppm) = l 1.5(1H, s), 8.09(2Η, s), 8.02(1Η, s), 7.63(1Η, dd, J = 8.3 and 2.0Hz) , 7.59(1H, s), 7.56(1H, d, J = 2.0Hz), 7.12(1H, d, J = 8.8Hz), 4.89(1H, t, J = 5.4Hz), 4.5K2H, s), 4.05(2H, t, J = 5.1Hz), 3.85(3H, s), 3.75(2H, q, J = 5.4Hz). MS(ES) m/z: 521 (M + H) + . Melting point: 1 7 7 - 1 7 9 °C. (Example 41) 4-dimethylamino-3-(2-hydroxy-ethoxy)-7V-[5-(3-trifluoromethylbenzyl)-thiazol-2-yl]-benzidine Amine (Compound No. 10-85) (41a) 4-nitro-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoic acid methyl ester as in Example (lc) The title compound was obtained from the title compound: 8.94 g (yield: </ RTI> </ RTI> </ RTI> <RTIgt; %) yellow oil. NMR NMR (400MHz, CDC13): (5 (ppm) = 7.84 (lH, s), 7.83 (1H, d, J = 9.8 Hz), 7.71 (1H, d, J = 9.7 Hz), 4.73 (1H, t , J = 3.3Hz), 4.42-4.34(2H, m), 4.1 6-4.0 8 (1H, m), 3.97(3H, s), 3.92-3.83(2H, m), 3.57-3.52(lH, m ), 1. 86-1.7 1 (2H, m), 1.65 -1. 5 1 (4H, m). (4 lb) 4-amino-3-[2-(tetrahydro-pyran-2-yl) Oxy)-ethoxy]-benzoic acid methyl ester The 4-nitro-3-[2-(tetrahydro-pyran-2-yloxy) group obtained from the compound (41a) was obtained by the method of Example (8c). Ethyl ethoxy]-methyl benzoate (7.33 g), titled - 138 - 200906395 Compound 6.88 g (yield of quantitative) of colorless oil. MS (ES) m/z: 296 (Μ + H) + (41c) 4-Dimethylamino-3-[2-(tetrahydro-pyran-2-yloxy)ethoxy]-benzoic acid methyl ester obtained in Example (4 lb) 4-amino a solution of -3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoic acid methyl ester (1.91 g) in dichloromethane (20 mL) and methanol (30 mL) (0.37mL), formaldehyde (〇.5g), and sodium triethoxysulfonium borohydride (3.0 2 g). The reaction mixture was warmed to room temperature, and acetic acid, formic acid and sodium triethoxysulfonate were added to the reaction. End. Mix the reaction The mixture was concentrated and diluted with aq. EtOAc EtOAc EtOAc (EtOAc m. g (86%) colorless oil MS (ES) m/z: 324 ( Μ + Η) + . (4 ld) 4-dimethylamino-3-[2-(tetrahydro-pyran-2-yl) Oxy)-ethoxy]-benzoic acid imitation of the method of Example (le), 4-dimethylamino-3-[2-(tetrahydro-pyran-2-yloxy) obtained from Example (41c) Ethyl ethoxy]-methyl benzoate (1.79 g) gave the title compound 2. <RTI ID=0.0></RTI> - dimethylamino-3-(2-hydroxy-ethoxy)-, [5-(3-trifluoromethylbenzyl)-thiazol-2-yl]-benzamide compound (1 f) Method, 4-dimethylamino-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoic acid (136 mg) obtained from Example (41 d) and examples (lb) The obtained 5-(3-trifluoromethyl-benzyl)-thiazol-2-ylamine (103 mg) gave the title compound. The guanamine was deprotected with 1N EtOAc to afford titled compound - 139 - 200906395 37.5 mg (20%) as white solid. NMR NMR (500 MHz, DMSO-d6): δ (ppm) = 1 2.3 (1 Η, s), 7.67- 7.56 (6H, m), 7.35 (1H, s), 6.87 (1H, d, J = 8.8 Hz), 4.86(1H, t, J = 5.3Hz), 4.24(2H, s), 4.09(2H, t, J = 5.1Hz), 3.78(2H, q, J = 5.1Hz), 2.85(6H, s) MS (ES) m/z: 466 (M + H) +. Melting: 1 56 - 1 58 ° C. (Example 42) 7V-[5-(3-chlorobenzyl)-thiazol-2-yl]-4-dimethylamino-3-(2-hydroxy-ethoxy)-benzamide (Compound No. 10-55) 4-dimethylamino-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxylate obtained by the method of Example (1 1 d) Benzoic acid (135 mg) and 5-(3-chloro-benzyl)-thiazol-2-ylamine (97 mg) obtained in Example (12b) gave decylamine. The guanamine was deprotected with 1N aqueous hydrochloric acid to give the title compound (yield: 79 mg (41%)). Ή NMR (400MHz, CDCl3): &lt;5 (ppm) = 11.0 (1 Η, brs), 7.53 (1Η, s), 7.50 (1Η, s), 7.25-7.19(3Η, m), 7.1 6 - 7.1 3 (1 Η, m), 7.06(1Η, s), 6.90(1Η, d, J = 8.6Hz), 4.17(2Η, t, J = 4.5Hz), 4.06(2Η, s), 3.93(2Η, s), 2.95 (1Η, Brs), 2.87(6H, s). MS(ES) m/z: 432 (M + H)+. (Example 43) 4-dimethylamino-TV-[5-(3-fluorobenzyl)-thiazol-2-yl]-3-(2-hydroxy-ethoxy)-benzylguanamine (compound number 10-25) 4-dimethylamino-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]- obtained from the compound of Example (41d). Benzoic acid (179 mg) and 5-(3-fluoro-benzyl)-thiazol-2-ylamine (11 9 mg) obtained in Example (10b) gave decylamine. -140-200906395 This guanamine was deprotected with 1N hydrochloric acid to give the title compound 110 mg (46%) as pale white amorphous. NMR NMR (400MHz, CDCh): 5 (ppm) = 10.9 (lH, brs), 7.53-7.49 (2H, m), 7.3 2-7.24 (2H, m), 7.07 - 7.0 2 (2H, m), 6.97 - 6.87(2H, m), 4.17(2H, t, J = 4.5Hz), 4.08(2H, s), 3.92(2H, t, J = 4.1Hz), 3.37(1H, brs), 2.87(6H, s). MS (ES) m/z: 41 6 (M + H)+. (Example 44) 7V-[5-(3,5-Dichlorobenzyl)-thiazol-2-yl]-4-dimethylamino-3-(2-hydroxy-ethoxy)-benzidine Amine (Compound No. 10-145) 4-dimethylamino-3-[2-(tetrahydro-pyran-2-yloxy)-B obtained by the method of Example (41d). Ethyl]-benzoic acid (154 mg) and 5-(3,5-dichloro-benzyl)-thiazol-2-ylamine (126 mg) obtained in Example (17b) gave decylamine. The guanamine was deprotected with 1N aqueous hydrochloric acid to give the title compound 69 mg (31%) as pale white. NMR (400MHz, DMSO-d6): 5 (pp m) = 1 2.3 (1 Η, brs), 7.66 (2H, brs), 7.50 (1H, brs), 7.39 (2H, brs), 7.37 (1H, Brs), 6.89(1H, d, J = 8.6Hz), 4.88(1H, brs), 4.15(2H, brs), 4.10(2H, brs), 4.10(2H, brs), 2.86(6H, brs). MS (ES) m/z: 467 (M + H) +. (Example 45) 4-Diethylamino-3-(2-hydroxy-ethoxy)-7V-[5-(3-trifluoromethylbenzyl)-thiazol-2-yl]-benzylguanamine (Compound No. 10-86) (45a) 4-Diethylamino-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoic acid methyl ester imitation Example (41c) The method of the present invention (41b) 4-amino-3-[2-(-141 - 200906395 tetrahydro-pyran-2-yloxy)-ethoxy]-benzoic acid methyl ester U.〇9g ) 'The title compound was 543 mg (42%) of yellow oil. MS(ES) m/z: 352 (Μ + H) + . (45b) 4-diethylamino-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzene Formic acid imitation of the method of Example (1 e), 4-diethylamino-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]- obtained from Example (45 a) Methyl benzoate (543 mg) was obtained as the title compound 503 mg (96%). MS (ES) m/z: 3 3 8 (Μ + H) + . (45c) 4-diethylamino 3-(2-hydroxy-ethoxy)-, [5-(3-trifluoromethyl) 4-benzylamino-3-[2-(tetrahydro-pyran-) obtained from the compound of Example (45b) by the method of the example (If) of benzyl)-thiazol-2-yl]-benzylamine. 2-(2-oxy)-ethoxy]-benzoic acid (112 mg) and 5-(3-trifluoromethyl-benzyl)-thiazol-2-ylamine (77.9 mg) obtained in Example (lb) Amines. The title compound (69.4 mg (47%) of white solid. NMR (400 MHz, DMSO-d6): (5 (ppm) = 12.3 (1H, s), 7.68 - 7.56 (6H, m), 7.35 (1H, s), 6.87 (1H, d, J = 8.2 Hz) , 4.82(1H, t, J = 5.3Hz), 4.24(2H, s), 4.08(2H, t, J = 5.2Hz), 3.78(2H, q, J = 5.3Hz), 3.29(4H, m) , 1.04 (6H, t, J = 7.1 Hz). MS (ES) m/z: 494 (M + H) + . Melting point: 1 2 6 -1 2 8 ° C. (Example 46) 7V-[5 -(3-chloro-benzyl)-thiazol-2-yl]-4-diethylamino-3-(2-hydroxy-ethoxy)-benzamide (Compound No. 10-56) Method of If), 4-diethylamino-3--142-200906395 [2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoic acid (I26 mg) obtained from Example (45b) And 5-(3-chloro-benzyl)-thiazol-2-ylamine (75 mg) obtained in Example (12b) gave decylamine. The title compound (30 mg) 19%) White solid. NMR (400MHz, CDCl3): 5 (ppm) = 10.4 (lH, brs), 7.57 (1H, d, J = 2.3 Hz), 7.51 (1H, dd, J = 8.4, 2.1 Hz ), 7.24-7.23 (3 H, m), 7.14 (1H, d, J = 6.7Hz), 7.07(1H, s), 6.96(1H, d, J = 8.2Hz), 4.19(2H, t, J = 4.5Hz), 4.06(2H, s), 3.83 - 3.80(2H, m), 3.29(4H, q, J = 7.0Hz), 3.29(1H, s), 1.1 1 (6H, t, J = 7.0 Hz). MS (ESI) m/z: 460 (M + H) + . Base-, [5-(3,5-difluorobenzyl)-thiazol-2-yl]-3-(2-hydroxy-ethoxy)-benzamide (Compound No. 10-116) Method of If), 4-diethylamino-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoic acid (126 mg) obtained from Example (45b) and examples (19b) The obtained 5-(3,5-difluoro-benzyl)-thiazol-2-ylamine (84 mg) gave the title compound. The guanamine was deprotected with 1N EtOAc (EtOAc m. NMR NMR (400MHz, CDCh): (5 (ppm) = 1 0.2 (1 H, brs), 7.57 (1Η, d, J = 2.3Hz), 7.51 (1H, dd, J-8.2, 1.9Hz), 7.11 (1H, s), 6.97 (1H, d, J = 8.2Hz), 6.78-6.76(2H, m), 6.7 1 - 6.67 (1 H, m), 4.20(2H, t, J = 4.7Hz), 4.07(2H, s), 3.84 - 3.8 1 (2H, m), 3.29(4H, q, J = 7.0Hz), 3.29(1H, s), 1.12(6H, t, J = 7.0Hz). MS( ESI) m/z: 462 (M + H) + . -143 - 200906395 Melting point: 1 4 6 - 1 4 8 ° C. (Example 48) 3-(2-hydroxy-ethoxy)-4-?啉-4-yl-, [5-(3-trifluoromethylbenzyl)-thiazol-2-yl]-benzylguanamine (Compound No. 10-90) (48a) 4-morpholin-4-yl- 4-[2-(Tetrahydro-pyran-2-yloxy)-ethoxy]-benzoic acid methyl ester 4-amino-3-[2-(tetrahydro-pyridyl) obtained from the compound (4 lb) Methyl-2-methyloxy)-ethoxy]-benzoate (457 mg) and 1-bromo-2-(2-bromo-ethoxy)-ethane (0.23 mL) %) colorless oil MS (ESI) m/z: 366 ( Μ + H) + . (48b) 4-Methyl-4-yl-3-(2-(tetrachloro-p-pyran-2-yloxy) _ ethoxy]-benzoic acid imitation of the method of Example (le), 4-morpholin-4-yl-3-[2-(tetrahydro-pyran-2-yloxy) obtained from Example (48a) )-ethoxy] Methyl benzoate (3 7 mg), mpjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Oxy)-4-morpholin-4-yl-TV_[5-(3-trifluoromethylbenzyl)-thiazol-2-yl]-benzamide compound method (If), by way of example (48b) 4-(morpholine-4-yl-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoic acid (35 mg) obtained, obtained in Example (lb) (3-Trifluoromethyl-benzyl)-thiazol-2-ylamine (29 mg), mp EtOAc (EtOAc) %) white solid. NMR (400MHz, CDCh): 5 (ppm) = 10.0 (lH, brs), 7.52-7.49 (4H, m), 7.45-7.44 (2H, m), 7.14 (1H, s), 6.95 (1H, d, J = 8.2Hz), 4.2K2H, t, J = 4.5Hz), 4.16(2H, s), 3.9 0 - 3 . 8 8 (2H, -144- 200906395 m), 3.8 5 ( 4H, t, J = 4.7 Hz), 3.2 6 (1 H, brs), 3 .1 6 (4H, t, J = 4.7 Hz). MS (ESI) m/z: 508 (M + H) + . Melting point: 1 5 0 -1 5 1 °C. (Example 49) 4-Ethylamino-3-(2-hydroxy-ethoxy)-TV-[5-(3-trifluoromethyl-benzyl)-thiazol-2-yl]-benzylguanamine (Compound No. 10-83) (4 9 &amp;) 4-ethylamino-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoic acid methyl ester imitation example (41c Method of 4-amino-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoic acid methyl ester (4.45 g) obtained from Example (41b) and acetaldehyde (6.50 mL) gave the title compound 3. MS (ESI) m / z: 324 ( Μ + H) + . (49b) 4 · ethylamino-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoic acid 4-Diethylamino-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoic acid methyl ester obtained from the compound of Example (49a) (514 mg) gave 385 mg (78%) MS (ESI) m/z: 310 ( Μ + H) + . (49c) 4-ethylamino 3-(2-hydroxy-ethoxy)-7V-[5-(3-trifluoromethyl- Benzyl)-thiazol-2-yl]-benzylguanamine The method of Example (If), 4-ethylamino-3-[2-(tetrahydro-pyran-2-) obtained from Example (49b) Hydroxyl-ethoxy]-benzoic acid (114 mg), and 5-(3-trifluoromethyl-benzyl)-thiazol-2-ylamine (95 mg) obtained in Example (lb) 122 mg (60%). The title compound was deprotected with 1N EtOAc (EtOAc m. -145- 200906395 NMR (400 MHz, DMSO-d6): 5 (ρ ρ m) = 1 2 . 1 (1 Η , s), 7.67-7.56 (6 Η, m), 7.32 (1 Η, s), 6.58 ( 1Η, d, J = 8.6Hz), 5.78(1Η, t, J = 5.6Hz), 4.98(1Η, t, J = 6.3Hz), 4.23(2H, s), 4.03(2H, t, J = 4.7 Hz), 3.7 9 - 3.7 5 ( 2 H , m), 3.24- 3. 17(2H, m), 1. 19(3H, t, J = 7.2Hz). MS(ESI) m/z:466 ( M + H) + . Melting point: 1 94-1 97 °C. (Example 50) 7V-[5-(3-Chloro-benzyl)-thiazol-2-yl]-4-ethylamino-3-(2-hydroxy-ethoxy)-benzamide (Compound No. 3-53) 4-Ethylamino-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzene obtained by the method of Example (49b) Formic acid (89 mg), and 5-(3-chloro-benzyl)-thiazol-2-ylamine (65 mg) obtained in Example (12b) gave 60 mg (40%). The title compound was obtained as a white solid. NMR (400MHz, DMSO-d6): ό (ppm) = 12.1 (1H, s), 7.67 (1H, d, J = 6.6 Hz), 7.57 (1H, s), 7.40-7.3 5 (2H, m) , 7.3 2-7.27 (3 H, m), 6.60 (1H, d, J = 8.6Hz), 5.79(1H, t, J = 5.7Hz), 4.99(1H, t, J = 6.2Hz), 4.14( 2H, s), 4.05(2H, t, 1 = 4.7Hz), 3.78(2H, t, J = 4.7Hz), 3.26-3. 19(2H, m), 1.21(3H, t, J = 7.0Hz MS (ESI) m/z: 432 (M + H) +. Melting: 1 7 7 - 1 7 9 ° C. (Example 51) 7V-[5-(3,5-Dichloro-benzyl)-thiazol-2-yl]-4-ethylamino-3-(2-hydroxy-ethoxy)-benzylguanamine (Compound No. 10-143) 4-Ethylamino-3-[2-(-146-200906395 tetrahydro-indolepyran-2-yloxy) obtained by the method of Example (49). )-ethoxy]-benzoic acid (87 mg), and 5-(3,5-dichloro-benzyl)-thiazol-2-ylamine (73 mg) obtained in Example (17b). (30%). The guanamine was deprotected with 1N EtOAc (EtOAc m. Ή NMR (500MHz, DMSO-d6): &lt;5 (ppm) = 12.1 (lH, s), 7.65 (1H, d, J = 8.3 Hz), 7.55 (1H, s), 7.48 (1H, s), 7.38 (2H, s), 7.33 (1H , s), 6.58 (1H, d, J = 8.8Hz), 5.79(1H, brs), 4.98(1H, t, J = 5.9Hz), 4.14(2H, s), 4.03(2H, t, J = 4.6Hz), 3.77 - 3.7 6(2H, m), 3.23-3.18(2H, m), 1.19(3H, t, J = 7.1Hz). MS(ESI) m/z:466 (M + H) + Melting point: 1 7 3 - 1 7 5 °C. (Example 52) iV-[5-(3,5-Difluoro-benzyl)-thiazol-2-yl]-4-ethylamino-3-(2-hydroxy-ethoxy)-benzylguanamine (Compound No. 10-113) 4-Ethylamino-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy] obtained by the method of Example (10b). - benzoic acid (88 mg), 5-(3,5-difluoro-benzyl)-thiazol-2-ylamine (65 mg) obtained in Example (19b), afforded ytamine 45 mg (27%). The guanamine was deprotected with 1N EtOAc (EtOAc) (jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj = 6.7Hz), 7.28(1H, s), 7.56(1H, d, J = 2.0Hz), 7.12- 7.07(1H, m), 7.03(2H, d, J = 6.6Hz), 6.58(1H, d , J = 8.6Hz), 5.7K1H, brs), 4.98(1H, t, J = 5.9Hz), 4.12(2H, s), 4.03(2H, t, J = 4.7Hz), 3.7 8-3.7 5 ( 2H, m), 3.2 3 - 3 .17 (2H, m), 1.19 (3H, t, J = 7.2 Hz). -147- 200906395 MS (ESI) m/z: 434 (Μ + H) + . : 1 68-170 ° C. (Example 53) 4-ethylamino-3(2-hydroxy-ethoxy)-[5-(3-trifluoromethyl-benzyl)-thiadiazole 2-yl]-benzylguanamine (Compound No. 11-83) The method of the embodiment (If), 4-Ethylamino-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoic acid (118 mg) obtained in Example (49b), and 5- obtained from Example (5a) (3-Trifluoromethyl-benzyl)-thiadiazol-2-ylamine (99 mg) 'Decanamine 1 4 7 mg (70%). Deprotection of this guanamine with 1 N hydrochloric acid' The title compound was obtained as a white solid (yield: EtOAc: EtOAc: EtOAc: EtOAc (EtOAc: EtOAc) 7.62(1H, d, J = 7.5Hz), 7.58(1H, s), 6.60(1H, d, J = 8.6Hz), 5.89(1H, brs), 5.01(1H, t, J = 6.2Hz), 4.50(2H, s), 4.03(2H, t, J = 4.5Hz), 3.7 9 - 3.7 5 (2H, m), 3.23-3.19(2H, m), 1.19(3H, t, J = 7.1Hz) MS (ESI) m/z: 467 (M + H) + . melting point: 2 1 0 - 2 1 1 ° C. (Example 54) 4-Ethylamino 3-(2-hydroxy-ethoxy)-W-[5-(3-trifluoromethyl-benzyl)-thiazol-2-yl]-benzidine Amine (Compound No. 10-88) (54a) 4-Ethylamino-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoic acid methyl ester in Example (4 Lb) a solution of 4-amino-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoic acid methyl ester (405 mg) in tetrahydrofuran (10 mL) Amine (0.57 mL) and acetic anhydride (〇. 14 mL). The reaction mixture was stirred at room temperature for 1.5 hours and heated to 60 °C. While adding triethylamine and acetic anhydride, it was heated to 60 ° C until the end of the reaction. After the reaction was completed, the reaction mixture was evaporated, evaporated, evaporated, evaporated, evaporated The residue was purified by chromatography EtOAcjjjjjjjj MS (ESI) m/z: 336 (Μ - Η) + . (54b) 4-ethylamino- 3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzene Formic acid imitation of the method of Example (le), 4-acetamido-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoic acid obtained from Example (54a) The ester (220 mg) gave the title compound as a colourless oil. MS (ESI) m/z: 322 (Μ - Η) + . (5 仏) 4-ethylaminoamino-3-(2-hydroxy-ethoxy)-[5-(3-trifluoromethyl) -benzyl)-thiazol-2-yl]-benzamide amide. The method of Example (If), 4-acetamido-3-[2-(tetrahydro-pyran-) obtained from Example (54b) 2-(2-oxy)-ethoxy]-benzoic acid (120 mg), 5-(3-trifluoromethyl-benzyl)-thiazol-2-ylamine (96 mg) obtained in Example (lb) 200 mg (93%). The guanamine was deprotected with 1N aqueous EtOAc (EtOAc:EtOAc) Ή NMR (400MHz, DMSO-d6): 5 (ppm) = 12.5 (lH, s), 9.22 (1H, s), 8.28 (1H, d, J = 8.2 Hz), 7.77 (1H, d, 1 = 1,6Hz), 7.69-7.66(2H, m), 7.64-7.5 7 (3 H, m), 7.38(1H, s), 5.12(1H, t, J = 6.1Hz), 4.25(2H, s) , 4.14(2H, t, J = 4.7Hz), 3.82-3.79(2H, m), 2.17(3H, s). MS (ESI) m/z: 480 (M + H) + . Melting point: 1 7 7 - 1 7 9 °C. (Test Example 1) -149- 200906395 (1) Human stearyl sulfhydryl-based CoA desaturase expression vector cDNA clone of human stearyl sulfhydryl-based CoA desaturase (OnGene, AB-1 323 D07) as a template , using an upstream primer (t triglyceride gatccggcccact triglyceride c triglyceride caggacg) and a downstream primer (ttaagcttcagccactct triglyceride vinegar tagtttcc) according to PCR amplification, the reaction product is treated with restriction enzymes BamHI, Hindlll, inserted The mammalian cell expression vector pCMV-Tag2A (Stratagene) BamHI, Hindlll site. It is transformed into coliform cells and purified as a plastid. The DNA fragment inserted in the vicinity of the insertion site and the DNA sequence near the insertion site were determined, and the sequence of the human sterol-based CoA desaturase was confirmed to be inserted in the correct translation frame as a human sterol thiol-based CoA desaturase expression vector. (2) Preparation of human stearyl sulfhydryl-based CoA desaturase enzyme fractionation HEK293 cells were maintained in an incubator containing 10% fetal calf serum in high glucose DMEM, 37 ° C, 5% carbon dioxide gas. The cells were transferred in a human-type hard vinegar-based CoA desaturase expression vector using Lipofectamine 2000 (Invitrogen) according to the instructions attached to the product. After 48 hours, the cells were washed with PBS, recovered from the culture dish, and disrupted by a homogenizer. After the cell disrupted solution was centrifuged at 4 ° C, 700 g for 10 minutes, the supernatant was further changed to 4 ° C, 1 6 5,000 g, and centrifuged for 60 minutes. The resulting precipitate was suspended as 0.25 M sucrose, 1 M EDTA, 10 mM Tris pH 7.4 as a divided suspension of human stearyl sulfonate CoA desaturase enzyme. (3) Determination of sterol oxime-based CoA desaturase activity according to the method described in the literature (Bioc. Phar. 1 998; 55, 1 045-58), in a suspension of a hard ester sulfhydryl-based CoA desaturase enzyme ( Protein concentration 250 -150- 200906395 β g/ml) 10&quot; 1 Add test compound 1 /z 1 dissolved in DMSO, incubate for 10 minutes before 37 ° C, add 250 mM sucrose, 150 mM potassium chloride, 40 mM fluorinated Sodium, 1 mM sodium phosphate, pH 7.4, 1 mM ATP, 1.5 mM reduced glutathione, 0.06 mM reduced CoA, 0.33 mM nicotine guanamine, 5 mM sodium chloride, 1 mM NADH, 0.01 V Ci [1- 14C] a reaction solution of stearic acid, which was reacted at 37 ° C for 1 hour. The reaction mixture was quenched with 50 ul of 10% potassium hydroxide to stop the reaction, and heat-treated at 80 ° C for 30 minutes. After the reaction solution was returned to room temperature, 5N hydrochloric acid 15 β 1 and ethyl acetate 100 vl were added, stirred and mixed, and the aqueous layer was separated by centrifugation. The organic layer was recovered from the upper organic layer 30 #1, and passed through a thin layer containing 10% silver nitrate gum. Chromatography was carried out with a developing solvent (chloroform:methanol:ethyl acetate:water=90:8:1:0.8). After expansion, air-drying was used to quantify the radioactive activity of stearic acid and oleic acid by the BAS2500 image analyzer, and the conversion ratio of stearic acid to oleic acid was an indicator of the activity of the hard ester sulfhydryl-based CoA desaturation. The sterol oxime-based CoA desaturase activity when the compound was not added was 100%, and the inhibition rate was calculated from the activity of the hard ester sulfhydryl-based CoA desaturase when the test compound 1 was added. Examples 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14, 15 ' 16, 17, 18 ' 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32 ' 33, 34 ' 35, 36, 37, 38, 39, 40, 41, 42, 43 ' 44, 45, 46, 47, 48, 49, 50, The compounds of 51 '52, 53 and 54 showed an inhibition rate of 50% or more at a concentration of the test compound of 1 // Μ. From the above results, it is known that the compound of the present invention has excellent SCD inhibition as -151 - 200906395 for 'as obesity, obesity, hyperlipidemia, hypertriglyceridemia, abnormal lipid metabolism, diabetes, arteriosclerosis, A therapeutic agent and/or a preventive agent for fatty liver, nonalcoholic steatohepatitis or hyperlipidemia, hypertriglyceridemia, abnormal lipid metabolism, diabetes, arteriosclerosis, or hypertension caused by obesity. Formulation Example 1: Capsules Compound of Example 1 or 50 5 Omg Lactose 1 2 8 mg Corn starch 70 mg Magnesium stearate 2 mg 25 Omg The powder of the above formulation was mixed, sieved through a 60-mesh sieve, and the powder was charged into 250 mg. Gelatin capsules are used as capsules. Formulation Example 2: Tablets The compound of Example 1 or 50 5 Omg Lactose 1 26 mg Corn starch 3 mg Magnesium stearate 1 mg 200 mg The powder of the above prescription is mixed, granulated with corn starch paste, dried, and then beaten with a tablet machine. Ingot, a tablet of 20 〇mg of 1 tablet was prepared. This lozenge can be coated with sugar if necessary. -152-200906395 [Industrial Applicability] The guanamine derivative or its pharmacologically acceptable salt of the formula (I) of the present invention has an excellent SCD inhibitory action, and can be used as an obesity, obesity, or the like for warm-blooded animals (especially human). Hyperlipidemia, hypertriglyceridemia, abnormal lipid metabolism, insulin resistance syndrome, abnormal glucose tolerance, diabetes, diabetes mellitus, cataract, gestational diabetes, polycystic ovary syndrome, atherosclerosis, atherosclerosis Atherosclerosis, diabetic atherosclerosis, fatty liver, nonalcoholic steatohepatitis, or hyperlipidemia caused by obesity, hypertriglyceridemia, abnormal lipid metabolism, insulin resistance syndrome, abnormal glucose tolerance, Diabetes, Diabetes Mellitus, Cataract, Gestational Diabetes, Polycystic Ovary Syndrome, Atherosclerosis, Atherosclerosis, Diabetic Atherosclerosis, Hypertension, Cerebrovascular Disorder, Coronary Artery Disease, Fatty Liver, Respiratory Abnormal, low back pain, deformed knee joint disease, gout, or cholelithiasis, should be obese, obese, high Hyperemia, hypertriglyceridemia, abnormal lipid metabolism, diabetes, atherosclerosis, fatty liver, nonalcoholic steatohepatitis, or hyperlipidemia caused by obesity, hypertriglyceridemia, abnormal lipid metabolism Disease, diabetes, atherosclerosis, or hypertension, especially for obesity, obesity, hyperlipidemia, hypertriglyceridemia, diabetes, fatty liver or nonalcoholic steatohepatitis, and/or prevention Agents (especially therapeutic agents) are useful. [Simple description of the diagram] 〇 J \ \\ [Main component symbol description] ίκ. j\w -153 -

Claims (1)

200906395 X. Patent application scope: 1. - The following formula (I) indoleamine derivative or its pharmacologically acceptable salt, R3Μ ρτ Ο R1 (0 [wherein R is a thiol group, a Cl_C6 alkoxy group, a C2-C6 azoxy group, a (Cl-Cs alkoxy group)-(Ci-C6 alkoxy) group, a di-(Ci-Ce alkane) Amino-(C^-Ce alkoxy) group, a 4-morpholinyl 1 substituted Ci-Ce alkoxy group, (Ci-Ce alkylthio MC丨-C6 alkoxy) group, Ci-C6 alkylsulfinyl)-(c丨-c6 alkoxy) group, (〇-0% alkanesulfonyl)-((: 1-(:6 alkoxy) group, amine group, single -(:1_(:6 alkylamino, bis-(Ci-C6 alkyl)amino, mono-Ca-C-alkylcarbonylamino or 4-morphinyl, R2 is hydroxy, Cl_C6 alkoxy, C2 -C6 hydroxyalkoxy, (c丨-C6 alkoxy MCi-Cs alkoxy) or bis-(Ci-Cs alkyl)amino-(Cl_C6 alkoxy) group, R1 and R2 are not simultaneously Hydroxy or Ci-Cs alkoxy, R is a gas atom, a tooth atom, a Ci-C6 or a thiol group, and R4 is a GC which may be independently selected from the group of substituent A to 5 substituents. Or may have a group selected from substituent group A independently to three substituted heterocyclic groups, V is a group of the formula -NH- or a single bond, W is a group of the formula -NH- or a single bond, and V and W are different When the formula is -NH- or a single bond, -154- 200906395 T is =C(R5)· or a nitrogen atom, R5 is a hydrogen atom, a halogen atom or a Ci-C6 alkyl group, Q is a group of the formula =C(R6)- or a nitrogen atom, and R6 is a hydrogen atom, a halogen atom or an alkane The substituent group A is a halogen atom 'Ci-Ce alkyl group, a Ci-Ce halogenated alkyl group, a C丨-C6 hydroxyalkyl group, a (C!-C6 alkoxy MChCe alkyl) group, a Ci-Ca alkane. Oxy, Ci-Ce halogenated alkoxy, Ci-Ce alkylthio, carboxyl, C2-C7 alkylcarbonyl, C2-C7 alkoxycarbonyl, nitro, amine, mono-c2-c7 alkylcarbonylamine, single - C!·^alkylamino group, bis-(Ci-Cs alkyl)amino group, cyano group, hydroxyl group and amine carbenyl group] 2. Amidoxime derivative as claimed in claim 1 Or a pharmacologically acceptable salt thereof, wherein R1 is a Ci-G alkoxy group, a mono-C丨-c6 alkylamino group, a bis-(C丨-c6 alkyl)amino group or a 4-morpholinyl group. The indoleamine derivative or a pharmacologically acceptable salt thereof according to the item 1, wherein R1 is a methoxy group, an ethoxy group, an ethylamino group, a dimethylamino group, a diethylamino group or a 4-morpholinyl group. The indoleamine derivative or pharmacologically acceptable salt thereof, wherein R1 is ethylamino, dimethylamino, diethylamino or 4-morpholinyl 5. The indoleamine derivative or a pharmacologically acceptable salt thereof according to any one of claims 1 to 4, wherein R2 is an alkoxy group or a C2-C6 hydroxyalkoxy oxime. The indoleamine derivative or a pharmacologically acceptable salt thereof, wherein R2 is 2-hydroxyethoxy. 7. The guanamine derivative or the -155 - 200906395 pharmacologically acceptable salt thereof according to any one of claims 1 to 6, wherein R3 is a hydrogen atom. 8. The indoleamine derivative or the pharmacological agent thereof, wherein R4 is a halogen atom, a Ci-Ce hospital base, a Ci-Cs halogenated alkyl group, and a Ci, as claimed in any one of claims 1 to 7. -Cs Halogenated alkoxy) The selected group is independently 1 to 3 substituted phenyl groups. 9. The indoleamine derivative or a pharmacologically acceptable salt thereof according to any one of claims 1 to 7 wherein R4 is independently selected from (fluorine atom, chlorine atom and trifluoromethyl group) 1 or 2 Substituted phenyl. The indoleamine derivative or a pharmacologically acceptable salt thereof according to any one of claims 1 to 7, wherein R4 is 3-fluorophenyl, 3-chlorophenyl or 3-trifluoromethylphenyl , 3,4-difluorophenyl ' 3,5-difluorophenyl, 3-chloro-4-fluorophenyl, 4-fluoro-3-trifluoromethylphenyl, 3,5-dichlorophenyl Or 3,5-di-trifluoromethylphenyl. 1 1. A guanamine derivative or a pharmacologically acceptable salt thereof according to any one of claims 1 to 10, wherein V is a group of the formula -NH-, and W is a single bond. 1 2. A guanamine derivative or a pharmacologically acceptable salt thereof according to any one of claims 1 to 11, wherein T is a nitrogen atom and Q is a group of the formula =CH-. 13. The indoleamine derivative or pharmacologically acceptable salt thereof according to claim 1, wherein the compound of the formula (1) is: AM5-0-chloro-benzyl)-thiazol-2-yl]-4-ethylamino group- 3-(2-hydroxy-ethoxy)-anthracene β, ΑΜ5-(3-chloro-benzyl)-thiazol-2-yl]-4-diethylamino-3-(2-hydroxy-B Oxy)-benzylamine, 4-ethylamino-3-(2-hydroxyethyloxy)-, [5-(3-trifluoromethyl-benzyl-156- 200906395)-thiazole-2- Benzylamine, 4-ethylamino 3-(2-hydroxy-ethoxy)-, [5-(3-trifluoromethylbenzyl)-thiazol-2-yl]-benzylguanamine , AM5-(3'5-difluoro-benzyl)-thiazole-2yl] 4-ethylamino-3-(2-hydroxy-ethoxy)-benzylamine, 4-diethylamino- TV·[5-(3,5-difluorobenzyl)·soxazol-2-yl]-3-(2-hydroxyethyloxy)-benzylamine, or W-[5-(3,5 -Dichloro-benzyl)thiazolyl-2-yl]_4-ethylamino-3_(2•hydroxy-ethoxy)-benzylamine. And a pharmacologically acceptable salt of any one of the first to third aspects of the invention, or a pharmacologically acceptable salt thereof, as an active ingredient. A pharmaceutical composition comprising an indoleamine derivative or a pharmacologically acceptable salt thereof according to any one of claims 1 to π as an active ingredient. 16. A pharmaceutical composition as claimed in claim 15 for use in inhibiting a sterol-based CoA desaturase. 17. A pharmaceutical composition according to claim 15 for the treatment and/or prevention of a disease caused by the breakdown of the stearin-based CoA desaturase activity. 18. The pharmaceutical composition of claim 15 for the treatment and/or prevention of obesity, obesity, hyperlipidemia, hypertriglyceridemia, abnormal lipid metabolism, insulin resistance syndrome, and sugar tolerance Abnormalities, diabetes, diabetes mellitus, cataracts, gestational diabetes, polycystic ovarian syndrome, atherosclerosis, atherosclerosis, diabetic atherosclerosis, fatty liver or nonalcoholic steatohepatitis. -157- 200906395 1 9. The following medical treatments for the treatment and/or prevention of obesity as a pharmaceutical composition of Article 15 of the patent scope: hyperlipidemia, hypertriglyceridemia, abnormal lipid metabolism , insulin resistance syndrome, abnormal glucose tolerance, diabetes, diabetes mellitus, cataract, gestational diabetes, multi-cytoplasmic ovarian syndrome, atherosclerosis, atherosclerosis, diabetic atherosclerosis, hypertension, cerebrovascular Disability, coronary artery disease, fatty liver, respiratory abnormalities, low back pain, deformed knee joint disease, gout or cholelithiasis. 20. A pharmaceutical composition according to claim 15 for the treatment and/or prevention of diabetes. A use of a guanamine derivative or a pharmacologically acceptable salt thereof according to any one of claims 1 to 13 to produce a pharmaceutical composition. 22. The use of claim 21, wherein the pharmaceutical composition is a composition that inhibits the sterol-based CoA desaturase. 23. For use as set forth in claim 21, wherein the pharmaceutical composition is for the treatment and/or prevention of obesity, obesity, hyperlipidemia, hypertriglyceridemia, abnormal lipid metabolism, insulin resistance syndrome, sugar tolerance Abnormal ability, diabetes, diabetes mellitus, cataract, gestational diabetes, multi-cytoplasmic ovarian syndrome, atherosclerosis, atherosclerosis, diabetic atherosclerosis, fatty liver or non-alcoholic steatohepatitis . 24. For the use of the scope of claim 21, the pharmaceutical composition is the following diseases for the treatment and/or prevention of obesity: hyperlipidemia, hypertriglyceridemia, abnormal lipid metabolism, insulin resistance syndrome -158- 200906395 Abnormal sugar tolerance, diabetes, diabetes mellitus, cataract, gestational diabetes, multi-cytoplasmic ovarian syndrome, atherosclerosis, atherosclerosis, diabetic atherosclerosis, hypertension, cerebrovascular disease , coronary artery disease, fatty liver, respiratory abnormalities, low back pain, deformed knee joint disease, gout or cholelithiasis. 2 5. The use of claim 21, wherein the pharmaceutical composition is a composition for the treatment and/or prevention of diabetes. 2 6. A method for inhibiting a sterol oxime C ο A desaturase, which is a pharmacologically effective amount of a guanamine derivative or a pharmacologically acceptable salt thereof according to any one of claims 1 to 13 With warm-blooded animals. 27. A method for the treatment and/or prevention of a disease, which comprises administering a pharmacologically effective amount of a guanamine derivative or a pharmacologically acceptable salt thereof according to any one of claims 1 to 13 to a warm-blooded animal. . 28. The method of claim 27, wherein the disease is obesity, obesity, hyperlipidemia, hypertriglyceridemia, abnormal lipid metabolism, insulin resistance syndrome, abnormal glucose tolerance, diabetes, diabetes 倂Symptoms, cataracts, gestational diabetes, polycystic ovarian syndrome, atherosclerosis, atherosclerosis, diabetic atherosclerosis, fatty liver or nonalcoholic steatohepatitis. 29. The method of claim 27, wherein the disease is caused by obesity: hyperlipidemia, hypertriglyceridemia, abnormal lipid metabolism, insulin resistance syndrome, abnormal glucose tolerance, diabetes, Diabetes mellitus, cataract, gestational diabetes, multi-cytoplasmic ovarian syndrome, atherosclerosis, atherosclerosis, diabetes -159- 200906395 Atherosclerosis, hypertension, cerebrovascular disease, coronary artery disease, fatty liver Abnormal breathing, low back pain, deformed knee joint disease, gout or cholelithiasis. 3 〇 . The method of claim 27, wherein the disease is diabetes. The method of any one of claims 26 to 30, wherein the warm-blooded animal is a human. -160- 200906395 VII. Designation of representative representatives: (1) The representative representative of the case is: None. (2) A brief description of the symbol of the symbol of the representative figure te 〇 JWS 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention. R2 R1 (I)