MXPA98002534A

MXPA98002534A - Thiazole derivative as protein kinase c inhibitors

Info

Publication number: MXPA98002534A
Application number: MXPA/A/1998/002534A
Authority: MX
Inventors: Mori Toyoki; Nakaya Kenji; Tominaga Michiaki; Nagami Kazuyoshi; Tabusa Fujio; Takemura Isao; Abe Kaoru; Shinohara Tomoichi; Tanada Yoshihisa; Yamauchi Takahito
Original assignee: Otsuka Pharmaceutical Company Limited
Priority date: 1996-07-31
Filing date: 1998-03-31
Publication date: 1998-11-12

Abstract

A thiazole compound of formula (I), wherein T is lower alkylene;u is 0 or 1;R 1 and R 2 are the same or different and are each H, or lower alkyl, etc.;R 3 is (1) or (2);R 4 is H or lower alkanoyloxy-lower alkyl, which shows inhibitory activity or protein kinase C(PKC, Ca 2+/phospholipid-depending serine/threonine protein phosphatase), and are useful as a protein kinase C inhibitor.

Description

DERIVATIVE OF TIAZOL AS PROTEIN INHIBITOR CINASE C ? ANPQ TECHNICAL The present invention relates to a novel t-azole derivative.

TECHNICAL BACKGROUND To date there have been several known thiazole derivatives, among which some compounds having substituents similar in some way to those of the present invention are described in the following literatures. JP-A-2-306916 discloses inhibitors for platelet adhesion comprising a benzazole compound of the following formula: where X is S or > IM-R = "(Ra is Hr lower alkyl, etc.); R is halogen, cyano, substituted lower alkoxy with cyano-phenyl-alkyl having a substituent on the benzene ring, substituted-alkoxy-substituted alkyl substituted pyrrolidyl, substituted amino, alkyl or substituted amino alkoxy, etc .; Ra is pyrrolyl which optionally has an alkyl, thienyl, pyridyl, substituent, or alkyl substituent. the lower, phenyl group optionally having 1 to 3 substituents selected from lower alkoxy, lower alkyl, OH, halogen or -0-Y-NR * R * (Y is lower alkylene »Rm and R * are each H, lower alkyl , cycloalkyl or both combine to form a saturated heterocyclic group of 5 or S members containing nitrogen, or -IMRa- Ra-a- (Rxo and R ** - are each H, lower alkyl substituted phenyl, or both combine to form a heterocyclic group.) However, the benzazole compounds in this literature are signifcantly different from the thiazole compounds of the present invention in the substituents of the 2-position of the thiazole nucleus. The text does not disclose compounds having protein kinase C inhibitory activities as in the present invention European patent 31B 084 (= US patents Nos. 4,957,932 and 5,037, B40) discloses that benzoheterazoles of the following formula are antagonists from leucotrie no and inhibitors of leukocotriene biosynthesis and are useful as antiasthmatic, antiallergic, anti-inflammatory and cytoprotective agents. wherein R 4 is H, halogen, alkyl "etc .; R * is alkyl "alken lo" etc .; Ra is H or R »; R- * eß H. halogen. -NO ^, etc. »Rß is H. halogen, -NO ^, etc .; R7 eß H or alkyl "Xa and Xa" are 0. S, S (0), etc .; X- »is NR3, O or S; Zx and Z * are -CONR3- or -HET (-R *, - Rß &-; and QA and Q * are -COOR3, -CONHS.O) ¡2R * 3. -CN etc. However, the benzoheterazoles in this literature are essentially different from the t-azole compounds of the present invention in the substituent of the 2-position of the azole nucleus. Further »this literature does not disclose compounds having protein kinase C inhibitory activity. Some thiazole or benzothiazole compounds having a chemical structure similar to the benzoheterazoles of European patent 318084 above are also described in PCT publications WO 93/21168 and WO 93/21169, and there it is mentioned that these compounds are useful as leukotriene antagonists, but the thiazole or benzotholol compounds of these literatures are clearly different from the thiazole compounds of the present invention in the substituent of the 2-position. and furthermore, these literatures also do not describe any compound having protein kinase C inhibitory activity.

DESCRIPTION OF THE INVENTION The thiazole derivatives of the present invention are novel compounds which have not been described in any literature and which have the following formula (1). wherein T is a lower alkylene; u is 0 or 1 »R and R * are the same or different and are each a hydrogen atom or a lower alkyl» or both combine to form a group: - (CHrlc) "~ (n is 4 or 5) or to form a benzene ring which can be optionally substituted by a member selected from a lower alkyl, a lower alkoxy, a nitro, an amino optionally having a lower alkyl substituent or a halogen atom; R3 is a group of the formula: where R a - * >; > p »Rxxß are as defined above; A is a lower alkylene Z is 0 or S; s is 0 or 1 »e © 1 or 2; f * - is a hydrogen atom or a lower alkoxy-lower alkyl; The Rßs are the same or different and are each a member selected from (a) a hydrogen atom. (b) an alkyl optionally having a hydroxy substituent "(c) a halogen atom" (d) a group of the formula - (O? ^ - A -CO), - NR ^ R * (where t is 0 or 1. A is a lower alkylene "1 is 0 or 1" and R7 and Rβ are the same or different and are each a hydrogen atom or a lower alkyl "or both combine with the nitrogen atom to which they are attached to form a saturated 5- to 7-membered heterocyclic group which can be intervened with a nitrogen or oxygen atom, said heterocyclic group being optionally substituted by a member selected from the group of the formula: - <A)., - R ^ R40 (wherein A and 1 are as defined above, and R * and R4 ° are the same or different and each is a hydrogen atom or a lower alkyl, or both combine with the nitrogen atom to which they are attached to form a saturated 5- to 7-membered heterocyclic group that can be intervened with a nitrogen or oxygen atom »d a heterocyclic group optionally has a lower alkyl substituent), a lower alkyl optionally having a hydroxy substituent, a hydroxy group and a lower alkanoyl), (e) a lower alkoxycarbonyl-lower alkyl "(f) a lower alkanoyloxy-lower alkyl" (g) a lower alkoxy optionally having a halogen substituent »< h > a lower alkyl substituted with halogen »(i) a lower alkyl substituted with carboxyl, (j) a lower alkoxycarbonyl, (k) a lower alkenyloxy, (1) a phenyl-lower alkoxy» (m) a cycloalkyloxy, (n) a phenyl. < o) a phenyl? i, (p) a hydroxy. (q) a lower alkylthio »(r) a lower alkenyl or (s) an amino optionally having a lower alkyl substituent; Rβ is a group of the formula: (1) -C0-CH = CR44C, - (C0) ß-R44- or (2) -CO-CsC-COR * - * •• »p is 0 or i; R11B is a hydrogen atom or a lower alkyl; R44β is a hydroxy »a lower alkoxy or a saturated or unsaturated heterocyclic group» monocyclic or dicyclic 5- to 10-membered containing 1 to 4 heterogeneous atoms selected from a nitrogen atom »of oxygen or of sulfur as a ring member» said heterocyclic group optionally has 1 to 3 substituents selected from the group consisting of (i) a lower alkyl. (ii) a group of the formula: - (B) .-- NR4aeR43 (wherein 1 is as defined above.B is -CO-A- (A is as defined above), a carbon or a lower alkylene , and R "and R43 are the same or different and are each a hydrogen atom" a lower alkyl or a lower alkyl substituted by an amino having optionally a lower alkyl substituent "or both combine with each other with the atom of nitrogen to which they are bonded to form a 5- or 12-membered saturated "monocyclic" or "cyclic monocyclic" heterocyclic group which can be intervened with a nitrogen or oxygen atom "said heterocyclic group optionally has a substituent selected from a lower alkyl »A lower alkoxycarbonyl» a lower alkyl substituted with lower alkoxy »an amino optionally having a substituent of lower alkyl and a lower alkyl substituted hydroxy), (iii) a lower alkoxycarbonyl, (iv) an lower alkyl or substituted hydroxy, (v) a pyridyl which is optionally substituted by a lower alkyl optionally having a halogen substituent on the pyridine ring, (vi) a lower alkyl substituted with halogen »(vi) a lower alkoxy, (viii) ) a cycloalkyl, (ix) a hydroxy, (x) a lower alkyl substituted with tetrahydropyranyl "loxi, (xi) a pyrimidyl, (xi? lower alkyl substituted with lower alkoxy »(xiii) a carboxyl, (xi) a lower lo-alco, (xv) a lower phenyl-1-lower alkyl optionally having a lower alkyldioxy on the phenyl ring» (xvi) ) a lower alkoxyol, and (xvi i) a piperidyl which optionally has a lower alkyl substituent on the piperidine ring; R4 * 4 is a hydroxy or a lower alkoxy; and when m is 1 »the groups A and Rβ can be combined to form a group of the formula: R6 (where Rβ is as defined above "and r is 0» 1 or 2) "or when m is 2» two Rβ groups can be combined to form a lower alkyndiioxy »a lower alkylene or a group of the formula: - (CHa ) a-C0NH-, or the groups Rß and R * can be combined to form a group of the formula -CO-CWR5 * -) - CH (R2ß ') - W- (where Raß and Raß * are a hydrogen or a carboxyl group, as long as both Raß and R * ßt are not simultaneously a carboxyl group, and W is -N (Raßß) - or -N-Ra »t» -X- I RβBb (wherein Rat 9 is a hydrogen atom or a lower alkyl, Raßt> is a lower alkyl and X is a halogen atom), or a salt thereof. The thiazole derivatives of the formula (I) show inhibitory activity in the C-chain protein C (PKC, Ca ^ / se / threonine-dependent phospholipid, protein phosphatase) and are useful as an inhibitor of protein kinase C. has proven that PKC plays an important role in the regulation of several biological functions such as regulation of metabolism, cell proliferation, cell differentiation, neurotransmitter release reaction, etc. Therefore, it is indicated that a PKC inhibitor may be useful in the prophylaxis or treatment of various diseases caused by the hyperaction of the aforementioned biological functions that are involved by PKC. Most particularly, inhibitors of protein kinase C containing as an active ingredient the present thiazole derivative are useful as an agent for the treatment of autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis, etc., several Allergic diseases such as Crohn's disease »ulcerative colitis» asthma, atopic dermatitis; an agent for protection against rejection in organ transplantation, GVHD reaction, etc .; an agent for the prophylaxis or treatment of various ischemic diseases in organs such as heart, liver, kidneys, brain, etc., acute pacreatitis, sepsis, multiple organ failure introduced by burns »ARDS. inhibiting the production of cytokinin derived from T cells such as IL-2 or noninflammatory cytokine such as TNF-a. In addition, by means of other biological functions such as cell proliferation, hormone secretion, metabolism regulation, etc. that are related to PKC. The protein kinase C inhibitors of the present invention are useful in the prophylaxis or treatment of cancer, diabetes, Alzheimer's disease, arteriosclerosis. HIV infection. nephritis, angiitis »etc. Each group of formula (1) above especially means the following groups. The lower alkyl group includes a straight chain or branched chain C? -Cß alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, etc. The lower alkoxy group includes an alkoxy group of Straight chain or branched chain Ca_-Cß, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, te -butoxy-pentyloxy. hexyloxy »etc. The halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. The lower alkyl group substituted with lower alkanoyloxy includes a straight chain or branched chain C-β alkyl group which is substituted by 1 or 2 straight chain or branched chain Ca-Cß alkane groups, for example, acetyl loxymethi lo, 2-propioni loxieti lo, l-butiri loxietilo, 3-aceti loxipropi lo, 4-aceti loxibuti lo, 4-isobutiri loxibuti lo, 5-pentanoloxipenti lo »6-aceti loxi hexi lo, 6-te -buti locarboni loxihexi it, 1,1-dimeti 1-2-hexanoi loxieti lo, 2-meti 1-3-aceti loxipropi lo, diacetyloxymethyl, 1 »3-diaceti loxipropi lo» etc. The alkyl group optionally has a hydroxy substituent and includes a straight chain or branched chain C -Cm alkyl group which may be optionally substituted with 1 to 3 hydroxy substituents 'eg' methyl 'ethyl', propyl 'isopropyl' butyl, isobutyl . tei-butyl »pentyl, hexyl. heptyl, octyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl, 1,1-dimethyl 1-2-hydroxyl, 1,3-dihydroxypropyl it, 5 »5» 4-trihydroxypenti lo »5-hydroxypenti lo» 6-hydroxyhexyl. l-hydroxy isopropyl. 2-methyl 1-3-hydroxypropyl »7-hydroxyheptyl, 8-hydroxyoctyl lo. etc. The lower alkylene group includes a straight chain or branched chain alkylene group, for example, methylene. ethylene »trimethylene» 2-methyl-1-trimethylene »2» 2-d eti 1 trimethyl-wood »1-methyl trimethylene. metilmeti log, eti I et log, tetrameti log, pentamethylene »he? ameti le or, etc. The saturated 5- to 7-membered heterocyclic group, which is formed by combining R "* and Rβ" or R9 and R4 ° with each other with the adjacent nitrogen atom with or without the intervention of another nitrogen atom or an oxygen atom, for example, pyrrole dinyl, piperidinyl, piperazyl, morpholino, ho or piperazinyl, homomorphol, etc. The lower alkyl group optionally having a hydroxy substituent includes, in addition to the above lower alkyl groups, a C-alkyl group. -Cß straight chained or branched chain which may optionally have 1 to 3 hydroxy substituents, for example hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2,3-hydroxypropyl 4-hydroxy, 1 , 1-di eti 1-2-hydroquinone, 5.5.4-hydroxypentyl, 5-hydroxypentyl, 6-hydroxyhexyl, 1-hydroxy isopropyl, 2-methyl, 1-3-hydroxypropyl, etc. The group lower alkanoyl includes a straight chain or branched chain CX-C alkanoyl group, for example, milo, acetyl, propionyl. butyryl. isobutyryl. pentanoi lo. t-but Icarboni lo. hexanoyl. etc. The above heterocyclic group which is substituted by a group of the formula: - (A)., NRßN4 ° (A is a lower alkylene group, 1 eß O or 1, R »and R4 ° are the same or different and each is a hydrogen atom or a lower alkyl group "or R * and R4 ° combine with each other with a nitrogen atom which bind to form a 5- or 7-membered saturated heterocyclic group with or without being intervened with another nitrogen atom or an oxygen atom "and said heterocyclic group optionally has a lower alkyl substituent), a lower alkyl group optionally having a hydroxy substituent. a hydroxy group and a lower alkanoyl group. it includes the aforementioned heterocyclic groups having 1 to 3 substituents selected from a group of the formula: - (A)., NRβN40 (A is a straight or branched chain alkyl group. 0 or 1, R * and R4 ° are the same or different and each is a hydrogen atom or a straight chain or branched chain C -CM alkyl group, or R9 and RAO combine with each other with the nitrogen to which they are bonded to form a 5- or 7-membered saturated heterocyclic group with or without intervention with another nitrogen atom or an oxygen atom, and said heterocyclic group optionally has 1 to 3 straight chain or branched chain alkyl substituents) "a straight chain or branched chain alkyl group having optionally from 1 to 3 hydroxy substituents" a group hydroxy and a straight chain or branched chain alkanoyl CA-Cß group, for example. 4-methylpiperazine lo. 2, (4-meth 1-l-piperazinyl) meti lomorfol no. 4- (4-methyl-1-piperaz nor 1) piperidine lo. 4-methi loho o-pipera? In lo, 4- (2-hydroxyethyl) piperazinyl, 4-morphol and opiperidinii, 2-C (1-uroligol il) meti 1 Dmorfol ino, 4-hydro? Ipiperidinyl, 4- aceti Ipiperazini lo, 4-dimeti la inopiperidini lo, 4- (4- et ll-ho opiperaz n 1) piperidini lo, 4- (4, 5-di eti 1-1-ho opiperaz ni 1) -piperidini lo, 4 - (3-meti 1-4-et 1-1-piperazini 1) piperidini lo, 4- (3- eti 1-4-n-propi 1-1-piperazini 1) piperidim "lo, 4- (3,4 -dimeti ll-piperazini 1) piperidini lo, 4- (4-isoprop 1-3-meti Ipiperazini 1) piperidini lo, 4- (4-meti 1-3-isopropi lopiperazi ni 1) piperid ni lo, 2-meti Ipirrol idini lo, 3-eti Ipirrol idin lo, 2, 3-dimeti Ipirrol idini lo, 2.3,4-tri meti Ipirrol dini lo, 2-propi l orfol ino, 3- (l-pirrol idini 1) pirrol dini lo, 3 -isopropy I orfolin, 2,3-dimethylopholino, 4-n-butypiperidinyl, 3,4,5-trimethylpiperidine »3-pentipiperidinyl» 4-methyl-1-homopiperazine »4» 5-dimethyl-1-homopiperazine 4-hexy-1-omopiperazione, 3-meti-1-4-ethyl-piperazi, or 3-meti 1-4- n-propi 1-1-piperazim'lo. 3.4-dimeti Ipiperazini lo. 4-isopropi 1-3-meti Ipiperazini lo. 4-meti 1-3-isopropi Ipiperazini lo. 4-methyl-homo orfol ino. 3-propionylpyrrole dini lo. 4-butiri lpiperidin lo. 4-pentanoi Ipiperazini lo. 3-hexanoi lmorfolino. 4-acetyl homopiperazine lo. 3-hydroxymethylol. 4-hydroxyhomopiperazin it. 4-hydroxypipera? Ini lo »3-hydroxypyrrole dini lo» 3-hydro? Imeti Ipirrol idini lo, 3- (3-hydro? Ipropi 1) morphol ino, 2-hydroxy et Iho omorfol, 2- (4-methyl) -piperazini 1) methi lhomomorfol ino »4- (l» 3-dihydroxy-2-propyl) piperazim "lo» 4-eti 1 homopiperazi i lo. 3- (4-meti 1-1-homopiperazi i 1) pyrrol i di 4-meti 1-3- (1-p peri dini 1) met 1-p perazi i lo. 4-meti l-3- (4-methyl-1-homopiperazini 1) methyl-piperazinyl, 4-methyl) 1-3- (4-methyl-piperazin 1) methylpipe-zinyl, etc. The above heterocyclic group substituted by a lower alkyl group includes the above heterocyclic groups substituted by 1 to 3 straight chain C -Cß alkyl groups or of branched chain, for example, 4-meti Ipiperazinii, 3,4-dimethylpiperazinyl, 3-and Ipyrrol idini lo, 2-prop Ipyrrol idini lo, 1-meti-1-pyrrol idini lo, 3,4,5-trimethopiperidini »4-butylpiperidini it» 3-penti lmorfol ino »4-eti 1 homopiperazini it» 4-methy Ihomopiperazin it »4-hexi Ipiperazini it 4-meti 1 omopiperazin it »4» 5-dimet Ipiperazini it »3-roet 1-4-ethyl-piperazini it» 3-roeti 1-4-n-propi lpiperazi i lo, 4-isopropi 1-3-meti Ipiperazini it »4-meti 1-3-i sopropi Ipiperazini lo, 4-met Iho omorfol, etc. The lower alkyl group substituted with lower alkoxycarbonyl includes a straight chain or branched chain C -C alkyl group which is substituted by a straight chain or branched chain alkoxycarbonyl group having 1 to 6 carbon atoms, for example, methoxycarbonylmethyl , 3-methoxycarbonylpropane, ethoxycarbonylmethyl, 3-ethoxycarbonylpropane, 4-ethoxycarbonylbutyl, 5-isopropocarbonyl Ipentyl, 6-propoxycarbonylhexyl. 1,1-Dimeti-1-2-butoxycarbon leti lo, 2- eti 1-3-tert-butoxycarboxy "1propylo, 2-penti loxycarboni leti lo, hexy loxycarboni Imeti lo, etc. The lower alkyl group substituted with lower alkanoyloxy it includes a straight chain or branched chain C 1 -C 2 alkyl group, which is substituted by a straight chain or branched chain alkanoyloxy group, for example, acetyloxy etiolo, -propioni loxieti lo, 1- butiri loxietilo, 3-aceti lox ropi lo, 4-aceti loxibutilo, 4-isobuti i 1 oxyi buti 1o, 5-pentanoi 1oxypentilo, 6-aceti 1oxi hexilo, 6-te »-buti 1 carboni loxihex what, 1,1-dimeti 1-2-hexanoi loxieti lo, 2-meti 1-3-aceti loxipropi lo, etc. The lower alkoxy group optionally having a halogen substituent includes a straight chain or branched chain C ^ -C, alkoxy group optionally having 1 to 3 halogen substituents, eg, in addition to the above lower alkoxy groups, trifluoromethoxy , trichloromethoxy, chloromethoxy, broomethoxy, fluoromethoxy »iodomethoxy. difluoromethoxy. dibromomethoxy. 2-chloroethoxy. 2 »2» 2-trifluoroethoxy »2» 2 »2-trichloroethoxy» 3-chloropropoxy »2,3-dichloropropoxy» 4 »4» 4-trichlorobutoxy »4-fluorobutoxy, 5-chloropentyloxy» 3-chloro-2-methyl-1propox »6 -bromohexi loxi. 5.6-dichlorohexy loxi »etc. The lower alkyl group substituted with halogen includes a straight chain or branched chain C-C alkyl group having 1 to 3 halogen substutents, for example. trifluoromethyl. trichloromethyl. chloromethyl. bromomethyl »fluoromethylo, iodomethyl, difluoromethyl, dibromometho, 2-chloroetheyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 3-chloropropyl. 2.3-dichloropropy lo »4.4,4-trichlorobutyl, 4-fluorobutyl lo. 5-chloropenti lo. 3-chloro-2-methyl propyl, 6-bromohexyl, 5,6-dichloroheyl, etc. The lower alkyl group substituted with carboxy includes a carboyalkyl group in which the alkyl portion is a straight-chain or branched-chain CA-Cß alkyl group, for example, carboxymethyl, 2-carboxyethyl, 1-carboxyethoyl, 3-carboxypropyl, 4-carboxybutyl, 5-carboxypentyl, 6-carboxyhexyl, 1,1-dimethyl-1-2-carboxyethyl, 2- ethyl-1-3-carboxypropyl, etc. The lower alkoxycarbonyl group includes a straight-chain or branched-chain alkoxycarbonyl group having 1 to 6 carbon atoms in the alkoxy moiety, for example, methoxycarbonyl, ethoxycarbon or propoxycarbonyl. isopropoxy carbom "lo» butoxycarbonyl »tert-butoxycarboni lo» penti loxycarboni lo »hexy loxycarboni lo etc. The lower alkoxy group substi tuted with aminocarbonyl optionally having a lower alkyl group includes a straight chain C 1 -C alkoxy group or branched chain "which has an aminocarbonyl group optionally having straight or branched chain 2-alkyl groups of C -Ca, for example, aminocarboni 1-ethoxy, 2-aminocarbonyl-letoxy, 1-aminocarbonyl-letox, 3-aminocarboni-lpropoxy »4-ami nocarboxy 1 butoxy» 5-anocarboni Ipenti loxi, 6-amicarboni lhex loxi, 1,1-dimeti 1-2-amicarbonylketoxy »2-methy1-3-aminocarboni 1propoxy» methylaminocarboni I ethoxy, l-eti laminocarboni letoxy »2-propylaminocarboni letoxy» 1-eti laminocarbom "letoxy. 2-prop lami ocarboni letoxi, 3-i sopropi lami ocarboni lpropoxi, 4-buti 1aminocarboni 1 utoxi, 5-penti lami nocarboni Ipenti loxi. 6-he i lami ocarboni lhe i loxi, di eti laminocarboni 1 methox, 2-diethylaminocarboni letoxi, 2-dimeti laminocarboni letoxi, (N-ethyl-N-propi lamino) carboni lometoxi, 2- (N-meti 1-N- hexi the ino) -carboni letoxi, etc. The lower to unsubstituted alkyl group optionally having a lower alkyl substituent includes an alkyl group of C -C? straight chain or branched chain which is substituted by an amino group optionally having 1 to 2 C -C alkyl substituents, for example, aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 4-aminobutyl. 5-aminopentyl or »6-aminohexyl» 1,1-dimethyl-1-2-aminoethyl, 2-methyl-1-3-amylopropyl, ethyl-methyl, l-ethyl-laminoethyl, 2-propylaminoetyl, 3-isopropyl-laminopropyl , 4-buty laminobutyl, 5-penti laminopentyl, 6-hexy laminohexyl, dimethyl laminomethyl, (N-ethyl-1-N-propylamino) methyl. 2- (N-methyl-1-N-hexylamino) ethyl, etc. The 5- to 12-membered heterocyclic heterobicyclic or heterospiroccyclic heterocyclic group which is formed by combining R4Se and R43 with each other with the adjacent nitrogen atom to which they are linked, with or without being intervened with another nitrogen atom or a nitrogen atom. oxygen, includes, for example, pyrrole dini lo, piperidinyl, piperazinyl, morpholino, homopiperazine lo, ho omorfol ino. 1.4-diazabicycloC4.3.03noni lo »1.4-d azabicycloC4, .4.03deci lo. l.4-diazaespiroC5.53undec lo. etc . The lower alkyl group substituted with lower alkoxy includes a straight chain or branched chain C-C alkyl group having 1 to 3 straight chain or branched chain C 1 -C 6 alkoxy groups, for example, methoxymethyl. 3-methoxypropyl. ethoxymethyl, 2-methoxyethyl, 3-ethoxypropyl, 4-ethoxybutyl, 5-isopropoylpentyl, S-propoxy-hexylo, 1,1-dimetyl-2-buto-iethi »2-methyl 1-3 -ter-butoxipropyl »2-pentyloxyeti lo» hexi lox meti lo. etc. The amino group optionally having a lower alkyl substituent includes an amino group optionally having 1 to 2 C ^-C alkyl groups. straight chain or branched chain "eg, amino, methylamino, ethylamino, propylamino, isopropy lamio. buti lamino, tert-buti lamino »penti lamino» hexi lamino »dimethylami or» dieti lamino »dipropylamino. dibuti lamino, dipenti lamino, dihexylamino. N-methyl-N-et lam no. N-eti 1-N-prop lami o. N-methyl 1-N-but-lamino. N-meti 1-N-he? I lamino, etc. The above heterocyclic group having a substituent selected from a lower alkyl group, a lower alkyl group substituted with lower alkoxy, a carbonyl group substituted with lower alkoxy, an amino group optionally having a lower alkyl substituent and a lower alkyl group substituted with hydroxy, includes the aforementioned heterocyclic groups having 1 to 3 substituents selected from a straight-chain or branched-chain C-Cm alkyl group, a straight chain or branched chain alkyl group having 1 to 3 carbon atoms; to 3 C -C alkoxy groups? straight chain or branched chain, an alkoxycarbon group straight chain or branched chain having 1 to S carbon atoms in the alkoxy portion, an amino group optionally having 1 to 2 C, -C, alkyl groups straight-chain or branched chain and a straight-chain or branched-chain Cx-Cm alkyl group having 1 to 3 hydroxy substituents, for example, 4-methylpiperazinyl, 3,4-dimethylpiperazinyl, 4- eti Ipiperazini lo, 4-meti lhomopiperazini lo, 4-dimeti laminopiperazin it, 4-te-butoxicarbonilhomopiperazini lo, 4-n-butilhomopiperazin it.4- (2-hydroxyethyl) piperazinyl. 3-meti ipiperazini lo. 4- (i, 3-dihydro-i-2-prop l) piperazinyl »4- (1, 3-dihydroxy-2-propyl) homopiperazine, 3,4,5-trimethylpiperazine, 4-isopropylpiperazinyl» 3.3 »4-trimethylpiperazine it »4,5-dimethyl omopiperazi i lo» 3-met 1-4-eti Ipiperazini lo »3-meti 1-4-n-propi Ipiperazini lo. 3-n-propi 1-4-meti Ipiperazini lo. 3-meti 1 -4-isopropy Ipiperazinyl, 3-eti 1-4-me ti Ipiperazim "lo» 3-methyl-4- (2-methoxyeti 1 >piperazim "lo» 3-meti l-4- (2-h rox eti 1) p peraz n lo. 3- sopropi 1-4-meti Ipiperazini lo »4-methyl-l» 4-diazaspiroC5.5.-] undec le 3-ami ol, 4-di azabi ci c1 oC4.4.0-Idee ilo. 5-hi drox imeti 1-1, 4-diazabicycloC4.3.0] noni lo, 3-etox i carboni lhomomorfol no, 3-diethyla orole ino, 3-methoxymethi Ipyrrol idini lo, etc. The lower alkyl group optionally having a halogen substituent includes, for example, in addition to the above lower alkyl groups and the lower alkyl groups substituted with halogen. optionally a lower alkyl substituent which may optionally have a halogen substituent on the pyridine ring includes a pyridyl group having 1 to 3 straight chain or branched chain Cx-Cß alkyl groups which may optionally have the 3 halogen substituents on the pyridine ring, for example, pyridyl, 3-methylpyridyl, 4-pyridyl, 2-propylpyridyl, 3-butyl, pyridyl, 4-pentilpyrim. say it, 4-hexi Ipiridi lo. 3.4-Dimethylpiperidyl, 3,4,5-tri-ethylpyridyl, 3-trifluoromethylpyridyl, 2-chloromethylpyridyloyl 4- (5-bromohexy-1) pyridyl, 3-iodo and pyridyl. 4- (2.2.2, -trifluoroeti 1) pyridi lo, 4- (5,6-dichlorohe? I 1) pyridi lo, etc. The cycloalkyl group includes a C3-Cβ cycloalkyl group, for example, cyclopropyl, cyclobutyl, cyclopentyl , cic lohexi lo »cyclohepti lo, cyclooctyl, etc. The lower alkyl group substituted with tetrahydropyrani loxy includes an alkyl group substituted with tetrahydropyran loxy wherein the alkyl portion is a straight chain or branched chain C-Cm alkyl group, for example, (2-tetrahydropyranyl) oxymethyl, 2- (3-tetrahydropyrani 1) oxyethlo, l- (4-tetrahydropyranyl) oxyethi, 3- (2-tetrahydropyran 1) oxypropyl, 4- (3-tetrahydropyrani 1) - o? Ibutyl, 5 ~ (4-tetrahydropyrani 1 ) oxypentyl, 6- (2-tetrahydropyrani 1) oxyhexyl, 1,1-d methi 1-2- (3-tetrahydropyrani 1) oxyethi, 2-methyl-3- (4-tetrahydropyrani "1) -oxipropyl, etc. The lower alkyl-phenyl group includes a phenylalkyl group in which the alkyl portion is a straight chain or branched chain C -Cm alkyl group, for example, benzyl, 2-phenotene, 3-phenylpropo , 4-Pheni, 1-butyl, 5-phenyl-1-phenyl, S-phem, 1-methyl-3-phene, 1,1-dimethyl, 1-2-phenylethi, etc. The lower alkoxy-phenyl group includes a phenylalkoxy group in which the alkoxy portion is a straight-chain or branched-chain Ci-c-β alkoxy group, for example, benzyloxy, 2-phen? letox, 1-phenylethyloxy, 3-phenopropoxy, 4-phenylbutoxy, 5-phenyl, Ipenti loxi, 6-pheny1-hexyloxy, 1,1-dimethyl-1-2-phenylethoxy. 2-methyl-1 -3-phenopropoxy. etc. The lower alkanoyloxy group includes an alkanoyloxy group of C ^ -C. straight chain or branched chain, for example, form loxi, acet loxí, propioni loxi, butyryloxy, isobutyryloxy, pentanoi loxi, te -buti Icarboni loxi, hexanoiloxi, etc. The piperidinyl group optionally having a lower alkyl substituent on the piperidine ring includes a piperidinyl group optionally having a C -C alkyl group. straight chain or branched chain, for example, piperidinyl, 1-meti 1-4-piperidini lo, 1-eti 1-3-p peridini lo, 1-et 1-2 piperidi ilo, 1-propi 1-4 -p per di i lo, 1-buti 1-4-piperidin it, l-pentyl-4-piperidini lo, l-hexyl-4-piperidini lo »1-isobuti 1-3-? iperidini lo» 1-te - buti 1-2-piperidinyl »etc. The lower alkyl-phen group which optionally has a lower alkyndiioxy substituent on the phenyl ring includes a phenyl group which optionally has a straight chain or branched chain alkyndiioxy group on the phenyl ring. wherein the alkyl portion is a straight chain or branched chain C -Ca alkyl group in addition to the above lower phenyl-alkyl groups, for example, 3,4-methylenedioxybenzyl. 2- (3 »4-eti lend o? Ifeni 1) eti it» l- (3 »4-eti lendioxifeni 1) et lo» 3- (2 »3-trimeti lendioxifeni 1) propi lo. 4- (3,4-tetramethyl-1-endioxy-phenyl) butyl. 5- (3 >; 4-meti lendioxifeni 1) penti lo. 6- (2 »3-trimeti lendio ifeni 1) he? Ilo» etc. The lower alkyndiioxy group includes a straight chain or branched chain alkylenedioxy group, for example, methylenedioxy, ethylenedioxy, trimethyndiioxy, tetramethylenedioxy, etc.

The saturated or unsaturated heteromonocyclic or heterobicyclic residue of 5 to 10 members having 1 to 4 heterogeneous atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom includes, for example, pyrro! idini lo, peridinyl, piperazinyl, morpholino »1-azabicycloocti lo» homopiperazine lo »homomorphol» 1 »4-diazabicycloC4.3.03nonyl» l »4-diazabicycloi: 4.4.0Ddecyl. pyridyl »l» 2,5, S-tetrahydropyridyl, thienyl, 1,2,4-triazolyl, 1,2,3,4-tetrazolyl, 1,3,4-triazolyl, quinolyl, 1,4-dihydroquinol i lo, benzoyl azole, pyrazyl, pyrimidyl pyridazinyl, pyrrolyl, pyrrolinyl »carboetiri lo» 1,3-dio? olanyl »thio orfolone» 3 »4-dihydrocarbonster» 1 »2» 3,4-tetrahydroquinolyl »2» 3 »4» 5-tetrahydrofuryl »indolyl» isoindolyl »3H-indolyl» indolylol »indol idinol» indazolyl »benzimidazolyl» benzylolol »imidazolin» imidazol idini lo. isoquinolyl »nafti 1 idini lo» quinazo! idino lo »quinoxali i lo» cinolinyl »phthalazinyl» chryloyl »isoindole nor» isocro anyl »pyrazolyl» 1,3,4-oxadiazole lo, 3 »4-thiadiazolyl» thienyl »imidazolyl» pyrazole idini lo »benzofuryl» 2,3-dihydrobenzoCbDf ryl »benzothienyl, tetrahydropyranyl» 4H-chrinoyl »lH-indazole» lo-2-imidazole »lo-2-pyrrole inyl, oxazolyl» isoxazole »thiazolyl» thiazole inyl »isothiazolyl» pyranyl »Pyrazole idini lo» 2-pyrazole ini lo, quinucl idini lo, 1,4-benzo? Azin it »3,4-dihydro-2H-l, 4-benzoxazinilo, 3» 4-dihidro-2H-l, 4-benzotiazini it »1,4-benzothiazinyl» l »2» 3,4-tetrahydroisoquinolyl »1» 2 »3» 4-tetrahydroquinoxal -ini lo »1,3-di tia-2,4-dihidronaftaleni lo, 1,4-di tianaftaleni lo , 2,5-dihydrofuranoC3.4-c3pirid it, 2,3,4,5,6,7-hexa idro-lH-azepini lo, 1,2,3,4,5,6,7, B-octahydroazocinyl, 1,2,3,4,5,6-tetrahydrooxepini lo , 1,3-dioxolanyl. 3 »4? 5 »6-tetrahydro-2H-pirani lo» 5 »6-dihydro-2H-pyranyl» etc. The above heterocyclic groups having 1 to 3 substituents selected from (i) a lower alkyl group; (ii a group- (B)? -NR4aR43 (1 is the same as defined above »B is a group: -CO-A- (A is the same as defined above)» a carbonyl group or a lower alkylene group »R43 and R43 are the same or different and each is a hydrogen atom» a lower alkyl group, an amino substituted lower alkyl group optionally having a lower amino substituent, or combine with each other with the nitrogen atom adjacent to the amino which are linked to form a 5 to 12-membered heterominocyclic heterobicyclic or spi6cyclic ring with or without intervention with another nitrogen atom or an oxygen atom, said heterocyclic group optionally having a substituent selected from a group lower alkyl, a lower alkoxycarbonyl group, a lower alkyl group substituted with lower alkoxy, an araino group optionally having a lower alkyl substituent and a lower alkyl group substituted with lower alkyl oxy), (iii) a lower alkoxycarbonyl group »(iv) a hydroxy substituted lower alkyl group; (v) a pyridyl group which is optionally substituted by a lower alkyl group optionally having a halogen substituent on the pyridine ring; (vi) a lower alkyl group substituted with halogen; (vii) a lower alkoxy group; (vii) a cycloalkyl group, (ix) a hydroxy group; (x) a lower alkyl group substituted with tetrahydropyran loxy; (xi) a pyrimidyl group; (ii) a lower alkyl group substituted with lower alkox; (xi i) a carboxyl group; (xiv) a lower alkoxy-phenyl group; (xv) a lower alkyl-phenyl group optionally having a lower alkyndiioxy substituent on the phenyl ring; (xvi) a lower alkanoyloxy group and (xvi i) a piperidinyl group optionally having a lower alkyl substituent on the piperidine ring includes the above heterocyclic groups having 1 to 3 substituents selected from (i) an alkyl group of C -C? Straight chain or branched chain; (ii) a group - (B)., - NR SBR43 (1 is the same as defined above, B is a group: -CO-A- (A is the same as defined above), a carbonyl group or a straight-chain or branched-chain C al-C al alkylene group: R 4a and |,% 43 are the same or different, and each is a hydrogen atom, a straight-chain C grupo-C ,, alkyl group, or branched chain or a straight chain or branched chain C -Cβ alkyl group having an amino group optionally having 1 to 2 straight chain or branched chain alkyl substituents, or arabos combine with each other with the nitrogen adjacent to which they are bonded to form a heterocyclic heterocyclic ring or saturated spirocyclic ring of 5 to 12 members with or without being intervened with another nitrogen atom or an oxygen atom said heterocyclic group may optionally have 1 to 3 substituents selected from a straight chain or branched chain C -C alkyl group gives »an alkyl group of C -C? straight chain or branched chain "which has 1 to 3 substituents alkoxy C ^ -C. straight chain or branched chain, a straight chain or branched chain alkoxycarbonyl group having 1 to 6 carbon atoms in the alkoxy moiety »an amino group optionally having 1 to 2 straight chain C -C alkyl substituents or of branched chain and a straight or branched chain C, -C.sub.-C alkyl group having from 1 to 3 hydroxy substituents); (iii) an alkoxycarbonyl group having 1 to 6 carbon atoms in the alkoxy moiety; (iv) a straight-chain or branched-chain CA-Cß alkyl group having 1 to 3 hydroxy substituents; (v) a pyridyl group optionally having 1 to 3 straight chain or branched chain Cx-C alkyl groups optionally having 1 to 3 halo substituents on the pyridine ring; (vi) an alkyl group of C ^ -C. straight chain or branched chain that has 1 to 3 subsites halogen halogen; (vii) an alkoxy group of C ~ C? straight chain or branched chain; (viii) a cycloalkyl group of Ca-Cß; (ix) a hydroxy group; (x) an alkyl group substituted with tetrahydropyran loxy wherein the alkyl portion is a straight chain or branched chain Cx-Cß alkyl group; (xi) a pyrimidyl group; (xii) an alkyl group of C -C? straight chain or branched chain having 3 alkoxy substituents of straight chain or branched chain C-j.-Cß; (xiii) a carbon group; (xiv) a phenyl alkoxy group wherein the alkoxy portion is a straight chained or branched chain C-C alkoxy group; (xv) a phenylalkyl group optionally having a substituent to the straight-chain or branched chain C-C-lanedioxy in the phenyl ring where the alkyl portion is a straight chain Cx-Cß alkyl group or branched chain; (xvi) a straight chain or branched chain C alca-C alkanoyloxy group and (vii a piperidinyl group optionally having 1 to 3 straight chain or branched chain C substituß alkyl substituents on the piperidine ring. Example 4-meti Ipiperazini lo 4- (4-meti 1-1- Piperazi nil) pipen "di ni lo. 2- (4-meti ll-piperazini Imeti 1) morfol ino. 2- (4-meti llp perazi i lmeti 1) -pyrrol idim * lo. 3- <: 4-meti ll-piperazini 1) pyrrol idini lo, l-ethyl-1,2-3-4-tetrazol ilo, 1-tert-butocarboni Ipiperidin lo. -meti Ipiperidini lo., 2.2-dimeti 1-1.3-dioxolani lo. 4- (3-4-dimeti 1-1-pi? erazini 1) piperidinii, 4- (4-eti ll-piperazini 1) -piperidinyl. -CN- (2-diethylaminoeti 1) -N-methi lamino3piperidinyl »4- (4-meti 1-1-homopiperazini 1) pipe-ridimlo» 2- (4-eti ll-piperazine Imeti 1) morfol ino »4-dimet lami nopiperidi ni lo, 2-morfol inometi Ipirrol dini lo, 4- (l-pirrol idini 1) -piperdí "ni lo, 4- sopent Ipiperazini lo, 4- (2-h droxi eti 1) piperazi ni lo, 2- (l-pyrrole idini 1met l) morfol no »4-morfol nopiperidin lo, 2-ami ometi lmorfol ino, 1-dimeti lamino eti Icarboni Ipiperidin lo, 1-meti 1 midazol ilo4- (2-? Iridyl) piperazinyl »4- (3,4-methylenodi oxy benzyl) piperazyl, 1- (4-chlorobuty 1) -1,2,4,4-tetrazolyl, 2-methoxy carboni Ipyridyl, 2-carboxypyridyl, 4-isopropylpyridyl, 4-hydroxypropyl ether, 2-methyl-1-3-idroxy-2,5-dihydrofuran-C3,4-cDpyridyl, 1-cyclohexyl 1-1,2, 3,4-tetrazolyl, 3- (4-methyl-piperazyl) 1-pyrrol idini lo, 1-C3-3,4,5,6-tetrahido-2H-pyrani 1) methyl 3-1.2,3,4-tetrazole ilo »l- (3-chloropropyl) -l» 2 »3» 4-tetrazo! ilo, 2-carbamoi ipirrol idini lo, 4- (3-trifluoromet l-2? -pyridi 1) piperazini lo. 4-benzylpiperidine lo, 4-n-butyl-1.2.3.4-tetrazole i lo. 4-carbamoi Ipiperidini lo. 2- (4-methyl-1-piperazine 1) homomorphol-ino, 2-methylmorphol-ino, 2-methoxymethyl-1-orfol-ino, 2-chloromethyl-lmorphol. 2-hydroxymethylmorph ino. 2-n-butoximeti I orfol ino, 2- (4-meti 1-1-homopiperazini Imeti 1) morfol ino, 6 >; 7-dimethoxy-l, 2,3,4-tetrahydroisoquinol i lo, 2- (4-meti 1-1-homopiperazini lmeti 1) homomorphol ino, 2-chloro-methi lhomomorfol ino, 2-hydroxymethylhomomorphino-4-hydroxypiperazine lo »2- methox meti 1-1,2,3,4,5,6-hexahydrooxepini lo, 4- (2-phenyl-ethox) piperidin lo, 4-benz loxipiperidin lo, 4-hydroxy-3-meti Ipiperazini lo, 4-meti 1 homopiperazine lo, A- aceti loxípiperazini lo, 4-methoxypiperazin lo, 4- (4-tert-butoxycarbon 1-1-homo? Iperazini 1) piperidini lo. 4-4-n-buti 1-1-homo-p peraz ni 1) pi peridi ni lo. 4- (1-meti 1-4-piperidini 1) homopiperazine io »3- (4-methyl-1-ho opi erazi i 1) pi eri ini lo, 2- (4-d met lamino-l-piperidini lmeti 1 ) -morfol no, 2- (4-meti 1-1-pipera? i lmet 1) homomorfol ino, 2-C4- (2-hydroxeti 1) -l- piperazini lmeti 1 Ilmofol ino, 4- (3-meti 1 -1-pierazini 1) -piperidi i lo), 4- (4-eti 1-l-homopiperazi i 1) pipen "di ni lo, 3- (4-meti l-1-homo-iperazini 1) pyrrole lo, 4-C4- (1, 3-d hydrox i-2-prop l) -l-piperazini 1 D-piperidin lo »4-C4- (l» 3-dihidoxy-2-propyl) -l-homopiperazini 1 ]? iperidine lo »4-meti l-3- (l-pipep'di i 1 methyl) piperazini it» 4-meti 1-3- (4-meti ll-piperazini 1-meti 1) piperazini lo »4-meti l-3- (4-meti 1-1-homopiperazine Imet 1)? iperazine it »3» 4 »5-trimethoxypiperazine it» 4-isopropypiperazinyl »4- (1,4-diazabicycloC4.3.03-noni 1) piperidini it »(3,3,4-trimethyl-1-piperazine 1) piperidine lo, 4- (1,4-diazab-cyclo-C4.4.0Ddecy 1) piperidim" lo, 4- (3-meti 1-4-eti ll- piperazini 1) piperidini lo, 4- (3-meti l-4-propi 1-1-pip erazi ni 1) pipen 'dini lo, 4- < 3-propi 1-4-methyl-piperazyl 1) -piperidyl, 4- (3-methyl-1-4-isopropyl-piperazine 1) pipep "dini lo, 4- (3-ethyl-1-4-methyl) 1-1-piperazi il) piperidini lo »4-C3-meti l-4- (2-methoxyeti 1) -l-piperazine 1 -1-piperidini lo» 4-C3-methyl-4- (2-hydroxyeti 1) -l-piperazi i 1 Ipiperidlim "lo» 4- (4-meti 1-1-1,4-diazaspiroC4.4.1undeci 1) pipep "dim" lo. 4- (4-methy1-3-isopropyl-1-piperazinyl) pipen "dini lo. 4- (2-pyrimidi 1) piperazine lo.

The lower alkenyloxy group includes a straight chain or branched chain alkenyloxy group of C 1 -C 2, for example, vi, or "I oxy" 1-methyl-1-vinyloxy-2-dimethyl-1-vinyloxy. »L» 2-dimethyl ini lox »1-propyl vinyloxy» to iloxy, 2-buteni lox, 3-buteni loxi, 1-eti 1 ini lox, 1-methylalkyl 1, 1-penteni loxi, 2- pentenyloxy, 2-he? em "loxi, 3-methylo-1-buteni loxi, 1-buteni loxi" etc. The cycloalkyloxy group includes a C3-Ca cycloalkyloxy group, for example, cyclopropyloxy, cyclobutyloxy, cyclopentyl loxy, cyclohexyloxy, cyclohepti loxy, cyclooctyloxy, etc. The lower alkyl group includes a straight chain or branched chain alkylthio group, eg, methylthio, ethylthio, propylthio, isopropylium, butylthio, isobutylium, tert-butylthio, pentium, hexythio. etc. The lower alkenyl group includes a straight chain or branched chain alkenyl group of -jC », for example, vinyl, 1-methyl Ivintlo, 2-2-dimeti 1 vini lo, 1-2-dimeti 1 vin lo, 1 -propeni 1 vin lo, alilo, 2-butenilo, 3-butenilo »1-eti 1 vini lo. 1-methylalkyl, 1-pentenyl-2-pentenyl. 2-hexenyl. 3-meti 1-l-buteni lo. l-butenyl. etc. The present invention specifically includes the following compounds. (1) A thiazole derivative of the formula (1) wherein R4 and Ra are the same or different and each is a hydrogen atom or a lower alkyl group. R3 is a group of the formula (R44to, p and R44"are the same as those defined in formula (1)), R- * is a hydrogen atom and u is O, or a salt thereof. (2) A t-azol derivative of the formula ( 1) where R4 and R * are the same or different and each is a hydrogen atom or a lower alkyl group, R3 is a group of the formula: (R44to, p and R44β are the same as those defined in formula (1)), R "is a lower alkanoyloxy-lower alkyl, and u is 0, or a salt thereof. (3) A thiazole derivative of the formula (1) wherein R4 and R * are the same or different and each is a hydrogen atom or a lower alkyl group, R3 is a group of the formula: (R4) t>, p and R44ß are the same as those defined in formula (D), R-4 is a hydrogen atom and u is 1, or a salt thereof. (4) A thiazole derivative of the formula (1) wherein R4 and R2 are the same or different and each is a hydrogen atom or a lower alkyl group, R3 is a group of the formula: <R44e », p and Ri-i-sop the same as those defined in formula 1)), R "'is a lower alkanoyloxy-lower alkyl group, and u is a salt thereof. (5) A thiazole derivative of the formula (1) wherein R4 and Ra combine to form a group: - (CH-2) N- (n is 4), R3 is a group of the formula: (R44fc>, p and R4 ß are the same as those defined in formula (1)), R "4 is a hydrogen atom, and u is 0, or a salt thereof. (6) A thiazole derivative of the formula (1) wherein R4 and Ra combine to form a group: - (CH ^ J ^ -in is 4), R3 is a group of the formula: (R4413, p R44) * are the same as those defined in formula (1)), R- * is a lower alkanoyloxy-lower alkyl group, and u is 0, or a salt thereof. (7) A thiazole derivative of the formula (1) wherein R4 and R * combine to form a group - (CHz) "- (n is 4), R3 is a group of the formula: (Rllb. ß are the same as those defined in formula (1)), R-4 is a hydrogen atom and u is 1, or a salt of the same. (8) A thiazole derivative of the formula (1) wherein R4 and Ra combine to form a group: - (CHa) "- (n eß A). R 3 is a group of the formula: (R44e », p and R 4β are the same as defined in formula (1)), R- * is a lower alkanoyloxy-lower alkyl group and u is 1, or a salt thereof. (9) A thiazole derivative of the formula (1) wherein R4 and R2 combine to form a group - (CH-j.) ^ (N is 5) R3 is a group of the formula: (R44ID, p R44"are the same as defined in formula (1))" R "4 is a hydrogen atom, and u is O, or a salt thereof. (10) A thiazole derivative of the formula (1) wherein X is already combined to form a group: - (CH: ie &rt; - (n is 5), R3 is a group of the formula: (R44to , p and R4 ß are the same as those defined in formula (1)), R- * is a lower alkanoyloxy-lower alkyloxy group or a salt thereof. (11) A thiazole derivative of the Formula (1) where R4 and Ra combine to form a group: - (CH ^.),., - (n is 5) »R3 is a group of the formula: CO CH = CRllb reo. Rlla R (44e>, p and R44"are the is-moß5 that the definite ps" in the formula (D), R "4 is a hydrogen atom and u is 1, or a salt thereof. (12) A thiazole derivative of the formula (1) wherein R4 and Ra combine to form a group: - (CH ^) ^ - (n is 5), R3 is a group of the formula: R44t », p R44"are the same as those defined in formula (D), R- * is an alkanoyl group and lower i-lower alkyl and u is 1, or a salt thereof. (13) A thiazole derivative of the formula (1) wherein R4 and R * combine to form a benzene ring which may optionally have a substomer selected from a lower alkyl group, a lower alkoxy group, or a nitro group. »An amino group optionally having a lower alkyl substituent and a halogen atom» R3 is a group of the formula: R xt », p and A» are the same as those defined in formula (1)), R "4 is a hydrogen atom, and u is O, or a salt thereof. (14) A thiazole derivative of the formula (1) wherein R4 and * combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, an inner alkoxy group, a nitro group, an amino group optionally having a lower alkyl substituent and an atom of halogen, R3 is a group of the formula: lb- (C0) p-Rlla (R44 », p and R4" are the same as defined in formula (1)), R- * is a lower alkanoyloxy-lower alkyl group yu is O, or a salt thereof. (15) A thiazole derivative of the formula (1) wherein RX and »ge combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group optionally having a substituent lower alkyl and an halogen, R3 is a group of the formula: (R b, p and R44 * are the same as those defined in formula (1), R-4 is a hydrogen atom, and u is 1, or a salt thereof. (16) A thiazole derivative of the formula ( 1) where R4 and R * combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group optionally having a lower alkyl substituent and a halogen atom » R3 is a group of the formula: (R44t> p and R44β are the same as defined in formula (1)) »R * 4 is a lower alkanoyloxy-lower alkyl group and is a salt thereof. (17) A thiazole derivative of the formula (1) wherein and R "are the same or different and each is a hydrogen atom or a lower alkyl group. R3 is a group of the formula: (s is 0. Rß is a group: -C0-CH = CR 4C3- (C0) p-R44 * (R44e ». p and RAA »sor) same as those defined in formula (1)), Rβ, m» A and Z are the same as those defined in formula (1)) »R'4 is a hydrogen atom, yu is O , or a salt thereof. (18) A thiazole derivative of the formula (1) wherein R4 and R5 * are the same or different and each is a hydrogen atom or a lower alkyl group, R3 is a group of the formula: (s is O, Rβ is a group: -C0-CH = CR44e> - (C0),: .- R44- (R44b, p and R44ß are the same as those defined in formula (1)), Rß, m »A and Z are the same as defined in formula (1))» R "4 is an lower or lower alkyl alkanoyloxy group and is 0 or a salt thereof. (19) A thiazole derivative of the formula (1) wherein R4 and Ra are the same or different and each is a hydrogen atom or an alkyl group. R3 is a group of the formula: (s is O »Rß is a group: -C0-CH = CR44C, - (C0) t: .- R44- <R 4e>» and R44 * are the same as those defined in formula (l)) »Rß, m, A and Z are the same as those defined in formula (1)) »R-4 is a hydrogen atom, and u is 1, or a salt thereof. (20) A thiazole derivative of the formula (1) wherein R4 and R2 are the same or different and each is a hydrogen atom or? N alkyl group, R3 is a group of the formula: (s is 0, R "is a group: -C0-CH- = CR4 ß- (C0) t.-R44" (R e >, p and R44"are the same as those defined in formula (1)), R- * is a lower alkanoyloxy-lower alkyl group and is a salt thereof. (21) A thiazole derivative of the formula ( 1) where RA and R »combine to form a group: - (CH ^),., - (n is 4), R3 is a group of the formula: (s is 0. R« is a group: - C0-CH = CR44t »- (C0) ts-R44- (R44ß, p and R44 * are the same as those defined in formula (1))» R ". M» A and Z are the same as those defined in formula (1)) »R ** is a hydrogen atom and u is O, or a salt thereof. (22) A thiazole derivative of the formula (1) wherein R4 and R2 combine to form a group: - (CH ^),., - (n is 4), R3 is a group of the formula: (s) es =, R «is a group: -C0-CH = CR4 te- (C0) t:, - R44» < R4 t ». py RAA. are the same as those defined in formula (1)), R ", m, A and Z are the same as those defined in formula (1))» R- * eß a lower alkanoyloxy-lower alkyl group and u eß 0. or a salt of it. (23) A thiazole derivative of the formula (1) wherein RA and Z combine to form a group: - (CH ^) ^ - (n is 4), R3 is a group of the formula: (s is O, R "is a group: -CO-CH = CR44ß- < CO).,: .- R44» (R44e >, p and RAA »are the same as those defined in formula (1))» Rß. , A and Z are the same as those defined in formula (1)), R-4 is a hydrogen atom and u is 1, or a salt thereof. (24) A thiazole derivative of the formula (1) wherein R4 and R2 combine to form a group: - (CH ^) ^ - (n is 4), R eß a group of the formula: (s is 0, R * is a group: -C0-CH = CR44t, - (C0) "- R44 * (R4 t>, p and R44" are the same as defined in the formula (1)), Rβ,, A and Z are the same as defined in formula (1)), R- is a lower alkanoyloxy-lower alkyl group and u is i, or a salt thereof. (25) A thiazole derivative of the formula (1) wherein R4 and R2 combine to form a group - (CH ^ J ^ -in is 5). R3 is a group of the formula: (ß eß O. R * eß a group: -C0-CH = CR 4c, - (C0)?;, - R44ß (R4413, p and R44 «are the miemos that were defined in formula (1)). A and Z are the mémos that were defined in formula (1)). R-4 is a hydrogen atom and u is 1, or a salt thereof. (26) A thiazole derivative of the formula (1) wherein R4 and R2 combine to form a group - (CH?) Rt- (r? Is 5). R3 is a group of the formula: (a is 0. R * is a group: -CO-CH = CR4 e> - (C0) "- R44» (R4413, p and R44 * are the same as defined in the formula (l >), Rβ , m, A and Z are the same as defined in formula (1)), R- * is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof. (27) A thiazole derivative of the formula (1) wherein R4 and R2 combine to form a group - (CH ^ J ^ -in is 5> R3 is a group of the formula: (s is O. Rβ is a group: -C0-CH = CR44, a- (C0) t.-R44β (R11B? p and R44 * are the same as defined in formula (1)) »Rß.m, A and Z are the same as ß defined in formula (1)) »R-4 is a hydrogen atom and u is 1» or a salt thereof. (28) A thiazole derivative of the formula (1) wherein R4 and R2 combine to form a group - (CHa) "- (n eß 5)» R3 is a group of the formula: = I ^ R6 (s is 0. R < * is a group: -C0-CH = CR4 O- (C0),: - R44 * (R to, p and R14"are the same as defined in the formula ( 1)), Rß »m, A and Z are the same as defined in formula (1)), R- * is a lower alkanoyloxy-lower alkyl group and u is 1, or a salt thereof. thiazole derivative of the formula (1) in which RA and R2 combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom »R3 is a group of the formula: (ß eß O »R * eß a group: -C0-CH = CR» - (C0),., - R44ß (R44ts »p and R44ß are the same as defined in formula (1))» Ra, m, A and Z are the same as defined in formula (1)), R-4 is a hydrogen atom and u is O, or a salt thereof. (30) A thiazole derivative of the formula (1) wherein R 4 and R 2 combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group. an amino group optionally having a lower alkyl substituent and a halogen atom. R3 is a group of the formula: < s is O. R "is a group: -C0-CH = CR C, - (C0),: - R44β (x ß, p and Rii. are Cough same as defined in formula (1))» Rß, m . A and Z are the same as defined in formula (1)), R * 4 is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof. (31) A thiazole derivative of the formula (1) wherein RX and ss combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, a group amino optionally having a substituent and lower alkyl and a halogen atom, R3 is a group of the formula: (s is 0, R * is a group: -C0-CH = CR44t »- (C0)?: .- R44- (R44to, p and R44" are the same as defined in formula (1)), Rβ, m, A and Z are the same as defined in formula (1)), R-4 is a hydrogen atom and u is 1, or a salt thereof (32) A thiazole derivative of the formula (1) wherein R4 and R2 combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group optionally having a lower alkyl substituent and a halogen atom »R3 is a group of the formula: / -V '< R5) '"(s is O, Rβ is a group: -C0-CH = CR ß- (C0), ..- R44» (R t>, p and R44ß are the same as defined in the formula (1 )), Rß, m, A and Z are the same as those defined in formula (D), R "4 is a lower alkanoyloxy-lower alkyl group and u is 1, or a salt thereof. (33) A derivative of thiazole of the formula (1) wherein RX and Rs on the same or different, and each is a hydrogen atom or a lower alkyl group, R3 is a group of the formula: (s is O, R is a group : -C0-CH = CR t »- (C0),:, - R44- (R 4t», p and R4 ß are the same as defined in formula (D), Rß »m and A are the same as defined in the formula (D) R * 4 is a hydrogen atom and u is O »or a salt thereof (34) A thiazole derivative of the formula (1) wherein RX and Rβ are the same or different» and each is a hydrogen atom or a lower alkyl group, R3 is a group of the formula: (ß eß 0, R * is a group: -C0-CH = CR 4t »- (C0)?, - R44β (R44e>, p and R44ß are the same as defined in formula (1)), Rβ, A and A are the mers defined in formula (1)), R- * is a lower alkanoyloxy-lower alkyl group, or O, or a salt thereof. (35) A thiazole derivative of the formula (1) wherein R4 and R2 are the same or different, and each is a hydrogen atom or a lower alkyl group, R3 is a group of the formula: (s is O, R * is a group: -CO-CH = CR, 3- (CO),., - R44- (RXA6>, P and RII «QOn 1 same as defined in the formula (1 )), RB, and A are the same as defined in formula (1)), R * 4 is a hydrogen atom and u is 1, or a salt of the same. (36) A thiazole derivative of the formula (1) wherein RX and R "are the same or different, and each is a hydrogen atom or a lower alkyl group, R3 is a group of the formula: - v / (R) m (s is O, R * is a group: -C0-CH = CR to- (C0) t., - R44"(R44t>, p and R44ß are the same as defined in formula (D), Rß, m and A are the same as defined in formula (1)), R "* is a lower alkanoyloxy-lower alkyl group, yu eß 1, or a salt thereof. (37) A thiazole derivative of the formula (1) where R4 and R2 combine to form a group - (CH _) _- (n eß 4), R 3 and a group of the formula: (ß is 1, Z eß an oxygen atom, R * eß a group: -C0-CH = CR44C »- (C0),:, - R44 '» < R t >, and R44- are the same as η defined in formula (1)), Rβ, and A are the same as ß defined in formula (1)), R "is a hydrogen atom and u is 0" or a salt thereof. (38) A derivative of thiazole of the formula (1) wherein R4 and R2 combine to form a group - (CHat) "- (n is 4), R3 is a group of the formula: (s is 1, Z is an oxygen atom »Rβ is a group: -C0- CH = CR44e, - (C0) -t ..- R44" »(R t>, p and R44 * are the same as defined in the formula (1)) »RB, m and A are the same as defined in the formula (1)), R-4 is a lower alkyloxy-lower alkyl group, and u is 0, or a salt thereof. (39) A thiazole derivative of the formula (1) wherein R4 and R2 combine to form a group is 4), R3 is a group of the formula: (ß eß 1, Z is an oxygen atom, R * is a group: -C0-CH = CR 4t »- (C0),:? - R4 ß (R 4to, p and R4 ß ßon loe same as ße defined in Formula (1)), Rβ, and A are the same as those defined in formula (1)), R 4 is a hydrogen atom, and 1 is a salt thereof. (40) A thiazole derivative of the formula (1) wherein R4 and R2 combine to form a group - (CHa) "- (n is 4)» R3 is a group of the formula: (s is 1, Z is an oxygen atom, R * is a group: -C0-CH = CR e, - (CO) "- R44" (R416 », p and R44" are the same as defined in formula (1)), RB, m and A are the same as those defined in formula (1)). R * 4 is a lower alkanoyloxy-lower alkyl group and? is 1 »or a salt thereof. (41) A thiazyl derivative of the formula (1) wherein R4 and R2 combine to form a group - (CH ^ J ^ -in is 5) »R3 is a group of the formula: (s is 1 »Z is an oxygen atom R * is a group: -C0-CH = CR4 C, - (CO),: .- R44" (R e>, p and R 4ß are the same as defined in formula (1)), RB, and A are the same as defined in formula (1)), R "4 eß a hydrogen atom and u is O, or a salt thereof. (42) A thiazole derivative of the formula (1) wherein RI and * combine to form a group - (CHat) r ^ - (r, is 5), R3 is a group of the formula: (s is 1, Z is an oxygen atom, R * is a group: -C0-CH = CR 4to- (C0) -R44- (R44to, p and R44 »are the same as defined in formula (1) ), RB, m and A are the same as defined in formula (D), R * 4 is a lower alkanoyloxyl-lower alkyl group and is 0. or a salt thereof. (43) A thiazole derivative of the formula (1) wherein R4 and R2 combine to form a group - (CH ^ ^ ^ -in is 5). R3 is a group of the formula: (s is 1. Z is an oxygen atom, R * is a group: -C0-CH = CR44, - »- (CO),:, - R:, - ß (R440, p and R44" »are the same. which were defined in formula (1)), RB, and A are the same as those defined in formula (1)) »R- is a hydrogen atom and u is 1» or a salt thereof. (44) A thiazole derivative of the formula (1) wherein R4 and R2 combine to form a group - (CHa) r, - (n is 5) »R3 is a group of the formula: (s eß 1 »Z eß an oxygen atom» R * eß a group: -C0-CH = CR44c > - (C0) -t:, - R44 '»(R44to' and R4 ß ßon the same as defined in the formula (1)) »Rβ» m and A are the same as defined in the formula (1)) »R-4 is a lower alkanoyloxy-lower alkyl group and is a salt thereof. (45) A thiazole derivative of the formula (1) wherein R4 and R2 combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, a group amino optionally having a lower alkyl substituent and a halogen atom. R3 is a group of the formula: < s eß 1 »Z is an oxygen atom. R * is a group: -C0-CH = CR44C, - (CO), ..- R ß (R4 ß, p and R44"are the same as defined in formula (1)). RB» and A are the same as defined in formula (1)) »R- * is a hydrogen atom yu eß O» or a salt thereof (46) A thiazole derivative of the formula (1) wherein RI and R * ßeße combine to form a benzene ring which may optionally have a substudent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group optionally having a lower alkyl substituent and a halogen atom, R3 is a group of the formula: (s is 1, Z is an oxygen atom, R * is a group: -C0-CH = CR4 ß- (C0),., - R44"(R44B>, p and R44" are the same as ß defined in the formula (1)), RB, m and A are the same as defined in formula (1)), R "* eß a lower alky lower alkyl group-lower alkyl and u is 0, or a salt thereof. (47) A thiazole derivative of the formula (1) wherein R4 and R2 combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, a aroino group optionally having a lower alkyl substituent and a halogen atom »R3 is a group of the formula: (s is 1, Z is an oxygen atom, R * is a group: -C0-CH = CR44e, - ( C0),., - R44 '* (R >;, p and R44ß are the same as defined in formula (1)), RB, m and A are the same as defined in formula (1)), R-4 is a hydrogen atom and u is 1 »or a come out of it (48) A thiazole derivative of the formula (1) wherein RI and »combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, a group amino optionally having a lower alkyl substituent and a halogen atom, R3 is a group of the formula: (s is 1, Z is an oxygen atom, R * is a group: -CO- CH = CR44ß- (C0) ,, - R44- (R44 *, p and R44- are the same as defined in the formula (D), RB, m and A are the same as defined in formula (1)) »R" * eß a lower alkanoyloxy-lower alkyl group and or is a salt thereof (49) A thiazole derivative of the formula (1) wherein R 4 and R 2 are the same or different, and each is a hydrogen atom or a lower alkyl group R 3 is a group of the formula: (s is 1, Z is an sulfur, Ra is a group: -CO-CH = CR44b- (CO) D-R4 ß (RE>, p and R44"are the same as defined in formula (1)), Rß, m and A are the same which were defined in the formula < D), R- * is a hydrogen atom and u is O, or a salt thereof. (50) A thiazole derivative of the formula (1) wherein R4 and R2 are the same or different, and each is a hydrogen atom or a lower alkyl group, R3 is a group of the formula: (s eß 1. Z is a sulfur atom, R * is a group: -C0-CH = CR44t '- (C0) c, -R44"(R4 ° rpy R44" are the same as defined in formula (1)), Rβ, m and A are the same as defined in the formula ( 1)), R- * is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof. (51) A thiazole derivative of the formula (1) wherein RA and Z are the same or different, and each is a hydrogen atom or a lower alkyl group, R3 is a group of the formula: (s is 1 , Z is a sulfur atom, R * is a group: -C0-CH = CR44 * »- (C0) ß-R44β (R44e>, p and R44ß are the same as defined in formula (1), RB , m and A are the same as defined in formula (D), R-4 is a hydrogen atom and u is 0, or a salt thereof (52) A thiazole derivative of the formula (1) wherein R 4 and R 2 are the same or different, and each is a hydrogen atom or a lower alkyl group, R 3 is a group of the formula: (ß is 1, Z is a sulfur atom, R * is a group: -CO-CH = CR44ß- (CO) ß-R44ß (R4 t>, p and R44"are the members defined in the formula ( 1)), Rβ, m and A are the mißmoß that were defined in the formula (1)), R-4 is a lower alkanoyloxy-lower alkyl group and u is 1, or a salt thereof. (53) A thiazole derivative of the formula (1) where R4 and R2 combine to form a group - (CHß) "- (n is 4). R3 is a group of laf ormu la: (ß ee 1. Z is a sulfur atom, Rβ is a group: -C0-CH = CR44t »- (CO ^ -R44- (R44ls, p R44" are the same as were defined in formula (1)), Rβ, m and A are the same as defined in formula (1)), R- * is a hydrogen atom and u is O 'or a salt thereof. (54) A thiazole derivative of the formula (1) wherein R4 and R2 combine to form a group - (CHss) "- (n is 4) Ra is a group of laf ormu la: (s eß 1. Z is an atom of sulfur, R * is a group: -C0-CH = CR446 »- (C0) ß-R44β (R4413, p and R44» ßon loe same as defined in formula (1) >, Rß, and A are loe same as defined in formula (1)), R- * eß a lower alkanoyloxy-lower alkyl group, and a 0, or a salt thereof. (55) A thiazole derivative of the formula (1) wherein RX and Ra combine to form a group - (CH ^ - ^ - ín is 4), R3 is a group of the formula: (s is 1. Z is a sulfur atom, R * is a group: -C0-CH = CR44, a- (CO ^ -R44 * »(R 4 °, p R44 ** are the same as defined in formula (1)) »Rβ, m and A are the same as defined in formula (1)), R" 4 is a hydrogen atom and u is 1, or a salt thereof. (56) A thiazole derivative of the formula (1) where RA and ge combine to form a group - (CH2) "- (n is 4), R3 is a group of the formula: (ß is 1. Z is a sulfur atom R * is a group: -C0-CH = CR44t > - (C0) ß-R44ß (R4413, p &R44 * ßon the mißmoß that were defined in the formula (1 )), Rß »m and A are the same as defined in formula (1)). R- * is a lower alkanoyloxy-lower alkyl group and a β 1"or a salt thereof. (57) A thiazole derivative of the formula (1) wherein R 4 and R 2 combine to form a group - (CH - ^^ - in is 5). R3 is a group of the formula: -A- (Z) s - ^^ '(s is 1, Z is a sulfur atom, R * is a group: -C0-CH = CR44t > - (CO) ß-R44 * (R4 ß, p R44β are the same as defined in formula (1): Rβ, m and A are the same as defined in formula (1)), R- »is a hydrogen atom and u is 0, or a salt thereof. (58) A thiazole derivative of the formula (1) wherein R4 and R2 combine to form a group - (CH ^ J ^ -tn is 5), R3 is a group of the formula (ß eß 1, Z is a sulfur atom, R * is a group: -C0-CH = CR4 B- (C0) ß-R44- (R4 &, and R44ß are the same as defined in the formula ( 1), RB, m and A are the same as defined in formula (1)), R- * is an alkanoyloxy group inferred »-lower alkyl and u is 0» or a salt thereof. (59) A thiazole derivative of the formula (1) wherein R4 and R2 combine to form a group - (CHa) "- (n is 5), R3 is a group of the formula: (s eß 1, Z eß a sulfur atom »Rß- eß a group: -C0-CH = CR44e» - (C0) -o-R44ß (R44to and R44m are the same as defined in formula (1) ), Rβ, m and A are the same as defined in formula (1)), R- * is a hydrogen atom and u is 1. or a salt thereof. (60) A thiazole derivative of the formula (1) wherein R4 and R2 combine to form a group - (CH2) r) - (n is 5) »R: is a group of the formula: (ß eß 1. Z is a sulfur atom, R «eß a group: -C0-CH = CR44t > - (CO) ß-R44" (R ° and R 4, 3on the same as defined in formula < D) .Rβ, m and A are the same as defined in formula (1).) R- * is a lower alkanoyloxy-lower alkyl group and is 1, or a salt thereof. (61) A derivative of thiazole of the formula (1) wherein RX and Ra combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group optionally having a β-substituent β-lower alkyl and a halogen atom, R3 is a group of the formula: (ß eß 1, Z is a sulfur atom, Rm is a group: -C0-CH = CR44to- (C0) ß-R44 * (R4413, p and R44"are the same as ß defined in formula (1)) , Rβ, and A are the same as defined in formula (1)), R- * is a hydrogen atom yu eßO, or a salt thereof (62) A thiazole derivative of the formula (1) where RX and E combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group optionally having a lower alkyl substituent and a halogen atom, R3 is a group of the formula: (ß is 1 »Z eß a sulfur atom» R * is a group: -C0-CH = CR44to- (CO) ß-R44ß (R4413 »p and R44" are the same as defined in formula (1)) , RB, m and A are the same as defined in formula (1)), R-4 is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof. (63) A thiazole derivative of the formula (1) where R4 and R2 combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group optionally having a lower alkyl substituent and a halogen atom, R3 is a group of the formula: (s eß 1, Z is a sulfur atom, R * is a group: -C0-CH = CR44t »- (C0) ß-R44ß (R44ß, p and R44» are the same as defined in formula (1) , RB, m and A are the moieties that were defined in formula (D), R "* eß a hydrogen atom yu eß 1, or a salt thereof. (64) A thiazole derivative of the formula (1) in where R.sup.4 and R.sup.2 combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group optionally having a lower alkyl substituent and a halogen atom, R3 is a group of the formula: (s is 1, Z is a sulfur atom, R * is a group: -C0-CH = CR 4to- (C0) ß-R44 * (R t>, p and R44 »are the same as defined in the formula (1), Rβ, and A are the same as defined in formula (1)), R ** is a lower alkanoyloxy-lower alkyl group, and / or is 1, or a salt thereof. thiazole of the formula (1) wherein R4 and R2 are the same or different, and each is a hydrogen atom or a lower alkyl group, R3 is a group of the formula: (ß ee 0, R * is a group: -C0-CH = C-C0R4 * (R4-4 is the same as defined in formula (1), Rß, Z, and A are the same as defined in the formula (D), R "* is a hydrogen atom and u is 0, or a salt thereof. (66) A thiazole derivative of the formula (1) wherein R4 and R2 are the same or different, and each is a hydrogen atom or a lower alkyl group. R3 is a group of the formula: (ß eß 0 »R * is a group: -C0-CH = C-C0R4 - »(R4-4 is the same as defined in formula (1)» RB.Z »m and A are the m ßmoß that were defined in formula (1) > .R" 4 eß a lower alkanoyloxy group- lower alkyl and u is 0, or a salt thereof. (67) A thiazole derivative of the formula (1) wherein R4 and R2 are the same or different, and each is a hydrogen atom or a lower alkyl group, R3 is a group of the (s eß O »R * is a group: -C0-CH = C-C0R" * (R4"4 eß the same as defined in formula (1), RB» Z »and A ßon the same as defined in the formula (1)) R- * is a hydrogen atom yu eß 1"or a salt thereof (68) A thiazole derivative of the formula (1) wherein R 4 and R 2 are the same or different» and each is a hydrogen atom or a lower alkyl group. R3 is a group of the formula: (s is O. R is a group: -CO-CH = C-COR4 * 4 ^ 4- * is the same as was defined in the formula (1) »RB» Z »m and A are the same as η defined in the formula <1>)» R * 4 is a lower alkanoyloxy-lower alkyl group yu eß 1 »or a ßal m. (69) A thiazole derivative of the formula (1) wherein RX already combine to form a group - CH ^ J ^ -i is 4) »R3 is a group of the formula: (ß is O »R« is a group: -CO-CHsC-COR4"4 (R4 ** is the same as defined in formula (1))» RB »Z. and A are the same as defined in formula (1)), R4 is a hydrogen atom and u is O, or a salt thereof (70) A thiazole derivative of the formula (1) wherein RX already combine to form a group - (CHa ^ -in is 4), R3 is a group of the formula: (s is O, Rβ is a group: -C0-CH = C-C0R4- * (R4- * is the same as defined in the formula (1 >), RB, Z, and A are the same as defined in formula (1)), R * 4 eß a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof (71) A thiazole derivative of the formula (1) wherein R4 and R2 are combined to form a group - (CHJB) r, - (n eß 4) »R3 is a group of the formula: (s is O »Rß ee a group: -CO-CH = C-COR4-4 (R4-4 is the moiety that was defined in formula (D) .RB» Z »and A are the same as ß defined in Formula (1)) R 4 is a hydrogen atom and is 1 or a salt thereof (72) A thiazole derivative of the formula (1) wherein R 4 and R 2 combine to form a group - (CH) - ^ - ín eß 4) »R3 is a group of the formula: (ß is O, R * is a group: -CO-CH = C-COR4-4 (R4-4 is the iß or that ß defined in formula (1)), RB, Z. and A are the same as formula (1)), R-4 eß were defined as a lower alkanoyl-lower alkyl-lower group yuß 1, or a salt thereof. (73) A thiazole derivative of the formula (1) wherein R4 and R2 combine to form a group - (CH ^ J ^ -in is 5), R3 is a group of the formula: (s is O? R * is a group: -CO-CH = C-COR4 '* (R4"4 eß the same as η defined in formula (1))» RB. Z »m and A are the same as defined in formula (1)) »R- * is a hydrogen atom and u is O. or a sa1 thereof. (74) A thiazole derivative of the formula (1) wherein R4 and R2 combine to form a group - (CH ^ J ^ -in is 5) »R3 is a group of the formula: (s is O »R * is a group: -CO-CH = C-COR4-4 (R4-4 is the same as defined in formula (1))» RB »Z, m and A are the same as defined in the formula < D), R-4 is a lower alkanoyl group-lower alkyl &u eß O »or a salt thereof. (75) A thiazole derivative of the formula (1) wherein RX and a combine to form a group - (CHa) r, - (n is 5> »R3 is a group of the formula: (s is O »R * ee a group: -CO-CH = C-COR4-4 (R4 * 4 eß the same as η defined in formula (1))» Rß »Z» m and A are the same as defined in formula (1)). R-4 is a hydrogen atom and u is 1 or a salt thereof. (76) A thiazole derivative of the formula (1) wherein RX and a combine to form a group - (CH ^ J ^ -in is 5). R3 is a group of the formula (s is O »R * is a group: -CO-CH = C-COR4-4 (R4- * is the same as defined in formula (1))» R °, Z »m and A are the mémos that η defined in formula (1)) »R-4 is a lower alkanoyloxy group-lower alkyl yu eß 1 or a salt thereof. (77) A thiazole derivative of the formula (1) wherein R4 and R2 combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, or a group amino optionally having a lower alkyl substituent and a halogen atom. R3 is a group of the formula: (ß is 0 »R * is a group: -CO-CH = C-COR4-4 (R4-4 is the same as ß defined in formula (1))» RB »Z» m and A are the same as defined in formula (1)) »R4 is a hydrogen atom yu eß 0, or an 8al thereof. (78) A thiazole derivative of the formula (1) wherein and R combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R3 is a group of the formula: (s is 0, R * is a group: -CO-CH = C-COR4- * (R4- * is the same as defined in formula (l)), RB, Z, and A are the same as defined in formula (1)), R-4 is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof. (79) A thiazole derivative of the formula (1) wherein RX and yae combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R3 is a group of the formula: (s is O, R "is a group: -CO-CH = C-COR4-4 (R4-4 is the same as defined in formula (1)), Rß, Z, m and A are the same as defined in formula (1)), R-4 is a hydrogen atom and u is 1, or a salt thereof. (80) A thiazole derivative of the formula (1) wherein R4 and R2 combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, a group amino optionally having a lower alkyl substituent and a halogen atom, R3 is a group of the formula: (s is 0, Rß is a group: -CO-CH = C-COR4-4 (R4-4 is the same as defined in formula (1)), Rß, Z, m and A are the same as defined in formula (1)). R-4 is a lower alkanoyloxy-lower alkyl group and? is 1, or a salt thereof. (Bl) A thiazole derivative of the formula (1) wherein R4 and R2 are the same or different, and each is a hydrogen atom or a lower alkyl group, R3 is a group of the fluorine: '(s is 1, Z is an oxygen atom, R * is an group: -CO-CH = C-COR4-4 (R4-4 is the same as defined in formula (D), RB, m and A are the same as defined in formula (1)), R + is a hydrogen atom yu eß 0, or a salt thereof (B2) A thiazole derivative of the formula (1) wherein R 4 and R 2 are the same or different, and each is a hydrogen atom or a lower alkyl group , R3 is a group of the formula: (s is 1, Z is an oxygen atom R * eß a group: -CO-CH = C-COR4-4 (R4- * eβ the same as defined in the formula 1)), Rβ, m and A are the mers defined in formula (1)), R ** is a lower alkanoyloxy-lower alkyl group and is O, or a salt thereof. (83) A thiazole derivative of the formula (1) wherein R4 and R2 are the same or different, and each is a hydrogen atom or a lower alkyl group, R3 is a group of the formula: (s is 1, Z is an oxygen atom R * is a group: -CO-CH = C-COR4-4 (R4"» is the same as defined in formula (1)) »Rß, my A are the same as defined in formula (1)), R- * is a hydrogen atom and y is 1, or a salt thereof (84) A thiazole derivative of the formula (1) wherein R 4 and R 2 are the same or different, and each is a hydrogen atom or a lower alkyl group R 3 is a group of the formula: (s is 1, Z is an oxygen atom, Rβ is a group: -CO-CH = C-COR4-4 (R4- * is the same as defined in formula (1)). the same ones that were defined in formula (1)). R "* is a lower alkanoyloxy group-lower alkyl and or 1. is a salt of the same. (85) A thiazole derivative of the formula (1) wherein R4 and R2 are combined to form a group - (CHse) r > - (n is 4), R3 is a group of the formula: (e ee 1, Z is an oxygen atom »Rß is a group: -CO-CH = C-COR4-4 (R4-4 is the same as defined in formula (1))» Rß »m and A they are the same as defined in formula (1)) »R- * is a hydrogen atom and u is 1» or a salt thereof. (86) A thiazole derivative of the formula (1) wherein RX and a ge combine to form a group - (CH ^ J ^ -in is 4), R3 is a group of the formula: (s is 1, Z is an oxygen atom »R * is a group: -CO-CH = C-COR4" * (R4-4 is the same as defined in formula (1)) »RB. are the same as defined in formula (1)) R 4 is a lower alkanoyloxy-lower alkyl group and is O or a salt thereof (87) A thiazole derivative of the formula (1) in where RX and a combine to form a group - (CHj,) ^ - (n is 4), R5 is a group of the formula: (ß is 1, Z eß an oxygen atom Rß is a group: -CO-CH = C-COR4-4 (R4-4 is the same as defined in formula (1)). Rß »m and A are the sameß that were defined in formula (1)) »R- * is a hydrogen atom and u is 1, or a salt of the same. (88) A thiazole derivative of the formula (1) wherein R4 and R2 combine to form a group - (CH ^ J ^ -in is 4), R3 is a group of the formula: (β is 1 »Z is an oxygen atom Rβ is a group: -CO-CH = C-COR4- * (R4- * is the same as defined in formula (1)), RB, m and A are the same as defined in Formula (1)), R4 * is a lower alkanoyloxy-lower alkyl group, and u is 1, or a salt thereof. (89) A thiazole derivative of the formula (1) wherein RX and R combine to form a group - (CHa?) R, - (n is 5) »R3 is a group of the formula: (ß is 1, Z is an oxygen atom, R * eß a group: -CO-CH = C-COR4"4 (R4" 4 eß the same as ß defined in formula (D). the same as defined in formula (1)) R- * eß a hydrogen atom yu is 0. or a salt thereof (90) A thiazole derivative of the formula (1) wherein R4 and R2 are combine to form a group - (CHa) "- (n is 5) .R3 is a group of the formula: (ß is 1. Z eß an oxygen atom »R * eß a group: -CO-CH = C-COR4-4 < R4" * eß the same as ß defined in formula (1)) »R", my A ßon the same as defined in formula (1)) »R- * is a lower alkanoyloxy-lower alkyl group and u is O. or a salt thereof. (91) A thiazole derivative of the formula (1) wherein RX and R e combine to form a group - (CHa,), --.- ^ is 5), R3 is a group of the formula: (s is 1 »Z is an oxygen atom, R * eß a group: -CO-CH = C-COR4" 4 (R4"* is the same as defined in formula (1)), RB» rn and A are the same as defined in formula (1)), R "* is a hydrogen atom, and? Is 1, or a salt thereof. (92) A thiazole derivative of the formula (1) wherein R4 and R2 combine to form a group - (CHS?) R, - (n is 5), R3 is a group of l a f ormu l a: (s is 1, Z is an oxygen atom, R * is a group: -CO-CH = C-COR4"4 (R4- * is the same as defined in the formula < D), Rβ, m &A they are the same as defined in formula (1)), R ** is a lower alkanoyloxy-lower alkyl group and u is 1, or a salt thereof. (93) A thiazole derivative of the formula (1) wherein RX and Ra combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group optionally having a lower alkyl substituent and a halogen atom, R3 is a group of the formula: (s is 1, Z is an oxygen atom, Rβ is a group: -CO-CH = C-COR4- * (R4"4 is the same as defined in formula (1)), Rβ, m and A are the same as defined in formula (1)), R ** is a hydrogen atom and u is 0, or a salt thereof. (94) A thiazole derivative of the formula (1) wherein R4 and R2 combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group optionally having a lower alkyl substituent and a halogen atom, R3 is a group of the formula: (s is 1, Z is an oxygen atom, R * is a group: -CO-CH = C-COR4"4 (R4- * is the same as defined in formula (1)), Rβ, m and A are the same as defined in formula (1)), R- * eß a lower alkanoyloxy group -lower alkyl and or is O, or a salt of the same. (95) A thiazole derivative of the formula (1) wherein RX and ge combine to form a benzene ring which may optionally have a β-substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group optionally having a lower alkyl substituent and a halogen atom. a group of the formula: (ß is 1 »Z is an oxygen atom» Rß is a group: -CO-CH = C-COR4"4 (R4-4 is the same as defined in formula (1)). Rß» m and A are the same as defined in formula (1)) R "* is a hydrogen atom and u is 1" or a salt thereof. (96) A thiazole derivative of the formula (1) wherein A and combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group optionally having a substituent, lower alkyl and a halogen atom, R3 is a group of the formula (ß eß 1, Z is an oxygen atom, R * is a group: -CO-CH = C-COR4"* (R4" 4 is the same as defined in formula (1)), RB, my A they are the same as those defined in the formula (D) R ** is a lower alkanoyloxy-lower alkyl group and is 1 or a salt thereof (97) A thiazole derivative of the formula (1) in where RX and Ra are TOS same or different, and each is a hydrogen atom or a lower alkyl group, R3 is a group of the formula: (ß is 1, Z is a sulfur atom, R * is a group: -CO-CH = C-COR4"* (R4-4 is the same as ß defined in formula (1)), RB, my A loson the moieties that were defined in the formula (1)), R- * is a hydrogen atom and u is 0 »or a salt thereof (98) A thiazole derivative of the formula (1) wherein R4 and R2 they are the same or different, and each is a hydrogen atom or a lower alkyl group, R3 is a group of the formula: (ß is 1, Z is a sulfur atom, R * is a group: -CO-CH = C-COR4"4 (R4-4 is the same as defined in formula (1)), RB, m and A are the same as defined in formula (1)), R- * is an alkanoyl group? i lower-lower alkyl yu ee O, or a salt thereof. (99) A thiazole derivative of the formula (1) wherein RX and R are the same or different, and each is a hydrogen atom or a lower alkyl group, R3 is a group of the formula: (ß eß 1, Z ee a sulfur atom, R * eß a group: - CO-CH = C-COR4-4 (R4- * ee the pn'emo that was defined in formula (1)), RB, and A are the same as defined in formula (1)), R- * it is a hydrogen atom and u is 1, or a salt thereof. (100) A t-azole derivative of the formula (1) wherein R4 and R2 are the mißmoß or different, and each is a hydrogen atom or a lower alkyl group »R3 eß a group of the formula: (ß eß 1. Z eß a sulfur atom »R * eß a group: -CO-CH = C-COR4" 4 (R4- * is the same as defined in formula (1)) .RB.m and A are the same which were defined in formula (1)) R- * eß a lower alkanoyloxy-lower alkyl group and? is 1, or a salt thereof (101) A thiazole derivative of the formula (1) wherein R4 and R2 combine to form a group - (CHse)? - (n is 4), R3 is a group of the formula: (s is 1, Z is a sulfur atom, Rβ is a group: -CO-CH = C -COR4"* (R4" * is the same as defined in 1 to formula (1)), RB, m and A are the same as defined in formula (D), R- * is a hydrogen atom and yu is 0, or a salt thereof (102) A thiazole derivative of the formula (1) wherein R4 and R2 combine to form a group - (CHSi) > - (n is 4 ), R3 is a group of the formula: (ß is 1, Z is a sulfur atom, Rβ is a group: -CO-CH = C-COR4"4 (R4-4 is the same as defined in formula (1)), Rβ, m and A are the same as defined in formula (1)), R "* is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof. (103) A thiazole derivative of the formula (1) wherein R4 and R2 combine to form a group - (CHae) r? - (n is 4), R3 is a group of the formula: (s is 1, Z is a sulfur atom, R * is a group: -CO-CH = C-COR4"4 (R4 ** is the same as defined in formula (1)), Rβ, m and A they are the same as defined in formula (D), R "* eß a hydrogen atom and u is 1, or a salt thereof (104) A thiazole derivative of the formula (1) wherein R4 and R2 are combine to form a group - (CHse) r, - (n es 4). R3 is a group of the formula: (s is 1 »Z is a sulfur atom» Rβ is a group: -CO-CH = C-COR4"* (R4" * is the same as defined in formula (1)). R »m and A are the same ones that were defined in formula (1)). R "* eβ is a lower alkanoyloxy-lower alkyl group and is 1, or a salt thereof (105) A t-azol derivative of the formula (1) wherein R4 and R2 combine to form a group - (CHae ) "- (n is ), R3 is a group of the formula: (s ee 1 »Z ee a sulfur atom» Rß eß a group: -CO-CH = C-COR4"* (R4" * is the same as η defined in formula (D), R ", m and A eon same as defined in formula (1)), R- * is a hydrogen atom yu e 0, or a salt thereof (106) A thiazole derivative of the formula (1) wherein R 4 and R 2 combine to form a group - (CHa) r? - (n is 5), R3 is a group of the formula: (s is 1, Z is a sulfur atom, R * is a group: -CO-CH = C-COR4-4 (R4 * 4 is the same as defined in formula (1)), RB, my A they are the same as defined in formula (1)) "R" 4 is a lower alkanoyloxy-lower alkyl group and is O "or a salt thereof. (107) A thiazole derivative of the formula (1) wherein R4 and R2 combine to form a group - (CHae) r, - (n is 5) »R3 is a group of the formula: (s is 1 »Z is a sulfur atom» R * is a group: -CO-CH = C-COR4"* (R4" * is the same as defined in formula (1)) »RB» m and A they are the same as defined in formula (1)) "R" * is a hydrogen atom yu is 1"or a salt thereof (108) A thiazole derivative of the formula (1) wherein R4 and R2 combine to form a group - (CH3í) r? - (n is 5) .R3 is a group of the formula: (s eß 1 »Z is a sulfur atom» R is a group. "-CO-CH = C-COR4" 4 < R4"* eß the same as defined in formula (1)). RB, my A are the members defined in formula (1)) »R" * is a lower alkanoyloxy group-lower alkyl yu eß 1, or a salt thereof. (109) A thiazole derivative of the formula (1) wherein R4 and R2 combine to form a benzene ring which may optionally have an eubstituent selected from a lower alkyl group a lower alkoxy group a nitro group a group amino optionally having a lower alkyl substituent and a halogen atom »R3 is a group of the formula: (s is 1» Z is a sulfur atom »Rβ is a group: -CO-CH = C-COR4- * ( R4-4 is the same as defined in formula (D), RB, m and A are the same as defined in formula (1)), R * 4 is a hydrogen atom and u is 0, or a salt of mißroo. (110) A thiazole derivative of the formula (1) wherein R 4 and R 2 combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group optionally having a β-lower alkyl substituent and a halogen atom, R 3 is a group of the formula la: (ß is 1, Z is a sulfur atom, R * is a group: -CO-CH = C-COR4-4 (R4 ** is the same as defined in the formula (1 > > , Rß, m and A are the mers defined in formula (1)), R- * eß a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof. (111) A t-azol derivative of the formula (1) wherein R 4 and R 2 combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group optionally having a lower alkyl substituent and a halogen atom, R3 is a group of the formula: (ß is 1, is a mole of sulfur, R * is a group : -CO / -CH = C-COR4"4 (R4- * is the same as defined in formula (1)), RB, m and A are the same as defined in formula (1)), R * * is a hydrogen atom yu eß 1, or a ßal of the moiety. (112) A thiazole derivative of the formula (1) wherein R 4 and R 2 combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group optionally having a lower alkyl substituent and a halogen atom, R3 is a group of the formula: (s is L? Z is a sulfur atom »Rβ is a group: -CO-CH = C-COR4" * (R4"* is the same as defined in formula (1))» RB »m and A are the same as defined in formula (1) ) »R- * is a g lower alkanoyloxy-lower alkyl radical and u is 1 or a salt of the lower. The compounds of the present invention of the formula (1), can be prepared by various processes. but preferably they are prepared by the following procedure.

REACTION SCHEME 1 where R4 »R2, R" *, RB, Z »m» s »T» u and A are the same as defined a »R4B is a group -CH = C (R44t >) (COR4β) (R44β is the same as defined a "and R4 * is a hydroxyl group or a lower alkoxy group), or a group: -CH = C-COR4 * 4 (R4- * is the same as defined a), and X is an atom The reaction between the compound (2) and the compound (3) or the compound (4) is called the Friedel-Crafts reaction and is carried out in the presence of a Lewis acid in a suitable solvent. of Lewis can be any of the conventional Lewis acids used in this type of Friedel-Crafts reaction and is, for example, »aluminum chloride» zinc chloride »iron chloride» boron chloride. boron tribromide ' »Boron trifluoride» concentrated ßulfuric acid, etc. The solvent can eg, »carbon disulfide» aromatic hydrocarbons such as nitrobenzene »chlorobenzene» hydrocarbon haloge nadoß such as dichloromethane »dichloroethane» carbon tetrachloride, tetrachloroethane. nitro aliphatic compounds such as nitroethane. nitromethane »or a mixture of these solvents.

The compound (3) and the compound (4) are each used at least in an equimolar amount, preferably in an amount of 1 to 5 moles, per 1 mole of the compound (2). The Lewis acid is usually used in an amount of 1 to 6 moles "per 1 mole of the compound (2). The reaction is usually carried out at O at 120 ° C »preferably at 0 to 70 ° C» for about 0.5 to 24 hours. The compound wherein R4B is a group: -CH = C (R44t >) (C0R ß) and the double bond thereof shows a cis configuration can be isomered in a compound where the double bond shows a trans configuration by heating it to about 50 ° C to 100 ° C in dimethylformamide. The compound (la), wherein R4ß is a group: -CH = C (R44t »HC0R4β) or a group: -C = C-COR4- *» and R4 * and R4- * are both a lower alkoxy group, can becoming a compound (Ia) wherein a corresponding R4ß and R4"* are a hydroxy group" by treating it under the same conditions as in the conversion reaction of the compound (Id) in the compound (le) in the reaction scheme 4, as it describes later on.

REACTION SCHEME 2 (Ib) (lc) wherein R 4, R 2, R "*, RB, R44» 3, Z »m» s »T» u and A are the same as defined a and R 4"7 are the heterocyclic residues β as defined a. defined for R44 * »» but having at least one _N in the heterocyclic nucleus.

The process of reaction scheme 2 is a conventional amido bond production reaction. and is carried out by reacting the thiazole compound (Ib) and the amine compound (5). The production reaction of the amido bond can be carried out under the same conditions as those of the conventional production reaction of the amino bond. for example »(a) a mixed acid anhydride process, that is, a reaction procedure of the carboxylic acid compound (Ib) with? n alkyl halogenocarbonate to form a mixed acid anhydride, and reacting the resulting compound with the amine compound (5); (b) an activated ester process, that is, a method of converting the carboxylic acid compound (Ib) into an activated ester such as p-nor trophenyl ester. ester of iM-hydroxysuccinyl 'ester' 1-hydroxy-benzotriazole ester. etc. and reacting the resulting compound with the amine compound (5) »(c) a carbodiimide process» that is »a condensation process of the carboxylic acid compound (Ib) and the amine compound (5) in presence of an activating agent such as dicyclohexylcarbodiimide. carboni Idi imidazole »etc .; (d) other methods »that is, a method of converting the carboxylic acid compound (Ib) into a carboxylic anhydride by treating it with a dehydrating agent such as acetic anhydride, and reacting the resulting compound with the amine compound (5); a process for reacting an ester of the carboxylic acid compound (Ib) with a lower alcohol and the amine compound (5) at high temperature under high pressure; a process for reacting an acid halide compound of the carboxylic acid compound (Ib), that is, a carboxylic acid halide. with the amine compound (5). The mixed acid anhydride used in the above process (a) of mixed acid anhydride obtains by the known reaction of Schotten-Baumann, and the reaction product uses β in the reaction mixture for the reaction with the compound of amine (5) to give the desired compound (1) of the present invention. The Schotten-Baumann reaction is usually carried out in the presence of a basic compound. The basic compound is any of the conventional compounds used for the Schotten-Baumann reaction and includes, for example, basic organic compounds such as triethylamine, trimethylamine, pyridine, dimethyl-1-ani-na, and N-methyl-morpholine, 4-dimet laminopyridine. »L» 5-diazabicyclo - [: 4.3.03noneno-5 (DBN). l »8-diazabicyclo-C5.4.0 -] undecene-7 (DBU). 1,4-diazabicycloC2.2.2Doctane (DABCO). etc., and basic inorganic compounds such as potassium carbonate, sodium carbonate, potassium acid carbonate, sodium acid carbonate, etc. The reaction is usually carried out at a temperature of about -20 ° C to about 100. ° C. preferably at a temperature of -20 ° C to about 50 ° C. for about 5 minutes to about 10 hours, preferably for 5 minutes to about 2 hours. The reaction between the mixed acid anhydride thus obtained and the amine compound (5) is carried out at a temperature of -20 ° C to about 150 ° C. preferably at a temperature of -20 ° C to about 50 ° C. for about 5 minutes to about 35 hours, preferably for about 5 minutes to 30 hours. The mixed acid anhydride process is usually carried out in a solvent in the presence of a basic compound. The basic compounds can be any of the basic compounds used in the previous Schbtten-Baumann reaction. The solvent may be any of the conventional solvents which are usually used in the acid anhydride process and include, for example, halogenated hydrocarbons (for example chloroform, chloromethane, dichloroethane, etc.). aromatic hydrocarbons (for example benzene »p-chlorobenzene, toluene, xylene» etc.) »ethers (for example» diethyl ether »isopropyl ether, tetrahydrofuran, dimethoxyethane, etc.), esters (for example. methyl acetate, ethyl acetate, etc.), polar aprotic ventee (for example, N, N-dimeti Iformamide, dimethyl sulfoxide, acetonitrile, hexamethylphosphate triamide, 1-methyl 1-2-pyrrole idinone (NMP). etc.). or a mixture of these solvents. The alkyl halogenocarbonate used in the mixed acid anhydride process includes, for example, methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, isobutyl chloroformate. and similar. In said process, the carboxylic acid compound (Ib), the alkyl halogenocarbonate ester and the amine compound (5) are usually used in equimolar amount each, but preferably the alkyl halocarbonate ester and the amine compound (5) are used in an amount of about 1 to 1.5 moles, per 1 mole of the carboxylic acid (Ib). Among the other procedures above (d). in the case of the process of reacting the carboxylic acid halide with the amine compound (5), the reaction is usually carried out in the presence of a basic compound in a suitable solvent. The basic compound is any of the conventional basic compounds and includes, for example, in addition to the basic compounds used in the Schotten-Baumann reaction mentioned above, sodium hydroxide, potassium hydroxide, sodium hydride. potassium hydride, and the like. The solvent includes, for example, in addition to the solvents used in the Mi? To acid anhydride process. alcohols (for example, methanol, ethanol, propanol, butanol, 3-metho-l-butanol, ethyl cellosolve, methyl cellulose, etc.). pyridine. acetone »water» or a mixture of two or more of these solvents and the like. The amount of the amine compound (5) and the carbohydrate halide is not critical »but the amine compound (5) is usually used at least in equimolar amount» preferably in an amount of about 1 to 5 moles »per l mole of carbohydric acid halide. The reaction is usually carried out at a temperature of about -70 ° C to about 180 ° C, preferably at a temperature of about -50 ° C to about 150 ° C, for about 5 minutes. Approximately 30 hours. Furthermore, the production reaction of the amide bond of reaction scheme 2 can also be carried out by reacting the carboxylic acid compound (Ib) and the amine compound (5) in the presence of a condensing agent such as phosphorus compounds ( for example »2» 2'-d phenylphosphine thiopyridine »difeni chloride Ifosfini lo» feni hydrochloride 1-N-pheni Ifosforamide »diethyl cyanophosphate» dipheni Ifosfopl azide, chloride N, N'-bis (2-o? o-3-o? azol idini 1) phosphinic »etc.). The reaction is usually carried out in the presence of the same solvent and the same basic compound which can be used in the above reaction of the carbonyl halide compound and the amine compound (5). The reaction is usually carried out at a temperature from -20 ° C to about 15 ° C »preferably at a temperature of from 0 ° C to about 10 ° C. for about 5 minutes to about 30 'hours. The condensation agent and the amine compound (5) are used at least in an equimolar amount. preferably in an amount of about 1 to 2 moles "per 1 mole of the carboxylic acid compound (Ib).

REACTION SCHEME 3 where R4. R2 »R3» R-4 »RB. Z »m» s, T. u. R4ß and A are the same as defined above. R4B and R4 are a lower alkoxy group and R22 is the same as defined below. The reaction of the compound (6) and the compound (7) is carried out in the presence of a basic compound in a suitable solvent. The basic compound includes basic inorganic compounds such as metallic sodium »metallic potassium» sodium hydride, sodium amide, sodium hydroxide, potassium hydroxide. eodium carbonate. potassium carbonate, ßodium acid carbonate »etc.» báßicoß organic compounds such as alkali metal alkoxide (for example »sodium methylate» sodium ethoxide »potassium t-butoxide), an alkyl lithium, aryl lithium or lithium amide ( for example »methyl lithium» n-butyl lithium »phenyl lithium» lithium diisopropylamide) »pyridine» piperidine »quinine! ina »triethylamine» N »l» -dimeti lani 1 ina »etc .. The solvent can be any that does not disturb the reaction» for example »water» ethers (for example »diethyl ether» dioxane, tetrahydrofuran, roonoglima, diglima, etc.), aromatic hydrocarbons (eg benzene, toluene, xylene, etc.), hydrocarbons to the phatic (for example, n-hexane, heptane, cyclohexane, etc.), amines (eg pyridine »NN-dimeti lani) 1 ina, etc.), sol ventee polar aprotic (for example, IM »-dimeti 1formamide, dimethyl sulfoxide, triamide hexamethi, etc.), halogenated hydrocarbons (for example, d chloromethane, chloroform, carbon tetrachloride, etc. .), alcohols (eg, methane, ethanol, isopropyl alcohol, etc.). ureas (for example »N» N-dimethylpipropa urea (DMPU), etc.), 1,3-dimethyl-3 »4» 5,6-tetrahydro-2 (lH) -pyrimidinone »or a mixture of these solvents . The reaction is usually carried out at -BO ° C to 150 ° C »preferably at about -BO ° C to 120 ° C» for 0.5 to about 15 hours. The compound (7) is usually used at least in an equimolar amount, preferably in an amount of 1 to 5 moles, per 1 mole of the compound (6). The conversion reaction of the compound (8) into the compound (10) is carried out in the presence of an oxidizing agent in a suitable solvent. The oxidizing agent includes, for example, benzoquinones (for example »2» 3-dichloro-5,6-dicyano-1 »4-benzoquinone CDDQ)» pyridinium chromates (for example »pyridinium chlorochromate» pyridinium dichlorochromate »etc.)» oxazolyl chloride sulfoxide »dichromic acid» dichromates (for example »sodium dichromate» potassium dichromate »etc.)» permanganic acid »permanganates (for example» potassium permanganate »sodium permanganate» etc.). manganese dioxide »etc. The solvent includes, for example, water, organic acids (for example, formic acid, acetic acid, trifluoroacetic acid, etc.). alcohols (eg, methanol, ethanol, etc.), halogenated hydrocarbons (eg, chloroform, dichloromethane, etc.), ethers (eg, tetrahydrofuran, diethyl ether, dioxane, etc.). dimethyl sulfoxide »dimethylformamide» or a mixture of these solvents. The oxidizing agent is preferably used in an amount that exceeds the amount of the starting composition. The above reaction is usually carried out at 0 ° C to 200 ° C "preferably at 0 ° C to about 150 ° C" for 1 hour to about 10 hours. The reaction of the compound (9) and the compue (7) is carried out under the same conditions as those in the reaction of the compound (6) and the compound (7). The reaction of the compound (10) and the compound (12) is carried out under the same conditions as those in the reaction of the compound (6) and the compound (7). The reaction of the compound (10) and the compound (20) is carried out under the same conditions as those in the reaction of the compound (6) and the compound (7).

REACTION SCHEME 4 wherein R 4, R 2, R 4, R b, Z »m» s »T, u» and A are the same as defined above »R 2 ° is a lower alkoxy group, M is an alkali metal such as lithium , sodium, potassium, etc., and R4 * "eß a lower alkoxy group The reaction of the compound (6) and the compound (13) is carried out in the presence of a basic compound in a suitable solvent, a - BO ° C at room temperature, for 5 minutes to 6 hours The solvent may be, for example, ethers (for example, diethyl ether, dioxide, tetrahydrofuran, etc.), aromatic hydrocarbons (for example, benzene, toluene, etc.), saturated hydrocarbons (for example »henian» heptane »pentane» cyclohexane »etc.)» ureas (for example »N» N-dimethylpropyl urea (DMPU) »etc.). are the same as those used in the reaction of compound (6) and compound (7) in reaction scheme 3. The compound (13) is usually used at least in an equimolar amount, preferably in n an amount of 1 to 5 moles »per 1 mole of the compound (6). The conversion reaction of the compound (11) into the compound (Id ') is carried out in the presence of a basic composition in a suitable solvent. The basic compound can be a basic organic compound such as triethylamine »trimethylamine. di sopropylamine »tri-n-butylamine, ethylamine, pyridine, dimethylamine 1, N-methylmorpholine, 4-dimethylaminopyridine, DBN. DBU, DABCO, etc. The solvent includes, for example, water, alcohols (for example, ethanol, methane, isopropanol, etc.). dimethylformamide. dimethyl sulfoxide, Ifosphoric hexamethia triamide or a mixture of these solvents. The reaction is usually carried out at room temperature at 150 ° C. preferably at room temperature at 1000C, for about 1 to 5 hours. The conversion reaction of the compound (11) into the compound (I) is carried out under the same conditions as those in the conversion reaction of the compound (8) in the compound (10) in the reaction scheme 3 above. The conversion reaction of the compound (ld into the compound (le) is carried out in the presence of an acid or a basic compound in a suitable solvent, or in a solvent The solvent includes, for example, water, lower alcohols (eg example »ethanol» methanol »iisopropanol» etc.) »ketones (eg acetone, methyl ethyl ketone, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform, carbon tetrachloride, etc.) ethers (eg. dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, etc.), fatty acids (eg acetic acid, formic acid, etc.) or a mixture of these solvents.The acid includes, for example, mineral acids (eg, hydrochloric acid »sulfuric acid, hydrobromic acid» etc.), organic acids (eg formic acid, acetic acid »trifluoric acid, aromatic sulfuric acids, etc.) The basic compound includes, for example, an alkali metal carbonate (eg example, c sodium arbonate, potassium carbonate, etc.). an alkali metal hydroxide (for example, sodium hydroxide. potassium hydroxide, calcium hydroxide, lithium hydroxide, etc.). etc. The reaction is usually carried out at room temperature at approximately 200 ° C. preferably at room temperature at 150 ° C, for approximately 10 minutes to 25 hours. The conversion reaction of the compound (I) into the compound (Ig> is carried out under the same conditions as those in the conversion reaction of the compound (I) into the compound (I), as mentioned above.

SCHOOL? OF EACCIÓ 5 wherein R4, R2, R- *, RB, Z, m, s, T, u and A are the same as defined above, X4 is a halogen atom, R24 is a faith group, R22 is a heterobicyl residue ico or saturated or unsaturated heterominocyte of 5 to 10 members (said heterocyclic residue optionally having 1 to 3 substituents selected from (i) a lower alkyl group; (ii) a group: - (B) t -NR42R43 <; J1 is the same as defined above. B is a group: -CO-A- (A is the same as defined above), a carbonyl group or a lower alkylene group. R42 and R43 are the same or different. and are each a hydrogen atom, a lower alkyl group, an amino substituted lower alkyl group optionally having a lower alkyl substituent, or which is combined together with the adjacent nitrogen atom to which they are attached to form a hetero ring I say. Heterobicyclic or heteromonocyclic saturated from 5 to 12 members' being or not interposed with another nitrogen atom or an oxygen atom. Said heterocyclic group may optionally have a substituent selected from a lower alkyl group, a lower alkoxycarbonyl group, a lower alkyl group substituted with lower alkoxy, an amino group optionally having a lower alkyl substituent and a lower alkyl group substituted with hydroxy. iii) a lower alkoxycarbonyl group; (iv) a lower alkyl group substituted with hydroxy; (v) a pyridyl group being optionally substituted by a lower alkyl group optionally having a halogen substituent on the pyridine ring "(vi) a lower alkyl group substituted with halogen" (vii) a lower alkoxy group "(viii) a cycloalkyl group; (ix) a hydroxy group; (x) a lower alkyl group substituted with tetrahydropyrani loxy f (xi) a pyrimidyl group; (xii) a lower alkyl group substituted with lower alkoxy; (xiii) a carboxyl group; (xiv) a lower alkoxy-phenyl group; (xv) a lower alkyl phenyl group optionally having a lower alkenylioxy substituent on the phenyl ring; (? vi) a lower alkanoyloxy group; and (xvi i) a piperidinyl group optionally having a lower alkyl substituent on the piperidine ring. The reaction of the compound (2) and the compound (14), and the reaction of the compound (2) and the compound (15), are carried out under the same conditions as those in the reaction of the compound (2) and the compound (3) or compound (4) in reaction scheme 1 above. The halogenation reaction of the compound (16) is carried out in the presence of a halogenating agent in a suitable solvent. The halogenating agent can be, for example, halogen molecules (for example, bromine, chlorine, etc.), iodine chloride, sulfuryl chloride, copper compounds (for example, copper (II) bromide, etc.). , N-halogenated succinimidase (for example, N-bromosuccinimide »N-chlorosuccinimide» etc.). The solvent can be, for example, halogenated hydrocarbons (for example, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, etc.), fatty acids (for example, acetic acid, propionic acid, etc.), carbon disulfide, etc. The halogenation agent is usually used in an amount of 1 to 10 moles, preferably in an amount of 1 to 5 moles, per 1 mole of compound 16. The reaction is usually carried out at 0 ° C to the point of boiling the solvent to be used, preferably at 0 ° C to 100 ° C, for about 5 minutes to 20 hours. The reaction of the compound (17) and the compound (18) is carried out in a suitable solvent at room temperature at 150 ° C, preferably at room temperature at about 100 ° C, for about 1 hour to 10 hours. The solvent may be the same solvents used in the reaction of the carboxyl halide and the amine compound (5) between the reactions between the compound (Ib) and the compound (5) in reaction scheme 2 above. The compound (18) is used at least in an equimolar amount, preferably in an amount of 1 to 1.5 moles, per 1 mole of the compound (17). In the above procedure, a compound of the formula (21) is obtained: wherein R 4, R 2, R "4» R b, Z, m, A, R 24, s »T» u and X are the same as defined above »which is further treated in the presence of a basic compound in a suitable solvent for give the compound (19) The solvent and the basic compound are the same as those used in the reaction of the carboxyl halide and the amine compound (5) in the reaction of the compound (Ib) and the compound (5) in the scheme of reaction 2. The reaction is usually carried out at 0 ° C to 100 ° C, preferably at 0 ° C to about 70 ° C, for about 1 hour to 5 hours The reaction of the compound (19) and the compound ( 20) is carried out under the same conditions as those in the reaction of the compound (6) and the compound (7) in the above reaction scheme 3. Alternatively, the reaction of the compound (19) and the compound (20) is It is usually carried out in a suitable solvent at 0 ° C to 150 ° C, preferably at room temperature at about 100 ° C, hard Approximately 0.5 hours to 8 hours. The solvent may be any that does not disturb the reaction, for example, water, alcohols (for example, methanol, ethanol, isopropanol, etc.), aromatic hydrocarbons (for example, benzene, toluene, xylene, etc.). example, diethyl ether »tetrahydrofuran» dioxane »diglyme» monoglyme »etc.). halogenated hydrocarbons (for example, dichloromethane, chloroform, carbon tetrachloride, etc.). polar aprotic solvents (for example, NN-dimethylformamide, dimethyl sulfoxide, Ifosphoric hexamethyl triamide, etc.), etc. The compound (20) is usually used at least in an equimolar amount, preferably in an amount of 1 to 5 moles. , for 1 mole of the compound (19). The reaction is promoted when paraaldehyde is added to the reaction system.

REACTION SCHEME 6 wherein R 4, R 2, R 4, R B, R b, Z, s, T, u and A are the same as defined above, q is 1, Ram is a lower alkyl group substituted with halogen, R B β is a group: A-NR ^ R * (A, R7, R "are the same as defined above) or a lower alkyl-lower alkyloxy group, R23 and a group: -NR" * Rβ (R? And R * ßon loe same as previously defined), or a lower alkanoyloxy group. The reaction of the compound (I) and the compound (22) is carried out in the presence or absence of a basic compound in a suitable inert solvent, or without a solvent. The inert solvent includes, for example, aromatic hydrocarbons (for example, benzene, toluene, xylene, etc.), ether (for example, tetrahydrofuran, dioxane, diethyl ether, diethyl ether, etc.), halogenated hydrocarbons (for example, dichloromethane, chloroform, carbon tetrachloride, etc.), lower alcohols (for example, methane, ethanol, ß-isopropanol, butanol, tert-butanol, etc.), water, acetic acid, ethyl acetate, acetone, acetonitrile, pyridine, dimethyl sulfoxide, dimethylformamide, Ifosphoric triamide hexamethi, or a mixture of these solvents. The basic compound includes, for example, an alkali metal carbonate (e.g., sodium carbonate, potassium carbonate, etc.), an alkali metal acid carbonate (e.g., sodium acid carbonate, potassium acid carbonate, etc.). .), a non-alkali metal hydroxide (eg »sodium hydroxide» potassium hydroxide, etc.), potassium hydride »potassium, sodium, sodium amide, an alkali metal alkoxide (for example, sodium methoxide, etc.). basic organic compounds (eg, pyridine, N-ethi isopropyl 1 amine, dimethylaminopyridine, triethylamine, 1,5-diazabicycloC4.3.03nonen-5- (DBN), 1,8-diazabicycloC5.4.0.3undecen-7 (DBU) , 1,4-diazabicycloiC2.2.23octane (DABCO), etc. The amount of the compound (li) and the compound (22) is not critical »but the composition (22) is usually used at least in equimolar amount» preferred. The reaction is usually carried out at 0 ° C to 200 ° C, preferably at 0 ° C to 170 ° C, for about 30 minutes at a temperature of 1 to 10 moles, per 1 mole of the compound (Li). 75 hours In the reaction system, an alkali metal halide, such as sodium iodide, potassium iodide or a copper polymer can be added.

SCHEME PE REACTION 7 (23) (1) wherein R4, R2, R3, R "4, T and u are the same as defined above The reaction of the compound (23) and the compound (24) is carried out under the same conditions as those in the reaction of the compound (Ib) and the compound (5) in the reaction scheme 2 above.

PE REACTION SCHEME 9 (lk) (i /) wherein R4, R2, R3, T, X and u are the same as defined above, and R-4 »is a lower alkyl-lower alkanoyloxy group. The reaction of the compound (lk) and the compound (25) is carried out under the same conditions as those in the reaction of the compound (li) and the compound (22) in the reaction scheme 6 above.

REACTION SCHEME 9 where R4 »R2. R-4, RB > Rβ, R "7, RB, Z» s, T »u and q are the same as defined above» and RBβ is a lower alkyl group substitituted with carboxy »RBel is a group: -A- C0-NR7RB (R" 7 and Rβ are the same as defined above). The reaction of the compound < lm) and the compound (26) is carried out under the same condition as those in the reaction of the compound (Ib) and the compound (5) in the reaction scheme 2 above. The starting compounds (2), (6) and (23) in the above reaction schemes are prepared by the following procedures.

REACTION SCHEME 10 (30) (2a) wherein Rx, Ra! »R < < # »RB» X, Z, T, u and m are the same as defined above, and R2-4 is a hydroxy group, a lower alkoxy group or a lower alkoxy-phenyl group, and A 'is a lower alkylene group. The reaction of the compound (27) and the compound (28) is carried out under the same conditions as those in the reaction of the compound (li) and the compound (22) in the reaction scheme 6 above. The conversion reaction of the compound (29), wherein R.sub.2-4 is a lower alkoxy group in the compound (30), is carried out under the same conditions oneß as that in the conversion reaction of the compound (Id) in the compound (le) in reaction scheme 4 above. The conversion reaction of the compound (29), wherein R2"4 is a lower alkoxy-phenyl group in the compound (30), is carried out under the same conditions as those in the conversion reaction of the compound (5b) in compound (5c) in reaction scheme 13, which is described below .. The reaction of compound (30) and compound (24) is carried out under the same conditions as those in the reaction of compound (Ib) and the compound (5) in the reaction scheme 2 above.

REACTION SCHEME 11 (6a) where R ^, Ra »R_ *. Rß »Ar. Z "R2" 4 .T "u and m are the same as defined above The reaction of the compound (31) and the compound (28) is carried out under the same conditions as those in the reaction of the compound (27) and the compound (28) in the above reaction scheme 10. The conversion reaction of the compound (32) »wherein R2" 4 is a lower alkoxy group in the compound (33). it is carried out under the same conditions as those in the conversion reaction of the compound (29). wherein R2- * is a lower alkoxy group in the compound (30) in the above reaction scheme. The conversion reaction of the compound (32). wherein R2-4 is a lower alkoxy-phenyl group in the compound (33). It is carried out under the same conditions as that laß in the reaction of the compound (5b) in the compound (5c) in the reaction scheme 13. which is described below. The reaction of the compound (33) and the compound (24) is carried out under the same conditions as those in the reaction of the compound (30) and the compound (24) in the reaction scheme 10 above.

SCHEME PE REACTION Z (34) (35) (23a > where Rß. Rß > m »A ', X, Z and R2" 4 are the same as defined above The reaction of the compote (34) and the compound (2B) is carried out under the same conditions as those in the reaction of the compound (27). ) and the compueate (28) in the reaction scheme 10. The conversion reaction of the compound (35), wherein R2"4 is a lower alkoxy group in the compound (23a), is carried out under the same conditions as those in the conversion reaction of the compound (29). wherein R2-4 is a lower alkoxy group in the compound (30) in the above reaction scheme.

The conversion reaction of the compound (35), wherein R2- * is a lower alkoxy-phenol group in the compound (23a), is carried out under the same conditions as those in the conversion reaction of the compound (5b) in the compound (5c) in the reaction scheme 13, which is described below. The starting compound (5) is prepared by the following procedures.

REACTION SCHEME 13 R42R43NH (36) RX-7. RSeß? R17b R2S R 7t »H (5a) (5b) (5c) wherein R42 and R43 are the same as defined above, R4"7" are the same groups for R4"7" having at least one oxo group in the heterocyclic group, R4"76" are the same groups for R4"7 Having at least one group: -l \ l-R4ßR43 (R42 and R43 are the same as defined above) in the heterocyclic group. and R2B is a lower alkyl group-phenyl. The reaction of the compound (5a) and the compound (36) is carried out in the presence of a reducing agent in a suitable solvent or without a solvent. The solvent can be. for example, water, alcohols (for example, methanol, ethanol, isopropanol, etc.). acetonitrile »formic acid» acetic acid »ethers (for example» dioxane »diethyl ether» diglyme »tetrahydrofuran, etc.). aromatic hydrocarbons (for example »benzene, toluene» xylene, etc.), or a mixture of these solvents. The reducing agent can be, for example, formic acid, an alkali metal salt of fatty acid (for example sodium formate, etc.), a hydrogenation agent (for example, sodium borohydride, sodium cyanoborohydride, sodium hydride, etc.). io-aluminum »etc.). catalysts (for example, palladium black, palladium carbon, platinum oxide, platinum black, Raney nickel, etc.). When formic acid is used as a reducing agent, the reaction is usually carried out at room temperature at about 200 ° C, preferably at 50 to 150 ° C, for 1 to about 10 hours. AND! formic acid is used in an amount that exceeds the amount of the compueßto (5a). When a hydrogenation agent is used as a reducing agent, the reaction is carried out usually at -30 ° C to about 100 ° C, preferably at 0 ° C to 70 ° C »for 30 minutes at about 12 hours. The hydrogenation agent is used in an amount of 1 to 20 moles, preferably in an amount of 1 to 6 moles, per 1 mole of the compound (5a). Especially when lithium aluminum hydride is used as a hydrogenation agent, the solvent may be ethers (for example diethyl ether, dioxane, tetrahydrofuran, diglyme etc.) or aromatic acidic carbonates (for example, benzene, toluene, xylene) , etc.).

When a catalyst is used as a reducing agent, the reaction is usually carried out under atmospheric pressure of 20 atmospheres, preferably under an atmospheric pressure of 10 atmospheres of hydrogen gas, in the presence of a hydrogen donor such as formic acid. ammonium »cyclohexene» hydrazine hydrate. etc., at a temperature of -30 ° C to about 100 ° C, preferably at a temperature of 0 ° C to 60 ° C, for about 1 to 12 hours. The catalyst is used in an amount of 0.1 to 40% by weight, preferably in an amount of 0.1 to 2054 by weight, based on the weight of the compound (5a). The compound (36) is usually used at least in equimolar amount, preferably in an amount of 1 to 3 moles, per 1 mole of the compound (5a). The conversion reaction of the compound (5b) to the compound (5c) is carried out by hydrogenation in the presence of a catalyst in a suitable solvent. The solvent may be, for example, water, acetic acid, alcohols (for example, methane, ethanol, isopropanol, etc.), hydrocarbons (for example, hexane, cyclohexane, etc.), ethers (for example, dioxane, tetrahydrofuran). , diethyl ether, ethylene glycol dimethyl ether, etc.), estereß (for example, ethyl acetate, methyl acetate, etc.), polar aprotic solvents (for example, dimethylformamide, etc.), or a mixture of these solvents. The catalyst can be, for example, palladium, palladium black, palladium hydroxide, palladium-carbon hydroxide, palladium carbon, platinum, platinum oxide, copper chromite, Raney nickel, etc. The catalyst is used usually in an amount of 0.02 to 1 time the amount of the compound (5b). The reaction is usually carried out at a temperature of -20 ° C to about 10 ° C, preferably at a temperature of 0 ° C to about 70 ° C, under 1 to 10 atmospheres of hydrogen gas, for about 0.5 to about 20 hours .

REACTION SCHEME 14 R R (MH (36) 17e-Rs fí -rc. - > R3? - R4_7-H (5g> (5h) wherein R42, R43 and Raß are the same as defined above, R4"7 * 8 are the same groups for R4" 7"but having at least one carboxyl group in the heterocyclic group, R4" 7 * are the same groups for R4"7, but having at least one -C0NR42R43 (R42 and R43 are the same as defined above) in the heterocyclic group, and R4" 7- are the same groups for R4"7, but having at least one -CHaNR42R43 (R42 and R43 are 1-membered as defined above) in the heterocyclic group.

The reaction of the compound (5d) and the compound (36) is carried out under the same conditions as those in the reaction of the compound (Ib) and the compound (5) in the reaction scheme 2 above. The conversion reactions of the compound (5e) into the compound (5f), and the conversion of the compound (5g) to the compound (5h > "are carried out under the same conditions as those in the compound conversion reaction. (5b) in the compound (5c) in the above reaction scheme 13. The conversion reaction of the compound (5e) in the compound (5g) is carried out by reduction using a hydrogenation agent.The hydrogenation agent can be , for example, thioaluminum hydride, sodium borohydride, diborane, etc., and is used at least in an equimolar amount, preferably in an amount of 1 to 15 moles, per 1 mole of the starting compound. Reduction is carried out in a suitable solvent such as water, a lower alcohol (for example, methanol, ethanol, isopropanol, etc.), ethers (for example, tetrahydrofuran, diethyl ether, diisopropyl ether, digüma, etc.). .), or a mixture of these solvents. It is usually carried out at a temperature of -60 ° C to 150 ° C, preferably at a temperature of -30 ° C to 100 ° C, for approximately 10 minutes to 5 hours. When lithium aluminum hydride or diborane is used as the hydrogenation agent, an anhydrous solvent such as tetrahydrofuran, diethyl ether, diisopropyl ether, diglyme etc. may be preferably used.

REACCIPN SCHEME 15 R42R43NH (36) R17 * -R2B »R4-7« -R2B * R -7 «H (5i) (5j) (5K) wherein R42 »R43 and R2B are the same as defined above» R4'7"* 'are the same groups for R4" 7, but having at least one lower alkyl group substituted with halogen in the heterocyclic group "and R" 7g are the same groups for R4"7" but having at least one -B'-i \ IR42R43 (B 'is a lower alkylene group, RZ and R43 are the same as defined above) in the heterocyclic group. The reaction of the compound < 5i) and the compound (36) is carried out under the same conditions as those in the reaction of the compound (li) and the compound (22) in the reaction scheme 6 above. The conversion reaction of the compound (5j) into the compound (5k) is carried out under the same conditions as those in the conversion reaction of the compound (5b) in the compound (5c) in the reaction scheme 13 above. The compound of the formula (1), wherein Rβ is a group of the formula: where R44e », p and R44ß are the same as defined above, and showing a trans configuration in the double bond of the above formula, can be isomerized into a cis compound in the corresponding double bond when exposed to sunlight and a adequate solvent. The solvent may be the same solvents used in the reaction of the carboxyl halide and the amine compound (5) in the reactions of the compound (Ib) and the compound (5) in the reaction scheme 2 above. The reaction is carried out at a temperature of 0 ° C to 70 ° C, preferably at 0 ° C at room temperature, for about 1 to 10 hours. Among the starting compounds (32) used in the reaction scheme 11, some compounds (32) are prepared by the following procedure.

REACTION SCHEME lß (37) (38) (28) 02a) wherein RB, m, Af, M and R2-4 are the same as defined above, and R2ß and R2 ^ are the same or different and are each a lower alkyl group. The conversion reaction of the compound (37) into the compound (38) is carried out in the presence of a basic compound in a suitable solvent. The solvent may be, for example, water, lower alcohols (for example, methanol, ethanol, isopropanol, etc.), ketones (for example, acetone, methyl ethyl ketone, etc.), halogenated hydrocarbons (for example, dichloromethane, chloroform). , carbon tetrachloride, etc.), ethers (eg, dioxane, tetrahydrofuran, dimethyl ether of ethyleneol, etc.), or a mixture of these solvents. The basic compound may be, for example, an alkali metal carbonate (eg, sodium carbonate, potassium carbonate, etc.), or an alkali metal hydroxide (eg, sodium hydroxide, potassium hydroxide), calcium, lithium hydroxide, etc.), etc. The reaction is usually carried out at room temperature at about 200 ° C, preferably at room temperature at about 150 ° C, for about 10 minutes to about 25 hours. The reaction of the compound (38) and the compound (28) is carried out under the same conditions as those in the reaction of the compound (27) and the compound (28) in the reaction scheme 10 above. Each step of the above reaction scheme 16 can be carried out in the system without isolating the compound (38) from! ifytem of reaction.

REACTION SCHEME 17 where R4, R2, R-4. Rß, Rß. s, T,?, q, Z and A are the same as defined above, RBβ is a lower alkenyloxy group, and RB * is a hydroxy group. The conversion reaction of the compound (lo) into the compound (lp) is carried out in the presence of a catalyst and an acid in a suitable solvent. The solvent may be, for example, water, acetic acid, alcohols (for example, methanol, ethanol, isopropanol, etc.), hydrocarbons (for example, hexane, cyclohexane, etc.), ethers (for example, dioxane, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, etc.), esters (eg, ethyl acetate, methyl acetate, etc.). polar aprotic solvents (eg, dimethylformamide, etc.). or a mixture of these solvents. The catalyst can be. for example, palladium. palladium black »palladium hydroxide» palladium hydroxide-carbon »palladium carbon» platinum »platinum oxide» copper chromite »Raney nickel» etc. E! acid includes »for example» organic acids such as p-toluenesulfonic acid »etc. The catalyst is used in an amount of 0.02 to 1 time the amount of the compound (lo). The acid is usually used in a catalytic amount. The reaction is usually carried out at a temperature from -20 ° C to about 150 ° C, preferably at a temperature from 0 ° C to about 120 ° C, for about 0.5 to about 20 hours.

REACTION SCHEME 18 (39) (40) (41) (24) (19a) (lq) where T, u, R4, R2, R-4, A '. Z. Rß »m, R24» R2- * and X are the same as defined above. The reaction of the compound (39) and the compound (28) is carried out under the same conditions as those in the reaction of the compound (li) and the compound (22) in the reaction scheme 6 above. The conversion reaction of the compound (40) into the compound (41) is carried out under the same conditions as those in the conversion reaction of the compound (16) in the compound (17) in the above reaction scheme. The reaction of the compound (41) and the compound (18) is carried out under the same conditions as those in the reaction of the compound (17) and the compound (18) in the reaction scheme 5 above. The conversion reaction of the compound (42). wherein R2-4 is a lower alkoxy group in the compound (43). is carried out under the same conditions as those in the conversion reaction of the compound (Id) into the compound (le) in the reaction scheme 4 above. The conversion reaction of the compound (42) »wherein R2- * is a lower alkoxy-phenol group in the compound (43). it is carried out under the same conditions as those in the conversion reaction of the compound (5b) in the compue (5c) in the reaction scheme 13 above. The reaction of the compound (43) and the compound (24) is carried out under the same conditions as those in the reaction of the compound (Ib) and the compound (5) in the reaction scheme 2 above. The reaction of the compound (19a) and the compound (44) is carried out in a suitable solvent in the presence of a basic compound »at 0 ° C to 150 ° C. preferably at room temperature at about 100 ° C, for approximately 0.5 to 8 hours. The solvent may be any solvent that does not disturb the reaction, and may be water, alcohols (eg, methanol, ethanol, isopropanol, etc.), aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.), ethers. for example, diethyl ether, tetrahydrofuran, d-oxan, diglyme, monoglyme, etc.). halogenated hydrocarbons (for example, dichloromethane, chloroform, carbon tetrachloride, etc.), polar solvents (for example, dimethylformamide, dimethyl sulfoxide, triamidehexamethylphosphine, etc.). or a mixture of these solvents. Compound (44) is usually used at least in an equimolar amount "preferably in an amount of 1 to 5 moles" per 1 mole of compound (19a). The basic compound can be the same basic compound that is used in the reaction of the compound (6) and the compound (7) in the above reaction scheme 3. The starting compound (9) can be prepared by, for example, the process of reaction scheme 19 or 20 »as explained below.

REACTION SCHEME 19 wherein T.sub.u.sub.4, R.sub.2, R.sub. », A ', Z, R.sub.β, M.sub.X, R.sub.2" 4 and R.sub.4"are the same as defined above The reaction of the compound (45) and the compound (28) it is carried out under the same conditions as in the reaction of the compound (Li) and the compound (22) in the above Scheme of Reaction 6. The conversion reaction of the compound (46), in which R2-4 is a lower alkoxy group, in the compound (47), is carried out under the same conditions as in the conversion reaction of the compound (Id. ) in the compound (le) in the above Reaction Scheme 4. The conversion reaction of the compound (46). wherein R2"4 is a lower phenylalkoxy group, in the compound (47), is carried out under the same conditions as in the conversion reaction of the compound (5b) in the compound (5c) in the above Reaction Scheme 13. The reaction of the compound (47) and the compound (24) is carried out under the same conditions as in the reaction of the compound (ib) and the compound (5) in the above Reaction Scheme 2.

REACTION SCHEME 20 wherein R4W, R * and m are the same as defined above, RJ-9m is a lower alkoxy group. The reaction of the compound (48) and the compound (49) is carried out in a suitable solvent in the presence of a basic compound. The solvents and basic compounds are the misroos that are used in the Reaction of the compound (6) and the compound (7) in the above reaction scheme 3. The compound (49) is usually used at least in an equimolar amount , preferably in an amount of 1 to 3 moles, per? mole of the compound (48). The reaction is carried out usually at room temperature up to 200 ° C, preferably at room temperature up to about 150 ° C for about 1 to about 60 hours. The conversion reaction of the compound (50) into the compound (9b) is carried out under the same conditions as in the conversion reaction of the compound (5b) in the compound (5c) in the above Reaction Scheme 13. The reaction of the compound (51) and the compound (52) is carried out in a suitable solvent in the presence of a basic compound as a catalyst. The solvent includes, for example, ethers (for example, diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme, etc.), aromatic hydrocarbons (for example, benzene, toluene, xylene, etc.), aliphatic hydrocarbons (e.g. -hexane »heptane» cyclohexane »etc.)» dimethylformamide, dimethyl sulfoxide »triamide-hexamethyl-1-phosphorus» or a mixture of estoß-βol vents. The basic compound may be the roismo which is used in the reaction of the compound (Ib) and the compound (5) using a carboxyl halide in the above Reaction Scheme 2. The catalyst includes »for example» palladium chloride. tetrakis (triphenylphosphine) palladium. palladium acetate »1» 3-bis (difeni Ifosfino) propane »or a mixture of these solvents. The reaction is carried out usually from 0 ° C to 200 ° C, preferably from room temperature to about 150 ° C for about 1 to about 20 hours.The compound (52) is usually used at least in an amount equimolar, preferably in an amount of 1 to 10 moles, per one mole of the compound (51) The basic compound is usually used at least in an equimolar amount, preferably in an amount of 3 moles, for one mole of the compound (51) The catalyst is used in at least an excess amount of the compound (51) The conversion reaction of the compound (53) into the compound (50) is carried out under the same conditions as in the conversion reaction of the compound (Id) in the compound (le) in the above Reaction Scheme 4.

SCHEME E REACCTPN ?? (10a) (lr) wherein T, u, RB, q, R4B, R4, R2, R-4, A, Z, s and W are the same as defined above, RBe * is an amino group optionally having an lower alkyl substituent, and a group -C (0) CHa! -P < 0) (R4-) and a group -Rβ ", are placed between ßi in the ortho position The reaction of the compound (10a) and the compound (44) is carried out under the same conditions as in the reaction of the compound (10) and the compound (12) in the above Reaction Scheme 3. The compound (Ir), in which is a group of the formula: + / -N X- \ wherein R = * ßc "and x- are the same as defined above, can be obtained by treatment with a hydrogen halide acid such as hydrochloric acid, hydrobromic acid, etc., after completion of the reaction.

ESQUEJ REACC? Q ZZ (l) (ít) where R4, R *. T. u, R- »R *. R4"and R33 are the same as defined above.

The reaction of the compound (54) and the compound (12) is carried out under the same conditions as in the reaction of the compound (10) and the compound (12) in the above Reaction Scheme 3. The conversion reaction of the compound (ls), in which R4ß is a lower alkoxy group, in the compound (lt), is carried out under the same conditions as in the conversion reaction of the compound (Id) in the compound (le) in the above scheme of Reaction 4. The reaction of the compound (54) and the compound (20), is carried out under the same conditions as the reaction of the compound (10) and the compound (20) in the above Reaction Scheme 3. The compound starting material (54) is prepared, for example, by the following procedure.

REACTION SCHEME 23 (58) (58a) wherein R4, R2, M, R4 * "and R4B are the same as defined above. The halogenation reaction of the compound (5B) is carried out under conventional halogenation conditions which are employed in the halogenation reaction of a carboxylic acid. The reaction of the carboxylic acid halide compound (58) and the compound (55) is carried out in the presence or absence of a basic compound in a suitable solvent. The solvent includes, for example, halogenated hydrocarbons (eg, methylene chloride, chloroform, etc.), aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.), ethers (eg, diethyl ether, tetrahydrofuran, dimethoxyethane). . etc.). éßtereß (for example, methyl acetate, ethyl acetate, etc.), polar aprotic alcohols (for example, N-dimethylformamide), dimethyl ether sulfoxide, hexamethylphosphoric triamide, etc.). alcohols (e.g., methanol, ethanol, propanol, butanol, 3-methoxy-1-butanol, eti lcelosol e »raet Icelosol ve» etc.) »pyridine» acetone »acetonitrile. water or a mixture of these solvents. The basic compound includes, for example, organic basic compounds such as triethylamine. trimethylamine, pyridine, dimethylamino, N-met Imorfol na, DBN »DBU» DABCO »etc.» or inorganic basic compounds such as potassium carbonate, sodium carbonate »potassium hydride» sodium hydride »hydrogenated potassium »sodium hydroxide» silver carbonate »sodium methoxide, sodium ethoxide, etc. The body (55) is used at least in an equimolar amount. preferably in an amount of 1 to 3 moles for one mole of the carboalkyl halide compound of the compound (5B). The reaction is carried out usually at -30 ° C to about 180 ° C, preferably at 0 ° C to about 150 ° C "for approximately 5 minutes to about 30 hours. The reaction of the compound (5Ba) and the compound (56) is carried out in a suitable solvent "or without solvent" at 0 ° C to about 200 ° C, preferably from room temperature to about 150 ° C. The solvent may be the solvent solvent used in the above reaction of the carboxyl halide of the compound (58) and the compound (55). The compound (55) is used at least in an equimolar amount »preferably in an amount of 1 to 1.5 moles for one mole of the coropuesto (58a). The reaction is carried out for about 1 hour to about 5 hours. The reaction of the coropuesto (58b) and the compound (7) is carried out under the same conditions as in the reaction of the compound (9) and the compound (7) in the Reaction Scheme (3).

ESQU MA PE REAC.CIPN » (lu) (lv) where R4. R.sub.2, R.sub.4, R.sub.44.sub.β, R.sub.4 and R.sub.4.sub.4 are the above-defined moiety.The reaction of the compound (lu) and the compound (5), is carried out under the same conditions as the reaction of the compound (Ib). and the compound (5) in the above Reaction Scheme 2. The starting compound (24) can be prepared, for example, by the method of Reaction Scheme 25, as explained below. (24a) wherein R4, R2, M, X and T are the same defined above, and R ° is a lower alkylsulfonyl group. The reaction of the compound (59) and the compound (60) is carried out under the same conditions as the reaction of the compound (li) and the compound (22) in the above scheme.

Reaction 6. The reaction of the compound (61) and the compound (62) is carried out under the same conditions as the reaction of the compound (li) and the compound (22) in the above Reaction Scheme 6. The reaction of conversion of the compound (63) into the compound (24a) is carried out by treating the compound (63) with hydrazine in a suitable solvent, or by hydrolysing the compound (63). The solvent used in the reaction with hydrazine can be, in addition to water, the same solvent used in the reaction using a carboxylic acid halide in the reaction of compound (Ib) and compound (5) in reaction scheme 2. The reaction is usually carried out at a temperature from room temperature to about 120 ° C, preferably at 0 ° C to about 100 ° C, for about 0.5 hours to about 5 hours. The hydrazine is usually used at least in an equimolar amount, preferably in an amount of 1 to 6 moles, for 1 mole of compound (63). The hydrolysis is carried out in a suitable solvent or without a solvent, in the presence of an acidic or basic compound. The solvent includes, for example, water, lower alcohols (eg methanol, ethanol, isopropanol, etc.), ketones (eg acetone, methyl-1-ethyl-1-ketone), ether (eg, diethyl ether, dioxane). tetrahydrofuran, dimethyl ether of ethylene glycol, etc.). fatty acid (for example, acetic acid, formic acid, etc.) or a mixture of solvent acids. The acid includes, for example, mineral acids (for example, hydrochloric acid, hydrobromic acid, etc.). organic acids (eg »formic acid, acetic acid» aromatic sulfonic acids »etc.). The basic compound includes, for example, an alkali metal carbonate (eg, sodium carbonate, potassium carbonate, etc.), an alkali metal or alkaline earth metal hydroxide (eg, sodium hydroxide, potassium hydroxide, calcium hydroxide). , etc). The reaction is usually carried out at a temperature from room temperature to about 200 ° C, preferably at room temperature to about 150 ° C, for about 10 minutes to about 25 hours. Among the desired compounds (1) of the present invention, the compounds having an acid group can be easily converted into salts by treating them with a pharmaceutically acceptable basic compound. The basic compound includes for example an alkali metal hydroxide such as sodium hydroxide, hydrated potassium, lithium hydroxide, calcium hydroxide, etc., an alkali metal carbonate such as sodium carbonate, etc., a bicarbonate of alkali metal such as potassium bicarbonate, an alkali metal alkali such as sodium iodide, potassium ethylate and the like In addition to the desired compounds of the present invention, the compounds having an The basic group can be easily converted into acid addition by treating them with a pharmaceutically acceptable acid The acid includes, for example, inorganic acids (eg sulfuric acid, nitric acid, hydrochloric acid, hydrobromic acid, etc.). and organic acids (eg »acetic acid, p-toluenesulfonic acid, ethanesulfonic acid, oxalic acid, maleic acid» fumaric acid »citric acid» acid succinic, benzoic acid, etc.) These salts can also be used as an active ingredient of the pharmaceutical composition of the present invention, as well as the compound (1) in a free form. In addition, the compounds of the present invention also include stereoisomers and optical isomers, and these isomers are also used as an active ingredient. The desired compound obtained in the above reaction schemes can be easily isolated and purified by conventional isolation methods from the reaction system. The methods of isolation are for example, the distillation method, the crystallization method, column chromatography »ion exchange chromatography» gel chromatography »affinity chromatography» preparative thin layer chromatography »solvent extraction, dilution method and the like. The compounds (1) of the present invention are useful as a protein kinase inhibitor and can be used in the form of a conventional pharmaceutical preparation. The preparation is done using diluents or conventional vehicles such as fillers. agentß thickener »agglutinant» agentß humectant. disintegrant. agents, surfactants, lubricants and the like. The pharmaceutical preparations can be selected in various ways according to the desired utility, and the representative forms are tablets, pills, powders, solutions, suspensions, emulsions granules, capsules, suppositories, injections (solutions, suspensions, etc.), and the like. . To form tablets, carriers are used, such as vehicles (for example lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc.) »binders (for example water »Ethanol» propanol »simple syrup» glucose solution »starch solution» gelatin solution »carboxymethylcellulose» shellac »methylcellulose, potassium phosphate, pol i vin Ipirrol idona etc.). disintegrators (eg, dry starch, sodium alginate, agar powder, laminarán powder, sodium carbonate, calcium carbonate, fatty acid esters of polyoxyethi len-sorbitan lauri Sodium isulfate, roonogl stearic acid, starch »lactose »Etc.)» disintegration inhibitors (eg »white sugar» stearin »cocoa butter» hydrogenated oils, etc.). promotion promoter (eg, quaternary ammonium baεe, iodide εulfate lauryl, etc.), wetting agents (eg, glycerin, starch, etc.), adsorbents (eg, starch, lactoßa, kaolin »bentonite» colloidal silicates »Etc.), lubricants (eg, purified talc, eßteratoß, boric acid powder» polyethylene glycol, etc.), and the like. In addition, the tablets may also be in the form of a conventional coated tablet such as sugar-coated tablets, gelatin-coated tablets, enteric coated tablets, film-coated tablets, or double or multiple-layer tablets. In the preparation of pills, the vehicles may be conventional and include for example vehicles (eg, glucose, lactose, starches, cocoa butter, hydrogenated vegetable oils, kaolin, talc, etc.), binders (eg, rubber powder). arabica »tragacanth powder» gelatin »ethanol» etc.), disintegrants (eg, laminating, agar, etc.), and the like. In the preparation of suppositories, the carriers can be conventional, and include for example polyethylene glycol, cocoa butter, higher alcohol alcohols and alcohol alcohols. gelatin, semisynthetic glycerides »and similaree. The capsules are prepared by mixing the active compound with a conventional carrier, and filling the mixture completely into hard gelatin capsules or soft gelatin capsules. In the preparation of injections, the solutions and suspensions are sterilized and preferably made isotonic with the blood. In the preparation of these solutions, emulsions and suspensions are conventional diluents such as water, ethyl alcohol, macrogol, propylene glycol, isobutyl alcohol co-ethylated, isobutyl alcohol co-ethylated. ethers of fatty acid of pol iet lensorbi tan and the like. In this case, pharmaceutical preparations can also be incorporated with sodium chloride »glucose or glycerin in an amount sufficient to make them isotonic» and can also be incorporated with conventional solubilizers »buffers» anesthetizing agents. In addition, pharmaceutical preparations can optionally be incorporated with coloring agents, »preservatives» perfumes »flavors, sweetening agents and other medications, if required. The amount of the desired compound (1) of the present invention or a salt thereof to be incorporated in the pharmaceutical preparation is not specified but can be selected from a scale-up, but is usually preferred in the range from about 1 to 7054 by weight , preferably on the scale of about 5 to 5054 by weight. The pharmaceutical preparation of the present invention can be administered in any method, and the method suitable for administration can be determined according to various forms of preparations, ages, sex and other conditions of the patient, the degree of severity of the diseases and ßimi lareß. For example, laß tablets, pills, solucioneß suspensions, emulsions, granules and capsules are administered orally. The injections are administered intravenously alone or together with a conventional auxiliary liquid (eg, glucose and amino acid solutions), and also optionally administered alone in the intramuscular »subcutaneous or subcutaneous or intraperitoneal route» if required. Suppositories are administered by the intrarectal route. The dosage of the pharmaceutical preparation of the present invention may be selected according to the age, age, sex and other conditions of the patients, the degree of severity of the disease and the like, but is usually on the scale of about 0.6 to 50 mg of the compound (1) or a salt thereof per 1 kg of body weight of the patient per day. The active compound is contained in an amount of about 10 to 1000 mg per unit of the dosage form.

PREFERRED MODALITIES OF THE INVENTION The present invention is illustrated in more detail by the following pharmaceutical composition preparations, procedural reference examples for preparing the starting compounds that are used for the disclosed compounds of the present invention, and examples of methods for preparing the desired compounds. experiment of the activities of the desired compounds of the present invention.

Preparation 1 Film-coated tablets were prepared from the following components.

Component Quantity 2-C2-Methoxy-4-C3-C4- (4-methyl-1-piperazinyl) -1-piperidine Icarboni 1 -lacri loi 1} phenoxymethi-1-carboni-lamino-ibenzothiazole 150 g Avicel (trademark of micro-glass cellulose manufactured by Asahi Chemical Industry Co. Ltd.) 40 g Corn starch 30 g Magnesium stearate 2 g Hydroxypropylmethylcellulose 10 g Polyethylene glycol 6000 3 g Rine oil 40 g Ethanol 40 g The active compound of the present invention »Avicel, corn starch and magnesium stearate» are mixed and kneaded »and the powder is compressed into tablets by means of a conventional punching machine (R 10 mm) for coating with sugar. The tablets obtained in this way are coated with a film coating agent consisting of hydroxypropylmethylcellulose, polyethylene glycol 6000, castor oil and ethanol to give film-coated tablets.

Preparation 2 Tablets were prepared from the following components.

Components Quantity 2-C3-Methoxy-4-C3-C4- (3,4-dimeti l-l-piperazini 1) - 1-piperidini 1 carbom'l Dacr loi 1} phenoxymethi 1- carboni lami no 3benzimidazole 150 g Citric acid 1.0 g Lactose 33.5 g Dicalcium Phosphate 70.0 g Pul! onic F-6B 30.0 g Lauri Sodium Isulfate 15.0 g Pol vini Ipirrol idona 15.0 g Polyethylene glycol (Carbowax 1500) 4.5 g Polyethylene glycol (Carbowax 6000) 45.0 g Corn starch 30.0 g Dry sodium stearate 3.0 g Dry magnesium stearate 3.0 g Ethanol c.s.

The active compound of the present invention, citric acid »lactose, dicalcium phosphate» Pullonic F-68 and sodium lauryl sulphate are mixed. The mixture is sieved with No. 60 mesh and granulated with an alcohol solution containing polyvinylpyrrolidone »Carbowax 1500 and 6000. If required, an alcohol is added thereto so that the powder mixture becomes a mass with consistency pasty . The corn starch is added to the mixture and the mixture is continuously stirred to form uniform particles. The resulting particles are passed through a No. 10 screen and placed in a tray and then dried in an oven at 100 ° C for 12 to 14 hours. The dried particles are screened with No. 16 mesh and dry sodium lauryl sulfate and dry magnesium stearate are added thereto, and the mixture is compressed into tablets to obtain the desired shape. The core tablets prepared in this way are varnished and sprinkled with talc to protect them from wetting. A lower coating is applied to the core tablets. To administer the tablets orally, the core tablets are varnished several times. To give round shape and smooth surface the tablets, it is applied to them more lower coating and coating with lubricant. Then, the tablets are coated with a coloring coating material until the desired color of the tablets is obtained. After drying, the coated tablets are covered to obtain the desired tablets having uniform luster.

Preparation 3 An injection preparation is made from the following components.

Carity components 2-C2- (3-Mofol inopropyl) -4-C3- (4-pyridi 1) acri 1 oil} - Icarboni phenoxymethyl lamino} benzothiazole 5 g Polyethylene glycol (molecular weight: 4000) 0.. 3 g Sodium Chloride 0, .9 g Monooleate polyoxieti lensorbi tan 0.4 g Sodium metabisulphite 0.1 g Met lparabeno 0.18 g Propylparaben 0.02 g Distilled water for injection 10.0 ml The above parabens, sodium metabisulfite and sodium chloride dissolve with agitation in half the previous volume of distilled water at 80 ° C. The solution thus obtained is cooled to 40 ° C, the active compound of the present invention is dissolved in the above solution, and then polyethylene glycol and polyoxyethyleneoxide monooleate. Water destined for injection is added to the solution to adjust to the desired volume, and the solution is sterilized by filtering with an appropriate filter paper to give an injection preparation.

E EMLO PE DEFERENCE l A solution of o-isopropyl-1-phenol (39.5 g), potassium carbonate (40 g) and ethyl a-bromoacetate (40 ml) in dimethylformamide (300 ml) is heated for 8 hours with stirring at 80 ° C. Water is added to the mixture and the mixture extracted with ethyl acetate. The extract is washed with water, and concentrated under reduced pressure to remove the solvent. The residue thus obtained is dissolved in a solution of sodium hydroxide (20 g) in water (300 ml) and ethanol (200 ml). and the mixture is refluxed for 1.5 hours. After cooling, the mixture is acidified with concentrated hydrochloric acid and the precipitated crystals are collected by filtration to give oc- (2-isopropyl-lphenoxy) acetic acid (37 g). White powder 4H RMiM (CDCl ,,) óppm: 1.24 (6H, d »J = 7 Hz), 3.39 (1H, sept, J = 7 Hz), 4.69 (2H, s), 6.75 (1H, dd, J = l Hz , J = 8 Hz), 6.95-7.3 (3H, m).

REFERENCE EXAMPLE 2 A solution of - (2-isopropi Ifenoxi) acetic acid (13.1 g) in t-butyl chloride (30 ml) is refluxed for 30 minutes. The mixture is concentrated under reduced pressure to remove the thionyl eεcene, and the resultant is dissolved in dichloromethane (50 ml). The mixture is added dropwise to a solution of 2-aminobenzothiazole (9.1 g) and pyridine (7.2 ml) in dichloromethane (100 ml) under ice-cooling. The mixture is stirred at the same temperature for 5 hours, and then washed with water, dried and concentrated under reduced pressure. Ethanol is added to the residue to give 2- (2-iβ-propyl-1-pheno-imeti-Icarboni-lamino) -benzothiazole (16.66 g). Yellow powder H NMR (CDCl ,,,)? Ppm: 1.32 (6H, d, J = 7 Hz), 3.43 (1H, sept, J = 7 HZ). 4.78 (2H. E). 6.85 (1H, dd, J = 1 Hz, J = 8 Hz), 7.0-7.55 (5H, m), 7.8-7.9 (2H, m), 9.74 (1H, br).

REFERENCE EXAMPLE 3 To a solution of dimethyl methophephonate (19.5 ml) in anhydrous tetrahydro-urane (300 ml) is added a 1.72 M solution of n-butyllithium in n-hexane (107 ml) at -50 ° C. Thirty minutes later, 2- (2-methoxy-4-formi-lphenox and icarboni lami-no) benzothi-azole (20.5 g) was added portionwise under nitrogen. The mixture is stirred at -50 ° C for one hour, and water is added thereto. The mixture is acidified with concentrated hydrochloric acid, and extracted with ethyl acetate. The residue is purified by means of silica gel column chromatography (solvent: dichloromethane: methanol = 200: 1 30: 1) to give C2-C3-methoxy-4- < 2-benzothi azol ami nocarboni l methoxy) feni 13-2-hydroxyeti 1} dimethyl phosphonate (19.0 g). H NMR (CDC13) .ppm: 2.05-2.35 (2H, m), 3.73, 3.76. 3.78 and 3.81 (6H each S). 3.98 (2H, d »J = 2.5 HZ), 4.01 (3H.S), 4.77 (2H, 8), 5.0-5.15 (1H, m), 6.90 (1H, dd, J = 2 Hz, J = 8 Hz ), 6.9B (1H »d.J = 8 HZ). 7.07 (1H, d.J = 2 Hz). 7.25-7.5 82H, m > 7.8-7.9 (2H. Rn), 10.66 (1H.br). To a solution of. { "2-C3-metho? I-4- (2-benzothiazoi laminocarboni lmeto? I) feni 1 D-2-hydro? Iethi.]. Dimethyl phosphonate (19.0 g) in chloroform (300 ml) is added active manganese dioxide (17.7 g) and the mixture is refluxed for 3 hours Active manganese dioxide (IB g) is added to the mixture and the mixture is refluxed for 3 hours. add more active manganese dioxide (20 g), and the mixture is refluxed for 3 hours.The manganese dioxide is collected by filtration, and washed with chloroform.The filtrate and the washings are combined and concentrated under reduced pressure. to remove the chloroform The residue is purified by silica gel column chromatography (solvent: dichloromethane: methanol = 200: 50: 1) to give C3-methoxy-4- (2-benzothiazole and laminocarbonylmethyl) - benzoi 1 Umeti 1.}. dimethyl phosphonate (7.76 g), white powder, H NMR (CDCl) <5ppm: 3.62 (2H.D. J = 22.5 Hz) »3.79 < 6H »d. J = 11.2 Hz), 4.04 (3H, S), 4.85 (2H, S), 7.02 (1H, d.J = 8.5 HZ), 7.3-7.55 (2H, m), 7.6-7.7 (2H, m), 7.8-7.9 82H, m), 10.31 (1H, br).

EXAMPLE P PE REFERENCE To a solution of chloroacetyl chloride (10.0 ml) in anhydrous 1,2-di chloroethane (250 ml) is added aluminum chloride (12 g) at room temperature and the mixture is stirred for 20 minutes. To the mixture is added in one portion 2- (2-isopropyl-1-pheno-imeti-Icarboni-lamino) benzothiazole (20 g), and the mixture is stirred at room temperature for one hour. The reaction mixture is poured into water, and to this is added n-hexane. The precipitates are collected by filtration, washed with water, and dried to give 2-C2-isopropyl-l-4- (2-chloroacet-1) phenoxy-methyl-Icarboni-lamino-d-benzothiazole (25.9 g). White powder 4 H NMR (DMSO-dβ) éppm: 1.24 (6H, d, J = 7 Hz), 3.38 81H, m), 5.12 (4H, s), 7.01 (1H, d, J = 9 Hz), 7.25-7.55 ( 2H, m), 7.7-7.95 (3H, m), 7.97 (1H, d, J = 8 Hz), 13.00 (1H, br).

REFERENCE EXAMPLE 5 A suspension of 2-C2-ieopropyl-4- (2-chloroaceti-1) pheno-imet -carboni laminolbenzimidazole (4.0 g) and triphenylphosphine (2.8 g) in chloroform (100 ml) is refluxed for 7 hours. The reaction mixture is concentrated under reduced pressure and the residue is crystallized from dichloromethane-diethyl ether to give C3-i chloride sopropi 1-4- (2-benzothiazole and lamicarboni 1 methoxy) enzoi 1 Dmeti 1 trifeni 1- Phosphonium (3.8 g). 4 H NMR (DMSO-d ,,,), ppp: 1.23 (6H »d, J = 7 Hz), 3.40 (1H, m) »5.18 < 2H »s), 6.19 (2H» d »J = 13.5 Hz)» 7.09 (1H »d, J = 9 HZ). 7.25-7.5 (2H, m), 7.6-8.05 (19H.m), 12.77 (1H. 8). To a solution of C3-isopropyl-l-4- (2-benzothiazole and laminocarbonyl-1-methoxy) methyl triphenylphosphonium chloride (3.3 g) in methanol (50 ml) is added DBU (1 ml) and the mixture is stirred at room temperature for 2 hours. The precipitated crystals are collected by filtration, washed with methane, and dried to give C3-isopropyl-4- (2-benzothiazole and laminocarbonyl-Imethoxy) -benzoyl-1-dimethylfensifine (2.27 g). White powder 4 H NMR (CDCl 3,): ppp: 1.32 (6H. D »J = 7 Hz)» 3.42 (1H. Sept.J = 7 Hz), 4.2-4.6 (1H, m), 4.73 (2H, s), 6.75 (1H, J = 8.5 HZ), 7.25-8.0 (21H, m), 10.01 (1H, br). Using the appropriate starting compounds, the following compound is obtained in the same manner as in reference example 5. C3- (3-chloropropy1) -4- (2-benzothiazole il-ami nocarboni 1 methoxy) benzoyl chloride 1 I-metí * lentri eni 1 phosphonium White powder. 4H NMR (CDC1)? Ppm: 2.11 (2H, tt, J = 6.6 Hz) »2.86 (2H.t» J = 8.0 Hz), 3.71 (2H »t» J = 6.6 Hz) »5.20 (2H» ß) , 6.17 (2H, d, J = 12.8 Hz), 7.13 (1H, d, J = 8.7 Hz>, 7.34 (1H, t, J = 7.5 Hz), 7.48 (1H, t, J = 7.0 Hz), 7.76-8.02 (19H, m> 12.75 (1H »br).

REFERENCE EXAMPLE 6 To dimethylformamide (200 ml) is added 2-metho-i-4-acetyl phenol (20 g). Ethyl s-bromoacetate (15 rol) and potassium carbonate (IB.3 g) and the mixture is stirred at room temperature overnight. After the reaction is over, water is added to the mixture and the mixture is brought with ethyl acetate. The extract is washed with aqueous sodium hydrogen carbonate solution and dried over magnesium sulfate and concentrated under reduced pressure to remove the solvent. The resulting crystals are collected and washed with n-hexane-diethyl ether to give ethyl α- (2-methox-4-ace-1-phenoxy) -acetate (23.86 g). To chloroform (230 ml) is added a- (2-metho? I-4-acetylphene? I) -ethyl acetate (23 g) and copper (II) bromide (55 g) »and the mixture is added to reflux for 3.5 hours. After the reaction is complete the mixture is filtered through a pad of cerita to remove the precipitates, and washed with sodium hypochlorite. The filtrate is dried over magnesium sulfate and concentrated under reduced pressure to remove the solvent and then crystallized to give α-C2-metho? I-4- (2-bromoacetyl) pheno? Ethyl acetate (21.2B g) . To chloroform (200 ml) is added ot-C2-methoxy-4- (2-bromoacetyl) -phenoxy ethyl acetate (20 g) and triphenylphosphine (20.6 g) in an ice bath, and the mixture is stirred for one hour. After confirming that the starting compounds are well consumed, the mixture is washed with an aqueous solution of potassium carbonate. The mixture is dried over magnesium sulfate and concentrated under reduced pressure to remove the solvent. Methanol (200 ml) is added to the residue, and sodium hydroxide is added dropwise in an ice bath. After confirming that the starting compounds are well consumed, concentrated hydrochloric acid is added to the mixture. The precipitated crystals are washed with water and diethyl ether, and dried to give (3-methoxy-4-carboxymethoxybenzoi-1) -methi lentrifem "lphosphorane (25 g). To dichloromethane (50 ml) is added (3-methoxy). 4-carboxymethoxybenzoi 1) methi lentrifen Ifosphorane (5 g), 2-aminobenzothiazole (1.9 g), bis- (2-oxo-3-o? Azole dini 1) phosphinic chloride (2.93 g) and triethylamine (3.3 ml), and the mixture is stirred overnight.After finishing the reaction, the mixture is washed with aqueous sodium hydrogen carbonate solution, and dried over magnesium sulfate to remove the solvent, and then recrystallized from toluene to give C3. -meto? -4- (2-benzothiazole and laminocarboni lmeto?) - benzoi 1 Dmeti lentp'feni Ifoeforane (5.17 g) .Slight yellow powder. H NMR CCDC1 ,,,) áppm: 4.03 (3H, S >;, 4.12-4.62 (1H, m), 4. 79 (2H »S), 6.96 (1H, d, J = 8.3 Hz)» 7.25-7.90 (22H »m) REFERENCE EXAMPLE 7 To a solution of N-benzyl 1-4-piperidone (B.O g) and 3 »4-Dimeti-1-piperazine (9.5 g) in ethanol (100 ml) is added with 5% platinum-carbon (2 g> and acetic acid (14.4 ml) and the mixture is subjected to catalytic hydrogenation at room temperature under atmospheric pressure, the catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure, water is added to the resulting product, and the mixture is made alkaline with an aqueous solution of sodium hydroxide at 5 > 4. The mixture is extracted with diethyl ether, the extract is washed with water, dried and concentrated under reduced pressure to remove the solvent, the residue is dissolved in ethanol, and concentrated hydrochloric acid is added to give a hydrochloride. The resulting white product is collected by filtration. "It is dissolved in water and made alkaline with an aqueous 5% sodium hydroxide solution. The mixture is extracted with diethyl ether, washed with water, dried and concentrated under reduced pressure to give 4- (3,4-dimeti ll piperazini 1-l-benci Ipiperidina (4.2 g). H NMR (CDC13) .ppm: 1.04 (3H, d, J = 6 Hz), 1.45-2.5 (12H, m), 2.27 (3H, s>, 2.7-3.05 (4H, m), 3.48 (2H, s), 7.31 (5H, m) To a solution of 4- (3,4-dimet-l-piperazin-1) -l-benzylpiperidine (4.2 g) in ethanol (50 ml) is added palladium hydroxide- carbon to 20J4 (0.4 g) and the mixture ß ome to catalytic hydrogenation at 50 ° C under atmospheric pressure The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure The residue ε evaporates to give 4- ( 3,4-dimet ll-piperazini 1) pipemdine (1.65 g), colorless oil, bp 145 ° C (0.3 mmHg) 4H NMR (CDCl ,, -) éppm: 1.05 (3H, d.J = 6 Hz) , 1.25-1.55 (2H, m), 1.75-3.3 (14H, m), 2.31 (3H, ß).

REFERENCE EXAMPLE 8 A solution of 1-benzyl-1-L-proline (50 g) in dichloromethane (300 ml) is cooled with ice. To this solution is added N-methylmorphol (22.5 g) and then, dropwise, isobutyl chloroformate (30 g) is added thereto. The mixture is stirred at the same temperature for about one hour, and pyrrolidine (18.B ml) is added dropwise at the same temperature. The mixture is warmed to room temperature and stirred for 2 days. The mixture is washed twice with water (250 ml) and dried over magnesium sulfate. The mixture is concentrated under reduced pressure and the residue is recrystallized from ethyl acetate to yield 2- (1-pyrrol idine 1) carboni 1-1-benzylpyrrole idine (31 g), as a powder. White color. Quench in ethanol (300 ml) 5% palladium-carbon (3 g), and to this is added 2- (l-pyrrole idini 1) carbon 1-1-benzylpyrrole idine (30 g), and the mixture is mixed. undergoes catalytic hydrogenation at room temperature under atmospheric pressure. The mixture is filtered, and the filtrate is concentrated under reduced pressure to remove the remaining solvent to give 2- (1-pyrrol idini 1) carboni Ipyrrolidine (approximately IB g) as an oleo product. Lithium aluminum hydride (9 g) is suspended in dry tetrahydrofuran (100 ml) under ice-cooling, and a solution of 2- (l-pyrro! Idini 1) carboni Ipirrol idine () is added thereto dropwise. 33 g) in tetrahydrofuran eeco (BO ml). The mixture is refluxed under nitrogen atmosphere for 4 hours. The mixture is cooled with ice and a saturated aqueous solution of sodium sulfate (approximately 15 ml) is added thereto and then the mixture is further stirred at room temperature for 3 hours. The precipitated sodium sulfate is removed by filtration, washed well with chloroform. The filtrate and washings are combined, concentrated under reduced pressure and evaporated to give 2- (1-pyrrol idini 1) methyropyrrol dine (22 g). Colorless oil P.e. 99-101 ° C (20 mmHg).

REFERENCE EXAMPLE 9 4-Benzyl-1-2-chloromethylolmorphol (15 g) and 4- (2-hydroxyethyl) -piperazine (25 ml) are mixed and the mixture is heated with stirring at 130 ° C for 5 hours. After finishing the reaction, the mixture is extracted with chloroform, and the extract is dry over magnesium sulfate. The residue thus obtained is concentrated under reduced pressure to give 4-benzyl-2-C4- <; 2-hydro? Ieti 1) -l-piperazinyl Imeti Imorfol ina (16 g). 4H NMR (CDC! A) apppm: 1.B6 (1H, t, J = 10.6 Hz). 2.07-2.27 (2H, m), 2.37-3.05 (14H, m). 3.49 (2H. D, J = 2.3 Hz). 3.57-3.B9 (5H.m), 7.24-7.33 (5H, m). Dissolve 4-benzyl-2-C4- (2-hydroxyethyl) -l-piperazine Dmethylmorphine (16 g) in ethanol (160 ml) and to this is added palladium hydroxide (1.6 g) The mixture is de-benzonated at 50 ° C under hydrogen atmosphere.Five hours after the mixture is filtered through a pad of cerite and the filtrate is concentrated under reduced pressure.The resulting crystals are washed with ether Ethyl ico-n-hexane to give 2-C4- (2-hydroxyethy1) -l-piperazinyl Dmeti Iroorfol na (9.09 g), MP 73-75.5 ° C. White powder 4H NMR <CDC13) .ppm: 2.25. 1H, dd, J = 4.2 Hz, J = 13.0 Hz), 2.37-2.74 (11H, rn.). 2.74-3.02 (6H, m). 3.49-3.77 (4H, m), 3.B5-3.93 (1H.m). Using the appropriate starting compounds, the compounds listed in Tables 1 to 4 are obtained in the same manner as in Reference Example 1.

TABLE 1 Reference example 10 RB: CH3 (position 2) m: 1 A: -O Crystalline Forroa: White powder Form: Free NMR (1) Reference example 11 Rß: CaHß (poεition 2) m: 1 A: -CHa- Forroa crißtalin: White powder Form: Free NMR (2) Reference example 12 RB: - (CHse) aCH3 (position 2) m: 1 A: -CH, - Crystalline form: White powder Form: Free NMR (3) Reference example 13 RB: - (CHa.) 3CH3 (position 2) n: 1 A: -CHa- P.f. 102-104 ° C Ethanol-water recrystallization solvent: Crystalline form: White powder Form: Free.

GWAPRQ t Reference example 14 RB: - (CH2) _ "CH3 (position 2) m: 1 A: -CH-g-P.-f. 71.4-74.4 ° C Solvent for Ethanol-water recrystallization: Crystalline form: White powder Form: Free Reference example 15 RB: F (position 2) ra: 1 A: -CH, Forroa cri stal i na: Pol vo bl anco Form: Li bre NMR (4) Reference example 16 R «: Cl (position 2) m: 1 A: -CH" - Crystalline form: White powder Form: Free NMR (5) Reference example 17 RB: - (CH ^) ^ - (combined in positions 2 and 3) ro: 2 A: -CHa- Crystalline form: White powder Form: Free NMR (6) Reference example 18 RB: CH3 (posic oneß 2 and 3) m: 2 -CH, Crystalline Forroa: White powder Shape: Free NMR (7) CUAPRP 3 Reference example 19 RB: CH3 (positions 2 and 6) m: 2 A: -CH-g- Crystalline form: Yellow powder Form: Free NMR (8) Reference example 20 RB: CH3 (positions 3 and 5) m: 2 A: -CH., .- Crystalline form: White powder Form: Free NMR (9) Reference example 21 Rß: CH 3 (position 3) m: 1 A: -CHa- Crystalline form: White powder Form: Free NMR (10) Reference example 22 RB: rg a (position 3) m: 1 A: -CHa- P. -f. 102-104 ° C Recrystalline Ethanol-water solvent recrystallization: Crystal form: White powder Form: Free Reference Example 23 RB: - (CHae) 5? CH3 (position 3) m: 1 A: -CHX- P.f. 63.5-66..0 ° C Ethanol-water recrystallization solvent: Forroa cristal na: White powder Forroa: Free gWAPRP 4 Reference example 24 RB: - (CHZ) 3CH (position 3) m: 1 A: -CHa- P.f. 69.0-72.5 ° C Solvent for recrystalline Ethanol-water zac ón: Crystal form: Shape: Free NMR (11) color prisms Reference example 25 CH3 (position 3) m: 1 A: -CHa- / R «-CH CH3 Crißtaline form: White solid Form: Free NMR (12) Reference example 26 RB: Cl (3) m: 1 A: -CHa- Form crißtalin: White powder Form: Free NMR (13) Reference example 27 Rß: F (position 3) m: 1 A: -CHa- Forroa crystal na: White powder Shape: Free NMR (14) Reference example 28 RB: CH30 (position 3) ro: 1 A: -CHa- Form crißtaline: Beige powder Shape: Free NMR (15) Reference Example 29 RB: C ^ H-HO (partition 3) ro: 1 A: -CHa- Form crißtaline: Beige powder Shape: Free NMR (16) The spectra of 4 H-NMR (NMR (1) to NMR (17) )) coroo described in Tables 1 to 4 are the following: NMR (1) (DMSO-d, ..) éppm: 2.19 (3H, S) »4.6B (2H, S), 6.B3 (2H, dd, J = 7.8HZ, J = 13.2Hz), 7.12 (2H, t, J = 7. BHZ), 12.96 (1H, S) NMR (2) (DMSO-d ,,) óppm: 1.14 (3H, t , J = 7.5HZ), 2.61 (2H, q, J = 7.5HZ), 4.69 (2H, ß), 6.7B-6.95 (2H, m), 7.05-7.20 (2H.m), 12.97 (1H, s ) NMR (3) (CDC! 3) éppm: 0.95 (3H, t, J = 7.4Hz) »1.5-1.8 (2H, m), 2.65 (2H» t, J = 7.4HZ) »4.65 (2H, S ) »6.73 (1H, d, J = 8.3Hz), 6.9-7.05 (1H, m), 7.15 (2H» t »J = 7.2Hz). 9.4-10.1 (1H, m) NMR (4) (DMSO-dβ) éppm: 4.77 (2H »ß), 6.88-7.30 (4H, ro), 13.09 (1H. ß) NMR (5) (CDC13) óppm: 4.76 (2H. 8), 6.B9 (1H, dd.

J = 1.5HZ, J = 8.0HZ), 6.99 (1H, dt »J = 1.5HZ, J = 7.6Hz)» 7.23 (1H »dt, J = 1.5HZ, J = 7.6HZ), 7.41 (1H, dd »J = 1.5Hz J = 8.0Hz)» B.16 (1H »br) NMR (6) (DMSO-d :) éppm: 1.6-1.85 (4H» ro) »2.55-2.75 (4H, m), 4.63 (2H »ß)» 6.57 (1H, d.J = 8Hz), 6.65 (1H. d »J = 7.5Hz>, 6.9-7.05 (1H» ro) »12.94 (1H.br) NMR (7) (DMSO-d, *) éppro: 2.10 (3H »ß), 2.20 (3H. 8)» 4.63 (2H, S> 6.64 (1H, d.J = BHZ) »6.75 (1H, d, J = 7.5Hz), 6.95-7.1 (1H, m), 12.9 (1H, br) NMR (B) (DMSO-dw) óppm: 2.22 (6H. ß), 4.35 (2H, ß), 6. 87-7.06 (3H, m). 12.87 (1H, ß) NMR (9) < DMSO-d? Í :) óppm: 2.22 (6H, s), 4.48 (2H »s), 6.48 (2H. S). 6.60 (1H, s) NMR (10) (DMSO-d, *) óppm: 2.26 (3H »s)» 4.62 (2H.S), 6.60-6.B0 (3H.m), 7.11-7. IB (1H »m) NMR (11) (DMSO-d, ¥) .ppm: 0.85 (3H» t, J = 7.2Hz) »1.17- 1.3B (2H.m). 1.45-1.60 (2H, m), 2.49-2.57 (2H, m), 4.63 (2H, S), 6.66-6.79 (3H, m), 7.13-7.21 (1H, m), 13.00 (1H, br) NMR (12) (CDC13) óppm: 1.22 (6H, d, J = 6.9Hz), 2.77-3.00 (1H, m). 4.68 (2H, 8), 6.66-6.76 (1H, m), 6.81-6.95 (2H »m), 7.17-7.29 (1H, m)» 8.65 (1H, brs) NMR (13) (CDC13) óppm: 4.69 (2H.S), 6.79-6.85 (1H.m). 6.85-7.04 (2H.ro) »7.19-7.28 (1H» m). 8.00 (1H »br) NMR (14) (CDC13) .ppm: 4.69 (2H. S)» 6.62-6.79 OH »m)» 7.20-7.32 (1H, m). 9.07 (1H. Br) NMR (15) (CDC13) óppm: 3.79 (3H »s)» 4.67 (2H »S), 6. 47-6.61 (3H »m), 7.16-7.26 (1H.m)» 9.12 (1H »br) NMR (16) (CDC1) .ppm: 1.40 (3H, t» J = 7.0Hz). 4.01 (2H »q» J = 7.0HZ), 4.66 (2H, S), 6.45-6.62 (3H, m), 7.13-7.25 (1H, m), 8.34 (1H, br) Using the appropriate starting materials » The procedures as listed in Table 5-9 are obtained in the same way as Reference Example 2.

TABLE 5 Reference example 30 RB: CH3 (position 2) m: 1 A: -CH. * - R- »: H Crystal form: Yellow powder Shape: Free NMR (l) Reference example 31 RB: C3Hß (position 2) m: 1 A: -CH * - R- »: H Crystalline form: Forroa: Free NMR (2) pale yellow powder Reference example 32 R ": - (CHae) aCH3 (position 2) m: 1 A: -CHZ- R- *: H Crystalline form: Yellow powder Form: Free NMR (3) Reference example 33 RB: - < CHa) 3CH3 (position 2) m: 1 A: -CH ^ - R- »: H Crystalline form: Yellow solid Form: Free NMR (4) CUA R 6 Reference example 34 RB: H (poeic 2) m: 1 A: -CH, .- R- »: H Criatalin form: Shape: Free NMR (5) pale yellow powder Reference example 35 RB: - (CHSE) ^ CH3 (poem 2) m: 1 A: -CHa- R- »: H Crietaline form: Yellow powder Shape: Free NMR (6) Solvent for recrystallisation: Acetate lo-n-he? Anum Reference example 36 Rß: F (position 2) m: 1 A: -CH_- R- »: H Crystal form: Shape: Free NMR (7) pale yellow powder Reference example 37 R ": Cl (position 2) m: 1 A: -CH -.- R: H Crystal form: Powder Shape: Free NMR (8) amari 1 lo Reference example 38 RB: - (CH _.) ^ - < combed in position 2 and 3) m: 2 A: -CH, R "»: H Crißtal form na: White powder Forroa: Free NMR (9) CUA Q 7 Reference example 39 RB: CH3 (positions 2 and 3) m: 2 A: -CHa- R- *: H Crystalline form: Yellow powder Form: Free NMR (10) Reference example 40 R ° ": CH3 (positions 2 and 6) m: 2 A: -CHa- R-»: H Crystalline form: Yellow powder Form: Free NMR (11) Reference example 41 RB: CH3 (positions 3 and 5) m: 2 A: -CHa- R- »: H Crystalline form: White powder Form: Free NMR (12) Reference example 42 RB: - (CHa) 3Cl (position 2) m: 1 A: -CHa- R- *: H Crystalline form: Yellow powder Form: Free NMR (13) Reference example 43 RB: - < CHa) aCl (position 2) m: 1 A: -CHa- R- »: H Crystal form: White powder Form: Free NMR (14) GUAPRP 8 Reference example 44 Rß: CH 3 (position 3) m: 1 A: -CH "- R-»: H Solvent for Rectal Crystal Acetate: Crystal Shape: Form: Free NMR (15) pale brown powder Reference example 45 RB: CaHB (position 3) m: 1 A: -CHa-R * "»: H Crystal shape: Shape: Free NMR (16) beige needles Reference example 46 RB: - (CHa) aCH3 (position 3) m: 1 A: -CHa- R- »: H P.f. 110.0-111.0 ° C Solvent for recrystallization: Eti lo-n-hexane acetate Crystalline forroa: Shape: Free pale yellow needles Reference example 47 RB: - (CHa) 3CH3 (position 3) m: 1 A: -CHa- R - »: H P.f. 110.5-111.0 ° C Solvent for recrystallization: Ethyl acetate-n-hexane Form crystal na: Shape: Free pale yellow needles Reference example 48 CH3 (item 2) m: A: -CH "- R- *: H / RB: -CH \ CH3 Pf 93.7-94.0 ° C Reagent Solvent: Ethyl-N-Acetate Acetate Crystalline Form: Pink Powder Shape: Free ? and RQ 9 Reference example 49 R ": Cl (position 3) pt: 1 A: -CHa- R-»: H Crystal form: Form: Free NMR (17) pale yw powder Reference example 50 RB: F (position 3) m: 1 A: -CHa- R- *: H Crystalline form: Shape: Free NMR (18) pale yw powder Reference example 51 RB: CH30 (position 3) m: 1 A: -CH. R- »: H Crystal shape: beige powder Shape: Free NMR (19) Reference example 52 RB: CaHß0 (position 3) m: 1 A: -CHa- R- »: H Crißtal form na: Brown powder Shape: Free NMR (20) Loe spectra of 4H-NMR (NMR (1) to NMR (20)) as described in tables 5 to 9 are the following: NMR (1) (DMS0-dw) óppm: 2.45 (3H, S), 4.95 (2H, s), 6.T1-6.95 (2H, m), 7.10-7.22 (2H, m), 7.32 (1H, t, J = 6.1Hz), 7.45 (1H, t, J = 6.4HZ), 7.77 (1H, d, J = 6.4HZ), 7.99 ( 1H, d, J = 6.3HZ) »12.60 (1H» s) NMR (2) (DMSO-d ,,,) óppro: 1.18 (3H »t» J = 7.5Hz), 2.67 (2H, q, J = 7.5HZ), 4.96 (2H »S). 6. B9 (2H, dd, J = 8, OHz.

J = 12.5HZ). 7.09-7.23 (2H, m), 7.2B-7.38 (1H, m), 7.40-7.52 (1H, ro), 7.77 (1H, d, J = 8.0HZ), 7.9B (1H, d, J = 7 BHz) »12.58 (1H, S) NMR (3) < CDC13) óppm: 1.03 (3H »t» J = 7.4Hz), 1.6-1.8 (2H, m), 2.73 (2H.t.J = 7.4Hz), 4.76 (2H »8). 6.B4 (1H.D. J = B.OHz), 7.01-7.50 (5H, m), 7.79-7.86 (2H, m). 9.6-9.8 (1H »S > NMR (4) < CDC13) óppm: 0.95 (3H.t J = 7.2Hz), 1.37-1.55 (2H, m), 1.59-1.74 (2H, m), 2.71 (2H, d, J = 7.2HZ) »4.77 (2H, 8) »6.82 (1H» d, J = 8.1HZ) »6.98-7.06 (1H» m) »7.16-7.26 (2H» m), 7.30-7.38 (1H, m) »7.41-7.50 (1H.m) 7.79-7.86 (2H.m) » 9. 78 (1H, brs) NMR (5) (CDC13) óppm: 4.76 (2H, ß) »6.95-7.11 (3H, m), 7.26-7.47 (4H.m), 7.79-7.87 (2H, m)» 9.92 (1H »br) NMR (6) (CDC13) ppm: 0.92 (3H» t, J = 6.8Hz), 1.30- 1.55 (4H »m)» 1.55-1.90 (2H, m). 2.71 (2H, t, J = 7.6Hz) »4.77 (2H, s), 6.82 (1H, d, J = B.OHz). 6.9B-7.05 (1H.m., 7.17-7.26) (2H, m) »7.31-7.3B (1H, m)» 7.42-7.50 (1H, m) »7.79-7.87 (2H» ro), 9.73 (1H, brs) NMR (7) (DMSO-d ,, ) .ppm: 5.03 (2H, s>, 6.90-7.07 (1H »m), 7.07-7.20 (2H, m>, 7.20-7.50 (2H, m), 7.45 (1H, dt, J = 1.3HZ, J = 7.3Hz), 7.77 (1H, d, J = 7.BHz) 7.99 (1H »dd, J = 0.7HZ, J = 7.7HZ)» 12.63 (1H, ß) NMR (8) (CDC13) óppm : 4.80 (2H, 8), 6.95-7.10 (2H, m), 7.23-7.49 (4H, m), 7.85 (2H, dd, J = 2.0H ?, J = 6.6Hz), 9.97 (1H, br) NMR (9) (CDC13) óppm: 1.75-2.0 (4H, m), 2.75-2.9 (4H, m), 4.74 (2H, S), 6.63 (1H, d, J = 8Hz), 6.82 (1H, d , J = BHz), 7.05-7.15 (1H, m), 7.3-7.5 (2H, m), 7.75-7.9 (2H, m), 9.73 (1H, br) NMR (10) (CDC13) óppm: 2.29 ( 3H, s), 2.32 (3H, s) » 4. 75 (2H, S). 6.70 (1H, d.J = 8Hz), 6.90 (1H, d, J = 7.5Hz) »7.05- 7.15 (1H, m), 7.3-7.5 < 2H, m) »7.75-7.9 (2H» m) »9.76 (1H» br) NMR (11) (DMS0-dw) .ppm: 2.27 (6H. ß). 4.63 (2H »8), 6.90-7.12 (3H.S). 7.29-7.40 (1H »m)» 7.42-7.52 (1H, s), 7.76 (1H »d» J = 7.8HZ), 8.02 (1H »d» J = 7.4Hz) »12.49 (1H, S) NMR (12) (CDC13) óppm: 2.32 (6H, S), 4.73 (2H, S) ), 6.61 (2H, S), 6.72 (1H, 8), 7.3-7.55 (2H, m), 7.8-7.95 (2H, m) 9.86 (1H, br) NMR (13) (CDC13) óppro: 2.18 ( 2H, tt, J = 7.0Hz, J = B.0HZ), 2.96 (2H, t, J = 7.0Hz), 3.63 (2H, t, J = 8.0Hz), 4.80 (2H, 8), 6.87 (1H, d, J = 8.5HZ) » 7.04 (1H »t» J = 7.2Hz) »7.15-7.29 (2H, m), 7.34 (1H, t» J = 8.9HZ) »7.43 (1H» t, J = 8.0Hz) »7.79-7.87 (2H »M). 9.73 (1H »br) NMR (14) (CDC13) óppm: 3.22 (2H» t »J = 7.0Hz), 3.82 (2H, t, J = 7.0HZ). 4.81 (2H. 8), 6.86 (1H, d, J = B.2Hz), 7.05 (1H, t, J = 7.2HZ), 7.15-7.52 (4H, ra), 7.81 (2H, t, J = 8.4 HZ), 9.78 (1H, br) NMR (15) (CDC13) .ppm: 2.37 (3H.s) »4.74 (2H» ß) »6.74-6.85 (2H» m). 6.85 (1H. D »J = 7.3Hz). 7.17-7.30 (1H »m). 7.30-7.40 (1H »m)» 7.40-7.54 (1H »m), 7.77-7.90 (2H, m). 9. B8 (1H. Brs) NMR (16) (CDC13) óppm: 1.25 (3H.t »J = 7.6HZ), 2.65 (2H.q» J = 7.6HZ). 4.74 (2H, 8). 6.74-6.84 (2H, m), 6.8B-6.95 (1H, m), 7.21-7.50 (3H, m), 7.79-7.86 (2H, m), 9.94 (1H, b) NMR (17) (CDCl 3 ) éppm: 4.73 (2H, 8). 6.75-6.84 (1H »m). 6.84-6.9B (1H, m), 7.01-7.OB, (1H.m) »7.21-7.46 (3H, m), 7.B2 (2H.t» J = B.4HZ). 10.09 (1H »br) NMR (18) (DMS0-d" ¥) óppm: 4.94 (2H, s) »6.75-6.92 (3H» m). 7.27-7.47 (3H, m). 7.75 (1H »d, J = 8.0HZ)» 7.97 (1H. d, J = B.OHZ) NMR (19) (CDC13) .ppm: 3.81 (3H, s). 4.73 (2H, s) »6.53-6.65 (3H, m), 7.20-7.51 (3H» m), 7.79-7.86 (2H, m), 9.89 (1H. Br) NMR (20) (CDC13) óppm: 1.43 OH »t» J = 7.0Hz) »4.04 (2H» q, J = 7.0HZ). 4.73 (2H, S), 6.50-6.66 OH, m), 7.18-7.51 OH, m), 7.78-7.90 (2H, m), 9.87 (1H, br) Using the appropriate starting compounds, the coroo compounds are free in table 10 they are obtained in the same way as reference example 3.

TABLE 10 Reference example 53 RB: CaHβO (position 2) m: i A: -CH-: H R 4": CH30 Cri ßtal form: Form: Free NMR (l) powder pale yellow Reference example 54 Cha (position 3) ro: i -CH. / RB: -OCH \ CH- R-: H CH30 Crißtaline form: White powder Form: Free NMR (2) Reference example 55 RB: CF3CHaO (position 3) m: i A: -CH. R- *: H R4B: CH30 Crystalline form: White powder Shape: Free NMR (3) Reference example 56 RB: CF3 (position 2) m: l A: -CH. R - »: H R4": CH, 0 Crystalline form: Form: Free NMR (4) white powder Reference example 57 RB: CH30 (position 3) m: l A: -CHa- R "*: H R4ß»: CH30 Crystalline Forroa: White powder Form: Free NMR (5) The spectrum of 4H-NMR (NMR (1) to NMR (17)) as described in tables 1 to 4 are as follows: NMR (1) (CDC13) ppp: 1.5B OH »t, J = 7.0Hz). 3.61 (2H »d» J = 22.BHZ), 3.76 OH. S), 3.82 OH. S), 4.25 (2H., J = 7.0HZ), 4.85 (2H.s). 7.04 (1H. d, J =? 6Hz). 7.33 (1H.

J = 7.5HZ). 7.46 (1H.t. J = 7.5Hz), 7.60-7.65 (2H, m), 7.79-7.86 (2H, m), 10.28 (1H, br) NMR (2) (CDC13) éppm: 1.47 (6H, d, J = 6.0Hz) »3.74 OH» s) »3.79 OH» s) »3.85 (2H» d J = 20.2HZ), 4.69 (1H sept, J = 6.0Hz), 4.79 (2H.S) »6.51-6.56 (2H» m) »7.36 (1H, t, J = 7.0Hz), 7.49 (1H , t, J = 7.0Hz), 7.79-7.8B OH, m), 9.98 (1H, br) NMR O) (CDC13) éppm: 3.76 (2H »d, J = 21.3Hz), 3.75 OH S ) . 3.80 OH »S)» 4.40 (2H., J = 7.9Hz), 4.79 (2H, 8), 6. 44 (1H, d, J = 2.2HZ), 6.60 (1H, dd, J = 2.2HZ, J = 8.BHz), 7.34 < 1H, dt, J = 1.3HZ, J = 7.3Hz), 7.45 (1H, dt, J = 1.3HZ, J = 7.3Hz), 7. 75-7.86 OH, m) NMR (4) (DMS0-d? V.) Éppm: 3.62 OH, S), 3.68 OH, S), 3.93 (2H, d, J = 22.5HZ> 5.27 < 2H »8), 7.3-7.55 OH» m), 7.78 (1H, d.J = BHz), 7.98 (1H, d, J = 8Hz) »B.2-B.35 (2H, m), 12.6B ( lH. br) NMR (5) (CDC13) éppm: 3.74 OH, S), 3.80 OH. s), 3.81 (2H, d.J = 21HZ), 3.95 OH, S), 4.81 (2H, ß), 6.5-6.65 (2H, m), 7.25-7.55 (2H, m), 7.75-7.95 OH, m), 10.01 (1H.s) Using the appropriate starting compounds, the compounds as listed in tables 11-13 are obtained in the same manner as reference example 4.

CUAPRQ 11 Reference example 58 RB: H m: i A: -CH _.- R - *: H X: Br Crißtaline form: Form: Free NMR (1) pale yellow powder Reference example 59 RB: CH (position 2) m: i A: -CHa- R - »: H X: C1 Crystal shape: beige powder Shape: Free NMR (2) Reference example 60 RB: CaHß (position 2) ra: l A: -CHa- R - »: H X: C1 Crystal form: beige powder Shape: Free RMN O) Reference example 61 RB: - (CHa) 3CH3 (position 2) m: i A: -CHa- R - ": H X: C1 Crystalline form: White powder Form: Free NMR (4) TABLE 12 Reference example 62 Rß: Cl (position 2) m: i A: -CHa- R - *: H X: C1 P.f. 199-201 ° C Solvent for recrystallization: 1,2-Dichloroethane-n-hexane Crystalline form: White powder Form: Free Reference example 63 RB: - (CHa) aCl (position 2) ro: i A: -CHa- R- ": H X: Br Crystal crystalline: Form: Free NMR (5) powder pale yellow Reference example 64 RB: - (CHa) 3Cl (position 2) m: i A: -CHa- R- »: H X: Br Crystalline form: Form: Free NMR (6) powder pale yellow Reference example 65 RB: - (CHa) _ «Cl (position 2) p»: i A: -CHa-R "*: HX: C1 Pf 146.5-149 ° C Solvent for recrystallization: Acetate of et lo-n -he? ano Crystal shape: White powder Form: Free TABLE 13 Reference example 66 RB: - (CH-g) sgCO-gC-gHβ (position 2) m: i A: -CHa- R - ": H?: Cl Pf 131.0-133.0 ° C Solvent for recrystallization: Acetate eti lo-n-hexane Crystal form: White powder Shape: Free Reference example 67 RB: - (CHa) aCOaCH3 (position 2) m: i A: -CH, R?,: H X: C1 Crystalline form: White powder Form: Free NMR (7) Reference example 68 RB: OCOCH3 (position 2) ro: l A: -CH "- -CHaCHCHaOCOCH, R -": H X: C1 Crystalline form: White powder Forraa: Free NMR (8) Reference example 69 P.f. 206-208 ° C Solvent for recrystallization: Dimeti lformamide-ethanol Crystal form: White powder Form: Free Loe the spectra of 4H-NMR (NMR (1) to NMR (8)) as described in tables 11 to 13 are the following: NMR (1) (CDC13) óppm: 4.41 (2H, S), 4.84 (2H. 8), 7.07 (2H.D. J = 9.0HZ). 7.36 (1H, t, J = 7.3HZ), 7.45 (1H.t.J = 7.3HZ). 7.8B (2H, t, J = B.5Hz). 8.03 (2H, d, J = 9.0Hz) NMR (2) (DMSO-dw.) Óppm: 2.30 OH, S), 5.11 (4H, S), 7.00-7.10 (1H, m), 7.28-7.40 (1H , ro), 7.40-7.55 (1H, m), 7.70-7.93 OH, m), 7.98 (1H.D. J = 7.1Hz), 12.68 (1H.s) NMR) (DMSO-d,.,.) óppm: 1.21 OH. t, J = 7.4Hz), 2.72 (2H., J = 7.4HZ), 5.12.5.13 (4H, every 8). 7.02 (1H, you.

J = B.6HZ). 7.31 (1H dt J = 1.2Hz J = 7.3Hz) 7.45 (1H dt.

J = 1.3HZ. J = 7.3HZ). 7.75-7.92 OH. ro), 7.95-8.00 (1H, m), 12.68 (1H, brs) NMR (4) (CDC13) éppm: 0.97 OH, t, J = 7.2Hz), 1.39-1.59 (2H, m), 1.59-1.86 (2H, m), 2.77 (2H.t, J = 7.6Hz), 4.67 (2H, ß>, 4.86 (2H, 8), 6.89 (1H, d.J = 8.6Hz), 7.32-7.39 (1H, m), 7.43-7.51 (1H.m), 7.79-7.87 (4H, m) 9.10-10.01 (1H.brs) NMR (5) (CDC13) óppm: 3.16 (2H, t.J = 6.9Hz), 3.92 (2H, t »J = 6.9HZ). 4.B3 (2H »8)» 5.13 (2H, S), 7.07 (1H »d» J = 9.4H?), 7.31 (1H »t, J = 6.9Hz)» 7.45 (1H.t, J = 8.3 Hz), 7.76 (1H »d» J = 7.9Hz), 7.82-8.06 OH, m) NMR (6) (CDCl ,,,) éppm: 2.17 (2H, tt, J = 6.1Hz, J = 7.5HZ), 3.03 (2H.t.J = 7.5Hz), 3.64 (2H »t» J = 6.1Hz), 4.40 (2H. 8), 4.8B (2H »S)» 6.95 (1H. di J = 9.3Hz), 7.35 (1H »t.J = 6.8HZ)» 7.47 (1H »t» J = 9.4HZ), 7.80 -7.94 (4H, m), 9.68 (1H, br) NMR (7) (CDCl 3) éppm: 2.75 (2H, t, J = 7.0HZ). 3.13 (2H.t, J = 7.0Hz). 3.74 OH »s)» 4.65 (2H »8)» 4.89 (2H.), 6.89 (1H, d, J = 8.4Hz), 7.30-7.37 (1H »m), 7.41-7.48 (1H.m), 7.78-7.B9 (4H »m)» 9.00-11.30 (1H, brs) NMR (8) (CDC13) óppm: 2.00 OH »s)» 2.09 OH, s), 3. 08 (1H, dd, J = 8HZ, J = 14Hz), 3.23 (1H, dd, J = 6Hz, J = 14Hz), 4.14 (1H, dd, J = 5.5HZ, J = 12Hz), 4.33 (1H, dd, J = 3Hz, J = 12Hz), 4.64 (2H, S), 4.5 (2H, S), 5.49 (1H, m), 6.90 (1H, d, J = 9Hz), 7.3-8.0 (6H, m ), B.79 (1H, br) Using the appropriate starting compounds, the compounds as set forth in Tables 14-22 are obtained in the same manner as Reference Example 5 or 6.

TABLE 14 Reference Example 70 RB m: i A: -CH -.- R - »: H Crystal Shape i na: Pale yellow powder Shape: free NMR (l) Reference Example 71 Rß: CH 3 (2-position) m: i A: -CHa- R - »: H Inca Crystal Shape: Pale yellow powder Shape: free NMR (2) Reference Example 72 RB: CaHß (2-position) m: i A: -CHa- R - »: H Shape Crystal ina: White powder Form: free RM O) Reference Example 73 CH3 (3-position) m: i A: -CH "- R-": H RB: / -CH \ CH, Crystal Form ina: White powder Form: free NMR (4) CUAPRQ 5 Reference Example 74 Rß: - (CHa) 3CH3 (2-position) ro: i A: -CH. RH Forroa Cristal ina: Pale yellow powder Form: free NMR (5) Reference Example 75 Rß: Cl (2-position) m: i A ^ CH -.- R - *: H Forroa Crystal i na: ol or pale yellow Shape: free NMR (6) Reference Example 76 RB: F (2-position) m: 1 A: -CH, .- R < *: H Shape Crystal i na: White powder Shape: free NMR (7) Reference Example 77 RB: - (CHa) to Cl (2-position) m: 1 A: -CHa- R- »: H Form Crystal ina: White powder Form: free NMR (B) Reference Example 78 Rß :-( CHa) ^ Cl (2 position) m: 1 A: -CHa- R- *: H Form Crystal ina: White needles Shape: free NMR (9) CUAPRp 16 Reference Example 79 RB :-( CHa) aCOaCaHß (2-position) m: i A: -CHa- R - »: H Crißtal Form i na: White powder Form: free RM (10) Reference Example BO Rß: OCOCH- ,, (2-position) m: i -CHaC IHCHaOCOCH3 A: -CHa-R **: H Form Crystal ina: White polymer Form: free RM (11) Reference Example 81 R ": - (CH2) 2-N ^ O <2-Position) m: i A: -CHa- R- *: H Form Crystal ina: White powder Form: free NMR (12) Reference Example 82 Rß: < 2-position) m: i A: -CHa- R - *: H Form Crystal ina: Amorphous pale yellow Form: free NMR (13) TABLE 17 Reference Example 83 Rß- (CHa) 3N (CaHβ) a (2-position) m: l A: -CHa- R - *: H Form Crystal ina: White polymer Form: free NMR (14) Reference Example 84 R ": (2-position) ro: l A: -CHa- R-»: H Form Crystal ina.'Polvo blanco Form: free NMR (15) Reference Example 85 - (fCCHH2 ^) 3-N N'CH3 (2-position) m: i A: -CHa- R *: H Shape Crystal i na: White powder Shape: free NMR (16) Reference Example B6 A: -CHa- R - »: H M.p. 153-155 ° C Solvent for recrystallization: Ethyl acetate Forma Cristal ina: ol vo blanco Form: free BOX IB Reference Example 87 RB: - (CH2) 3-N? ~ N- (CH2) 2OH < 2-position) m: l A: -CHa- R - »: H Form Crißtal ina: White amorphous Form: free NMR (17) Reference Example 8B (2-position) m: i A: -CHa- R- »: H Form Crystal ina: White amorphous Form: free NMR (IB) Reference Example 89 (2-position) m: l A: -CHa- R - »: H Form Crystal ina: Colorless Aroorph Forroa: free NMR (19) Reference Example 90 Rß: (2-polarization) ro: i A: -CHa-R * »: H Form Crystal ina: amorphous colorless Form: free RM (20) TABLE 19 Reference Example 91 RB * - (CH2) 3-N ^ -1 ^ N-CH3 (2-position) m: i A: -CH% - R - *: H Form Crystal ina: Yellow amorphous Form: free RM (21) Reference Example 92 m: i A: -CHa- R - »: H Shape Crystal i na: Colorless amorphous Shape: free RM (22) Reference Example 93) Form Crystal ina: Amorphous yellow Form: free RM (23) Reference Example 94 R ": - (CH2) 3-l { ^ N-CH, < 2-P" > ..c.6n > m: i A: -CHa- R **: H Form Crystal ina: Yellow amorphous Form: free RM (24) TABLE 20 Reference Example 95 RB: _ (CH2) 4-N > < 2- ~ ÍCIÓ "> m: l A: -CH ,, - R -»: H Shape Crystal i na: ol vo white Shape: free RMN (25) Reference Example 96 - _ (rCcHH2,)? 4 .-- NN_N-CH3 (2-position) ro: 1 A: -CH.K- R - »: H Form Crystal ina: Pale yellow powder Form: free NMR (26) Reference Example 97 RB * - (CH,). NíC.H ..). (2-position) m: i A: -CH -.- R "': H Crißtal form ina: Amorphous white Forroa: free NMR (27) Reference Example 28 RB: sru. ^ 3 (2-polarition) - (CHA? O m: i A: -CHa- R - »: H Forroa Crystal ina: White amorphous Form: free NMR (28) TABLE 21 Reference Example 99 CH, / (2-position) m: i A: -CH _.- R- ": H Crißtal form i na: white amorphous Form: free RM (29) Reference Example 100 icion) Forroa Cristal ina: White amorphous Form: free RMNOO) Reference Example 101 Rß: (2-position) m: i A: -CH, .- R - *: H Form Crystal ina: Yellow amorphous Form: free RM Ol) Reference Example 102 Rß: -C00CH3 (2-position) m: l A: -CHa- R - »: H Form Crystal ina: Amorphous pale yellow Form: free RM (32) TABLE 22 Reference Example 103 Rß "- (CHa) aCONH- (combined in laß positions 2 and 3) m: 2 A: -CHa- R - *: H Form Crystal ina: Yellow amorphous Form: free RMN03) Reference Example 104 Rß and A combine to form: m: 1 R "»: H Crystal Form i na: White polymer: c Shape: free RM (35) The H-NMR spectra (NMR (1) to NMR (35)) as described in tables 14-22 are the following: NMR (1) (CDCl3) óppm: 4.37 (1H, d, J = 24 Hz) , 4.77 (2H, s) 6.91 (2H, d, J = 8.8 Hz), 7.16 (1H, t J = 7.3 Hz), 7.32 (1H, t, J = 7.3 Hz), 7.38-7.B2 (17H , m), 7.89 (2H, d, J = 8.B Hz) NMR (2) (CDCl 3) óppm: 2.35 OH, s), 4.41 (1H, brs). 4. 70 (2H, S), 6.70 (1H, d.J = S.2 Hz) »7.20-8.00 (21H, m) NMR O) (DMSO-d, v.) Éppm: 1.19 OH» t »J = 7.4 Hz). 2.69 (2H. Q, J = 7.4 HZ) »4.43 (1H, d.J = 2.5 Hz)» 5.00 (2H, s). 6.83 (1H. D »J = 8.9 HZ). 7.25-7.38 (1H, ro). 7.38-7.85 (9H, m). 7.98 (1H, d, J = 7.1 HZ) »12.65 (1H» brs) NMR (4) (CDCl 3) óppm: 1.32 (6H »d» J = 7 Hz) »3.42 (1H» sept »J = 7 Hz) . 4.2-4.6 (1H »m)» 4.73 (2H, S), 7.25-8.0 (21H.m), 10.01 (1H, br) NMR (5) (CDCl3) éppm: 0.B6 OH. t. J = 7.2 Hz)), 1.31-1.51 (2H, m), 1.51-1.72 (2H.m). 2.65-2.72 (2H, m) 3.76 OH. s) 4.34 (1H, br-d, J = 24.7 HZ). 4.66 (2H, s). 5.98 (1 H. br-s). 6.66 (1H, d, J = 8.3 HZ) »6.99-7.10 (1H, m)» 7.19-7.31 < 1H, m), 7.3B-7.60 (1H, m), 7.60-7.87 (BH, m) NMR (6) (DMSO-d ,, :) .ppm: 4.52 (1H, d, J = 23 Hz), 5.12 (2H, 8), 7.07 (1H, td, J = 7.6 Hz, J = 1.0 Hz), 7.45 B1H, td, J = 6 HZ »J = 1.4 HZ), 7.45-8.15 (19H, m), 12.6B (1 H, s) NMR (7) (CDCl 3) óppm: 4.34 (1 H, d »J = 22 Hz). 4.79 (2H »s») »6.97 (1H, t, J = 8.4 Hz). 7.30-7.38 (2H.m). 7.38-7.92 (19H.m). 9.97 B1H, br) NMR (B) (DMSO-d,.) Óppm: 3.16 (2H.t, J = 7.0 Hz), 3.92 (2H, t, J = 7.0 HZ), 4.83 (2H, e) 5.13 ( 2H, s), 7.07 (1H, d, J = 9.4 HZ), 7.34 (1H, t, J = 6.5 Hz), 7.44 (1H, t, J = 6.5 Hz), 7.60-8.12 (19H, m) , 12.70 (1H, br) NMR (9) (CDCl 3) óppm: 1.67-1.90 (4H, m), 2.64-2.82 (2H, m), 3.6B (1H, bt, J = 6.0 Hz), 5.19 (2H , 8), 6.12 (2H, d, J = 14.0 Hz), 7.10 (1H, d, J = 10.0 Hz), 7.29-7.41 (1H, m) 7.41- 7.52 (1H, m), 7.69-7.95 (17H , m), 7.95-B.06 (2H, m), 12.74 (1H, NMR (10) (DMSO-d "..) óppm: 1.10 OH, t» J = 7.1 Hz) »2.62 (2H, t »J = 8.0 HZ)» 2.90 (2H.t »J = 8.0 Hz)» 4.00 (2H »q, J = 7.1 HZ), 4.33 (1H. D »J = 30.0 Hz)» 5.01 (2H »8). 6.B2 (1H, d, J = 14.0 Hz), 7.29-7.38 (1H, m), 7.40-7.50 (1H, m), 7.50-7.80 (18H, m) »8.00-8.02 (1H» d, J = 4.0 Hz). 12.61 (1H »brs) NMR (11) (CDCl3) óppm: 2.00 OH, 8), 2.05 OH, s), 3.0-3.15 (2H, m), 4.0-4.35 (2H, m), 4.93, 5.05 (2H , ABq, J = 16 Hz), 5.40 (1H, m), 6.1-6.6 B2H, b), 6.9B (1H, d, J = 8 Hz), 7.2-8.5 (2H, m) NMR (12) ( CDCl3) éppm: 2.54-2.78 (6H, m), 2.78-3.12 (2H, m), 3.69-3.90 (4H, m), 4.36 (1H, d, J = 24.0 Hz), 6.77 (1H, d, J = 8.5 HZ). 7.27-7.8B (21H. M) NMR (13) (CDCl3) .ppm: 2.27 OH. 8), 2.32-2.76 (10H, m), 2.76-3.05 (2H, m), 4.36 (1H, d.J = 26.0 Hz), 4.71 (2H, 8), 6.77 (1H, d, J = 8.3 Hz ) »7.27-8.02 (21H. M) NMR (14) (CDCl) óppm: 1.00 (6H» t »J = 7.1 Hz), 1.80- 2.00 (2H, rn), 2.4B-2.62 (6H, m), 2.7B (2H, t, 6.2 Hz), 4.37 (1H, d, J = 24.2 Hz), 4.76 (2H, 8), 6.80 (1H, d, J = 6.8 Hz) »7.32 (1H, t» J = 7.3 Hz), 7.39-7.93 (20H, m) NMR (15) (CDCl3) óppm: 1.72-2.05 (2H, m), 2.30-2.57 84H, m) 2.70-2.89 (2H, m), 3.54-3.83 ( 4H, ro) 4.37 81H, d, J = 28.0 Hz), 4.74 < 2H, S), 6.77 (1H, d, J = B.3 Hz), 7.33 (1H, t, J = 7.3 HZ), 7.40-7.96 (20H, m) NMR (16) (CDCl3) óppm: 1.81- 2.01 (2H, m), 2.22 OH, S), 2.28-2.68 (10H, m), 2.79 (2H, t.J = 6.9 Hz), 4.37 (1H »d, J = 24.0 HZ)» 4.76 (2H, s). 6.79 (1H »d.J = 8.4 Hz), 7.33 (1H, t.J = 8.8 Hz)» 7.40-7.64 (10H »m), 7.64-7.95 810H. m) NMR (17) (CDCl 3) óppm: 1.7-3.3 (16H, m). 3.59 (2H »m). 4.B1 (2H »s). 6.82 (1H, d »J = 8.5 Hz), 7.2-BO (21H» m) NMR (18) (CDCl3) éppm: 1.4-1.7 (2H »m)» 1.75-2.0 (4H, m), 2.2-2.4 (2H, m), 2.4-2.6 (2H, m), 2.65-2.9 (4H, m), 3.65 (1H, m) 4.1-4.8 (2H, br), 4.68 (2H, s), 6.70 (1H, d.J = 8.5 Hz), 7.2-7.9 (21H, m) NMR (19) (CDCl 3). : 1.41-2.31 (9H,,) »2.24 (6H, S)» 2.46 (2H »t.J = 7.5 Hz), 2.77 (2H, t, J = 7.5 Hz). 2.93-3.12 (2H.m), 4.23-4.60 81H, br), 4.73 (2H, s), 6.75 (1H, d, J = 8.5 Hz), 7.23-7.92 (21H, m) NMR (20) (CDCl3 ) óppm: 1.48.2.28 (9H, ro) 2.36-2.61 (6H, m), 2.77 (2H, t, J = 7.5 Hz), 2.92-3.13 (2H, m), 3.65 (4H, t, J = 4.5 Hz), 4.19-4.5B (1H, m), 4.70 (2H, s), 6.71 (1H, d, J = 8.5 Hz), 7.02-7.94 (21H, m) NMR (21) (CDCl3) óppm: 1.41 -2.03 (8H, m), 2.05-2.80 (13H, m), 2.77 (2H, t »J = 7.6 Hz), 2.8B-3.07 (2H» m). 4.73 (2H, S). (1H, d »J = 8.5 Hz). 7.32 (1H »t, J = 6.4 Hz), 7.40-7.90 (29H, m) NMR (22) (CDCl3) óppm: 1.62-2.23 (8H, m), 2.29-2.97 (12H, m), 3.48-3.93 OH, m), 4.22-4.57 (1H, br), 4.69 (2H, s) »6.70 (1H, d, J = B.5 Hz), 7.22-B.04 (21H.m) NMR (23) ( CDCl. ,,) óppm: 1.69-2.00 (H. m), 2.00-2.62 (16H »m), 2.62-2. B7 (4H »m)» 3.50-3.92 OH, m), 4.37 (1H, d, J = 26.B HZ), 4.75 (2H, S), 6.77 (1H, d, J = B.4 Hz), 7.2B-7.92 (2H, m) NMR (24) (CDCl3) éppm: 1.82-2.22 (4H, m) »2.50 OH» ß). 2.54-3.12 (12H.m). 4.73 (2H »S)» 6.71 (1H. d, J = 8.6 Hz), 7.29-7.B8 (21H, m) NMR (25) (CDCl3) .ppm: 1.55-1.85 (4H, m), 2.3-2.5 (6H, III), 2.7-2.9 82H, m), 3.67 (4H, t, J = 4.5 Hz), 4.25-4.55 82H, m), 4.76 (2H, s), 6.78 (1H.D. J = 8.5 Hz) »7.25-7.95 (21H, m) NMR (26) (DMSO-dβ) éppm: 1.37-1.70 (4H.m), 2.08 OH, 3), 2.14-2.43 (10H, m), 2.60-2.77 ( 2H, m), 4.33 (1H, d.J = 26.0 Hz). 4.96 (2H »S)» 6.B0 81H »d» J = 10.0 Hz) »7.27-7.38 (1H» m), 7.38-7.80 (19H.m). 7.90-8.03 (1H, m) NMR (27) (CDCl 3) óppm: 1.00 OH »t» J = 7.0 Hz) »1.01 OH »t» J = 7.0 HZ) »2.68 (2H, t J = 6.9 Hz)» 3.12-3.27 (4H, m), 3.35-3.46 (2H, m), 4.25-4.60 (1H, m), 4.96 (2H, S), 6.67 (1H. D, J = 8.5 HZ), 7.23-7.27 (1H, m), 7.29-7.57 (10H, ID), 7.68-7.81 (9H, m), 7.92 (1H, brs ), 11.97 (1H, brs) NMR (28) (CDCl 3) óppm: 2.14-2.39 (4H.m), 2.22 OH, s), 2.74 (2H, t, J = 6.3 Hz), 2.98-3.20 (2H. m). 3.29-3.48 (2H, m) »3.63-3.80 (2H» m). 4.17-4.54 (1H.m) »4.73 (2H, 8). 6.67 (1H. D »J = 8.6 HZ)» 7.26-7.33 (1H, M) »7.33-7.62 (10H, m), 7.62-7.85 (9H, m), 7.90 (1H, brs) NMR (29) ( CDCl3) éppm: 0.89 OH, t, J = 7.1 Hz), 1.00 OH, t, J = 7.1 HZ), 2.35-4.47 (15H, ro), 4.73 (2H, S), 6.67-6.74 (1H, m), 7.20-7.61 (11H, m), 7.61-7.85 (9H, m), 7.85-7.93 (1H.m) NMR (30) (CDCl) .ppm: 1.01-1.47 (2H, m) »1.65-1.90 82H» m). 2.29 OH, s), 2.35-2.65 (11H, m), 2.65-2.91 (2H, m), 3.03-3.22 (2H, ra), 3.73-3.91 (1H, m), 4.22-4.54 (1H, m) 4.73 (2H, S). 4.75-4.92 (1H, m), 6.69 (1H, d, J = 8.6 Hz) »7.22-7.63 (11H, m), 7.63-7.88 (9H, m >;, 7.88-8.00 (1H, m)) NMR (31) (CDCl 3) óppm: 2.18-3.50 (20H, m), 3.50-3.71 (1H, m), 3.71-3.95 (1H, m), 4.20-4.82 (4H, m), 6.65-674 (1H, m), 7.20-7.63 (12H, m), 7.63-7.B6 (9H, m), 7.86-7.98 (1H, m) NMR (32) (CDCl3) ppp: 4.09 OH, 8), 4.42 (1H, d, J = 22.9 HZ), 4.85 (2H, S), 6.93 (1H. d, J = 8.7 Hz) »7.00-7.18 (1H» m) »7.18- 7.9B (1BH »m), B.19 (1H» dd »J = 2.2 Hz, J = 8.7), 8.60 (1H, d, J = 2.2 HZ), 11.50 (1H, р) NMR (33) (CDCl3 ) éppm: 2.73 (2H, t, J = 7.4 Hz), 3.37 (2H, t, J = 7.4 HZ), 4.06 (1H, d.J = 20.6 Hz) »4.84 (2H» S) »6.77 (1H» d.J = 8.6 Hz), 7.28-7.77 (20H.m) »10.85 (1H.br). 12.16 (1H, br) NMR (35) (DMSO-d ^ éppm: 2.03-2.46 (2H, m), 2.67-3.06 (2H, ro), 4.28-4.52 (1H, m), 4.94-5.24 (1H, m), 6. B3-B .11 (22H.) Using the appropriate starting compounds, the compounds as listed in tables 23-31 are obtained in the same manner as reference example 2.

TABLE 23 Reference Example 105 R4 »H R2: H R - ** HR": H m: 1 Crystal Form i na: White polymer Form: free NMR (l) The spectrum of 4 H-NMR (NMR (1)) as described in Table 23 are the following: NMR (!) (CDCl ,,,) óppm: 4.81 (2H, ß), 7.05 (1H, d, J = 3.5 Hz), 7.25-7.35 (2H, m), 7.45 -7.65 (2H, tu), 7.50 (1H, d, J = 3.5 Hz), 10.00 (1H, s), 10.06 (1H, brs) TABLE 24 Reference Example 106 R4t H R2: H R - * «H RB: H m: 1 A: - (CHa) 3- Crystal Shape i: Yellow particles Shape: free NMR (l) Reference Example 107 Crystal Form na: Yellow particles Shape: free NMR (2) Reference Example 108 R4 'H R2: H R- »: H RB: CH3 (positions 2 and 6) m: 2 A: -CHa- Crystal Form i na: ol vo yellow Shape: free RMNO) TABLE 25 Reference Example 109 R4 / "^ RB: CHa iCaH-g); * (2-p? 8iCln) R2 ^ fí- *: H ro: 1 A: -CHa- Crystal Shape i na: White pol. Shape: free NMR (4) Reference Example 110) Crystal Shape i na: Yellow powder Shape: free NMR (5) Reference Example 111) Crystal Form na: Brown powder Form: HCl NMR (6) Reference Example 112 Crißtal form ina: White powder Form: 2HC1 NMR (7) TABLE 26 Reference Example 113 Form Crystal ina: White powder Form: free NMR (8) Reference Example 114 R4 / ^ RB: - (CH2) 3; f ^ _N "CH3 (2-position) R2"- ^ R - *: H m: 1 A: -CH -, - Form Crystal ina: Particles yellow Shape: free NMR (9) pale Reference Example 115 R4 / ^ RB: -CHaN (CaHβ) a (2-position) R2 ^ R - »: H m: 1 A: - (CHa) β- Forroa Crystal ina: Yellow oil Shape: free NMR (IO) ) Reference Example 116 Form Crystal ina: Yellow amorphous Form: free NMR (ll) 1B1 CVA R 27 Reference Example 117 Form Crißtal ina: Particulae yellow Form: free NMR (12) Reference Example 118 R4 / ^ RB: - (CH2) 3-N ~ V-N O (2-position) R2 HX? R - »: H m: 1 A: - CH-. - Form Crystal ina: Yellow powder Form: 2HCl NMR (13) Reference Exercise 119 R * / ^ RB: - (CH2) 3 ~ N ^ -N (C2H5) 2 (2-po8Ition) R2 ^^ R - »: H m: 1 A: -CH_ ...- Form Crystal ina: Particles yellow Shape: 2HCl NMR (14) Reference Exercise 120 Form Crystal ina: ol vo yellow Shape: free NMR (15) TABLE 2B Reference Example 121 R4: CH3 R2: H R- *: H Rß: H m: 1 A: -CH. ^ - Form Crystal ina: Powdered coffee pale Shape: free NMR (16) Reference Example 122 R4: (CH3) 3C- R2: H R- *: H RB: H m: 1 A: -CH,? - Form Crystal ina: White pol v. Shape: free NMR (17) Reference Example 123 R4 '. RB: H -O R2: H R- »: H m: 1 A: -CH, Crystal Form i na: Yellow particles Shape: free NMR (IB) Reference Exercise 124 (2-position) R ** »: H m: 1 A: -CH." - Form Cristal ina: Oil love shape Form: free RM (19) pal gone 1B3 CUA RQ Z? Reference Example 125 R- *: H m: l A: -CH -.- Form Crystal ina: Amorphous yellow Forroa: free NMR (20) Reference Example 126 R4 / ^ RB: - (CH2) 3-N. JL "" "? (2-position) R- »: H m: 1 A: -CH _.- Form Crystal ina: Yellow amorphous Form: free NMR (21) Reference Example 127 .z-position) R **: H m: 1 A: -CHa- Form Crystal ina: Amorphous yellow Form: free NMR (22) Ej (2-position) R- *: H m: 1 A: -CH ..- Form Crystal ina: Amorphous love Form: free NMR (23)? UAPRP -SQ Example R4 (2-position) R2 1 A: -CH.?.- Crystal form ina: Amorphous yellow Form: free NMR (24) Ex Crystal Form i na: Amorphous yellow Shape: free NMR (25) pale Reference Example 131 Crystal form ina: Amorphous yellow Form: free NMR (26) Reference Example 132 R4 (2-position) R2 A: -CHa- Form Crystal ina: Amorphous yellow Form: free NMR (27) TABLE 31 Reference Example 133 H m: 1 A: -CHa- Crystal Shape na: Yellow Aroorfa Shape: free RM (28) Reference Example 134 CH3 O-position) R "*: H m: 1 A: -CHa- Form Crißtal ina: Colorless amorphous Form: free RM (29) Reference Example 135 R ": R-": H m: 1 Form Crystal ina: White oil Form: free RMNOO) The spectra of - "- H-NMR (1) to NMR (30)) as described in tables 24-31 are as follows: NMR (1) (DMSO-d, r.) Opp: 2.08 (2H, q , J = 6.6 Hz), 2.62 (2H, T, J = -7.2 Hz), 4.13 (2H, t, J = 4.1 Hz), 7.10 (2H »d» J = 8.6 m HZ). 7.19 (1H. J = 3.6 Hz) 7.45 (1H, d »J = 3.6 Hz)» 7.85 (2H »d» J = 8.6 HZ) »9.86 (1H) s, 12.13 (1H» S) NMR (2) (DMS0 -dw) épp: 5.07 (2H »s)» 7.19 (2H, d.

J = 8.7 HZ), 7.27-7.40 (1H, m), 7.40-7.56 (1H, m), 7.77 (1H, d »J = 7.5 HZ), 7.90 (2H, d, J = 8.8 Hz). 7.98 (1H, d, J = 7.1 Hz), 9.89 (1H.s) »12.1-13.0 (1H, br) NMR O) (CDCl3) ppm: 2.38 (6H» S> 4.57 (2H »S), 7.06 (1H, d »J = 3.6 HZ), 7.51 (1H, d» J = 3.6 Hz), 7.61 (2H, S), 9.92 (1H »S)» 10.10 (1H.brs) NMR (4) (CDCl3 ) óppm: 1.13 (6H »t, J = 7.1 Hz), 2.93 (4H, q, J = 7.1 HZ)» 3.79 (2H.S), 5.01 (2H.S), 7.08 (1H »d.J = 8.2 HZ) »7.23-7.35 (1H» m) 7.35-7.45 (1H.m) »7.74-7.87 (4H» m) 9.92 (1H, s) »10.71 (1H» s) NMR (5) (CDCl3) óppm: 2.33 OH »s), 2.42-2.88 (8H, ra), 3.71 (2H, S), 4.92 (2H, s). 7.02 (1H »d, J = 8.2 Hz), 7.27-7.40 (1H, m), 7.40-7.59 (1H, m), 7.67-7.93 (1H» m), 9.93 (1H »s) NMR (6) ( CDCl3) .ppm: 1.29 (6H »t» J = 7.1 Hz) »2.98-3.48 (8H.m). 5.20 (2H. S) »7.22 (1H» d »J = 9.0 Hz)» 7.35 (1H »d» J = 7.6 HZ), 7.49 (1H, d, J = 9.0 Hz), 7.B0 (1H, d , J = 7.8 Hz), 7. B5-7.98 (2H, m), 8.01 (1H, d, J = 7.4 Hz), 9.91 (1H, s), 10.36 (1H, br), 12. B4 (1H, br) NMR (7) (CDCl3) óppm: 2.86 OH, S), 3.14-4.00 (12H.m.> 5.21 (2H.s) »7.22 (1H, d.J = 7.8 Hz), 7.35 (1H.t, J = 7.6 Hz), 7.49 (1H, t, J = 7.6 Hz), 7.78-7.B7 OH, m), 8.01 (1H, d, J = Bl HZ), 9.90 (1H, s) »11.60 (2H. Br)» 12.75 (1H, br) NMR (8) (CDCl) éppm: i: B3-2.11 (2H, m), 3.06 (2H, t, J = 7.3 Hz) »3.B5 < 2H. t, J = 5.2 Hz), 4.22 (1H, br) »4.85 (2H» S) »6.98 (1H» d, J = 8.2 HZ). 7.28-7.41 (1H.m). 7.41-7.49 (1H, m), 7.74-7.86 (4H, m). 9.92 81H, s). 11.84 (1H, br) NMR (9) (CDCl 3) ppm: 1.83-2.06 82H »m)» 2.25 OH. S). 2. 32-2.76 (10H.m). 2.B8 82H, t, J = 7.7 Hz). 4. B7 (2H, s), 6.97 (1H, d.J = B.3 Hz), 7.30-7.42 (1H.m), 7.42-7.51 81H, m), 7.72- 7.87 84H, m). 9.94 (1H, s) NMR (10) (CDCl3) ppm: 0.99 86H, t, J = 7.1 Hz). 1. 40.1.61 (2H.m), 1.70-1.92 (4H.m), 2.43-2.63 (6H.m). 3.56 (2H. 8) »3.95 (2H, t» J = 6.3 Hz), 6.86 (1H, d, J = 8.5 Hz), 7.28- 7.40 (1H.m). 7.40-7.51 (1H, m), 7.70-7.91 OH, m), 7.95 (1H, d, J = 2.1 HZ), 9.89 (1H, e), 10.39-13.00 (1H, brs) NMR (11) (CDCl3 ) éppm: 0.97 (6H, t, J = 7.1 Hz), 2.10- 2.40 (2H, ITI), 2.40-2.6B (6H, m), 3.54 (2H, 8), 3.95-4.23 (2H, m), 6.84 (1H, t, J = 8.5 Hz), 7.20-7.40 (2H, m), 7.58-7.88 OH, m), 7.90 (1H, d, J = 2.1 Hz), 9.87 (1H, s) NMR (12 ) (CDCl3) éppm: 1.38-1.76 (2H, m), 1.76-2.13 (6H, m), 2.13-2.70 (14H, m), 2.88 (2H, t, J = 7.6 Hz), 2.95-3.18 (2H, m) »4.86 (2H» S) »6.97 (1H» d »J = 8.2 Hz). 7.31-7.42 (1H.m), 7.42-7.57 (1H, m), 7.73-7.87 (4H, m), 9.91 (1H, S) NMR (13) (DMSO-dβ) .ppm: 1.92-2.45 (6H, rn), 2.60-3.21 (9H, m), 3.21-3.76 84H, m), 3.76-4.16 (4H.m) »5.17 (2H.s), 7.15 81H» d »J = 8.B Hz). 7.31 (1H »t, J = 6.90 Hz), 7.45 (1H, t.

J = 6.9 Hz), 7.68-7.92 OH, ro) »7.99 (1H» d.J = 7.0 Hz) »9.87 (1H. 8) »10.73 (1H» br) »11.78 (1H» br). 12.80 (1H »S) NMR (14) (DMSO-d, v) .ppm: 1.28 (6H, t, J = 7.1 Hz), 2.00- 2.38 (6H» m), 2.68-2.90 (2H, m), 2.90 -3.25 (BH, m), 3.47-3.83 OH, m), 5.18 (2H.S), 7.18 (1H. d, J = 8.7 Hz), 7.34 (1H »t» J = 7.7 HZ). 7.45 (1H.t. J = 7.7 Hz). 7.7B-7.86 OH. m), 8.00 (1H. d, J = 7.0 Hz), 9.90 (1H, s), 10.78 (2H, or), 12.80 (1H, br) NMR (15) (DMSO-dβ) óppm: 2.40 OH, s), 5.06 (2H, s) ), 7.15-7.40 OH, m), 7.65 ((1H, d, J = 8.4 Hz), 7.77 (1H, s), 7.89 < 2H.d, J = 8.6 Hz), 9.88 (1H, s), 12.61 (1H, s) NMR (16) (DMS0-d, y.) .pppi: 2.27 OH, d, J = 0.9 Hz), 4.98 82H, s > , 6.79 (1H »d, J = 1. O Hz), 7.12-7.25 (2H, m), 7.82-7.96 (2H, m), 9.B8 (1H» s), 12.0-12.7 (1H »br) NMR (17) (DMS0-dβ) éppm: 1.26 OH »S). 4.98 (2H »s)» 6.78 (1H, S) »7.15 (2H, d, J = B.8 Hz), 7.90 (2H, d, J = 8.8 Hz), 9.88 (1H, s), 12.42 (1H , S) NMR (18) (DMSO-d?) Óppm: 5.05 (2H, S), 7.19 (2H, d »J = 8.8 HZ)» 7.25-7.55 (3H »m), 7.69 (1H, s), 7.80-B .02 (4H, m), 9.B9 (1H, s). 12.60 (1H »s) NMR (19) (DMS0-dβ) éppm: 1.57-1.84 (7H» m), 1.84-2.05 OH »m). 2.20 (1H, q, J = B .5 Hz). 2.30-2.72 (8H, m), 2.74-3.12 OH. m). 3.16-3.30 (1H, m), 4.87 (2H, s), 6.97 (1H, d, J = 8.3 Hz), 7.27-7.41 (1H, m), 7.41-7.53 (1H, m), 7.70-7.93 (4H, m), 9. 91 (1H, s) NMR (20) (CDCl 3) éppm: 1.67-2.95 (20H, m), 3.55-3.95 OH, m), 4.90 (2H, S), 6.96 (1H, d, J = 8.3 Hz) , 7.25-7.53 (2H, m), 7.55-7.95 (4H, m), 9.90 (1H, s) NMR (21) (CDCl 3) óppm: 1.55-3.80 (23H, m), 4.91 (2H, s) , 6.96 (1H, d, J = 8.4 HZ), 7.25-7.52 (2H, m), 7.65-7.78 < 1 HOUR, S) NMR (22) (CDCl 3) óppm: 1.75-2.95 (16H, m), 3.55-3.95 (7H, m), 4.88 (2H, s) »6.95 (1H» d, J = 8.3 Hz). 7.2B-7.55 (2H, m). 7.65-7.95 B4H, m). 9.90 (lh, s) NMR (23) (CDCl 3) óppm: 1.75-3.00 (20H, m). 2.27 OH. S). 3.58-3.98 OH, m), 4.88 (2H, s), 6.95 (1H, d, J = 8.3 Hz), 7.30-7.52 (2H, m), 7.65-7.90 (4H, m), 9.89 (1H, s ) NMR (24) (CDCl 3) éppm: 1.5-3.4 (15H, m), 2.40 (4H, t, J = 4.5 HZ), 3.61 (4H, t, J = 4.5 Hz), 4.88 (2H, S), 6.99 (1H, d, J = 8.5 HZ), 7.3-7.55 (2H, m), 7.7-7.9 ( 4H, m), 9.92 (1H, s) NMR (25) (CDCl3) orppro: 1.5-3.1 (23H, m), 2.24 OH, S), 4.91 (2H, S), 7.00 (1H, d, J = 8 Hz), 7.3-7.5 (2H, m), 7.7-7.9 (4H.m>, 9.91 (1H, S) NMR (26) (CDCl) éppm: 1.7-2.0 (4H, m), 2.33 OH, s), 2.5-3.0 (12H.m), 4.87 (2H, S). 6.97 (1H, d, J = 8 Hz), 7.3-7.9 (6H, m), 9.91 (1H, S) NMR (27) (DMS0-d, y.) Éppm: 1.30-3.51 (25H, m), 3.51-3.75 (2H.m., 5.16 (2H, S), 7.09 (1H, d, J = B.9 Hz), 7.27-7.39 (1H, m), 7.39-7.52 (1H, ro), 7.70 -7.84 OH, m), 7.98-B.09 (1H, m), 9.B6 (1H, S), 10.58-11.17 OH, m) NMR (28) (DMSO-d ,, ..) óppm: 1.45 86H. S), 2.68-3.01 (2H, m), 2.77 OH, s), 3.21-3.85 (10H, m), 5.24 (2H, s), 7.10 (1H, d, J = 8.3 HZ), 7.29-7.40 ( 1H, m), 7.40-7.52 (1H, m). 7.74-7.89 OH »m)» 7.93-B.05 (1H »m)» 11.10-13.00 OH »m) NMR (29) (CDCl3) óppro: 1.86 (2H, quint, J = 7.5 Hz)» 2.18-2.63 (10H »m). 2.30 OH »S). 3.05 (2H.t, J = 7.5 Hz), 4.82 (2H, S). 6.24-7.01 (2H.m). 7.10-7.59 OH, m), 7.73-7.93 OH, m), 10.17 (1H, S) NMR (30) (CDCla) orppro: 3.46 (1H, dd J = 6.5 Hz, J = 16.5 Hz). 3.68 (1H, dd, J = 10.5 Hz, J = 16.5 H?), 5.67 (1H, dd, J = 6.5 HZ, J = 10.5 Hz), 7.08 (1H, d.J = 8.5 Hz), 7.25.7.55 (2H.m), 7.75-7.85 OH. m). 7.99 (2h, d, J = 8.5 Hz), 9.B4 (1H, s) Using the appropriate starting compounds. the compounds as listed in tables 32-37 are obtained in the same manner as in reference examples 7. 8 or 9.

EtiAPRQ 32 Reference example 136 Reference example 137 P.e. : 145 ° C (0.3 mmHg) Inactive crystal form: Yellow oil Inactive crystal form: Colorless oil Form: free Form: free NMR (1) NMR (2) Reference example 138 Reference example 139 Crystalline form: Colorless oil Inacid crystal form: Brown oil Forroa: 1 i rt Form: 1 nd NMR (3) NMR (4) Reference example 140 Reference example 141 Form crystal ina: Acei te cafe P.e .: 90-95 ° C (15 mmHg) Shape: free Form crystal ina: Aceite colorless NMR (5) Form: free Reference example 142 Reference example 143 form (cis) P.e .: 107 ° C (0.35 mmHg) P.e .: 90-95 ° C (0.23 mmHg) Glass form ina: Colorless oil Form cp "stalina: Colorless oil Form: free Form: free TABLE 33 Reference example 144 Exercise or reference 145 Form crystal ina: Sun gone white P.e. : 160-165 ° C (0.25-0.3 mmHg) Form: free Form ina crystal: Colorless oil NMR (6) Form: lbre Reference example 146 Reference example 147 P.e. : 135-140 ° C (0.25-0.3 mroHg) Inacid crystal form: Colorless oil Inacid crystal form: Colorless oil Form: free Form: free NMR (8) NMR (7) Reference example 14B Reference example 149 Form crystal ina: Colorless oil Form crißtal ina: White amorphous Form: free Form: free NMR (9) NMR (10) Reference example 150 Reference example 151 HO (CH2) 2- and xX ™ CH30 (CH2) 2-N ipf NH CH3 CH3 Cristallic form ina: Aceite coffee Brown crystal form: Brown oil Shape: 1 lb Form: 1 NMR (11) NMR (12) TABLE 34 Reference example 152 Reference example 153 CH3-Nv /] N- NH C2H5 -W -CNH P.e .: 110-115 ° C (0.22 mroHg) Inacid crystal form: Pale yellow oil Form cp "stalina: Colorless oil Form: free Form: free NMR (13) Reference example 154 Reference example 155 Inactive crystal form: Yellow powder P.e .: 110 ° C (0.35 mmHg) Form: free Cristallic form ina: Colorless oil NMR (14) Form: 1 i bre Reference example 156 Reference example 157 P. e. : 110-115 «» C (0. 28 mraHg) P.e .: 120-127 ° C (12 mmHg) Inacid crystal form: Colorless oil Inacid crystal form: Colorless oil Forroa: l Brief Form: 1 i g Reference example 15B Reference example 159 P.e .: 113-130 ° C (18 mmHg) P.e .: 165-170 ° C (15 mmHg) Forroa cp'stalina'.Colourless oil Crystal form ina: Colorless oil Form: free Form: l i bre NMR (15) C »APR.Q 39 Reference example 160 Reference example 161 P.e .: 180-1B5 ° C (15 mmHg) P.e .: 138-143 ° C (12 mmHg) Crystal form: Aceite colorless Crystal form ina: Aceite colorless Form: free Form: 1 ibre NMR (16) Reference example 162 Reference example 163 C2H5- P.e .: 112-116 ° C (0.23 mmHg) P.e .: 116 ° C (0.23 mmHg) m.p. 39-14 ° C Form crystal ina: Aceite colorless Form crystal ina: Aceite colorless Shape: free Shape: free Reference example 164 Reference example 165 P.e .: 10B ° C (0.3 mmHg) P.f .: 73-75.5 ° C Form crystal ina: Colorless oil Form crystal ina: White powder Forroa: free Shape: free Reference example 166 Reference example 167 P.e .: 134-137 ° C (2.5 mmHg) P.e .: 124-130 ° C (0.7 mroHg) Inactive crystal form: Colorless oil Inactive crystal form: Colorless oil Forroa: free Form: free CVAPPP 36 Reference example 16B Reference example 169 Inactive crystal form: White poly Forroa: free Shape: 3HC1 NMR (IB) NMR (17) Reference example 170 Sample reference 171 Crystal form: Colorless oil Crystal form ina: Colorless oil Form: 1 ibre Form: free NMR (19) NMR (20) Reference example 172 Reference example 173 P.e .: 110-12B ° C (20 mmHg) P.e .: 115-136 ° C (20 mmHg) Inactive crystal form: Colorless oil Chronic form na: Colorless oil Forroa: free Form: 1 i bre Reference example 174 Reference example 175 CH3 ~ I N-? H2 HOCH2.GH_M. / - \ P.e .: 115-133 ° C (20 mmHg) Inacid crystal form: White powder Inacid crystal form: Colorless oil Form: 3HC1 Form: 1 nd NMR (21) QUA R 7 Reference example 176 P.e .: 165-170 ° C (IB mmHg) Inactive crystal form: Yellow oil Form: free NMR (22) The spectra of 4H-NMR (RMN (l) to NMR (22)) as ß deßc ibe in tables 32-37 are as follows: NMR (1) (CDCl 3) ppm: 1.05 OH. d. J = 6 Hz), 1.25-1.55 (2H, m), 1.75-3.3 (14H, m), 2.31 OH, S) NMR (2) (CDCl3) óppm: 0.B9 83H, t, J = 7.5 Hz) , 1.17-1.54 OH, m), 1.54-1.78 (1H, m), 1.78-1.94 (2H, m), 1.94-2.18 OH, m), 2.18-2.49 (6H.m). 2.49-2.72 (2H, m). 2.72-2.95 OH, m), 3.03-3.27 (2H, m) NMR) (CDCl3) óppm: 0.91 OH, t, J = 7 Hz), 1.15-1.7 (5H, m), 1.75-2.15 (6H, m ), 2.28 Oh, S). 2.15-2.45 OH, m), 2.45-2.65 (2H.m), 2.7-2.95 83h, m), 3.05-3.25 (2h, m) NMR (4) (CDCl3) óppm: 0.85-0.94 B6H. m) »1.23-1.54 (2h» m), 1.62 (lh »br)» 1.80-1.96 OH, m), 1.96-2.18 (2H, m), 2.18-2.45 (6H, m), 2.45-2.68 (2H) , ro), 2.68-2.92 OH, m), 3.00-3.24 (2H, m) NMR (5) (CDCl) óppm: 1.06-1.98 (15H, m>, 2.20.2.47 (5H, m), 2.47- 2.61 (1H, m), 2.61-2.90 (6H, m), 3.09-3.33 (2H »m) NMR (6) (CDCl3) óppm: 1.06 (6H, d» J = 6.5 Hz) »1.25-1.55 (2H , m) »1.75-1.95 (2H, m), 2.2-2.4 (1H, m), 2.45-2.75 (11H.m>, 3.05-3.2 (2H.m) NMR (7) (CDCl3) .ppm: 1.25 -1.6 OH »ro), 1.6-2.75 (14H, m), 2.85 (1H, dd, J = 2 Hz, 11.5 Hz), 2.9-3.3 (5H, m> NMR (B) (CDCl) éppm: 1.00 OH, t J = 7.3 Hz), 1.04 OH, J = 6.3 Hz), 1.24-1.51 B2H, ra), 1.70-1.92 OH, m), 2.03 (1H, t, J = 10.7 HZ), 2.20 -2.50 (5H, m). 2.50-2.69 (2h. M), 2.69-3.00 (4H, m), 3.07-3.22 (2H.m) NMR (9) (CDCl3) óppm: 0.84 OH, t, J = 7.3 Hz), 1.03 Oh D. J = 6.2 HZ), 1.25-1.65 (4H.m), 1.65-1.93 OH, m), 2.02 (1H, q, J = 10.7 Hz), 2.19-2.48 (5H, m), 2.4B-2.95 (6H , m), 3.05-3.21 (2H, m) NMR (10) (CDCl3) óppm: 0.89 OH, d, J = 6.5 Hz), 1.03 (6H, dd, J = 6.5 HZ, J = 15.1 Hz), 1.44 -1.69 (2H »m). 1.80-2.00 (2H »m). 2.05-2.24 (2H »m)» 2.24-2.50 (2H.m) »2.50-2.95 86H, m). 3.13-3.40 OH. m), 4.B5 (1H »br) NMR (11) (CDCl3) .ppm: 1.03 OH, d. J = 6.2 Hz), 1.33-1.52 < 2H »m)» 1.72-3.08 (16h, ra). 3.08-3.23 (2H »m). 3.45-3.80 (2H.m) NMR (12) (CDCl3) éppm: 1.04 OH »d» J = 6.2 Hz), 1.49- 1.68 (2H m) »1.80-1.99 (2H, m), 2.06 < 1H »t, J = 10.1 Hz), 2.24-2.55 (5H, m), 2.57-2.88 (4H, m), 2.90-3.10 (2H, m), 3.15-3.31 OH, m), 3.34 OH, s) , 3.44-3.62 (2H, ro) NMR (13) (CDCl3) óppm: 1.07 OH, t, J = 7.1 Hz), 1.40 (4H. dq »J = 3.B Hz» J = 12.0 Hz) »1.65- 1.98 (5H.m). 2.39-2.72 (9H, m), 2.72-2.84 (4h.m). 3.05-3.22 (2H, m) NMR (14) (CDCl3) óppm: 0.91 OH, t, J = 7.1 Hz), 1.14-1.5B (5H, m), 1.58-2.13 (5H, m), 2.22-2.87 (13H, m), 3.01-3.24 (2H, m) NMR (15) (CDCl3) óppm: 2.0-3.2 (17H, ra), 2.26 OH, s), 2. 32 OH, e) NMR (16) (CDCl 3) óppm: 1.8-1.9 (2H, ro), 2.0-3.2 (17H, m), 2.33 OH. 8), 2.34 OH, 8) NMR (17) (DMSO-d,:) .ppm: 1.94-2.46 (6H, m), 2.69 OH, d. J = 3.7 Hz), 2.84-3.16 (2H, m), 3.16-4.30 (11H, m), 9.56 (1H, br), 9.99 (lHm br), 11.04 (1H, br), 12.06 (1H, br) NMR (18) (CDC13) óppm: 1.08 OH, d, J = 6.2H?), 1.28-1.55 (2H, m), 1.55-1.95 (5H, m), 2.38 OH. S > , 2.40-2.99 (10H.m) »3.02-3.22 (2H, m) NMR (19) (CDC13) éppm: 1.05 OH» d »J = 6 Hz). 1.25- 1.55 (2H, m) »1.75-3.3 (14H.m)» 2.31 OH, s) NMR (20) (CDC13) óppro: 1.05 OH »d» J = 6 Hz) »1.25-1.55 (2H. ) »1.75-3.3 (14H.m)» 2.31 OH »s) NMR (21) (DMSO-d ,,;) óppm: 1.78-2.47 (6H» m) »2.6B-3.06 (2H» m>; 3.14-4.32 (16H, m) 5.20-5.78 (2H, m) 9.1-9.82 (2H »m) 10.54-11.36 (1H, ro), 11.82-12.3B (1H, m) NMR (22) ( CDC13) éppm: 1. 3-1 .7 (6H, m), 2.0-3.2 (13H, m), 2.32 OH, s) Reference example 1B2 To a solution of 9.7 g of tert-butyl propiolate in 300 ml of tetrahydrofuran is added dropwise a 1.6 M solution of 4 ml of n-butyl lithium in n-hexane at -70 ° C, and the mixture is reacted for 10 minutes. A solution of 10 g of 2-f is added dropwise to the mixture. (2-methoxy-4-formi Ifenoxi) meti Icarboni lamino3benzothiazole in 200 ml of tetrahydrofuran and 20 ml of N, N-dimet Iprspileno urea at the same temperature for a period of 20 minutes. The reaction mixture is further reacted for 20 minutes and the reaction vessel is removed from the frozen bath and the mixture is stirred for a further 10 minutes. To the mixture is added 5 ml of acetic acid and the mixture is diluted with ethyl acetate. The organic layer is washed with an aqueous solution of sodium hydrogen carbonate, dried over sodium sulfate, concentrated and the residue thus obtained is recrystallized from ethyl acetate-n-hexane. The crystals are collected by filtration to give 13 g of 2-C2-raetoxy-4-O-t-butoxy carboni 1-l-hydroxypropargi 1) phenoxymethyl-1-carbon lane-3-benzothiazole as a white powder. ? .iemptft dft rp ^ rg ?? to 19 A solution of 4.92 g of sodium hydroxide in 5 ml of water is diluted with 80 ml of ethanol and the mixture is deaerated and then placed under a nitrogen atmosphere. To the mixture is added 20 g of 3-methoxy-4-dimethylaminocarboni Itiobenzaldehyde and the mixture is refluxed for 14 hours. After cooling, 9.74 ml of ethyl bromoacetate is added to the mixture and the mixture is stirred at room temperature for 3 hours. To the mixture η add ethanol, hydrochloric acid 1.5 N and water and the mixture is extracted with chloroform. The extract is dried over sodium sulfate and concentrated and the residue is purified by silica gel column chromatography (solvent; n-hexane: ethyl acetate = 9: 1 5.6: 14: 1) to give 11.8 g of 3 -methoxy-4-ethoxycarbonylmethyl-thiobenzaldehyde as a white solid. 4H-NMR (CDC13) éppm: 1.21 OH, t, J = 7.1 Hz), 3.74 (2H, S), 3.99 OH »S), 4.14 (82H, q.J = 7.1 Hz). 7.32-7.48 OH »m)» 9.92 (1H »S) EJB "Plff from rsfftrsn? Ia 1 & Using the appropriate starting compounds, the following compound is obtained in the same manner as in Reference Example 1. α- (2-Methoxy-4-formy-1-phenoxymethyl) acetic acid: Yellow powder H-NMR (DMSO-d ,,,) .ppm: 3.84 OH. 8) »4.82 (2H, s). 7.05 (1H. D »J = 8 HZ), 7.41 (1H, d, J = 2 Hz). 7.51 (1H »dd» J = 2Hz, J = 8 HZ) »9.B3 (1H.S). 13.14 (1H »br) ? .pig. clft re grgncja 95 Using the appropriate starting compounds, the following compound is obtained in the same manner as in reference example 2. 2- (2-methoxy-4-formyl-1-phenoxy-methylcarbon-lamino) benzimidazole a: yellow powder. NMR (CDCl ,,,) óppro: 4.06 OH »S)» 4.86 (2H, s) »7.09 (1H, d» J = 8.5 Hz) »7.3-7.55 (4H» m) »7.B-7.9 (2H , m) 9.91 (1H, S), 10.25 (1H. br) 2- (2-Ethoxy-4-formi Ifeno imeti Icarbsni lami no) benzimidazole a: White powder 4H-NMR (CDC13) éppm: 1.60 OH, t , J = 7.0 Hz) »4.26 (2H» q, J = 7.0 Hz) »4.87 (2H» S), 7.11 <1H »d, J = 8.3 Hz), 7.30-7.49 (4H» m) 7.79- 7.B8 (2H, ro) »9.90 (1H, 8) .10.34 (1H. Br) 2 - . 2-C2-Diethylaminocarboni Iroetoxy) - 4 -formi Ifenoximeti Icarboni 1 aroi noD-benzimi dazo1 a: White powder 4H-NMR (CDCl "): 1.16 (3H, t, J = 7 Hz), 1.30 OH, t, J = 7 HZ) »3.35 (2H. Q» J = 7 Hz) »3.49 (2H» q, J = 7 Hz), 4.92 (2H.8) »5.00 (2H, ß), 7.09 (1H, d, J = B Hz)» 7.25-7.55 (4H.m), 7.7-7.85 (2H.m), 9.86 (1H, s) ? ierapleQ dq re erence 196 Using the appropriate starting materials, the following compound is obtained in the same manner as in reference example 5. Bromide of C3- (2-chloroethyl) -4- (2-benzothiazole-aminocarbonyl-Imethoxy) benzoyl-13-methy1-triphenylphosphonium : 4 H-NMR (DMSO-dβ) óppm: 3.16 < 2H, t, J = 7.0 Hz), 3.92 (2H, t, J = 7.0 Hz). 5.18 (2H.S>, 6.12 (2H. d, J = 13.1 Hz) 7.14 (1H »d, J = 9.4 HZ)» 7.31 (1H.t »J = 6.5 Hz) 7.44 (1H» t » J = 6.5 HZ) 7.60-8.12 (19H.m), 12.70 <1H, br) C3- (2,3-di acetyl lox i propyl) -4- (2-benzo-thiazole and laminocarbonyl) methoxy) benzoyl chloride Itrifeni Ifosphonium: H-NMR (CDCl ,,) óppm: 2.00 OH »S), 2.05 OH, S), 3.0-3.15 (2H, m), 4.0-4.35 (2H, m), 4.93, 5.05 (2H, AB -q, J = 16 Hz) »5.40 (1H, m), 6.1-6.6 (2H, br), 6.98 (1H, d» J = 8 Hz). 7.2-B.5 (21H »ro) Reference example 1B7 To a solution of 25.1 g of methyl 2 »4-dihydro-ibenzoate in 250 ral of acetone is added 14.9 ml of methyl bromoacetate and 21.7 g of potassium carbonate and the mixture is refluxed for 3 hours. The mixture is filtered and the filtrate concentrated and the residue is purified by silica gel column chromatography (solvent, n-hexane: ethyl acetate = 3: 1) to give 31.5 g ethyl acetate 2- (3 - idroxy-4-methoxycarbom "1 phene i) White solid 4H-NMR (CDCl ,,,) éppm: 3.81 OH» s), 3.91 OH, s), 4.65 (2H, s), 6.39 (1H, d, J = 2.6 Hz), 6.45 (1H, dd, J = 2.6 Hz, J = TB Hz), 7.73 (1H, d, J = 8.8 Hz), 10.97 (1H, S) Reference example 1BB To 50 ml of ethanol is added 3.37 g of 2- (2-phthalimide) roeti Ibenzothiazole and 3 ml of hydrazine monohydrate, and the mixture is refluxed for 30 minutes. After confirming that the starting compounds were consumed, the solid precipitate is removed by filtration and the filtrate is concentrated. To the residue, an aqueous solution of potassium carbonate is added and the mixture is extracted with dichloromethane. The extract is dried over magnesium sulfate and concentrated under reduced pressure to remove the solvent to give 1.42 g of 2-aminomethyl-l-benzothiazole. Yellow powder 4H-NMR (CDC13) .ppm: 1.B3 (2H, br), 4.30 (2H, s), 7.33-7.51 (2H, m), 7.85-7.99 (2H. Ra) Reference example 189 To 50 ml of dichloromethane is added 2 g of 2-hydroxymethylbenzothiazole and 2.5 ml of triethylamine and in addition thereto 1.03 ml of chloride-sulfonyl chloride is added under freezing and the mixture is stirred at the same temperature for 1 hour. After the reaction is complete the mixture is washed with hydrochloric acid, dried over magnesium sulfate and concentrated under reduced pressure to remove the solvent. The resulting crude product is dissolved in 50 ml of dimethylformamide and thereto is added 5.6 g of potassium phthalimide. The mixture is heated with stirring at 70 ° C for one hour. After the reaction is complete, the reaction mixture is poured into water and the precipitated crystals are collected by filtration. Separately, the filtrate is extracted with ethyl acetate and the extract is concentrated under reduced pressure. The residue and the crystals obtained above are combined and washed with n-hexane-diethyl ether to give 3.37 g of 2- (2-phthalide) methyl benzothiazole. Yellow powder 4H-NMR (CDCl .3.) Éppm: 5.30 (2H, 8), 7.35-7.47 (2H »m), 7.74-8.02 (6H.ra) Axis reference 190 A solution of 12.33 g of methyl p-formi 1 benzoate »16 g of malonic acid and 1 ml of piperidine in 100 ml of pyridine is refluxed for 2 hours. The reaction mixture is poured into ice water and the precipitated white powder is collected by filtration and washed with water, to give 14.7 g of 4-methoxycarbonyl Icinaroic acid. White powder H-NMR (DMSOd ,,) éppm: 3.85 OH »S)» 6.65 (1H. d »J = 16 Hz)» 7.63 (1H, d.J = 16 Hz) »7. B2 (2H, d» J = 8 Hz). 8.01 (2H. D, J = 8 Hz). 12.57 (1H, br) Reference example 191 To a solution of 4.64 g of 4-methocarboni-1-cinnamic acid in 300 ml of acetic acid is added 0.5 g of palladium-carbon to 10X and the mixture is subjected to hydrogenation at 70 ° C under atmospheric pressure for 2 hours. The catalyst is removed by filtration and the filtrate is concentrated under reduced pressure. Water is added to the residue, and the precipitated white powder is collected by filtration to give 3.B7 g of 3- (4-methoxycarboni Ifeni 1) propionic acid White powder 4H-NMR (CDC13) ppm: 2.71 (1H, t, J = 7.5 Hz), 3.02 (2H, t, J = -7.5 Hz), 3.91 OH. 8). 7.29 (2H.D, J = 8.5 Hz), 7.97 (2H.D, J = 8.5 Hz) Reference example 192 To a suspension of 6.5 g of 2-carboxybenzothiazole in 100 g of anhydrous dichloromethane is added 3.2 ml of oxalyl chloride and one drop of dimethylformamide. The mixture is stirred at room temperature for 3 hours. The mixture is evaporated to remove the dichloromethane and the residue is dissolved in 100 ml of acetone and added dropwise to an aqueous solution of 5 g of sodium acid and 20 ml of water under freezing. The mixture is stirred at the same temperature for 3 hours, and water is added thereto. The precipitated crystals are collected by filtration and dissolved in 50 ml of dichloromethane, dried and concentrated under reduced pressure to remove the solvent. To the residue is added 50 ml of benzene and the mixture is refluxed for 4 hours. To the mixture is added 5.7 g of eti 1-4-pipep'dincarboxylate and the mixture is refluxed for 6 hours. Water is added to the reaction solution and the mixture is extracted with ethyl acetate. The extract is washed with water, dried and concentrated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography (solvent, dichloromethane: methanol = 200: 100: 1) to give 4.0 g of 2- (4-ethoxycarbonyl 1-1-piperidinyl) -carbonylaminobenzothiazole. White powder 4H-NMR (CDCl ,,) .ppm: 1.25 OH »t, J = 7 Hz)» 1.65-2.05 (4H »m)» 2.4-2.6 (1H, m) »2.95-3.2 (2H. Ro)» 4.0-4.2 (2H. Ra), 4.14 (2H, q, J = 7 Hz), 7.15-7.45 (2H, m), 7 .58 (1H, d »J = 8 HZ)» 7.75 (1H »d.J = 8 Hz). 10.11 (1H, br) Reference example 193 • 5 To a solution of 26.8 g of 2-methoxy-4-trifluoromethanesulfonyloxy-benzoate. 62.5 ml of tert-butyl acrylate, 25 rolls of triethylamine in 100 ml of anhydrous dimethylformamide is added 0.4 g of palladium acetate and 0.74 g of 0 l, 3-bis (difeni ifosfino) propane under argon atmosphere, and the mixture it was heated with stirring at 75 ° C for 16 hours. The reaction solution is concentrated under reduced pressure to remove the solvent, and water is added thereto. The mixture is extracted with ethyl acetate and the extract is washed with water, dried and concentrated under reduced pressure. The residue 8e is purified by silica gel column chromatography (solvent, ethyl acetate: n-hexane = 1: 5) to give 23.5 g of tert-butyl or 3-methoxy-4-methoxycarbonylcincinate. Yellow powder 0 4H-NMR (CDCl ,,) éppm: 1.54 (9H, s), 3.90 OH. s) »3.94 OH. S). 6.42 (1H.D. J = 16 Hz) »7.07 (1H» d »J = 1.5 Hz). 7.13 (1H, dd »J = 1.5» 8 Hz), 7.55 (1H, d, J = 16 Hz), 7.80 (1H »d» J = 8 HZ) Reference example 194 To a solution of 23.5 g of tert-butyl 3-methoxy-4-methoxycarbonylcitanoate in 100 ml of anhydrous dichloromethane is added 50 ml of acetic acid under freezing and the mixture is stirred at room temperature overnight. The reaction solution is concentrated under reduced pressure to remove the solvent and the residue is recrystallized from ethanol to give 8.35 g of 3-methoxy-4-methoxycarbonyl-1-cinnamic acid. White 4H-NMR powder (CDCl3 + CDCl-d-ß) óppm: 3.BB OH. s). 3.94 OH. 8). 6.50 (1H, J = 16 Hz), 7.13 (1H, S>, 7.15 (1H, d, J = 8 Hz), 7.62 (1H, d, J = 16 Hz), 7.78 (1H, d, J = 8 Hz) Example, ge ra er ^ pis 495 To a suspension of B.35 g of 3-metho-i-4-roethoxycarbonyl cinnamic acid in 200 ml of acetic acid, 1.0 g of palladium-carbon is added to the 105 I and the mixture is subjected to hydrogenation at room temperature. The catalyst is removed by filtration and the filtrate is concentrated under reduced pressure. The residue is stirred from diethyl ether-n-hexane to give 7.5 of 3- (3-methoxy-4-roethoxycarbonyl-lfeni-1) propionic acid. White powder H-NMR (CDC13) éppm: 2.70 (2H.t, J = 7.5 Hz), 2.98 (2H, t, J = 7.5 HZ), 3.8B OH, ß), 3.89 OH, 8), 5.71 (1H , Dr), 6. 75-6.9 (2H, m), 7. 75 (1H, d, J = 8 Hz) Reference example 196 To a solution of 7.7 ml of dimethyl methylphosphonate in 100 ml of anhydrous tetrahydrofuran is added dropwise a 1.66 M solution of n-butyl lithium in 43 ml of n-hexane at -50 ° to -60 ° C. Subsequently, B.72 g of a solution of 2-C2- (3-metho-4-methoxycarboni lfeni 1) eti 1 - "Icarboni laminobenzothiazole in 50 ml of anhydrous tetrahydrofuran is added dropwise to the reaction solution. Sticky yellow is generated in the reaction mixture and 10 ml of 1 -3-dimethyl-3 »4» 5 »6-tetrahydro-2- (lH) pyrimidinone is added thereto and the mixture is stirred at the same temperature for 2 hours. The reaction mixture is added with a saturated aqueous solution of ammonium chloride and the mixture is acidified with dilute hydrochloric acid, the mixture is extracted with ethyl acetate and the extract is washed with water, dried and concentrated under reduced pressure. reduced pressure The residue is purified by silica gel column chromatography (dichloroethane: methanol! = 100: 1 10: 1 solvent) to give 6.4 g of CC3-ratoxy-4-C2- (2-benzothiazole). ) aminocarboni 1) eti 1 Dbenzoi 1.}. methi 1 D phosphonate »by means of which 3.1 g of the active compound is also recovered Yellow powder 4H-NMR (CDCl 3) óppm: 2.B0 (2H. t. J = 7.5 Hz) »3.05 (2H.t, J = 7.5 Hz), 3.73 OH, S), 3.78 OH, s), 3.79 OH, s), 3. B2 (2H, d, J = 21.5 Hz), 6.65-6. B (2H, m), 7.25-7.45 (2H, m), 7. 60 (1H, d, J = 8.5 HZ), 7.64 (1H, d, J = 7.5 Hz), 7.82 (1H, dd, J = l Hz, J = 7.5 HZ), 11.49 (1H, br) g.ifWPTQ Ql rgfgren? iq 1 ^ 7 3.9 ral of methyl Ifosfonato dimetilico, 22 ml of 1.65M of n-butylic lithium and 4.0 g of 2- (4-ethoxycarboni 1-1-piperidinil) carbonylaminobenzothiazole are treated in the same manner as in the reference example 196 for give 2.5 g of dimethyl 1 Cl- (2-benzothiazole i 1) ami nocarboni 1) - 4-piperidiniylcarboni 1-methyl-1-phosphonate. Pale yellow oil H-NMR (CDCl ,,.) Éppm: 1.5-2.05 (4H, m), 2.75-3.1 OH, m), 3.16 (2H, d, J = 2B Hz), 3.76 (3H, S), 3.82 (3H, S), 4.1-4.35 (2H, m), 7.15-7.45 (2H, m), 7.57 (1H, d, J = 7.5 Hz), 7.74 (1H, d, J = 8 Hz), 10.04 (1H, br) Using the appropriate starting compounds, the following compound is obtained in the same manner as in the reference excerpt 1.

TABLE 36-1 Using the appropriate starting compounds the compounds are obtained as listed in tables 36-2 to 36-9, in the same manner as in reference example 2. ? i RQ 35-2 TABLE 36-3 QU? PRQ 36-4 Reference example 224 R ?. »: -OCH3 (position 4) Rß: -0CH2 --o < f (position-3) P.f. 197.0-197.5 ° C Crystalline form: yellow powder Solvent for recrystallization: Ethyl acetate-dimethylformamide Form: Free Reference example 225 R * -9: -OCH, (position 4) R ": -OCHaCH ^ CH-j (position-3) Mp 130-132 ° C Crystalline form: light yellow powder Solvent for recrystallization: Acetate of eti lo-n- Hexane Shape: Free Reference example 226 P.f. 131.5-132.5 ° C Crystalline form: white powder Solvent for recrystallization: Ethyl lo-n-hexane-dichloromethane acetate Form: Free Reference example 227 1 R ": H A ^ CHa- m: i R * \ ^ R * - »: -OCH ,,, (position 4) Rß:) (position-3) P.f. 169. -170.3 ° C Crystalline form: light yellow powder Solvent for recrystallization: Ethyl-n-hexane acetate Form: Free TABLE 36-5 Reference example 22B Fía. »: -OCH ,,. (position 4) Rß: - (CHa) aCHß (position-2) and -OCH3 (position-3) P. f. 147.0-147.5 ° C Crystalline form: light yellow powder Solvent for recrystallization: Ethyl lo-n-hexane acetate Form: Free Reference example 229 R-t- »: -OCH ,, (position 4) Rß: -Q- ~ y (position 3) P.f. 142.0-143.0 ° C Cristalline form: white powder Solvent for recrystallization: Ethyl-n-hexane acetate Form: Free Reference example 230 R4- ^: I R: H A: -CH_- m: i Fía. »: -0CH (position 4) Rß: -SCH_ (position-3) NMR (22) Crystalline form: light yellow powder Form: Free Reference example 231 Rlß: -OCH .. ,, (position 4) RB: - (CH2) CH3 (position-2) and -OCH3 (position 3) NMR (27) Crystalline form: light yellow powder Free form CUAPRQ 36-6 Reference example 232 RiB: -OCH, "(position 4) Rß: -CH3 (position-2) and -OCH3 (position 3) NMR (35) Crystalline form: orange powder Form: Free Reference example 233 R * »: -OCH ,,, (position 4) Rß: -CHaCHß (position-2) and -OCHa (position-3) NMR (36) Crißtaline form: orange powder Reference example 234 21T RA »: -0CH3 (position 4) RB: -OCH3 (position-3) P.f 186-188 ° C Crystalline form: white powder Free form Reference example 235 R * »: -OCH, (position 4) RB: -CHaCH = CH2 (position-2) and -0CH3 (position-5) P.f.1B7 ~ 189 ° C Crystalline form: light yellow powder Form: Free CI ßRQ 3fr-7 Reference example 236 R * - »: -OCH" (position 4) RB: -OCH3 (position-2) and -N (CH3) ß (position-3) NMR (46) Crystalline form: white powder Form: Free Reference example 237 R * »: -OCH ,, (position 4) RB: -N (CHß) a (poßition-2) NMR (65) Crystalline form: white powder Form: Free TABLE 36-B Reference example 23B R ^ »: -0CH3 (position 4) Rß: -0CHß (position-3) T: -CHa- u: l NMR (4B) Crystalline form: white powder Form: Free ? yjAPqp 3S-9 Reference example 239 Rx ^^: I R- ": HA ^ -CH-j) ^ - m: i R * • ^ R * -9: -OCH,., (Position 4) RB: H NMR (73) Crystal form: yellow powder Shape: Free Reference example 240 m: i R * - »: -0CH", (position 4) RB: -OCH3 (position-3) NMR (75) Crystalline form: yellow powder Form: Free Using the appropriate starting compounds the compounds are obtained as listed in Tables 36-10 to 36-16 »in the same manner as in Reference Example 3.

TABLE 36-10 Reference example 241 -COCHaPOiR "1 -") ^: -COCHaPO (OCH3) a (position-4) Ra: -OCHaCHsCHg. (POSITION-3) P.-f. 134-135 ° C Crystalline form: White powder Solvent for recrystallization: N-hexane ethyl acetate Free form Reference example 242 -COCHaPOiR "1 -») ^: -COCHaPO (OCH?) A (poßiCiÓn-4) Rß: I \ (position-3) NMR (8) -o KJ- ~ HQ> Crystalline form: Yellow oil Form: Free Reference example 243 -C0CHafP0 (RAß) 3t: -C0CHaP0 (0CH3) 2 (position-4) RB: -i (position-3) NMR (10) Crystalline form: Yellow oil Form: Free TABLE 36-11 Reference example 244 -COCHaPOIR3 - "») ^: -COCHa 0 (OCH3) a (posiCion-4) Rß: - (CHa) aCH3 (position-2) and -OCH3 (Position-3) Pf 156.5-157.4 ° C Crystalline form: Needles white Solvent for recrystallization: Ethyl acetate n-hexane Free form Reference example 245 -COCHaPO (R - * - «a" -COCHaPOt OCH3) a (position-4) R °: -K ..-.}. (Position-3) NMR (16) Cristalline form: Amorphous yellow Form: Free Reference Example 246 R- R "1: HA: -CH, - m: i R- -COCHa OtR3-") -COCHaPO (O H3) a (position-4) Rβ: _SCH3 (position-3) NMR ( 23) Crystal Forraa: Light brown powder Shape: Free Reference example 247 -COCHaPO (RA *). .: -COCH? PO (OCH,) to (position-4) Re < CHa) H3 (position-2) and -OCH3 (position-3) NMR (2B) Crystalline form: White powder Form: Free gUAPPQ 36- Z Reference example 248 -COCH "PO (RA *), -COCH. , PO (OCHß) to (position-4) RB: -CH3 (position-2) and -OCH3 (poßici n-3) NMR (37) Crystalline form: Light red powder Forraa: Free Reference example 249 COCH »PO (Ra -" "') to: -COCH_ POÍOCHa). (position-4) R * -CHaLH (position-2) and -OCH. , (position-3) NMR (3S) Crystalline form: Light red powder Form: Free Reference example 250 -C0CHaP0 (R? -ß) to "-COCHaPOí 0CH3) z (p? SiCion-4) RB: -0CH3 (position-3) P.f. 140-142 ° C Crystalline form: Colorless prisms Solvent for recrystallization: Ethanol Form: Free Reference example 251 -COCHAPO (4ß) to "-COCHaPH OCHa) to < p? 8iCion-4) RB: -CHa H = CHa (position-2) and -0CH3 (position 5) Pf 125-12B ° C Crystalline form: Prismas brown Clear Shape: Free EJEWP ^ Q 36-13 Reference example 252 -COCHaPOíR3- ")," -COCHa OtOCH, "» (position-4) R ": -CH3 (position-2) and - ÍCH.)» (Position 3) NMR (47) Forraa crißtalina: Light yellow powder Free form Reference example 253 RA / ^: R ": H A: -CHa ~ m: 2 Ra ^^ -C0CHa 0 (Rlß) a "~ COCHa O <OCH3) 2 (position-4) RB: -Br (position-2) and -OCH3 (position 5) Pf 196-199 ° C Crystalline form: White powder Solvent for recrystallization: Ethanol Form: Free Reference example 254 -C0CHa 0 (Riß) to "-C0CHaP0 <0CH3 to <P0STIÍ0n-4) RB: -N <3) -2 (position-2) NMR (66) Crystalline form: Love yellow Form: Free Reference example 254A -C0CHaP0 (R "" - • > a- '-C0CHaP0 (0CH3) a (posiCion-4) RB: -CH3 (position-2) NMR (77) Crystalline form: White powder Form: Free CUAPRQ 3 $ -14 Reference example 255 R ": H A: -CHaM: 2 R * ^ -C0CHaP0 (R * -ß) to "-C0CHa 0 (0CH3) a (position-4) RB: -OCH3 (position-3) T: -CH. U: NMR (49) Crystalline form: Oil Cafe Shape: Free CUADRQ 3 ^ -15 Reference example 256 -COCHAP (Riß) to "- OCHAPO (OCH3) 2 (position-4) RB: H NMR (74) Crystalline form: Light brown oil Form: Free Reference example 257 -COCHAP (Ra - ») to" -COCHaPO (OCH3) a (position-4) Rß: -OCH_3 (position-3) NMR (76) Crystalline form: Yellow powder Form: Free Using the appropriate starting corpuscles, they obtain the commands as listed in Table 36-16 in the same way as in Reference Example 5 or 6.

CU? P P 5-lß Reference example 258 Rx / ^: J R ": H A: -CH. M: 2 Ra * ^ RB: -0CH3 (positions 2 and 3) NMR (67) F Foorrmmaa ccrriisstalina: Light yellow amorphous Free form Reference example 259 R ^ 5: J R "": H A: -CHa ~ m: i Ra \ ^ RB: -0 (CHa> 3CI (position-3) NMR (6B) Crystalline form: Colorless amorphous Free form Reference example 260 RB: -0 (CH2) 3 ^ (position-3) NMR (69) Crystalline form: Light yellow amorphous Form: Free Reference example 261 RB: -OCh3 (position-3) NMR (70) Crystal shape na: Dark amorphous coffee Shape: Free Using the appropriate starting compounds, they obtain the compounds as listed in Table 36-17 in the same manner as in Reference Example 7, 8 or 9.

TABLE 36-17 Reference example 262 Colorless oil form: free NMR (71) Reference example 263 Light yellow oil shape: free NMR (72) Using the appropriate starting compounds ", they obtain the compounds as listed in Tables 36-18 to 36-21 in the same manner as in Reference Example 187.

EXAMPLE 36-18 Reference Example 264 RB: -OH (position-3) A: -CHa ~ p > : i -COR * 1- »: -COOCH-3 (position 4) ^ R8" * »: -0CH3 NMR (1) Crystalline form: white solid Form: Free Reference example 265 Free form Reference example 266 RB: -0CHaCH = CH3 (position-3) A A :: - CCHH33-- m: i -COR ": -COOCH. (Position-4) R * -»: -OCH3 NMR (4) Crystalline form: Colorless oil Form: Free Reference example 267 RB: (position-3) A: -CH "-m: i: ~ < ) -CORx »: -COOCH3 (position-4) R * - *: -OCH .. NMR (6) Cristalline form: Yellow oil Form: Free Reference example 26B R: - ¿< position-3) A: -CH2- m: i -COR4- »: -COOCH3 (position-4) R38- *: -OCH3 NMR (9) Crystalline form: Colorless oil Form: L Reference example 269 RB: -CH2CH = CH (position-2) and -OH (position-3) A: -CHZ-m: 2 -COR4- »: -C00CH3 (os -position 4) R *": -0CH3 Mp 93.1-93.8 ° C Crystalline form: Colorless needles Solvent for recrystallization: ethyl acetate-n-hexane Form: Free Reference Example 270 Rß: - (CHa) aCH 3 (postion-2) and -OH (position-3) A: -CH 3 -COR 4 - »: -COOCH 3 (position-4) R 5» "»: -OCH. NMR (12) Crystalline form: White solid Form: Free TABLE 36-19 Reference example 271 RB: - (CHa> ß H3 (postion-2) and -OCH_3 (position-3) A: -CH - * - m: 2 -COR4- »: -COOCH3 (position-4) R * - *: -OCH NMR (13) Crystalline form: Colorless oil Form: Free Reference example 272 RB: "-0- (position-3) A: -CHa ~ m: i -COR- *: -COOCH3 (? Osici n-4) R2- *: -OCH3 NMR (15) Crystal form na: Colorless oil Form: Free Reference example 273 RB: -SCH3 (position-3) A: -CH2- p *: -COR4- »: -COOCH3 (? -osition-4) Ra- *: -OCH3 NMR (20) Crystalline form: Light yellow powder Free form Reference example 274 RB: - (CHa> 3CH3 (position-2) and -0H3 (? Osition-3) A: -CH2- -COR4- »: -COOCH3 (position-4) R ***: -OCH3 NMR (24) Crystalline form: Light brown powder Shape: Free Reference example 275 RB: - (CHa> 3CH3 (position-2) and -OCH3 (position-3) A: -CHa m: 2 -COR4- »: -COOCH3 (position-4) R» «*: - OCH NMR (25) Crystalline form: White powder Form: Free Reference example 276 RB: -CH3CH3 (position-2) and -0H3 (position-3) A: -CH * m: 2 -COR4- »: -C00CH3 (position-4) R ***: -0CH3 NMR (29) Crystalline form: White powder Form: Free Reference example 277 RB: -CHaCH3 (position-2) and -0H3 (position-3) A: -CH * m: 2 -COR4- »: -C00CH3 (position-4) R * -»: -OCHs NMR (30) Crystalline form: White powder Form: Free TABLE 36-20 Reference example 278 RB: -CH3 (position-2) and -0CH3 (position-3) A: -CH12 m: 2 -COR4- »: -COOCH3 (position-4) R *" *: -OCH3 NMR ( 31) Crystal form: Colorless needles Free form Reference example 279 RB: -CHaCH3 (position-2) and -OCH3 (position-3) A: -CH "" * m: 2 -COR4- »: -COOCH3 (position-4) R * - *: - OCH3 NMR (32) Crystal form na: Colorless oil Form: L bre Reference example 280 RB: -OH (position-3) A: -CHa m: i -COR4- »: -COOCH3 (position-4) Ra-»: -OCaHß NMR (40) Crystalline form: Colorless oil Free form Reference example 281 RB: -OCH3 (position-3) A: -CHa-m: 1 -COR4- »: -COOCH3 (position n-4) R * -»: -OCaHß NMR (41) Crystalline form: Light brown powder Shape: Free Reference example 282 RB: -OCH3 (position-3) A: - (CHa), r m: i -COR- »: -CO0CH3 (position-4) R5 * - *: -OCH3 P.-F. 4B-50 ° C Crystalline form: White powder Recrystallization solvent: Ethyl-n-hexane acetate Form: Free Reference example 283 R «: -OCH3 (position-2) and -NHa (position-3) A: - CH2- m: 2 -COR4- »: -COOCH3 (position-4) R * - *: -OCH. NMR (44) Crystalline form: Yellow oil Shape: Free Reference example 284 RB: -OCH3 (position ~ 2) and -N (CH3) 2 (position-3) A: -CH2- m: 2 -COR4- »: -COOCH3 (position-4) R2-»: - OCH. NMR (45) Crystalline form: Brown oil Shape: L b TABLE 36-21 Reference example 285 RB: Br (position-2) and -OH (position-5) A: -CH2- m: 2 -COR4- »: -COOCH3 (position-4) R2- *: -OCH3 NMR (56 ) Crystal form: White powder Shape: Free Reference example 286 RB: Br (? -suite-2) and -OCH (-5-position) A: -CH2-m: 2-COR4- »: -COOCH3 (position-4) R2- *: -OCH. NMR (57) Cristallicine form: White powder Form: Free Reference example 287 RB: -NHa < Position-2) and -OCHa (? Osition-5) A: -CH2- m: 2 -COR4- »: -COOCH3 (position-4) R2-»: -OC3He NMR (59) Crystalline form: White powder Form: Free Reference example 28B R * "": -N (CHa) 2 (position-2) A: -CH2- m: i -COR4- »: -COOCH- (position n-4) =: -OCH2H ^ NMR (63 ) Crystal form: Yellow oil Shape: L b Using the appropriate starting compounds, compounds such as those listed in Tables 36-22 to 36-23 are obtained in the same manner as in Reference Example 1 → 194.

TABLE 36-22 Reference example 2B9 R °: - (position-3) A: -C ß- m: i -C0R - * - »: - C00H3 (position-4) NMR (3) Crystalline form: White solid Form: Li re Reference example 290 RB: -OCH_CH = CH_ (position-3) A: -CHa ~ m: i -CORJ - »: - COOH: 9 (position-4) NMR (5) Crystalline form: White solid Form: Free Example 291 Rß: -p- (position-3) A: -CHß- p * "l -COR": -COOH3 (position-4) NMR (7) Crystalline form: Light yellow oil Free form Reference example 292 RB: ___ / \ < position-3) A: -CHa ~ m: i -C0RA »: - C00H3 (position-4) P.f. 124.5-126.0 ° C Crystalline form: White powder Solvent for recrystallization: Ethyl acetate Form: Free Reference example 293 RB: (CH2) 2CH3 (position-2) and -0CH3 (position-3) A: -CH3-m: 2 -C0RJ - »: - C00H :? (position-4) NMR (14) Crystalline form: White solid Form: Free Reference example 294 - «- O (posic on-3) A: -CHa ~ m: l -C0RJ -»: - C00H3 (position-4) P.f. 131.5-132.0 ° C Crystalline form: Light yellow powder Solvent for recrystallization: Ethyl acetate Form: Free Reference example 295 RB: -SCHa- (position-3) A: -CH3- m: i -COR - «-»: - COOH3 (position-4) NMR (21) Crystalline Forra: White powder Form: Free? G ? PRO 36-23 Reference example 296 R "3 *: (CHa> a H3 (position-2) and -OCH3 (position-3) A: -CHß ~ p» '2 -CORx *: - COOH3 (position-4) NMR (26) Crystalline form: White powder Shape: Free Reference example 297 Rß: ~ CH3 (position-2) and -0CH3 (position-3) A: -CHß-m: ¡2 -C0R4 - »: - COOH3 (position-4) NMR (33) Crystalline form: White powder Reference example 29B RB: -CH3CH3 (position-2) and -OCH3 (position-3) A: -CH3- m: 2 -COR - »: - COOH3 (position-4) NMR (34) Crystalline form: White powder Reference example 299 RB: -OCH3 (position-3) A: - (CH2) 3- p »: l -CORa -»: - C0OHa (position-4) P.f.B9-90 ° C Crystalline form: Colorless needles Solvent for recrystallization: Water-ethanol Form: Free Reference example 300 Rβ: -CH 3 CH = CHa (po-sition-2) and -OCH 3 (? Osition-5) A: -CH 3 -? »: 2 -COR -« - »: - COOH 3 (pssition-4) NMR (43 ) Crystal form: White powder Shape: Free Reference example 301 RB: Br (poßition-2) and -OCH3 (position-5) A: -CHa ~ "" "" 2 -COR - * - »: - COOH3 (position-4) NMR (58) Crystalline form: White powder Forraa: Free Reference example 302 R "" ": N (CH3) (position-2) A: -CH2- tn: i -C0R -« - »: - C00H3 (position-4) NMR (64) Crystalline form: White amorphous Free form Reference example 303 Using the appropriate starting compounds, the following compounds are obtained in the same manner as in reference example 6. a- (2.3-Dihydra? I-4-acetylphenoxy) methyl acetate: white powder NMR aH (DMSO-d ^ óppm: 2.56 (3H, s). 3.69 (3H. S), 4. 91 (2H, s). 6.49 (1H, d.J = 9.1 Hz) »7.35 (1H» d, J = 9.1 Hz), 8.79 (1H.s). 12.31 (1H »s) a- (2» 3-dimethoxy-4-acetylphenoxy) methyl acetate: White solid NMR AH (CDCl ,,.) .ppm: 2.60 (3H »s), 3.81 (3H. S), 3.93 (3H, 8), 3.99 (3H. S). 4.75 < 2H »s)» 6.57 (1H. D.J = 8.9 Hz) »7.48 (1H, d.J = 8.9 Hz) a-C2.3-Dimeto i-4- (2-bromoacetyl 1> phenoxy-acetate) raeti lo: Colorless oil NMR - * - H (CDCl ,,,) óppm: 3081 (3H »s)» 4.07 (3H. s), 4.57 (2H, S), 4.76 (2H, s), 6.58, (1H »D, J = 8.9 Hz)» 7.54 (1H.D. J = 8.9 HZ) (2 »3-D metho-4-methoxycarboni l meto i benzoi 1) methi len-t i feni 1 phosphorane Amorphous colorless NMR * H (CDCl ,, ppp: 3.77 (3H »s)» 3.94 (6H »s) 4.61 (1H, brd» J = 27.B Hz) »4.70 (2H, S)» 6.56 (1H. 8.8 Hz), 7.38-780 (16H, m) a-E3- (3-Chloropropoxy) -4-acetyl-1-phenoxy) ethyl acetate: Yellow acid NMR AH (CDC13) ppm: 1.31 (3H, t, J = 7 Hz), 2.2-2.5 (2H, m), 2.57 (3H, s), 3.77 (2H, t, J = 6.5 Hz), 4.30 (2H, t.J = 7 Hz) »4.66 (2H, 8 & , S.47 (1H , dd, J = 2H, J = 8.5 Hz), 6.57 (1H, d, J = 2 HZ), 7.81 <1H, J = 8.5 Hz) a-C3- (3-Chloropropoxy) -4- ( 2-bromoacetyl 1) phenoxy ethyl acetate: colorless oil NMR JH (CDC13) ppm: 1.31 (3H, t, J = 7 Hz), 2.2-2.55 (2H, m), 3.55-3.85 (2H, m) 4.15- 4.4 (4H, m), 4.50 (2H, s), 4.68 (2H, s), 6.51 (1H, dd, J = 2 Hz, J = 9 Hz), 6.59 (1H. d, J = 2 Hz), 7.89 (1H, d, J = 9 Hz) C2- (3-Chloropropoxy) -4-ethoxycarboni 1-methoxy-benzoyl-13-methy lentrifeni lfanorane: light brown amorphous NMR AH (CDC13) ppm: 1.31 (3H, t, J = 7 Hz), 2.2-2.7 (2H, m), 3.67 (2H, d, J = 5.5 Hz), 4.27 (2H, q, J = 7Hz), 4.2-4.4 (2H, m), 6.20 (1H, br), 6.47 (1H, dd, J = 2Hz, J = 9 Hz), 6.57 (1H, d, J = 2HZ), 7.4-8.0 (16H, m) Chloride (2,3-Di methoxy-4-carboxy-methoxy-benzoyl-1) -methyl-1 triphenyl Ifosphonium: Colorless prisms (recrystallized from dilute hydrochloric acid Pf 137-151 ° C (decomposed) H-NMR (DMSO-d ^) ppp: 3.78 (3H, s), 3.81 (3H, s), 4.69 (2H, s), 6.63 (1H, d, J = 8.9 Hz), 7.28 (1H, d, J = 8.9 Hz) 7.50-7.80 ( 15H, pt) C2.3-Chloropropoxy) -4-carboxymethoxy-benzoyl chloride 1) methyl 1 tri enyphosphonium: light yellow amorphous NMR AH (CDC13) ppm: 2.1-2.45 (2H, m), 3.63 (2H, t , J = 6.5 HZ), 4.04 (2H, t, J = 5 Hz), 4.49 (2H, S) 6.35 (1H, dd, J = 2 Hz, J = 7 Hz), 6.48 (1H. d, J = 2 Hz), 7.35-7.9 (16H, m) The NMR spectra 4-H (NMR (1) to NMR (77)) as described in Tables 36-1 to 36-23 are corao follows: NMR (1) ) (CDC13) óppm: 3.81 (3H. S), 3.91 (3H, s>, 4.65 (2H, s), 6.39 (1H, d.J = 2.6 Hz), 6.45 (1H, dd, J = 2.6 Hz , J = 8.8 HZ), 7.73 (1H, d, J = 8.8 Hz) 10.97 (1H, ß) NMR (2) (CDC13) óppm: 3.80 (3H, s) 3.97 (3H, s), 4.64 (2H. ß), 5.16 (2H, S), 6.42 (1H, dd, J = 2.4 Hz, J = 8.7 Hz), 6.60 (1H, d, J = 2.4 HZ, 7.30-7.43 (3H, Til), 7.49-752 (2H, m), 7.85 (1H, d, J = 8.7 Hz) NMR (3) (DMSO-d, * > ppp: 3.76 (3H, s), 4.76 (2H, 8), . 19 (2H, 8), 6.54 (1H, dd, J = 2.3 Hz), J = 8.7 Hz), 6.76 (1H, d.

J = 2.3 HZ), 7.27-7-44 (3H, m), 7.49-7.53 (2H, m), 7.69 (1H, d, J = 8.7 Hz), 13.07 (1H, brs) NMR (4) (CDC13 ) óppm: 3.B2 (3H, s) 3.86 (3H, S), 4. 58-4.62 (2H, m), 4.66 (2H, s). 5.58 (2H, m). 5.98-6.19 (1H.m). 6.41 (1H, dd, J = 2.4 Hz »J = 8.7 Hz), 6.54 (1H, d, J = 2.4 Hz), 7. 83 (1H, d, J = 8.7 Hz) NMR (5) (DMSO-d,), ppp: 3.74 (3H, s) 4.59-4.63 (2H, m), 4.75 (2H, s). 5.21-5.29 (2H, m). 5.93-6.09 (1H, m), 6.52 (1H, dd, J = 2.3 Hz. J = 8.7 Hz). 6.64 (1H, d, J = 2.3 Hz), 7.67 (1H, d, J = 8.7 HZ). 13.05 (1H, brs) NMR (6) (CDC13) .ppm: 1.52-2.00 (8H, m) 3.82 (3H, s), 3. 84 (3H, s), 4.66 (2H, S), 4.73-4-84 (1H, m), 6.37 (1H, dd, J = 2.4HZ, J = 8.7 Hz), 6.53 < 1H, d, J = 2.4 Hz), 7.79 (1H, d, J = 8.7 HZ) NMR (7) (CDCl 3) ppm: 1.52-2.03 (8H, m) 3.B4 (3H, s), 4. 71 (2H »s). 4.30-5.20 (2H »m), 6.40 (1H, dd, J = 2.4 HZ, J = 2.4 HZ, J = 8.7 Hz), 6.54 (1H, d, J = 2.4 Hz), 7.80 (1H, d, J = 8.7 Hz) NMR (8) (CDCla) óppm: 1.65-2.12 (8H, m) 3.74 ( 3H, S >, 3. 78 (3H, S), 3.70-3.88 (2H, m), 4.79 (2H, s), 4.83-4.94 (1H, m), 6.40-6.62 (2H.m), 7.32-7.42 (1H, m), 7.44-7.52 < 1 HOUR. ra), 7. 79-7.90 (3H, m), 8.31-10.20 (1H, brs) NMR (9) (CDCl 3) óppm: 3.61 (3H, S) 3. Bl (3H, S) 4.70 (2H, s>, 6.B3-6.97 (2H, m), 7.22-7.33 (2H, m), 7.33-7.45 (3H, m), 7.85 (1H, d, J = 8.B HZ) NMR (10) (CDC13) óppm: 3.50-3.70 (BH, m) 4.79 (2H, 8) 6. 77 (2H, m), 7.09-7.49 (8H, m). 7.5B-7.89 (2H, m). 9.97-10.81 (1H, brs) NMR (11) (CDC13) .ppm: 0.88 (3H, t, J = 7.2 Hz), 1.26-1.47 (2H, m). 1.47-1.66 (2H.m), 2.56 (2H.t, J = 7.5 Hz), 3.78 (3H, S) 3.78 (3H, 8), 4.66 (2H, S). 6.33 (1H d, J = 2.4 Hz), 6.46 (1H, dd, J = 2.4 Hz), J = 8.3 Hz), 7.05 (1H, d, J = 8.3 Hz) NMR (12) (CDC13) óppm: 0.92 (3H, t, J = 7.4 Hz), 1.48-1.70 (2H.m). 2.65-2.78 (2H, m), 3.79 (3H, s), 3.90 (3H, s), 4. 70 (2H, s). 6.25 (1H, d.J = 8.9 Hz), 7.65 (1H, d, J = 8.9 Hz). 11. OB (1H, s). NMR (13) (CDC13) .ppm: 0.94 (3H.t, J = 7.3 Hz) »1.49-1.71 (2H, m), 2.63-2.77 (2H.m), 3.B0 (3H, s). 3.B3 (3H, s), 4.70 (2H.s), 6.48 (1H.D. J = 8.8Hz), 7.70 (1H, D.J = 8.8Hz) 770 (1H, d, J = 8.8Hz) . NMR (14) (CDC13) .ppm: 0.93 (3H, t, J = 7.3 Hz), 1.47-1.70 (2H, m), 2.62-2.76 (2H.m). 3.B3 (3H. S). 3.90 (3H, s). 4.74 (2H .S). 6.51 (1H, d.J = 8. BHz), 7.20 (1H, brs), 772 (1H, d, J = 8.8 Hz). NMR (15) (CDC13) óppm: 3.77 (3H, S), 3.79 (3H, ß,), 4.59 (2H, 6.45 (1H, d, J = 2.5 Hz), 6.65 (1H, dd, J = 2.5 Hz , J = 8.B HZ,), 6.92-7.03 (2H, m), 7.03-7.17 (1H, m), 7.26-740 (2H, m), 7.91 (1H, d.J = 8.8 Hz). (16) (CDC13) óppm: 3.72 (3H, s), 3.B1 (2H, d, J = 21.6 Hz), 4.68 (2H, s), 6.34 (1H, d, J = 2.4 Hz), 6.62 ( 1H, dd, J = 2.4 HZ), 7.04-7.15 (2H, m), 7.15-7.47 (5H, m), 7.68-7, B3 (2H »m), 7.86 (1H.d, J = 8.8Hz) »10.65 (1H, brs) .NMR (17) (DMSO-d,.,.) .ppm: 2.02 (3H, S), 3.75 (3H, s), .64 (2H, s), 6.47 (1H. , J = 8.3 Hz9; S.60 (1H, d.J = 8.3 Hz), 7. 07 (1H, t, J = 8.3 Hz), 12.93 (1H, brs). NMR (18) < DMS0-dβ) óppm: 0.86 (3H, t, J = 7.2 Hz), 1. 13-1.51 (4H, m), 2.59 (2H.t, J = 7.6 Hz). 3.74 (3H. S), 4.63 (2H, s), 6.46 (1H, d, J = 8.3 Hz), 6.59 (1H, d.J = 8.3 Hz), 7.06 (1H, t, J = 8.3 Hz), 12.89 (1H.brs). NMR (19) (CDC13) .ppm: 0.97 (3H, t, J = 7.1 Hz), 1.31- 1.68 (4H, m). 2.77 (2H, t J = 7.0 Hz). 3.84 (3H, s). 4.75 (2H, s). 6.51 (1H d, J = 8.2 Hz), 6.64 (1H d, J = B.2 Hz). 7.14 (1H, t, J = 8.2 Hz). 7.26-7.39 (1H, m), 7.39-7.52 (1H, m), 7.73-7.90 (2H, m), 9.70 (1H, brs). NMR (20) (CDC13) ppm: 2.43 (3H, s), 3.82 (3H, s) » 3. 88 (3H, s). 4.70 B2h. S), 6.59 (1H, dd, J = 8.8 hz, J = 2.4 hz), 6. B1 81H, d, J = 2.4 hz), 8.00 (1H, d.J = 8.8 Hz). NMR (21) (DMSO-d,) .ppm: 2.39 (3H, s), 3.77 (3H, 8), 4. 81 (2H, s). 6.62-6B3 (2H, m), 7.89 (1H, d, J = 9.1 Hz), 13.14 (1H, brs). NMR (22) (CDC13) óppm: 2.48 (3H, s), 3.90 < 3H, s), 4. 82 (2H, s), 6.69 (1H, dd, J = 8.7 Hz, J = 2.4 Hz), 6.86 (1H, d, J = 2.4 HZ), 6.86 (1H, d, J = 2.4 Hz), 7.36 ( 1H, dt, J = 1 .2 Hz, Jßl.2 HZ, J = 7.7 HZ), 7.48 (1H, d, J = 1.2 Hz, J = 7.7 Hz), 7.B4 (2H, t, J = 7.7 Hz), 8.05 (1H, d, J = 8.7 Hz), 9.91 (1H, brs). NMR (23) (CDC13) óppm: 2.41 83H, s), 3.63 (2H, d »J = 22.6 Hz), 3.B0 (6H, d, J = 11.2 Hz), 4.82 (2H, s), 6.71 ( 1H, dd, J = 8.8 HZ, J = 2.4 Hz), 6.85 (1H, d, J = 2.4 Hz), 7.34 (1H, dt, J = 1.3 Hz, J = 9.2 HZ), 7.47 (1H, dt, J = 1 .3 H, J = 9.2 Hz), 7.82 (2H, t, J = 9.2 HZ). 8.01 (1H, d.J = 8.8 Hz). NMR (24) (CDCl 3) óppm: 0.93 (3H, t, J = 7.0 Hz), 1.19- 1.62 (4H, m), 2.73 (2H, t.J = 7.0 Hz), 3.79 (3H, s), 3.91 (3H, s), 4.70 (2H, s), 6.27 (1H, d, J = 9.0 Hz), 7.67 (1H, d, J = 9.0 hz). 11.07 (1H, s). NMR (25) (CDC13) óppm: 0.94 (3H, t, J = 7.2 Hz), 1.29- 1.63 (4H, m), 2.72 (2H, t, J = 7.1 Hz), 3.80 (3H. S), 3.83 < 3H, S), 3.89 (3H, S), 4.70 (2H, S), 6.50 (1H, d, J = 8.8 Hz), 7.72 (1H, d, J = 8.8 Hz). NMR (26) (DMS0-dβ) óppm: 0.B8 (3H, t, J = 7.1 Hz), 1. 19-1.61 (4H, m), 2.60 (2H, t, J = 6.7 Hz) 3.70 (3H, s), 3.78 (3H, s), 4.77 (2H, s), 6.71 81H, d, J = B. 8 Hz), 7.60 (1H, d, J = 8.8 Hz). 13.05 81H, brs). NMR (27) (CDC13) .ppm: 0.99 (3H, t, J = 7.1 Hz). 1.37-1.71 (4H, m), 2.80 (2H, t, J = 6.9 Hz), 3.87 (3H, s), 3.91 (3H, S), 4.82 (2H. S), 6.66 (1H, d, J = 8.8 hz) 7.34 (1H, dt, J = 1 .3 HZ, J = 7.7 Hz), 7.46 (1H, dt, J = 1 .3 Hz. J = 1 .7 Hz). 7.69-7.90 (3H, m), 9.62 (1H, brs). NMR (28) (CDC13) óppm: 1.00 (3H, t, J = 7.0 Hz), 1.39-1.73 (4H, m), 2.78 (2H, t, J = 8.0 Hz), 3.76 (6H, d.J = 11.4hz), 3. 79 (3H, S), 3.81 (2H, d.J = 22.1 Hz), 4.82 (2H, 8), 6.69 (1H, d, J = 8.8 Hz), 7.34 81H, t, J = 8.6 Hz), 7.46 (1H, t, J = 8.6 Hz), 7. 57 (1H. d, J = 8.B Hz), 7.82 < 2H, t, J = 8.6 Hz), 9.87 (1H.brs). NMR (29) (CDCl 3) óppm: 1.14 (3H, t, J = 7.5 Hz), 2.75 (2H, q, J = 7.5 Hz), 3.80 (3H, s), 3.91 (3H. ß), 4.71 ( 2H, 8), 6.28 (1H, d, J = 9.0 HZ), 7.67 (1H, d, J = 9.0 Hz), 11.08 (1H, ß > NMR (30) CCDC13) óppm: 2.18 (3H, s), 3.80 (3H, s) »3.91 (3H, s), 4.71 (2H, S), 6.2B (1H, d, J = 9.0 H), 7.67 (1H, d, J = 9.0 Hz). 11.11 (1H, s). NMR (31) (CDC13) óppm: 2.34 (3H, s), 3.81 (3H, s), 3.82 (3H, s). 3.B9 (3H.S), 4.70 (2H, S), 6.51 (1H. d, J = 8.8 Hz), 7.71 (1H, d, J = 8.B Hz). NMR (32) (CDC13) óppm: 1.18 (3H, t, J = 7.5 Hz), 2.76 (2H, q, J = 7.5 Hz), 3.B0 (3H, s), 3.84 (3H, s), 3 B9 (3H, 8), 4.71 (2H, s), 6.51 (1H, d, J = B.8 Hz), 7.73 (1H, d, J = 8.8 Hz). NMR (33) < DMSO-d, *) óppm: 2.10 (3H, s), 3.70 (3H, s), 3. 78 (3H, S). 4.78 (2H.S), 6.72 (1H, d, J = 8.9Hz), 7.59 (1H, d, J = 8.9H?), 13.11 (1H, brs) NMR (34) (DMSO-d, *) ppm : 1.08 (3H, t, J = 7.4Hz), 2.62 (2H, q, J = 7.4HZ), 3.72 (3H, S), 3.78 (3H.S), 4.79 (2H, s), 6.72 (1H, d, J = 8.9HZ), 7.60 (1H, d.J = 8.9Hz), 13.09 (1H, brs) NMR (35) (CDC13) óppm: 2.31 (3H, s), 3.85 OH, s), 3.90 ( 3H, s), 4.82 (2H, S), 6.65 (1H, d, J = 8.8HZ), 7.34 (1H, dt, J = 1.2HZ, J = 7.6HZ), 7.46 (1H, dt, J = l .2Hz, J = 7.6Hz), 7.69- 7.89 (3H, m), 9.79 (1H, brs) NMR (36) (CDC1) ppm: 1.27 (3H, t, J = 7.6Hz), 2.83 (2H, q, J = 7.5HZ), 3.87 (3H, 8), 3.91 (3H, S), 4.83 (2H, S), 6.66 (1H, d, J = B.BHZ), 7.30 (1H, dt , J = l .3Hz, J = 7.3Hz), 7.70-7.90 (3H, m), 9.72 (1H, brs) NMR (37) (CDC13) .ppm: 2.33 (3H, S), 3.77 (6H, d, J = 11.1HZ), 3.B0 (3H.S), 3.81 (2H, d, J = 22.0Hz), 4.B2 (2H, 8), 6. 69 (1H, d.J = B.BHZ), 7.35 (1H, dt, J = 1.3Hz, J = 7.9Hz), 7.47 (1H, dt, J = 1.3HZ, J = 7.9Hz). 7.61 (1H, d, J = 8.8Hz). 7.82 (2H, t, J = 7.9Hz), 9.B7 (1H, bre) NMR (38) (CDCl 3) óppm: 1.29 (3H, t, J = -7.5Hz> 2.83 (2H, q, J = 7.5Hz), 3.76 (6H, d, J = 11.2Hz), 3.80 (2H, d, J = 22.1Hz), 3.81 (3H, S). 4.83 (2H, S), 6.70 (1H, d.J = B.8Hz), 7. 38 (1H, dt, J = 1.4Hz, J = 8.6Hz> 7.47 (1H.DT, J = 1.4Hz, B.6HZ), 7. 59 (1H, d, J = 8.8Hz). 7.B3 (2H.t.J = B.6Hz), 9.73 (1H, brs) NMR (39) (CDCl 3) .ppm: 2.24 (3H, s). 3.B5 (3H, s), 4.75 (2H, s), 6.51 (1H, d, J = 8.3Hz). 6.63 (1H, d, J = 8.3Hz), 7.14 (1H, t, J = B.3Hz), 7.29-7.40 (1H, m), 7.40-7.52 (1H, m), 7.74-7.91 (2H, m ) NMR (40) (CDC13) óppm: 1.30 (3H, t, J = 7Hz) »3.91 (3H, ß), 4.27 (2H, q, J = 7Hz), 4.63 (2H, S), 6.41 (1H, d, J = 2.5Hz). 6.48 (1H. dd, J = 2.5Hz, J = 9Hz), 7.75 (1H, d, J = 9Hz), 10.96 (1H, S) NMR (41) (CDC13) .ppm: 1.30 (3H, t, J = 7Hz), 3.85 (3H, S), 3.89 (3H, s), 4.28 (2H, q, J = 7Hz). 5.43 (1H, dd, J = 2.5HZ, J = 8.5HZ), 5.48 (1H, d, J = 2.5Hz), 7.84 (1H.d, J = 8.5Hz) NMR (42) (CDC13) óppm: 1.69 (3H, d, J = 7Hz), 3.80 (3H, ß), 4.95 (1H, q.J = 7Hz), 6.45-6.7 (3H, m), 7.15-7.5 (3H, m), 7.7-7.9 ( 2H, m), 9.77 (1H, br) NMR (43) (CDCl 3) óppm: 3.38 (2H, d »J = 6.5Hz), 3.84 (3H, S), 3.86 (3H, S), 4.74 < 2H, 8), 4.95-5.15 (2H, m), 5.85-6.1 (1H, m), 6.34 (1H, s), 7.69 (1H, s), 9.28 (1H, br) NMR (44) (CDC1 » ) óppm: 3.80 (3H, ß). 3.84 (3H, s), 3. 88 (3H, s), 4.73 (2H, s), 5.98 (2H, br), 6.12 (1H, d, J = 9Hz>, 7.59 (1H, d, J = 9.1HZ) NMR (45) (CDCl 3) ppm: 2.88 <6H, s), 3.80 (3H, S), 3.83 (3H, S). 3.87 (3H, s), 4.71 (2H.S), 6.48 (1H, d.J = 8.7HZ). 7.29 (1H.J = 8.7Hz) NMR (46) (CDC13) óppm: 2.91 (6H. S), 3.B8 (3H, s), 3. 89 (3H, S). 4.80 (2H.s), 6.64 (1H, d, J = B.71H?). 7.30-7.3B (2H, m). 7.42-7.51 (1H, m), 7.80-7.89 (2H.m). 10.24 (1H, br) NMR (47) (CDCl 3) ppm: 2.90 (6H, s), 3.69 (3H, S), 3.74 (2H, d.J = 21.7Hz), 3.75 (3H, S). 3.90 (3H.s), 4.83 (2H.s). 6.74 (1H, d, J = 8.6Hz>, 7.26 (1H, d = 8.6Hz), 7.34 (1H, t, J = 9.1HZ), 7.43 (1H, t, J = 9.1Hz). -7.90 (2H.m), 10.10 (lH.br) NMR (48) (CDC1) .ppm: 3.86 (3H, S), 3.89 (3H, S), 4.65 (2H, s) 4.97 (1H, d, J = 5.9Hz), 6.49-6.55 (2H.m), 7.34-7.54 (3H, m), 7.B4-7.B9 (1H, m), 7.98 (1H, d, J = 7.3Hz) NMR ( 49) (CDC13) óppm: 3.72 (3H, s), 3.78 (3H, s), 3.79 < 3H, d, J = 21.7Hz), 3.92 (3H, S), 4.66 (2H, s), 4.97 ( 2H, d, J = 5.9Hz), 6.53-6.61 (2H, m), 7.39-7.54 (3H, m). 7.B2-7.90 (2H, m), 7.98 (1H, d, J = 7.6Hz) NMR (50) (DMSO-d,. ,,) óppm: 1.13 (6H, d, J = 7.0Hz), 3.08 - 3.35 (1H, m), 3.69 (3H, s), 4.66 (2H, ß), 6.38 (1H, J = 2.4HZ), 6.48 (1H, d, J = 2.4Hz, J = 8.4Hz) , 7.07 (1H, d »J = 8.4HZ). 12.93 (1H, s) NMR (51) (DMSO-d, ..) óppm: 0.69-1.00 (3H, m), 1.08-1.62 (3H, m), 2.32-2.63 (2H, m), 3.6B ( 3H, s), 4.65 (2H, s), 6.30-6.53 (2H, m), 7.00 (1H, d, J = 8.2Hz), 12.92 (1H, s) NMR (52) (CDC13) óppm: 2.31 ( 3H. S). 3.78 (3H, S), .74 (2H, S). 6.42 (1H.d, J = 2.4Hz), 6.52 (1H, dd, J = 2.4Hz, J = 8.8H?). 7.12 (1H, d, J = 8, BHz). 7.25-7.53 (2H.m), 7.72-7.94 (2H, m), 9.71 (1H.s) NMR (53) (CDCl 3) .ppm: 1.30 (6H, d, J = 6.9Hz), 3.19- 3.46 ( 1H, m). 3.79 (3H, s), 4.75 (2H, S), 6.44 (1H, d »J = 2.4Hz), 6.60 (1H, dd, J = 2.4Hz, J = B.5HZ), 7.20 (1H, d, J = 8.5Hz), 7.24-7.53 (2H, m), 7.72-7.94 (2H, m), 9.51-9.82 (1H, brs) NMR (54) (CDC13) óppm: 0.78-0.99 (3H, m), 1.18-1.77 (8H, m). 2.67 (2H.t, J = 7.9Hz). 3.78 (3H, S). 4.74 (2H. S), 6.43 (1H, d, J = 2.4Hz), 6.55 (1H, dd, J = 2.4HZ »J = 8.3HZ), 7.12 (1H, d, J = 8.3HZ), 7.23- 7.52 (2H, m), 7.75-7.92 (2H, m), 9.56-9.80 (1H, brs) NMR (55) (DMS0-d, s) .ppm: 2.09 (3H, s), 3.6B (3H, S ), 4. 66 (2H, s), 6.32-6.52 (2H, m), 7.02 (2H, d, J = 8.1Hz), 12.95 (1H, 8) NMR (56) < CDC13) .ppm: 3.82 (3H, s), 3.93 (3H, 8), 4.73 (2H, s), 6.34 (1H, S), 8.02 (1H, S), 10.93 (1H. S) NMR (57) ( CDC13) óppm: 3.82, 3.86, 3.8B (every 3H, every s), 4.77 < 2H. s). 6.40 (1H, S). 8.07 (1H, d.J = 3.1Hz) NMR (58) (DMS0-dβ) óppm: 3.74, 3.82 (each 3H, each S), 4.97 (2H, s), 6.74 (1H, S), 7.83 (1H , d, J = 3.6Hz), 12.B2-13.44 (1H, br) NMR (59) < DMS0-dβ) óppm: 3.73, 3.74 (each 3H, each S), 4.63 (2H, S), 6.76 (1H, s), 7.30 (1H, S), 10.66 (1H, brs) NMR (60) (DMSO-d, .-.) Óppm: 3.66 (3H. ). 3.70 (3H.S), 4.64, 4.73 (total 1H, each s), 6.34-6.52 (2H.m). 6.79-6.96 (1H, m). 12.88-13.03 (1H.m) NMR (61) (CDC13) .ppm: 3.77 (3H.s). 3.97 < 3H, S), 4.78 (2H, s), 6.51-6.72 (2H.m), 6.89 (1H. d, J = 8.8Hz). 7.21-7.56 (2H. M). 7.73-7.92 (2H, m) NMR (62) (DMSO-d, ¥) óppm: 1.27 (3H, t J = 7.0Hz). 3.65 (3H .S). 3.92 (2H, q, J = 7.0Hz), 4.65 (2H, S). 6.32-6.52 (2H, m), 6.78-6.93 < 1 H »m), 12.81-13.01 (1H, brs) NMR (63) (CDC13) .ppm: 2.84 (6H, S), 3. B9 (3H, S). 4. 81 (2H, S), 5.23 (2H, 8), 6.70 (1H, d.J = 9.0Hz), 7.26-7.40 (5H, m), 7.60-7.64 (2H, m) NMR (64) (CDC13) ppp: 2.91 (6H, s>, 3.93 (3H, S), 4.73 (2H, ß), 7.14 (1H, d.J = 7. BHZ) »7.90-7.94 (2H, m), 9.72 (1H, br) NMR (65) (CDCl 3) ppm: 3.03 (6H, s), 3.91 (3H, s), 4.92 (2H, S), 7.12 (1H, d, J = 8.3Hz), 7.29 (1H, dt , J = 1.2Hz, J = 7.8HZ), 7.43 (1H, dt, J = 1 .2HZ, J = 7.8Hz), 7.78-7.86 (4H, m), 13.22 (1H, br) NMR (66) ( CDC13) óppm: 3.03 (6H, s), 3.61 (2H, d, J = 22.7HZ), 3.77 (3H »8), 3.81 (3H, S), 4.94 (2H, s), 7.15 (1H, d, J = 8.4HZ), 7.30 (1H, t, J = 7.BHz ), 7.43 (1H, t, J = 7.8HZ), 7.76-7.86 (4H, m) NMR (67) <; CDC13) óppm: 3.96 (3H, s), 4.03 (3H, s), 4.55 (1H, brd, J = 27.4Hz), 4.76 (2H, s). 6.71 (1H, d, J = B.7HZ), 7.25-7.38 (1H, m), 7.39-7.88 (19H, m), 10.50 (1H, brs) NMR (6B) (CDCl 3) óppm: 2.10-2.30 (2H, m), 3.58 (2H, t, J = 6.6HZ), 4.04-4.19 (2H, m), 4.3B-4.72 (1H, m). 4.65 (2H, s), 6.39 (1H, dd, J = 2.3Hz, J = B.6Hz), 6.52 (1H, d, J = 2.3HZ), 7.28-7.95 (20H, tu), 10.5B (1H , brs) NMR (69) (CDC13) .ppm: 1.82-2.11 (2H, m). 2.11-2.38 (4H, m), 2.3-2.61 (2H.m). 3.49-3.75 (4H.m). 4.04 (2H, t, J = 5.9HZ), 4.50-4.93 (1H, m), 4.6B (2H.s). 6.40 (1H, dd, J = 2.2Hz, J = 8.6Hz>, 6.54 (1H, d, J = 2.2Hz), 7.23-7.37 (1H, m), 7.37-7.62 (10H, rn >, 7.62 -7.96 (9H, m), 10.37 (1H, brs) NMR (70) (CDC13) .ppm: 3.00 (6H, s>, 3. B9 (3H, 8), 4. 70 (2H, s), 6.49 (1H, dd, J = 2.5Hz, J = 8.5H?). 6.57 (1H, d.J = 2.5HZ), 6.93 (1H, dd, J = 2.5Hz, J = 9Hz), 7.08 (1H, d, J = 2.5HZ), 7.20-8.05 (16H, m). B.55-8.65 (1H, m), 9.90 (1H, br) NMR (71) (CDC13) ppm: 1.21-1.56 (2H, m), 1.67 (1H, br), 1.75-1.94 (2H, m) , 2.01 (1H, t, J = 10.6Hz), 2.01-2. B9 (14H, m), 3.02-3.28 < 2H, m), 3.55-3.78 (2H, m), 3.85-4.02 (1H, m) NMR (72) (CDC13) óppm: 1. B3 (1H, br), 2.15 (1H, dd, J = 4.1HZ , J = 12.8Hz), 2.26 (6H, S), 2.43 (1H, dd, J = 7.8Hz, J = 12.8HZ), 2.53 (1H, dd, J = 10.2Hz, J = 12.1Hz), 2.68- 2.98 (3H.m), 3.50-3.72 (2H, m), 3.78-3.99 (1H.m) NMR (73) (CDCl 3) .ppm: 2.78 (2H, t, J = 7.5Hz), 3.09 (2H, t, J = 7.5HZ), 3.90 (3H, S), 7.15 (2H, d, J = 8.5HZ), 7.8-7.95 (1H, m), 7.90 (2H, d, J = T.5HZ) NMR ( 74) < CDC13) óppm: 2.77 (2H, t, J = 7.5Hz), 3.06 (2H, t, J = 7.5HZ), 3.66 (2H, d.J = 22.6Hz), 3.75 (3H, s), 3.81 (3H, s), 7.10-7.22 (2H, m), 7.26-7.49 (2H, m>, 7.63-7.68 (1H, m), 7.81-7.90 (3H, m) NMR (75) (CDCl 3) p.ppm: 2.79 (2H, t, J = 7.5Hz), 3.06 (2H, t, J = 7.5Hz), 3.76 (3H.s), 3.86 (3H.s), 6.65 (1H, d, J = 8HZ) , 6.72 (1H, s), 7.25-7.5 (2H.m), 7.6-7.75 (2H, m), 7.85 (1H, d.J = 7.5Hz), 11.40 (1H.br) NMR (76) (CDCL3 ) óppm: 2.80 (2H, t J = 7.5Hz), 3.05 (2H, t, J = 7.5HZ), 3.73 (3H, s), 3.78 (3H, s), 3.79 (3H, s), 3.82 ( 2H.D, J = 21.5Hz), 6.65-6.B (2H, m), 7.25-7.45 (2H.m), 7.60 (1H. d.

J = 8.5HZ), 7.64 (IH.d.J = 7.5Hz> 7.82 (1H, dd, J = 1HZ, J = 7.5Hz), 11.49 (1H, br) NMR (77) (CDC13) óppm: 3.62 (1H, d, J = 22.5Hz), 3.77, 3.82 (6H, each s), 4.04 (3H, s), 4.85 (2H, s), 7.02 (1H, d, J = 8.5HZ>, 7.3 -7.55 (1H, m) 7.6-7.7 (2H, m), 7.8-7.9 (2H, m), 10.31 (1H, br) EXAMPLE 1 A solution of 6.5 g of 2- (2-ißopropi Ifenoximeti Icarboni lamino) benzoti azol was added. 3.9 g of anhydrous maleic acid and 8.0 g of aluminum chloride in 50 ml of 1,2-dichloroethane at room temperature for 7 hours. Water is added to the mixture in order to decompose the aluminum chloride, and ethyl acetate is added thereto and the mixture is stirred. The precipitated crystals are collected by filtration, washed with ethyl acetate and dried to give a mixture of 7.3 g of a trans compound and a cis compound.

The mixture thus obtained is dissolved in 50 ml of dimethylformamide, thereto is added 1 ml of concentrated hydrochloric acid and the mixture is stirred at 60 ° C for 30 minutes. Water (approximately 100 ml) is added to the mixture and the precipitated crystals are collected by filtration, washed with methanol and dried to give 6.2 g of 2-C2-i sopropi l-4- (trans-3-carboxyalkyl). ) phenoxymethicarboni 1-aminoDbenzothiazole JH-NMR (DMS0-dβ) ppp: 1.25 (6H, d, J = 7Hz), 3.40 (lH, sept, J = 7Hz), 5.12 (2H, s), 6.64 (1H, d , J = 15.5Hz), 7.03 (1H, d, J = 8.5 Hz), 7.25-7.5 (2H, m), 7.77 (1H, d, J = 7.5Hz). 7.85-8.05 (4H, m), 12.70 (1H, br), 13.10 (1H, br) EMPLP To a solution of 1.0 g of 2-C2-isopropi 1-4- (3-carboxyacri loi 1) phenoxymethylcarboni laminoDbenzothiazole and 0.4 ml of triethylamine in 20 ml of dichloromethane is added dropwise 0.32 ml of isobutyl chloroformate under freezing. To the mixture 0.27 ml of N-me piperazine is added at the same temperature and the mixture is stirred for 2.5 hours. The reaction solution is washed with water, concentrated and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (sol; dichloromethane-dichloromethane: methanol = 30.1), and recrystallized from ethanol to give 0.80 g of 2-C2-isopropi 1-4-3- (4-methyl). ll-Piperazine Icarboni 1) Acryloyl D Phenoxymethyl Icarboni Lamino} benzothiazole Brown coffee powder gone P.f. 190-192 ° C EXAMPLE 3 A solution of 1.0 is stirred at room temperature for 10 hours. g of 2-C4- (3-carboxyacri loi 1) phenoxymethylcarbonyi amino3-benzothiolol »0.23 ml of thionyl chloride and one drop of 20 ml of dimethylformamide in 20 ml of dichloromethane. The solution is added dropwise to a solution of 0.5 g of 4- (4-methyl-1-piperazine 1) piperidine and 1 ml of pyridine in 20 ml of dichloromethane under freezing. To the reaction solution, add water and the mixture is made alkaline with an aqueous solution of 5 * 1 sodium hydroxide. The mixture is extracted with dichloromethane and the extract is washed, it is dried and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; dichloromethane.'methane! = 50: 1 10: 1). The compound thus obtained is converted into a hydrochloride thereof by a conventional method and recrystallized from ethanol-diethyl ether to give 0.14 g of 2-C4-C3-C4- (4-methyl-piperazine 1-bichloride. -1-piperidini Icarboni 1) acri loi 1} phenoxy-methyl Icarboni lamino-3-benzothiazole. White powder P.f. 202.5-225 ° C (decomposition) J-H-NMR (DMS0-dβ) óppm: 1.35-1. B (2H, m), 2.0-2.3 (2H, m), 2.6-3.9 (11H, m)), 2.81 (3H, s), 4.1-4.3 (1H, m) 4.5-4.7 (1H, m), 5.0B (2H, s), 7.15 (2H, d, J = 9HZ), 7.3-7.55 (3H, m), 7. 76 (1H, d, J = 14Hz), 7.77 (1H, d, J = 8.5HZ), 7.98 < 1H, d, J = 8Hz), 8.05 (2H, d, J = 9Hz, 12.67 (1H, br) ? Efl Q 4 To a solution of 0.97 g of 2-C2-isopropi 1-4- (3-carboxyacri loi 1) pheno? Imet? Icarboni lami noDbenzoti azole in 10 ral of dimethylformamide is added by dripping 0.65 g of 4- (4-methyl-piperazine 1) pipep "dina and 0.6 ml of diethyl cyano-phosphate at room temperature. The mixture is stirred at room temperature for 10 minutes, water is added to the mixture and the mixture is extracted with ethyl acetate.The extract is washed with water, dried and concentrated under reduced pressure. purify by silica gel column chromatography (solvent, dichloromethane: methanol = 100: 1 10: 1) The compound thus obtained is converted into a hydrochloride thereof in ethanol by a conventional method and recrystallized from ethanol-ether diethyl to give 0.45 g of 2- {2-isopropyl-4-C3-C4- (-methyl-piperazinyl) -1-piperidim "Icarboni 1 Dacryl loi 13-phenoxymethi-1-carbonyl-lamino) -benzothiazole bichloride. Yellow powder P f. 186-190 ° C (decomposition) E EM LO 5 To a solution of 4.0 g of dibutyl tartrate in 100 ml of methanol is added a solution of 3.0 g sodium periodate in 30 ml of water and the mixture is stirred for 10 minutes and extracted with ethyl acetate. Separately, to a suspension of 5.7 g of dimethyl. { C 3 -methoxy-4 - (2-benzothiazole and laminocarbonyl lmethoxy) benzoyl 1] -methyl 1} Phosphonate in 100 ml of tetrahydrofuran is added an aqueous solution of 5% sodium hydroxide under freezing until the reaction solution becomes uniform, and then a solution of glyoxalate, which is previously prepared, is added thereto by dripping. from dibutyl tartrate, in 30 ml of tetrahydrofuran under freezing. The mixture is stirred for 30 minutes and acidified with 5% hydrochloric acid and concentrated under reduced pressure to remove the tetrahydrofuran. The precipitated crißtals are collected by filtration and washed with dichlororaethane. The dichloromethane layer is concentrated under reduced pressure and the residue is purified by silica gel column chromatography (solvent, dichloromethane: methanol = 200: 1) to give 2.85 g of 2-C2-methoxy-4- (3-butoxycarboni). lacri loi l) phenoxymethicarboni 1-aminoDbenzothiazole, which is further stirred in tetrahydrofuran-aqueous solution of sodium hydroxide at 5Ji at room temperature for 30 minutes to give 2.9 g of 2-C2-methoxy 1-4- (3- carboxyacri loi l) phenoxymethi Icarboni lami no3benzo i azole. - "- H-NMR (DMSO-d ,,,) óppm: 3.89 (3H, s), 5.09 (2H. S), 6.67 (1H, d, J = 15.5Hz), 7.08 (1H, d, J = 8.5Hz), 7.25-7.55 (2H, m), 7.57 (1H, m), 7.7-B .1 (4H.m), 11.68 (1H, br) EXAMPLE 6 To a solution of 17.7 ml of ethyl propiolate in 450 ml of tetrahydrofuran is added dropwise a 1.71 M solution of n-butyl lithium in 102 ml of n-hexane at -78 ° C. and the mixture is stirred for 10 minutes. To the solution is added dropwise a solution of 20 g of 2- (2-methoxy-4- formi ifenoximeti Icarboni lamino) benzothiazole in 400 ml of tetrahydrofuran and 40 ml of N, N-dihydroxypropyl urea at the same temperature during a period of 5 minutes. The mixture is stirred further for 10 minutes and the reaction vessel is taken out of an ice bath and stirred for a further 20 minutes. To the mixture 11 ml of acetic acid is added and the mixture is diluted with ethyl acetate. The ethyl acetate layer is washed with a saturated aqueous solution of sodium carbonate and dried over sodium sulfate and concentrated. The 8β residue is purified by silica gel column chromatography (solvent, dichloromethane: methanol = 100: 1 50: 1) to give 33.7 g of 2-C2-methoxy-4- (3-methoxycarboni 1-1 + hydroxyproparg 1) phenoxy-methyl Icarboni laminolbenzothiazole as a dark brown oil.

To a solution of 3.7 g of 2-C2-methox i carboni 1-1-hydroxyproparg 1) phenoxymethyl Icarboni lami olbenzothia? Ol in 150 ml of dimethylformamide is added 14.3 ml of tri-n-butylamine and the mixture is stirred at room temperature. environment for 1.5 hours. The mixture is diluted with ethyl acetate and washed with 0.15N hydrochloric acid, and dried over sodium sulfate. The mixture is concentrated under reduced pressure to remove the solvent and the precipitated crystals are collected by filtration to give 2-C2-methoxy-4- (3) -methocarboxylacri loi 1) phenoxymethylcarboni 1-ami no] enzoti azole (Compound A, 5.5 g) as a pale yellow powder. On the other hand, the filtrate is concentrated under reduced pressure and crystallized from ethanol-diethyl ether to give 2-C2-methoxy-4- (cis-3-methoxycarbonylalkyl).phenox imeti 1-carboni laminoDbenzothiazole (Compound B, 6.0 g) as a pale yellow powder.

Compueßto A: ^ H-NMR (DMSO-d ^,) óppm: 1.26 (3H, t J = 7.1 Hz) 3.92 (3H, ß) 4.21 (2H, q, J = 7.1Hz), 5.11 (2H, 8), 6.71 (1H, d, J = 15.5HZ). 7.08 (1H, d.J = 8.6Hz), 7.31-7.37 (1H, m), 7.44-7.50 < 1 HOUR. m). 7.59 (1H, d, J = 2, OHz), 7.75-7.81 (2H, m), 7.9B (1H, d, J = 15.5 HZ), 8.00-B.02 (1H, m), 12.67 (1H, brβ) Compueßto B: AH-NMR (DMSO-dβ) óppm: 1.05 (3H, t, J = 7.1 Hz), 3.89 ( 3H, 8), 3.97 (2H, q, J = 7.1Hz), 5.11 (2H. S), 6.35 (1H, d, J = 12.3HZ), 7.05 (1H, d, J = 8.8 Hz), 7.21 (1H, d, J = 12.3Hz), 7.31-7.37 (1H, m), 7.44-7.44-7.50 (3H, m), 7.7B + -7B1 (1H, m), 7.99-B.02 (1H, m). 12.62 (1H.brs) ? JEMP Q 7 A solution of 100 mg of 2-f.2-isopropyl-4-Ctrans-3- (4-methyl-1-piperazine and 1) -carbonylurea-3-phenoxymethylcarbonylamino is allowed to stand} benzothiazole in 100 ml of dimethylformamide for 6.5 hours through a window in order to expose it to direct sunlight. Water is added to the mixture, the precipitated crystals are collected by filtration and recrystallized from ethanol to give 45 mg of 2-C2-isopropi 1-4-Cc i s-3- (-meti 1-1-piperazini 1) carbom "lacri loi 1] phenoxymethyl Icarboni lamino.} Benzothiazole pale yellow powder Pf 114-115 ° C EXAMPLE B To a solution of 1.7 g of < "C3-methoxy-4- (2-benzothiazole and laminocarbonyl-methoxy) benzoyl-13-methyl-1-phosphonate and 0.5 g of pyridine-4-aldehyde in 30 ml of tetrahydrofuran add 6 ml of an aqueous solution of sodium hydroxide. at 5% by cooling, and the mixture is stirred for 5 hours.The mixture is neutralized with acetic acid and the precipitated crystals are collected by filtration, then recrystallized from dichloromethane-ethanol-diethyl ether to give 1.3 g of 2 g. -C2-methoxy-4-C3-4 (4-pyridi 1) acri loi 1"Ifeniximeti Icarboni lamino} -benzothiazole. Yellow powder P.f. 206-207 ° C S E? P Q 9 To a solution of 1 g of 2-C2-methoxy-4- (3-t-butoxycarboni 1-1-hi doxipropargi 1) -phenoxymethyl Icarboni lami noD-benzothiazole in 50 ml of chloroform is added 1 g of active manganese dioxide and the mixture is refluxed for two hours. In addition, 1 g of active manganese dioxide is added to the mixture and the mixture is refluxed for 1.5 hours. The mixture is filtered through a pad of cerite and the filtrate is concentrated. The residue is recrystallized from ethanol to give 0.5 g of 2-C2-methoxy-4- (3-tert-butoxycarboni ipropiol i 1) phenoxymethylcarbonylamino} benzothiazole E E? PIQ IQ To a solution of 0.5 g of 2-C2-methoxy-4- (3-butoxycarbonylpropiolo-1) phenoxymethyl-Icarboni-lamino-benzo-thiazole in 30 ml of methylene chloride is added 10 ml of trifluoroacetic acid and the mixture is stirred at room temperature. environment for 4 hours. The mixture is concentrated and methylene chloride is added to the residue. The mixture is shaken and the precipitated crystals are collected by filtration and recrystallized from dichloromethane-trifluoroacetic acid to give 0.26 g of 2-C2-methoxy-4- (3-carboxypropionyl) 1-phenoxymethyl-1-aminoabenzothiazole as coffee powder P.f. 174-176 ° C Using the appropriate starting compounds, they obtain the following compounds in the same manner as in Example 1 or 5.

CVAPRP ge Example 11 R: H A: -CHß- Z :? RB: CH3 (position 2) m: 1 P.f. 261-262 ° C Crystalline form: beige powder Solvent for recrystallization: Dimethylformamide-pietanol Form: Free Example 12 R- ": HA: -CHa- Z'O RB: CaHß (position 2) m: 1 Pf 245-246cC Form crißtalina: beige powder Solvent for recrystallization: Dimeti lformamide-methane! Shape: Free Example 13 R ": H A: -CH3- Z" 0 RB: propyl (position 2) m: 1 Crystalline form: yellow powder Form: Free NMR (1) TABLE 39 Example 14 R "*: HA: -CH9- Z: Rß: Isopropyl (position 2> m: 1 Pf .225-240 ° C (decomp.) Cristalline form: yellow powder RMNI2) Solvent for recrystallization: Dimet lformami da-methane1 Forroa: Free Example 15 R "1: HA: -CHa- Z: RB: n-Butyl (position 2) m: 1 Pf 1B7.5-190 ° C Crystalline form: Light yellow powder Solvent for recrystallization: Chloroform-dimethylformamide Form : Free Example 16 R ": H A: -CH3- Z: R * 8: H m: 1 P.f. 250-275 ° C (decomp.) Crystalline form: white powder Solvent for recrystallization: Dimeti Iformami da-methane1 Form: Free Example 17 R "*: HA: -CHa ~ Z: ° RB: n-Pentyl (position 2) m: 1 Pf 139-163 ° C Crystalline form: Light yellow powder NMR (4) Solvent for recrystallization: Dimeti lforraamide-dichloromethane Free form TABLE 40 Example 18 R "': H A: -CHa- 2: 0 R °: F (position 2) m: 1 P.f. 233-234 ° C Crystalline form: Light brown powder Solvent for recrystallization: Dimeti lformamide-methane1 Form: Free Example 19 R- ": H A: -CH3- 2 = 0 Rß: Cl (position 2) m: 1 Crystalline Forra: yellow powder Form: Free NMR (5) Example 20 R- ": H A: -CHa ~ z: 0 RB: (CH,.) ^ (Combined in positions 2 and 3) ra: 2 Crystalline form: yellow powder NMR (6) Form: Free Example 21 R "*: H A: -CHß- Z: 0 RB: CH (positions 2 and 3) m: 2 Crystalline Forra: yellow powder NMR (7) Form: Free? YAPRQ 41 Example 22 R- ": HA: -CHa- Z:? RB: CH3 (positions 2 and 3) m: 2 Form crißtalin: beige powder NMR (8) Solvent for recrystallization: Dimeti Iformamide-methane1 Form: Free Example 23 R * : HA: -CHa- Z:? RB: CH3 (positions 3 and 5) m: 2 Crystalline form: yellow powder Form: Free NMR (9) Example 24 R- »: HA: -CHa- 2: 0 RB: - (CH2) 2COaCaHß (position 2) m: 1 Pf 199.6-203 B ° C Crystalline form: Light yellow powder Solvent for recrystallization: Chloroform-dime and lforraamide Forraa: Free Example 25 R "*: HA: -CHa ~ Z : 0 RB: - < CHa > ^ 0C0CH3 (position 2) m: 1 P.f. 176-177.5 ° C Crißtaline form: Light yellow powder Solvent for recrystallization: Chloroform Form: Free? UAPPQ Example 26 R "': H A: -CHa ~ Z: RB: CaHβO (position 2) m: 1 Crystalline form: yellow powder NMR (10) Free form Example 27 R- ': H A: -CHa- Z: ° Rß: CH 3 (position 3) m: 1 P.f. 290 ° C (decomp.) Crystalline form: White needles NMR (11) Sol for recrystallization: D methyl formamide Form: Free Example 2B R "*: H A: -CHa ~ z: ° R" *: C3HB (position 3) m: 1 Crystalline form: yellow powder NMR (12) Form: Li re Example 29 R- *: H A: -CHa- Z: ° RB: n-Propyl (position 3) m: 1 P.f. 2B2 ° C (decomp.) Crystalline form: Clear brown needles Solvent for recrystallization: Dimeti Iformaroida-dichloromethane Form: Free EU? PRP 43 Example 31 R "1: H A: -CHß- z: ° RB: n-Butyl (position 3) m: 1 P. 267-279 ° C (decomp.) Crystalline form: pink powder Shape: Free NMR (14) Example 32 R- *: H A: -CH3- z "0 Rβ: Isopropyl (3-position) m: 1 P.f. 262.5-2.65.5 ° C Crystalline form: yellow powder Solvent for recrystallization: Dimeti Iformamide-dichloromethane Form: Free Example 33 R "1: H A: -CHaZ: 0 RB: Cl (position 3) m: 1 Crystalline form: Light yellow powder NMR (15) Form: Free TABLE 44 Example 34 R- ": H A: -CHa- Z: 0 R * 8: F (position 3) m: 1 Crystalline form: Light yellow powder NMR (16) Free form Example 35 R ": H A: -CHa- Z: 0 RB: CH30 (position 3) m: 1 Crystalline form: yellow powder NMR (17) Free form Example 36 R ": H A: -CH3- Z: RB: CaHß0 (position 3) m: 1 Crystalline form: yellow powder NMR (18) Form: Free Example 37 R "1: H ra: 1 Z: RB: and A combine to form: 1 k ^ Pf 294-295 ° C (decomp) Crystalline form: white powder Solvent for recrystallization: Dimet lformamide Form: Free? UAPRP Four. Five Example 38 R "": H A: -CHa ~ z: 0 RB: CH3O (position 2) m: 1 Crystalline form: yellow powder NMR (19) Free form Example 39 R "': H A: -CHa ~ z: 0 RB: (CH3) aCHO- (position 3) m: 1 Crystalline form: Light yellow powder NMR (20) Free form Example 40 R ": H A: -CHa- Z: 0 RB: CF3CH30- (position 3) m: 1 Crystalline form: Light yellow powder NMR (21) Form: Free Example 41 R "1: H A: -CH3- Z: 0 Rβ: CF3 (position 2) ra: 1 Crystalline form: Colorless powder NMR (22) Form: Free? UAppQ 4S Example 42 R- *: H A: -CH3- Z: 0 RB: -OCHACO (C3Hß) a (position 2) ra: 1 Crystal form na: yellow powder NMR (23) Form: Free Example 43 R- ": H A: -CHa ~ Z" 0 RB: COOCH, s (position 2) m: 1 Crystalline form: Light yellow powder NMR (24) Form: Free Example 44 R "»: HA: -CHa ~ z: 0 RB: - (CHa) 3-CONH- (combined in positions 2 and 3) m: 2 Crystalline form: yellow powder NMR (25) Form: Free Example 45 R,: HA: -CHa ~ z "0 RB: (CH3) 3C- (position 2) m: 1 Pf 263-266 ° C (decomp.) Cristalline form: yellow powder Solvent for recrystallization: Dimeti Iformamide-d Chloromethane Form: Free 26B TABLE 47 Example 46 R - ": H A: -CHa ~ z: 0 RB: - (CH2) 2COOCH3 (position 2) m: i Crystal Shape: Yellow NMR Powder (26) Free form Example 47 R - ": H A: -CH3- Z :? R "" *: - (CHa) aCO (CH3) 3 (position 2) m: i Crystal form: Pale yellow powder RMN (27) Shape: Free Example 48 R ": H A: -CHa- Z: ° RB *. - CHa > aCO (CaHß> a (position 2) m * .l Form crißtalina: Yellow amorphous NMR (2B) Form: Free Example 49 R- ^ H A: -CHa ~ z "0 RB: Cl (position 2) m: l P.of f. 235.5-237 ° C Form crißtalina: Yellow powder Solvent for recrystallization: Dimeti Iformami da-agua Form: Free CUAPRQ 46 Example 50 R "': H A: -CHa" Z: 0 RB: - (CH2) 2COOC2HB (position 2) ra: i P.of f. 199.6-203.8 ° C Crystalline form: Pale yellow powder _ Solvent for recrystallization: Chloroform-dimeti Iformamide Form: Free NMR (29) Example 51 R "': H A: -CH Z:? RB: n-butyl (position 2) m: i P.of f. 187.5-190 ° C Crystalline form: Palored yellow powder Solvent for reclosing: Chloroform-dimeti Iformamide Form: Free Example 52 R - ': H A: -CHa- Z: o RB: - (CHa > - »OCOCH3 (position 2) m: i P.from 176-177.5 ° C Crystalline form: Pale yellow powder Solvent for recrystallization: Chloroform Form: Free TABLE 49 Example 53 R - ": H m: 1 Z :? RB and A combine to form: P.of f. 2B5-2B7 ° C (decomposition) Crystalline form: White powder Solvent for recrystallization: Dimeti Iformami da-agua Form: Free Example 54 R - ": H A: -CHa- Z: 0 RB: n-heptyl (position 2) m: i P.of f. 187-188.5 ° C Crystalline form: Pale yellow powder Sun for recrystallization: Di c 1 ororaethane-dimeti 1 formami da Form: Free Example 55 R "': H A: -CHa- Z: S RB: CH30 (position 2) m: i P.of f. 241-244 ° C Crystalline form: Yellow powder Shape: Free Spectrum of AH-NMR (NMR (1) to NMR (29)), as described in tables 38-49, is as follows: NMR (l) (DMS0 -dß) óppm:? .92 (3H, t, J = 7.4Hz), 1.58- 1.69 (2H, m), 2.69 (2H, t, J = 7.4HZ), 5.12 (2H, S), 6.65 ( lH, d, J = 15.4Hz), 7.03 (1H, d, J = 8.6Hz), 7.31 (1H.t.J = 7.6H?), 7.44 (lH, t, J = 7.7Hz), 7.76 (1H , d, J = 7.7Hz), 7.87-7.99 (4H, m) NMR (2) (DMS0-d6) óppm: 1.25 (6H, d, J = 7Hz),), 7.03 (lH, d, J = 8.5 Hz), 7.25-7.5 (2H, m), 7.77 (lH, d, J = 7.5Hz), 7.85-S.05 (4H, m>, 12.70 (lH, br), 13.10 (1H, br) NMR (3) (DMS0-d6) óppm: 5.07 (2H, s), 6.65 (lH, d, J = 15.5Hz), 7.15 (2H, d, J = 9Hz), 7.1-7.5 (2H, m), 7 , 76 (1H, d, J = 7Hz), 7.89 (lH, d, J = -15.5Hz), 7.99 (1H, d, J = 7Hz), 8.05 (2H, d, J = 9Hz), 12.70 (IH .br), 13.04 (lH.br) NMR (4) (DMS0-d6) .ppm:? .89 (3H.t, J = 6.4Hz), 1.21- 1.50 (4H, m), 1.53-1.79 (2H, m), 2.69 (2H, t, J = 8.0Hz), 5.14 (2H, S), 6.64 (lH, d, J = 15.5Hz), 7.04 (1H, d, J = 8.5Hz), 7.30-7.38 ( lH, m), 7.43-7.51 (lH »m>, 7.78-7.82 (lH, d, = 7. 9Hz), 7.85-8.10 (4H, m) NMR (5) (DMS0-d6) óppm: 5.22 (2H, 8), 6.67 (lH, d, J = 15.5Hz), 7.24-7.49 (3H, m), 7.77 (lH, d, J = 7.6Hz), 7. S9 (1H, d, J = 15.5Hz), 7.96-B.12 (3H, m), 12.83 (lH, br) NMR (6) (DMS0- d6) óppm: i.6-1.9 (4H, m), 2.65-3.0 (4H, m), . 06 (2H, S), 6.45 (lH, d, J = 16Hz). 6.82 (1H, d, J = B.5Hz), 7.25- 7.65 (4H, m), 7.75 (lH, d, J = 8Hz), 7.97 (lH, d, J = 8Hz), 12.85 (lH, br) NMR (7) (DMS0-d6) óppm: 2.22 (3H, ß), 2.3K3H.S), . 05 (2H, S), 6.44 (lH, d, J = 15.5Hz), 6. B5 (1H, d, J = 8.5HZ), 7.25-7.6 (4H, m), 7.76 (lH, d, J = 8Hz), 7.98 (1H, d, J = 8Hz), 12.83 (lH, br) NMR (8) (DMS0-d6) óppm: 2.36 (6H, S), 4.75 (2H, S), 6. 67 (lH, d, J = 15.5Hz), 7.30-7.53 (2H, m), 7.77 (lH, d, J = 8.9Hz), 7.79 (2H, S), 7.91 (lH, d, J = 15.5Hz ), 8.00 (1H, d, J = 7.00Hz), 12.09-13.2 (2H, br) NMR (9) (DMS0-d6) .ppm: 2.10 (6H, s), 4.95 (2H, s). 6. 22 (lH, d, J = 16HZ), 6.78 (2H, S), 7.02 (1H, d, J = 16Hz), 7.25-7.5 (2H, m), 7.76 (lH, d, J = 8Hz). 7.9B (lH.d, J = 7.5Hz). 12.9 (2H, br) NMR (IO) (CDCl ,, -) óppm: l.37 (3H, d, J = 7.0Hz), 4.14 (2H, qJ = 7.0Hz), 5.09 (2H, S), 6.65 1H, d, J = 15.5HZ), 7.06 (lH, d, J = 8.6Hz), 7.31 (lH.d, J = 7.4Hz), 7.44 (1H, t, J = 7.4HZ) »7.55 (1H , S), 7.67-7.78 (2H.m), 7.90 (lH, d, J = 15.5HZ), 7.98 (lH, d, J = 7.4HZ), 12.74 (2H, br) NMR (ll) (DMS0- d6) óppm: 2.45 (3H, S), 5.03 (2H, S), 6.45 (lH, d, J = 15.6Hz) »6.90-7.06 (2H, m), 7.28-7.35 (lH.m). 7.41-7.48 (lH, m). 7.56 (lH, d, J = 15.6Hz), 7.75 (2H, t, J = 7.4Hz), 7.97-B.OO (lH, m), 12.80 (2H, brs) NMR < 12) (DMSO-dβ) óppm: 1.13 (3H, t, = 7. HZ), 2.80 (2H, q, J = 7.4Hz), 5.03 (2H, s), 6.47Í1H, d, J = 15.6Hz) , 6.94 (lH »dd, J = 2.5HZ, J = 8.6HZ), 7.01 (1H, d, J = 2.5Hz), 7.27-7.50 (2H, m>, 7.53 (1H, t, J = 15.6Hz ) »7.68-7.8K 2H, m), 7.92-8.03 (lH, m), 12.86 (2H, br) NMR (14) (DMS0-d.) .ppm:? .82 (3H, t, J = 7.2Hz ), 1.17-1.40 (2H, m), 1.40-1.61 (2H, m), 2.72-2.90 (2H, m), 5.06 (2H, s), 6.46 (lH, d, J = 15.7HZ), 6.91- 7.07 (2H.m), 7.30-7.41 (lH.m), 7.41- 7.54 < lH, m), 7.5K 1H, d, J = 15.7Hz), 7.74-7.82 (2H, m), 8.00-B.04 (lH.m) RM (15) (DMSO-d.) ppm: 5.08 ( 2H, s). 6.50 (1H, d = 15.7Hz), 7.13 (lH, dd, J = 2.5HZ, J = 8.7Hz), 7.27-7.49Í4H, m), 7. 71 (lH, d, J = 8.7Hz), 7.76 (1H, d, J = 7. OHZ), 7.99 (1H, d, J = 7. OHz), 12.85 (lH.br) NMR (16) (DMSO -d.) óppm: 5.09 (2H. S), 6.61 (1H, d, J = 15.6Hz), 6.98-7.13 (2H, m), 7.30 (1H, t, = 7.1Hz), 7.44 (1H, t , J) 7.1Hz), 7.63 (lH, dd, = 3.4HZ, J = 15.6Hz), 7.74-7.90 (2H, m), 7. 97 (lH, d, J = 7.1HZ), 12.8B (lH.br) NMR (17) (DMS0-d.) .ppm: 3.89 (3H »s), 5.06 (2H, s), 6. 51 (lH, d, J = 15.5Hz), 6.7K1H. d. J = 2.2Hz, J = 2.2Hz. J = B.7Hz), 6.82 (lH, d, J = 2.2HZ), 7.25-7.50 (2H, m), 7.66 (1H, d, J = 8.7Hz), 7.70 < lH, d, J = 15.5HZ), 7.74-7.81 (1H, pt), 7.94-B.03I1H, m), 12.80 (2H, br) NMR (18) (DMSO-d.) .ppm: 1.34 (3H. t, J = 6.9Hz), 4.15 (2H, q, J = 6.9Hz), 5.05 (2H, S), 6.45 (1H, d, = 15.5Hz), 6.68 (lH, dd, J = 2.0Hz, J = 8.7Hz), 6.77 (1H, d, J = 2.0Hz), 7.26-7.50 (2H, m), 7.66 (lH, d, J = 8.7Hz), 7.72-7.81 (1H, m), 7. 79 (lH, d, J = 15.5Hz), 7.91-8.05 (lH, m), 12.77 (2H, br) NMR (19) (DMS0-d.) .ppm: 3.89 (3H, s), 5.09 (2H, s), 6. 67 (lH.d, J = 15.5Hz), 7.08 (1H, d, J = 8.5Hz), 7.25-7.55 (2H, m), 7.57 (lH, m), 7.7-8.1 (4H, m), 11.68 (lH, br) RM (20) (DMSO-d.) óppm: 1.29 (6H, d, J = 6.OHz), 4.82 (lH, sept, J = 6.0Hz), 5.05 < 2H, s). 6.43 (1H, d, J = 15.5Hz), 6.89 (lH, dd, J = 2.3HZ, J = 8.7HZ), 6.78 (1H, d, = 2.3Hz), 7. 31 (lH, t J = 7.0Hz). 7.45 (lH, t, J = 7.0HZ), 7.66 (1H, d.J = B.7Hz), 7.78 (lH.d, J = 15.5HZ), 7.80 (1H. d, J = 7.OHz), 7.99 (1H, d, J = 7.0Hz), 12.76 (lH, br) NMR (21) (DMS0-d.) .ppm: 4.92 (2H, q, J = 8.7Hz), 5.07 (2H, s > 6.48 (lH, d, J = 15.5Hz), 6.8K 1H. dd, J = 2.3Hz, J = B.8Hz), 6.93 (lH, d, J = 2.3Hz), 7.32 (1H, t, J = 7.OHz), 7.45 (1H, t, J = 7.OHz), 7.62-7.79 (3H, m), 7.99 (lH.d, J = 7.OHz). 12.78 (lH, br) NMR (22) (DMS0-d.) .ppm: 5.28 (2H, S), 6.69 (1H, d, J = 15.5Hz), 7.25-7.55 < 3H, m), 7.77 (1H.d, J = 8Hz), 7.92 (1H, d, J = 15.5Hz), 7.98 (lH, d.J = 7.5Hz), 8.15-8.45 (2H, m), 12.8 B (lH, br) RM (23) (DMSO-d.) .ppm: 1.03 (3H, t, J = 7Hz), 1.18 (3H, t, J = 7HZ), 3.1-3.5 (4H, m), 4.96 (2H, S), 5.10 (2H, S), 6.63 (lH.d, J = 15.5Hz), 7.10 (lH,, = 8.5Hz), 7.25-7.55 (3H, m), 7.7-7.85 (2H, rn), 7.86 (lH, d, J = 15.5Hz), 7.98 (1H, d, J = 7.5Hz), 12.66 (lH, br) NMR (24) (DMSO-d.) óppm: 3.90 (3H, S ), 5.18 (2H, S), 6. 67 (lH, d, J = 15.5Hz), 7.28-7.36 (2H, tn), 7.46 (1H, t, J = 7.6Hz), 7.7B (lH, d, J = 7.6Hz), 7.89 (1H, d, J = 15.5Hz). 7.99 (1H, t, J = 7.6Hz), 8.25 (lH.dd, J = 2.3Hz »J = B.9Hz). 8.38 (lH.d.J = 2.3Hz) NMR (25) (DMS0-d.) Óppm: 2.4B (2H, t, J = 7.5Hz), 3.12 (2H.t, J = 7.5Hz), 5.04 ( 2H, s). 6.52 (1H, d, = 15.7Hz), 7.13 (lH, d, J = B.7HZ), 7.341H, t, J = 7.2Hz), 7.42-7.63 (3H, m), 7.80 (lH, d , J = 7.6Hz), 8.02 (lH, d, J = 7.2Hz>, 10.33 (1H, br), 12.98 (lH, br) NMR (26) (DMSO-d.) .ppm: 2.71 (2H, t , J = 7.6HZ), 2.98 (2H, t, J = 7.6Hz), 3.59 (3H, 8), 5.13 (2H, S), 6.60-6.75 (1H, m), 7.04-7.0B (lH, m ), 7.27-7.3B (lH, m), 7.38-7.51 (lH, m), 7.55-7.78 (lH, m), 7.84-7.99 (4H, m), 9.40 (2H, brs) NMR (27) ( DMSO-d. + CDCl 3) .ppm: 2.66 (2H, t, J =? 8Hz), 2.84 (3H »S), 2.89-3.06 (5H, m), 5.0K2H.S), 6.57-6.75 (1H , m), 6.90-7.10 (lH.m), 7.1B-7.30 (lH, m), 7.30-7.41 (lH.m). 7.63-7.72 (lH.m). 7.72-7.90 (3H, m), 7.96 (lH.s). 11.50-13.00 (2H, brs) NMR (28) (DMSO-d.) .ppm: l.OOOH, t, J = 7. OHZ), 1.07 (3H, t, J = 7.0Hz). 2.68 (2H, t, J = 7.4Hz), 3.0K2H, t, = 7.4Hz), 3.15-3.46 (4H.m). 5.06 (2H, s), 6.7B (2H, d, J = 15.4Hz), 6.95-6.99 (lH, m), 7.25-7.30 (lH, ra), 7.38-7.43 <; lH.m), 7.72-7.85 (5H, m) NMR (29) (DMS0-d.) ppm: l.l2 (3H, t, J = 7.1HZ), 2.69 (2H, t, J = 7.BHZ), 2.9B (2H, t »J = 7.8Hz), 4.00 (2H» q.J = 7.1Hz) »5.13 (2H, s), 6.61 (lH, d, J = 15.4Hz) , 7.04 (1H, d, J = 8.8Hz), 7.30-7.40 (1H, m>, 7.55 (lH, m), 7.75 (1H, d, J = 7.3H?), 7.86 (lH, d, J = 15.4Hz), 7.91-8.10 (3H, m), 12.40-13.30 (2H, m) Using the appropriate starting compounds, the compounds included in Tables 50 to 125 are obtained in the same manner as in Examples 3 or Four.

TABLE 50 Example 56 Rx / ^: I R - »: H A: -CH2- m: i R »^ *«: H R4- "" ": _N" ~ CH3 Rß: H P. of f. 175-185 ° C Crystalline form: White powder Solvent for recrystallization: Ethanol Form: Free NMR (l) Example 57 R- »: H A: -CH2- m: 1 Ra \ ^ R" J-t, "H R4 -" "*: __ 'N-CH3 RB." Isopropi / (position 2) P. de f.l90-192 ° C Crystalline form: Pale brown powder Solvent for recrystallization i zac ion: Ethanol Form: Li re Trans form TABLE 51 Example 58 RB: H of f .2 (decomposition) Crystalline form: White powder NMR (2) Solvent for recrystallization: Ethanol-diethyl ether Form: 2HC1 Example 59 Yellow powder Solvent for recrystallization: Ethanol-diethyl ether Form: 2HC1 Example 60 P. of f .202-206 ° C Crystalline form: Yellow powder Form: 2HC1 Solvent for recrystallization: Ethanol-diethyl ether 27B TABLE 52 Example 61 lo P. de f.H4-115 ° C Crystalline form: Pale yellow powder Form: cis Solvent for recrystallization: Ethanol-water Form: Free Example 62 ion 2) P. of f .206.5-209 ° C Crystalline form: White powder Solvent for recrystallization: Ethanol-water Form: Free Example 63 R *: CHa R - »: HA: -CHa-m: l Ra: H R -« - ': H R4- * ": V-CH3 Rß'H P. of f.138.5-141.5 ° C Crystal form: White powder Form: Free CU? PRQ 53 Example 64 R4-4 - * »^ R4-" "": -N P. of f.221-222 -xx-CH3: H .5 ° C Crystalline form: Yellow powder Form: Free Example 65 > : H '": -O N N-CH3 RB: C1 (position 2) P. de f.lBl-183 ° C Crystalline form: White powder Solvent for recrystallization: Ethanol-diethyl ether Form: Free Example 66 2) P. of f.261-262 ° C Crystalline form: Yellow powder Solvent for recrystallization: Ethanol Form: 2HC1 TABLE 54 Example 67 P. of f.227-229 ° C Crystalline form: Yellow powder Solvent for recrystallization: Ethanol Form: 2HC1 Example 6B R "2) P. of f.226-227 ° C Crystalline form: Brown powder Solvent for recrystallization: Ethanol Form: 2HC1 Example 69 Solvent for recrystallization: Ethanol Crystalline form: Pale yellow powder Form: 3HC1 NMR) TABLE 55 Example 70 P. de f.l57-160 ° C Crystalline form: Pale yellow powder Solvent for recrystallization: Ethanol Form: 3HC1 Example 71 2) Solvent for recrystallization: Ethanol Crystalline form: Brown powder Form: 3HC1 NMR (4) Example 72 R "b: H - - < N-CH3 RB: n-prop i 1 or position 2) Crystalline form: Yellow powder Form: 3HC1 NMR (5) CPAPRQ 56 Example 73 2 P . of f, .200 ° C Crystalline form: Yellow powder Solvent for recrystallization: Ethanol-water Form: 2HC1 Example 74 2) P. of f.H5-118 ° C Crystalline form: Beige powder Solvent for recrystallization: Ethanol Form: 2HC1 Example 75 P. of f.l88-191 ° C Crystalline form: White powder Form: 2HC1 Sun for recrystallization: Ethanol-water-diethyl ether GU RQ 57 Example 76 i l 2) Crystalline form: Pale yellow powder Form: 3HC1 NMR (6) Example 77 P. de f.22B-230 ° C Crystalline form: Yellow powder 1 palled Solvent for recrystallization: Ethanol Form: 2HC1 Example 78 P. from f.203-205 ° C Form crißtalina: White powder Form: 3HC1 Solvent for recrystallization: Methanol-diethyl ether CUAP Q 5S Example 79 opilo n 2) from f.202-204 ° C Crystalline form: White powder Solvent for recrystallization: Eti lo-n-hexane acetate Form: 3HC1 Example BO pillar 2) Crystal form: Yellow powder Shape: 2HC1 NMR (9) Example Bl ) P. of f.71 ° C Crystalline form: Pale yellow powder Form: 2HC1 Solvent for recrystallization: Ethanol-water TABLE 59 Example 82 P. of f.233-235 ° C Crystalline form: Solvent powder for recrystallization: Ethanol Form: Free Example 83 P. of f.206-210 ° C Crystalline form: Solvent powder for recrystallization: Ethanol Form: Free Example 84 ) P. of f.205-208 ° C Crystalline Forra: White powder Solvent for recrystallization: Ethanol-water Form: 2HC1 TABLE ßO Example 85 P. of f.l73-l75 ° C Crystalline form: Pale yellow powder Solvent for recrystallization: Ethanol-water-diethyl ether Form: 2HC1 Example B6")" - P. of f .152.4-156.3 ° C Crystalline form: White powder Solvent for recrystallization: Ethanol-water-diethyl ether Form: 3HC1 Ejeroplo 87 ) P. of f.l50-153 ° C Crystalline form: Dust love "1 palmed Solvent for recrystallization: Di chloromethane-diethyl ether Form: Free Ct PRO SA Example 88 / - ^ R4-4- »3 ^ R4- * 7: -? D) > "-NNv. N-CH3 RB: CH30 (position 2) Glass crystal: Pale yellow powder Form: 2HC1 Solvent for recrystallization: Ethanol-water NMR (11) Example 89 P. from f.203-206 ° C Crystalline Forra: Pale yellow powder Solvent for recrystallization: Ethanol-water-diethyl ether Form: 2HC1 Example 90 Butyl (position 2) P. of f .161.7-165 ° C Crystalline substance: Pale yellow powder Solvent for recrystallization: Ethanol-water-diethyl ether Form: 3HC1 TABLE 62 Example 91 butyl 2) P. of f.153-155.5 ° C Crystalline form: Yellow powder 1 palled Solvent for recrystallization: Ethanol-water-diethyl ether Form: 3HC1 Example 92 R «" "»: H R4- "7: _X _N_? N_CH3 R" -CI- \ "\ / \ - / (position 2) P. of f.l85-187 ° C Crystalline form: Pale yellow powder Solvent for Recrystallization: Isopropyl ico-water alcohol Form: 2HC1 Example 93 ) P. of f.l75-178 ° C Crystalline form: Pale yellow powder Solvent for recrystallization: Ethanol-water Form: 2HCl CUAPPQ 63 Example 94 P. of f.l5l-l54 ° C Crystalline form: White powder Solvent for recrystallization: Ethanol-water-diethyl ether Form: 3HC1 Example 95 P. of f.l67-16B ° C Crystalline form: White powder Solvent for recrystallization: Ethanol-water FormaOHCl Example 96 lime n 2) P. of f.l35-137 ° C Crystalline form: Pale yellow powder Solvent for recrystallization: Ethanol-water-diethyl ether FormaOHCl TABLE 64 Example 97 P. of f .183.5-1B6 ° C Crystalline form: Dust love "1 Solvent for recrystallization: Ethanol-water Form: 2HCl Example 98 R - »: H A: -CH.T- m: i R > * "" H? ) P. of f .174-176 ° C Crystalline form: Pale yellow powder Solvent for recrystallization: Ethanol-water FormaOHCl Example 99 R »- * CH30 2) P. of f.l53-154 ° C Crystalline form: Dust love Solvent for recrystallization: Ethanol-water FormaOHCl TABLE 65 Example 100 2) P. de f.177.5-179.5 ° C Crystalline form: Solvent powder for recrystallization: Ethanol-water FormaOHCl Example 101 ) P. of f.l65-168 ° C Crystalline form: Pale yellow powder Solvent for recrystallization: Ethanol-water-diethyl ether Form HCl Example 102 R4-4- "3 ^ R4- * 7: _ -xNi N-GCHH, 3 RB: CH, G0 (position 2) P. of f.l61-164 ° C Crystalline form: Yellow powder Solvent for recrystallization: Ethanol-water Form: HCl TABLE 66 Example 103 P. de f.lBl-183 ° C Crystalline form: White powder Solvent for recrystallization: Ethanol-water FormaOHCl Example 104 R4- 0 R- *: H A: -CH - »- m: 1" ) P. of f.l74-177 ° C Crystalline form: Pale yellow powder HCl form Solvent for recrystallization: Ethanol-water-alcohol and ß-propyl ico-diethyl ether Example 105 , H.Oon 2) P. of f.94-196 ° C Crystalline form: Yellow powder FormaOHCl Solvent for recrystallization: Ethanol-water-alcohol isopropyl ico-diethyl ether TABLE 67 Example 106 R4-4- * 3 ^ R4- "7: - ^ T? -N N-CH3 RB: CH, rO \ / N- (position 2) P. of f.200-203 ° C Crystalline form: Pale yellow powder Solvent for recrystallization: Ethanol-water FormaOHCl Example 107 -: H R4- "7: _ ^ ~ \ N ^ H.cn R-OH3O \ / \ f (position 2) P. of f.l69-170 ° C Crystalline form: Pale yellow powder Solvent for recrystallization: Ethanol FormaOHCl Example 108 / -s R4 - "^ R4- * 7: _X _NG_? N-CH3 RB: CH3? (Position 2) P. of f.l81-189 ° C Crystalline Forra: Pale yellow powder Solvent for recrystallization: Ethanol-water FormaOHCl NMR (12) TABLE 6B Example 109 B: CH30 on 2) P. of f.l58-160 ° C Crystalline form: Pale yellow powder Solvent for recrystallization: Ethanol-water FormaOHCl Example 110 P. of f.176.5-181.5 ° C Crystalline form: Yellow powder Solvent for recrystallization: Ethanol-water FormaOHCl NMR (13) Example 111 P. of f.l41-l42 ° C Crystalline Forraa: White powder Solvent for recrystallization: Ethanol-dichloromethane Form: Free TABLE 69 Example 112 2) P. of f .131.5-133 ° C Crystalline form: Pale yellow powder Solvent for recrystallization: Ethanol-dichloromethane Form: 1 i bre Example 113 R4-4-13 ^ 4 * "': -N ~ VN N-CH3 RβOHaO (position 2) Crystalline Forraa: Pale yellow amorphous Form: Free NMR (14) Example 114 P. of f.l40-142 ° C Shape: Metansul fonato Solvent for recrystallization: Ethanol-diisopropyl ether Crystal form: Pale yellow powder U RQ 70 Example 115 ion 2) P. of f .168.5-169 ° C Crystalline form: White powder Solvent for recrystallization: Ethanol-dichloromethane Form: Free Example 116 P. of f.128.2-131.5 ° C Crystalline form: Dust love "1 lo Form: Free Solvent for recrystallization: Ethanol-diethyl ether -dichloromethane Example 117 :2) P. of f.l44-l46 ° C Crystalline form: Pale yellow powder Solvent for recrystallization: Ethanol Form: Methansulfonate? UA RO 71 Example 11B 0- P. of f.l90-192 ° C Crystalline form: Dust love "lio Solvent for recrystallization: Ethanol-alcohol isopropyl ico-ether diethyl ico-water Example 119 RX R - *: HA: -CH ..- m: i R * X ^ - ^ CH2N N-CH3 R4-4- »3 ^ R17: / - \ - / RB: CH3qoc CHa) a- -N or (position 2) P. of f.llO-lll ° C Crystalline form: Pale yellow powder Solvent for recrystallization: Ethanol Form: Free Example 120 a) a ~ P. of f .162.5-164 ° C Crystalline form: Yellow powder Solvent for recrystallization: Ethanol-water Form: HCl TABLE 72 Example 121 aO 2) P. of f.205-207.5 ° C Crystalline form: Pale yellow powder Solvent for recrystallization: Ethanol-water Form: 2HC1 Example 122 Solvent for recrystallization: Ethanol-water Form: 2HC1 Example 123 2) P. of f.190.5-192.5 ° C Crystalline form: Yellow powder Form: Free Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether CT PPQ 73 Example 124 P. of f .148.2-149 ° C Crystalline form: Pale yellow powder Form: Free Solvent for recrystallization i zac ion: Ethanol-dichloromethane-diethyl ether Example 125 2) P. of f.211-211.5 ° C Crystalline form: Pale yellow powder Solvent for recrystallization: Ethanol-dichloromethane Form: Free Example 126 R4-4- »3 ^ R4- * 7: _M ^ s RB: CH3O-? - f (position 2) P. from f.204-206 ° C Crystalline form: White needles Solvent for recrystallization: Ethanol-dichloromethane Form: Free TABLE 74 Example 127 P. of f.168-170.4 ° C Crystalline form: White needles Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether 1 ico Example 128 R4- / ^ R - *: H A: -CH. »- m: i R3 \ ^ ) P. of f.175.8-177.2 ° C Crystalline form: White powder Solvent for recrystallization: Ethanol-dichloromethane-form: Free Example 129 R4-4- * 3 ^ R4- * 7: _ -N JNH RB: C2HB (position 2) P. of f.130-132.5 ° C Form: Dimetansulfonate Solvent for recrystallization: Ethanol-diethyl ether Crystalline form: Yellow powder TABLE 75 Example 130 . of f.225-226 ° C Crystalline form: Yellowish-yellow powder Solvent for recrystallization: Di-oromethane-ethanol Form: Free Example 131 P. of f.222-223 ° C Crystalline form: White powder Solvent for recrystallization: Methane-di chloromethane Form: Free Example 132 P. of f .122.5-125 ° C Crystalline form: Pale yellow powder Solvent for recrystallization: Ethanol-dichloromethane Form: Free TABLE 76 Example 133 ) P. of f.l62-i63 ° C Crystalline form: White powder Solvent for recrystallization: Ethanol-dichloromethane Form: Free Example 134 P. of f .177.2-178 ° C Crystalline form: Pale yellow powder Solvent for recrystallization: Ethanol-dichloromethane Form: Free Example 135 P. of f, 140-55 ° C Crystalline form: White powder NMR (27) Solvent for recrystallization: Ethanol-di-chloromethane-diethyl ether Form: Free TABLE 77 Example 136 ) P. of f .171-172.2 ° C Crystalline form: White needles Form: Free Solvent for recrystallization: Ethanol-dicl oromethane-diethyl ether 1 ico Example 137 R4-4--3 ^ R4- * 7: _N ^? _ C0NH2 RB: CH30 \ / (position 2) P. de f .232.5-233 ° C Crystalline form: Yellow powder Solvent for recycling: Di-oromethane-ethanol Form: Free Example 138 Crystal form: Pale yellow amorphous NMR (28) Shape: 3HC1 TABLE 78 Example 139 P. de f.! 92-l94 ° C Crystalline form: Yellow powder Solvent for recrystallization: Ethanol-dichloromethane Form: Free Example 140 ) P. from f.201-204 ° C Crystalline form: Yellow powder Solvent for recrystallization: Ethanol-dichloromethane Form: Free Example 141 CH2C1 R4-4- * 3 ^ R4- * 7: / - (RB: CH., 0 -NO (position 2) P. of f.l72-175 ° C Crystalline form: Yellow powder Solvent for recrystallization: Ethanol-dichloromethane Form: Free TABLE 79 Example 142 2) P. of .146.5-148 ° C Crystalline form: Yellow powder Solvent for recycling: Ethanol-dichloromethane Form: Free Example 143 R4-4-) P. of f.H4-ll7 ° C Crystalline form: Pale yellow powder Solvent for recrystallization: Ethanol-dichloromethane Form: Free Example 144 n 2) Pale yellowish powder Form: 2HC1 Solvent for recrystallization: Ethanol-water-diethyl ether NMR (29) BO CHART Example 145 P. de .106.5-108.2 ° C Crystalline form: Palored yellow powder Solvent for recrystallization: Ethanol-diethyl ether-n-hexane Form: Free Example 146 P. of f.l89-190 ° C Crystalline form: White powder Solvent for recrystallization: Ethanol-dichloromethane Form: Free Example 147 or Solvent for recrystallization: Ethyl acetate-diethyl ether Form: Free TABLE 81 Example 148 P. of f.l45-147 ° C Crystalline form: White powder Form: Free Solvent for recrystallization: Ethyl acetate - chloroform Example 149 aO n 2) P. of f .189-190.5 ° C Crystalline form: Pale yellow powder Solvent for recrystallization: Ethyl acetate-chloroform Form: Free Example 150 R4-4- * 3 ^ R4- * 7: _ -? N'_yN-OH Rß: Isopropyl (position 2) P. of f.l96-l99 ° C Crystalline form: Pale yellow powder Solvent for recrystallization: Ethanol-dichloromethane Form: Free 30B TABLE 82 Example 151 R4- / ^? R. R- »: H A: -CH ..» - m: i Ra \ ^ P. of f.l55-158 ° C (decomposition) Crystal form: Yellow powder or Form: Free Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether Example 152 P. of f.l62-164 ° C Crystalline form: White powder Solvent for recrystallization: Ethyl acetate-diethyl ether Form: Free Example 153 R4-4-13 ^ - -NXJN-OH RB: n-propylo (position 2) P. of f.l37-139 ° C (decomposition) Crystalline form: Pale yellow powder Solvent for recrystallization: Ethanol-dichloromethane Form: Free TABLE 83 Example 154 H? 2?) P. of f.l5B-159 ° C Crystalline form: White powder Form: Free Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether Example 155 2) P. of f.154-154.5 ° C Crystalline form: White powder Form: Free Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether Example 156 Rx - ^: I R - »: HA: -CH ...- m: i R- ^ Rxa.í .:: _ CH R RX - 7; • RB: CH" 0 (position 2) P. of f.180-181.5 ° C Crystalline form: Dark yellow powder Form: HCl Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether CHART 84 Example 157 _ / CH3 R4-4- * 3 ^ R4- * 7: / - (Rß: CaHß ~ __N_0H (position 2) P. of f.i65-175 ° C (decomposition) Crystalline form: Yellow powder NMR (30) Solvent for recrystallization: Dichloromethane-ethanol-diethyl ether Form: Free Example 158 P. of f.l25-128 ° C Crystalline form: Yellow powder Form: L bre Solvent for recrystallization: Ethanol-dichloromethane Example 159 R * "* / ^: R -»: HA: -CH., - m: i R »^ R4-4- * 3 ^ R4-" 7: _N -OH RB: CH, rO \ - / ( position 2) P. of f.195-195.5 ° C Crystalline form: Pale yellow powder Form: Free Solvent for recrystallization: Ethanol-dichloromethane g RQ BS Example 160 R4-4- »3: H R4-" 7: - N-OH Rβ: CF N-J '(position 2) P.f. 18B-190 ° C Crystalline form: Yellow powder Form: Free Solvent for recrystallization: Ethanol-dichloromethane Example 161 H - -XJN-OH RB: F (position 2) P.f. 197-200 ° C Crystalline form: Pale yellow powder Form: Free Solvent for recrystallization: Ethanol-dichloromethane Example 162 R4-4- * 3: H white Shape: Free BOX 86 Example 163 R4-4- * 3: H R4- * 7: - N-CH3 is; C n (position 2) P.f. 155.5-158 ° C Crystalline form: Pale brown powder Form: Free Solvent for recrystallization: Ethanol-dichloromethane Example 164 R4-4- * 3: H R4- "7: -N N-OCOCH3 Rß: CH3 (position 2) P.f. 163-166 ° C Crystalline form: Brown powder Form: Free Solvent for recrystallization: Dichloromethane-ethanol-diethyl ether Example 165 P.f. 161-163.4 ° C Crystalline Form: Yellow powder Form: 2HC1 Solvent for recrystallization: Ethanol -di chloromethane-water TABLE 87 Example 166 2) P.f. 137-139 ° C Crystalline form: Pale brown powder Form: Free Solvent for recrystallization: Ethanol-dichloromethane-water Example 167 R4- / ^ R * 1: H A: -CH-- m: i R = ^ J R4-4- * 3: H R4- "7: -N N-0CH3 Rf: CH3 (position 2) P.f. 215-217 ° C Crystalline form: Pale yellow powder Form: Free Solvent for recrystallization: Ethanol-dichloromethane Example 168 pale Form: 2HC1 Solvent for recrystallization: Ethanol-dichloromethane-water BOX BB Example 169 R4- ^ R ": H A: -CH2- ra: l R * '- ^ R * - «: H R4-" 7: -NN-OH RB: n-hept lo ^ - f (position 2) Pf 152-153.5 ° C Crystalline form: White powder Form: L b Solvent for Recrystallization: Ethanol-dichloromethane-water Example 170 R4- '^ H A: -CH, .- m: l R * ^ X R41b: H -xMxo Rβ: n-heptyl (po 2) P.f. 166.5-169.3 ° C - position Crystalline form: Yellow powder Solvent for recrystallization: Ethanol-dichloromethane Forraa: Free Example 171 Solvent for recrystallization: Ethanol-dichloromethane-water NMR (31) CUA O gg Example 172 R4-4- * 3: H - -? Nj > RB: CH .. ,, 0 (position 2) P.f. 219-220 ° C Crystalline form: Dark yellow powder Form: L b Solvent for recrystallization: Ethanol-dichloromethane Example 173 Rx / ^: R- »: HA: -CH-) 3 ~ m: i R * ^ J R4-4- * 3: H R4- * 7: -) ~ N ~ CH3 R": CHa0 - - (position 2) Pf 177-1B5 ° C Crystalline form: Dark yellow powder Form: 3HC1 Solvent for recrystallization: Ethanol-dichloromethane-water NMR (32) TABLE 90 Example 175 H B2-184 ° C Fo -rma c-ristal * i-nCaH3 CaHß0 (position 2) P.f. 1: Pale yellow powder Form: 2HC1 Solvent for recrystallization: Ethanol-water-diethyl ether Example 176 R4- x ^: R- *: HA: -CHß- m: i Ra Hj R4-4- * 3: H R4- "7: Rß: CH., (Position 2) Pf 265-270 ° C Form crystalline: Pale yellow powder Form: 2HC1 Solvent for recrystallization: Ethanol-water-diethyl ether NMR (33) Example 177 R4-4- * 3: H R47: / - \\ I '? NT-G-UH, RRß :: ifssooppropropylo "• O" ^ (position 2) P.-F. 203-207 ° C Crystalline Form: Pale yellow powder Form: 2HC1 Solvent for recrystallization: Ethanol-water-diethyl ether TABLE 91 Example 17B P.f. 234-238 ° C Crystalline form: Pale yellow powder Form: 2HC1 Solvent for recrystallization: Ethanol-water-diethyl ether Example 179 R "H R4-" -O j? N-CH3 R ?: F V V ((ppoossiicc-ion 2) P.f. 214-217 ° C Crystalline form: Pale yellow powder Form: 2HC1 Solvent for recrystallization: Ethanol-water Example 1BO P.f. 188-190 ° C Crystalline Form: Pale yellow powder Form: 2HC1 Solvent for recrystallization: Ethanol-water 31B TABLE 92 Example 1B1 R4-4- * 3: H R4- "7: _N V-N? N-CH3 R? * N-propyl \ - / V (position 2) Mp 164-167 ° C Crystalline form: Yellow powder Form: 2HC1 Solvent for Recrystallization: Ethanol-water Example 182 R4-4- * 3: H R4- * 7: '\', t u RB: CHßO ~ N_ NvA / N_CH3 (position 3) P.f. 165-16B ° C Crystal shape: pale yellow powder Form: 2HC1 Solvent for recrystallization: Ethanol-water NMR (56) Example 1B3 Form: Free Solvent for recrystallization: Ethanol-dichloromethane CWAPRQ 93 Example 184 H R, x4 - '"7 :: --NNO> -N / NN-CH3 Rβ: H P.f. 215-218.5 ° C Crystalline form: White powder Solvent for recrystallization: Ethanol-water-diethyl ether Form: 2HC1 Example 185 R4-4- * 3: H R4- "7: -N VN W? N-CH3 RB: CF (position 2) Pf 101-106 ° C Crystalline form: White powder Form: 2HC1 Solvent for recrystallization: Diethyl ether ico- NMR ethanol-water (34) Example 186 RA / ^: R ": H A: -CH ..- m: i R »^ Rß: CH00 (position 2) P.f. 179.5-1B3 ° C Crystalline Form: White powder Form: 2HC1 Solvent for recrystallization: Ethanol-water-diethyl ether TABLE 94 Example 187 R- *: H A: -CH -.- m: i R * ^ J RB: CaHßCH (CH3) - (position 2) P.f. 129-131 ° C Crystalline form: Pale yellow powder Solvent for recrystallization: Alcohol-sopropylic-water Form: Dioxalate Example 188 R? ^: R- ": H A: -CH -, - m: i R- ^ J R4-4- "3: H R4- * 7: RB: C-H. (Position 3) P.f. 163-165 ° C Crystalline form: Pale yellow powder Form: 2HC1 Solvent for recrystallization: Water-ethanol-di-chloromethane Example 189 Form: 2HC1 Solvent for recrystallization: Isopropyl ico-water alcohol TABLE 95 Example 190 P.f. 166-168 ° C Crystalline form: Yellow powder Form: 2HC1 Solvent for recrystallization: Water-ethanol-dichloromethane TABLE 96 R Example 191 RXX *: H R4- "7: -N ^ N ^ -CH3 R1 CH.3O (position 2) P.f. 175-177 ° C Crystalline form: White powder Form: 2HC1 Solvent for recrystallization: Ethanol-water-diethyl ether Example 192 RB: CHa (positions 2 and 3) RXX-o; H Rx7: _N V-N? N "CH3 P.f. 158-162 ° C Crystalline Form: Pale yellow powder Form: Succinate Solvent for recrystallization: Ethanol-diisopropyl ether Example 193 R-4: H A: -CHaro: 2 R ^ RB: CHa (positions 2 and 3) P.f. 126--128, .5 * »C Crystalline Form: Yellow powder Form: Succinate Solvent for recrystallization: Ethanol-diethyl ether TABLE 97 Example 194 x /, H-CH2- m: l R * "'^ R4-4- * 3: H R4-" 7: -N NH Rβ "CF (position 2) Mp 166-171 ° C Crystalline form: Dust pale yellow Form: HCl Solvent for recrystallization: Isopropyl alcohol-ethanol NMR (35) Example 195 R4-4- * 3: H R4- "7: --NI ^ NN - CCHH, 3 R" CHaO (position 3) P.f. 175-178 ° C Crystalline form: Yellow powder Form: Free Solvent for recrystallization: Methane! Example 196 R4-4- * »: H R- > -7: _ -NNA? / --CCHH33 Rß "CH3O (posi ci on 3) P.f. 240-245 ° C Crystalline Form: Pale yellow powder Form: HCl Solvent for recrystallization: Ethanol-water TABLE 9B Example 197 Rß: CH3 (position 3) stalina: White powder Form: 2HC1 Solvent for recrystallization: Ethanol-water Example 19B RB: - (CH.?) ^ - (combined in positions 2 and 3) R4-4- * 3: H R4- "7: - N ~ - N? N-CH3 P.f. 180-190 ° C Crystalline form: Yellow powder Form: 2HC1 Solvent for recrystallization: Ethanol-diethyl ether NMR (36) Example 199 Rx / ^ R **: HA: -CH2- mO R »^ J R4-4-" 3: HR * »- 7: X \\ t, Rß * CHa 11: - - N-CH3 (positions 3 and 5) Mp 210-216 ° C Crystalline Form: White powder Forraa: 2HC1 Solvent for recrystallization: Ethanol-water-diethyl ether NMR (37) TABLE 99 Example 200 ilo (position 3) P.f. 177.5-180.5 ° C Crystalline form: light yellow powder Solvent for recrystallization: Ethanol-water Form 2HC1 Example 201 R4-: '' | R- *: H A: -CH "- m: 1 R * ^ J R4-4- * 3: H R4-" 7: -N N ~ CH3 R ": CH ,,. (positions 3 and 5) P.f. 119-122.5 ° C Crystalline form: White powder Solvent for recrystallization: Ethanol-diisopropyl ether Form: Methanesulfonate Example 202? / ^: R "*: HA: -CH" - m: 1 R * ^ J R4-4- "3: H R4-" 7: - VN? N-CH3 RB: -C00CH..f - 'VV ( position 2) Mp 169-172 ° C Crystalline form: White powder Solvent for recrystallization: Ethanol-diisopropyl ether Form: Dimethanesulfonate TABLE 100 Example 203 H R4- "7: - • NOV-Ní N" CH3 R: CH-.O (position 3) P.f. 214-220 ° C Crystalline form. "Light yellow powder Solvent for recrystallization: Methanol Form: free Example 204 P.f. 195-197 ° C Crystalline form: Yellow powder Solvent for recrystallization: Dichloromethane-methanol Form: 1 1 i bre Example 205 R ^ s: J R- *: H A: -CH "- ra: 2 RB: - (CH - ») J, - (combined in positions 2 and 3) M '- .N- (CH2) 2OH P.f. 151-153 ° C Crystalline form: Light yellow powder Solvent for recrystallization: Water Form: free TABLE 101 Example 206 P.f. 148-150.4 ° C Crystalline form: Light yellow powder Solvent for recrystallization: Isopropyl alcohol 1-water-diethyl ether Form: 2HC1 Example 207 R4-4- * 3: H R4- "7: - VN.H> -N? N ~ CH3 RB: (CHa) aC- VV (position 2) Mp 142-144.5 ° C Crystalline form: Light yellow powder Solvent for recrystallization: Alcohol i soprop 1 ico-water Form: Oxalate Example 208 R4-4-13: H R4- "7: - -NN NN - CCHHi3 Rβ" CH: ^ - y (position 3) P.f. 139.2-140.8 ° C Crystalline form: Light yellow powder Solvent for recrystallization: Ethanol-water Form: Methanesulfonate 32B TABLE 102 Example 209 aO n 3) P.f. 158-163 ° C Crystalline form: Light yellow powder Solvent for recrystallization: Ethanol-water-diethyl ether Form: 2HC1 NMR (38) Example 210 R4-4- * 3: H -G ^ __ / N-CH3 RB: n-butyl (position 3) P.f. 84-86 ° C Crystalline form: Amorphous yellow Shape: free Example 211 R H R4- * 7:? A ?? \ f Nt- ~ C? 'Hn3s R: n-propyl (position 3) P.f. 121-124 ° C Crystalline form: Light yellow powder Solvent for recrystallization: Isopropyl alcohol ico-water Forroa: Dio? Alato TABLE 103 Example 212 Rx? T »: H R": - N-CH3 Rß: CHa > - / (positions 2 and 3) P.f. 140-150 ° C Crystalline form: Yellow powder NMR (39) Solvent for recrystallization: Acetone-water Form: Methanesulfonate Example 213 RB: (CHa) a-CO H- (combined in positions 2 and 3) R4-4- »3: H R4-" - * Q- * Í N-CH3 Pf 173-175 ° C Crystalline form: Dimethanesulfonate Solvent for recrystallization: Diethyl ether ico-ethanol-water Crystalline Form: Yellow powder Example 214 ) P.f. 168-172 ° C (dec.) Crystalline form: Yellow powder Solvent for recrystallization: Ethanol-diethyl ether Form: 2HC1 TABLE 104 Example 215 P.f. 155-160 ° C NMR (40) Crystalline form: Light yellow powder FormaOHCl Solvent for recrystallization: Ethanol-water-alcohol and sopropholyl-diethyl ether Example 216 RB: CH00 (position 3) Solvent for recrystallization: Ethanol-water Form: 2HC1 Example 217 R4-: CH R- »: H A: -CH3- m: R3 *: CH3 RB: CH30 (position 3) P.f. 190-193 ° C (dec.) Crystalline form: Yellow powder Solvent for recrystallization: Ethanol-water Form: 2HC1 and RQ 1Q5 Example 218 R "* - 3- * 3: H R '" 4- "7 :: - N VK-N? N-CH3 R?; CHa0 vv (position 2) P.f. 174.4-176.5 ° C Crystalline form: Yellow powder Solvent for recrystallization: Ethanol-water-diethyl ether Form: 2HC1 TABLE 106 Example 219 62-165 ° C Crystalline form: Light yellow powder Solvent for recrystallization: Diethyl ether-water-ethanol Form: 2HC1 Example 220 3) P.f. 206-211 ° C Crystalline form: Light yellow powder Form: 2HC1 Solvent for recrystallization: Ethanol-water-diethyl ether co-alcohol isopropyl 1-NMR (41) Example 221 P.f. 16B-172 ° C Crystalline form: Yellow powder Form 2HC1 Solvent for recrystallization: Ethanol-water-al chol i sopropí 1 ico-diethyl ether TABLE 107 Example 222 H CH2N N-CH3 / (- / -N O P.f. 203-20B ° C Crystalline form: Light yellow powder Solvent for recrystallization: Ethanol-water-alcohol isopropyl 1-ether diethyl ether NMR (42) Form: 2HC1 Example 223 P.f. 1B0-1B5 ° C Crystalline form: White powder Form: 2HC1 Solvent for recrystallization: Ethanol-water NMR (43) Example 224 ) P.f. 180-190 ° C Crystalline form: Yellow powder Form: 2HC1 Solvent for recrystallization: NMR ethanol (44) TABLE 10B Example 225 P.f. 157-160 ° C Crystalline form: Light yellow powder Solvent for recrystallization: Ethanol-water Form: 2HC1 Example 226 R- ": H A: -CH2- m: 1 R * ^ fí Xl H R4- *) P.f. 171-174 ° C Crystalline form: Light yellow powder Solvent for recrystallization: Ethanol-water Form 2HC1 Example 227 R1": H -CH2OH -N N -CHC CH..0 CH2OH (position 3) P.f. 236-238 ° C Crystalline form: Light yellow powder Solvent for recrystallization: Ethanol-water Form: HCl GUAPEO 1Q9 Example 228 CH, 0 (position 3) P.f. 16l-l65 ° C Crystalline Forra: Light yellow powder Form: 2HC1 Solvent for recrystallization: Ethanol-water-diethyl ether co-alcohol isopropyl 1 ico Example 229 R4-4- "3: H R4-" 7: / ^ / H2N? N-CH3 Rβ "CH, 0 -w f v v (position 3) P.-f. 191-194 ° C Crystalline form: Light yellow powder Form: 2HC1 Solvent for recrystallization: Ethanol-water Example 230 RB: CH3O (position 3) P.f. 200-210 ° C (dec.) Crystal form: Yellow powder RM (45) Solvent for recrystallization: Ethanol-water-diethyl ether Form: 2HC1? GAPRQ no Example 231 RB ". CH30 (position 3) P.f. 165-170 ° C Crystalline form: Yellow powder Form 2HC1 Solvent for recrystallization: Dietary ether 1 ico-ethanol-alcohol and soprop 1 ico-water Example 232 P.f. 150-170 ° C Crystalline form: Yellow powder NMR (47) Solvent for recrystallization: Isopropyl alcohol Form: Dimethanesulfonate Example 233 ) P.f. 166-169 ° C Crystalline form: Light yellow powder Solvent for recrystallization: Ethanol-water Forraa 2HC1 CUAPRO 111 Example 234 3) P.f. 1B6-200 ° C (dec.) Crystalline form: Yellow powder Form 3HC1 Solvent for recrystallization: Isopropyl alcohol NMR (48) Example 235 R4-: CHa R - »: HA: -CH2- m: i Ra" CHa R_: CH3O (position 3) R4-4- * 3: H -G * Í N-CH3 Mp 204-210 ° C ( desc.) Crystalline form: Yellow powder Form: 2HC1 Solvent for recrystallization: Ethanol-water-diethyl ether NMR (49) Example 236 R ^ H R- »: HA: -CH2- m: 1 Ra: H Rß: CHaO (position 3) R4-4- *»: H R4- "7: Pf 15B-160 ° C Form (crystalAina- : cP * ol or yellow Solvent for recrystallization: Ethanol-water Form: 2HC1 TABLE 112 Example 237 R4-: H R- »: H A: -CH. m: l R *: H RB: CH "0 (position 3) R4-4-13: H R4-" 7: -N Pf 83.1-85.5 ° C (dec.) Crystalline form: Yellow powder Form: 1 i bre Solvent for recrystallization : Ethanol-diethyl ether-n-hexane Example 238 A /: R- »: H A: -a- - m: 1 R3 * ^ R t»: H R ": -N and -N? N-CH3 RB: F (position 3) P.f. 215-220 ° C Crystalline form: White powder Form: 2HC1 Solvent for recrystallization: Ethanol-alcohol isopropyl ico-ether diethyl ico-water Example 239 - m: 1 RB: CH30 (position 3) Light yellow powder Forraa 2HC1 Solvent for recrystallization: Ethanol-water-alcohol ißopropylic acid-diethyl ether TABLE 113 Example 240 3) light yellow Shape: l bre Solvent for recrystallization: Ethanol-isopropyl alcohol Example 241 a3C- 2) P.f. 181-183.8 ° C Crystalline form: Light yellow powder Forraa: 2HC1 Solvent for recrystallization: Ethanol-water-diethyl ether Example 242 R4-: CHa R- *: H A: -CHa ~ m: 1 ion 3) lina: Yellow powder Form: 2HC1 Solvent for recrystallization: Ethanol-water NMR (52) TABLE 114 Example 243 R4-4- "3: H R4- * 7: __) N? N-CH3 RB: C, HßO (position 3) P.f. 166-170 ° C Crystalline form: Light yellow powder Form: 2HC1 Solvent for recrystallization: Ethanol-water Example 244 Crystalline form: Light yellow powder Form: dimetanosul fonato NMR (53) Solvent for recrystallization: Ethanol-water-diethyl ether ico-isopropyl alcohol Example 245 R4-4 - "*": H R4- "7: -N) ^? / 1" 0 * 3 Rß: CF, CHaO (position 3) Mp 179-1B3 ° C Crystalline form: Light yellow powder Form: 2HC1 Solvent for recrystallization: Isopropyl alcohol-ethanol-water-diethyl ether TABLE 115 Example 246 H R «: _] ^ __ Í ^ N_CH3 P. f. 1B2-185 ° C Crystalline form: Light yellow powder Solvent for recrystallization: Ethanol-water FormaOHCl f trans form Ejeroplo 247 CH3O (positions 3 and 5) R4- "H -AA ACH> P.f. 177-1B3 ° C Crystalline form: Light yellow powder Solvent for recrystallization: Ethanol-water Form 2HC1 TABLE 116 Example 248 O 3) crystalline substance: Light yellow powder Form: 2HC1 Solvent for recrystallization: Ethanol-water-diethyl ether Example 249 3) P.f. 167-171 ° C (dec.) Crystalline form: Yellow powder Solvent for recrystallization: Ethanol-water Forroa 3HC1 Example 250 R4-: CHa R- »: H A: -CHa m: 1 R3 *: CH3 RB: CHaO (position 3) P.f. 137-140 ° C Crystalline form: Yellow powder Solvent for recrystallization: Ethanol-water Form: methanesulfonate TABLE 117 Example 251 R4-: (CH3) 3C- (position 3) R- »: H A: -CHa-m: 1 Ra: H Ra: CH30 (position 3) R4-4 - »-»: H R4- "7: -N" N-CH3 P.f. 129-131 ° C Crystalline form: Light yellow powder Solvent for recrystallization: Ethanol-water-diethyl ether ico-isopropyl alcohol Form: Dimethanesulfonate Example 252 R4 - "» - * 3: H R4- "7: V ^ tr Rß: CHaO - ^ N-CH3 (position 3 > P.f. 230-231 ° C Crystalline form: Light yellow powder Solvent for recrystallization: Ethanol-water Form: Dimethanesulfonate Example 253 P.f. 159.164 ° C (deßc.) Cristalline form: Light yellow powder Solvent for recrystallization: Ethanol-water Form 2HC1 NMR (54)? GAPFP 119 Example 254 R4-4- »3: H R RX * -7 - I S. f \ CH3 RB: CHa0 (position 3) CH3 P.f. 202-205 ° C (dec.) Crystalline form: White powder Solvent for recrystallization: Ethanol-water Form: 2HC1 Example 255 ) P.f. 115-120 ° C Crystalline form: Light brown powder NMR (55) Solvent for recrystallization: Ethanol-water-alcohol isopropyl ico-diethyl ether Form: Methanesulfonate Example 256 A: -CH "- m: i Rß: CHaO (position 3) P.f. 168.5-171.5 ° C Crystalline form: White powder Solvent for recrystallization: Ethanol-water Form: 2HC1 TABLE 119 Example 257 3) P.f. 163-166 ° C Crystalline form: White powder Solvent for recrystallization: Ethanol-water Form: 2HC1 Example 25B 0 n 3) P.f. 177.5-179 ° C Crystalline form: White powder Solvent for recrystallization: Ethanol-water Form 2HC1 Example 259 Rx? ß: H RX- ,: O ^ ^ Rß. CHa0 1 \ / \ I (position 3) P.f. 165-16B.5 ° C Crystalline form: Light yellow powder Form: 2HC1 Solvent for recrystallization: Ethanol-water-diethyl ether QM PRO 3120 Example 260 3) P.f. 159-160 ° C Crystalline form: Light yellow powder Solvent for recrystallization: Ethanol-water Form: 2HC1 Example 261 n 3) P.f. 177-17B.2 ° C Forraa cristal na: Light yellow powder Solvent for recrystallization: Ethanol-water Forraa 2HC1 Compound S (-): High? : -5.75 ° C (c = 2f water) Example 262 3) P.f. 173-175 ° C Crystalline form: Light yellow powder Solvent for recrystallization: Ethanol-water Form: 2HC1 Compound R (+): Zal0? St + 4.35 ° (c = 2 »water) TABLE 121 Example 263 3) P.f. 168-170.5 ° C Crystalline form: White powder Solvent for recrystallization: Ethanol-water Form: 2HC1 Example 264 RX ^,: 1 R "*: H A: -CH2- p>: 1 R * ^ J R4-4- * 3: H R4- "7: RB: CHaO (position 3) P.f. 156-159 ° C Crystal form: Light yellow powder Solvent for recrystallization: Ethanol-water Form: 2HC1 Example 265 R ^: I R- »: H A: -CH3-ra: 1 R3 * * RB: CaHß0 (position 3) P.-f. 176-179 ° C Crystalline form: Light yellow powder Solvent for rectalisation: Ethanol-water Forraa: 2HC1 -VAPUQ Z Example 266 Crystalline form: Yellow powder Form: 2HC1 Solvent for recrystallization: Ethanol-water-alcohol and ß-propyl ico-diethyl ether Example 267 R R- »: H A: -CHÍ? - ro: 1 R3 »-: CoHa R-: CHaO (position 3) P.f. 166-169 ° C Crystalline form: Yellow powder Solvent for recrystallization: Ethanol-water-diethyl ether ico-isopropyl alcohol Example 268 RB: CaHßO (position 3), CH3 R4-4- * 3: H "" = -N r- -N rXN-C2H5 P.f. 215-217 ° C Crystalline form: White powder Solvent for recrystallization: Ethanol-water Form: 2HC1 TABLE 123 Example 269 3) P.f.174-177 ° C Crystalline form: Yellow powder Form: free Solvent for recrystallization: Ethanol-water Example 270 RB: CH-0 (position 3) Form: 2HC1 Solvent for recrystallization: Ethanol-water Example 271 RB: CH - ,, 0 (position 3) P.f .155-158 ° C Crystalline form: Yellow powder Form: 2HC1 Solvent for recrystallization: Ethanol-water-alcohol di sopropí 1 ico-ether diét 1 ico PICTURE 124 Example 272 R4-4- * 3: H R4- "" W N-CH3 RB: CH ^ O (position 3) P.f. 202-204 ° C Crystalline form: Light yellow powder Form: 2HC1 Solvent for recrystallization: Ethanol-water Example 273 Example 274 P.f. 160-162 ° C Crystalline Forra: Light yellow powder Solvent for recrystallization: Ethanol-water Form 2HC1 TABLE 125 Example 275 3) P.f. 158-160 ° C Crystalline form: Light yellow powder Form: 2HC1 Solvent for recrystallization: Ethanol-diethyl ether ico-water Example 276 C, H "330- ón 3) P.f. 164-166 ° C Crystalline form: Light yellow powder Form 2HC1 Solvent for recrystallization: Ethanol-water Using the appropriate starting compounds "the compounds listed in tables 126-128 are obtained in the same manner as in example 5.

CUAPRQ Z < ? Example 277 R4 - * -: C2Hβ R4-4-13: H Rβ: H P.-f. 130.5-132 ° C Crystalline form: Light orange powder Forraa: free Solvent for recrystallization: Dimet If ormami da-methane 1 TABLE 127 Example 278 R4 - * -: C2Hβ ZO R4-4- »3: H RB: H P.f. 183.5-184 ° C Form crystal ina: Pol or white Solvent for recrystallization: Di cl oromethane-ethanol Form: Free Example 279 A / ^: R- *: H A: -CH "- m: i R3 * ^ J R - * - * -: C2Hß 2: 0 llb: H RB: (CH2) 3N N-CH3 (position 2) P.f. 221 ° C (dec.) Inactive crystal form: Light yellow powder Solvent for recrystallization Diethyl ether ico-ethanol FormaOHCl STEP 1? 8 Example 280 R ^^. 'CH ,, 2: 0 RXXB; CH3 Rβ; CH30 (p? SÍCl "Ón 2) P.f. 124-126.5 ° C Crystal form: Light yellow powder Solvent for recrystallization: Ethyl-n-hexane acetate Form: Free Example 2B1 Riß-: CaHß Z: S R4-4-'3: HR * "*: CH.:?> 0 (position 2) Mp 156-159 ° C Inactive crystal form: Yellow polymer Solvent for recrystallization Otanol-dichloromethane Form : Free Using the appropriate starting compounds "the compounds listed in Tables 129-149 were obtained in the same manner as in Example 8.

C1APR0 1? 9 Example 2B2 R: / **,: J R- »: H A: -CH_- m: i R-: ^ RB: Isopropi lo (position 2) P.f. 137-138 ° C Inacid crystal shape: Light yellow powder Shape: Free Example 283 ibre Solvent for recrystallization: Dichloromethane-ethanol ? UAPRQ 130 Example 284 ) P.f. 240 ° C (dec.) Crystal form: Light yellow powder Solvent for recrystallization: Ethanol-water FormaOHCl Example 285 o) P.f. 169.5-170 ° C Inactive crystal form: White powder Form: Free Solvent for recrystallization: Ethanol Example 286 Crystal crystal form: Light brown powder Form: HCl NMR (7) TABLE 131 Example 287 R t »: H M; RB :-( CH?) "0H lí (position 2) N N P.f. 170.5-175.5 ° C Intentional cri stal form: Light yellow pol Form: Free Solvent for recrystallization: Eti lo-n-hexane acetate Example 288 A: -CH. my RB: H P.f. 201.5-202.5 ° C (dec.) Crystal lining: Light yellow powder Solvent for recrystallization: Ethanol-dichloromethane Form: Free Example 289 P.f. 195-19B ° C Form Crystal i na: Yellow powder FormaOHCl Solvent for recrystallization: Ethanol-water? GAQRQ 3 Example 290 pi lo n 2) P.f. 101-103.5 ° C Form crystal ina: Love "amorphous lime Form: Free Example 291 x ./^ R- »: H A: -CH2- m: i R * ^ R4-4- * 3: H R": X? Rß: (CH) 4N - ~ H3 (position 2) P.f. 148.2-153 ° C Formal crystal form: Light brown powder Forraa OHC1 Solvent for recrystallization: Ethanol-diethyl ether NMR (10) Example 292 R3 -? - ta: H - A? / \ position 2) • (CH ^ l- ^ N-CHs P.f. 1B4-187 ° C Form Crystal i na: ol light yellow Solvent for recrystallization: Ethanol-water-diethyl ether FormaOHCl TABLE 133 Example 293 isopropyl alcohol Example 294 2) P.f. 207.209 ° C Inactive crystal form: White powder Form: Free Solvent for recrystallization: Eti lo-n-hexane acetate Example 295 R / ^: 1 R- »: H A: -CH ...- m: i R3"^ T Rxxt,: H R22: t RB: C1 (position 2) H P.f. 164-166 ° C Form Crystal na: Light yellow powder Solvent for recrystallization: Methanol-diethyl ether Form: HCl TABLE 134 Example 296 R4-4- * 3 n 2) P.-f. 141-141.5 ° C Cristallic form: White powder Form: L b Solvent for recrystallization: Dichloromethane-diethyl ether Example 297 n 2) P.-f. 186.5-191 ° C (dec) Crystalline form: Yellow powder 1 light solvent for recrystallization: Ethanol ~ diethyl ether Form: Methane 1 fonate Example 298 2) Crystal form ina: Love "1 the amorphous clear form: Free NMR (15) CUAPRQ gg Example 299 2) Crystal shape na: love 1 light amorphous shape: Free NMR (16) Example 300 Rxxß: H Rasr; 7 ^ NH R: CaHß0 (position 2) P.f. 202.5-203 ° C Forraa crystal ina: Pol or clear Solvent for recrystallization: Ethanol-alcohol isopropyl ico-water-ethyl ether 1: Forraa: Me anosulfonate Example 301 P.f. 1B6-189 ° C Crystal Shape: Light yellow powder Solvent for recrystallization: Water-ethanol-diethyl ether FormOHCl TABLE 136 Example 302 R4-- H R ** 3": -O NH;: CH3? (Position 2) P.f. 135-145 ° C Inactive crystal form: White powder Form: Free Solvent for recrystallization: Ethanol-dichloromethane NMR (17) Example 303 2) Crystal form ina: Love '1 the amorphous clear form.' Free NMR (18) Example 304 P.f. 146.5-150 ° C Form Crriissttaall iinnaa :: White powder Solvent for recrystallization: Ethanol-water FormaOHCl TABLE 137 Example 305 P.f. 115-120 ° C Crystal shape: Light yellow powder NMR (19) Solvent for recrystallization: Ethanol-diethyl ether Form: Metanosu1 fonate Example 306 P.f. 207-208.5 ° C Inactive crystal form: White polymer Solvent for recrystallization Oxyte diethyl ico-ethanol Forra: Methanesulfonate Example 307 2) orma Crystal i na: Love * 1 the amorphous clear form. "Free RMN (20) TABLE 138 Example 308 R4-4- * 3 ^ R31 *: J jj RB: / ^ (position 2) "" "^ O - (CH2) 2CON N-CH3 P.f. 139-l4l ° C Inactive crystal form: Yellow pol Solvent for recrystallization izationOtanol Form: ethanesulfonate Example 309 2) P. 194-197 ° C Inactive crystal form: Pol or white Solvent for recrystallization: Ethanol-water Form: Dimetanosul fonate Example 310 R "B: HR»: RB: / - \ (position 2) Q (CH2) 3N ^ N-CH3 Pf 21B-2200C Form Crystal ina: Light yellow powder Solvent for recrystallization: Ethanol-water Form: Dimetanosul fonato PICTURE 139 Example 311 P.f. 182.5-1B6 ° C Inactive crystal form: Yellow powder Solvent for recrystallization: Ethanol-diethyl ether FormOHCl Example 312 R ^ OHa R - »: H A: -CH2- m: i R **: CH.,. R4-- H Ras (position 2) Ina crystal form: White powder Form: ethanesul fonate Solvent for recrystallization: Ethanol-diethyl ether NMR (21) Example 313 ) C.H. P.f. 140-14l ° C Cristallic form: White powder Forraa: ethanesulfonate Solvent for recrystallization Otanol-alcohol and soptyl-diethyl ether TABLE 140 Example 314 R4-4- "3: H H (position 2) P.f. 166-177 ° C Crystal form: White polymer NMR (22) Solvent for recrystallization: Ethanol-diethyl ether FormOHCl Example 315 óónn 2) P.f. 156-157 ° C Form crystal ina: Pol or white Solvent for recrystallization: ethanol Form: free Example 316 n 2) P.f. 191-192 ° C Form Crystal i na: White polymer FormaOHCl Solvent for recrystallization: Ethanol-water-alcohol-isopropyl ico TABLE 141 Example 317 2) Crystal shape na: Amari 1 the amorphous clear form: Free NMR (23) Example 318 Crystal shape na: Amorphous colorless Shape: Free NMR (24) Example 319 ) P.f.178-l? O ° C Form Crystal ina: Pol or white Forraa OHC1 Solvent for recrystallization: Ethanol-isopropanol-diethyl ico-water ___ 36B TABLE 142 Example 320 ) Crystal form ina: Amari 1 the amorphous clear form: Free NMR (25)Example 321 P.f. 19B-20l ° C Inactive crystal form: Light yellow powder FormaOHCl Solvent for recrystallization: Ethanol-water Example 322 ibre Solvent for recrystallization: Diethyl ico-ethane 1-dic1 oromethane TABLE 143 Ejemp E >; H RB and A combine to form P.f. 234-235 ° C Forraa cristal i na: Pol vo b: olanco Shape: Free Solvent for recrystallization: Eti lo-n-hexane acetate Example 324 P.f. 206-207.5 ° C Form crystal ina: Pol or light yellow Form: ibre Solvent for recrystallization: Dichloromethane-ethanol-ether-diethyl ico Example 325 x / ^: I R **: H A: -CH2- m: i R * ^ J P.f. 195.5-196.5 ° C Forma Cristal ina: Needles light yellow Solvent for recrystallization: Ethanol-dichloromethane Form: Free TABLE 144 Example 326 OCOCH, x? T »: H Rß: 1 (position 2) R * -CHaCHCH20C0CH3 P.f. 134-136 ° C (dec) Forraa cristal i na: Pol vo amar AillAo Form: Free Solvent for recrystallization: Dichloromethane-ether di soprop l ico Example 327 OH R4-4- »3: H RB¡: | (position 2) Ra -CH2CHCHaOH P.f. 207.6-214 ° C (dec.) Inactive crystal form: White powder Solvent for recrystallization: Dichloromethane NMR (26) Form: Free Example 328 P.f. 191-193 ° C Form Crystal ina: Light yellow powder Solvent for recrystallization: Ethanol-dichloromethane Form: Free TABLE 145 Example 329 P.f. 112-114 ° C Inactive crystal form: Light yellow powder Form: Free Solvent for recrystallization: Ethyl acetate-diethyl ether Example 330 P.f. 209-211 ° C Crystalline form: Yellow powder Solvent for recrystallization: Ethanol-water FormaOHCl Example 331 P.f. 20B-210 ° C Crystalline Form: Light yellow powder Solvent for recrystallization: Ethanol-dichloromethane Form: Free CUAQRQ 146 Example 332 P.f. 200-203 ° C Form crystal ina: Pol or yellow Form: Free Solvent for recrystallization: Ethanol-isopropyl alcohol-di-chloromethane Example 333 P.f. 196-197 ° C Cristallic form: White powder Form: Free Solvent for recrystallization: Ethanol-dichlororaethane Example 334 P.f. 203-2O4oC Crystalline Form: White powder Form: Free Solvent for recrystallization: Dichloromethane-ethanol-isopropyl alcohol VAPRQ * 47 Example 335 P.f. 206-20B ° C Inactive crystal form: Light yellow powder Form: Free Solvent for recrystallization: Dichloromethane-n-hexane Example 336 : i P.f. 190-192 ° C Ina crystal form: Light yellow needles Shape: Free Solvent for recrystallization Oloroform-ethyl acetate Example 337 'P .f. 207-209 ° C Crystalline Form: Light yellow powder Form: Free Solvent for recrystallization: Ethyl acetate-diisopropyl ether CHART 14B Example 33B P.f. 199.5-200.5 ° C Inactive crystal form: White powder Solvent for recrystallization: Methanol-dimethylformamide Form: Free Example 339 P. f. 204-206 ° C Inactive crystal form: Light yellow powder Form: L b Solvent for recrystallization: Ethanol-di chloromethane Example 340 R e,: H RB: C 2 H 2 O (position 2) R .. * 3 *: - - A P.f. 115-117 ° C Forraa Crystalline: Light yellow powder Form: Free Solvent for recrystallization: Ethyl acetate-diisopropyl ether PICTURE 149 Example 341 P.f. 225-227 ° C Crystal form: Light yellow powder Form: Free Solvent for recrystallization: Ethyl acetate-di isopropyl ether Example 342 P.f. 196.5-19B ° C Inactive crystal form: Light yellow powder Form: Free Solvent for recp'stal izationOloroform-ethyl acetate Example 343 P.f. 192-194 ° C Crystalline Form: Light yellow powder Solvent for recrystallization: Ethyl acetate-di isopropyl ether Form: Free Spectrum of '-H NMR (NMR (1) to NMR (55)) as described in Tables 50-149 as follows: NMR (1) (CDC13) óppm: 2.33 (3H, S), 2. AS (AH, t, J = 5Hz), 3.6-3. B (4H, m). 4.85 < 2H, S), 7.09 (2H, d.J = 9Hz), 7.3-7.55 (2H, m), 7.50 (1H, dr J = 15Hz), 7.8-7.95 (2H, m), 7.93 (1H, d, J = 15Hz, B.10 <2H, d, J = 9Hz), 9.88 (1H, br) NMR (2) (DMSO-d ,,.) Óppm: 1.35-1.8 (2H, m), 2.0-2.3 (2H.m> 2.6-3.9 (11H, m), 2.B1 OH, S), 4.1-4.3 (1H, m), 4.5- 4.7 (1H.m), 5.08 (2H, s), 7.15 (2H, d, J = 9Hz), 7.3-7.55 (3H, m), 7.76 (1H., J = 14HZ), 7.77 (1H, d, J = 8.5HZ). 7.9B (1H, Ü, J = 8HZ). 8.05 (2H, d, J = 9HZ). 12.67 (1H, br) NMR (3) (DMSO-d ,,,) ppm: 2.32 (3H, S), 2.45-4.50 (20H, m, 2.50 (8)), 5.14 (2H, s), 7.04 ( 1H, d, J = 9.3Hz), 7.26-7.52 (3H, m), 7.70-8.10 (5H, m), 11.30-12.35, 12.35-13.20 (all 3H, br) NMR (4) (DMSO-d, ,,) óppm: 2.60-4.50 (20H, m), 5.23 (2H, S), 7.20-7.55 (4H, m), 7.70-8.10 (5H, m), 11.30-13.20 (3H, br) NMR (5) (DMSO-d ^) óppm: 0.926 (3H, t, J = 7.4Hz), 1.5- 1.9 (4H, m), 2.05-2.3 (2H, m), 2.6-2.8 (3H, m) , 2.81 (3H, s), 3.0-3.3 (1H.m), 3.3-3.9 (9H.m), 4.15-4.35 (1H, m), 4.5-4.8 (1H, m), 5.12 (2H, s), 7.02 (1H, d, J = 8.6Hz), 7.27-7.47 (3H, ra), 7.74-7.99 (4H, m), 7.91 (1H, d, J = 15Hz), 11.5-13.0 (3H, br) NMR (6) (DMSO-d?) Óppm: 0.93 (3H, t, J = 7.4Hz), 1.55-1.75 (2H, m), 2.6-2.B (4H, m), 2.79 (3H, s) , 3.0-4.15 (14H, ra), 4.2-4.4 (1H, m), 5.12 (2H, S), 7.03 (1H, d, J = 8.5Hz), 7.25-7.55 (2H, ra), 7.45 (1H , s), 7.75-7.9 (4H, m), 7.79 (1H, d, J = S.5Hz) NMR (7) (DMSO-dβ) óppro: 1.25 (6H, d, J = 7Hz), 1.3-2.0 (4H, m), 2.6-3.5 (6H, m), 5.12 (2H, 2), 6.77 (1H, dd, J = 6Hz, J = 15.5HZ), 7.00 (1H, d, J = 8.5Hz), 7.17 (1H, d, J = 15.5Hz), 7.25-7.5 (2H, m), 7.7-8.05 (4H, m), 9.14 (2H, br), 12.73 (1H, br) NMR (8) (CDC13) ppm: 1.62 (3H, t, J = 7.3 Hz) - 1.76- 2.03 (4H, m), 2.B5-3.09 (2H, m), 3.95-4.11 (2H, m), 4.52 (2H, q, J = 7.3HZ), 4.BB (2H, S), 5.2B (1H, brs), 6.9B (1H, d, J = 7.5 HZ), 7.32-7.43 (1H, m), 7.43-7.55 (1H, m), 7.56 (1H, d, J = 15.2HZ). 7.77-7.93 (2H, m), 8.00-8.12 (2H, m), 8.35 (1H, d, J = 15.2HZ), 10.85 (1H, brs) NMR (9) (DMS0-dft!) .ppm: 0.93 ( 3H, t, J = 7.4Hz), 1.5-1.8 (2H.m), lB-2.2 (4H, m), 2.69 (2H, t, J = 7.4Hz), 2.8 (3H, S), 3.0-4.3 (12H, m), 4.3-4.6 (1H, m), 5.13 (2H, S), 7.03 (1H, d, J = 8.6Hz), 7.17 (1H, d, J = 15.1Hz), 7.30 (1H, t, J = 7Hz), 7.74-7.99 (5H, m), 11.5-12.3 (1H, br), 12.3-13.3 (1H, br) NMR (10) (DMSO-d ,,;) óppm: 1.56-1.91 (4H, m), 2.70-2.90 (7H, m), 3.10-3.52 (BH, m), 5.14 (2H, s), 6.65-6.75 (1H, m), 6.99-7.15 (2H, m), 7.28 -7.40 (1H, ra), 7.40-7.52 (1H, m), 7.52-7.60 (2H, m), 7.72-7.85 (1H, rn), 7.90-B.OB (4H, m), 10.90-13. IB (3H, m) NMR (11) (DMSO-dw): 1.40-1.89 (2H, m), 1.96-2.32 (2H, m), 2.58-2.96 (4H, m), 2.96-3.83 (10H, m), 3.89 (3H, 8), 4.06-4.34 (1H, ra), 4.42-4.71 (1H, p »), 5.08 (2H, S), 7.07 (1H, d, J = 8.5 Hz), 7.31 ( 1H, t, J = 7.0Hz), 7.3B-7.69 (3H, m), 7.69.7.92 (3H, m), 7.98 (1H, d, J = 8.5Hz), 11.76 (2H, br), 12.71 ( 1H, b), NMR (12) (DMSO-d,.,) .ppm: 1.40-1.85 (2H, m), 2.00-2.23 (2H, m), 2.40 OH, S), 2.60-2. BB (1H, m), 2.81 OH, S), 3.00-3.B0 (10H, m), 3.89 (3H, S), 4.10-4.30 (1H, m), 4.48-4.7B (1H, m), 5.06 (2H, S), 7.04 (1H, d, J = B.5Hz), 7.21-7.31 (1H, m), 7.40 (1H, d, J = 15.2Hz), 7.52-7.60 (1H, m), 7.60-7. B8 (4H, m), 11.02-12.33 (2H, m), 12.33-12.80 (1H.m) NMR (13) (DMSO-d ,,,.) Óppm: 2.40 (3H, s), 2.81 OH, S ), 2.90-4.35 (15H, m), 3.89 OH, S), 5.07 (2H, S), 6.99-7.12 (1H, m), 7.12-7.35 (2H, rn), 7.52-7.60 (1H, m) , 7.60-7.91 (4H, m), 11.00-13.28 (3H, m) NMR (14) (DMSO-d,., ..) óppm: 1.31-1.64 (2H, m), 1.77-2.07 (2H, m ), 2.21-2.87 (10H, ni), 2.29 OH, S), 2.67 OH, s), 3.06-3.26 (1H, m), 3.96-4.2B (1H, m), 4.10 OH, s), 4.62- 4.78 (1H, m), 4.87 (2H, 8) f 7.07 (1H, d, J = 8.1Hz), 7.14-7.32 (2H, m), 7.52 (1H, d, J = 14.9Hz), 7.61-7.77 (3H, m), 7.91 (1H, d, J = 14.9HZ) NMR (15) (CDCl 3) ppm: 1.20-2.16 (4H, m), 2.31-2.72 (3H, m), 2.44 OH, s) , 2.72-3.34 (2H, m), 4.85 (2H, s), 6.76-7.06 OH, m), 7.21-7.58 (2H, ra), 7.72-B.00 (4H, m) NMR (16) (CDC13 ) óppm: 1.43-2.13 (4H, m), 2.2B (6H, S), 2.45 OH, 8), 2.53-3.28 (5H, m), 3.56-4.56 (2H, m), 4.86 (2H, S), 6.80-7.11 (3H, m), 7.2B-7.53 (2H, m), 7.74-7.93 < 4H, m) NMR (17) (CDC13) ppm: 1.3-1.5 (2H, m), 1.7-1.9 (2H, m), 2.6-2.8 (2H, m), 2.B-3.3 (2H, m) , 3.90 (3H, 8), 4.80 (2H, s), 6.5-6.65 (2H, ra), 6.73 (1H, d, J = 15.5Hz), 6.B7 (1H, dd, J = 15.5Hz, J = 6HZ), 7.3-7.55 (2H, m), 7.6-7.95 (4H, m) NMR (18) < CDC13) óppm: 1.12 (3H, t, J = 5.9Hz), 1.2B-3.78 (11H, m), 4.97 (1H, t, J = 5.3Hz), 6.68-7.53 (5H, m), 7.70-B .14 (4H, m) NMR (19) (DMSO-d ,,): 1.29-2.11 (4H, m), 2.32 OH, S), 2.60-3.0B (3H, m), 3.08-3.56 OH, m), 3.91 (6H, S), 4.85 (2H, 3), 6.73-6.93 (1H, m), 7.19-7.54 (5H, m), 7.71-7.83 (1H, ra), 7.93-8.05 (1H, m), B.29-8.80 (1H, m), 12.14 (1H, brs) NMR (20) (CDC13) óppm: 1.86-2.13 (2H, m), 2.39 OH, S), 2.48-3.06 (12H, m), 3.82 OH, s), 4.87 (2H, S) 6.82-8.09 (9H, m), 7.04 (1H, S), 7.21 (1H, 8) NMR (21) (DMS0-dβ) ppm: 1.4-2.2 (6H, m), 2.35 OH, s), 2.65-2. B5 (2H, m), 2.95-4.05 (14H, ra), 5.07 (2H, s), 6.78 (1H, dd, J = 7HZ, J = 15.5Hz), 7.02 (1H, d, J = 8.5Hz), 7.16 (1H, d, J = 15.5Hz), 7.26 (1H, d, J = 3.5Hz) , 7.50 (1H, d, J = 3.5Hz), 7.8- TO (2H, m), 9.5B (1H, br), 12.45 (1H, br) NMR (22) (DMS0-d ", :) .ppm: 1.33-1.71 (5H, m), 1.B0-2.00 (1H, m), 2.00-2.21 (2H, m), 2.65-2.77 (2H, m), 2.80 OH, s), 2.88-3.10 (4H, m), 3.10-4.00 (14H, m), 4.00-4.23 (1H, m), 4.47-4.66 (1H, til), 5.13 < 2H, s), 6.71-6.87 (1H, ni), 6.98-7.09 (1H, m), 7.09-7.22 (1H, m), 7.26-7.40 (1H, m), 7.40-7.52 (1H, m), 7.72-7.83 (1H, m), 7.83-7.97 (2H, m), 7.97-8.08 (1H, m), 11.32-12.55 (2H, m), 12.70 (1H, brs) NMR (23) (CDC13) ppm : 1.43-2.28 (12H, m), 2.28-3.01 (13H, m), 3.23-3.56 (2H, m), 3.56-4.09 (5H.m), 4.87 (2H, s), 6.74-7.02 (3H, ra), 7.22-7.53 (2H, m), 7.70-7.97 (4H, m) 3B0 NMR (24) (CDCl 3) Ob: 1.43-2. IB (12H, m), 2.37-2.6B (8H, m), 2.B6 (2H, t, J = 7.7Hz), 2.97-3.16 (2H, m), 3.25-3.53 (2H, m), 3.56 -3.80 (4H, m), 3.82-4.03 < 2H, m), 4.85 (2H, s), 6.79-7.00 OH, m), 7.22-7.53 (2H, m), 7.68-7.93 (4H, m) NMR (25) (CDC !,) óppm: 1.4B -3.22 (19H, m), 1.62 OH, t, J = 7.4HZ), 3.57-3.78 (4H, m), 4.54 (2H, q, J = 7.4Hz), 4.89 (2H, s), 6.99 (1H , d.J = 8.5Hz), 7.22-7.53 (3H, m), 7.59 (1H, d, J = 15.2HZ), 7.76-7.90 (2H, m), 7.92-B.09 (1H, m), 8.36 (1H, d, J = 15.2HZ) NMR (26) (DMS0-dβ) ppm: 2.65-2. B (1H, ra), 2.9-3.05 (1H, m), 3.3-3.45 (2H.m), 3.8 (1H, ra), 4.65 (2H, br), 5.11 (2H, s), 7.06 < 1H, d, J = 8.5HZ), 7.25-7.5 (2H, m), 7.64 (1H, d.J- = 15.5Hz). 7.75-7.9 OH, m), 7.95-B.2 (4H, m), 8.66 (2H, br), 12.58 (1H, br) NMR (27) (CDCl 3) ppm: 1.36 OH, t, J = 7.5 Hz), 2.6-3.6 (6H, ro), 2.86 (2H, q, J = 7.5Hz). 4.05 (1H, m), 4.50 (1H, m), 4.87 (2H, S), 6.93 (1H, d, J = 8Hz), 7.3-7.55 (3H, m), 7.8-8.0 (5H, m), 9.66 (1H, br) NMR (28) (DMSO-d,., :) .ppm: 1.67-1.97 (2H, m), 2.80 OH, S), 2.88-4.35 (17H, m), 3.90 (3H, 8 ), 5.10 (2H. S), 7.08 (1H, d, J = B.6HZ), 7.20-7.66 (4H, m). 7.66-7.95 (3H, m), 7.99 (1H, d, J = 7.1HZ), 12.70 (1H, s) NMR (29) (DMS0-d, ¥) ppm: 2.05-2.35 (2H, m), 2.55 -4.18 (22H, m), 4.18-4.42 (1H, m), 5.09 (2H, s), 7.07 (1H, d, J = 8.6HZ), 7.27-7.57 (4H, m), 7.74-7.77 OH, m), 7.98 (1H, d, J = 7.1Hz), 11.52 (2H, br), 12.55 (1H, br) NMR (30) (CDC13) .ppm: 1.1-1.4 (3H, m), 1.37 (3H, t, J = 7.5HZ), 2.5-2.8 (2H, ra), 2.86 (2H, q, J = 7.5Hz), 2.9-3.1 (1H, ra), 3.2-3.6 (2H, m), 3.8-4.1 (1H , m), 4.5-4.8 (1H, m), 4.87 (2H, s), 5.35 (1H, br), 6.93 (1H, d, J = 9Hz), 7.25-7.6 (3H, m), 7.75-8.05 (5H, ro), 9.60 (1H, br) NMR ( 31) (DMS0-dw) óppm: 0.74-0.91 (3H, m), 1.12-1.44 (6H, m), 1.50-1.71 (2H, m), 2.55-2.90 OH, ra), 2.79 OH, s), 2. 90-3.80 (13H, m), 3.80-4.12 (4H, m), 4.19-4.42 (1H, m), 5.11 (2H, s), 7.01 (1H, d, J = 8.7H?), 7.27-7.51 OH, m), 7.71-8.02 (5H, m), 11.00-13.00 OH, m) NMR (32) < DMSO-d ,, ..) óppm: 1.45-1.89 (2H, m), 2.00-2.38 (6H, m), 2.55-2.86 (6H, m), 3.01-3.22 (1H, m), 3.22-3.94 (9H, m), 3.77 (3H, S), 3.99-4.50 (3H.m), 4.50 -4.70 (1H, m), 7.07-7.20 (1H, m), 7.20-7.37 (1H, m), 7.37-7.54 OH, m), 7.67-7.89 (3H, m), 7.89-B.03 (1H , ra), 11.06-12.62 OH, m) NMR (33) (DMS0-d, ¥) óppm: 1.40-1.92 (2H, m), 1.92-2.30 (4H, m), 2.31 OH. s), 2.55-2.90 (4H, m), 2.90-4.03 (10H, m), 4. 03-4.34 (1H, m) 4.44-4.73 (1H, m), 5.11 (2H, S), 7.23 (1H, d, J = 9.3H), 7.31 (1H, t, J = 6.9HZ), 7.32-7.48 (2H, m). 7.74-7.86 (2H, m), 7.86-B.05 OH, m), 10.88-12.00 < 2H, m), 12.70 (1H, br) NMR (34) (DMS0-d,.,): 1.48-1.94 (2H, m), 2.00-2.39 (4H, m), 2.57-2.85 (4H, m), 2.85-4.03 (10H, m), 4.10-4.39 (1H, m), 4.48-4.71 (1H, m), 5.29 (2H, s), 7.21 -7.57 (4H, m), 7.75- 7.83 (2H, m), 7.98 (1H, d, J = 7.4Hz), 8.23 (1H, S >;, T.32 (1H, d, J = 8.7Hz), 10.89-12.06 (2H, m), 12.76 (1H, br) NMR (35) (DMSO-d ,,) óppm: 2.88-3.28 (4H, m), 3.73-4.31 (4H, m), 5.30 (2H, S), 7.31 (1H, t, J = 6.9Hz), 7.35-7.48 OH, m), 7.75-7.85 (2H, m), 7.97 ( 1H, d, J = 7.1Hz), 8.23 (1H, s), 8.33 (1H, d, J = B.7Hz), 9.37 (2H, br), 12.78 (1H, br) NMR (36) (DMS0- dß) óppm: 1.2-1.5 (2H, m), 1.6-1.85 (BH, m), 2.31 OH, S), 2.5-3.15 (15H, m), 3.9-4.0 (1H,), 4.4- 4.5 (1H , m), 5.04 (2H, S), 6.81 (1H, d, J = B.5HZ), 7.20 (1H, d, J = 15.5HZ), 7.25-7.5 OH, m), 7.55 (1H, d, J = 8.5Hz), 7.75 (1H, d, J = 7.5 HZ), 7.97 (1H, d, J = 7Hz) NMR ( 37) (DMS0-dβ) óppm: 1.4-1.9 (2H, m), 2.12 (6H, S), 2.0-4.0 (19H, m), 4.45-4.6 (1H, m), 4.95 (2H, S). 6.77 (2H, S), 6.88 (1H, d, J = 16Hz), 7.03 (1H, d, J = 16Hz), 7.35-7.5 (2H, m), 7.76 (1H, d, J = 7.5HZ), 7.99 (1H, d, J = BHz), 11.24, 12.04 (all 1H, br), 11.74 (1H, br), 12.64 (1H, br) NMR (38) (DMSO-d,.,) Óppm: 2.54- 2.93 (5H, m), 2.93-3.7B (10H, m), 3.7B-4.17 (7H, m), 4.17-4.44 (1H, m), 5.07 (2H, s), 6.65-6.78 (1H, m ), 6.78-6.90 (1H, m), 7.18-7.71 (5H, m), 7.76 (1H, d, J = 7.5Hz), 7.98 (1H, d, J = 7.1HZ), 11.28 (2H, br) , 12.6B (1H, br) NMR (39) < DMS0-d,.,) Óppm: 2.22 (3H, 8), 2.33 OH, s), 2.36 OH, S), 2.80 OH, d »J = 4Hz), 2.9-3.6 (6H, m), 4.15-4.3 (1H, m), 4.4-4.55 (1H, m), 5.06 (2H, S), 6.85 (1H, d, J = 9Hz), 7.24 (1H, d, J = 15.5HZ), 7.37 (1H, d , J = 15.5Hz), 7.25-7.55 OH, m), 7.76 (1H, d, J = 7HZ), 7.98 (1H, d, J = 7Hz), 9.76 (1H, br), 12.60 (1H. NMR (40) (DMS0-d, v) ppm: 2.05-2.35 (2H, m), 2.54-2.98 (5H, m), 2.98-3.85 (10H, ra), 3.85-4.19 (7H, m), 4.19-4.47 (1H, m>, 5.07 (2H, S), 6.65-6.79 (1H, m), 6.79-6.90 (1H, m), 7.18-7.71 (5H, m), 7.77 (1H, d, J = 7.7Hz), B.00 (1H, d, J = 7. BHz), 11.22 (2H, br ), 12.68 (1H, br) NMR (41) (DMSO-d, ¥) ppm: 1.89-2.44 (4H, m), 2.53-3.7B (16H, m), 3.78-4.13 < 6H, m), 4.13-4.42 (1H, m), 5.07 (2H, s), 6. 70 (1H, dd, J = 2.2Hz, J = 8.7Hz). 6.81 (1H, d, J = 2.2Hz), 7.19-7.73 (5H, m), 7.76 (1H, d, J = 7.BHz), 7.9B (1H, d, J = 7.0Hz), . 61 (1H, br), 11.27 (1H, br), 12.71 (1H, br) NMR (42) (DMSO-d,.,) .ppm: 1.30 (6H, d, J = 5.9H?), 2.55-4.19 (19H, m), 4.19-4.41 (1H, m), 4.82 (1H, sept, J = 5.9Hz), 5.07 (2H, S), 6.60-6.71, (1H, m), 6.76-6.79 (1H, m), 7.22-7.49 OH, m), 7.64 (1H, d, J = 8.7Hz). 7.71-7.90 (2H, ra), 7.9B (1H, d, J = 7.1HZ), 11.81 (2H, br), 12.5B (1H, br) NMR (43) (DMS0-d, ¥) óppm: 1.35 OH, d, J = 6Hz), 1.5-2.2 (4H, m), 2.5-3.B (1.3H, m), 3.BB OH, S), 4.1-4.3 (1H, m), 4.45-4.65 (1H, m), 5.06 (2H, s), 6.70 (1H, d, J = 9Hz), 6.81 (1H, s), 7.27 (1H, d, J = 15.5HZ), 7.25-7.5 (2H, m ), 7.56 (1H, d, J = 15.5HZ), 7.64 (1H, d, J = 8.5Hz), 7.77 (1H, d, J = 8Hz), 7.99 (1H, d, J = 8Hz), 12.5- 13 OH, br) NMR (44) (DMSO-d ,,;) óppm: 1.30 OH, d, J = 6.5 Hz), 1.5-2.3 (4H, m), 2.55-2.8 (1H, m), 3.0- 4.7 (13H, m), 3.88 OH, S), 5.07 (2H, S), 6.70 (1H, d, J = 9HZ), 6.81 (1H, m), 7.27 (1H, d, J = 15.5Hz), 7.25-7.5 (2H, ra), 7.56 (1H, d, J = 15.5H?), 7.64 (1H, d, J = B.5HZ>, 7.77 (1H, d, J = 8HZ), 7.9B ( 1H, d, J = 7.5Hz), 9.85 (1H. Br), 10.01 (1H, br), 12.25 (1H, br) NMR (45) (DMS0-dβ) .ppm: 2.05-2.20 (2H, m), 2.5-4.0 (1BH, m), 3.88 OH, S), 4.1-4.25 (1H, m), 4.5-4.65 (1H, ra), 5.06 (2H, s), 6.70 (1H, d.J = 8.5Hz ), 6.B1 (1H, m>, 7.28 (1H, d, J = 15Hz), 7.25-7.5 (2H, m), 7.56 ( 1H, d, J = 15Hz), 7.64 (1H, d, J = B.5HZ), 7.77 (1H, d, J = BHz), 7.99 < 1H, d, J = 7.5HZ), 10.78 (1H, br), 11.94 (1H, br), 12.66 (1H, br) NMR (46) (DMSO-d ,,) .ppm: 1.43-1.85 (2H, m ), 1.97-2.42 (4H, m), 2.58-2.82 (1H, m), 2.82-4.0B (18H, m), 4.0B-4.30 (1H, m), 4.42-4.72 (1H, m), 5.06 (2H, S), 5.22-5.6B (2H, m), 6.62-6.7B (1H, m), 6.78-6.95 (1H, m), 7.24-7.70 (5H, m), 7.77 (1H, d, J = 6.2Hz), 7.99 (1H, d, J = 5.8HZ), 10.35 (2H, br), 11.48 (1H, br) NMR (47) (DMS0-dβ) óppm: 1.3-2.0 (6H, m) , 2.37 (6H, S), 2.B-4.2 (16H, m), 3.BB OH, S), 5.07 (2H, S), 6.71 (1H, dd, J = 7H, J = 2Hz). 6.B1 (1H, d, J = 2Hz), 7.25 (1H, d, J = 15Hz, 7.25-7.5 OH, m), 7.65-7.75 (2H, m), 7.77 (1H, d, J = 7Hz) , 7.98 (1H, d, J = 6HZ), 9.40 (1H, br) NMR (48) (DMSO-d,.,) .ppm: 2.4-4.5 (23H, m). 3.8B OH, S), 5.09 (2H, S), 6.71 (1H, d, J = 9Hz), 6.82 (1H, S), 7.2-7.75 (5H, m), 7.77 (1H, d.J = 8HZ ), 7.98 (1H, d, J = 7Hz), 10.98 (1H, br), 11.5B (1H, br), 12.71 (1H, br) NMR (49) (DMS0-d, ¥): 2.16 OH, ß), 2.23 OH, s), 2. 74 OH, d, J = 4HZ), 2.85-3.7 (6H, m), 3.86 OH, ß), 4.15-4.6 (2H, ra), 4.95 (2H, s), 6.66 (1H, d, J = 8.5Hz), 6.79 (1H, m), 7. 27 (1H, d, J = 15Hz), 7.61 < 1H, d, J = 15Hz), 7.63 (1H, d, J = 8.5HZ), 11.42 (1H, br) NMR (50) (DMS0-d, r.): 1.39-1.90 (2H, m), 1.9B-2.37 (4H, ra), 2.58-2.90 (4H, m), 2.9B-3.99 (10H, m). 4.11-4.32 (1H, m), 4.48-4.70 (1H, m), 5.09 (2H, s). 6.93-7.15 (2H.m), 7.20-7.62 (4H, m), 7.80-7.92 (2H, m), 7.99 (1H, d, J = 7.3Hz), 10.80-11.95 (2H, m), 12.68 ( 1H, br) NMR (51) (DMSO-d,.,): 1.67-2.03 (2H, m), 2.B0 OH, S > . 2.99-4.35 (20H, ra), 5.07 (2H, s), 6.70 (1H, dd, J = 2.2Hz, J = B .7Hz), 6.82 (1H, d, J = 2.2Hz), 7.19-7.74 ( 5H, m), 7.77 (1H, d, J = 7.5HZ), 7.99 (1H, d, J = 7.9Hz), 10.80-12.32 (2H, br), 12.69 (1H, br). NMR (52) (DMSO-d,.,) Óppm: 2.15 OH, S), 2.22 OH, s), 2. 83 OH, s), 2.5-4.4 (17H, m), 3.86 OH, s), 4.94 (2H, S), 6.65 (1H, d, J = T.5HZ), 6.78 (1H, 8,), 7.2 -7.7 OH, m), 12.05 (1H, br). NMR (53) (DMS0-dβ) óppm: 2.36 (6H, ß), 2.55-4.45 (20H, m), 4.92 (2H, q, J = 8.9Hz), 5.0B (2H, 6), 6.80 (1H , dd, J = 2.3HZ), J = B.9HZ), 6.94 (1H, d, J = 2.3 Hz), 7.21-7.75 (5H, m), 7.77 (1H, d, J = 8.1HZ), 7.98 < 1H, d, J = 7.1Hz), 9.95 OH, br), 12.63 (1H, br). NMR (54) (DMS0-dβ) óppm: 1.40 (6H, d, J = 6.0 Hz), 1.51-1.86 (2H, m), 2.05-2.30 (2H, m), 2.57-2.73 (1H, m), 2.79 OH, S), 2.9B-3.B7 (SH, m). 3.B8 OH, 8), 4.14-4.25 (1H, m), 4.40-4.70 (1H, m), 5.06 (2H, 8), 6.70 (1H, dd, J = 2.2 Hz, J = 8, BHz) , 6.81 (1H, d, J = 2.2 Hz), 7.23-7.66 (5H, m), 7.77 (1H, d, J = 7.6Hz), 8.00 (1H, d, J = 7.0 Hz), 11.40 -13.10 OH , m). NMR (55) (DMS0-ßß) óppm: 1.4-2.4 (4H, m), 2.34 OH, S), 2.7-5.0 (9H, m), 3.BB OH, S), 5.06 (2H, ß), 6.71 (1H, dd, J = 2HZ, J = 9HZ), 6.B2 (1H, d, J = 2Hz), 7.2-7.5 OH, m), 7.55-7.8 OH, m), 7.99 (1H, d, J = 7Hz), 9.6.10.2 (1H, m), 12.60 (1H, br). NMR (56) (DMS0-d,.,) .ppm: 1.40-1.84 (2H, m), 2.00-2.42 (4H, m), 2.67 (1H, t, J = 12.5HZ), 2.77 OH, s), 3.12 (1H, t, J = 12.5Hz), 3.24.4.05 (12H, m), 4.10-4.31 (1H, m), 4.48-4.71 (1H, ro), 5.07 (2H, S), 6.70 (1H, dd, J = 2.1Hz, J = 8.7Hz), 6.82 (1H, d, J = 2.1Hz), 7.19-7.62 (4H, m), 7.64 (1H, d, J = B.6HZ), 7.77 (1H , d, J = 8.1HZ), 7.99 (1H, d, J = 7.9Hz), 11.05-12.10 (2H, m), 12.68 (1H, br).

E SUPtP 344 ^ 0.55 g of 2 { 3-alioxy-4-C3- (l-piperidinyl) carbonylalkyl-1-phenoxymethyl-carbon-lamino-3-benzothiazole in 70 ml of methanol and 40 ml of dioxane, and 0.5 g of 10% palladium-carbon was added thereto, 70 mg of toluenesulfonic acid monohydrate and 3 ml of water. The mixture was subjected to deaeration, the mixture was refluxed under nitrogen atmosphere overnight. The mixture is filtered through a pad of cerite, and water-methylene chloride is added to the filtrate, and the mixture is separated and dried over sodium sulfate. The residue is crystallized from ethanol-methyl chloride, and recrystallized from dimethylformamide-ethanol to give 120 mg of 2C3-alkyloxy-4-C3- (1-piperidini 1) carbon lacri loi 11 phenoxymethylcarboni lamino } benzothiazole Yellow powder P.f. 207.3-210 ° C ? ^ Pl, Q 35 To a solution of 6.4 g of dimethyl-1-CC2-methoxy-4-C2- (2-benzothiazole and lamino-carboni-1) -eti-1] benzoyl-13-methyl-D-phosphonate in 100 ml of tetrahydrofuran is added 7.7 ml of glyoxylic acid at 40 ° C. in addition, 70 ml of an aqueous sodium hydroxide solution is added dropwise to the 5'Á under freezing. The mixture is stirred for 30 minutes and the mixture is acidified with hydrochloric acid to 554. The precipitated yellow powder is collected by filtration, washed with ethanol, dried and subsequently recrystallized from dimethylformamide-ethanol to give 4.0 g of 2- 2-Cmethoxy-4- (trans-3-carboxiacp * loi 1) fem "1 -leti Icarboni lamino"} -benzothiazole Yellow powder P.f. 260-261 ° C TEMPLE 346 To 50 ml of tetrahydrofuran is added 4.70 g of 1 C dimeti. * 2-dimethylamino-4 -C (2-benzothiazole i 1) aminocarbonyl-methoxy-3-benzoyl} meti 1 Dfosfonato »and to the same add 40 ml of 5% aqueous solution of sodium hydroxide and 3.5 ml of glyoxylic acid under freezing, and the mixture is stirred at the same temperature for 10 minutes. After confirming that the starting compounds have been consumed, the mixture is acidified with hydrochloric acid and concentrated under reduced pressure to remove the solvent. The precipitated crystals are collected by filtration, dissolved in 100 ml of dimethylformamide and the mixture is heated with stirring at 100 ° C for 30 minutes. After cooling, isopropyl alcohol is added to the solution and the precipitated crystals are collected by filtration. The crystals are recrystallized from dimethyl Iformamide-isopropyl alcohol to give 2.46 g of 1,1-dimethyl-l-2-carboxy-4-oxo-7-C (2-benzothiazol-yl) -aminocarbonylmethyl-3-1 chloride. , 2,3,4-tetrahydroquinol inium. Pale green powder P.f. 184.5-1B6.5 ° C The compounds listed in tables 150-160 are obtained in the same manner as in example 1 or 5 using the appropriate starting compounds. 3B9 TABLE 150 Example 347 RB: H A • ~ CH * 5g- '»> 5S * "" m: i s: 0 RA: H R - »: H Position of -COCH = CHCOOH: Position P.f. 235.5-255 ° C Crystalline form: White powder Solvent for recrystallization: Dimeti Iformamide-ethanol Form: Free Example 348 RB: -OCH3 (position 3) A: -CH, CH. m: i s: 0 Z: - R *: H R - »: H COCH position = CHCOOH: Position 4 P.f. 260-261 ° C Crystalline form: Yellow powder Solvent for recrystallization: Dimeti 1 formami da-etaño1 Shape: Free Example 349 RB: (position 5) A: -CHr, - m: i s: i Position of -COCH = CHCOOH: Position 4 P.f. 184-186 ° C Crystalline form: Pale yellow powder Solvent for recrystallization: Dimeti Iformamide-ethanol-water Form: Free TABLE 151 Example 350 RB: -0CH3 (position 3) A: -CH2- m: i s: i 2: 0 RA: ~ (CH3) 2 (position 6) R - *: H Position of -C0CH = CHC00H: Position 4 P.f. 263-264 ° C (deßcomposición) Crystalline form: Pale brown powder Solvent for recrystallization: Dimeti lformamide-ethanol-water Form: Hydrate Example 351 RB: -0CH2"/ (position 3) A: -CHa- m: is: l Z: 0 RA: H R -»: H Position of -C0CH = CHC00H: Position 4 Pf 294-2 7 ° C Form crystalline: Yellow powder Solvent for recrystallization: Dimeti 1 formamide Form: Free Example 352 RB: -0CH2CH = CHa (position 3) A: -CHa- m: i s: i ZO R: H R - »: H Position ** n of -C0CH = CHC00H: Position 4 P.f. 248-254 ° C Crystalline form: Pale yellow powder Solvent for recrystallization: Dilute hydrochloric acid NMR (36) Form: Free TABLE 152 Example 353 R: ~ ° _J (position 3) A: -CH, .- m: l s: i Z: 0 R- *: H Position of -C0CH = CHC00H: Position 4 P.f. 270-271.5 ° C Crystalline form: Pale yellow powder Solvent for recrystallization: Dimeti Iformamide-dichloromethane Form: free Example 354 -o (position 3) A: -CH -.- m: i s: i Z: 0 R **: H Position of -C0CH = CHCO0H: Position 4 P.f. 270-273.3 ° C Crystalline form: Yellow powder Solvent for recrystallization: Dimeti Iformamide-dichloromethane Form: Free Example 355 RB: - CHa > 3CH3 (position 2) & -OCH3 (position 5) A: -CH.? - mO s: i ZO R - »: H Position of -C0CH = CHCO0H: Position 4 P.f. 203-206.3 ° C Crystalline form: Yellow powder Solvent for recrystallization: Dimeti lformamide-dichloromethane Form: Free CM? PPQ 153 Example 356 RB: - CHa > aCHa (position 2) & -OCH3 (position 3) A: -CH.? - m s: i Z :? R - *: H Position of -COCH = CHCOOH: Position 4 P.f. 232-234 ° C Crystalline form: Yellow powder Solvent for recrystallization: Tetrahydrofuran-water Form: Free Example 357 R: -OA A (position 3) A .'- CH, .- m: i s: i Z: 0 R- »: H Position of -C0CH = CHC00H: Position 4 P.f. 237-245 ° C (decomposition) Crystalline form: White Pplvo Solvent for recrystallization: Tetrahydrofuran-water NMR (37) Form: Free Example 358 R ** ": -CH2CH3 (position 2) &-0CH3 (position 5) A: -CH.? - mO s: i ZO R" *: H Position of -C0CH = CHC00H: Position 4 P.f. 127-138 ° C Crystalline form: Pol or yellow Solvent for recrystallization: Dimeti Iformami da-acetonitri the NMR (38) Form: Free C APRQ 15 Example 359 R «: -0CH3 (position 2 and 6) A: -CH ....- mO s: i Z: 0 R -»: H. / Position of -COCH = CHCOOH: Position 4 P.f. 137-138 ° C Crystalline form: Yellow powder Solvent for recrystallization: Dimethylformamide-ethanol-diethyl ether-hexane-form: Free Example 360 RB: -OCH3 (position 2 and 3) A: -CH.? - mO s: i Z :? R - *: H Position of -C0CH = CHC00H: Position 4 P.f. 235-237 ° C Crystalline form: Yellow powder Solvent for recrystallization: Dichloromethane-dimeti Iforraamide Shape: Free Example 361 RB: -OCH3 (position 2) and -OCH3 (position 3) A: -CH ..- roo s: i ZO R - »: H Poßici n of -C0CH = CHC00H: Poßition 4 Crißtaline form: Pale yellow powder NMR (39) Form: Free Example 362 RB: -OCH3 (poßition 2) and -0CH3 (position 3) A: -CHW-m: 2 s: i Z: 0 R- ^ H Poßic ón of -C0CH = CHC00H: Poßition 6 Crystalline form: Brown powder pale NMR (40) Forroa: Free TABLE 155 Example 363 RB: - (CH2) 3CH3 (position 2) and -OCH3 (position 3) A: -CH ...- mO s: i Z ".0 R - *: H Preparation of -COCH = CHCOOH: Poß tion 6 Crystal Shape: Yellow powder NMR (41) Shape: Free Example 364 RB: -SCH3 (position 3) A: -CH., - ra: is: i Z: 0 R - »: H Poi tion of -COCH = CHCOOH: Poi tion 6 Crystalline form: Yellow powder NMR (42) Form: Free Example 365 Rß: -CHaCHa (position 2) and -OCH3 (position 3) A: -CH .., - mO s: i Z :? R - »: H Position of -C0CH = CHC00H: Position 4 Crystal forra: Pale brown powder NMR (43) Shape: Free Example 366 RB: -OCH3 (position 3) A: -CH (CH3) - m: i s: i Z :? R - ": H Position of -C0CH = CHC00H: Position 4 P.f. 225-22B ° C (decomposition) Crystalline form: Pale brown powder Solvent for recrystallization: Dimeti Iformamide-ethanol-diethyl ether-water-form Form: Free TABLE 156 Example 367 y- \ RB: (position 2 and 3) A: -CH ..-.- m: 2 s: i Z: 0 f R - *: H Position of -COCH = CHCOOH: Position 4 P.f. 255-256 ° C (decomposition) Crystalline form: Yellow powder Solvent for recollection: Dimeti Iformamide-acetoni tri lo Form: Free Example 368 RB: -CHa (position 3) A :-( CH,) 3- m: i s: i Z :? f R - ": H Position of -C0CH = CHC00H: Position 4 P.f. 239-241 ° C (descorapo- tion) Form crißtaline: Pale yellow powder Solvent for recrystallization: Dimeti lformarai da- acetoni trilo Shape: Free Example 369 RB: - (CHa> aCH (position 2) and -0CH (position 5) A: -CH., - m: 2 s: i ZO ^ R "»: H Position of -C0CH = CHC0OH: Position 4 Pf 222-224 ° C (decomposition) Crystalline form: Pale yellow powder Solvent for recrystallization: Diraet Iformamide- acetonitrile Form: Free Example 370 RB: -CHaCH = CHa (position 2) and -0CHa (poem 5) A: -CH., - m: 2 ß: i Z: 0 t R - *: H Poßic ón of -C0CH = CHC00H: Poßition 4 Pf 224-225 ° C (decsc.) Crystalline form: Yellow powder Solvent for recollection: Dimeti 1 formamide-acetonitrile Form: Free TABLE 157 Example 371 RB: -OCH3 (positions 2 and 5) A: -CH ..- m: Z R - »: H Position of -COCH = CHCOOH: Position 4 NMR (44) Crystalline Forroa: Yellow powder Form: Free Example 372 RB: -CH3 (position 2) and -OCH3 (position 5) A: -CH., - m: 2 R "»: H Position of -COCH = CHCOOH: Position 4 NMR (45) Crystalline form: Yellow powder Example 373 RB: -OCaHß (position 2) and -OCH3 (position 5) A: -CH ..- mO R "': H Position of -C0CH = CHC00H: Position 4 Pf 202-204 ° C (deßcompoßición) Form crißtalina : Yellow powder Solvent for recycling: Dimeti Iformaraide- acetoni tri lo Form: Free CM? D- RQ * 5g Example 374 RB: -Br (position 2) and -0CH3 (position 5) A: -CH.? .- mO R - ": H Position of -COCH = CHCOOH: Position 4 Pf 238-239 ° C (decomposition) Form crystalline: Yellow powder Solvent for recrystallization: Dimeti Iformamide-acetoni tri lo Form: Free Example 375 RB: -CH (CHa) (position 2) and -OCHa (position 5) A: -CH.it- mO R - «: H Position of -COCH = CHCOOH: Position 4 NMR (46) Crystalline form: Dust Yellow Shape: Free Example 376 RB: - (CH2) aCH3 (position 2) and -0CHa (position 5) r \: -CH.:;:- m R "-: H Position of -COCH = CHCOOH: Position 4 NMR (47) Form Crystalline: Yellow powder Shape: Free Example 377 RB: -N (CHa) a (position 2) A: -CH ..- ra: i R- ": H Position of -COCH = CHCOOH: Position 4 NMR (48) Crystalline form: Pale yellow powder Form: Free 39B TABLE 159 Example 378 RB: -OCHa (position 3) A: -CH, - m: i R - ": HT: -CHa- u: i Position of -COCH = CHCOOH: Position 4 NMR (49) Crystalline Forra: Yellow powder Form : Free CMAPRQ 160 Form: Free Solvent for recrystallization: Dimeti Iformamide-methane1 Using the appropriate starting compounds, the compounds as listed in Tables 161-197 are obtained in the same manner as in Examples 3 or 4.

TABLE 161 P. f. 187.5-188.5 ° C Cristallicine form: White powder Solvent for recrystallization: Ethanol-diethyl ether Form: Free Example P.f. 164-166 ° C Crystalline form: White powder Solvent for recrystallization: Ethanol-diethyl ether Forraa: 2HC1 TABLE 162 Example P.f. 148.4-151.2 ° C Crystalline form: Yellow powder Solvent for recrystallization: Ethanol-diethyl ether Form: 2HC1 Example R - ": H P.f. 200-210 ° C (decomposition) Crystalline form: Pale brown powder Solvent for recrystallization: Ethanol-water-diethyl ether NMR (1) Form: 2HC1-H" 0 Example R ": H P.f. 160.2-162.3 ° C Crystalline form: Pale yellow powder Solvent for recrystallization: Ethanol-diethyl ether Form: 2HC1 TABLE 163 Example 3 R "1: H P.f. 156-166 ° C Crystalline form: Pale brown powder Solvent for recrystallization: Ethanol-water-diethyl ether NMR (2) Form: 3HC1-3H-.0 Example R "': H P., 178-179 ° C Crystalline form: Pale yellow powder Solvent for recrystallization: Ethanol Form: Free Example R "*: H P.f. 252-253 ° C Crystalline form: White powder Solvent for recrystallization: Ethanol-water-diethyl ether Form: Li-I PICTURE 164 Example R ": H P.f. 244-246 ° C (decomposition) Crystalline form: Pale brown powder Recyclation solvent: Ethano-cl oroform Form: Free Example 389 R - ': H P.f. 173-176 ° C Crystalline form: Pale yellow powder Solvent for recrystallization: Ethanol-water-diethyl ether Form: 2HC1 Example 390 R- ^ H P.f. 161.2-163.0 ° C Crystalline form: Pale yellow powder Solvent for recrystallization: Ethanol-water-diethyl ether Form: 2HC1 TABLE 165 Example 3 R - ': H P.f. 172-176 ° C Crystalline form: White powder Solvent for recrystallization: Ethanol-water-diethyl ether Form: Free o Solvent for recrystallization: Ethanol-water Form: Free Example Solvent for recrystallization: Diethyl ethanol - Form: Dimetansulfonate TABLE 166 Example R ": H P.f. 167.0-16B.5 ° C Crystalline form: Pale yellow powder Solvent for recrystallization: Ethanol-water Form: 2HC1 E jemp Solvent for recrystallization: Ethanol Form: Free R "': H P.f. 237.5-238.5 ° C Crystalline form: Yellow powder Solvent for recrystallization: Ethanol-water Form: 2HC1 TABLE 167 Example 397 R - «: H P.f. 15B.0-1S1.0 ° C Crystal shape: Yellow powder Solvent for recrystallization: Ethanol-water Form: 2HC1 Example R - ": H P.f. 162.0-164.3 ° C Crystalline form: Pale yellow powder Solvent for recrystallization: Ethanol-water Form: 2HC1 Example 399 R - ": H P.f. 133-136 ° C Crystalline form: Yellow powder Solvent for recrystallization: Ethanol-water Form: Methansulfonate CU? DRQ 169 Example 4 R - ": H aryl Solvent for recrystallization: Dimeti lformami da-ethanol Shape: Free Pale yellow powder Solvent for recrystallization: Ethanol-diethyl ether NMR O) Form: 2HC1 Yellow powder Solvent for recrystallization: Diethyl ethanol-based NMR (4) Form: HCl TABLE 169 Example Orange powder Solvent for recrystallization: Diethyl ethanol-NMR (5) Form: 2HC1 Example 404 / - \ (CH2) 3CH3 H C0-Y JN-CH3 R "»: H P.f. 138.5-140.3 ° C Crystal form: Yellow powder Solvent for recrystallization: Ethanol-water-diethyl ether Form: Methanesulfonate di chloromethane Form: Methanesulfonate TABLE 170 Example R "': H P.f. 13B.2-139.5 ° C Crystalline form: Pale yellow powder Solvent for recrystallization: Ethanol-water-diethyl ether Form: Methanesulfonate Example R- ^ H P.f. 168.5-171.0 ° C Crystalline form: Yellow powder Solvent for recrystallization: Ethanol-water-diethyl ether Form: Methanesulfonate Form: 2HC1 Example R- ^ H P.f. 132-134 ° C Crystalline form: White powder Solvent for recrystallization: Ethanol-diethyl ether Forra: Methanesulfonate TABLE 171 Example R- ^ H P.f. 190-193 ° C Crystalline form: Yellow powder Solvent for recrystallization: Ethanol-acetone-ether-diethyl ester Form: 2HC1 Example R - ': H P.f. 110-150 ° C (decomposition) Crystalline form: Pale yellow powder Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether Form: Dimethanesulfonate NMR (6) Example R "*: H P.f. 190-240 ° C (decomposition) Crystalline form: Pale yellow powder Solvent for recrystallization: Ethanol-diethyl ether Form: 2HC1 NMR (7) TABLE 172 Example 4 R "': H P.f. 190-210 ° C (decomposition) Crystalline form: Pale yellow powder Solvent for recrystallization: Ethanol-diethyl ether Form: 2HC1 NMR (8) Example R - '*: H P.f. 167.0-169.0 ° C Crystalline form: Yellow powder Solvent for recrystallization: Ethanol Form: 2HC1 Ahem R - ": H P.f. 200-220 ° C Crystalline form: Pale yellow powder Solvent for recrystallization: Ethanol-water-diethyl ether Form: 2HC1 NMR (9) TABLE 173 Ejerop R "*: H P.f. 177-180 ° C Crystalline form: Yellow powder Solvent for recrystallization: Dichloromethane-diisopropyl ether Form: 2HC1 Example R "*: H P.f. 179-182 ° C Crystalline form: Yellow powder Solvent for recrystallization: Dichloromethane-diisopropyl ether Form: 2HC1 Example 417 R "*: H P.f. 15B-159 ° C Crystalline form: Yellow powder Solvent for recrystallization: Dichloromethane-di-sopropyl ether Fora: 2HC1 TABLE 174 Example R - ": H P.f. 230-232 ° C Crystalline form: Yellow powder Solvent for recrystallization: Methanol-diethyl ether Form: 2HC1 Example R - *: H P.f. 221-224 ° C Crystalline form: Yellow powder Solvent for recrystallization: Methanol-diethyl ether Form: 2HC1 Example R - '.' H P.f. 179-182 ° C Crystalline form: Yellow powder Solvent for recrystallization: Methanol-diethyl ether Form: 2HC1 TABLE 175 Example R - ": H P.f. 146.2-248.5 ° C Crystalline form: Gray powder Solvent for recrystallization: Ethanol Form: HCl Example Solvent for recrystallization: Dichloromethane Form: 2HC1 Ejeroplo 423 R "': H P.f. 225-228 ° C Crystalline form: Pale yellow powder Solvent for recrystallization: Ethanol Form: Metansul fonate gM? P Q 76 Form: Metansul onate Example R "': H P.f. 140-143 ° C Crystalline form: Pale yellow powder Solvent for recrystallization: Ethanol Form: Methanesulfonate Example R "': H P.f. 152.4-154.8 ° C FFoorrmmaa ccrriissttaalliinnaa :: Pale yellow powder Solvent for recrystallization: Acetone-dichloromethane-water Form: 2HC1 TABLE 177 Example R - ": H P.f. 154-155 ° C Crystalline form: Yellow powder Solvent for recrystallization: Ethanol-diethyl ether Form: Metansul fonate Ejerop R "': H P.f. 165-168 ° C Crystalline form: Yellow powder Solvent for recrystallization: Dichloromethane-diethyl ether Forra: Metansul fonate Example o Solvent for recrystallization: Dichloromethane-diethyl ether Forraa: Methansulfonate CUAPRO 17B Example R - ": H P.f. 195-200 ° C (decomposition) Crystalline form: Yellow powder Solvent for recrystallization: Acetone-water-diethyl ether NMR (11) Form: Methanesulfonate Example R "*: H MP 183-220 ° C (decomposition) Crystalline form: White powder Solvent for recrystallization: Acetone-water-diethyl ether NMR (12) Forraa: 2HC1 Ejerop R "*: H P.f. 159-161 ° C Crystalline form: Yellow powder Solvent for recrystallization: Ethanol-acetone-diethyl ether Form: 2HC1 TABLE 179 Example R - ": H P.f. 177-180 ° C Crystalline form: Yellow amorphous Solvent for recr stallation: Ethanol-water-diethyl ether Form: 2HC1 Example R - ": H P.f. 17B-1B1 ° C Crystalline form: Yellow powder Solvent for recrystallization: Ethanol-water Form: 2HC1 Example R "': H P.f. 199-202 ° C Crystalline form: Pale orange powder Solvent for recrystallization: Ethanol-water Form: Methanesulfonate TABLE 1BO Example R "»: H NMR (13) Crystalline form: Amorphous yellow Form: 2HC1 Example R - ": H P.f. 151-154 ° C Crystalline form: Yellow powder Solvent for recrystallization: Ethanol-diethyl ether Form: Methanesulfonate Example R "': H P.f. 114-116 ° C Crystalline form: Yellow powder Solvent for recrystallization: Acetone-water Form: Methanesulfonate TABLE 181 Example Solvent for recrystallization: Acetone-water Form: 2CH1 Example R "': H P.f. 185-190 ° C (decomposition) Crystalline form: Pale yellow powder Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether NMR (14) Form: Methanesulfonate Example R - ": H P.f. 160-180 ° C (decomposition) Crystalline form: pale yellow powder Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether NMR (15) Form: 2HC1 TABLE 1B2 Example R - ": H P.f. 170-190 ° C Crystalline form: Pale yellow powder Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether NMR (16) Form: 2HC1 Example NMR (17) Form: 2HC1 Example R- ^ H P.f. 138-150 ° C (decomposition) Crystalline form: Pale brown powder Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether NMR (18) Form: MethanesulfonTABLE 183 Example NMR (19) Form: Methanesulfonate Example R - ": H P.f. 169-171 ° C Crystalline form: Pale yellow powder Solvent for recrystallization: Ethanol-w Form: 2HC1 Example R - «: H P.f. 178-180 ° C Crystalline form: Pale yellow powder Solvent for recrystallization: Ethanol-w-diethyl ether Form: 2HC1 CUAPRO 9 Example Solvent for recrystallization: Ethanol-w-diethyl ether Form: 2HC1 R "": H P.f. 172-175 ° C Crystalline Forroa: Pale yellow powder Solvent for recrystallization: Ethanol-w Form: 2HC1 Example R- ^ H P.f. 167-170 ° C Crystalline form: Pale yellow powder Solvent for recrystallization: Ethanol-w Form: 2HC1 TABLE 1B5 Example R- ": H P.f. 20B-209 ° C Inactive crystal form: yellowish powder dissolved Solvent for recrystallization: Ethanol-w Form: Metanosulonate Solvent for recrystallization: Ethanol-w Form: 2HC1 Example Solvent for recrystallization: Ethanol-w Form: 2HC1 TABLE 186 Example R - ": H P.f. 167-169 ° C Crystalline form: Pale yellow powder Solvent for recrystallization: Ethanol-w Form: 2HC1 Example R - ": H P.f. 170-173 ° C Crystalline form: Pale yellow powder Solvent for recrystallization: Ethanol-w Form: 2HC1 Pale yellow powder Solvent for recrystallization: Ethanol-d Chloromene Form: 2HC1 TABLE 187 R -'-. H P.f. 1S2.0-1S3.5 ° C Crystalline form: Yellow powder Solvent for recrystallization: Ethanol-w Form: Metanos l onato Example R-'iH P.f. 209.5-212.5 ° C Crystalline form: White powder Solvent for recrystallization: Ethanol-w Form: 3HC1 Solvent for recrystallization: Ethanol-dichloromethane, diethyl ether NMR (20) Form: MethanesulfonTABLE 18B Example R - ": H P.f. 180-215 ° C (decomposition) Crystalline form: Pale yellow powder Solvent for recrystallization: Ethanol-dichloromethane, diethyl ether NMR (21) Form: 2HC1 Example R "*: H P.f. 220-225 ° C (decomposition) Crystalline form: Pale yellow powder Solvent for recrystallization: Ethanol-dichloromethane, diethyl ether NMR (22) Form: 2HC1 Example R ": H P.f. 180-215 ° C (decomposition) Crystalline form: Pale yellow powder Solvent for recrystallization: Ethanol-dichloromethane »diethyl ether NMR (23) Form: 2HC1 TABLE 1B9 Example R, - ,: H P.f. 1B5.5-192 ° C Crystalline form: Yellow powder Solvent for recrystallization: Ethanol-w NMR (24) Form: 2HC1 Example 4 R - ": H P.f. 159.5-161.2 ° C Crystalline form: Pale yellow powder Solvent for recrystallization: Ethanol-diethyl ether ico-w Form: 2HC1 Example 4 R "*: H P.f. 150-15B ° C (decomposition) Crystalline form: Pale yellow powder Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether NMR (25) Form: MethanesulfonTABLE 190 NMR (26) Form: 2HC1 NMR (27) Form: 2HC1 NMR (28) Form: 2HC1 TABLE 191 Example R - ": H P.f. 131-1G0 ° C (decomposition) Crystalline form". Pale yellow powder Solvent for recr? stallation: di chloromethane-ethanol-diethyl ether NMR (29) Form: Methanesulfonate Example NMR (30) Form: 2HC1 R "*: H P.f. 231-235 ° C (decomposition) Crystalline form: Yellow pale powder Solvent for recrystallization: dichloromethane-ethanol-diethyl ether Form: 2HC1 TABLE 192 NMR (31) Form: 2HC1 Example 4 R - ": H P.f. 175-205 ° C (decomposition) Crystalline Forroa: Pale yellow powder Solvent for recrystallization: dichloromethane-ethanol-diethyl ether NMR (32) Form: Methanesulfonate Example R - ": H P.f. 185-230 ° C (decomposition) Crystalline form: Pale yellow powder Solvent for recrystallization: dichloromethane-ethanol-diethyl ether NMR (33) Form: 2HC1 TABLE 193 Example Crystalline form: Pale yellow powder Solvent for recrystallization: Ethanol-w NMR (34) Form: Dimetanosulf onate Ejerop R - ': H P.f. 172-17B ° C Crystalline form: Pale yellow powder Solvent for recrystallization: Ethanol-water NMR (35) Form: 3HC1 Example R - * ': H P.f. 1B5.2-186.0ßC Crystalline form: White powder Solvent for recrystallization: Ethanol Forraa: Free Using the appropriate starting compounds, the compounds are obtained as listed in Table 194, in the same manner as in Example 8.

CU? PRO 194 Solvent for recrystallization: Ethanol-dietic ldi-di chloromethane Form: 2HC1 Example R - ": H Pf lll.5-114.5 ° C Crystalline form: Yellow powder Solvent for recrystallization: Ethanol-water-isopropyl alcohol Form: 2HC1 Using the appropriate starting compounds, the compounds are obtained as listed in Table 195, in the same way as in Example 3 or 4.

CUADRC > 194 Example R "': H T: -CH,? - U: 1 P.f. 147.5-150.0 ° C Crystalline form: Yellow powder Solvent for recrystallization: Ethanol-water-diethyl ether ico-alcohol isopropyl 1 ico Form: 2HC1 The H-NMR (NMR (l) to NMR (49) spectra as described in tables 150-195 are as follows: NMR (1) (DMSO-d ^)? Ppm: 2.65-2.8 (4H, m ), 3.06 (9H, s), 3.87 OH, s), 4.15-4.65 (4H, m), 5.07 (2H, s), 6.70 (1H, dd, J = 2Hz, J = 8.5 Hz), 6.B1 (1H, d, J = 2 Hz), 7.29 (1H, d, J = 15 Hz), 7.48 (1H, br), 7.62 (1H, d, J = 15 Hz), 7.65 (1H, d, J = 8.5 Hz), 7.77 (1H, d, J = 9 Hz), 7.93 (1H, br), 11.0 (1H, br), 12.7 (1H, br) NMR (2) (DMSO-d ^) dppm: 1.65 ( 2H, br), 2.05-2.40 (4H, m), 2.55-2.9 (4H, m). 3.13Í6H, s), 3.25-4.8 (15H, m), 5.10 (2H, s), 6.70 (1H, dd, J = 2 HZ, J = 9 Hz), 6.81 (H, d, J = 2 Hz) , 7.26 (H, d, J = 15 Hz), 7.55Í1H, d, J = 15 Hz), 7.64 (1H, d, J = 8.5 Hz), 7.7-7.8 (1H, m), 7. BB (1H , d, J = 9H z), 8.31 (1H, br), 11.2-12.2 (2H, m) NMR (3) (DMS0-d6) óppm: 1.61 OH, d. J = 6.N5 Hz), 1.6 (2H, br), 2.12 (4H, br), 2.5-2.85 (4H, m), 2.95-4.05 (13H, m), 4.1-4.3 (1H, m), 4.4 -4.7 (1H, m), 5.35 (1H, q, J = 6.5 Hz), 6.63 (1H, dd, J = 2 Hz.9 Hz), 6.77 (1H, d, J = 2 Hz), 7.15-7.7 (4H, m), 7.69 (1H, d, J = 9Hz), 7.76 (1H, d.J = 7.5 Hz), 7.9B (1H, d, J = 7.5 Hz), 11.1-13.1 OH, m) NMR (4) (DMS0-dβ) óppm: 1.61 OH, d, J = 6.5Hz), 2.73 (3H, d, J = 4 Hz), 2.8-4.1 (6H, m), 3.85 (3H, S), 4.1 -4.35 (1H, m), 4.35-4.6 (1H, m), 5.38 (1H, q, J = 6.5 Hz), 6.63 (1H, dd, J = 2 HZ, 9 HZ), 6.78 (1H, d, J = 2 Hz), 7.26 (1H, d, J = 15 Hz), 7.25-7.5 (2H, m), 7.59 (1H, d, J = 15 Hz), 7.63 (1H, d, J = Hz), 7.76 (1H, d, J = 7.5 HZ), 7.97 (1H, d, J = 7 Hz), 11.40 (1H, br), 12.9 (1H, br) NMR (5) (DMS0-dβ) óppm: 1.61 OH , d, J = 6.5 Hz), 2.35-4.4 (23H, m), 5.37 (1H, q, J = 6.5 Hz), 6.63 (1H, dd, J = 2 Hz, J = 8.5 HZ), 6.78 (1H, d, J = 2 Hz), 7.1-7.7 (5H, ro), 7.76 (1H, d, J = 7.5 Hz), 7.98 (1H, d, J = 7 Hz), 11.85 (2H, br), 12.90 (1H, br) NMR (6) DMS0-dβ) ppm: 2.42 (6H, s), 2.82 OH, d, J = 4 HZ), 2.9-3.25 OH, m), 3.3-3.6 OH, m), 4.15-4.6 (6H, m), 5.03 (2H, s), 6.6B (1H, d, J = 9 Hz), 7.23 (1H, d, J = 9 Hz), 7.31 (1H, d, J = 15 HZ), 7.15-7.5 (2H, m), 7.61 (1H, d, J = 15 Hz), 7.76 (1H, d, J = 7.5 HZ), 7.9B (1H, d, J = 7 Hz), 9. B5 (1H, br ) NMR (7) (DMSO-d ^) óppm: 1.64 (2H, br), 2.17 (4H, br), 2.55-2.7 (4H, m), 2.95-4.0 (10H, m), 4.05-4.7 (6H , m), 5.03 (2H, s), 6.68 (1H, d, J = 9 Hz), 7.22 (1H, d, J = 9 Hz), 7.25-7.6 (4H, m), 7.76 (1H, d, J = 7.5 Hz), 7.98 (1H, d, J = 7.5 Hz), 11.1-12.2 (2H, m), 12.65Í1H, br) NMR (8) (DMSO-d, *) óppm: 2.55-2.7 (1H , m), 2.79 OH, S), 2.B5-4.5 (20H, m), 5.04 (2H, S), 6.6B (1H, d, J = B.5 Hz), 7.15-7.7 (5H, m ), 7.76 (1H, d, J = 7.5 Hz), 7.98 (1H, d, J = 7 Hz), 11.4-13.1 (2H, m) NMR (9) (DMSO-d ^) óppm: 1.35 OH, d , J = 5.5 Hz), 1.64 (2H, br), 2.14 (2H, br), 2.55-2.95 (4H, m), 2.95-4.0 (9H, m), 6.0 (1H, d, J = 9 Hz) , 7.22 (1H, d, J = 9 Hz), 7.29 (1H, d, J = 15.5 Hz), 4.05-4.7 (6H, m), 5 .03 (2H, 8), 7.4-7.5 (1H, m), 7.53 (1H, d, J = 15.5 HZ), 7.76 (1H, d, J = 7.5 Hz), 7.98 (1H, d, J = 7 Hz), 11.5-13.0 (2H, m) NMR (10) (DMS0-d? ¥) óppm: 2.16 OH, s), 2.37 OH, s), 2.77 OH, d, J = 4.2 Hz), 2.B3 -3.19 OH, m), 3.29-3.58 OH, S), 4.12-4.57 (2H, m), 4.65 (2H, s), 6.95 (1H, d, J = 8.8 Hz), 7.19-7.37 (2H, m ), 7.37-7.50 (1H, ro), 7.50-7.66 (2H, m), 7.75 (1H, d, J = 7.9 Hz), 7.99 (1H, d, J = 7.9 Hz), 9.B2 (lH. brs), 11.95-12.71 (1H, ro) NMR (11) (DMS0-dβ) óppm: 2.17 (2H, br), 2.34 OH, S), 2.82 OH, S), 3.05 (4H, br), 3.4 ( 2H, br), 4.05-4.4 (4H, m), 4.49 (1H, br), 5.05 (2H, s), 6.83 (1H, d, J = 9 Hz), 7.28 (1H, d, J = 15 HZ ), 7.29 (1H, d, J = 9 Hz >; , 7.25-7.35 (1H, m), 7.35-7.5 (1H, m), 7.52 (1H, d, J = 15 Hz), 7.76 (1H, d, J = 7.5 Hz), 7.98 (1H, d, J = 7 Hz), 9.81 (1H, br), 12.6 (1H, br) NMR (12) (DMSO-dβ) ppm; 1.61 (2H, br), 2.15 < 4H, br), 2.55-2.9 (4H, m), 3.0-4.3 (11H, m), 4.4.4.7 (1H, m), 5.09 (2H, S), 7.12 (1H, dd, J = 2.5 Hz, J = 8.5 Hz), 7.25-7.41 (4H, m), 7. 4-7.5 (1H, m), 7.69 (1H, d, J = 8.5 Hz), 7.77 (1H, d, J = 7.5 Hz), 7.99 (1H, d, J = 7 Hz), 11.0-12.2 (2H, m) NMR (13) (DMS0-dβ) óppm; 0.91 OH, t, J = 7.2 Hz), 1.20-1.86 (6H, m), 1.93-2.39 (4H, m), 2.58-2.89 (4H, m), 2.76 OH, 8), 2.95-3.9B (9H , m), 3.64 OH, s), 4.07-4.31 (lH, m), 4.41-4.69 (lH.m), 5.09 (2H, S), 6.B3 (lH, d, J = 8.9Hz), 7.20 -7.64 (5H, m), 7.76 (1H, d, J = 7.9 Hz), 7.97 (1H, d, J = 7.9 Hz), 11.11-12.29 < 2H, m), 12.72 (1H, brs) NMR (14) (DMS0-dw) ppm; 2.0-2.2 (2H, m), 2.34 OH, s), 2.68 (2H, t, J = 7 Hz), 2.B1 OH, d, J = 3Hz), 2.9-3.2 (2H, m >, 3.3 -3.65 (4H, m), 3.79 OH, S), 4.15 (2H, t, J = 6 Hz), 4.2-4.4 (1H, m), 4.4-4.6 (1H, m), 6.55-6.7 (2H, m), 7.2-7.35 (1H, m), 7.27 (1H, d, J = 15 HZ), 7.35-7.5 (1H, m), 7.63 (1H, S, J = 9.5 Hz), 7.63 (1H, d , J = 15 Hz), 7.72 (1H, d, J = 7.5 Hz), 7.9-8-0 (1H, m), 9.79 (1H, br), 12.38 (1H, br) NMR (15) (DMS0- d "r.) óppm; 1.64 (2H, br), 2.0-2.4 (6H, ra), 2.55-2.9 (6H, m), 2.95-4.0 OH, m), 4.0-4.35 OH, m), 4.4-4.7 (1H, m), 6.55-6.75 (2H, ra), 7.0 (1H, br), 7.2-7.35 (2H, m), 7.35-7.45 (1H, ro), 7.5-7.65 (2H, m), 7.65-7.75 (1H, ra ), 7.9-8-0 (1H, m), 11.2-12.6 (2H, m) NMR (16) (DMS0-d ,,,) .ppm; 2.0-2.2 (2H, m), 2.69 (2H, t, J = 7HZ). 2.80 OH, s), 2.9-4.4 (22H, m), 6.4-6.75 (2H, m), 7.15-7.5 OH, m), 7.5-7.8 OH, m), 7.96 (1H, d, J = 7 Hz ), 11.95 (1H, br), 12.41 (iH, br) NMR (17) (DMS0-d? ,,) ppm; 1.45-1.9 (2H, m), 2.0-2.35 (4H, m), 2.55-2.95 (SH, m), 2.95-3.25 (1H, m), 3.3-3.95 (12H, m), 4.0-4.35 OH, m), 4.4-4.65 (1H, m), 6.4-6.75 (2H, m), 7.25 (1H, d, J = 15 Hz), 7.2-7.5 (2H, m), 7.55 (1H, d, J = 15 Hz), 7.61 (1H, d, J = 9.5Hz), 7.71 (1H, d, J = 7.5Hz), 7.96 (1H, d, J = 7HZ), 11.9-12.8 (2H, m) NMR (18) (DMSOd ,,.) Ppm; 1.16 OH, t, J = 7.5 Hz), 1.9-2.2 (2H, m>, 2.48 (3H, s), 2.62 (2H, q, J = 7.5 Hz), 2.82 OH, d, J = 4.5 Hz) , 3.0-3. B (5H, m), 3.84 OH, s), 3.9-4.3 OH, m), 5.16 (2H, S), 6.71 (1H, s), 7.22 (1H, d.J = 15 Hz), 7.25-7.35 (1H, m), 7.4-7.5 (1H, m), 7.51 (1H, s), 7.66 (1H, dd, J = 5.5 Hz, J = 15 HZ), 7.77 (1H, d, J = 7.5 Hz) , 7.98 (1H, d, J = 7 Hz), 9.55 (1H, br), 11.7 (1H, br) NMR (19) (DMS0-dβ) ppm: 1.15 (3H, t, J = 5Hz), 1.35- 1.7 (2H, m), 1.9-2.1 (2H, m), 2.36 OH, s), 2.5-2.7 OH, m), 2.73 (3H, S), 2.75 (3H, S), 3.0-3.2 (1H, m), 3.3-3.55 (1H, ro), 3.84 OH, s), 4.05-4.25 (1H, m), 4.45-4.65 (1H, ro), 5.16 (2H, s), 6.71 (1H, S), 7.26 (1H, d, J = 15 Hz), 7.25-7.35 (1H, m), 7.4-7.5 (1H, rn), 7.50 (1H, s), 7.58 (1H, d, J = 15 Hz), 7.77 (1H, d, J = 7.5 Hz), 7.98 (1H, d, J = 7 Hz), 9.58 (1H, br) NMR (20) (DMSO-d ..,). 0.90 OH, t, J = 5 Hz), 1.57 < 2H, tq, J = 7.5 Hz, J = 8 Hz), 2.35 OH, S), 2.57 (2H, t, J = 8 Hz), 43B 2. 81 OH, d, J = 3.5 HZ). 2.9-3.25 OH, m), 3.3-3.7 OH, m), 3.83 OH, s), 4.15-4.4 (1H, m), 4-4-4.65 (1H, m), 5.16 (2H, s), 6.70 (1H, s), 7.28 (1H, d, J = 15 Hz), 7.25-7.4 (1H, m), 7.4-7.5 (1H, m), 7.49 (1H, s), 7.66 (1H, d, J = 15 Hz), 7.77 (1H, d, J = 8 Hz), 7.98 (1H, d, J = 7.5 Hz), 9.85 (1H, br), 12.6 (1H, br) NMR (21) (DMSO-d ,,,) óppm; 0.89 OH, t, 7.5 Hz), 1.4-1.9 (4H, m), 2.0-2.4 (4H, m). 2.5-2.85 (6H, m), 3.0-4.05 (10H, m), 3.84 (3H, s), 4.05-4.3 (1H, m), 4.45- .7 (1H, m), 5.17 (2H, s) . 6.71 (1H, s), 7.15-7.35 (2H, m), 7.35-7.5 (1H, m), 7.48 (1H, s), 7.58 (1H, d, J = 15H?), 7.77 (1H, d) , J = 7.5 Hz), 7.98 (1H, d, J = 7 Hz), 11.1-13.2 (2H, m) NMR (22) (DMS0-d ,,,), ppp; 0.90 OH, t, J = 7.5 Hz), 1.4-lB (4H, m), 1.95-2.25 (2H, ro), 2.57 (2H, t, J = 8 Hz), 2.6-2.9 (1H, m), 2.81 OH, s), 2.95-4.0 (10H, m), 3.84 OH, S), 4.05-4.3 (1H, m), 4.4-4.65 (1H, m), 5.16 (2H, s), 6.70 (1H, s), 7.26 (1H, d, J = 15 Hz). 7.25-7.35 (1H, m), 7.35-7.5 (1H, m), 7.48 (1H, s), 7.58 (1H, d, J = 15 Hz), 7.77 (1H, d, J = 5 Hz), 7.98 (1H, d, J = 7 Hz), 11.4-13.0 OH, m) NMR (23) (DMS0-d, ¥) óppm; 0.90 OH, t, J = 7.5 HZ), 1.57 (2H, tq J = 7.5 HZ, J = 8 Hz), 2.57 (2H, t, J = 8 Hz), 2.65-4.4 (17H, m), 2.79 OH, S), 3.84 OH, S), 5.18 (2H, S). 6.71 (1H, s), 7.15-7.5 OH, m), 7.48 (1H, S), 7.5-7.B (2H, m), 7.9B (1H, d, J = 7 Hz), 11.0-13.0 OH , m) NMR (24) (DMS0-d, ") ppm; 1.11 OH, t, J = 7.4 Hz), 2.53-4.17 (16H, m), 2.59 (2H, q, J = 7.4 Hz), 2.79 OH, s), 3.84 OH, s), 4.17-4.40 (1H, m), 5.20 (2H, S), 6.73 (1H, S), 7.18-7.3B (2H, m), 7.3B-7.54 (2H, rn), 7.54-7.74 (1H, m), 7.74-7.81 (1H, m), 7.92-8.05 (1H, m), 11.32-13.11 OH, m) NMR (25) (DMSOd ^) ppm; 2.35 OH, S), 2.80 OH, d, J = 3.5 Hz), 2.85-3.6 (SH, m), 3.85 OH, s), 4.04 < 2H, br), 4.2-4.6 (2H, m), 5.0-5.25 (4H, m), 5.81-6.1 (1H, m), 6.74 < 1H, s), 7. 28 (1H, d, J = 15 Hz), 7.25-7.55 (2H, m), 7.48 (lH, s), 7.65 (1H, d, J = 15 Hz). 7.77 (1H, d, J = 7.5 Hz), 7.98 (1H, d, J = 7 Hz), 9. 99 (1H, br), 12.6 (1H, br) NMR (26) (DMS0-d, ") oppro; 1.65 (2H. Br), 2.0-2.4 (4H, m), 2.55-2.95 (4H, m), 3.0-3.25 (1H, m), 3.25-4.25 (14H, m), 4. 05-4.3 (1H.m), 4.45-4.7 (1H, m), 4.95-5.3 (4H, m), 5.85-6.1 (1H, m), 6.75 (1H, s), 7.15-7.7 (5H, m), 7.77 (1H, d, J = 8 Hz), 7. 9B (1H, d, J = 7.5 HZ), 11.1-13.0 OH, m) NMR (27) (DMSOd ,,,), ppp; 1.4-1.85 (2H, m), 1.95-2.3 (2H, m), 2.55-2.95 (4H, m), 2.95-3.2 (1H, m), 3.2-3.95 (11H, m), 5.86 OH, s) , 4.1-4.3 (1H, m), 4.45-4.7 (lH, m), 4.95-5.25 (4H, m), 5.86-6.1 < 1H, rn), 6.74 (1H, s), 7.26 (1H, d, J = 15 Hz), 7. 25-7.55 OH, m), 7.56 (1H, d, J = 15 Hz), 7.77 (1H, d, J = 7.5 HZ), 7.98 (1H, d, J = 7 Hz), 11.3-13.2 OH, m) NMR (28) (DMSO-d,;), ppp; 2.55-4.45 (25H, m), 4.9-5.3 (4H, m), 5.85-6.1 (1H, m), 6.75 (1H, s>, 7.15-7.85 (6H, ra), 7.98 (1H, d, J = 7 Hz), 11.0-13.3 OH, m > NMR (29) DMSO-d ^) óppm; 1.32 OH, t, J = 7 Hz), 2.33 OH, 8), 2.80 OH, 8), 2.9-3.2 OH, m), 3.3-3.5 OH, m), 3.81 (3H, s), 4-03 (2H, q, J = 7 Hz), 4.2- 4.65 (2H, m), 5.15 (2H, S), 6. 83 (1H, s), 7.2-7.4 OH, m), 7.44 (1H, t, J = 8 Hz), 7.69 (1H, d, J = 15 HZ), 7.77 (1H, d, J = 8 Hz) 7.98 (1H, d, J = 8 Hz), 9.83 (1H, br), 12.60 (1H, br) NMR (30) (DMSO-d- ,.) .ppra; 1.32 OH, t, J = 7 Hz), 1.4-1.9 (2H, ra), 2.05-2.4 (4H, m), 2.6-3.9 (4H, m), 3.05-3.95 (13H, m), 4.04 OH, q, J = 7 Hz), 4.1-4.3 (1H, m), 4.5-4.7 (1H, m), 5.17 (2H, S), 6.83 (1H, s), 7.2-7.4 OH, m), 7.44 ( 1H, t, J = B Hz), 7.60 (1H, d, J = 15.5 Hz), 7.76 (1H, d, J = 8 Hz), 7.9B (1H, d, J = 8 Hz), 11.25-12.2 (2H, m) NMR (31) (DMSO-d,.,) .ppm; 1.32 OH, t, J = 7 Hz), 2.55-4.5 (19H, m), 2.80 OH, s), 3.82 OH, s), 5.17 (2H, s), 6.84 (1H, s), 7.2-7.4 OH , m), 7.44 (1H, t, J = 8 Hz), 7.64 (1H, d, J = 15.5 Hz), 7.76 (1H, d, J = 8 Hz), 7.9B (1H, d, J = B Hz), 11.5-12.5 (2H, m) NMR (32) (DMSO-d,.) Óppra; 2.32 OH, s), 2.81 (3H, S), 3.4-3.7 (4H, m), 3.25-3.6 (2H, m), 3.86 OH, S), 4.15-4.65 (2H, m), 5.26 (2H, s), 6.89 (1H, S), 7.32 (1H, d, J = 15 Hz), 7.32 (1H, t, J = 7.5 HZ), 7.45 (1H, t J = 8 Hz). 7.61 (1H, d, J = 15 Hz), 7. 77 (1H, d, J = 8H z), 7.83 (1H, S), 7.98 (1H, d, J = 7.5 Hz), 9. 78 (1H, br), 12.65 (1H, br) NMR (33) (DMS0-d, r.) .ppm; 1.4-1.85 (2H, ra), 2.1-2.4 (4H, m), 2.6-3.9 < 4H, m), 3.05 (14H, m), 4.5-4.65 (1H, m), 5.27 (2H, S), 6.B9 (1H, S), 7.2-7.4 (2H, ro), 7.4-7.6 ( 2H, m), 7.77 (1H, d, J = B HZ), 7.81 (1H, 8), 7.98 (1H, d, J = 8 Hz), 11.1-12.1 (2H, m) NMR (34) (DMS0 -d, ¥) óppm; 2.35 (S, 6H), 2.82 (s, 3H), 2. 92-3.27 (m.9H), 3.30-3.59 (m, 3H), 4.18 (br.lH), 4.19-4.34 (m.lH), 4.47-4.65 (m, lH), 5.24 (S.2H). 7.33 (t, J = 7.6 Hz, 2H), 7.44 (d, J = 7.3 Hz, 1H), 7.46 (d, J = 15.1 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7. B4 (d.J = 15.1 Hz, 1H), 7.96-8.15 (m, 3H), 9.82 (br, 1H), 12.66 (br, 1H) NMR (35) (DMSO-d, ") .ppm; 1.42-1.88 (m, 2H >, 1.93-2.39 (m, 4H), 2.59-2.85 (m.4H), 3.13 (s, 6H), 3.26-3.96 (m, 10H), 4.05-4.28 (m.lH), 4.51-4.68 (m, 1H), 5.26 (S, 2H), 7.29-7.35 (m, 2H), 7.42-7.48 (m, 2H), 7.74-7.80 (m, 2H), 7.96-8.04 (m, 2H), 8.19 (br, lH), 1105 -12.13 (m, 2H) NMR (36) (DMSO-d ,,,.) .ppm; 4.61-4.78 (2H, m), 5.05 (2H, s), 5.18-5.50 (1H, m), 5.91-6.17 (1H, m), 6.46 (1H, d, J = 15.5 Hz), 6.62-6.78 ( 1H, m), 6.78-6.88 (1H, m), 7.28-7.39 (1H, m), 7.39-7.52 (1H, m), 7.54-7.81 (2H, m), 7.71 (1H, d, J = 15.5 Hz), 7.92-8.05 (1H, m), 12.72 (2H, brs) NMR (37) (DMSO-d, ") oppm; 4.97 (2H, s), 6.40-6.58 (2H, m), 6.91 (1H, dd, J = 2.4 Hz, J = 8.8 Hz), 7.00-7.22 OH, m), 7.22-7.51 (4H, ro), 7.61-7.B9 (3H, m), 7.89-18.04 (1H, m), 12.75 (2H, brs) NMR (38) (DMS0-d, ") .ppm; 1.12 OH, t, J = 7.4 Hz), 2.60 (2H, q, J = 7.4 Hz), 3.B5 OH, S > , 5.15 (2H, 8), 6.46 (1H, d, J = 15.5 HZ), 6.71 (1H, S), 7.26-7.39 (1H.m), 7.39-7.50 (1H, ro), 7.51 (1H, s), 7.68 (1H, d, J = 15.5 Hz), 7.72-7.81 (1H, ro), 7.91-B.03 (1H, m), 12.75 (2H, brs) NMR (39) (DMSO-d ,,,), ppp; 2.19 OH, s), 3.64 OH, s), 5.07 (2H, s), 6.54 (1H, d, J = 15.6 Hz), 6.85 (1H, d, J = 8.7 Hz), 7.25-7.40 (1H, m ), 7.40-7.51 (1H, m), 7.54 (1H, d, J = B.8 Hz), 7.68 (1H, d, J = 15.6 Hz), 7.76 (1H, d, J = 7.5 Hz), 7.98 (1H, d, J = 7.5 Hz), 12.41-13.16 (2H, m) NMR (40) (DMS0-d, ¥> ppm, 2.16 OH, 8), 3.88 OH, s), 4.64 (2H, 8 ), 6.52 (1H, d, J = 15.6 Hz), 6.95 (1H, d, J = 8.B Hz), 7.21-7.3B (1H, m), 7.3B-7.51 (1H, m), 7.55- 7.80 OH, m), 7.98 (1H, d, J = 7.1 HZ) NMR (41) (DMSO-d,.,) .ppm; 0.91 OH, t, J = 7.3 Hz), 1.20-1.65 (4H, m), 2.54-2.7B (2H, m), 3.63 OH, S), 5.07 (2H, S), 6.5B (1H, d. J = 15.6 Hz), 6.B4 (1H, d, J = 8.7 Hz), 7.21-7.39 (1H, m), 7.39-7.51 (1H, m), 7.55 (1H, d, J = 8.7 Hz), 7.67 (1H, d, J = 15.S HZ), 7.76 (1H, d, J = 7.8 Hz), 7.97 (1H, d, J = 7.8 Hz), 12.05-13.51 (2H, m) NMR (42) (DMSO-d,.,) Óppm; 2.41 OH, S), 5.10 (2H, S), 6.56 (1H, J = 15.5 Hz), 6.90 (1H, dd, J = 8.B Hz, J = 2.2 Hz), 6.98 (1H, d, J = 2.2 Hz), 7.32 (1H, t, J = 7.2 HZ), 7.45 (1H, t, J = 7.2 HZ), 7.65-7.85 (2H, m), 7.99 (1H, d, J = 7.7 Hz), 8.05 (1H, d, J = 8.8 HZ), 12.06-13.45 (2H, m) NMR (43 ) (DMSO-d ,,,) óppro; 1.17 OH, t, J = 7.5 Hz), 2.70 (2H, q, J = 7.5 Hz), 3.65 OH, s), 5.09 (2H, s), 6.57 (1H, d, J = 15.6 Hz), 6.85 ( 1H, d, J = B.9 Hz), 7.30 (1H, dt, J = 1.2 Hz, J = 7.1 HZ), 7.43 (1H, d, Jal.2 Hz), J = 7.1 Hz), 7.56 (1H , d, J = 8.9 HZ), 7.67 (1H, d, J = 15.6 Hz), 7.76 (1H d, J = 7.1 Hz), 7.97 (1H, d, J = 7.1 HZ), 12.51-13.12 (2H , m) NMR (44) (DMS0-d, ") oppm; 3.79 OH, s), 3.83 OH, ß > , 5.12 (2H, 8), 6.51 (1H, d, J = 15.5 Hz), 6.84 (1H, S), 7.15-7.54 OH, m with 1H, d in 7.26), 7.61-7.B6 (2H, m with 1H, d in 7.76 J = 15.5 HZ), 7.99 (1H, d, J = 7.1 Hz), 12.20-13.25 (2H, m) NMR (45) (DMSO-d,.,) ppp; 2.19 OH. ß), 3.B5 OH, s), 5.14 (2H. s), 6.49 (1H, d, J = 15.5 Hz), 6.70 (1H, S), 7.20-7.56 OH, m, with 1H s in 7.52) , 7.60-7.82 (2H, m, with 1H d in 7.71 J = 15.5 HZ), 7.98 (1H, d, J = 7.0 HZ, 12.41-13.17 (2H, m) NMR (46) (DMS0-d, ") p.119 (6H, d, J = 6.9 Hz), 3.10-3.42 (1H, m), 3.86 OH, ß), 5.16 (2H, s), 6.50 (1H, d, J = 15.5 Hz), 6.70 ( 1H, s), 7.21-7.60 OH, m with 1H s in 7.55), 7.65-7.82 (2H, m with 1H d in 7.73 J = 15.5 Hz), 7.89-B.OB (1H, ra), 12.42-13.12 (2H, m) NMR (47) (DMS0-dw) ppm; 0.68-0.92 OH, m), 1.08-1.64 (BH, m>, 2.3B-2.68 (2H.m), 3.85 OH, S), 5.14 OH. s), 6.49 (1H, d, J = 15.5 Hz), 6.71 (1H, S), 7.20-7.57 OH, ra), 7.62-7.85 (2H, m with 1H d in 7.72 J = 15.5 Hz), 7.8BB .05 (1H, m), 12.45-13.12 (2H, m) NMR (4B) (DMSO-d ,, ..) .ppm; 3.17 (S, 6H>, 5.2B (2, 2H), 6.71 (d, J = 15.5HZ, 1H), 7.29-7.49 (m, 3H), 7.78 (d, J = 8.0Hz, 1H), 7.91 -8.06 (m, 2H), 8.09 (d, J = 8.4Hz, 1H), B.25 (8, 1H), NMR (49) (DMS0-dβ) óppm, 3.87 (8, 3H), 4.75 (d) , J = 5Hz, 2H), 4.77 (ß, 2H), 6.50 < d, J = 15.5Hz, 1H), 6.72 (dd, J = 2.2Hz J = 8.6Hz, 1H), 6.7B (d, J = 2.2Hz, 1H), 1.33-7.57 (m, 2H), 7.66 ( d, J = 8.6Hz, 1H), 7.69 (d, J = 15.5Hz, 1H), 7.94 (d, J = 7.4HZ, 1H), 8.05 (d, J = 6.9Hz, 1H), 9.18 (t, J = 5.1Hz, 1H), 12.99 (br, 1H).

PHARMACOLOGICAL EXPERIMENTS (1) Protein kinase C inhibitory activity (PKC) Method for determining PKC activity: The purification of PKC using soluble fractions from rat brain was carried out by a method of KiKkawa and others (see Us io ikka to »Yoshimi Takai , Ryoji M nakuchi, Sim'chi Inohara and Yasutorai Nishizuka: The Journal of Biological Chemistry, Vol. 257, No. 22, pp. 13341-13348 (1982) .PKC activity was determined by the transfer of radioactivity from adenosine triphosphate C ~ 3seP "] (TFA) to a histone Hl derived from calf thymus in the presence of mM Tris-HCl buffer pH (pH 7.5), histone Hl derived from calf thymus (200 μg / ml), 10 μM C> -8PllFA, 5 mM magnesium acetate, 8 μg / ml phosphatidyl serine, 2 μg / ml of acylglycerol and 0.3 mM of Ca * - "-. test in dimethylformamide and the solution of the test compound was added to the test system to adjust the final concentration thereof to 0.854. The reaction mixture was incubated at 30 ° C for 30 minutes and the reaction was quenched with dichloroacetic acid at 2554. The acid-insoluble protein was collected on a trocelulose membrane by suction filtration. Radio activity of aaP was determined by counter-scintillation. The PKC inhibitory activity of the test compound ß expressed by ICβ, which is the concentration of the test compound that is required to reduce PKC activity by 5054. The results are shown in Table 196. Results: CU? PRQ IS-ß (2) A tritiß in mouse collagen 0.1% bovine-type II collagen was emulsified (provided by Col 1 agen Gijyutsu Kensyukai) with adjuvant Fle? Nd complete (AFC) (50%) (manufactured by DIFCO, Ltd), and the emulsion thus obtained was injected intracutaneously to mice in the tail (primary sensitization). Three weeks later, 0.1% of bovine-type II collagen was injected again into the mice intraperitoneally (secondary sensitization). Three weeks later, inflammation of the extremities of the mice was observed and was evaluated by 4 ° C as from 0 to 3 for each extremity. Grade (0 to 3) was added to each limb and the results were used as arthritis marks. That is, the maximum degree is 12 (degree 3 X 4 extremities). This test compound was orally administered to mice once a day, which started after two weeks of primary sensitization. In the mice treated with the compound of Example 182 in a dose of 30 to 50 mg / kg, the arthritis score was significantly reduced compared to the control mice. In the mice treated with the compounds of Example 160, 192 or 197 in a dose of 50 mg / kg, the arthritis score was significantly reduced compared to the control mice. < 3 > Mouse IC V EH (cronoral graft model-versuß-host disease) Loe female mice (DBA / ZNCrj) ß attacked an operation by dislocation of the cervical vertebra and the spleen was excised to give the preparation of spleen cells. The preparation was adjusted to 37.5 x 10"7 cells / ml and administered to BDF1 female mice in the tail vein in a dose of 200 μl by a mouse, two weeks later the blood was collected in the absence of heparin and the anti-DNA antibody therein by the ELISA test The compound of Example 182 was orally administered to the mice in a dose of 30 to 50 mg / kg once a day for two weeks and the effect of the test compound on EH IC was determined.The amount of anti-DNA antibody in the blood was determined with 0D ^ oß.The amounts of anti-DNA antibody were 0.348 ± 0.111 (mean ± se) in the control group, 0.255 + 0.062 (average ± se) in the group treated with the compound of Example 182 in doßis of 30 mg / kg and 0.094 ± 0.026 (mean ± ß.e.) in the group treated with the compound of Example 182 in a dose of 50 mg / kg From the results, it was proved that the compound of Example 182 reduced the anti-DNA antibody in the blood depending on the dose, compared to the control group. In addition, the compound of Ejeraplo 6 was also administered orally to the mouse at 30 mg / kg once a day for two weeks and the effect of the corpus envelope on ICVEH was also determined. The amount of anti-DNA antibody in the ßangre was determined with 0D ^ oß. The amounts of anti-DNA antibody were 0.258 ± 0.0B4 (mean ± s.e.) in the control group and 0.177 ± 0.061 (mean ± s.e.) in the group treated with the compound of Example 100 in a dose of 30 mg / kg. From the results it was proved that the Compound 100 compound reduced the anti-DNA antibody in the blood compared to the control group. (4) Rat Kidney Regeneration Model The right kidney of a male SD rat was excised, and the artery of the left kidney was covered, and subsequently, it underwent reperfusion to give a kidney ischemic reperfusion model. The effect of the compounds of Examples 71, 89 and 100 on the kidney ischemic reperfusion model was calculated. The compound of Ejeraplo 71 was administered intravenously to the rat in a doßiß of 3 mg / kg 5 minutes before ischemic. Twenty-four hours later the blood was collected from the vein of the tail and the amounts of creatine and nitrogen of urea were determined. The amount of creatine in the ßangre was 2.19 ± 0.21 (mean ± s.e.) in the control group; 1.4 ± 0.11 (mean ± se) in the group treated with the compound of Example 71 and the amount of urea nitrogen in the blood was 78.B ± 5.6 (mean ± se) in the control group and 54.1 ± 5.0 (average ± se) in the group treated with the compound of Example 71. That is to say, the compound of Ejeraplo 71 significantly reduced the ß amounts of both creatine and urea nitrogen compared to the control group. The compound of Example 89 was administered intravenously to the rat in a dose of 3 mg / kg 5 minutes before ischemia and reperfusion. Forty-eight hours the blood was then collected from the tail vein and the amounts of creatine and urea nitrogen were determined. The amount of creatine in the blood was 4.31 ± 0.53 (average ± s .e.) In the control group; 2.34 ± 0.46 (averaged or ± se) in the group treated with the compound of Example 89. and the amount of urea nitrogen in the blood was 155.1 ± 15.4 (mean ± se) in the control group and 99.1 ± 16.0 (prorogene ± se) in the group treated with the compound of Example 89. That is, the compound of Example 89 significantly reduced the amounts of both creatine and urea nitrogen compared to the control group. The compound of Example 100 was orally administered to the rat at a dose of 30 mg / kg one hour before ischemia. Forty-eight hours later the blood was collected from the tail vein and the amounts of creatine and urea nitrogen were determined. The amount of creatine in the blood was 2.48 ± 0.59 (mean ± s.e.) in the control group; of 1.53 ± 0.20 (mean ± se) in the group treated with the compound of Example 100 and the amount of urea nitrogen in the blood was 91.3 ± 20.1 (mean ± se) in the control group and 63.1 ± 10.3 ( prorogene ± se) in the group treated with the compound of Example 100. In this way it was proved that the compound of Example 100 reduced the amounts of both creatine and urea nitrogen compared to the control group. < 5) Model of acanthosis, phorbol ester (TPA) - mouse induced auricular edema A phorbol ester of 200 μg / ml (TPA) (10 μl) was applied to one side of the ear of a female mouse (ICR). Twenty-four hours later the thickness of the mouse atrium was determined using a dial thickness indicator and the increase in atrial thickness was calculated. A test compound was dissolved in acetone and the solution of a test corpuscle was applied on both sides of the ear 30 minutes before the application of TPA. The coropuesto of Example 88 was applied to the ear in a dois of 20 μl of 0.3% or 1% solution. The increase in the thickness of the atrium in the control group eß of 215 ± 40 μm (mean ± ß.e.) deßpuéß of 24 hours, whereas it was of T7 ± 53 μm (mean ± se) in the group treated with the compound of Example 88 in 0.3%, and 67 ± 23 μm (averaged or ± se) in the group treated with the Compound 8B compound in 1%. In this way, the compound of Example 88 significantly reduced the increase in atrial thickness compared to the control group. (6) Mouse atopic derroatitiß model 10 μl of 1% tr or trobenzene (TNCB) was applied to each side of the ear of female mice (Balb / c), once every two days for 24 days. Twenty-four days of the mice were pooled and the thickness of the mouse atrium was determined using a dial gauge and the increase in the thickness of the atrium was calculated. The compounds of Examples 88 and 89 were dissolved in acetone at a concentration of 1%. The compound of Example 182 was dissolved in a mixture of acetone: methanol in a concentration of 0.75%. Twenty-four days after beginning the experiment, the solution of a test compound was applied to each side of the ear 30 minutes before and after the application of TNCB once a day for two weeks. The compound of Example 88 inhibited the increase in atrial thickness by 25 to 30% and the compounds of Examples 89 and 182 inhibited the increase in atrial thickness by approximately 25%. In this manner, it was proved that the compounds of the present invention are useful in the treatment of acanthosis induced by the application of TNCB.

Claims

NOVELTY OF THE INVENTION CLAIMS

1. - A thiazole compound of the formula: wherein T is a lower alkylene; u eß O or i; R4- and R * are the same or different and are each a hydrogen atom or a lower alkyl, or both combine to form a group: - (CHa) "- (n is 4 or 5) or to form a ring benzene which can be optionally substituted by a member selected from a lower alkyl, a lower alkoxy, a nitro, an amino optionally having a substituent, lower alkyl or a halogen atom; R3 »is a group of the formula: wherein R4-4- * 3, p, R4-4- "are as defined above; A is a lower rent; Z is O or S; s is O or i; m is i or 2; R "is a hydrogen atom or a lower alkanoxy-lower alkyl; the Rs are the same or different and are each a member selected from (a) a hydrogen atom, (b) an alkyl optionally having a hydroxy substituent" ( c) a halogen atom, (d) a group of the formula - (0) + - A- (CO) 1 -NR "*" R * "(where t is O or 1, A is a lower alkylene, 1 is 0 or 1, and R "7 and Rβ are the same or different and are each a hydrogen atom or a lower alkyl, or both combine with the nitrogen atom to which they are bonded to form a saturated heterocyclic group of 5 to 7 members that can be intervened with a nitrogen or oxygen atom, said heterocyclic group being optionally substituted by a member selected from the group of the formula: - (A)., - NR ^ R4-0 (where A and 1 is as defined above, and R * and R or are the same or different and each is a hydrogen atom or a lower alkyl, or both are combined with The nitrogen atom to which they are bonded to form a saturated 5- to 7-membered heterocyclic group which can be intervened with a nitrogen or oxygen atom, said heterocyclic group optionally having a lower alkyl substituent), a lower alkyl having optionally a hydroxy substituent, a hydroxy group and a lower alkanoyl), (e) a lower alkoxycarbonyl-lower alkyl, (f) a lower alkanoyloxy-lower alkyl, (g) a lower alkoxy optionally having a halogen substituent, (h) a lower alkyl substituted with halogen, (i) a lower alkyl substituted with carboxyl, (j) a lower alkoxycarbonyl, (k) a lower alkenyloxy, (1) a lower phenyl-lower alkoxy, (m) a cycloalkyloxy, (n) ) a phenyl, (o) a phenyloxy, (p) a hydroxy, (q) a lower alkylthio, (r) a lower alkenyl or (s) an amino optionally having a lower alkyl substituent; R * is a group of the formula: (1) -CO-CH = CRi4 - '"- (CO)" - R4-4-- or (2) -CO-C = C-COR4 - "*; p is 0 or i; R4-4- "" "is a hydrogen atom or a lower alkyl; R4-4- "is a hydroxy, a lower alkoxy or a saturated or unsaturated, monocyclic or dicyclic 5- to 10-membered heterocyclic group containing 1 to 4 heterogeneous atoms selected from a nitrogen, oxygen atom 0 of sulfur or a member of the ring, said heterocyclic group optionally has the 3 substituents selected from the group consisting of (i) a lower alkyl, (ii) a group of the formula: - (B) 1-NR4- "ZR4- 3 (where 1 is as defined above, B is -CO-A- (A eß as defined above), a carbonyl or a lower alkylene, and fíxa and fíxa ßon e? same or different and each one is a hydrogen atom, a lower alkyl or a lower alkyl substituted by an amino optionally having a lower alkyl substituent, or both combine with each other with the nitrogen atom to which they are bonded to form a heterocyclic, monocyclic, dicyclic or spirocyclic saturated group of 5 to 12 members that can be intervened with a nitrogen or oxygen atom, said heterocyclic group optionally having a substituent selected from a lower alkyl, a lower alkoxycarbonyl, a substi tuted lower alkyl with lower alkoxy, an amino having optionally a lower alkyl substituent and a lower hydroxy substituted alkyl), (iii) a lower alkoxycarbonyl, (iv) a hydroxy substituted lower alkyl, (v) a pyridyl which is optionally substituted by a lower alkyl optionally having a halogen substituent on the pyridine ring, (vi) a lower alkyl substituted with halogen, (vii) a lower alkoxy, (viii) a cycloalkyl, (ix) a hydroxy, (x) a lower alkyl substituted with tetrahydropyrani loxi, (xi) a pyrimidyl, (xii) lower alkyl substituted with lower alkoxy, (x) ii) a carboxyl, (xiv) a lower phenyl-lower alkyl, (xv) a lower alkyl-phenol optionally having a lower alkyndiioxy on the phenyl ring, (xvi) a lower alkoxy, and (xvi i) a piperidinyl optionally having a lower alkyl substituent on the piperidine ring; R4 - * is a hydroxy or a lower alkoxy; and when m is 1, the groups A and Rβ can be combined to form a group of the formula: (wherein R4 * eß as defined above, and r is 0, 1 or 2), or when m and 2, doβ R groups can be combined to form a lower alkyndiioxy, a lower alkylene or a group of the formula: - ( CHa) a-C0NH-, or the groups Rβ and Rβ can be combined to form a group of the formula -CO-CHIR "* -) - CH (Raß ') - W- (where R *" "ß and R5 * "*" * are a hydrogen atom or a carboxyl group, as long as both R "" and R * "" "» "are not simultaneously a carboxyl group, and is -N (R2 ***) - or -N - R * »*» -? - R Izßt > (wherein Ra9m is a hydrogen atom or lower alkyl, R "*» * 3 is a lower alkyl and X is as defined above)), or a salt thereof. according to claim 1, further characterized in that u is 0; R4- and R * are the same or different and are each a hydrogen atom or a lower alkyl, and R3 * is a group of the formula: ^ -CO R11 * (wherein R4-4- * 3, R4-4- "» and p are coroo was defined in claim 1), or a salt thereof 3. The thiazole compound according to claim 1, further characterized in that u is 0; R4- and R * "are the same or different and are each a hydrogen atom or a lower alkyl, and Ra is a group of the formula: (wherein A, Rβ, R * and m are as defined in claim 1, and s is O), or a salt thereof. A .- The thiazole compound according to claim 1, further characterized in that u is O; R4- and Ra are the same or different and are each a hydrogen atom or a lower alkyl, and R3 is a group of the formula: (where A, R, R * and m are as defined in rei indication 1, s is 1 and Z is O), or a salt thereof. 5. The thiazole compound according to the rei indication 1, further characterized in that u is O; R4- and Ra are the same or different and are each a hydrogen atom or a lower alkyl, and Ra is a group of the formula: (wherein A, Rβ, R * and m are as defined in claim 1, ß eß 1 and Z is S), or a salt thereof. 6. The thiazole compound according to claim 1, further characterized in that u is O; R4- and R58 combine to form a group: - (CH ^ J ^ - (n is 4), and Ra eß a group of the formula: (where R4-4- * 3 »R4-4- *» and p are as defined in claim 1), or a salt of the misrao. 7. The thiazole compound according to claim 1, further characterized in that u eß 0; R4- and R3 combine to form a group: (n is 4); and R3 is a group of the formula: (wherein A, Rβ, R * and m are as defined in claim 1, and s is 0), or a salt thereof. B. The thiazole compound according to claim 1, further characterized in that u eß 0; R4- and R3 combine to form a group: - (CH ^) ,, - (n is 4); and R3 is a group of the formula: (wherein A, R, R "* and m are as defined in claim 1, s is I and Z is 0), or a salt thereof. 9. The thiazole compound according to claim 1, further characterized in that u eß 0; R4- and R3 combine to form a group: - (CH ^) "- (n is 4); and R3 is a group of the formula: (wherein A, RB, R * and m are as defined in claim 1, s is 1 and Z is S), or a salt of the misrao. 10. The thiazole compound according to claim 1, characterized in that u is 0; R4- and R3 combine to form a group: - (CH ^) ,,, - (n is 5); and R3 is a group of the formula: (wherein R4-4-13, R4-4- * and p are as defined in claim 1), or a salt of the misrao. 11. The thiazole compound according to claim 1, further characterized in that u is 0; R4- and R3 combine to form a group: - (CH ^) ,, - (n is 5); and R3 is a group of the formula: (wherein A, RB, R "* and m are coroo was defined in claim 1, and s is 0), or a salt of the same. 1

2. The thiazole compound according to claim 1, further characterized in that u is 0; R4- and R3 combine to form a group: - CH ^) ,, - (n is 5); and R3 is a group of the formula: (wherein A, Rβ, R * and m ßon as defined in claim 1, s is 1 and Z is 0), or a salt thereof. 1

3. The thiazole compound according to the rei indication 1, further characterized in that u is 0; R4- and R3 combine to form a group: - (CH ^ í ^, - (n is 5), and R3 is a group of the formula: (wherein A »Rβ, Rβ and m are as defined in claim 1, s is 1 and Z is S), or a salt thereof. 1

4. The thiazole compound according to claim 1, further characterized in that u is 0; R 4 - and R 3 combine to form a benzene ring which may be optionally substituted by a member selected from a lower alkyl, a lower alkoxy, a nitro, an amino optionally having a lower alkyl substituent or a halogen atom; and R * is a group of the formula: (wherein R4-4- * 3, Rm and p are as defined in claim 1), or a salt thereof. 1

5. The thiazole compound according to claim 1, further characterized in that u is 0; R4- and R3 are combined to form a benzene ring which can be optionally substituted by a member selected from a lower alkyl, lower alkoxy, nitro, amino optionally having a lower alkyl substituent or a halogen atom; and R3 is a group of the formula: (where A, Rm, R «* and m are as defined in re vindication 1, and s is 0), or a salt thereof. 1

6. The thiazole compound according to claim 1, further characterized in that u is 0; R 4 - and R 3 combine to form a benzene ring which may be optionally substituted by a member selected from a lower alkyl, a lower alkoxy, a nitro, an amino optionally having a lower alkyl substituent or a halogen atom; and R1 is a group of the formula: (wherein A. Rβ, Rβ and ra are as defined in claim 1. s is I and Z eß O), or a salt thereof. 1

7. The thiazole compound according to claim 1, further characterized in that u is 0; R4- and R3 are combined to form a benzene ring which may be optionally substituted by a member selected from a lower alkyl, a lower alkoxy, a nitro, an amino optionally having a lower alkyl substituent or a halogen atom; and R3 is a group of the formula: (where A, Rm, R * and m are as defined in re vindication 1, s is 1 and Z is S), or a salt thereof. IB.- The thiazole compound according to claim 4, characterized in that R * eß is a group of the formula: -C0-CH = CR- "3- (C0)" - R "1-4-- in where R4-4- * 3 and p are as defined in claim 1, and R4-4- "" is a hydroxy or a lower alkoxy, or a salt thereof. 19. The thiazole coropuesto according to claim 4, further characterized in that R * is a group of the formula: -CO-CH = CR4-4-t »- (CO) -.- R4-4-β in where R4-4- * 3 is as defined in claim 1, p is 1 and R4-4- "» is a saturated or unsaturated, monocyclic or dicyclic 5- to 10-membered heterocyclic group containing 1 to 4 heterogeneous atoms selected of a nitrogen, oxygen or sulfur atom as a ring member, said heterocyclic group optionally having 1 to 3 substituents selected from the group consisting of (i) a lower alkyl, (ii) a group of the formula: (B) 1-NR-3R4-3 (wherein 1 is corao ße defined above, B is -CO-A- (A is as defined above), a carbonyl or lower alkylene, and R4-3 and R4- 3 are the same or different and are each a hydrogen atom, a lower alkyl or a lower alkyl substituted by an amino optionally having a lower alkyl substituent, or They combine with each other with the nitrogen atom to which they are bonded to form a heterocyclic, monocyclic, dicyclic or spirocyclic saturated group of 5 to 12 members that can be intervened with a nitrogen or oxygen atom, said heterocyclic group optionally having a substituent selected from a lower alkyl, a lower alkoxycarbonyl, a lower alkyl substituted with lower alkoxy, an amino optionally having a lower alkyl substituent and a lower alkyl substituted hydroxy), (iii) a lower alkoxycarbonyl, (iv) a lower alkyl hydroxy substituted, (v) a pyridyl which is optionally substituted by a lower alkyl optionally having a halogen substituent on the pyridine ring, (vi) a lower alkyl substituted with halogen, (vii) a lower alkoxy, (vi ii) a cycloalkyl, (ix) a hydroxy, (x) a lower alkyl substituted with tetrahydropy ram'loxi, (xi) a pyrimidyl, (xii) lower alkyl substituted with lower alkoxy, (xii i) a carboxyl, (xiv) a lo-lower alkoxy, (xv) ) a phenyl-lower alkyl optionally having a lower al lenedioxy in the phenyl ring, (xvi) a lower alkoxyloxy, and (xvi i) a piperidinyl optionally having a lower alkyl substituent in the piperidine ring, or a salt of the same. 20. The thiazole compound according to the rei indication 4, further characterized in that Rβ is a group of the formula: -C0-CH = CR-4-t, - (C0).: - R4-4- "in where R4-4- * 3 is as defined in claim 1, p is 0 and R4-4- * ee corao was defined in claim 19, or a salt thereof 21.- The thiazole compote in accordance with re vindication 4, characterized in that R * eß is a group of the formula: -CO-CC-COR4-- ", where R4 -» is as defined in claim 1, or a salt thereof. 22. The thiazole compound according to claim 16, further characterized in that R * is a group of the formula: -CO-CHsCR '- ^ - OO ^ -R4-4- * where R4-4- * 3 and p are as defined in claim 1, and R4-4- »is a hydroxy or a lower alkoxy, or a salt thereof. 23. The thiazole compound according to claim 16, further characterized in that R * is a group of the formula: -CO-CH = CR-e >;-( CO) ß-R-4-ß wherein R4-4- * 3 is as defined in claim 1, p eß 1 and R4-4- "is as defined in claim 19, or a salt 24. The thiazole compound according to claim 16, further characterized in that R * is a group of the formula: -C0-CH = CR4-4- "3- (C0) ß-R" * - 4-ß wherein R4-4-13 is as defined in claim 1, p is O and R4-4- »is as defined in claim 19, or a salt of the roismo. thiazole according to claim 16, further characterized in that R * is a group of the formula: -C0-C = C-C0R "" • - "-, wherein R4 - * is as defined in claim 1 , or a salt of misrao. 26. The thiazole compound according to claim 1, characterized in that u is 1 and R3 is a group of the formula: (wherein R4-4- * 3, R4-4- "and p are as defined in claim 1), or a salt thereof 27.- The thiazole compound according to claim 1, further characterized in that is i; R4- and R3 are the same or different and are each a hydrogen atom or a lower alkyl, and R3 is a group of the formula: (wherein A, Z, s, Rβ, R «" and m are as defined in rei indication 1), or a salt thereof 2

8. The thiazole compound according to claim 1, further characterized in that is i; R4- and R3 combine to form a group: - (CH ^) ,, - (n is 4), and R3 is a group of the formula: (wherein A, Z, ß, RB, R * and m ßon coroo εe defined in claim 1), or an 8al thereof. 2

9. The thiazole compound according to the rei indication 1, further characterized because u is i; R4- and R3 combine to form a group: - (CH ^) ^ - (n is 5); and R3 is a group of the formula: (wherein A. Z, s, Rβ, R * and m are as defined in claim 1), or a salt of the misrao. 30. The thiazole compound according to claim 1, further characterized in that u is 1 »R4- and R3 combine to form a benzene ring which can be optionally substituted by a member selected from a lower alkyl, a lower alkoxy, a nitro, an amino optionally having a lower alkyl substituent or a halogen atom; and R3 is a group of the formula: (where A, Z, s, Rß, R * and m are as defined in rei indication 1), or a salt of raismo. 31. The thiazole coropuesto according to any of claims 2, 3, 6-15 and 17-30, further characterized in that the heterocyclic group for R4-4- * eß is a member selected from the group consisting of pyrrole idini lo , piperidinyl, piperazinyl, morpholino, 1-azacyclooctylo, homopiperazine, homoroorpholine, 1,4-diazabicycloC4.3.o: inoni lo, 1,4-diazabicycloC4.4.0Dedelo, pyridyl, 1,2,5,6 -tetrahydropyridyl, thienyl, 1,2,4-triazolyl, 1,2,3,4-tetrazolyl, 1,3,4-triazole, 1-quinolyl, 1,4-dihydroquinolyl, benzothiazole, pyrazyl, pyrimidyl, pyridyl, pyrrolyl, pyrrolinyl, carboetheryl, 1,3-dioxolanyl. thiomorpholine, 3,4-dihydrocarbostyle, 1,2,3,4-tetrahydroquinolyl, 2,3,4,5-tetrahydrofuran, indolyl, isoindolyl, 3H-indolyl, indolinyl, idolol, indazolyl, benzimidazole ilo, benzoxazolyl, imidazole, imidazole idini lo, isoquinolyl, naphthalide, quinazole idini lo, quinoxal in i lo, cinolinyl, phthalazinyl, chromanyl, isoindol ini lo, isochromani lo, pyrazolyl, 1,3,4- oxadiazoli, 1,3,4-thiadiazole, thienyl, imidazolyl, idolyl pyrazol, benzofuryl, 2,3-dihydrobenzoCb * lfuryl, benzothienyl, tetrahydropyranyl, 4H-chromenyl, lH-indazolyl, 2-imidazole, 2-pyrrole inyl, furyl, oxazolyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, pyranyl, pyrazole idini lo, 2-pyrazole ini lo, qui nucí idini lo, 1,4-benzoxazini lo, 3,4-dihidro-2H- l, 4-benzoxazini lo, 3,4-dihidro-2H-l, 4-benzotiazini lo, 1,4-benzotiazin lo, 1,2,3,4-tetrahidroisoquinol i lo, 1,2,3,4-tetrahidroquinoxal inyl, 1,3-di-thia-2,4-dihydronaphthalene, 1,4-dithiaphthalene, 2,5-dihydrate rofuranoC3.4-c3piridi lo, 2,3,4,5,6, 7-hexahydro-lH-azepinyl, 1,2,3,4,5,6,7,8-octahydroazocini, 1,2, 3,4,5,6-tetrahydrooxepini lo, 1,3-dioxolanyl, 3,4,5,6-tetrahydro-2H-pyrani and 5,6-dihydro-2H-pyranyl. 32. A thiazole compound selected from the group consisting of (1) 2-C (3-methoxy-4- (3- (4- (4-methyl-1-homopiperazine 1) -l-piperidini-icarboni) acri loi 1) phenoxy) roeti 1-carboni lamino} benzothiazole, (2) 2-C (2-i sopropi 1-4-O- (4- (4-methyl-piperazine 1) -l-piperidini 1-carboni 1) acp * oi 1) phenoxy) -methylcarboni lamino enzotiazol, O) 2-. { (2-methoxy-4- (3- (2- (4-methyl-pi erazin 1) -methyl 1-4-morphol and nocarboni 1 lacri loi 1) -pheno i) methyl Icarboni lamino.}. Enzotiazole, ( 4) 2-C-ethoxy-4- (3- (4- (4-methyl-1-piperazine 1) -l-pipep * dini 1-carboni 1) acri loi 1) -phenoxy) meti Icarboni lami no} benzothiazole, (5) 2-CO-rnethyl-4- (3- (4- (4-methyl-1-1-homopiperazine 1) -l-piperidini-1-carbom "1-lacri-loi-1-phenoxymethyl-Icarbonyl-lamino}. benzothiazole, (6) 2- (3-methoxy-6-eti 1-4-O- (4- (4-meti 1-1-homopiperazi m'l) -l-pipep "dini Icarbom '1) -acri loi 1) phenoxy) meti Icarboni lamino} benzothiazole, (7) 2-C-methoxy-6-eti 1-4-O- (4-methyl-1-piperazine 1) acri loi 1) -phenoxy) -methylcarbonylamino} ben? otiazole (B) 2-C <; 2-trifluoromethyl-4-O- (4-hydroxy-1-piperazine 1) acri loi 1) -phenoxy) methyl 1 carboni laraine} -benzothiazole (9) 2-C (2-fluoro-4- (3- (2- (4-methyl-1-pipera? ini 1) methyl 1-4-morphol in-carbonol) acri loi 1) phenoxy) 1-amino carboni } benzothiazole, (10) 2-C < 2-methoxy-4- (3- (4- (4-methyl-1-piperazine 1) -l-pipep "dini 1-carboni 1) acp" loi 1) phenoxy) methi 1-carboni lamino} benzothiazole, (ll) 2-C < 2,3-Dimethyl-4- (3- (4- (4-met-1-1-homopiperazine 1) -l-piperidine Icarboni 1) acri loi 1) -phenoxy) methylocarboni lamino} benzothiazole, (12) 2- (4-nitroxy) 4- (3- (4- (3,4-dimethyl-1-piperazin-1) -l-piperidinium-1-carbonyl) -acri-loi-1-phenoxy) -methylcarbonylamino} benzothiazole, (13) 2CO-me > t-oxi-6-i8opropi 1-4- (3- (4-methyl-1-piperazine 1) -carboni 1) -acri loi 1) phenoxy) methycarboxylamino} benzothiazole, (14) 2-C-throetoxy-4- (3- (4- (4-methyl-1-homopiperazine 1) -l-pipep "dini 1-carboni 1) acri loi 1) phenoxymethylcarbonate no.} benzoti azol, (15) 2- (2-n-buti 1 -A- (3- (4- (4-methyl-1-1-homopi perazi nil) -1-piperidini-1 -carboni) acri loi 1) pheno i) met Icarboni 1 aroi no.} benzothiazole, or a salt thereof 33.- A protein kinase C inhibitor comprising as an active ingredient a thiazole compound or a salt thereof in accordance with claim 1. 34.- A process for preparing a thiazole compound according to claim 1, comprising the following steps of (a) reacting a compound of the formula (2): wherein R4-, R2, R- ", RB, Z, m, s, T, u and A are the same as those defined in 1 to claim 1, with a compound of the formula (3): wherein R4-4-13 is the same as that defined in claim 1 or a compound of the formula (4): Or II < 4) X-CR4 - "" * where R4 - "* eß a group: -CH = C (R4-4-13) (COR4- *) (R4-4- * 3 eß the same as defined in Re vindication 1, and R * - is a hydroxy group or a lower alkoxy group), or a group: -CSC-COR4 - ** (R4 - * is the same as defined in claim 1), and X is a halogen atom, to give a coropuesto of the formula ( the ) : wherein R4-, R2, R "" »» Rβ, Z, ra, s, T, u, and A are the same as those defined in claim 1, and R 4 - "" "is the same as defined above (b) reacting a compound of the formula (Ib): wherein R4-, R2, R-4, RB, R4-4-13, Z, m, s, T, u and A are the same as those defined in claim 1, with a compound of the formula (5) : R - * --- * H (5) where R4 - * "* is the heterocyclic residues as defined for R4-4- *" but having at least one / -N \ in the heterocyclic nucleus, for give a compound of the formula (lc): wherein R4-, R2, R "-, R., R4-4- * 3, Z, m, s, T, u and A are the same as those defined in claim 1, and R4-" 7 is the same than the one defined above; (c) reacting a compound of the formula (10): wherein R4-, R2, R- ", Rs, Z, m, s, T, u and A are the moieties defined in claim 1, R4-3 is a lower alkoxy group, with a compound of the formula (12): • C-CHO (12) wherein R4-3 is the same as defined above, to give a compound of the formula (Id): wherein R4-, R2, R ** > Rβ, Z, m, s, T. u and A are the same as those defined in claim 1, and R 4 - * is the same as defined above; (d) reacting a compound of the formula (10): where R4-, R2, R **, RB, Z, m, s »T, u and A ßon are the same as those defined in claim 1, and R4-3 is the same as defined above, with a compound of the formula (20): R22CH0 (20) wherein R22 is a saturated or unsaturated heterobicyclic, heteroradiocyclic residue of 5 to 10 members (said heterocyclic residue optionally has the 3 substituents selected from (i) a lower alkyl group (ii) a group: - (B)., - NR-3R3-3 (1 is the same as defined above, B is a group -CO-A- (A is the same as defined above), a carbonyl group or a lower alkylene group, R4-3 and R4-3 are the same or different, and are each a hydrogen atom, a lower alkyl group, a lower aroino-substituted lower alkyl group optionally having a lower alkyl substituent , or which is combined together with the nitrogen atom adjacent to which they are bound to form a heteromonocyclic, heterobicyclic or hetero ring saturated ro-spiro of 5 to 12 members with or without being intervened with another nitrogen atom or an oxygen atom, said heterocyclic group can optionally have a substituent selected from a lower alkyl group, a lower alkoxycarbonyl group, an alkoxy lower alkyl group inferred -substituted, an amino group optionally having a lower alkyl substituent and a hydroxy substi tuted lower alkyl group); (iii) a lower alkoxycarbonyl group; (iv) a hydroxy-substituted lower alkyl group; (v) a pyridyl group which is optionally substituted by a lower alkyl group optionally having a halogen substituent on the pyridine ring; (vi) a halogen-substituted lower alkyl group; (vii) a lower alkoxy group; (viii) a c-cloalkyl group; (ix) a hydro group i; (x) a loxy-substituted tetrahydropyranyl lower alkyl group; (xi) a pyrimidyl group; (xii) a lower alkyl group substituted with lower alkoxy; (xiii) a carboxyl group; (xiv) a lo-substi tuted phenyl lower alkoxy group; (xv) a lowe-substituted phenyl lower alkyl group optionally having a lower alkyndiioxy substituent on the phenyl ring; (xvi) a lower alkanoyloxy group; and (xvi i) a piperidinyl group optionally having a lower alkyl substituent on the piperidine ring, to give a compound in the formula (Ih): wherein R4-, R2, R "*, Rs, Z, m, s, T, u and A are the same as defined in claim 1, and Rx and R22 are the same as defined above; convert a coropuesto of the formula (11): wherein R4-, R2, R * 4, Ra, Z, m. s, T, u and A are the same as those defined in claim 1, and R3 ° is a lower alkoxy group, in a compound of the formula (Id '): where R4-, R2. R- *, RB, Z, m, s, T, u and A are the same as defined in claim 1, and R4 - ** »is a lower alkoxy group, in the presence of a basic compound, optionally followed by the conversion of the compound (id ') to a compound of the formula (le): wherein R4-, R2, R- ", RB, Z, m, ß, T, u and A are the same as defined in rei indication 1, in the presence of an acid or basic compound; (f) converting a compound of formula (11): wherein R4-, R2, R * 4, R, Z, m, s, T, u and A are the same as those defined in claim 1, and R3 ° is a lower alkoxy group, in a coropuesto of the formula (lf): crc = c- -R20 wherein R4-, R2, R "4» RB, Z, m, s, T, u and A are the same as those defined in claim 1, and R3 ° is the same as defined above, in the presence of a oxidizing agent, optionally followed by the conversion of the compound (lf) to a compound of the formula (lg): wherein R4-, R2, R- *, RB, Z, m »s, T, u and A are the same as those defined in claim 1, in the presence of an acidic or basic compound; (g) reacting a compound of the formula (19): wherein R4-, R2, R * 4, RB, Z, m, s, T, u and A are the same as those defined in claim 1, and R34- is a phenyl group, with a co-tax of the formula ( 20): R22CH0 (20) wherein R22 is the same as defined above, to give a compound of the formula (lh): < ^ -CH = CH-R22 O wherein R4-, R2, R "4» RB, Z, m, s, T, u and A are the same as defined in claim 1, R22 is the raismo that defined above, (h) take reaction a co-formula of the formula (23): O || (23) R3-COH wherein R3 is the same as defined in claim 1, with a co-formula of formula (24): R1 H? N- (T) U _- s -R2 < 24) wherein R4-, R2, R-4, T and u are the same as those defined in claim 1, to give a compound of the formula (1): wherein R4-, R2, R3, R * 4, T and u are the same as those defined in claim i; (i) reacting a compound of the formula (19a): wherein T, u, R4-, R2, R-4, Z, RB and m are the same as those defined in claim 1, and R34- is the same as defined above, and A 'is a lower alkylene group , with a compound of the formula (44): OHC-COOH (44) to give a compound of the formula (lq): wherein T, u, R 4 -, R 2, R "4, At, Z» RB and m are the same as defined in claim 1; (j) reacting a compound of formula (54): wherein R 4 -, R 2, T, u and R * are the same as those defined in claim 1, and R 9 is the same as defined above, with a compound of formula (12): wherein R is the same as defined above, to give a compound of the formula (ls): wherein R4-, R2, T, u and R * are the same as those defined in claim 1, and R4-3 is the same as defined above, optionally followed by the conversion of the compound (ls) to a compound of the formula (lt): wherein R4-, R2, T, u and R- * are the same as defined in claim i; (k) reacting a compound of the formula (lu): where R4-, R2, T, u, R * 4 and R la are the mics defined in rei indication 1, with a co-formula of formula (5): R ^ H (5) in which R4 - "7 is the same as defined above, to give a compound of the formula (lv): 0 wherein R4-, R2, T, u, R "4 and Rii are the same as those defined in claim 1, and R4- * 7 is the same as defined above, or (1) reacting a composed of the formula (54): -5 0 wherein R4-, R2, T, u, R * 4 and R4-3 are the same as those defined above, with a compound of the formula (20): R22CH0 (20) wherein R22 is the same as the one defined above, to give a compound of the formula (lw): wherein R4-, R2, T, u and R * 4 are the same as those defined in rei indication 1, and R22 is the same as defined above. FQMME-N P? THE INVENCIÓ A thiazole compound of the formula wherein T is lower alkylene; u is O or i; R4- and R2 are the same or different and each are H or lower alkyl, etc .; form 3 pag. 436; R- "is H or alkanoyloxy and lower ioi-alkaline, which shows inhibitory activity on protein kinase C (PKC, serine / threonine phosphatase protein dependent Ca2 + / phospholipid), and which is useful as an inhibitor of the protein kinase C. JN / JJ / M6 / EA / IV / blm * ehp * mram * apm * amm * e1 t * ram * fac * P97 / 1478F