HK1016586B - Thiazole derivative - Google Patents

Description

Thiazole derivatives

Technical Field

The present invention relates to novel thiazole derivatives.

Background

Heretofore, various thiazole derivatives have been known, and among them, some compounds having relatively similar substituents as compared with the compounds of the present invention are disclosed in the following documents.

JP-A-2-306916 discloses platelet adhesion inhibitors comprising the following indazole compounds:

wherein X is S or > N-R³(R³Is H, lower alkyl, etc.); r¹Is halogen, cyano-substituted lower alkoxy, phenyl-alkyl with substituents on the phenyl ring, substituted furyl-alkoxy, substituted pyrrolidinyl-alkyl, substituted amino-alkyl or-alkoxy, etc.; r²Is pyrrolyl, thienyl, pyridylthio-lower alkyl having an optional alkyl substituent, phenyl optionally having 1 to 3 substituents selected from the group consisting of lower alkoxy, lower alkyl, OH, halogen and-O-Y-NR ⁸R⁹(Y is lower alkylene, R⁸And R⁹Each of which isIs H, lower alkyl, cycloalkyl, or together form a nitrogen-containing 5-or 6-membered saturated heterocyclic group, or-NR¹⁰R¹¹(R¹⁰And R¹¹Each H, lower alkyl, substituted phenyl, or together form a heterocyclic group). However, the thiazole compounds described in this document differ significantly from the thiazole compounds of the present invention in the substituent at the 2-position of the thiazole nucleus. Furthermore, this document does not disclose any compounds having the activity of the protein kinase C inhibitors described in the present invention.

European patent 318084 (= U.S. Pat. Nos. 4,957,932 and 5,037,840) discloses benzoheteroazoles of the formulaWherein R is¹Is H, halogen, alkyl, etc.; r²Is alkyl, alkenyl, etc.; r³Is H or R²；R⁴Is H, halogen, -NO₂Etc.; r⁵Is H, halogen, -NO₂Etc.; r⁷Is H or alkyl; x²And X³O, S, S (O), etc.; x⁴Is NR³O or S; z¹And Z²is-CONR³-or-HET (-R)³、-R⁵) -and Q¹And Q²is-COOR³、-CONHS(O)₂R¹³CN, -CN, etc. However, in practice, the benzoxazole compounds described in this document differ from the thiazole compounds described in the present invention in the substituent at the 2-position of the oxazole nucleus. Furthermore, this document also does not disclose any compounds having protein kinase C inhibitor activity.

Certain thiazole or benzothiazole compounds having a similar chemical structure to that described in the above-mentioned european patent 318084 are also disclosed in PCT publications WO 93/21168 and WO93/21169, which mention that these compounds are useful as leukotriene antagonists, but, as such, the thiazole or benzothiazole compounds described in these documents differ significantly in the substituent at the 2-position from the thiazole compounds described in the present invention, and these documents do not disclose any compounds having protein kinase C inhibitor activity.

Disclosure of Invention

The thiazole derivative of the present invention is a novel compound represented by the following formula (1) or a salt thereof, which has not been disclosed in any literature

Wherein T is lower alkylene;

u is 0 or 1;

R¹and R²May be the same or different and are each a hydrogen atom or a lower alkyl group, or together form a group: - (CH)₂)_n- (n is 4 or 5) or form a benzene ring which may be optionally substituted by a substituent selected from lower alkyl, lower alkoxy, nitro, amino optionally having a lower alkyl substituent, or a halogen atom;

R³is a group of the formula:

wherein R is^11b、p、R^11aAs defined below; a is lower alkylene; z is O or S; s is 0 or 1; m is 1 or 2;

R⁴is hydrogen or lower alkanoyloxy-lower alkyl;

Each R⁵May be the same or different and are each selected from (a) a hydrogen atom, (b) an alkyl group optionally substituted with a hydroxyl group, (c) a halogen atom, (d) a group of the formula: - (O)_t-A-(CO)_l-NR⁷R⁸(wherein t is 0 or 1, A is lower alkylene, l is 0 or 1, and R⁷And R⁸May be the same or different and are each a hydrogen atom or a lower alkyl group, or together with the nitrogen atom to which they are attached form a 5-or 7-membered saturated heterocyclic group which may be interrupted by a nitrogen atom or an oxygen atom, said heterocyclic group being optionally substituted by a group selected fromThe group is selected from the group of the following formula: - (A)_l-NR⁹R¹⁰(wherein A and l are as defined above, and R⁹And R¹⁰May be the same or different and are each a hydrogen atom or a lower alkyl group, or together with the nitrogen atom to which they are attached form a 5-or 7-membered saturated heterocyclic group which may be interrupted by a nitrogen atom or an oxygen atom, said heterocyclic group may optionally have a lower alkyl substituent, a lower alkyl group optionally having a hydroxyl substituent, a hydroxyl group and a lower alkanoyl group), (e) a lower alkoxy-carbonyl-lower alkyl group, (f) a lower alkanoyloxy-lower alkyl group, (g) a lower alkoxy group optionally having a halogen substituent, (h) a halogen-substituted lower alkyl group, (i) a carboxyl-substituted lower alkyl group, (j) a lower alkoxycarbonyl group, (k) a lower alkenyloxy group, (l) a phenyl-lower alkoxy group, (m) a cycloalkoxy group, (n) a phenyl group, (o) a phenoxy group, (p) a hydroxyl group, (q) lower alkylthio, (r) lower alkenyl, or(s) amino optionally substituted with lower alkyl;

R⁶Is a group of the formula:

(1)-CO-CH=CR^11b-(CO)_p-R^11aor (2) -CO-C ≡ C-COR¹⁴

p is 0 or 1;

R^11bis hydrogen or lower alkyl;

R^11ais hydroxy, lower alkoxy or a 5-to 10-membered mono-or bicyclic, saturated or unsaturated heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen, oxygen or sulfur atoms as ring atoms, said heterocyclic group optionally carrying 1 to 3 substituents selected from: lower alkyl, (ii) a group of the formula: - (B)_l-NR¹²R¹³(wherein l is as defined above, B is-CO-A- (A is as defined above), carbonyl or lower alkylene, and R¹²And R¹³Which may be the same or different and are each a hydrogen atom, a lower alkyl group or a lower alkyl group substituted by an amino group optionally having a lower alkyl substituent, or together with the nitrogen atom to which they are attached form a 5-to 12-membered saturated, monocyclic, bicyclic or spirocyclic heterocyclic group which may be interrupted by nitrogen or oxygen atoms, said heterocyclic groupOptionally bearing substituents selected from: lower alkyl, lower alkoxycarbonyl, lower alkyl substituted by lower alkoxy, amino optionally substituted by lower alkyl and lower alkyl substituted by hydroxy, (iii) lower alkoxycarbonyl, (iv) lower alkyl substituted by hydroxy, (v) pyridyl optionally substituted by lower alkyl has halogen substituent on the pyridine ring, (vi) lower alkyl substituted by halogen, (vii) lower alkoxy, (viii) cycloalkyl, (ix) hydroxy, (x) tetrahydropyranyl-substituted lower alkyl, (xi) pyrimidinyl, (xiii) lower alkyl substituted by lower alkoxy, (xiii) carboxy, (xiv) phenyl-lower alkoxy, (xv) phenyl-lower alkyl optionally substituted by lower alkylenedioxy on the benzene ring, (xvi) lower alkanoyloxy, and (xvii) piperidinyl optionally bearing a lower alkyl substituent on the piperidine ring;

R¹⁴Is hydroxy or lower alkoxy; and

when m is 1, the groups A and R⁵Together may form a group of the formula:

(wherein R is⁶As defined above, and R is 0, 1 or 2), or when m is 2, two R⁵The groups may together form a lower alkylenedioxy group, a lower alkylene group or a group of the formula: - (CH)₂)₂-CONH-, or a group R⁵And R⁶Together may form a group of the formula: -CO-CH (R)²⁸)-CH(R^28＇) -W- (wherein R²⁸And R^28′Is a hydrogen atom or a carboxyl group, with the proviso that R²⁸And R^28′Not both being carboxyl, and W is-N (R)^29a) -or(wherein R is^29aIs hydrogen or lower alkyl, R^29bIs a lower alkyl group, and X is a halogen atom)).

Thiazole derivatives of formula (1) on protein kinase C (PKC, Ca)²⁺Phospholipid-dependent serine/threonine protein phosphatases) having inhibitory activityAnd are useful as protein kinase C inhibitors.

It has now been found that PKC plays a very important role in the regulation of various biological functions, such as metabolic regulation, cell proliferation, cell differentiation, neurotransmitter release responses, and the like. Therefore, PKC inhibitors are useful for preventing or treating various diseases caused by the aforementioned biological hyperactivity in which PKC participates.

In particular, protein kinase inhibitors containing the thiazole derivatives of the present invention as an active ingredient are useful for the treatment of autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis and the like; agents for various allergic diseases such as crohn's disease, ulcerative colitis, asthma, atopic dermatitis; agents for preventing rejection reactions in organ transplantation, GVHD reactions, and the like; an agent for preventing or treating ischemic diseases of organs such as heart, liver, kidney and brain, acute pancreatitis, sepsis, organ failure caused by burn, ARDS, or by inhibiting the production of T-cell-derived cytokine (cytokine) such as IL-2 or inflammatory cytokine such as TNF-alpha.

In addition, the protein kinase C inhibitor of the present invention can be used for preventing or treating cancer, diabetes, alzheimer's disease, arteriosclerosis, HIV infection, nephritis, vasculitis, etc. through other biological functions related to PKC, such as cell proliferation, hormone secretion, metabolic regulation, etc.

Each group in the above formula (1) specifically means the following group.

The lower alkyl group includes a straight chain or a branched chain C₁-C₆Alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexane and the like.

The lower alkoxy group includes a straight chain or a branched chain C₁-C₆Alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy and the like.

The halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

Said lower alkanoyloxy-substituted lower alkyl group includes C which is substituted by 1 or 2 straight or branched chains₂-C₆Alkanoyloxy group substituted straight or branched chain C₁-C₆Alkyl groups such as acetoxymethyl, 2-propionyloxyethyl, 1-butyryloxyethyl, 3-acetoxypropyl, 4-acetoxybutyl, 4-isobutyryloxybutyl, 5-valeryloxypentyl, 6-acetoxyhexyl, 6-tert-butylcarbonyloxyhexyl, 1-dimethyl-2-hexanoyloxyethyl, 2-methyl-3-acetoxypropyl, diacetoxymethyl, 1, 3-diacetoxypropyl and the like.

The alkyl group optionally having a hydroxyl substituent includes a straight chain or branched C group optionally having 1 to 3 hydroxyl substituents₁-C₈Alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2, 3-dihydroxypropyl, 4-hydroxybutyl, 1-dimethyl-2-hydroxyethyl, 1, 3-dihydroxypropyl, 5, 4-trihydroxypentyl, 5-hydroxypentyl, 6-hydroxyhexyl, 1-hydroxyisopropyl, 2-methyl-3-hydroxypropyl, 7-hydroxyheptyl, 8-hydroxyoctyl and the like.

The lower alkylene group includes a straight chain or a branched chain C₁-C₆Alkylene groups such as methylene, 1, 2-ethylene, 1, 3-propylene, 2-methyl-1, 3-propylene, 2-dimethyl-1, 3-propylene, 1-methyl-1, 3-propylene, methylmethylene, ethylmethylene, 1, 4-butylene, 1, 5-pentylene, 1, 6-hexylene, and the like.

Said is prepared from R⁷And R⁸Or R is⁹And R¹⁰5-to 7-membered saturated heterocyclic groups such as pyrrolidinyl, piperidinyl, piperazinyl, morpholino, homopiperazinyl, etc., which are formed together with their adjacent nitrogen atoms with or without being interrupted by other nitrogen atoms or oxygen atoms.

Said lower alkyl optionally substituted by hydroxy, other than the above-mentioned lower alkylIn addition to these radicals, straight-chain or branched C optionally having 1 to 3 hydroxyl substituents₁-C₆Alkyl groups such as hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2, 3-dihydroxypropyl, 4-hydroxybutyl, 1-dimethyl-2-hydroxyethyl, 5, 4-trihydroxypentyl, 5-hydroxypentyl, 6-hydroxyhexyl, 1-hydroxyisopropyl, 2-methyl-3-hydroxypropyl and the like.

The lower alkanoyl group includes straight or branched C₁-C₆Alkanoyl groups such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, tert-butylcarbonyl, hexanoyl and the like.

The substituted group of the formula: - (A)_l-NR⁹R¹⁰(wherein A is lower alkylene, l is 0 or 1, and R⁹And R¹⁰May be the same or different and are each a hydrogen atom or a lower alkyl group, or R⁹And R¹⁰Together with the nitrogen atom to which they are attached, form a 5-or 7-membered saturated heterocyclic group optionally interrupted by other nitrogen or oxygen atoms, said heterocyclic group optionally bearing lower alkyl substituents), lower alkyl optionally bearing hydroxy substituents, hydroxy and lower alkanoyl, said heterocyclic group substituted by 1 to 3 substituents selected from the group consisting of the following groups: - (A) _l-NR⁹R¹⁰(wherein A is a straight or branched chain C₁-C₆Alkylene, l is 0 or 1, R⁹And R¹⁰May be the same or different and are each a hydrogen atom or a straight or branched chain C₁-C₆Alkyl, or R⁹And R¹⁰Together with the nitrogen atom to which they are attached form a 5-or 7-membered saturated heterocyclic group, optionally interrupted by other nitrogen or oxygen atoms, and which optionally carries 1 to 3 straight or branched chains C₁-C₆Alkyl substituents), alkyl optionally bearing 1-3 hydroxyl substituents, hydroxyl and straight or branched C₁-C₆Alkanoyl radicals, e.g. 4-methylpiperazinyl, 2- (4-methyl-1-piperazinyl) methylmorpholino, 4- (4-methyl-1-piperazinyl) piperidinyl, 4-methylpiperazinyl, 4- (2-hydroxypiperazinyl)Ethyl) piperazinyl, 4-morpholinopiperidinyl, 2- [ (1-pyrrolidinyl) methyl]Morpholino, 4-hydroxypiperidinyl, 4-acetylpiperazinyl, 4-dimethylaminopiperidinyl, 4- (4-methyl-1-homopiperazinyl) piperidinyl, 4- (4, 5-dimethyl-1-homopiperazinyl) piperidinyl, 4- (3-methyl-4-ethyl-1-piperazinyl) piperidinyl, 4- (3-methyl-4-n-propyl-1-piperazinyl) piperidinyl, 4- (3, 4-dimethyl-1-piperazinyl) piperidinyl, 4- (4-isopropyl-3-methylpiperazinyl) piperidinyl, 4- (4-methyl-3-isopropylpiperazinyl) piperidinyl, 2-methylpyrrolidinyl, piperidinyl, piperazinyl, piperidinyl, 3-ethylpyrrolidinyl, 2, 3-dimethylpyrrolidinyl, 2,3, 4-trimethylpyrrolidinyl, 2-propylmorpholino, 3- (1-pyrrolidinyl) pyrrolidinyl, 3-isopropylmorpholino, 2, 3-dimethylmorpholino, 4-n-butylpiperidinyl, 3,4, 5-trimethylpiperidinyl, 3-pentylpiperidinyl, 4-methylpiperazinyl, 4, 5-dimethylpiperazinyl, 4-hexylhomopiperazinyl, 3-methyl-4-ethyl-piperazinyl, 3-methyl-4-n-propyl-1-piperazinyl, 3, 4-dimethylpiperazinyl, 4-isopropyl-3-methylpiperazinyl, 4-methyl-3-isopropylpiperazinyl, N-propylpiperidinyl, N-butylpiperidinyl, N-isopropylpiperidinyl, N-ethylpiperazinyl, N-isopropylpiperidinyl, N-, 4-methyl homopiperazino, 3-propionyl pyrrolidinyl, 4-butyrylpiperidinyl, 4-pentanoyl piperazinyl, 3-hexanoyl morpholino, 4-acetyl homopiperazino, 3-hydroxymorpholino, 4-hydroxy homopiperazino, 4-hydroxypiperazino, 3-hydroxypyrrolidinyl, 3-hydroxymethyl pyrrolidinyl, 3- (3-hydroxypropyl) morpholino, 2-hydroxymethyl homopiperazino, 2- (4-methyl-1-piperazinyl) methyl homopiperazino, 4- (1, 3-dihydroxy-2-propyl) piperazinyl, 4-ethyl homopiperazino, 3- (4-methyl-1-homopiperazinyl) pyrrolidinyl, 4-methyl-3- (1-piperidinyl) methyl piperazinyl, 4-methyl-3- (4-methyl-1-homopiperazinyl) methylpiperazinyl, 4-methyl-3- (4-methyl-1-piperazinyl) methylpiperazinyl and the like.

The above heterocyclic group substituted with lower alkyl includes a group substituted with 1 to 3 straight or branched C₁-C₆Alkyl-substituted heterocyclic groups as mentioned above, such as 4-methylpiperazinyl, 3, 4-dimethylpiperazinyl, 3-ethylpyrrolidinyl, 2-propylpyrrolidinyl, 1-methylpyrrolidinyl, 3,4, 5-trimethylpiperidinyl, 4-butylpiperidinyl, 3-pentylmorpholino, 4-ethylpiperazinyl, 4-methylpiperazinyl, 4-hexylpiperazinyl, 4-methylpiperazinyl, 4, 5-dimethylpiperazinyl3-methyl-4-ethylpiperazinyl, 3-methyl-4-n-propylpiperazinyl, 4-isopropyl-3-methylpiperazinyl, 4-methyl-3-isopropylpiperazinyl, 4-methylphomomorpholino and the like.

The lower alkyl group substituted with a lower alkoxycarbonyl group includes a straight chain or branched C group substituted with a straight chain or branched alkoxycarbonyl group having 1 to 6 carbon atoms₁-C₆Alkyl groups such as methoxycarbonylmethyl, 3-methoxycarbonylpropyl, ethoxycarbonylmethyl, 3-ethoxycarbonylpropyl, 4-ethoxycarbonylbutyl, 5-isopropoxycarbonylpentyl, 6-propoxycarbonylhexyl, 1-dimethyl-2-butoxycarbonylethyl, 2-methyl-3-tert-butoxycarbonylpropyl, 2-pentoxycarbonylethyl, hexyloxycarbonylmethyl and the like.

The lower alkanoyloxy-substituted lower alkyl group includes C which is a straight chain or branched chain ₂-C₆Alkanoyloxy substituted straight or branched chain C₁-C₆Alkyl groups such as acetoxymethyl, 2-propionyloxyethyl, 1-butyryloxyethyl, 3-acetoxypropyl, 4-acetoxybutyl, 4-isobutyryloxybutyl, 5-valeryloxypentyl, 6-acetoxyhexyl, 6-tert-butoxycarbonyloxyhexyl, 1-dimethyl-2-hexanoyloxyethyl, 2-methyl-3-acetoxypropyl and the like.

The lower alkoxy group optionally having halogen substituent includes straight chain or branched C optionally having 1 to 3 halogen substituents₁-C₆The alkoxy group, for example, includes, in addition to the above-mentioned lower alkoxy groups, trifluoromethoxy group, trichloromethoxy group, chloromethoxy group, bromomethoxy group, fluoromethoxy group, iodomethoxy group, difluoromethoxy group, dibromomethoxy group, 2-chloroethoxy group, 2,2, 2-trifluoroethoxy group, 2,2, 2-trichloroethoxy group, 3-chloropropoxy group, 2, 3-dichloropropoxy group, 4,4, 4-trichlorobutoxy group, 4-fluorobutoxy group, 5-chloropentyloxy group, 3-chloro-2-methylpropoxy group, 6-bromohexyloxy group, 5, 6-dichlorohexyloxy group and the like.

The halogen-substituted lower alkyl group includes a straight or branched chain C having 1 to 3 halogen substituents₁-C₆Alkyl radicals, e.g. trifluoromethyl, trichloromethyl, chloro Methyl, bromomethyl, fluoromethyl, iodomethyl, difluoromethyl, dibromomethyl, 2-chloroethyl, 2,2, 2-trifluoroethyl, 2,2, 2-trichloroethyl, 3-chloropropyl, 2, 3-dichloropropyl, 4,4, 4-trichlorobutyl, 4-fluorobutyl, 5-chloropentyl, 3-chloro-2-methylpropyl, 6-bromohexyl, 5, 6-dichlorohexyl and the like.

The carboxyl-substituted lower alkyl group includes wherein the alkyl group is straight or branched C₁-C₆The carboxyalkyl group of the alkyl group is, for example, carboxymethyl, 2-carboxyethyl, 1-carboxyethyl, 3-carboxypropyl, 4-carboxybutyl, 5-carboxypentyl, 6-carboxyhexyl, 1-dimethyl-2-carboxyethyl, 2-methyl-3-carboxypropyl, etc.

The lower alkoxycarbonyl group includes a straight or branched alkoxycarbonyl group having 1 to 6 carbon atoms in the alkoxy moiety, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and the like.

Said aminocarbonyl-substituted lower alkoxy group optionally having a lower alkyl group includes a lower alkoxy group optionally having 1 to 2 straight or branched C₁-C₆Straight-chain or branched C of aminocarbonyl of alkyl group₁-C₆Alkoxy, for example aminocarbonylmethoxy, 2-aminocarbonylethoxy, 1-aminocarbonylethoxy, 3-aminocarbonylpropoxy, 4-aminocarbonylbutoxy, 5-aminocarbonylpentoxy, 6-aminocarbonylhexyloxy, 1-dimethyl-2-aminocarbonylethoxy, 2-methyl-3-aminocarbonylpropoxy, methylaminocarbonylmethoxy, 1-ethylaminocarbonylethoxy, 2-propylaminocarbonylethoxy, 3-isopropylaminocarbonylpropoxy, 4-butylaminocarbonylbutoxy, 5-pentylaminocarbonylpentoxy, 6-hexylaminocarbonylhexyloxy, dimethylaminocarbonylmethyloxy, 2-aminocarbonylethoxy, 6-aminocarbonylhexyloxy, 3-isopropylaminocarbonylpropoxy, 4-butylaminocarbonylbutoxy, 5-pentylaminocarbonylpentoxy, 6-hexylaminocarbonylhexyloxy, dimethylaminocarbonylmethyloxy, 2-, 2-diethylaminocarbonylethoxy, 2-dimethylaminocarbonylethoxy, (N-ethyl-N-propylamino) carbonylmethoxy, 2- (N-methyl-N-hexylamino) carbonylethoxy and the like.

The above-mentionedThe lower alkyl group optionally substituted with amino optionally substituted with a lower alkyl substituent includes a lower alkyl group optionally substituted with 1 to 2 carbon atoms₁-C₆Amino-substituted straight or branched C of alkyl substituents₁-C₆Alkyl groups include, for example, aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl, 1-dimethyl-2-aminoethyl, 2-methyl-3-aminopropyl, methylaminomethyl, 1-ethylaminoethyl, 2-propylaminoethyl, 3-isopropylaminopropyl, 4-butylaminobutyl, 5-pentylaminopentyl, 6-hexylaminohexyl, dimethylaminomethyl, (N-ethyl-N-propylamino) methyl, 2- (N-methyl-N-hexylamino) ethyl and the like.

Said is prepared from R¹²And R¹³The 5-to 12-membered saturated heteromonocyclic, heterobicyclic or heterospirocyclic groups formed together with the adjacent nitrogen atom(s) to which they are bonded (with or without spacing by other nitrogen or oxygen atoms) include, for example, pyrrolidinyl, piperidinyl, piperazinyl, morpholino, homopiperazinyl, homomorpholino, 1, 4-diazabicyclo [4.3.0 ]]Nonyl, 1, 4-diazabicyclo [4.4.0 ]]Decyl, 1, 4-diazabicyclo spiro [5.5 ]]Undecyl and the like.

The lower alkyl group substituted with lower alkoxy includes a lower alkyl group having 1 to 3 straight or branched C ₁-C₆Straight or branched chain C of alkoxy₁-C₆Alkyl groups such as methoxymethyl, 3-methoxypropyl, ethoxymethyl, 2-methoxyethyl, 3-ethoxypropyl, 4-ethoxybutyl, 5-isopropoxypentyl, 6-propoxyhexyl, 1-dimethyl-2-butoxyethyl, 2-methyl-3-tert-butoxypropyl, 2-pentoxyethyl, hexyloxymethyl and the like.

Amino groups optionally bearing lower alkyl substituents include those optionally bearing 1-2 straight or branched chain C₁-C₆Amino groups of alkyl radicals, e.g. amino, methylamino, ethylamino, propylamino, isopropylamino, butylamino, tert-butylamino, pentylamino, hexylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, dipentylamino, dihexylamino, N-methyl-N-ethylamino, N-ethyl-N-propylamino group, N-methyl-N-butylamino group, N-methyl-N-hexylamino group and the like.

The above heterocyclic group having a substituent selected from the group consisting of a lower alkyl group, a lower alkyl group substituted by a lower alkoxy group, a lower alkoxycarbonyl group, an amino group optionally substituted by a lower alkyl group and a lower alkyl group substituted by a hydroxyl group includes those having 1 to 3 substituents selected from the group consisting of a straight chain or branched C₁-C₆Alkyl, with 1-3 straight or branched C ₁-C₆Straight or branched chain C of alkoxy₁-C₆Alkyl, straight or branched alkoxycarbonyl containing from 1 to 6 carbon atoms in the alkoxy moiety, optionally with 1 to 2 straight or branched C₁-C₆Amino groups of alkyl groups and straight-chain or branched C with 1-3 hydroxy substituents₁-C₆The above-mentioned heterocyclic group which is a substituent of an alkyl group, for example, 4-methylpiperazinyl, 3, 4-dimethylpiperazinyl, 4-ethylpiperazinyl, 4-methylpiperazinyl, 4-dimethylaminopiperidinyl, 4-t-butoxycarbonylhomopiperazinyl, 4-n-butylpiperazinyl, 4- (2-hydroxyethyl) piperazinyl, 3-methylpiperazinyl, 4- (1, 3-dihydroxy-2-propyl) piperazinyl, 4- (1, 3-dihydroxy-2-propyl) homopiperazinyl, 3,4, 5-trimethylpiperazinyl, 4-isopropylpiperazinyl, 3, 4-trimethylpiperazinyl, 4, 5-dimethylpiperazinyl, 3-methyl-4-ethylpiperazinyl, 3-methyl-4-n-propylpiperazinyl, 3-n-propyl-4-methylpiperazinyl, 3-methyl-4-isopropylpiperazinyl, 3-ethyl-4-methylpiperazinyl, 3-methyl-4- (2-methoxyethyl) piperazinyl, 3-methyl-4- (2-hydroxyethyl) piperazinyl, 3-isopropyl-4-methylpiperazinyl, 4-methyl-1, 4-diazaspiro [5.5]Undecyl, 3-amino-1, 4-diazabicyclo [4.4.0]Decyl, 5-hydroxymethyl-1, 4-diazabicyclo [4.3.0 ]Nonyl, 3-ethoxycarbonyl homomorpholino, 3-diethylaminomorpholino, 3-methoxymethylpyrrolidinyl, and the like.

The lower alkyl group optionally having halogen substituents includes, for example, halogen-substituted lower alkyl groups in addition to the above-mentioned lower alkyl groups.

Said lower alkyl substituent optionally having halogen substituent on pyridine ringThe pyridyl group of (A) includes a straight or branched C having 1 to 3 substituents optionally having 1 to 3 halogen substituents on the pyridine ring₁-C₆Alkyl pyridyl groups such as pyridyl, 3-methylpyridyl, 4-ethylpyridyl, 2-propylpyridyl, 3-butylpyridyl, 4-pentylpyridyl, 4-hexylpyridyl, 3, 4-dimethylpyridyl, 3,4, 5-trimethylpyridyl, 3-trifluoromethylpyridyl, 2-chloromethylpyridyl, 4- (5-bromohexyl) pyridyl, 3-iodomethylpyridyl, 4- (2,2, 2-trifluoroethyl) pyridyl, 4- (5, 6-dichlorohexyl) pyridyl and the like.

Said cycloalkyl group comprising C₃-C₈Cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

The tetrahydropyranyloxy substituted lower alkyl group includes tetrahydropyranyloxy substituted alkyl group wherein the alkyl group is straight or branched chain C ₁-C₆Alkyl groups such as (2-tetrahydropyranyl) oxymethyl, 2- (3-tetrahydropyranyl) oxyethyl, 1- (4-tetrahydropyranyl) oxyethyl, 3- (2-tetrahydropyranyl) oxypropyl, 4- (3-tetrahydropyranyl) oxybutyl, 5- (4-tetrahydropyranyl) oxypentyl, 6- (2-tetrahydropyranyl) oxyhexyl, 1-dimethyl-2- (3-tetrahydropyranyl) oxyethyl, 2-methyl-3- (4-tetrahydropyranyl) oxypropyl, and the like.

The phenyl-lower alkyl group includes phenylalkyl groups wherein the alkyl is straight or branched C₁-C₆Alkyl groups such as benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl, 1-dimethyl-2-phenylethyl, 2-methyl-3-phenylpropyl and the like.

Said phenyl-lower alkoxy group comprises a phenylalkoxy group wherein said alkoxy group is a straight or branched chain C₁-C₆Alkoxy, for example benzyloxy, 2-phenylethoxy, 1-phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy, 5-phenylpentyloxy, 6-phenylhexyloxy, 1-dimethyl-2-phenylethoxy, 2-methyl-3-phenylpropyloxyAnd the like.

The lower alkanoyloxy group includes a straight or branched chain C₁-C₆Alkanoyloxy groups such as formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, t-butylcarbonyloxy, hexanoyloxy and the like.

Said piperidinyl group optionally bearing a lower alkyl substituent on said piperidine ring includes those optionally bearing a straight or branched chain C₁-C₆Examples of the alkyl-piperidinyl group include piperidinyl, 1-methyl-4-piperidinyl, 1-ethyl-3-piperidinyl, 1-ethyl-2-piperidinyl, 1-propyl-4-piperidinyl, 1-butyl-4-piperidinyl, 1-pentyl-4-piperidinyl, 1-hexyl-4-piperidinyl, 1-isobutyl-3-piperidinyl and 1-tert-butyl-2-piperidinyl.

Said phenyl-lower alkyl group optionally bearing a lower alkylenedioxy substituent on said phenyl ring includes those optionally bearing a straight or branched chain C on said phenyl ring₁-C₄(ii) a phenylalkyl group of an alkylenedioxy group, wherein the alkyl group is a straight or branched C₁-C₆The alkyl group includes, in addition to the above-mentioned phenyl-lower alkyl group, for example, 3, 4-methylenedioxybenzyl, 2- (3, 4-ethylenedioxyphenyl) ethyl, 1- (3, 4-ethylenedioxyphenyl) ethyl, 3- (2, 3-trimethylenedioxyphenyl) propyl, 4- (3, 4-tetramethylenedioxyphenyl) butyl, 5- (3, 4-methylenedioxyphenyl) pentyl, 6- (2, 3-trimethylenedioxyphenyl) hexyl and the like.

The lower alkylenedioxy group includes a straight chain or branched chain C₁-C₄Alkylenedioxy groups such as methylenedioxy, ethylenedioxy, propylenedioxy, butylenedioxy and the like.

5-to 10-membered, saturated or unsaturated heteromonocyclic or heterobicyclic group containing 1 to 4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom such as pyrrolidinyl group, piperidinyl group, piperazinyl group, morpholino group, 1-azabicyclooctyl group, homopiperazinyl group, homomorpholino group, 1, 4-diazabicyclo [4.3.0] nonyl group, 1, 4-diazabicyclo [4.4.0] decyl group, pyridyl group, 1,2,5, 6-tetrahydropyridyl group, thienyl group, 1,2, 4-triazolyl group, 1,2,3, 4-tetrazolyl group, 1,3, 4-triazolyl group, quinolyl group, 1, 4-dihydroquinolyl group, benzothiazolyl group, pyrazolyl group, pyrimidinyl group, pyridazinyl group, pyrrolyl group, pyrrolinyl group, quinolone group, 1, 3-dioxolanyl group, thiomorpholino group, 3, 4-dihydroquinolone, 1,2,3, 4-tetrahydroquinolyl, 2,3,4, 5-tetrahydrofuryl, indolyl, isoindolyl, 3H-indolyl, indolinyl, perhydroindolyl (indolidinyl), indazolyl, benzimidazolyl, benzoxazolyl, imidazolinyl, imidazolidinyl, isoquinolyl, perhydronaphthyl, perhydrometanaphthyridinyl, quinoxalinyl, 1, 2-naphthyridinyl, 2, 3-naphthyridinyl, chromanyl, isoindolinyl, isochromanyl, pyrazolyl, 1,3, 4-oxadiazolyl, 1,3, 4-thiadiazolyl, thienyl, imidazolyl, pyrazolidinyl, benzofuranyl, 2, 3-dihydrobenzo [ b ] furanyl, benzothienyl, tetrahydropyranyl, 4H-benzopyranyl, 1H-indazolyl, 2-imidazolinyl, 2-pyrrolinyl, furyl, oxazolyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, pyranyl, pyrazolidinyl, 2-pyrazolinyl, quinuclidinyl, 1, 4-benzoxazinyl, 3, 4-dihydro-2H-1, 4-benzothiazinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 1,2,3, 4-tetrahydroquinoxalinyl, 1, 3-dithia-2, 4-dihydronaphthyl, 1, 4-dithianyl, 2, 5-dihydrofuro [3,4-c ] pyridyl, 2,3,4,5,6, 7-hexahydro-1H-azepine, 1,2,3,4,5,6,7, 8-octahydroazocinyl, 1,2,3,4,5, 6-tetrahydroxyheptinyl (oxepinyl), 1, 3-dioxolanyl, 3,4,5, 6-tetrahydro-2H-pyranyl, 5, 6-dihydro-2H-pyranyl, and the like.

The above heterocyclic group having 1 to 3 substituents selected from the group consisting of: lower alkyl; (ii) a group: - (B)_l-NR¹²R¹³(l is as defined above, B is A group: -CO-A- (A is as defined above), carbonyl or lower alkylene, R¹²And R¹³Are the same or different and are each a hydrogen atom, a lower alkyl group substituted with an amino group optionally having a lower alkyl substituent, or together with the adjacent nitrogen atom to which they are attached form a group which is substituted or not substitutedA 5-to 12-membered saturated heteromonocyclic, heterobicyclic or spiro-cyclic heterocyclic ring interrupted by another nitrogen atom or oxygen atom, which heterocyclic group may optionally have a substituent selected from the group consisting of lower alkyl, lower alkoxycarbonyl, lower alkoxy-substituted lower alkyl, amino optionally having a lower alkyl substituent and lower alkyl group substituted with hydroxy); (iii) a lower alkoxycarbonyl group; (iv) hydroxy-substituted lower alkyl; (v) pyridyl optionally substituted on the pyridyl ring by lower alkyl optionally substituted by halogen; (vi) halo-substituted lower alkyl; (vii) lower alkoxy; (viii) a cycloalkyl group; (ix) hydroxy; (x) a lower alkyl group substituted with tetrahydropyranyloxy; (xi) a pyrimidinyl group; (xii) lower alkyl substituted by lower alkoxy; (xiii) carboxyl; (xiv) phenyl-lower alkoxy; (xv) phenyl-lower alkyl optionally bearing a lower alkylenedioxy group on the phenyl ring; (xvi) lower alkanoyloxy, and (xvii) piperidinyl optionally bearing a lower alkyl substituent on the piperidine ring, including the aforementioned heterocyclyl containing 1 to 3 substituents selected from (i) straight or branched C ₁-C₆An alkyl group; (ii) a group: - (B)_l-NR¹²R¹³(l is as defined above and B is A radical: -CO-A- (A is as defined above), carbonyl or straight or branched C₁-C₆Alkylene radical, R¹²And R¹³Identical or different and each is a hydrogen atom, a linear or branched C₁-C₆Alkyl or straight or branched C with amino optionally bearing 1-2 straight or branched alkyl substituents₁-C₆Alkyl, or together with the adjacent nitrogen atom to which they are attached form a 5-to 12-membered saturated heteromonocyclic, heterobicyclic, or spiro-cyclic heterocyclic ring, optionally interrupted by other nitrogen or oxygen atoms, which may optionally bear 1-3 substituents selected from the group consisting of straight or branched chain C₁-C₆Alkyl, with 1-3 straight or branched C₁-C₆Straight or branched chain C of alkoxy substituents₁-C₆Alkyl, straight or branched alkoxycarbonyl containing from 1 to 6 carbon atoms in the alkoxy moiety, optionally with 1 to 2 straight or branched C₁-C₆Amino of alkyl substituent and straight or branched C containing 1-3 hydroxy substituents₁-C₆Alkyl groups); (iii) an alkoxycarbonyl group having 1 to 6 carbon atoms in the alkoxy moiety; (iv) straight-chain or branched C with 1-3 hydroxy substituents₁-C₆An alkyl group; (v) straight or branched C optionally having 1 to 3 halogen substituents optionally on said pyridine ring ₁-C₆A pyridyl group of an alkyl group; (vi) straight-chain or branched C with 1-3 halogen substituents₁-C₆An alkyl group; (vii) straight-chain or branched C₁-C₆An alkoxy group; (viii) C₃-C₈A cycloalkyl group; (ix) hydroxy; (x) tetrahydropyranyloxy substituted alkyl, wherein said alkyl is linear or branched C₁-C₆An alkyl group; (xi) a pyrimidinyl group; (xii) has 1-3 straight or branched C₁-C₆Straight or branched chain C of alkoxy substituents₁-C₆An alkyl group; (xiii) carboxyl; (xiv) phenylalkoxy wherein said alkoxy is straight or branched C₁-C₆An alkoxy group; (xv) optionally carrying a straight or branched chain C on the phenyl ring₁-C₄Phenylalkyl of an alkylenedioxy substituent, wherein said alkyl is straight-chain or branched C₁-C₆An alkyl group; (xvi) straight-chain or branched C₁-C₆Alkanoyloxy groups, and (xvii) optionally carrying 1-3 straight or branched chain C on the piperidine ring₁-C₆Piperidinyl group having an alkyl substituent, for example, 4-methylpiperazinyl group, 4- (4-methyl-1-piperazinyl) piperidinyl group, 2- (4-methyl-1-piperazinylmethyl) morpholino group, 2- (4-methyl-1-piperazinylmethyl) pyrrolidinyl group, 3- (4-methyl-1-piperazinyl) pyrrolidinyl group, 1-ethyl-1, 2,3, 4-tetrazolyl group, 1-tert-butoxycarbonylpiperidinyl group, 1-methylpiperidinyl group, 2-dimethyl-1, 3-dioxolanyl group, 4- (3, 4-dimethyl-1-piperazinyl) piperidinyl group, 4- (4-ethyl-1-piperazinyl) piperidinyl group, and the like, 4- [ N- (2-diethylaminoethyl) -N-methylamino ]Piperidinyl, 4- (4-methyl-1-homopiperazinyl) piperidinyl, 2- (4-ethyl-1-piperazinylmethyl) morpholino, 4-dimethylaminopiperidinyl, 2-morpholinomethylpyrrolidinyl, 4- (1-pyrrolidinyl) piperidinyl, 4-isopentylpiperazinyl, 4- (2-hydroxyethyl)) Piperazinyl, 2- (1-pyrrolidinylmethyl) morpholino, 4-morpholinopiperidinyl, 2-aminomethylmorpholino, 1-dimethylaminomethylcarbonylpiperidinyl, 1-methylimidazolyl, 4- (2-pyridinyl) piperazinyl, 4- (3, 4-methylenedioxybenzyl) piperazinyl, 1- (4-chlorobutyl) -1,2,3, 4-tetrazolyl, 2-methoxycarbonylpyridinyl, 2-carboxypyridinyl, 4-isopropylpyridinyl, 4-hydroxypiperidinyl, 2-methyl-3-hydroxy-2, 5-dihydrofuran [3,4-c ]]Pyridyl, 1-cyclohexyl-1, 2,3, 4-tetrazolyl, 3- (4-methyl-1-piperazinyl) pyrrolidinyl, 1- [ (3-3,4,5, 6-tetrahydro-2H-pyranyl) methyl]-1,2,3, 4-tetrazolyl, 1- (3-chloropropyl) -1,2,3, 4-tetrazolyl, 2-carbamoylpyrrolidinyl, 4- (3-trifluoromethyl-2-pyridyl) piperazinyl, 4-benzylpiperidinyl, 4-n-butyl-1, 2,3, 4-tetrazolyl, 4-carbamoylpiperidinyl, 2- (4-methyl-1-piperazinyl) homomorpholino, 2-methylmorpholino, 2-methoxymethylmorpholino, 2-chloromethylmorpholino, 2-hydroxymethylmorpholino, 2-n-butoxymethylmorpholino, 2- (4-methyl-1-homopiperazinylmethyl) morpholino, 6, 7-dimethoxy-1, 2,3, 4-tetrahydro-isoquinolinyl, 2- (4-methyl-1-homopiperazinylmethyl) homomorpholino, 2-chloromethyl homomorpholino, 2-hydroxymethyl homomorpholino, 4-hydroxypiperazinyl, 2-methoxymethyl-1, 2,3,4,5, 6-hexahydroheptinyl, 4- (2-phenylethoxy) piperidinyl, 4-benzyloxypiperidinyl, 4-hydroxy-3-methylpiperazinyl, 4-acetoxypiperazinyl, 4-methoxypiperazinyl, 4- (4-tert-butoxycarbonyl-1-homopiperazinyl) piperidinyl, 4- (4-n-butyl-1-homopiperazinyl) piperidinyl, 4- (1-methyl-4-piperidinyl) homopiperazinyl, 3- (4-methyl-1-homopiperazinyl) piperidinyl, 2- (4-dimethylamino-1-piperidinylmethyl) morpholino, 2- (4-methyl-1-piperazinylmethyl) homomorpholino, 2- [4- (2-hydroxyethyl) -1-piperazinylmethyl ]Morpholino, 4- (3-methyl-1-piperazinyl) piperidinyl, 4- (4-ethyl-1-homopiperazinyl) piperidinyl, 3- (4-methyl-1-homopiperazinyl) pyrrolidinyl, 4- [4- (1, 3-dihydroxy-2-propyl) -1-piperazinyl]Piperidinyl, 4- [4- (1, 3-dihydroxy-2-propyl) -1-homopiperazinyl]Piperidinyl, 4-methyl-3- (1-piperidinylmethyl) piperazinyl, 4-methyl-3- (4-methyl-1-piperazinylmethyl) piperazinyl, 4-methyl-3- (4-methyl-1-homopiperazinylmethyl) piperazinyl, 3,4, 5-trimethoxypiperazinyl, 4-isopropylpiperazinyl, 4- (1-piperidinylmethyl) piperazinyl4-diazabicyclo [4.3.0 ]]Nonyl) piperidyl, (3,3, 4-trimethyl-1-piperazinyl) piperidyl, 4- (1, 4-diazabicyclo [4.4.0 ]]Decyl) piperidyl, 4- (3-methyl-4-ethyl-1-piperazinyl) piperidyl, 4- (3-methyl-4-propyl-1-piperazinyl) piperidyl, 4- (3-propyl-4-methyl-1-piperazinyl) piperidyl, 4- (3-methyl-4-isopropyl-1-piperazinyl) piperidyl, 4- (3-ethyl-4-methyl-1-piperazinyl) piperidyl, 4- [ 3-methyl-4- (2-methoxyethyl) -1-piperazinyl]Piperidinyl, 4- [ 3-methyl-4- (2-hydroxyethyl) -1-piperazinyl]Piperidinyl, 4- (4-methyl-1-1, 4-diazaspiro [ 5.5)]Undecyl) piperidyl, 4- (4-methyl-3-isopropyl-1-piperazinyl) piperidyl, 4- (2-pyrimidinyl) piperazinyl, and the like.

Said lower alkenyloxy group includes C₂-C₆Straight-chain or branched alkenyloxy groups such as vinyloxy, 1-methylvinyloxy, 2-dimethylvinyloxy, 1-propylvinyloxy, allyloxy, 2-butenyloxy, 3-butenyloxy, 1-ethylvinyloxy, 1-methylallyloxy, 1-pentenyloxy, 2-hexenyloxy, 3-methyl-1-butenyloxy, 1-butenyloxy and the like.

The cycloalkoxy group comprises C₃-C₈Cycloalkoxy groups, such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy, and the like.

Said lower alkylthio group includes C₁-C₆Straight-chain or branched alkylthio groups such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert-butylthio, pentylthio, hexylthio and the like.

Said lower alkenyl group comprising C₂-C₆Straight-chain or branched alkenyl groups such as vinyl, 1-methylvinyl, 2-dimethylvinyl, 1-propenylvinyl, allyl, 2-butenyl, 3-butenyl, 1-ethylvinyl, 1-methylallyl, 1-pentenyl, 2-hexenyl, 3-methyl-1-butenyl, and the like.

The present invention specifically includes the following compounds.

(1) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Identical or different and are each a hydrogen atom or a lower alkyl group, R³Is a group of the formula:(R^11bp and R^11aAs defined in formula (1), R⁴Is a hydrogen atom, and u is 0.

(2) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Identical or different and are each a hydrogen atom or a lower alkyl group, R³Is a group of the formula:(R^11bp and R^11aAs defined in formula (1), R⁴Is lower alkanoyloxy-lower alkyl, and u is 0.

(3) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Identical or different and are each a hydrogen atom or a lower alkyl group, R³Is a group of the formula:(R^11bp and R^11aAs defined in formula (1), R⁴Is a hydrogen atom, and u is 1.

(4) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Identical or different and are each a hydrogen atom or a lower alkyl group, R³Is a group of the formula:(R^11bp and R^11aAs defined in formula (1), R⁴Is lower alkanoyloxy-lower alkyl, and u is 1.

(5) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form the group: - (CH)₂)_n- (n is 4), R³Is a group of the formula:(R^11bp and R^11aAs defined in formula (1), R⁴Is a hydrogen atom, and u is 0.

(6) A thiazole derivative of the formula (1) or a salt thereof, wherein R ¹And R²Together form the group: - (CH)₂)_n- (n is 4), R³Is a group of the formula:(R^11bp and R^11aAs defined in formula (1), R⁴Is lower alkanoyloxy-lower alkyl, and u is 0.

(7) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form the group: - (CH)₂)_n- (n is 4), R³Is a group of the formula:(R^11bp and R^11aAs defined in formula (1), R⁴Is a hydrogen atom, and u is 1.

(8) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form the group: - (CH)₂)_n- (n is 4), R³Is a group of the formula:(R^11bp and R^11aAs defined in formula (1), R⁴Is lower alkanoyloxy-lower alkyl and u is 1.

(9) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form the group: - (CH)₂)_n- (n is 5), R³Is a group of the formula:(R^11bp and R^11aAs defined in formula (1), R⁴Is a hydrogen atom, and u is 0.

(10) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form the group: - (CH)₂)_n- (n is 5), R³Is a group of the formula:(R^11bp and R^11aAs defined in formula (1), R⁴Is lower alkanoyloxy-lower alkyl and u is 0.

(11) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form the group: - (CH)₂)_n- (n is 5), R³Is a group of the formula:(R^11bp and R^11aAs defined in formula (1), R⁴Is a hydrogen atom, and u is 1.

(12) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form the group: - (CH)₂)_n- (n is 5), R³Is a group of the formula:(R^11bp and R^11aAs defined in formula (1), R⁴Is lower alkanoyloxy-lower alkyl and u is 1.

(13) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form a benzene ring optionally having a substituent selected from the group consisting of lower alkyl, lower alkoxy, nitro, amino optionally having a lower alkyl substituent, and a halogen atom, R³Is a group of the formula:(R^11bp and R^11aAs defined in formula (1), R⁴Is a hydrogen atom, and u is 0.

(14) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form a benzene ring optionally having a substituent selected from the group consisting of lower alkyl, lower alkoxy, nitro, amino optionally having a lower alkyl substituent, and a halogen atom, R³Is a group of the formula:(R^11bp and R^11aAs defined in formula (1), R⁴Is lower alkanoyloxy-lower alkyl and u is 0.

(15) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form a benzene ring optionally having a substituent selected from the group consisting of lower alkyl, lower alkoxy, nitro, amino optionally having a lower alkyl substituent, and a halogen atom, R ³Is a group of the formula:(R^11bp and R^11aAs defined in formula (1), R⁴Is a hydrogen atom, and u is 1.

(16) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form a benzene ring optionally having a substituent selected from the group consisting of lower alkyl, lower alkoxy, nitro, amino optionally having a lower alkyl substituent, and a halogen atom, R³Is a group of the formula:(R^11bp and R^11aAs defined in formula (1), R⁴Is lower alkanoyloxy-lower alkyl and u is 1.

(17) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Identical or different and are each a hydrogen atom or a lower alkyl group, R³Is a group of the formula:(s is 0, R⁶Is the group: -CO-CH = CR^11b-(CO)_p-R^11a(R^11bP and R^11aAs defined in formula (1), R⁵M, A and Z are as defined in formula (1), R⁴Is a hydrogen atom, and u is 0.

(18) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Identical or different and are each a hydrogen atom or a lower alkyl group, R³Is a group of the formula:(s is 0, R⁶Is the group: -CO-CH = CR^11b-(CO)_p-R^11a(R^11bP and R^11aAs defined in formula (1), R⁵M, A and Z are as defined in formula (1), R⁴Is lower alkanoyloxy-lower alkyl and u is 0.

(19) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Identical or different and are each a hydrogen atom or a lower alkyl group, R ³Is a group of the formula:(s is 0, R⁶Is the group: -CO-CH = CR^11b-(CO)_p-R^11a(R^11bP and R^11aAs defined in formula (1), R⁵M, A and Z are as defined in formula (1), R⁴Is a hydrogen atom, and u is 1.

(20) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Identical or different and are each a hydrogen atom or a lower alkyl group, R³Is a group of the formula:(s is 0, R⁶Is the group: -CO-CH = CR^11b-(CO)_p-R^11a(R^11bP and R^11aAs defined in formula (1), R⁵M, A and Z are as defined in formula (1), R⁴Is lower alkanoyloxy-lower alkyl and u is 1.

(21) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form the group: - (CH)₂)_n- (n is 4), R³Is a group of the formula:(s is 0, R⁶Is the group: -CO-CH = CR^11b-(CO)_p-R^11a(R^11bP and R^11aAs defined in formula (1), R⁵M, A and Z are as defined in formula (1), R⁴Is a hydrogen atom, and u is 0.

(22) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form the group: - (CH)₂)_n- (n is 4), R³Is a group of the formula:(s is 0, R⁶Is the group: -CO-CH = CR^11b-(CO)_p-R^11a(R^11bP and R^11aAs defined in formula (1), R⁵M, A and Z are as defined in formula (1), R⁴Is lower alkanoyloxy-lower alkyl and u is 0.

(23) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form the group: - (CH)₂)_n- (n is 4), R³Is a group of the formula:(s is 0, R ⁶Is the group: -CO-CH = CR^11b-(CO)_p-R^11a(R^11bP and R^11aAs defined in formula (1), R⁵M, A and Z are as defined in formula (1), R⁴Is a hydrogen atom, and u is 1.

(24) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form the group: - (CH)₂)_n- (n is 4), R³Is a group of the formula:(s is 0, R⁶Is the group: -CO-CH = CR^11b-(CO)_p-R^11a(R^11bP and R^11aAs defined in formula (1), R⁵M, A and Z are as defined in formula (1), R⁴Is lower alkanoyloxy-lower alkyl and u is 1.

(25) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form the group: - (CH)₂)_n- (n is 5), R³Is a group of the formula:(s is 0, R⁶Is the group: -CO-CH = CR^11b-(CO)_p-R^11a(R^11bP and R^11aAs defined in formula (1), R⁵M, A and Z are as defined in formula (1), R⁴Is a hydrogen atom, and u is 0.

(26) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form the group: - (CH)₂)_n- (n is 5), R³Is a group of the formula:(s is 0, R⁶Is the group: -CO-CH = CR^11b-(CO)_p-R^11a(R^11bP and R^11aAs defined in formula (1), R⁵M, A and Z are as defined in formula (1), R⁴Is lower alkanoyloxy-lower alkyl and u is 0.

(27) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form the group: - (CH)₂)_n- (n is 5), R³Is a group of the formula:(s is 0, R⁶Is the group: -CO-CH = CR^11b-(CO)_p-R^11a(R^11bP and R^11aAs defined in formula (1), R ⁵M, A and Z are as defined in formula (1), R⁴Is a hydrogen atom, and u is 1.

(28) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form the group: - (CH)₂)_n- (n is 5), R³Is a group of the formula:(s is 0, R⁶Is the group: -CO-CH = CR^11b-(CO)_p-R^11a(R^11bP and R^11aAs defined in formula (1), R⁵M, A and Z are as defined in formula (1), R⁴Is lower alkanoyloxy-lower alkyl and u is 1.

(29) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form a benzene ring optionally having a substituent selected from the group consisting of lower alkyl, lower alkoxy, nitro, amino optionally having a lower alkyl substituent, and a halogen atom, R³Is a group of the formula:(s is 0, R⁶Is the group: -CO-CH = CR^11b-(CO)_p-R^11a(R^11bP and R^11aAs defined in formula (1), R⁵M, A and Z are as defined in formula (1), R⁴Is a hydrogen atom, and u is 0.

(30) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form a benzene ring optionally having a substituent selected from the group consisting of lower alkyl, lower alkoxy, nitro, amino optionally having a lower alkyl substituent, and a halogen atom, R³Is a group of the formula:(s is 0, R⁶Is the group: -CO-CH = CR^11b-(CO)_p-R^11a(R^11bP and R^11aAs defined in formula (1), R⁵M, A and Z are as defined in formula (1), R ⁴Is lower alkanoyloxy-lower alkyl and u is 0.

(31) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form a benzene ring optionally having a substituent selected from the group consisting of lower alkyl, lower alkoxy, nitro, amino optionally having a lower alkyl substituent, and a halogen atom, R³Is a group of the formula:(s is 0, R⁶Is the group: -CO-CH = CR^11b-(CO)_p-R^11a(R^11bP and R^11aAs defined in formula (1), R⁵M, A and Z are as defined in formula (1), R⁴Is a hydrogen atom, and u is 1.

(32) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form a benzene ring optionally having a substituent selected from the group consisting of lower alkyl, lower alkoxy, nitro, amino optionally having a lower alkyl substituent, and a halogen atom, R³Is a group of the formula:(s is 0, R⁶Is the group: -CO-CH = CR^11b-(CO)_p-R^11a(R^11bP and R^11aAs defined in formula (1), R⁵M, A and Z are as defined in formula (1), R⁴Is lower alkanoyloxy-lower alkyl and u is 1.

(33) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Identical or different and are each a hydrogen atom or a lower alkyl group, R³Is a group of the formula:(s is 1, Z is an oxygen atom, R⁶Is the group: -CO-CH = CR^11b-(CO)_p-R^11a(R^11bP and R^11aAs defined in formula (1), R ⁵M and A are as defined for formula (1), R⁴Is a hydrogen atom, and u is 0.

(34) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Identical or different and are each a hydrogen atom or a lower alkyl group, R³Is a group of the formula:(s is 1, Z is an oxygen atom, R⁶Is the group: -CO-CH = CR^11b-(CO)_p-R^11a(R^11bP and R^11aAs defined in formula (1), R⁵M and A are as defined for formula (1), R⁴Is lower alkanoyloxy-lower alkyl and u is 0.

(35) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Identical or different and are each a hydrogen atom or a lower alkyl group, R³Is a group of the formula:(s is 1, Z is an oxygen atom, R⁶Is the group: -CO-CH = CR^11b-(CO)_p-R^11a(R^11bP and R^11aAs defined in formula (1), R⁵M and A are as defined for formula (1), R⁴Is a hydrogen atom, and u is 1.

(36) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Are the same or different and are each a hydrogen atom or a lower alkaneRadical, R³Is a group of the formula:(s is 1, Z is an oxygen atom, R⁶Is the group: -CO-CH = CR^11b-(CO)_p-R^11a(R^11bP and R^11aAs defined in formula (1), R⁵M and A are as defined for formula (1), R⁴Is lower alkanoyloxy-lower alkyl and u is 1.

(37) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form the group: - (CH)₂)_n- (n is 4), R³Is a group of the formula:(s is 1, Z is an oxygen atom, R ⁶Is the group: -CO-CH = CR^11b-(CO)_p-R^11a(R^11bP and R^11aAs defined in formula (1), R⁵M and A are as defined for formula (1), R⁴Is a hydrogen atom, and u is 0.

(38) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form the group: - (CH)₂)_n- (n is 4), R³Is a group of the formula:(s is 1, Z is an oxygen atom, R⁶Is the group: -CO-CH = CR^11b-(CO)_p-R^11a(R^11bP and R^11aAs defined in formula (1), R⁵M and A are as defined for formula (1), R⁴Is lower alkanoyloxy-lower alkyl and u is 0.

(39) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form the group: - (CH)₂)_n- (n is 4), R³Is a group of the formula:(s is 1, Z is an oxygen atom, R⁶Is the group: -CO-CH = CR^11b-(CO)_p-R^11a(R^11bP and R^11aAs defined in formula (1), R⁵M and A are as defined for formula (1), R⁴Is a hydrogen atom, and u is 1.

(40) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form the group: - (CH)₂)_n- (n is 4), R³Is a group of the formula:(s is 1, Z is an oxygen atom, R⁶Is the group: -CO-CH = CR^11b-(CO)_p-R^11a(R^11bP and R^11aAs defined in formula (1), R⁵M and A are as defined for formula (1), R⁴Is lower alkanoyloxy-lower alkyl and u is 1.

(41) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form the group: - (CH)₂)_n- (n is 5), R³Is a group of the formula:(s is 1, Z is an oxygen atom, R⁶Is the group: -CO-CH = CR ^11b-(CO)_p-R^11a(R^11bP and R^11aAs defined in formula (1), R⁵M and A are as defined for formula (1), R⁴Is a hydrogen atom, and u is 0.

(42) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form the group: - (CH)₂)_n- (n is 5), R³Is a group of the formula:(s is 1, Z is an oxygen atom, R⁶Is the group: -CO-CH = CR^11b-(CO)_p-R^11a(R^11bP and R^11aAs defined in formula (1), R⁵M and A are as defined for formula (1), R⁴Is lower alkanoyloxy-lower alkyl and u is 0.

(43) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form the group: - (CH)₂)_n- (n is 5), R³Is a group of the formula:(s is1, Z is an oxygen atom, R⁶Is the group: -CO-CH = CR^11b-(CO)_p-R^11a(R^11bP and R^11aAs defined in formula (1), R⁵M and A are as defined for formula (1), R⁴Is a hydrogen atom, and u is 1.

(44) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form the group: - (CH)₂)_n- (n is 5), R³Is a group of the formula:(s is 1, Z is an oxygen atom, R⁶Is the group: -CO-CH = CR^11b-(CO)_p-R^11a(R^11bP and R^11aAs defined in formula (1), R⁵M and A are as defined for formula (1), R⁴Is lower alkanoyloxy-lower alkyl and u is 1.

(45) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form a benzene ring optionally having a substituent selected from the group consisting of lower alkyl, lower alkoxy, nitro, amino optionally having a lower alkyl substituent, and a halogen atom, R ³Is a group of the formula:(s is 1, Z is an oxygen atom, R⁶Is the group: -CO-CH = CR^11b-(CO)_p-R^11a(R^11bP and R^11aAs defined in formula (1), R⁵M and A are as defined for formula (1), R⁴Is a hydrogen atom, and u is 0.

(46) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form a benzene ring optionally having a substituent selected from the group consisting of lower alkyl, lower alkoxy, nitro, amino optionally having a lower alkyl substituent, and a halogen atom, R³Is a group of the formula:(s is 1, Z is an oxygen atom, R⁶Is the group: -CO-CH = CR^11b-(CO)_p-R^11a(R^11bP and R^11aAs defined in formula (1), R⁵M and A are as defined for formula (1), R⁴Is lower alkanoyloxy-lower alkyl and u is 0.

(47) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form a benzene ring optionally having a substituent selected from the group consisting of lower alkyl, lower alkoxy, nitro, amino optionally having a lower alkyl substituent, and a halogen atom, R³Is a group of the formula:(s is 1, Z is an oxygen atom, R⁶Is the group: -CO-CH = CR^11b-(CO)_p-R^11a(R^11bP and R^11aAs defined in formula (1), R⁵M and A are as defined for formula (1), R⁴Is a hydrogen atom, and u is 1.

(48) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form a benzene ring optionally having a substituent selected from the group consisting of lower alkyl, lower alkoxy, nitro, amino optionally having a lower alkyl substituent, and a halogen atom, R ³Is a group of the formula:(s is 1, Z is an oxygen atom, R⁶Is the group: -CO-CH = CR^11b-(CO)_p-R^11a(R^11bP and R^11aAs defined in formula (1), R⁵M and A are as defined for formula (1), R⁴Is lower alkanoyloxy-lower alkyl and u is 1.

(49) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Identical or different and are each a hydrogen atom or a lower alkyl group, R³Is a group of the formula:(s is 1, Z is a sulfur atom, R⁶Is the group: -CO-CH = CR^11b-(CO)_p-R^11a(R^11bP and R^11aAs defined in formula (1), R⁵M and A are as defined in formula (1),R⁴is a hydrogen atom, and u is 0.

(50) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Identical or different and are each a hydrogen atom or a lower alkyl group, R³Is a group of the formula:(s is 1, Z is a sulfur atom, R⁶Is the group: -CO-CH = CR^11b-(CO)_p-R^11a(R^11bP and R^11aAs defined in formula (1), R⁵M and A are as defined for formula (1), R⁴Is lower alkanoyloxy-lower alkyl and u is 0.

(51) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Identical or different and are each a hydrogen atom or a lower alkyl group, R³Is a group of the formula:(s is 1, Z is a sulfur atom, R⁶Is the group: -CO-CH = CR^11b-(CO)_p-R^11a(R^11bP and R^11aAs defined in formula (1), R⁵M and A are as defined for formula (1), R⁴Is a hydrogen atom, and u is 1.

(52) A thiazole derivative of the formula (1) or a salt thereof, wherein R ¹And R²Identical or different and are each a hydrogen atom or a lower alkyl group, R³Is a group of the formula:(s is 1, Z is a sulfur atom, R⁶Is the group: -CO-CH = CR^11b-(CO)_p-R^11a(R^11bP and R^11aAs defined in formula (1), R⁵M and A are as defined for formula (1), R⁴Is lower alkanoyloxy-lower alkyl and u is 1.

(53) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form the group: - (CH)₂)_n- (n is 4), R³Is a group of the formula:(s is 1, Z is a sulfur atom, R⁶Is the group: -CO-CH = CR^11b-(CO)_p-R^11a(R^11bP and R^11aAs defined in formula (1), R⁵M and A are as defined for formula (1), R⁴Is a hydrogen atom, and u is 0.

(54) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form the group: - (CH)₂)_n- (n is 4), R³Is a group of the formula:(s is 1, Z is a sulfur atom, R⁶Is the group: -CO-CH = CR^11b-(CO)_p-R^11a(R^11bP and R^11aAs defined in formula (1), R⁵M and A are as defined for formula (1), R⁴Is lower alkanoyloxy-lower alkyl and u is 0.

(55) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form the group: - (CH)₂)_n- (n is 4), R³Is a group of the formula:(s is 1, Z is a sulfur atom, R⁶Is the group: -CO-CH = CR^11b-(CO)_p-R^11a(R^11bP and R^11aAs defined in formula (1), R⁵M and A are as defined for formula (1), R⁴Is a hydrogen atom, and u is 1.

(56) A thiazole derivative of the formula (1) or a salt thereof, wherein R ¹And R²Together form the group: - (CH)₂)_n- (n is 4), R³Is a group of the formula:(s is 1, Z is a sulfur atom, R⁶Is the group: -CO-CH = CR^11b-(CO)_p-R^11a(R^11bP and R^11aAs defined in formula (1), R⁵M and A are as defined for formula (1), R⁴Is lower alkanoyloxy-lower alkyl and u is 1.

(57) A thiazole derivative of the formula (1) or a salt thereofIn R¹And R²Together form the group: - (CH)₂)_n- (n is 5), R³Is a group of the formula:(s is 1, Z is a sulfur atom, R⁶Is the group: -CO-CH = CR^11b-(CO)_p-R^11a(R^11bP and R^11aAs defined in formula (1), R⁵M and A are as defined for formula (1), R⁴Is a hydrogen atom, and u is 0.

(58) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form the group: - (CH)₂)_n- (n is 5), R³Is a group of the formula:(s is 1, Z is a sulfur atom, R⁶Is the group: -CO-CH = CR^11b-(CO)_p-R^11a(R^11bP and R^11aAs defined in formula (1), R⁵M and A are as defined for formula (1), R⁴Is lower alkanoyloxy-lower alkyl and u is 0.

(59) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form the group: - (CH)₂)_n- (n is 5), R³Is a group of the formula:(s is 1, Z is a sulfur atom, R⁶Is the group: -CO-CH = CR^11b-(CO)_p-R^11a(R^11bP and R^11aAs defined in formula (1), R⁵M and A are as defined for formula (1), R⁴Is a hydrogen atom, and u is 1.

(60) A thiazole derivative of the formula (1) or a salt thereof, wherein R ¹And R²Together form the group: - (CH)₂)_n- (n is 5), R³Is a group of the formula:(s is 1, Z is a sulfur atom, R⁶Is the group: -CO-CH = CR^11b-(CO)_p-R^11a(R^11bP and R^11aAs in formula (1)Definitions) of R)⁵M and A are as defined for formula (1), R⁴Is lower alkanoyloxy-lower alkyl and u is 1.

(61) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form a benzene ring optionally having a substituent selected from the group consisting of lower alkyl, lower alkoxy, nitro, amino optionally having a lower alkyl substituent, and a halogen atom, R³Is a group of the formula:(s is 1, Z is a sulfur atom, R⁶Is the group: -CO-CH = CR^11b-(CO)_p-R^11a(R^11bP and R^11aAs defined in formula (1), R⁵M and A are as defined for formula (1), R⁴Is a hydrogen atom, and u is 0.

(62) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form a benzene ring optionally having a substituent selected from the group consisting of lower alkyl, lower alkoxy, nitro, amino optionally having a lower alkyl substituent, and a halogen atom, R³Is a group of the formula:(s is 1, Z is a sulfur atom, R⁶Is the group: -CO-CH = CR^11b-(CO)_p-R^11a(R^11bP and R^11aAs defined in formula (1), R⁵M and A are as defined for formula (1), R⁴Is lower alkanoyloxy-lower alkyl and u is 0.

(63) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form a benzene ring optionally having a substituent selected from the group consisting of lower alkyl, lower alkoxy, nitro, amino optionally having a lower alkyl substituent, and a halogen atom, R³Is a group of the formula:(s is 1, Z is a sulfur atom, R⁶Is the group: -CO-CH = CR^11b-(CO)_p-R^11a(R^11bP and R^11aAs defined in formula (1), R⁵M and A are as defined for formula (1), R⁴Is a hydrogen atom, and u is 1.

(64) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form a benzene ring optionally having a substituent selected from the group consisting of lower alkyl, lower alkoxy, nitro, amino optionally having a lower alkyl substituent, and a halogen atom, R³Is a group of the formula:(s is 1, Z is a sulfur atom, R⁶Is the group: -CO-CH = CR^11b-(CO)_p-R^11a(R^11bP and R^11aAs defined in formula (1), R⁵M and A are as defined for formula (1), R⁴Is lower alkanoyloxy-lower alkyl and u is 1.

(65) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Identical or different and are each a hydrogen atom or a lower alkyl group, R³Is a group of the formula:(s is 0, R⁶Is the group: -CO-C ≡ C-COR¹⁴(R¹⁴As defined in formula (1), R⁵Z, m and A are as defined for formula (1), R ⁴Is a hydrogen atom, and u is 0.

(66) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Identical or different and are each a hydrogen atom or a lower alkyl group, R³Is a group of the formula:(s is 0, R⁶Is the group: -CO-C ≡ C-COR¹⁴(R¹⁴As defined in formula (1), R⁵Z, m and A are as defined for formula (1), R⁴Is lower alkanoyloxy-lower alkyl and u is 0.

(67) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Identical or different and are each a hydrogen atom or a lower alkyl group, R³Is a group of the formula:(s is 0, R⁶Is the group: -CO-C ≡ C-COR¹⁴(R¹⁴As defined in formula (1), R⁵Z, m and A are as defined for formula (1), R⁴Is a hydrogen atom, and u is 1.

(68) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Identical or different and are each a hydrogen atom or a lower alkyl group, R³Is a group of the formula:(s is 0, R⁶Is the group: -CO-C ≡ C-COR¹⁴(R¹⁴As defined in formula (1), R⁵Z, m and A are as defined for formula (1), R⁴Is lower alkanoyloxy-lower alkyl and u is 1.

(69) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form the group: - (CH)₂)_n- (n is 4), R³Is a group of the formula:(s is 0, R⁶Is the group: -CO-C ≡ C-COR¹⁴(R¹⁴As defined in formula (1), R⁵Z, m and A are as defined for formula (1), R⁴Is a hydrogen atom, and u is 0.

(70) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form the group: - (CH)₂)_n- (n is 4), R³Is a group of the formula:(s is 0, R⁶Is the group: -CO-C ≡ C-COR¹⁴(R¹⁴As defined in formula (1), R⁵Z, m and A are as defined for formula (1), R⁴Is lower alkanoyloxy-lower alkyl and u is 0.

(71) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form the group: - (CH)₂)_n- (n is 4), R³Is a group of the formula:(s is 0, R⁶Is the group: -CO-C ≡ C-COR¹⁴(R¹⁴As defined in formula (1), R⁵Z, m and A are as defined for formula (1), R⁴Is a hydrogen atom, and u is 1.

(72) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form the group: - (CH)₂)_n- (n is 4), R³Is a group of the formula:(s is 0, R⁶Is the group: -CO-C ≡ C-COR¹⁴(R¹⁴As defined in formula (1), R⁵Z, m and A are as defined for formula (1), R⁴Is lower alkanoyloxy-lower alkyl and u is 1.

(73) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form the group: - (CH)₂)_n- (n is 5), R³Is a group of the formula:(s is 0, R⁶Is the group: -CO-C ≡ C-COR¹⁴(R¹⁴As defined in formula (1), R⁵Z, m and A are as defined for formula (1), R⁴Is a hydrogen atom, and u is 0.

(74) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form the group: - (CH) ₂)_n- (n is 5), R³Is a group of the formula:(s is 0, R⁶Is the group: -CO-C ≡ C-COR¹⁴(R¹⁴As defined in formula (1), R⁵Z, m and A are as defined for formula (1), R⁴Is lower alkanoyloxy-lower alkyl and u is 0.

(75) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form the group: - (CH)₂)_n- (n is 5), R³Is a group of the formula:(s is 0, R⁶Is the group: -CO-C ≡ C-COR¹⁴(R¹⁴As defined in formula (1), R⁵Z, m and A are as defined for formula (1), R⁴Is a hydrogen atom, and u is 1.

(76) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form the group: - (CH)₂)_n- (n is 5), R³Is a group of the formula:(s is 0, R⁶Is the group: -CO-C ≡ C-COR¹⁴(R¹⁴As defined in formula (1), R⁵Z, m and A are as defined for formula (1), R⁴Is lower alkanoyloxy-lower alkyl and u is 1.

(77) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form a benzene ring optionally having a substituent selected from the group consisting of lower alkyl, lower alkoxy, nitro, amino optionally having a lower alkyl substituent, and a halogen atom, R³Is a group of the formula:(s is 0, R⁶Is the group: -CO-C ≡ C-COR¹⁴(R¹⁴As defined in formula (1), R⁵Z, m and A are as defined for formula (1), R⁴Is a hydrogen atom, and u is 0.

(78) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form a benzene ring optionally having a substituent selected from the group consisting of lower alkyl, lower alkoxy, nitro, amino optionally having a lower alkyl substituent, and a halogen atom, R³Is a group of the formula:(s is 0, R⁶Is the group: -CO-C ≡ C-COR¹⁴(R¹⁴As defined in formula (1), R⁵Z, m and A are as defined for formula (1), R⁴Is lower alkanoyloxy-lower alkyl and u is 0.

(79) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form a benzene ring optionally having a substituent selected from the group consisting of lower alkyl, lower alkoxy, nitro, amino optionally having a lower alkyl substituent, and a halogen atom, R³Is a group of the formula:(s is 0, R⁶Is the group: -CO-C ≡ C-COR¹⁴(R¹⁴As defined in formula (1), R⁵Z, m and A are as defined for formula (1), R⁴Is a hydrogen atom, and u is 1.

(80) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form a benzene ring optionally having a substituent selected from the group consisting of lower alkyl, lower alkoxy, nitro, amino optionally having a lower alkyl substituent, and a halogen atom, R³Is a group of the formula: (s is 0, R⁶Is the group: -CO-C ≡ C-COR¹⁴(R¹⁴As defined in formula (1), R⁵Z, m and A are as defined for formula (1), R⁴Is lower alkanoyloxy-lower alkyl and u is 1.

(81) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Identical or different and are each a hydrogen atom or a lower alkyl group, R³Is a group of the formula:(s is 1, Z is an oxygen atom, R⁶Is the group: -CO-C ≡ C-COR¹⁴(R¹⁴As defined in formula (1), R⁵M and A are as defined for formula (1), R⁴Is a hydrogen atom, and u is 0.

(82) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Identical or different and are each a hydrogen atom or a lower alkyl group, R³Is a group of the formula:(s is 1, Z is an oxygen atom, R⁶Is the group: -CO-C ≡ C-COR¹⁴(R¹⁴As shown in formula (1)) In (2) definition), R⁵M and A are as defined for formula (1), R⁴Is lower alkanoyloxy-lower alkyl and u is 0.

(83) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Identical or different and are each a hydrogen atom or a lower alkyl group, R³Is a group of the formula:(s is 1, Z is an oxygen atom, R⁶Is the group: -CO-C ≡ C-COR¹⁴(R¹⁴As defined in formula (1), R⁵M and A are as defined for formula (1), R⁴Is a hydrogen atom, and u is 1.

(84) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Identical or different and are each a hydrogen atom or a lower alkyl group, R ³Is a group of the formula:(s is 1, Z is an oxygen atom, R⁶Is the group: -CO-C ≡ C-COR¹⁴(R¹⁴As defined in formula (1), R⁵M and A are as defined for formula (1), R⁴Is lower alkanoyloxy-lower alkyl and u is 1.

(85) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form the group: - (CH)₂)_n- (n is 4), R³Is a group of the formula:(s is 1, Z is an oxygen atom, R⁶Is the group: -CO-C ≡ C-COR¹⁴(R¹⁴As defined in formula (1), R⁵M and A are as defined for formula (1), R⁴Is a hydrogen atom, and u is 0.

(86) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form the group: - (CH)₂)_n- (n is 4), R³Is a group of the formula:(s is 1, Z is an oxygen atom, R⁶Is the group: -CO-C = C-COR¹⁴(R¹⁴As shown in formula (1)Yi), R⁵M and A are as defined for formula (1), R⁴Is lower alkanoyloxy-lower alkyl and u is 0.

(87) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form the group: - (CH)₂)_n- (n is 4), R³Is a group of the formula:(s is 1, Z is an oxygen atom, R⁶Is the group: -CO-C ≡ C-COR¹⁴(R¹⁴As defined in formula (1), R⁵M and A are as defined for formula (1), R⁴Is a hydrogen atom, and u is 1.

(88) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form the group: - (CH)₂)_n- (n is 4), R³Is a group of the formula:(s is 1, Z is an oxygen atom, R ⁶Is the group: -CO-C ≡ C-COR¹⁴(R¹⁴As defined in formula (1), R⁵M and A are as defined for formula (1), R⁴Is lower alkanoyloxy-lower alkyl and u is 1.

(89) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form the group: - (CH)₂)_n- (n is 5), R³Is a group of the formula:(s is 1, Z is an oxygen atom, R⁶Is the group: -CO-C ≡ C-COR¹⁴(R¹⁴As defined in formula (1), R⁵M and A are as defined for formula (1), R⁴Is a hydrogen atom, and u is 0.

(90) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form the group: - (CH)₂)_n- (n is 5), R³Is a group of the formula:(s is 1, Z is an oxygen atom, R⁶Is the group: -CO-C ≡ C-COR¹⁴(R¹⁴As shown in formula (1)Yi), R⁵M and A are as defined for formula (1), R⁴Is lower alkanoyloxy-lower alkyl and u is 0.

(91) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form the group: - (CH)₂)_n- (n is 5), R³Is a group of the formula:(s is 1, Z is an oxygen atom, R⁶Is the group: -CO-C ≡ C-COR¹⁴(R¹⁴As defined in formula (1), R⁵M and A are as defined for formula (1), R⁴Is a hydrogen atom, and u is 1.

(92) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form the group: - (CH)₂)_n- (n is 5), R³Is a group of the formula:(s is 1, Z is an oxygen atom, R⁶Is the group: -CO-C ≡ C-COR ¹⁴(R¹⁴As defined in formula (1), R⁵M and A are as defined for formula (1), R⁴Is lower alkanoyloxy-lower alkyl and u is 1.

(93) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form a benzene ring optionally having a substituent selected from the group consisting of lower alkyl, lower alkoxy, nitro, amino optionally having a lower alkyl substituent, and a halogen atom, R³Is a group of the formula:(s is 1, Z is an oxygen atom, R⁶Is the group: -CO-C ≡ C-COR¹⁴(R¹⁴As defined in formula (1), R⁵M and A are as defined for formula (1), R⁴Is a hydrogen atom, and u is 0.

(94) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form a phenyl ring optionally bearing substituents selected from lower alkyl, lower alkoxy, nitro, optionally substituted with lower alkylAmino and halogen atoms of radicals, R³Is a group of the formula:(s is 1, Z is an oxygen atom, R⁶Is the group: -CO-C ≡ C-COR¹⁴(R¹⁴As defined in formula (1), R⁵M and A are as defined for formula (1), R⁴Is lower alkanoyloxy-lower alkyl and u is 0.

(95) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form a benzene ring optionally having a substituent selected from the group consisting of lower alkyl, lower alkoxy, nitro, amino optionally having a lower alkyl substituent, and a halogen atom, R ³Is a group of the formula:(s is 1, Z is an oxygen atom, R⁶Is the group: -CO-C ≡ C-COR¹⁴(R¹⁴As defined in formula (1), R⁵M and A are as defined for formula (1), R⁴Is a hydrogen atom, and u is 1.

(96) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form a benzene ring optionally having a substituent selected from the group consisting of lower alkyl, lower alkoxy, nitro, amino optionally having a lower alkyl substituent, and a halogen atom, R³Is a group of the formula:(s is 1, Z is an oxygen atom, R⁶Is the group: -CO-C ≡ C-COR¹⁴(R¹⁴As defined in formula (1), R⁵M and A are as defined for formula (1), R⁴Is lower alkanoyloxy-lower alkyl and u is 1.

(97) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Identical or different and are each a hydrogen atom or a lower alkyl group, R³Is a group of the formula:(s is 1, Z is a sulfur atom, R⁶Is the group: -CO-C ≡ C-COR¹⁴(R¹⁴As in formula (1)Definitions) of R)⁵M and A are as defined for formula (1), R⁴Is a hydrogen atom, and u is 0.

(98) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Identical or different and are each a hydrogen atom or a lower alkyl group, R³Is a group of the formula:(s is 1, Z is a sulfur atom, R⁶Is the group: -CO-C ≡ C-COR¹⁴(R¹⁴As defined in formula (1), R ⁵M and A are as defined for formula (1), R⁴Is lower alkanoyloxy-lower alkyl and u is 0.

(99) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Identical or different and are each a hydrogen atom or a lower alkyl group, R³Is a group of the formula:(s is 1, Z is a sulfur atom, R⁶Is the group: -CO-C ≡ C-COR¹⁴(R¹⁴As defined in formula (1), R⁵M and A are as defined for formula (1), R⁴Is a hydrogen atom, and u is 1.

(100) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Identical or different and are each a hydrogen atom or a lower alkyl group, R³Is a group of the formula:(s is 1, Z is a sulfur atom, R⁶Is the group: -CO-C ≡ C-COR¹⁴(R¹⁴As defined in formula (1), R⁵M and A are as defined for formula (1), R⁴Is lower alkanoyloxy-lower alkyl and u is 1.

(101) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form the group: - (CH)₂)_n- (n is 4), R³Is a group of the formula:(s is 1, Z is a sulfur atom, R⁶Is the group: -CO-C ≡ C-COR¹⁴(R¹⁴As defined in formula (1))，R⁵M and A are as defined for formula (1), R⁴Is a hydrogen atom, and u is 0.

(102) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form the group: - (CH)₂)_n- (n is 4), R³Is a group of the formula:(s is 1, Z is a sulfur atom, R⁶Is the group: -CO-C ≡ C-COR¹⁴(R¹⁴As defined in formula (1), R ⁵M and A are as defined for formula (1), R⁴Is lower alkanoyloxy-lower alkyl and u is 0.

(103) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form the group: - (CH)₂)_n- (n is 4), R³Is a group of the formula:(s is 1, Z is a sulfur atom, R⁶Is the group: -CO-C ≡ C-COR¹⁴(R¹⁴As defined in formula (1), R⁵M and A are as defined for formula (1), R⁴Is a hydrogen atom, and u is 1.

(104) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form the group: - (CH)₂)_n- (n is 4), R³Is a group of the formula:(s is 1, Z is a sulfur atom, R⁶Is the group: -CO-C ≡ C-COR¹⁴(R¹⁴As defined in formula (1), R⁵M and A are as defined for formula (1), R⁴Is lower alkanoyloxy-lower alkyl and u is 1.

(105) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form the group: - (CH)₂)_n- (n is 5), R³Is a group of the formula:(s is 1, Z is a sulfur atom, R⁶Is the group: -CO-C ≡ C-COR¹⁴(R¹⁴As shown in formula (1)Yi), R⁵M and A are as defined for formula (1), R⁴Is a hydrogen atom, and u is 0.

(106) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form the group: - (CH)₂)_n- (n is 5), R³Is a group of the formula:(s is 1, Z is a sulfur atom, R⁶Is the group: -CO-C ≡ C-COR¹⁴(R¹⁴As defined in formula (1), R⁵M and A are as defined for formula (1), R ⁴Is lower alkanoyloxy-lower alkyl and u is 0.

(107) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form the group: - (CH)₂)_n- (n is 5), R³Is a group of the formula:(s is 1, Z is a sulfur atom, R⁶Is the group: -CO-C ≡ C-COR¹⁴(R¹⁴As defined in formula (1), R⁵M and A are as defined for formula (1), R⁴Is a hydrogen atom, and u is 1.

(108) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form the group: - (CH)₂)_n- (n is 5), R³Is a group of the formula:(s is 1, Z is a sulfur atom, R⁶Is the group: -CO-C ≡ C-COR¹⁴(R¹⁴As defined in formula (1), R⁵M and A are as defined for formula (1), R⁴Is lower alkanoyloxy-lower alkyl and u is 1.

(109) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form a benzene ring optionally having a substituent selected from the group consisting of lower alkyl, lower alkoxy, nitro, amino optionally having a lower alkyl substituent, and a halogen atom, R³Is a group of the formula:(s is 1, Z is a sulfur atom, R⁶Is the group: -CO-C ≡ C-COR¹⁴(R¹⁴As defined in formula (1), R⁵M and A are as defined for formula (1), R⁴Is a hydrogen atom, and u is 0.

(110) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form a benzene ring optionally having a substituent selected from the group consisting of lower alkyl, lower alkoxy, nitro, amino optionally having a lower alkyl substituent, and a halogen atom, R ³Is a group of the formula:(s is 1, Z is a sulfur atom, R⁶Is the group: -CO-C ≡ C-COR¹⁴(R¹⁴As defined in formula (1), R⁵M and A are as defined for formula (1), R⁴Is lower alkanoyloxy-lower alkyl and u is 0.

(111) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form a benzene ring optionally having a substituent selected from the group consisting of lower alkyl, lower alkoxy, nitro, amino optionally having a lower alkyl substituent, and a halogen atom, R³Is a group of the formula:(s is 1, Z is a sulfur atom, R⁶Is the group: -CO-C ≡ C-COR¹⁴(R¹⁴As defined in formula (1), R⁵M and A are as defined for formula (1), R⁴Is a hydrogen atom, and u is 1.

(112) A thiazole derivative of the formula (1) or a salt thereof, wherein R¹And R²Together form a benzene ring optionally having a substituent selected from the group consisting of lower alkyl, lower alkoxy, nitro, amino optionally having a lower alkyl substituent, and a halogen atom, R³Is a group of the formula:(s is 1, Z is a sulfur atom, R⁶Is the group: -CO-C ≡ C-COR¹⁴(R¹⁴As defined in formula (1), R⁵M and A are as defined for formula (1), R⁴Is lower alkanoyloxy-lower alkyl and u is 1.

The compound of formula (1) of the present invention can be prepared by various methods, but is preferably prepared by the following method.

Reaction scheme-1

Wherein R is¹、R²、R⁴、R⁵Z, m, s, T, u and A are as defined above, R¹⁵Is the group: -CH = C (R)^11b)(COR¹⁶)(R^11bAs defined above, and R¹⁶Is hydroxy or lower alkoxy) or a group: -C ≡ C-COR¹⁴(R¹⁴As defined above), and X is a halogen atom.

The reaction between the compound (2) and the compound (3) or the compound (4) is called a Friedel-Crafts reaction and is carried out in the presence of a Lewis acid in a suitable solvent. The Lewis acid may be any conventional Lewis acid used in such Friedel-Crafts reactions and is, for example, aluminum chloride, zinc chloride, ferric chloride, stannous chloride, boron tribromide, boron trifluoride, concentrated sulfuric acid, and the like. The solvent may be, for example, carbon disulfide, aromatic hydrocarbons such as nitrobenzene, chlorobenzene, halogenated hydrocarbons such as dichloromethane, dichloroethane, carbon tetrachloride, tetrachloroethane, aliphatic nitro compounds such as nitroethane, nitromethane, or mixtures of these solvents. The compound (3) and the compound (4) are each used in an at least equimolar amount, preferably 1 to 5 moles, relative to 1 mole of the compound (2). The Lewis acid is usually used in an amount of 1 to 6 moles relative to 1 mole of the compound (2). The reaction is generally carried out at 0 to 120 deg.C, preferably 0 to 70 deg.C, for about 0.5 to 24 hours.

Wherein R is¹⁵Is the group: -CH = C (R)^11b)(COR¹⁶) And said compound in which said double bond is in the cis configuration can be isomerized to said compound in which said double bond is in the trans configuration by heating it in dimethylformamide at a temperature of about 50 ℃ to 100 ℃.

Wherein R is¹⁵Is the group: -CH = C (R)^11b)(COR¹⁶) Or a group: -C ≡ C-COR¹⁴And R is¹⁶And R¹⁴Said compound, which is simultaneously lower alkoxy, can be converted into R wherein R is¹⁶And R¹⁴A compound (1a) which is a hydroxyl group.

Reaction scheme-2

Wherein R is¹、R²、R⁴、R⁵、R^11bZ, m, s, T, u and A are as defined above, R¹⁷Is R^11aSaid heterocyclyl, except that it contains at least one-N <, in said heterocyclic nucleus.

SCHEME-2 is a method of conventionally producing an amide bond reaction and is carried out by reacting the thiazole compound (1b) with the amine compound (5). The amide bond-forming reaction can be carried out under the same conditions as the following conventional amide bond-forming reaction,

(a) a mixed acid anhydride method in which the carboxylic acid compound (1b) is reacted with a halogenated alkyl carbonate to produce a mixed acid anhydride and the resultant product is reacted with the amine compound (5);

(b) an active ester method, i.e., a method of converting the carboxylic acid compound (1b) into an active ester such as p-nitrophenyl ester, N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester or the like and reacting the resulting product with the amine compound (5);

(c) Carbodiimide method, i.e., condensing the carboxylic acid compound (1b) with the amine compound (5) in the presence of an activator such as dicyclohexylcarbodiimide, carbonyldiimidazole, etc.;

(d) other methods, that is, a method of converting the carboxylic acid compound (1b) into a carboxylic acid anhydride by treating it with a dehydrating agent such as acetic anhydride and reacting the resulting product with the amine compound (5); a method of reacting the ester of the carboxylic acid compound (1b) with a lower alkanol and the amine compound (5) at high temperature and high pressure; a method of reacting an acid halide compound of the carboxylic acid compound (1b), i.e., a carboxylic acid halide, with the amine compound (5).

The mixed acid anhydride used in the above-mentioned mixed acid anhydride method (a) can be obtained by a well-known Schotten-Baumann reaction, and the reaction product is used directly for the reaction with the amine compound (5) without being separated from the reaction mixture to obtain the desired compound (1) of the present invention. The Schotten-Baumann reaction is usually carried out in the presence of basic compounds. The basic compound may be any conventional compound used in the Schotten-Baumann reaction and includes, for example, organic basic compounds such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, 1, 5-diazabicyclo [4.3.0] nonene-5 (DBN), 1, 8-diazabicyclo [5.4.0] undecene-7 (DBU), 1, 4-diazabicyclo [2.2.2] octane (DABCO), etc., and inorganic basic compounds such as potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, etc. The reaction is typically carried out at a temperature of from about-20 ℃ to about 100 ℃, preferably from-20 ℃ to about 50 ℃ for from about 5 minutes to about 10 hours, preferably from 5 minutes to about 2 hours.

The reaction between the resulting mixed anhydride and the amine compound (5) is generally carried out at a temperature of-20 ℃ to about 150 ℃, preferably-20 ℃ to about 50 ℃, for about 5 minutes to about 35 hours, preferably about 5 minutes to about 30 hours. The mixed anhydride process is generally carried out in a solvent in the presence of a basic compound. The basic compound may be any of the basic compounds used in the Schotten-Baumann reaction described above. The solvent may be any conventional solvent generally used in the mixed acid anhydride method, for example, halogenated hydrocarbons (e.g., chloroform, dichloromethane, dichloroethane, etc.), aromatic hydrocarbons (e.g., benzene, p-chlorobenzene, toluene, xylene, etc.), ethers (e.g., diethyl ether, diisopropyl ether, tetrahydrofuran, dimethoxyethane, etc.), esters (methyl acetate, ethyl acetate, etc.), aprotic solvents (e.g., N-dimethylformamide, dimethyl sulfoxide, acetonitrile, hexamethylphosphoramide, 1-methyl-2-pyrrolidone (NMP), etc.), or a mixture of these solvents. The halogenated alkyl carbonates used in the mixed anhydride method include, for example, methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, isobutyl chloroformate, and the like. In the method, the carboxylic acid compound (1b), the alkyl halocarbonate and the amine compound (5) are generally used in equimolar amounts, but it is preferable that the alkyl halocarbonate and the amine compound (5) are used in an amount of about 1 to 1.5 moles with respect to 1 mole of the carboxylic acid (1 b).

In the above-mentioned other process (d), for the process of reacting the carboxylic acid halide with the amine compound (5), the reaction is usually carried out in a suitable solvent in the presence of a basic compound. The basic compound is any conventional basic compound and includes, for example, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, etc., in addition to the basic compound used in the Schotten-Baumann reaction described above. In addition to the solvent used in the mixed acid anhydride method, the solvent includes, for example, an alcohol (e.g., methanol, ethanol, propanol, butanol, 3-methoxy-1-butanol, 2-ethoxyethanol (ethylcellosolve), 2-methoxyethanol (methylcellosolve), etc.), pyridine, acetone, water, or a mixture of two or more of these solvents, and the like. The amounts of the amine compound (5) and the carboxylic acid halide are not particularly limited, but the amine compound (5) is usually used in an at least equimolar amount, preferably about 1 to 5 moles, relative to 1 mole of the carboxylic acid halide. The reaction is typically carried out at a temperature of from about-70 ℃ to about 180 ℃, preferably from about-50 ℃ to about 150 ℃ for from about 5 minutes to about 30 hours.

Further, the amide bond-forming reaction described in scheme-2 can also be carried out by reacting the carboxylic acid compound (1b) with the amine compound (5) in the presence of a condensing agent such as a phosphorus compound (e.g., phenylphosphine-2, 2 '-dithiopyridine, diphenylphosphine chloride, phenyl-N-phenylphosphamide chloride, diethyl cyanophosphate, diphenylphosphoryl azide, N' -bis (2-oxo-3-oxazolidinyl) phosphonyl chloride, etc.).

The reaction is usually carried out in the presence of the same solvent and the same basic compound as those usable in the reaction of the above carboxylic acid halide and amine compound (5). The reaction is typically carried out at a temperature of from-20 ℃ to about 150 ℃, preferably from 0 ℃ to about 100 ℃, for a period of from about 5 minutes to about 30 hours. The condensing agent and the amine compound (5) are usually used in at least equimolar amounts, preferably about 1 to 2 moles, relative to 1 mole of the carboxylic acid compound (1 b).

Reaction scheme-3Wherein R is¹、R²、R³、R⁴、R⁵、Z、m、s、T、u、R¹⁶And A is as defined above, R¹⁸And R¹⁹Is lower alkoxy, and R²²As defined below.

The reaction between the compound (6) and the compound (7) may be basic in a suitable solvent in the presence of a basic compound. The basic compound includes inorganic basic compounds such as metallic sodium, metallic potassium, sodium hydride, sodium amide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate and the like, organic basic compounds such as alkali metal salts of basic alkanols (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide), alkyllithium, aryllithium or lithium amide (e.g., methyllithium, N-butyllithium, phenyllithium, lithium diisopropylamide), pyridine, piperidine, quinoline, triethylamine, N-dimethylaniline and the like. The solvent may be any solvent that does not interfere with the reaction, for example, water, ethers (e.g., diethyl ether, dioxane, tetrahydrofuran, monoglyme, diglyme, etc.), aromatic hydrocarbons (e.g., benzene, toluene, xylene, etc.), aliphatic hydrocarbons (e.g., N-hexane, heptane, cyclohexane, etc.), amines (e.g., pyridine, N-dimethylaniline, etc.), aprotic solvents (e.g., N-dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, etc.), alcohols (e.g., methanol, ethanol, isopropanol, etc.), ureas (e.g., N' Dimethylpropyleneurea (DMPU), etc.), 1, 3-dimethyl-3, 4,5, 6-tetrahydro-2 (1H) -pyrimidinone, or a mixture of these solvents. The reaction is generally carried out at a temperature of from-80 ℃ to 150 ℃, preferably from about-80 ℃ to about 120 ℃, for a period of from 0.5 to about 15 hours.

The compound (7) is usually used in an at least equimolar amount, preferably 1 to 5 moles, relative to 1 mole of the compound (6).

The reaction for converting said compound (8) into said compound (10) can be carried out in a suitable solvent in the presence of an oxidizing agent. The oxidizing agent includes, for example, benzoquinones (e.g., 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone (DDQ)), pyridinium chromates (e.g., pyridinium chlorochromate, pyridinium dichlorochromate, etc.), dimethyl sulfoxide-oxazolyl chloride, dichromic acid, dichromate salts (sodium dichromate, potassium dichromate, etc.), permanganic acid, permanganates (e.g., potassium permanganate, sodium permanganate, etc.), manganese dioxide, and the like. The solvent includes, for example, water, organic acids (e.g., formic acid, glycolic acid, trifluoroacetic acid, etc.), alcohols (e.g., methanol, ethanol, etc.), halogenated hydrocarbons (e.g., chloroform, dichloromethane, etc.), ethers (e.g., tetrahydrofuran, diethyl ether, dioxane, etc.), dimethyl sulfoxide, dimethylformamide, or a mixture of these solvents. It is preferred to use an excess of the oxidizing agent relative to the starting compound. The above reaction is generally carried out at a temperature of 0 ℃ to 200 ℃, preferably 0 ℃ to about 150 ℃, for 1 hour to about 10 hours.

The reaction between the compound (9) and the compound (7) can be carried out under the same conditions as described for the reaction of the compound (6) and the compound (7).

The reaction between the compound (10) and the compound (12) can be carried out under the same conditions as described in the reaction of the compound (6) and the compound (7).

The reaction between the compound (10) and the compound (20) can be carried out under the same conditions as described in the reaction of the compound (6) and the compound (7).

Reaction scheme-4Wherein R is¹、R²、R⁴、R⁵Z, m, s, T, u and A are as defined above, R²⁰Is lower alkoxy, M is an alkali metal such as lithium,Sodium, potassium, etc., and R^16aIs a lower alkoxy group.

The reaction between the compound (6) and the compound (13) may be carried out in a suitable solvent at-80 ℃ to room temperature in the presence of a basic compound for 5 minutes to 6 hours. The solvent may be, for example, an ether (e.g., diethyl ether, dioxane, tetrahydrofuran, etc.), an aromatic hydrocarbon (e.g., benzene, toluene, etc.), a saturated hydrocarbon (e.g., hexane, heptane, pentane, cyclohexane, etc.), urea (e.g., N' -dimethylethyleneaminopropene urea (DMPU), etc.). The basic compound is the same as that used in the reaction of the compound (6) with the compound (7) described in the above reaction scheme-3. The compound (13) is usually used in an at least equimolar amount, preferably 1 to 5 moles, relative to 1 mole of the compound (6).

The reaction for converting said compound (11) into the compound (1 d') may be carried out in a suitable solvent in the presence of a basic compound. The basic compound may be an organic basic compound such as triethylamine, trimethylamine, diisopropylamine, tri-N-butylamine, ethylamine, pyridine, dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, DBN, DBU, DABCO, etc. The solvent includes, for example, water, an alcohol (e.g., ethanol, methanol, isopropanol, etc.), dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, or a mixture of these solvents. The reaction is usually carried out at room temperature to 150 ℃ and preferably at room temperature to 100 ℃ for about 1 to 5 hours.

The reaction for converting the compound (11) into the compound (1f) can be carried out under the same conditions as the reaction for converting the compound (8) into the compound (10) described in the above reaction scheme-3.

The reaction for converting said compound (1 d') into compound (1e) may be carried out in the presence of an acid or a basic compound in a suitable solvent or in the absence of a solvent. The solvent includes, for example, water, lower alkanol (e.g., ethanol, methanol, isopropanol, etc.), ketone (e.g., acetone, methyl ethyl ketone, etc.), halogenated hydrocarbon (e.g., dichloromethane, chloroform, carbon tetrachloride, etc.), ether (e.g., dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, etc.), fatty acid (e.g., acetic acid, formic acid, etc.), or a mixture of these solvents. The acid includes, for example, inorganic acids (e.g., hydrochloric acid, sulfuric acid, hydrobromic acid, etc.), organic acids (e.g., formic acid, acetic acid, trifluoroacetic acid, aromatic sulfonic acids, etc.). The basic compound includes, for example, alkali metal carbonates (e.g., sodium carbonate, potassium carbonate, etc.), alkali metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, etc.), and the like. The reaction is generally carried out at room temperature to about 200 deg.C, preferably room temperature to 150 deg.C, for about 10 minutes to 25 hours.

The reaction for converting said compound (1f) into compound (1g) can be carried out under the same conditions as the above-mentioned reaction for converting compound (1 d') into compound (1 e).

Reaction scheme-5Wherein R is¹、R²、R⁴、R⁵Z, m, s, T, u and A are as defined above, X¹Is a halogen atom, R²¹Is phenyl, R²²Is a 5-to 10-membered saturated or unsaturated heteromonocyclic, heterobicyclic group (the heterocyclic group optionally has 1 to 3 substituents selected from the group consisting of (i) a lower alkyl group, (ii) a group of the formula: (B)_l-NR¹²R¹³(l is as defined above, B is-CO-A- (A is as defined above), carbonyl or lower alkylene, R¹²And R¹³Which may be the same or different and are each a hydrogen atom, a lower alkyl group or a lower alkyl group substituted by an amino group optionally having a lower alkyl substituent, or together with the adjacent nitrogen atom to which they are attached form a 5-to 12-membered saturated heteromonocyclic, heterobicyclic or heterospirocyclic heterocyclic ring, which may optionally have substituents selected from the group consisting of: lower alkyl, lower alkoxycarbonyl, lower alkyl substituted with lower alkoxy, amino optionally substituted with lower alkyl, and lower alkyl substituted with hydroxy); (iii) a lower alkoxycarbonyl group; (iv) hydroxy-substituted lower alkyl; (v) pyridyl optionally substituted on the pyridyl ring by lower alkyl optionally substituted by halogen; (vi) halo-substituted lower alkyl; (vii) lower stage An alkoxy group; (viii) a cycloalkyl group; (ix) hydroxy; (x) a tetrahydropyranyloxy-substituted lower alkyl group; (xi) a pyrimidinyl group; (xii) lower alkyl substituted by lower alkoxy; (xiii) carboxyl; (xiv) phenyl-lower alkoxy; (xv) phenyl-lower alkyl optionally bearing a lower alkylenedioxy group on the phenyl ring; (xvi) lower alkanoyloxy groups; and (xvii) piperidinyl optionally bearing a lower alkyl substituent on the piperidine ring.

The reaction between the compound (2) and the compound (14) and the reaction between the compound (2) and the compound (15) can be carried out under the same conditions as those in the reaction of the compound (2) with the compound (3) or the compound (4) in the above-mentioned reaction scheme-1.

The halogenation reaction of the compound (16) may be carried out in a suitable solvent in the presence of a halogenating agent. The halogenating agent may be, for example, a halogen molecule (e.g., bromine, chlorine, etc.), an iodide, a chloride, thionyl chloride, a copper compound (e.g., copper (II) bromide, etc.), an N-halosuccinimide (e.g., N-bromosuccinimide, N-chlorosuccinimide, etc.). The solvent may be, for example, a halogenated hydrocarbon (e.g., dichloromethane, dichloroethane, chloroform, carbon tetrachloride, etc.), a fatty acid (e.g., acetic acid, propionic acid, etc.), carbon disulfide, etc. The halogenating agent is usually used in an amount of 1 to 10 mol, preferably 1 to 5 mol, relative to 1 mol of the compound (16). The reaction is generally carried out at 0 ℃ to the boiling point of the solvent used, preferably 0 ℃ to 100 ℃ for about 5 minutes to 20 hours.

The reaction between the compound (17) and the compound (18) may be carried out at room temperature to 150 ℃, preferably room temperature to about 100 ℃ for about 1 hour to 10 hours in a suitable solvent. The solvent may be the same as the solvent used for the reaction of the acid halide and the amine compound (5) in the reaction of the compound (1b) and the compound (5) described in the above reaction scheme-2. Compound (18) is used in an at least equimolar amount, preferably 1 to 1.5 moles, relative to 1 mole of compound (17).

In the above reaction, a compound of formula (21) can be obtained:

wherein R is¹、R²、R⁴、R⁵、Z、m、A、R²¹S, T, u and Z are as defined above, which are treated in a suitable solvent in the presence of a basic compound to give compound (19). The solvent and the basic compound are the same as those used in the reaction of the acid halide in the reaction of the compound (1b) with the compound (5) described in the above reaction scheme-2 with the amine compound (5). The reaction is generally carried out at 0 ℃ to 100 ℃, preferably 0 ℃ to about 70 ℃ for about 1 hour to 5 hours.

The reaction between the compound (19) and the compound (20) can be carried out under the same conditions as those in the reaction of the compound (6) with the compound (7) described in the above reaction scheme-3.

In addition, the reaction of compound (19) with compound (20) is usually carried out at 0 ℃ to 150 ℃, preferably at room temperature to about 100 ℃ in a suitable solvent for about 0.5 hours to 8 hours. The solvent may be any solvent that does not interfere with the reaction, for example, water, alcohols (e.g., methanol, ethanol, isopropanol, etc.), aromatic hydrocarbons (e.g., benzene, toluene, xylene, etc.), ethers (e.g., diethyl ether, tetrahydrofuran, dioxane, diglyme, monoglyme, etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, etc.), aprotic solvents (e.g., N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoramide, etc.), and the like. Compound (20) is usually used in an at least equimolar amount, preferably 1 to 5 moles, relative to 1 mole of compound (19). The reaction is promoted when polyoxymethylene is added to the reaction system.

Reaction scheme-6

Wherein R is¹、R²、R⁴、R⁵、R⁶Z, s, T, u and A are as defined above, q is 1, R^5aIs halogen-substituted lower alkyl, R^5bIs the group: -A-NR⁷R⁸(A、R⁷、R⁸As defined above) or lower alkanoyloxy-lower alkyl, R²³Is the group: -NR⁷R⁸(R⁷And R⁸As defined above) or lower alkanoyloxy.

The reaction between the compound (1f) and the compound (22) may be carried out in a suitable inert solvent or in the absence of a solvent in the presence or absence of a basic compound. The inert solvent includes, for example, an aromatic hydrocarbon (e.g., benzene, toluene, xylene, etc.), an ether (e.g., tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, etc.), a halogenated hydrocarbon (e.g., dichloromethane, chloroform, carbon tetrachloride, etc.), a lower alkanol (e.g., methanol, ethanol, isopropanol, butanol, t-butanol, etc.), water, acetic acid, ethyl acetate, acetone, acetonitrile, pyridine, dimethyl sulfoxide, dimethylformamide, hexamethylphosphoramide, 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 hydrogencarbonate (e.g., sodium hydrogencarbonate, potassium hydrogencarbonate, etc.), an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.), sodium hydride, potassium, sodium amide, an alkanol alkali metal salt (e.g., sodium methoxide, etc.), an organic basic compound (e.g., pyridine, N-ethyldiisopropylamine, dimethylaminopyridine, triethylamine, 1, 5-diazabicyclo [4.3.0] nonene-5 (DBN), 1, 8-diazabicyclo [5.4.0] undecene-7 (DBU), 1, 4-diazabicyclo [2.2.2] octane (DABCO), etc.). The amounts of the compound (1i) and the compound (22) to be used are not particularly limited, but the compound (22) is usually used in an at least equimolar amount, preferably 1 to 10 moles, relative to 1 mole of the compound (1 i). The reaction is generally carried out at 0 ℃ to 200 ℃ for about 30 minutes to 75 hours, preferably from 0 ℃ to 170 ℃. An alkali metal halide such as sodium iodide, potassium iodide or copper powder may be added to the reaction system.

Reaction scheme-7

Wherein R is¹、R²、R³、R⁴T and u are as defined above.

The reaction between the compound (23) and the compound (24) can be carried out under the same conditions as the reaction between the compound (1b) and the compound (5) described in the above reaction scheme-2.

Reaction scheme-8

Wherein R is¹、R²、R³T, X and u are as defined above, and R^4aIs a lower alkanoyloxy-lower alkyl group.

The reaction between the compound (1k) and the compound (25) can be carried out under the same conditions as in the reaction of the compound (1i) with the compound (22) in the above-mentioned reaction scheme-6.

Reaction scheme-9Wherein R is¹、R²、R⁴、R⁵、R⁶、R⁷、R⁸Z, s, T, u and q are as defined above, and R^5cIs lower alkyl substituted by carboxyl, R^5dIs the group: -A-CO-NR⁷R⁸(R⁷And R⁸As defined above).

The reaction between the compound (1m) and the compound (26) can be carried out under the same conditions as the reaction between the compound (1b) and the compound (5) described in the above reaction scheme-2.

The starting compounds (2), (6) and (23) described in the above reaction schemes are prepared as follows.

Reaction scheme-10

Wherein R is¹、R²、R⁴、R⁵X, Z, T, u and m are as defined above, and R²⁴Is hydroxy, lower alkoxy or phenyl-lower alkoxy, and A' is lower alkylene.

The reaction between the compound (27) and the compound (28) can be carried out under the same conditions as in the reaction of the compound (1i) with the compound (22) described in the above reaction scheme-6.

In which R is²⁴The reaction of converting compound (29), which is a lower alkoxy group, into compound (30) can be carried out under the same conditions as the reaction of converting compound (1d) into compound (1e) described in scheme-4 above.

In which R is²⁴The reaction of compound (29), which is phenyl-lower alkoxy, into compound (30) can be carried out under the same conditions as the reaction of compound (5b) into compound (5c) described in scheme-13 described below.

The reaction between the compound (30) and the compound (24) can be carried out under the same conditions as the reaction between the compound (1b) and the compound (5) described in the above reaction scheme-2.

Reaction scheme-11

Wherein R is¹、R²、R⁴、R⁵、A′、Z、R²⁴T, u and m are as defined above.

The reaction between the compound (31) and the compound (28) can be carried out under the same conditions as those in the reaction of the compound (27) with the compound (28) in the above-mentioned reaction scheme-10.

In which R is²⁴The reaction of converting compound (32) which is lower alkoxy into compound (33) can be carried out as described in the above-mentioned scheme-10²⁴The reaction of converting compound (29), which is a lower alkoxy group, into compound (30) is carried out under the same conditions.

In which R is²⁴The reaction of compound (32) which is phenyl-lower alkoxy to compound (33) can be carried out under the same conditions as the reaction of compound (5b) to compound (5c) described in the following reaction scheme-13.

The reaction between the compound (33) and the compound (24) can be carried out under the same conditions as those in the reaction of the compound (30) with the compound (24) in the above-mentioned reaction scheme-10.

Reaction scheme-12

Wherein R is⁵、R⁶M, A', X, Z and R²⁴As defined above.

The reaction between the compound (34) and the compound (28) can be carried out under the same conditions as those in the reaction of the compound (27) with the compound (28) in the above-mentioned reaction scheme-10.

In which R is²⁴The reaction of compound (35) which is lower alkoxy to compound (23a) can be carried out as described in the above-mentioned scheme-10²⁴The reaction of converting compound (29), which is a lower alkoxy group, into compound (30) is carried out under the same conditions.

In which R is²⁴The reaction of compound (35) which is phenyl-lower alkoxy to compound (23a) can be carried out under the same conditions as the reaction of compound (5b) to compound (5c) described in the following reaction scheme-13.

The starting compound (5) was prepared as follows.

Reaction scheme-13

Wherein R is¹²、R¹³As defined above, R^17aAnd R with said heterocyclic ring carrying at least one oxo group¹⁷Same as R^17bAnd said heterocycle carries at least one group: -N-R¹²R¹³(R¹²And R¹³As defined above) of R¹⁷Same, and R²⁵Is phenyl-lower alkyl.

The reaction between the compound (5a) and the compound (36) may be carried out in the presence of a reducing agent in a suitable solvent or in the absence of a solvent. The solvent may be, for example, water, alcohols (e.g., methanol, ethanol, isopropanol, etc.), acetonitrile, formic acid, acetic acid, ethers (e.g., dioxane, diethyl ether, diglyme, tetrahydrofuran, etc.), aromatic hydrocarbons (e.g., benzene, toluene, xylene, etc.), or a mixture of these solvents. The reducing agent may be, for example, formic acid, alkali metal fatty acid salts (e.g., sodium formate, etc.), hydrogenation agents (e.g., sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, etc.), catalysts (e.g., palladium black, palladium-carbon, palladium oxide, platinum black, raney nickel, etc.).

When formic acid is used as the reducing agent, the reaction is generally carried out at room temperature to about 200 ℃, preferably 50 to 150 ℃ for 1 to about 10 hours. Formic acid is used in excess with respect to the compound (5 a).

When a hydrogenation agent is used as the reducing agent, the reaction is generally carried out at-30 ℃ to about 100 ℃, preferably 0 ℃ to 70 ℃ for 30 minutes to about 12 hours. The hydrogenation reagent is used in an amount of 1 to 20 moles, preferably 1 to 6 moles, relative to the compound (5 a). In particular, when lithium aluminum hydride is used as the hydrogenation reagent, the solvent may be an ether (e.g., diethyl ether, dioxane, tetrahydrofuran, diglyme, etc.) or an aromatic hydrocarbon (e.g., benzene, toluene, xylene, etc.).

When a catalyst is used as the reducing agent, the reaction is generally carried out at a temperature of-30 ℃ to about 100 ℃, preferably 0 ℃ to 60 ℃, under a hydrogen pressure of normal pressure to 20atm, preferably normal pressure to 10atm, in the presence of a hydrogen donor such as formic acid, ammonium formate, cyclohexene, hydrazine hydrate or the like for about 1 to 12 hours. The catalyst is used in an amount of 0.1 to 40% by weight, preferably 0.1 to 20% by weight, based on the compound (5 a).

The compound (36) is usually used in an at least equimolar amount, preferably 1 to 3 moles, relative to the compound (5 a).

The reaction for converting compound (5b) into compound (5c) can be carried out by hydrogenation in a suitable solvent in the presence of a catalyst. The solvent may be, for example, water, acetic acid, alcohols (e.g., methanol, ethanol, isopropanol, etc.), hydrocarbons (e.g., hexane, cyclohexane, etc.), ethers (e.g., dioxane, tetrahydrofuran, diethyl ether, etc.), aprotic solvents (e.g., dimethylformamide, etc.), or mixtures of these solvents. The catalyst may be, for example, palladium black, palladium hydroxide-carbon, palladium-carbon, platinum oxide, copper cromite, raney nickel, and the like. The catalyst is generally used in an amount of 0.02 to 1 times that of the compound (5 b). The reaction is generally carried out at a temperature of from-20 ℃ to about 100 ℃, preferably from 0 ℃ to about 70 ℃, under a hydrogen pressure of from 1 to 10atm for from about 0.5 to about 20 hours.

Reaction scheme-14

Wherein R is¹²、R¹³And R²⁵As defined above, R^17cWith R in addition to the heterocyclic ring carrying at least one carboxyl group¹⁷Same as R^17dExcept that the heterocyclic ring carries at least one group: -CONR¹²R¹³(R¹²And R¹³As defined above) with R¹⁷Same, and R^17eExcept that the heterocyclic ring carries at least one group: -CH2NR¹²R¹³(R¹²And R¹³As defined above) with R¹⁷The same is true.

The reaction between the compound (5d) and the compound (36) can be carried out under the same conditions as the reaction between the compound (1b) and the compound (5) described in the above reaction scheme-2.

The reaction for converting compound (5e) into compound (5f) and the reaction for converting compound (5g) into compound (5h) can be carried out under the same conditions as the reaction for converting compound (5b) into compound (5c) described in scheme-13 above.

The reaction for converting compound (5e) into compound (5g) can be carried out by a reduction reaction using a hydrogenation reagent. The hydrogenation reagent may be, for example, lithium aluminum hydride, sodium borohydride, diborane, etc., and is used in at least an equimolar amount, preferably 1 to 15 moles, with respect to 1 mole of the starting compound. The reduction reaction may be carried out in a suitable solvent such as water, a lower alkanol (e.g., methanol, ethanol, isopropanol, etc.), an ether (e.g., tetrahydrofuran, diethyl ether, diisopropyl ether, diglyme, etc.), or a mixture of these solvents. The reaction is generally carried out at a temperature of-60 ℃ up to 150 ℃, preferably-30 ℃ to 100 ℃ for about 10 minutes to 5 hours. When lithium aluminum hydride or diborane is used as the hydrogenating agent, it is preferable to use anhydrous solvents such as tetrahydrofuran, diethyl ether, diisopropyl ether, diglyme and the like.

Reaction scheme-15

Wherein R is¹²、R¹³And R²⁵As defined above, R^17fWith the exception of lower alkyl bearing at least one halogen substitution on the heterocyclic ring¹⁷Same, and R^17gExcept that the heterocyclic ring carries at least one group: -B' -NR¹²R¹³(B' is lower alkylene, R¹²、R¹³As defined above) with R¹⁷The same is true.

The reaction between said compound (5i) and compound (36) can be carried out under the same conditions as in the reaction of said compound (1i) with compound (22) in the above-mentioned reaction scheme-6.

The reaction for converting compound (5j) into compound (5k) can be carried out under the same conditions as the reaction for converting compound (5b) into compound (5c) described in scheme-13 above.

A compound of formula (1) wherein R⁶Is a group of the formula:wherein R is^11b: p and R^11aAs defined above, and the double bond in the above formula is in the trans configuration, compounds in which the corresponding double bond is cis can be hetero-constituted by contact with light in a suitable solvent. The solvent may be the same as that used in the reaction of the acid halide with the amine compound (5) described in the above scheme-2. The reaction may be carried out at 0 ℃ to 70 ℃, preferably 0 ℃ to room temperature, for about 1 to 10 hours.

Among the starting compounds (32) used in scheme-11, certain compounds (32) can be prepared as described below.

Reaction scheme-16

Wherein R is⁵M, A', M and R²⁴As defined above, and R²⁶And R²⁷May be the same or different and are each lower alkyl.

The reaction for converting compound (37) into compound (38) can be carried out in a suitable solvent in the presence of a basic compound. The solvent may be, for example, water, lower alkanols (e.g., methanol, ethanol, isopropanol, etc.), ketones (e.g., acetone, methyl ethyl ketone, etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, etc.), ethers (e.g., dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, etc.), or mixtures of these solvents. The basic compound may be, for example, an alkali metal carbonate (e.g., sodium carbonate, potassium carbonate, etc.) or an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, etc.), and the like. The reaction is generally carried out at a temperature of from room temperature to about 200 deg.C, preferably from room temperature to about 150 deg.C, for a period of from about 10 minutes to about 25 hours.

The reaction between the compound (38) and the compound (28) can be carried out under the same conditions as those in the reaction of the compound (27) with the compound (28) described in the above reaction scheme-10.

The reactions of each step in the above reaction scheme-16 can be carried out without isolating the compound (38) from the reaction system by a one-pot method.

Reaction scheme-17

Wherein R is¹、R²、R⁴、R⁵、R⁶S, T, u, q, Z and A are as defined above, R^5eIs lower alkenyloxy, and R^5fIs a hydroxyl group.

The reaction for converting compound (1o) into compound (1p) can be carried out in a suitable solvent in the presence of a catalyst and an acid. The solvent may be, for example, water, glycolic acid, alcohols (e.g., methanol, ethanol, isopropanol, etc.), hydrocarbons (e.g., hexane, cyclohexane, etc.), ethers (e.g., dioxane, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, etc.), esters (e.g., ethyl acetate, methyl acetate, etc.), aprotic solvents (e.g., dimethylformamide, etc.), or mixtures of these solvents. The catalyst may be, for example, palladium black, palladium hydroxide-carbon, palladium-carbon, platinum oxide, coppercromite, raney nickel, and the like. The acid includes, for example, an organic acid such as p-toluenesulfonic acid and the like. The amount of catalyst used is 0.02 to 1 times that of compound (1 o). The amount of acid used is a catalytic amount. The reaction is typically carried out at a temperature of from-20 ℃ to about 150 ℃, preferably from 0 ℃ to about 120 ℃, for a period of from about 0.5 to about 20 hours.

Reaction scheme-18Wherein T, u, R¹、R²、R⁴、A′、Z、R⁵、m、R²¹、R²⁴And X is as defined above.

The reaction between the compound (39) and the compound (28) can be carried out under the same conditions as those in the reaction of the compound (1i) with the compound (22) described in the above reaction scheme-6.

The reaction for converting the compound (40) into the compound (41) can be carried out under the same conditions as the reaction for converting the compound (16) into the compound (17) described in the above reaction scheme-5.

The reaction between said compound (41) and said compound (18) can be carried out under the same conditions as those in the reaction of said compound (17) with said compound (18) in the above-mentioned reaction scheme-5.

In which R is²⁴The reaction of converting compound (42), which is a lower alkoxy group, into compound (43) can be carried out under the same conditions as the reaction of converting compound (1d) into compound (1e) described in scheme-4 above.

In which R is²⁴The reaction of compound (42) which is phenyl-lower alkoxy to compound (43) can be carried out under the same conditions as the reaction of compound (5b) to compound (5c) described in the above scheme-13.

The reaction between the compound (43) and the compound (24) can be carried out under the same conditions as those in the reaction of the compound (1b) with the compound (5) in the above-mentioned reaction scheme-2.

The reaction between said compound (19a) and compound (44) can be carried out in a suitable solvent in the presence of a basic compound at 0 ℃ to 150 ℃, preferably room temperature to about 100 ℃ for about 0.5 to 8 hours. The solvent may be any solvent that does not interfere with the reaction, and may be water, an alcohol (e.g., methanol, ethanol, isopropanol, etc.), an aromatic hydrocarbon (e.g., benzene, toluene, xylene, etc.), an ether (e.g., diethyl ether, tetrahydrofuran, dioxane, diglyme, monoglyme, etc.), a halogenated hydrocarbon (e.g., dichloromethane, chloroform, carbon tetrachloride, etc.), an aprotic solvent (e.g., dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, etc.), or a mixture of these solvents. The compound (44) is usually used in an at least equimolar amount, preferably 1 to 5 moles, relative to 1 mole of the compound (19 a). The basic compound may be the same as that used in the reaction of the compound (6) with the compound (7) described in the above reaction scheme-3. The starting compound (9) can be prepared, for example, by the method described in scheme-19 or 20 described below.

Reaction scheme-19

Wherein T, u, R¹、R²、R⁴、A′、Z、R⁵、m、R²⁴And R¹⁹As defined above.

The reaction between the compound (45) and the compound (28) can be carried out under the same conditions as in the reaction of the compound (1i) with the compound (22) described in the above reaction scheme-6.

In which R is²⁴The reaction of converting compound (46), which is a lower alkoxy group, into compound (47) can be carried out under the same conditions as the reaction of converting compound (1d) into compound (1e) described in scheme-4 above.

In which R is²⁴The reaction of converting compound (46), which is phenyl-lower alkoxy, into compound (47) can be carried out under the same conditions as the reaction of converting compound (5b) into compound (5c) described in scheme-13 above.

The reaction between the compound (47) and the compound (24) can be carried out under the same conditions as those in the reaction of the compound (1b) with the compound (5) described in the above reaction scheme-2.

Reaction scheme-20

Wherein R is¹⁹、R⁵And m is as defined above, R^19aIs a lower alkoxy group.

The reaction between the compound (48) and the compound (49) may be carried out in a suitable solvent in the presence of a basic compound. The solvent and the basic compound are the same as those used in the reaction of the compound (6) with the compound (7) in the above reaction scheme-3. The compound (49) is usually used in an at least equimolar amount, preferably 1 to 3 moles, relative to 1 mole of the compound (48). The reaction is generally carried out at room temperature to 200 deg.C, preferably room temperature to about 150 deg.C, for about 1 to about 60 hours.

The reaction for converting compound (50) into compound (9b) can be carried out under the same conditions as the reaction for converting compound (5b) into compound (5c) described in scheme-13 above.

The reaction between the compound (51) and the compound (52) can be carried out in a suitable solvent in the presence of a basic compound and a catalyst. The solvent includes, for example, ethers (e.g., diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme, etc.), aromatic hydrocarbons (e.g., benzene, toluene, xylene, etc.), aliphatic hydrocarbons (e.g., n-hexane, heptane, cyclohexane, etc.), dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, or a mixture of these solvents. The basic compound may be the same as that used in the reaction of the compound (1b) with the compound (5) with an acid halide as described in the above reaction scheme-2. The catalyst includes, for example, palladium chloride, tetrakis (triphenylphosphine) palladium, palladium acetate, 1, 3-bis (diphenylphosphino) propane, or a mixture of these solvents. The reaction is generally carried out at 0 ℃ to 200 ℃, preferably room temperature to about 150 ℃ for about 1 to about 20 hours. The compound (52) is usually used in an at least equimolar amount, preferably 1 to 10 moles, relative to the compound (51). The basic compound is usually used in an at least equimolar amount, preferably 1 to 3 moles, relative to 1 mole of the compound (51). The amount of the catalyst used at least exceeds the amount of the compound (51).

The reaction for converting the compound (53) into the compound (50) can be carried out under the same conditions as the reaction for converting the compound (1d) into the compound (1e) described in the above reaction scheme-4.

Reaction scheme-21

Wherein T, u, R⁵、q、R¹⁸、R¹、R²、R⁴A, Z, s and W are as defined above, R^5qIs amino optionally substituted with lower alkyl, and the group: -C (O) CH₂-P(O)(R¹⁸)₂And the group: -R^5qIn ortho-position to each other.

The reaction between the compound (10a) and the compound (44) can be carried out under the same conditions as in the reaction of the compound (10) with the compound (12) in the above-mentioned reaction scheme-3.

After completion of the reaction, compound (1r) can be obtained by treatment with a hydrohalic acid such as hydrochloric acid, hydrobromic acid, or the like, wherein W is a group of the formula:

wherein R is^29bAnd X^-As defined above.

Reaction scheme-22

Wherein R is¹、R²、T、u、R⁴、R¹⁶、R¹⁸And R²²As defined above.

The reaction between the compound (54) and the compound (12) can be carried out under the same conditions as those in the reaction of the compound (10) with the compound (12) described in the above reaction scheme-3.

In which R is¹⁶The reaction of converting compound (1s) which is a lower alkoxy group into compound (1t) can be carried out under the same conditions as the reaction of converting compound (1d) into compound (1e) described in the above scheme-4.

The reaction between the compound (54) and the compound (20) can be carried out under the same conditions as those in the reaction of the compound (10) with the compound (20) described in the above reaction scheme-3.

The starting compound (54) can be prepared, for example, by the following method.

Reaction scheme-23

Wherein R is¹、R²、M、R¹⁹And R¹⁸As defined above.

The halogenation reaction of the compound (58) can be carried out under the conventional halogenation reaction conditions used in the halogenation reaction of carboxylic acids. The reaction between the carboxylic acid halide compound of the compound (58) and the compound (55) may be carried out in a suitable solvent in the presence or absence of a basic compound. The solvent includes, for example, halogenated hydrocarbons (e.g., dichloromethane, chloroform, etc.), aromatic hydrocarbons (e.g., benzene, toluene, xylene, etc.), ethers (e.g., diethyl ether, tetrahydrofuran, dimethoxyethane, etc.), esters (e.g., methyl acetate, ethyl acetate, etc.), aprotic solvents (e.g., N-dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, etc.), alcohols (e.g., methanol, ethanol, propanol, butanol, 3-methoxy-1-butanol, 2-ethoxyethanol, 2-methoxyethanol, etc.), pyridine, acetone, acetonitrile, water, or a mixture of these solvents. The basic compound includes, for example, an organic basic compound such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, DBN, DBU, DABCO and the like, or an inorganic basic compound such as potassium carbonate, sodium carbonate, potassium hydride, sodium hydride, potassium hydroxide, sodium hydroxide, silver carbonate, sodium methoxide, sodium ethoxide and the like. The compound (55) is used in an at least equimolar amount, preferably 1 to 3 moles, relative to 1 mole of the carboxylic acid halide compound of the compound (58). The reaction is typically carried out at-30 ℃ to about 180 ℃, preferably 0 ℃ to about 150 ℃ for about 5 minutes to about 30 hours.

The reaction between compound (58a) and compound (56) can be carried out at 0 ℃ to about 200 ℃, preferably at room temperature to about 150 ℃ in a suitable solvent or in the absence of a solvent. The solvent may be the same as the solvent used in the above-mentioned reaction of the acid halide of compound (58) with compound (55). The compound (56) is used in an at least equimolar amount, preferably 1 to 1.5 moles, relative to 1 mole of the compound (58 a). The reaction is carried out for about 1 hour to about 5 hours.

The reaction between the compound (58b) and the compound (7) can be carried out under the same conditions as those in the reaction of the compound (9) with the compound (7) described in the above reaction scheme-3.

Reaction scheme-24

Wherein R is¹、R²、R⁴、R^11bT, u and R¹⁷As defined above.

The reaction between the compound (1u) and the compound (5) can be carried out under the same conditions as the reaction between the compound (1b) and the compound (5) described in the above reaction scheme-2. The starting compound (24) can be prepared, for example, by the method of scheme-25 described below.

Reaction scheme-25

Wherein R is¹、R²M, X and T are as defined above, and R³⁰Is a lower alkylsulfonyl group.

The reaction between the compound (59) and the compound (60) can be carried out under the same conditions as those in the reaction of the compound (1i) with the compound (22) described in the above reaction scheme-6. The reaction between the compound (61) and the compound (62) can be carried out under the same conditions as in the reaction of the compound (1i) with the compound (22) described in the above reaction scheme-6.

The reaction for converting said compound (63) into compound (24a) can be carried out by treating compound (63) with hydrazine in a suitable solvent or hydrolyzing compound (63). The solvent used in the reaction with hydrazine may be the same as the solvent used in the reaction using a carboxylic acid halide in the reaction of the compound (1b) and the compound (5) described in scheme-2, except for water. The reaction is typically carried out at room temperature to about 120 deg.C, preferably 0 deg.C to about 100 deg.C, for about 0.5 hours to about 5 hours. The hydrazine is usually used in an at least equimolar amount, preferably 1 to 6 moles, relative to 1 mole of the compound (63).

The hydrolysis reaction may be carried out in the presence of an acid or a basic compound in a suitable solvent or in the absence of a solvent. The solvent includes, for example, water, lower alkanol (e.g., methanol, ethanol, isopropanol, etc.), ketone (e.g., acetone, methyl ethyl ketone, etc.), ether (e.g., diethyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, etc.), fatty acid (e.g., acetic acid, formic acid, etc.), or a mixture of these solvents. The acid includes, for example, inorganic acids (e.g., hydrochloric acid, hydrobromic acid, etc.), organic acids (e.g., formic acid, acetic acid, aromatic sulfonic acids, etc.). The basic compound includes, for example, alkali metal carbonates (e.g., sodium carbonate, potassium carbonate, etc.), alkali metal or alkaline earth metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, calcium hydroxide, etc.). The reaction is generally carried out at room temperature to about 200 deg.C, preferably room temperature to about 150 deg.C, for about 10 minutes to about 25 hours.

Among the desired compounds (1) of the present invention, a compound having an acidic group can be easily converted into a salt by treating with a pharmaceutically acceptable basic compound. The basic compound includes, for example, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide and the like, alkali metal carbonates such as sodium carbonate and the like, alkali metal bicarbonates such as potassium bicarbonate, alkali metal alkoxides such as sodium methoxide, potassium ethoxide and the like.

In addition, in the desired compound (1) of the present invention, a compound having a basic group can be easily converted into an acid addition salt thereof by treatment with a pharmaceutically acceptable acid. The acid includes, for example, inorganic acids (e.g., sulfuric acid, nitric acid, hydrochloric acid, hydrobromic acid, etc.) and organic acids (e.g., acetic acid, p-toluenesulfonic acid, ethanesulfonic acid, oxalic acid, maleic acid, fumaric acid, citric acid, succinic acid, benzoic acid, etc.). These salts as well as the compound (1) in a free state can also be used as an active ingredient in the pharmaceutical composition of the present invention. In addition, the compounds of the present invention also include stereoisomers and optical isomers, and these isomers can also be used as active ingredients.

The desired compound obtained in the above-mentioned reaction scheme can be easily isolated and purified from the reaction system by a conventional isolation method. Examples of the separation method include distillation, recrystallization, column chromatography, ion exchange chromatography, silica gel chromatography, affinity chromatography, preparative thin layer chromatography, solvent extraction, dilution, and the like.

The compound (1) of the present invention is useful as a protein kinase inhibitor and can be used in the form of a conventional pharmaceutical preparation. The formulations may be prepared with conventional diluents or carriers such as fillers, thickeners, binders, wetting agents, disintegrants, surfactants, lubricants and the like. The pharmaceutical preparation may be selected from various forms according to the use, and the dosage forms are tablets, pills, powders, solutions, suspensions, emulsifiers, granules, capsules, suppositories, injections (solutions, suspensions, etc.) and the like. For the preparation of tablets, carriers such as excipients (e.g., lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc.), binders (e.g., water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone, etc.), disintegrants (e.g., dry starch, sodium alginate, agar powder, laminarin powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, glyceryl monostearate, starch, lactose, etc.), disintegration inhibitors (e.g., white sugar, stearin, cacao butter, hydrogenated oil, etc.), absorption promoters (e.g., quaternary ammonium base, sodium lauryl sulfate, etc.), wetting agents (e.g., glycerin, starch, etc.), adsorbents (e.g., starch, calcium carbonate, etc.), adsorption agents (e.g., lactose, kaolin, bentonite, colloidal silica, etc.), lubricants (e.g., pure talc, stearates, boric acid powder, polyethylene glycol, etc.), and the like. In addition, the tablets may also be in the form of conventional coated tablets, such as sucrose-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets or two-or multi-layered tablets. In preparing pills, the carrier may be a conventional carrier, and includes, for example, excipients (e.g., glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin, talc, etc.), binders (e.g., acacia powder, tragacanth powder, gelatin, ethanol, etc.), disintegrating agents (e.g., laminarin, agar, etc.), and the like. In preparing suppositories, the carrier may be a conventional one and includes, for example, polyethylene glycol, cacao butter, higher alkanol ester, gelatin, semisynthetic glyceride and the like. Such capsules can be prepared by mixing the active compound with conventional carriers and filling the mixture into hard or soft gelatin capsules. In preparing injections, the solutions and suspensions should be sterile and preferably made isotonic with body fluids. In the preparation of solutions, emulsions and suspensions, the customary diluents used are, for example, water, ethanol, microgels (microgels), propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, etc. In this case, the pharmaceutical preparation may also be mixed with sodium chloride, glucose or glycerol in an amount sufficient to be made into an isotonic form, and may also be mixed with conventional solubilizers, buffers, anesthetics. In addition, the pharmaceutical preparation may be optionally mixed with a coloring agent, a preservative, an aromatic agent, a flavoring agent, a sweetening agent, and other drugs, if necessary.

The amount of the compound (1) or a salt thereof as required in the present invention incorporated into the pharmaceutical preparation is not particularly specified but may be selected from a wide range, and generally, it is preferably in the range of about 1 to 70% by weight, preferably about 5 to 50% by weight.

The pharmaceutical preparation of the present invention can be administered by any method, and the appropriate method of administration can be determined according to the dosage form, the age, sex and other conditions of the patient, the severity of the disease, and the like. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules can be administered orally. The injection can be administered alone or together with conventional auxiliary liquids (e.g., glucose, amino acid solutions) intravenously, and if necessary, can also be administered alone intramuscularly, intracutaneously, intradermally, or intraperitoneally, as desired. Suppositories are administered rectally.

The dosage of the pharmaceutical preparation of the present invention may be selected depending on the use, age, sex and other conditions of the patient, severity of the disease, etc., but it is usually in the range of about 0.6 to 50mg of the compound (1) or a salt thereof per kg body weight of the patient per day. The active compound is present in an amount of about 10 to about 1000mg per unit dosage form.

Best mode for carrying out the invention

The present invention can be more specifically illustrated by the following preparations of the pharmaceutical composition, reference examples of the preparation methods of the starting compounds for preparing the desired compounds of the present invention and examples of the preparation methods of the desired compounds, and activity tests of the desired compounds of the present invention.

Preparation 1

Film coated tablets were prepared from the following ingredients.

Component amounts 2- [ 2-methoxy-4- {3- [4- (4-methyl-1-piperazinyl) -1-piperidinylcarbonyl) acryloyl } phenoxymethylcarbonylamino ] benzothiazole 150g Avicel (trade name of microcrystalline cellulose manufactured by Asahi Chemical Industry, Co.Ltd.) 40g corn starch 30g magnesium stearate 2g hydroxypropylmethylcellulose 10g polyethylene glycol-60003 g castor oil 40g ethanol 40g

The active compound according to the invention, Avicel, corn starch and magnesium stearate are mixed and kneaded. The mixture is formed into tablets using a conventional pounder (R10 mm) suitable for sucrose coating, and the resulting tablets are coated with a film coating agent consisting of hydroxypropylmethylcellulose, polyethylene glycol-6000, castor oil and ethanol to obtain film-coated tablets.

Preparation 2

Tablets were prepared from the following ingredients.

Component weight 2- [ 3-methoxy-4- {3- [4- (3, 4-dimethyl-1-piperazinyl) -1-piperidinylcarbonyl) acryloylphenoxymethylcarbonylamino ] benzothiazole 150g citric acid 1.0g lactose 33.5g calcium dihydrogen phosphate 70.0g Pullonic F-6830.0 g sodium dodecyl sulfate 15.0g polyvinylpyrrolidone 15.0g polyethylene glycol (Carbowax 1500) 4.5g polyethylene glycol (Carbowax 6000) 45.0g corn starch 30.0g sodium stearate anhydrous 3.0g magnesium stearate 3.0g ethanol appropriate amount

The active compound of the present invention, citric acid, lactose, monocalcium phosphate, Pullonic-68, and sodium lauryl sulfate are mixed.

The mixture was sieved through a No.60 sieve and granulated with an alcoholic solution containing polyvinylpyrrolidone, Carbowax1500 and 6000. If desired, an alcohol may be added thereto to make the powdery mixture into a paste. To the mixture was added corn starch and the mixture was then mixed to form a homogeneous granulate. The resulting granules were sieved through a No.10 sieve and collected in trays, and then dried in an oven at 100 ℃ for 12-14 hours. The dried granules were sieved through a No.6 sieve and anhydrous sodium lauryl sulfate and anhydrous magnesium stearate were added thereto, and the mixture was compressed into tablets of a desired shape.

The prepared tablet cores are scattered and talcum powder is applied to play a role in moisture resistance. The tablet core is subcoated. To obtain oral tablets, the tablet cores are sieved several times. To obtain tablets with round shape and smooth surface, further subcoating and coating with lubricants may be carried out. The tablets are further coated with a coloured coating material and the lipids give the tablets of the desired colour. After drying, the coated tablets are polished to give the desired tablets with a uniform gloss.

Preparation 3

An injection was prepared from the following components.

Component amount 2- {2- (3-Morpholinopropyl) -4- [3- (4-pyridyl) acryloyl } phenoxymethylcarbonylamino ] benzothiazole 5g polyethylene glycol (molecular weight: 4000) 0.3g sodium chloride 0.9g polyoxyethylene sorbitan monooleate 0.4g sodium metabisulfite 0.1g methyl p-hydroxybenzoate 0.18g propyl p-hydroxybenzoate 0.02g distilled water for injection 10.0ml

The above parabens, sodium metabisulfite and sodium chloride were dissolved in the above half volume of distilled water with stirring at 80 ℃. The resulting solution is cooled to 40 ℃ and the active compound of the invention, and in turn the polyethylene glycol and polyoxyethylene sorbitan monooleate, are dissolved in the above solution. Distilled water for injection is added to the solution to adjust to a desired volume, and the solution is filter-sterilized through a suitable filter paper to obtain an injection.

Reference example 1

A solution of o-isopropylphenol (39.5g), potassium carbonate (40g) and ethyl α -bromoacetate (40ml) in dimethylformamide (300ml) was heated with stirring at 80 ℃ for 8 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and concentrated under reduced pressure to remove the solvent. The resulting residue was dissolved in a solution of sodium hydroxide (20g) in water (300ml) and ethanol (200ml), and the mixture was refluxed for 1.5 hours. After cooling, the mixture was acidified with concentrated hydrochloric acid, and the crystal precipitated was collected by filtration to give α - (2-isopropylphenoxy) acetic acid (37 g).

White powder

¹H-NMR(CDCl₃)δppm:1.24(6H,d,J=7Hz),3.39(1H,sept,J=7Hz),4.69(2H,s),6.75(1H,dd,J=1Hz,J=8Hz),6.95-73(3H,m)

Reference example 2

A solution of α - (2-isopropylphenoxy) acetic acid (13.1g) in thionyl chloride (30ml) was refluxed for 30 minutes. The mixture was concentrated under reduced pressure to remove excess thionyl chloride, and the resulting product was dissolved in dichloromethane (50 ml). The mixture was added dropwise to a dichloromethane (100ml) solution of 2-aminobenzothiazole (9.1g) and pyridine (7.2ml) under ice-cooling, and the mixture was stirred at the same temperature for 5 hours, then washed with water, dried and concentrated under reduced pressure. Ethanol was added to the residue to give 2- (2-isopropylbenzyloxymethylcarbonylamino) benzothiazole (16.66 g).

Yellow powder

¹H-NMR(CDCl₃)δppm:1.32(6H,d,J=7Hz)3.43(1H,sept,J=7Hz),4.78(2H,s),6.85(1H,dd,J=1Hz,J=8Hz),7.0-7.55(5H,m),7.8-7.9(2H,m),9.74(1H,br)

Reference example 3

To a solution of dimethyl methylphosphonate (19.5ml) in dry tetrahydrofuran (300ml) was added a 1.72M solution of n-butyllithium in n-hexane (107ml) at-50 ℃. After 30 minutes, 2- (2-methoxy-4-formylphenoxymethylcarbonylamino) benzothiazole (20.5g) was added portionwise to the mixture under a nitrogen atmosphere, the mixture was stirred at-50 ℃ for 1 hour, and water was added thereto. The mixture was acidified with concentrated hydrochloric acid and extracted with ethyl acetate, the extract was washed with water, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent: dichloromethane: methanol = 200: 1 → 30: 1) to give dimethyl {2- [ 3-methoxy-4- (2-benzothiazolylaminocarbonylmethoxy) phenyl ] -2-hydroxyethyl } phosphonate (19.0 g).

¹H-NMR(CDCl₃) δ ppm 2.05-2.35(2H, m),3.73,3.76,3.78 and 3.81(6H, both s),3.98(2H, d, J =2.5Hz),4.01(3H, s),4.77(2H, s),5.0-5.15(1H, m),6.90(1H, dd, J =2Hz, J =8Hz),6.98(1H, d, J =8Hz),7.07(1H, d, J =2Hz),7.25-7.5(2H, m),7.8-7.9(2H, m),10.66(1H, br)

To a solution of dimethyl {2- [ 3-methoxy-4- (2-benzothiazoylaminocarbonylmethoxy) phenyl ] -2-hydroxyethyl } phosphonate (19.0g) in chloroform (300ml) was added activated manganese dioxide (17.7g), and the mixture was refluxed for 3 hours. To the mixture was further added active manganese dioxide (18g), and the mixture was refluxed for 3 hours. To the mixture was further added active manganese dioxide (20g) and the mixture was stirred for further 3 hours. Manganese dioxide was collected by filtration and washed with chloroform. The filtrate and washings were combined and concentrated under reduced pressure to remove chloroform, and the residue was purified by silica gel column chromatography (solvent: dichloromethane: methanol = 200: 1 → 50: 1) to give dimethyl { [ 3-methoxy-4- (2-benzothiazolylaminocarbonylmethoxy) benzoyl ] methyl } phosphonate (7.76 g).

White powder

¹H-NMR(CDCl₃)5ppm:3.62(2H,d,J=22.5Hz),3.79(6H,d,J=11.2Hz),4.04(3H,s),4.85(2H,s),7.02(1H,d,J=8.5Hz),7.3-7.55(2H,m),7.6-7.7(2H,m),7.8-7.9(2H,m),10.31(1H,br)

Reference example 4

To a solution of chloroacetyl chloride (10.0ml) in anhydrous 1, 2-dichloroethane (250ml) was added aluminum chloride (12g) at room temperature and the mixture was stirred for 20 minutes. 2- (2-isopropylbenzyloxymethylcarbonylamino) benzothiazole (20g) was immediately added to the mixture, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, to which n-hexane was added. The precipitate was collected by filtration, washed with water and dried to give 2- [ 2-isopropyl-4- (2-chloroacetyl) phenoxymethylcarbonylamino ] benzothiazole (25.9 g).

White powder

¹H-NMR(DMSO-d₆)δppm:1.24(6H,d,J=7Hz),3.38(1H,m),5.12(4H,s),7.01(1H,d,J=9Hz),7.25-7.55(2H,m),7.7-7.95(3H,m),7.97(1H,d,J=8Hz),13.00(1H,br)

Reference example 5

A suspension of 2- [ 2-isopropyl-4- (2-chloroacetyl) phenoxymethylcarbonylamino ] benzothiazole (4.0g) and triphenylphosphine (2.8g) in chloroform (100ml) was refluxed for 7 hours. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from methylene chloride-diethyl ether to give [ 3-isopropyl-4- (2-benzothiazolylaminocarbonylmethoxy) benzoyl ] methyltriphenylphosphonium chloride (3.8 g).

¹H-NMR(DMSO-d₆)δppm:1.23(6H,d,J=7Hz),3.40(1H,m),5.18(2H,s),6.19(2H,d,J=13.5Hz),7.09(1H,d,J=9Hz),7.25-7.5(2H,m),7.6-8.05(19H,m),12.77(1H,s)

To a solution of [ 3-isopropyl-4- (2-benzothiazoylaminocarbonylmethoxy) benzoyl ] methyltriphenylphosphonium chloride (3.8g) in methanol (50ml) was added DBU (1ml) and the mixture was stirred at room temperature for 2 hours. The crystal precipitated was collected by filtration, washed with methanol and dried to give [ 3-isopropyl-4- (2-benzothiazolylaminocarbonylmethoxy) benzoyl ] methylenetriphenylphosphorane (2.27 g).

White powder

¹H-NMR(CDCl₃)δppm:1.32(6H,d,J=7Hz),3.42(1H,sept,J=7Hz),4.2-4.6(1H,m),4.73(2H,s),6.75(1H,d,=8.5Hz),7.25-8.0(21H,m),10.01(1H,br)

The following compounds were obtained in the same manner as in reference example 5 using suitable starting compounds.

[3- (3-chloropropyl) -4- (2-benzothiazoylaminocarbonylmethoxy) benzoyl ] methylenetriphenylphosphonium chloride:

white powder

¹H-NMR(CDCl₃)δppm:2.11(2H,tt,J=6.6Hz,J=8.0Hz),2.86(2H,t,J=8.0Hz),3.71(2H,t,J=6.6Hz),5.20(2H,s),6.17(2H,d,J=12.8Hz),7.13(1H,d,J=8.7Hz),7.34(1H,t,J=7.5Hz),7.48(1H,t,J=7.0Hz),7.76-8.02(19H,m),12.75(1H,br)

Reference example 6

To dimethylformamide (200ml) were added 2-methoxy-4-acetylphenol (20g), ethyl α -bromoacetate (15ml) and potassium carbonate (18.3g), and the mixture was stirred at room temperature overnight. After completion of the reaction, water was added to the mixture, and the mixture was extracted with ethyl acetate. The extract was washed with an aqueous sodium bicarbonate solution and dried over magnesium sulfate, and the solvent was removed by concentration under reduced pressure. The resulting crystals were collected by filtration and washed with n-hexane-diethyl ether to give ethyl α - (2-methoxy-4-acetylphenoxy) acetate (23.86 g).

To chloroform (230ml) were added ethyl α - (2-methoxy-4-acetylphenoxy) acetate (23g) and copper (II) bromide (55g), and the mixture was refluxed for 3.5 hours. After completion of the reaction, the mixture was filtered through a layer of celite to remove the precipitate and washed with sodium hypochlorite. The filtrate was dried over magnesium sulfate and concentrated under reduced pressure to remove the solvent, followed by crystallization to give ethyl α - [ 2-methoxy-4- (2-bromoacetyl) phenoxy ] acetate (21.28 g).

To chloroform (200ml) were added ethyl α - [ 2-methoxy-4- (2-bromoacetyl) phenoxy ] acetate (20g) and triphenylphosphine (20.6g) in an ice bath, and the mixture was stirred for 1 hour. When it was confirmed that the starting compound had been consumed, the mixture was washed with an aqueous potassium carbonate solution. The mixture was dried over magnesium sulfate and concentrated under reduced pressure to remove the solvent. Methanol (200ml) was added to the residue, and sodium hydroxide was added dropwise thereto in an ice bath. When it was confirmed that the starting compound had been consumed, concentrated hydrochloric acid was added to the mixture. The precipitated crystals were washed with water and diethyl ether and dried to give (3-methoxy-4-carboxymethoxybenzoyl) methylenetriphenylphosphorane (25 g).

To methylene chloride (50ml) were added (3-methoxy-4-carboxymethoxybenzoyl) methylenetriphenylphosphane (5g), 2-aminobenzothiazole (1.9g), bis (2-oxo-3-oxazolidinyl) phosphinic chloride (2.93g) and triethylamine (3.3ml), and the mixture was stirred overnight. After completion of the reaction, the mixture was washed with an aqueous solution of sodium hydrogencarbonate, dried over magnesium sulfate, the solvent was removed, and further recrystallized from toluene to give [ 3-methoxy-4- (2-benzothiazoylaminocarbonylmethoxy) benzoyl ] methylenetriphenylphosphorane (5.17 g).

Light yellow powder

¹H-NMR(CDCl₃)δppm:4.03(3H,s),4.12-4.62(1H,m),4.79(2H,s),6.96(1H,d,J=8.3Hz),7.25-7.90(22H,m)

Reference example 7

To a solution of N-benzyl-4-piperidone (8.0g) and 3, 4-dimethylpiperazine (9.5g) in ethanol (100ml) were added 5% palladium-carbon (2g) and acetic acid (14.4ml), and the mixture was subjected to catalytic hydrogenation at room temperature under normal pressure. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. To the resulting product was added water, the mixture was basified with 5% aqueous sodium hydroxide solution, and the mixture was extracted with diethyl ether. The extract was washed with water, dried and concentrated under reduced pressure to remove the solvent. The residue was dissolved in ethanol, and concentrated hydrochloric acid was added thereto to obtain a hydrochloride. The resulting white powder was collected by filtration, dissolved in water and basified with 5% aqueous sodium hydroxide solution, and the mixture was extracted with ether, washed with water, dried and concentrated under reduced pressure to give 4- (3, 4-dimethyl-1-piperazinyl) -1-benzylpiperidine (4.2 g).

¹H-NMR(CDCl₃)δppm:1.04(3H,d,J=6Hz),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-dimethyl-1-piperazinyl) -1-benzylpiperidine (4.2g) in ethanol (50ml) was added 20% palladium hydroxide-carbon (0.4g) and the mixture was subjected to catalytic hydrogenation at 50 ℃ under normal pressure. The catalyst was filtered off, the filtrate was concentrated under reduced pressure, and the residue was evaporated to give 4- (3, 4-dimethyl-1-piperazinyl) piperidine (1.65 g).

Colorless oil

b.p.145℃(0.3mmHg)

¹H-NMR(CDCl₃)δppm:1.05(3H,d,J=6Hz),1.25-1.55(2H,m),1.75-3.3(14H,m),2.31(3H,s)

Reference example 8

A solution of 1-benzyl-L-proline (50g) in methylene chloride (300ml) was cooled with ice, N-methylmorpholine (22.5g) was added to the solution, and isobutyl chloroformate (30g) was further added dropwise thereto. The mixture was stirred at the same temperature for about 1 hour, and pyrrolidine (18.8ml) was added dropwise thereto at the same temperature. The mixture was warmed to room temperature and stirred for 2 days. The mixture was washed twice with water (250ml) and dried over magnesium sulfate. The mixture was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate-n-hexane to give 2- (1-pyrrolidinyl) carbonyl-1-benzylpyrrolidine (31g) as a white powder.

5% Palladium-carbon (3g) was suspended in ethanol (300ml), 2- (1-pyrrolidinyl) carbonyl-1-benzylpyrrolidine (30g) was added thereto, and the mixture was subjected to catalytic hydrogenation at room temperature under normal pressure. The mixture was filtered and the filtrate was concentrated under reduced pressure to remove the solvent to give 2- (1-pyrrolidinyl) carbonylpyrrolidine (about 18g), an oily product.

Under ice-cooling, lithium aluminum hydride (9g) was suspended in anhydrous tetrahydrofuran (100ml) and a solution of 2- (1-pyrrolidinyl) carbonylpyrrolidine (33g) in anhydrous tetrahydrofuran (80ml) was added dropwise thereto, and the mixture was refluxed for 4 hours under a nitrogen atmosphere. The mixture was ice-cooled, and a saturated aqueous sodium sulfate solution (about 15ml) was added thereto, followed by further stirring the mixture at room temperature for 3 hours. The precipitated sodium sulfate was filtered off and washed thoroughly with chloroform. The filtrate and washings were combined, concentrated under reduced pressure and evaporated to give 2- (1-pyrrolidinyl) methylpyrrolidine (22 g).

Colorless oil

B.p.99-101℃(20mmHg)

Reference example 9

4-benzyl-2-chloromethylmorpholine (15g) and 4- (2-hydroxyethyl) piperazine (25ml) were mixed and the mixture was stirred at 130 ℃ for 5 hours. After completion of the reaction, the mixture was extracted with chloroform, and the extract was dried over magnesium sulfate. The resulting residue was concentrated under reduced pressure to give 4-benzyl-2- [4- (2-hydroxyethyl) -1-piperazinyl ] methylmorpholine (16 g).

¹H-NMR(CDCl₃)δppm:1.86(1H,t,J=10.6Hz),2.07-2.27(2H,m),2.37-3.05(14H,m),3.49(2H,d,J=2.3Hz),3.57-3.89(5H,m),7.24-7.33(5H,m)

4-benzyl-2- [4- (2-hydroxyethyl) -1-piperazinyl ] methylmorpholine (16g) was dissolved in ethanol (160ml) and palladium hydroxide (1.6g) was added thereto. The mixture was debenzylated at 50 ℃ under hydrogen pressure and, after 5 hours, the mixture was filtered through a layer of celite and the filtrate was concentrated under reduced pressure. The resulting crystals were washed with diethyl ether-n-hexane to give 2- [4- (2-hydroxyethyl) -1-piperazinyl ] methylmorpholine (9.09 g).

M.p.73-75.5℃

White powder

¹H-NMR(CDCl₃)δppm:2.25(1H,dd,J=4.2Hz,J=13.0Hz),2.37-2.74(11H,m),2.74-3.02(6H,m),3.49-3.77(4H,m),3.85-3.93(1H,m)

The compounds listed in tables 1 to 4 can be prepared in the same manner as described in reference example 1 using suitable starting compounds.

TABLE 1

Reference example 10R5:CH3(2-position) crystalline form: white powder	m:1 state: free form	A:-CH2-NMR(1)
			Reference example 11R5:C2H5(2-position) crystalline form: white powder	m:1 state: free form	A:-CH2-NMR(2)
Reference example 12R5:-(CH2)2CH3(2-position) crystalline form: white powder	m:1 state: free form	A:-CH2-NMR(3)
			Reference example 13R5:-(CH2)3CH3(2-position) m.p.102-104 ℃ form: white powder	m:1	A:-CH2-
Recrystallization solvent: ethanol-water state: free form

TABLE 2

Reference example 14R5:-(CH2)4CH3(2-position) m.p.71.4-74.4 ℃ crystal form: white powder	m:1 A:-CH2-recrystallization solvent: ethanol-water state: free form
		Reference example 15R5Form F (2-position):white powder	m:1 A:-CH2-a state: free NMR (4)
Reference example 16R5Crystalline form of Cl (2-position): white powder	m:1 A:-CH2-a state: free NMR (5)
		Reference example 17R5:-(CH2)4Form (2-and 3-together) m: 2: white powder	A:-CH2-a state: free NMR (6)
Reference example 18R5:CH3(2-and 3-position) crystalline form: white powder	m:2 A:-CH2-a state: free NMR (7)

TABLE 3

Reference example 19R5:CH3(2-and 6-position) crystalline form: yellow powder	m:2 A:-CH2-a state: free NMR (8)
		Reference example 20R5:CH3(3-and 5-position) crystalline form: white powder	m:2 A:-CH2-a state: free NMR (9)
Reference example 21R5:CH3(3-position) crystal form: white powder	m:1 A:-CH2-a state: free NMR (10)
		Reference example 22R5:C2H5(3-position) m.p.102-104 ℃ form: white powder	m:1 A:-CH2-recrystallization solvent: ethanol-water state: free form
Reference example 23R5:-(CH2)2CH3(3-position) m.p.63.5-66.0 ℃ crystal form: white powder	m:1 A:-CH2-recrystallization solvent: ethanol-water state: free form

TABLE 4 reference example 24R⁵:-(CH₂)₃CH₃(3-position) m: 1A: -CH₂-m.p.69.0-72.5 ℃ recrystallization solvent: ethanol-crystal form: colorless prismatic state: free NMR (11) reference example 25m:1 A:-CH₂-a crystalline form: white solid state: free NMR (12) reference example 26R⁵Cl (3-position) m: 1A: -CH₂-a crystalline form: white powder state: free NMR (13) reference example 27R⁵: f (3-position) m: 1A: -CH₂-a crystalline form: white powder state: free NMR (14) reference example 28R⁵:CH₃O (3-position) m: 1A: -CH₂-a crystalline form: gray brown powder state: free NMR (15)Reference example 29R ⁵:C₂H₅O (3-position) m: 1A: -CH₂-a crystalline form: gray brown powder state: free NMR (16)

Tables 1 to 4¹The H-NMR spectra (NMR (1) to NMR (17)) were as follows:

NMR(1)(DMSO-d₆)δppm:2.19(3H,s),4.68(2H,s),6.83(2H,dd,J=7.8Hz,J=13.2Hz),7.12(2H,t,J=7.8Hz),12.96(1H,s)

NMR(2)(DMSO-d₆)δppm:1.14(3H,t,J=7.5Hz),2.61(2H,q,J=7.5Hz),4.69(2H,s),6.78-6.95(2H,m),7.05-7.20(2H,m),12.97(1H,s)

NMR(3)(CDCl₃)δppm: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-d₆)δppm:4.77(2H,s),6.88-7.30(4H,m),13.09(1H,s)

NMR(5)(CDCl₃)δppm:4.76(2H,s),6.89(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),8.16(1H,br)

NMR(6)(DMSO-d₆)δppm:1.6-1.85(4H,m),2.55-2.75(4H,m),4.63(2H,s),6.57(1H,d,J=8Hz),6.65(1H,d,J=7.5Hz),6.9-7.05(1H,m),12.94(1H,br)

NMR(7)(DMSO-d₆)δppm:2.10(3H,s),2.20(3H,s),4.63(2H,s),6.64(1H,d,J=8Hz),6.75(1H,d,J=7.5Hz),6.95-7.1(1H,m),12.9(1H,br)

NMR(8)(DMSO-d₆)δppm:2.22(6H,s),4.35(2H,s),6.87-7.06(3H,m),12.87(1H,s)

NMR(9)(DMSO-d₆)δppm:2.22(6H,s),4.48(2H,s),6.48(2H,s),6.60(1H,s)

NMR(10)(DMSO-d₆)δppm:2.26(3H,s),4.62(2H,s),6.60-6.80(3H,m),7.11-7.18(1H,m)

NMR(11)(DMSO-d₆)δppm:0.85(3H,t,J=7.2Hz),1.17-1.38(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)(CDCl₃)δppm:1.22(6H,d,J=6.9Hz),2.77-3.00(1H,m),4.68(2H,s),6.66-6.76(1H,m),6.81-6.95(2H,m),7.17-7.29(1H,m),8.65(1H,brs)

NMR(13)(CDCl₃)δppm:4.69(2H,s),6.79-6.85(1H,m),6.85-7.04(2H,m),7.19-7.28(1H,m),8.00(1H,br)

NMR(14)(CDCl₃)δppm:4.69(2H,s),6.62-6.79(3H,m),7.20-7.32(1H,m),9.07(1H,br)

NMR(15)(CDCl₃)δppm: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)(CDCl₃)δppm: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 suitable starting compounds, the following table was prepared in the same manner as described in reference example 2

5-9.

TABLE 5

Reference example 30R5:CH3(2-position) crystalline form: yellow powder	m:1 A:-CH2-a state: free form	R4:HNMR(1)
			Reference example 31R5:C2H5(2-position) crystalline form: light yellow powder	m:1 A:-CH2-a state: free form	R4:HNMR(2)
Reference example 32R5:-(CH2)2CH3(2-position) crystalline form: yellow powder	m:1 A:-CH2-a state: free form	R4:HNMR(3)
			Reference example 33R5:-(CH2)3CH3(2-position) crystalline form: yellow solid	m:1 A:-CH2-a state: free form	R4:HNMR(4)

TABLE 6

Reference example 34R5H (2-position) crystalline form: light yellow powder	m:1 A:-CH2- R4H state: free NMR (5)
		Reference example 35R5:-(CH2)4CH3(2-position) crystalline form: yellow powder redissolving agent: ethyl acetate-n-hexane	m:1 A:-CH2- R4H state: free NMR (6)
Reference example 36R5Form F (2-position): light yellow powder	m:1 A:-CH2- R4H state: free NMR (7)
		Reference example 37R5Crystalline form of Cl (2-position): yellow powder	m:1 A:-CH2- R4H state: free NMR (8)
Reference example 38R5:-(CH2)4- (2 and 3 together) m: 2A: -CH2-a crystalline form: white powder	R4H state: free NMR (9)

TABLE 7

Reference example 39R5:CH3(2-and 3-positions) m: 2A: -CH2-a crystalline form: yellow powder	R4H state: free form	NMR(10)
			Reference example 40R5:CH3(2-and 6-positions) m: 2A: -CH2-a crystalline form: yellow powder	R4H state: free form	NMR(11)
Reference example 41R5:CH3(3-and 5-positions) m: 2A: -CH2-a crystalline form: white powder	R4H state: free form	NMR(12)
			Reference example 42R5:-(CH2)3Crystalline form of Cl (2-position): yellow powder	m:1 A:-CH2-a state: free form	R4:HNMR(13)
Reference example 43R5:-(CH2)2Crystalline form of Cl (2-position): white powder	m:1 A:-CH2-a state: free form	R4:HNMR(14)

TABLE 8 reference example 44R⁵:CH₃(3-position) m: 1A: -CH ₂- R⁴H recrystallization solvent: ethyl acetate-n-hexane crystalline form: light brown powder state: free NMR (15) reference example 45R⁵:C₂H₅(3-position) m: 1A: -CH₂- R⁴Crystalline form H: gray-brown needle crystal state: free NMR (16) reference example 46R⁵:-(CH₂)₂CH₃(3-position) m: 1A: -CH₂- R⁴HM.P.110.0-111.0 deg.C recrystallization solvent: ethyl acetate-n-hexane crystalline form: light yellow needle crystal state: free reference example 47R⁵:-(CH₂)₃CH₃(3-position) m: 1A: -CH₂- R⁴HM.p.110.5-111.0 deg.C recrystallization solvent: ethyl acetate-n-hexane crystalline form: light yellow needle crystal state: free reference example 48 m:1 A:-CH₂- R⁴HM.p.93.7-94.0 deg.C recrystallization solvent: ethyl acetate-n-hexane crystalline form: pink powderThe state is as follows: free form

TABLE 9

Reference example 49R 5Crystalline form of Cl (3-position): light yellow powder	m:1 A:-CH2-a state: free form	R4:HNMR(17)
			Reference example 50R5Form F (3-position): light yellow powder	m:1 A:-CH2-a state: free form	R4:HNMR(18)
Reference example 51R5:CH3Crystal form of O (3-position): grayish brown powder	m:1 A:-CH2-a state: free form	R4:HNMR(19)
			Reference example 52R5:C2H5Crystal form of O (3-position): brown powder	m:1 A:-CH2-a state: free form	R4:HNMR(20)

Tables 5 to 9¹The H-NMR spectra (NMR (1) to NMR (20)) are as follows:

NMR(1)(DMSO-d₆)δppm:2.45(3H,s),4.95(2H,s),6.81-6.95(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-d₆)δppm:1.18(3H,t,J=7.5Hz),2.67(2H,q,J=7.5Hz),4.96(2H,s),6.89(2H,dd,J=8.0Hz,J=12.5Hz),7.09-7.23(2H,m),7.28-7.38(1H,m),7.40-7.52(1H,m),7.77(1H,d,J=8.0Hz),7.98(1H,d,J=7.8Hz),12.58(1H,s)

NMR(3)(CDCl₃)δppm:1.03(3H,t,J=7.4Hz),1.6-1.8(2H,m),2.73(2H,t,J=7.4Hz),4.76(2H,s),6.84(1H,d,J=8.0Hz),7.01-7.50(5H,m),7.79-7.86(2H,m),9.6-9.8(1H,s)

NMR(4)(CDCl₃)δppm:0.95(3H,tJ=7.2Hz),1.37-1.55(2H,m),1.59-1.74(2H,m),2.71(2H,d,J=7.2Hz),4.77(2H,s),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)(CDCl₃)δppm:4.76(2H,s),6.95-7.11(3H,m),7.26-7.47(4H,m),7.79-7.87(2H,m),9.92(1H,br)

NMR(6)(CDCl₃)δppm: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=8.0Hz),6.98-7.05(1H,m),7.17-7.26(2H,m),7.31-7.38(1H,m),7.42-7.50(1H,m),7.79-7.87(2H,m),9.73(1H,brs)

NMR(7)(DMSO-d₆)δppm: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=7.8Hz),7.99(1H,dd,J=0.7Hz,J=7.7Hz),12.63(1H,s)

NMR(8)(CDCl₃)δ5ppm:4.80(2H,s),6.95-7.10(2H,m),7.23-7.49(4H,m),7.85(2H,dd,J=2.0Hz,J=6.6Hz),9.97(1H,br)

NMR(9)(CDCl₃)δppm: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=8Hz),7.05-7.15(1H,m),7.3-7.5(2H,m),7.75-7.9(2H,m),9.73(1H,br)

NMR(10)(CDCl₃)δppm: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)(DMSO-d₆)δppm:2.27(6H,s),4.63(2H,s),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)(CDCl₃)δppm:2.32(6H,s),4.73(2H,s),6.61(2H,s),6.72(1H,s),7.3-7.55(2H,m),7.8-7.95(2H,m),9.86(1H,br)

NMR(13)(CDCl₃)δppm:2.18(2H,tt,J=7.0Hz,J=8.0Hz),2.96(2H,t,J=7.0Hz),3.63(2H,t,J=8.0Hz),4.80(2H,s),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)(CDCl₃)δppm:3.22(2H,t,J=7.0Hz),3.82(2H,t,J=7.0Hz),4.81(2H,s),6.86(1H,d,J=8.2Hz),7.05(1H,t,J=7.2Hz),7.15-7.52(4H,m),7.81(2H,t,J=8.4Hz),9.78(1H,br)

NMR(15)(CDCl₃)δppm:2.37(3H,s),4.74(2H,s),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),9.88(1H,brs)

NMR(16)(CDCl₃)δppm:1.25(3H,t,J=7.6Hz),2.65(2H,q,J=7.6Hz),4.74(2H,s),6.74-6.84(2H,m),6.88-6.95(1H,m),7.21-7.50(3H,m),7.79-7.86(2H,m),9.94(1H,br)

NMR(17)(CDCl₃)δppm:4.73(2H,s),6.75-6.84(1H,m),6.84-6.98(1H,m),7.01-7.08(1H,m),7.21-7.46(3H,m),7.82(2H,t,J=8.4Hz),10.09(1H,br)

NMR(18)(DMSO-d₆)δppm: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=8.0Hz)

NMR(19)(CDCl₃)δppm: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)(CDCl₃)δppm:1.43(3H,t,J=7.0Hz),4.04(2H,q,J=7.0Hz),4.73(2H,s),6.50-6.66(3H,m),7.18-7.51(3H,m),7.78-7.90(2H,m),9.87(1H,br)

using suitable starting compounds, the same procedures as described in reference example 3 were conducted to obtain the following compounds shown in Table 10

The compounds listed.

Watch 10Reference example 53R⁵:C₂H₅O (2-position) m: 1A: -CH₂- R⁴:H R¹⁸:CH₃Crystal form O: light yellow powder state: free NMR (1) reference example 54m:1 A:-CH₂-R⁴:H R¹⁸:CH₃Crystal form O: white powder state: free NMR (2) reference example 55R⁵:CF₃CH₂O (3-position) m: 1A: -CH₂-R⁴:H R¹⁸:CH₃Crystal form O: white powder state: free NMR (3) reference example 56R⁵:CF₃(2-position) m: 1A: -CH₂- R⁴:H R¹⁸:CH₃Crystal form O: white powder state: free NMR (4) reference example 57R ⁵:CH₃O (3-position) m: 1A: -CH₂- R⁴:H R¹⁸:CH₃Crystal form O: white powder state: free NMR (5)

Table 10 the description¹The H-NMR spectra (NMR (1) to NMR (5)) were as follows:

NMR(1)(CDCl₃)δppm:1.58(3H,t,J=7.0Hz),3.61(2H,d,J=22.8Hz),3.76(3H,s),3.82(3H,s),4.25(2H,q,J=7.0Hz),4.85(2H,s),7.04(1H,d,J=8.6Hz),7.33(1H,t,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)(CDCl₃)δppm:1.47(6H,d,J=6.0Hz),3.74(3H,s),3.79(3H,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),7.79-7.88(3H,m),9.98(1H,br)

NMR(3)(CDCl₃)δppm:3.76(2H,d,J=21.3Hz),3.75(3H,s),3.80(3H,s),4.40(2H,q,J=7.9Hz),4.79(2H,s),6.44(1H,d,J=2.2Hz),6.60(1H,dd,J=2.2Hz,J=8.8Hz),7.34(1H,dt,J=1.3Hz,J=7.3Hz),7.45(1H,dt,J=1.3Hz,J=7.3Hz),7.75-7.86(3H,m)

NMR(4)(DMSO-d₆)δppm:3.62(3H,s),3.68(3H,s),3.93(2H,d,J=22.5Hz),5.27(2H,s),7.3-7.55(3H,m),7.78(1H,d,J=8Hz),7.98(1H,d,J=8Hz),8.2-8.35(2H,m),12.68(1H,br)

NMR(5)(CDCl₃)δppm:3.74(3H,s),3.80(3H,s),3.81(2H,d,J=21Hz),3.95(3H,s),4.81(2H,s),6.5-6.65(2H,m),7.25-7.55(2H,m),7.75-7.95(3H,m),10.01(1H,s)

obtained by the same procedure as described in reference example 4 using a suitable starting compound

The compounds listed in tables 11-13 below.

TABLE 11

Reference example 58R5Crystalline form H: light yellow powder	m:1 A:-CH2- R4H state: free form	X:BrNMR(1)
			Reference example 59R5:CH3(2-position) crystalline form: grayish brown powder	m:1 A:-CH2- R4H state: free form	X:ClNMR(2)
Reference example 60R5:C2H5(2-position) crystalline form: grayish brown powder	m:1 A:-CH2- R4H state: free form	X:ClNMR(3)
			Reference example 61R5:-(CH2)3CH3(2-position) R4H X crystalline form of Cl: white powder	m:1 A:-CH2-a state: free form	NMR(4)

TABLE 12 reference example 62R⁵Cl (2-position) m: 1A: -CH₂- R⁴H X, ClM.p.199-201 ℃ recrystallization solvent: crystalline form of 1, 2-dichloroethane-n-hexane: white powder state: free reference example 63R⁵:-(CH₂)₂Cl (2-position) m: 1A: -CH ₂-R⁴H X crystalline form Br: light yellow powder state: free NMR (5) reference example 64R⁵:-(CH₂)₃Cl (2-position) m: 1A: -CH₂-R⁴H X crystalline form Br: light yellow powder state: free NMR (6) reference example 65R⁵:-(CH₂)₄Cl (2-position) m: 1A: -CH₂-R⁴H X, ClM.p.146.5-149 ℃ recrystallization solvent: ethyl acetate-n-hexane crystalline form: white powder state: free form

TABLE 13 reference example 66R⁵:-(CH₂)₂CO₂C₂H₅(2-position) m: 1A: -CH₂-R⁴:H X:ClM.p.131.0-1Recrystallization solvent at 33.0 ℃: ethyl acetate-n-hexane crystalline form: white powder state: free reference example 67R⁵:-(CH₂)₂CO₂CH₃(2-position) m: 1A: -CH₂-R⁴H X crystalline form of Cl: white powder state: free NMR (7) reference example 68(2-position) m: 1A: -CH₂-R⁴H X crystalline form of Cl: white powder state: free NMR (8) reference example 69R⁵Together with A to form m:1 R⁴H X, ClM.p.206-208 ℃ recrystallization solvent: dimethylformamide-ethanol crystalline form: white powder state: free form

Tables 11 to 13¹The H-NMR spectra (NMR (1) to NMR (8)) are as follows:

NMR(1)(CDCl₃)δppm:4.41(2H,s),4.84(2H,s),7.07(2H,d,J=9.0Hz),7.36(1H,t,J=7.3Hz),7.45(1H,t,J=7.3Hz),7.88(2H,t,J=8.5Hz),8.03(2H,d,J=9.0Hz)

NMR(2)(DMSO-d₆)δppm:2.30(3H,s),5.11(4H,s),7.00-7.10(1H,m),7.28-7.40(1H,m),7.40-7.55(1H,m),7.70-7.93(3H,m),7.98(1H,d,J=7.1Hz),12.68(1H,s)

NMR(3)(DMSO-d₆)δppm:1.21(3H,t,J=7.4Hz),2.72(2H,q,J=7.4Hz),5.12,5.13(4H,eachs),7.02(1H,d,J=8.6Hz),7.31(1H,dt,J=1.2Hz,J=7.3Hz),7.45(1H,dt,J=1.3Hz,J=7.3Hz),7.75-7.92(3H,m),7.95-8.00(1H,m),12.68(1H,brs)

NMR(4)(CDCl₃)δppm:0.97(3H,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,s),4.86(2H,s),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)(CDCl₃)δppm:3.16(2H,t,J=6.9Hz),3.92(2H,t,J=6.9Hz),4.83(2H,s),5.13(2H,s),7.07(1H,d,J=9.4Hz),7.31(1H,t,J=6.9Hz),7.45(1H,t,J=8.3Hz),7.76(1H,d,J=7.9Hz),7.82-8.06(3H,m)

NMR(6)(CDCl₃)δppm: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,s),4.88(2H,s),6.95(1H,d,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)(CDCl₃)δppm:2.75(2H,t,J=7.0Hz),3.13(2H,t,J=7.0Hz),3.74(3H,s),4.65(2H,s),4.89(2H,s),6.89(1H,d,J=8.4Hz),7.30-7.37(1H,m),7.41-7.48(1H,m),7.78-7.89(4H,m),9.00-11.30(1H,brs)

NMR(8)(CDCl₃)δppm:2.00(3H,s),2.09(3H,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),8.79(1H,br)

using a suitable starting compound, the following table was prepared in the same manner as described in reference example 5 or 6

14-22.

TABLE 14Reference example 70R⁵:H m:1 A:-CH₂- R⁴Crystalline form H: light yellow amorphous state: free NMR (1) reference example 71R⁵:CH₃(2-position) m: 1A: -CH₂- R⁴Crystalline form H: light yellow amorphous state: free NMR (2) reference example 72R⁵:C₂H₅(2-position) m: 1A: -CH₂- R⁴Crystalline form H: white powderThe state is as follows: free NMR (3) reference example 73 m:1 A:-CH₂- R⁴Crystalline form H: white powder state: free NMR (4)

Watch 15

Reference example 74R5:-(CH2)3CH3(2-position) crystalline form: light yellow powder	m:1 A:-CH2- R4H state: free NMR (5)
		Reference example 75R5Crystalline form of Cl (2-position): light yellow amorphous	m:1 A:-CH2- R4H state: free NMR (6)
Reference example 76R5Form F (2-position): white powder	m:1 A:-CH2- R4H state: free NMR (7)
		Reference example 77R5:-(CH2)2Crystalline form of Cl (2-position): white powder	m:1 A:-CH2- R4H state: free NMR (8)
Reference example 78R5:-(CH2)4Crystalline form of Cl (2-position): white needle-like shape	m:1 A:-CH2- R4H state: free NMR (9)

TABLE 16 reference example 79R⁵:-(CH₂)₂CO₂C₂H₅(2-position) m:1A: -CH₂- R⁴Crystalline form H: white powder state: free NMR (10) reference example 80A:-CH₂- R⁴Crystalline form H: white powder state: free NMR (11) reference example 81A:-CH₂- R⁴Crystalline form H: white powder state: free NMR (12) reference example 82A:-CH₂- R⁴Crystalline form H: light yellow amorphous state: free NMR (13)

TABLE 17 reference example 83R ⁵:-(CH₂)₃N(C₂H₅)₂(2-position) m:1A: -CH₂- R⁴Crystalline form H: white powder state: free NMR (14) reference example 84A:-CH₂- R⁴Crystalline form H: white powder state: free NMR (15) reference example 85A:-CH₂- R⁴Crystalline form H: white powder state: free NMR (16) reference example 86A:-CH₂- R⁴HM.p.153-155 ℃ recrystallization solvent: ethyl acetate crystalline form: white powder state: free form

TABLE 18 reference example 87A:-CH₂- R⁴Crystalline form H: white amorphous state: free NMR (17) reference example 88A:-CH₂- R⁴Crystalline form H: white amorphous state: free NMR (18) reference example 89A:-CH₂- R⁴Crystalline form H: colorless amorphous state: free NMR (19) reference example 90 A:-CH₂- R⁴Crystalline form H: colorless amorphous state: free NMR (20)

TABLE 19 reference example 91m:1 A:-CH₂- R⁴Crystalline form H: yellow amorphous state: free NMR (21) reference example 92A:-CH₂- R⁴Crystalline form H: colorless amorphous state: free NMR (22) reference example 93m:1 A:-CH₂- R⁴Crystalline form H: yellow amorphous state: free NMR (23) reference example 94A:-CH₂- R⁴Crystalline form H: yellow amorphous state: free NMR (24)

TABLE 20 reference example 95m:1 A:-CH₂- R⁴Crystalline form H: white powder state: free NMR (25) reference example 96m:1 A:-CH₂- R⁴Crystalline form H: light yellow powder state: free NMR (26) reference example 97m:1 A:-CH₂- R⁴Crystalline form H: white amorphous state: free NMR (27) reference example 98 m:1 A:-CH₂- R⁴Crystalline form H: white amorphous state: free NMR (28)

TABLE 21 reference example 99m:1 A:-CH₂- R⁴Crystalline form H: white amorphous state: free NMR (29) reference example 100m:1 A:-CH₂- R⁴Crystalline form H: white amorphous state: free NMR (30) reference example 101m:1 A:-CH₂- R⁴Crystalline form H: yellow amorphous state: free NMR (31) reference example 102R⁵:-COOCH₃(2-position) m: 1A: -CH₂- R⁴Crystalline form H: light yellow amorphous state: free NMR (32)

TABLE 22 reference example 103R⁵:-(CH₂)₂CONH- (2-and 3-together) m: 2A: -CH₂- R⁴Crystalline form H: yellow amorphous state: free NMR (33) reference example 104R⁵Together with A to formm:1 R⁴Crystalline form H: white powder state: free NMR (35)

Tables 14 to 22¹The H-NMR spectra (NMR (1) to NMR (35)) were as follows:

NMR(1)(CDCl₃)δppm:4.37(1H,d,J=24Hz),4.77(2H,s),6.91(2H,d,J=8.8Hz),7.16(1H,t,J=7.3Hz),7.32(1H,t,J=7.3Hz),7.38-7.82(17H,m),7.89(2H,d,J=8.8Hz)

NMR(2)(CDCl₃)δppm:2.35(3H,s),4.41(1H,brs),4.70(2H,s),6.70(1H,d,J=8.2Hz),7.20-8.00(21H,m)

NMR(3)(DMSO-d₆)δppm:1.19(3H,t,J=7.4Hz),2.69(2H,q,J=7.4Hz),4.43(1H,d,J=2.5Hz),5.00(2H,s),6.83(1H,d,J=8.9Hz),7.25-7.38(1H,m),7.38-7.85(19H,m),7.98(1H,d,J=7.1Hz),12.65(1H,brs)

NMR(4)(CDCl₃)δppm:1.32(6H,d,J=7Hz),3.42(1H,sept,J=7Hz),4.2-4.6(1H,m),4.73(2H,s),7.25-8.0(21H,m),10.01(1H,br)

NMR(5)(CDCl₃)δppm:0.86(3H,t,J=7.2Hz),1.31-1.51(2H,m),1.51-1.72(2H,m),2.65-2.72(2H,m),3.76(3H,s),4.34(1H,br-d,J=24.7Hz),4.66(2H,s),5.98(1H,br-s),6.66(1H,d,J=8.3Hz),6.99-7.10(1H,m),7.19-7.31(1H,m),7.38-7.60(11H,m),7.60-7.87(8H,m)

NMR(6)(DMSO-d₆)δppm:4.52(1H,d,J=23Hz),5.12(2H,s),7.07(1H,d,J=8.4Hz),7.31(1H,td,J=7.6Hz,J=1.0Hz),7.45(1H,td,J=7.6Hz,J=1.4Hz),7.45-8.15(19H,m),12.68(1H,s)

NMR(7)(CDCl₃)δppm:4.34(1H,d,J=22Hz),4.79(2H,s),6.97(1H,t,J=8.4Hz),7.30-7.38(2H,m),7.38-7.92(19H,m),9.97(1H,br)

NMR(8)(DMSO-d₆)δppm:3.16(2H,t,J=7.0Hz),3.92(2H,t,J=7.0Hz),4.83(2H,s),5.13(2H,s),7.07(1H,d,J=9.4Hz),7.34(1H,t,J=6.5Hz),7.44(1H,t,J=6.5Hz),7.60-8.12(19H,m),12.70(1H,br)

NMR(9)(CDCl₃)δppm:1.67-1.90(4H,m),2.64-2.82(2H,m),3.68(1H,bt,J=6.0Hz),5.19(2H,s),6.12(2H,d,J=14.0Hz),7.10(1H,d,J=10.0Hz),7.29-7.41(1H,m),7.41-7.52(1H,m),7.69-7.95(17H,m),7.95-8.06(2H,m),12.74(1H,br-s)

NMR(10)(DMSO-d₆)δppm:1.10(3H,t,J=7.1Hz),2.62(2H,t,J=8.0Hz),2.90(2H,t,J=8.0Hz),4.00(2H,q,J=7.1Hz),4.33(1H,d,J=30.0Hz),5.01(2H,s),6.82(1H,d,J=14.0Hz),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=4.0Hz),12.61(1H,brs)

NMR(11)(CDCl₃)δppm:2.00(3H,s),2.05(3H,s),3.0-3.15(2H,m),4.0-4.35(2H,m),4.93,5.05(2H,ABq,J=16Hz),5.40(1H,m),6.1-6.6(2H,br),6.98(1H,d,J=8Hz),7.2-8.5(2H,m)

NMR(12)(CDCl₃)δppm:2.54-2.78(6H,m),2.87-3.12(2H,m),3.69-3.90(4H,m),4.36(1H,d,J=24.0Hz),4.78(2H,s),6.77(1H,d,J=8.5Hz),7.27-7.88(21H,m)

NMR(13)(CDCl₃)δppm:2.27(3H,s),2.32-2.76(10H,m),2.76-3.05(2H,m),4.36(1H,d,J=26.0Hz),4.71(2H,s),6.77(1H,d,J=8.3Hz),7.27-8.02(21H,m)

NMR(14)(CDCl₃)δppm:1.00(6H,t,J=7.1Hz),1.80-2.00(2H,m),2.48-2.62(6H,m),2.78(2H,t,J=6.2Hz),4.37(1H,d,J=24.4Hz),4.76(2H,s),6.80(1H,d,J=6.8Hz),7.32(1H,t,J=7.3Hz),7.39-7.93(20H,m)

NMR(15)(CDCl₃)δppm:1.72-2.05(2H,m),2.30-2.57(4H,m),2.70-2.89(2H,m),3.54-3.83(4H,m),4.37(1H,d,J=28.0Hz),4.74(2H,s),6.77(1H,d,J=8.3Hz),7.33(1H,t,J=7.3Hz),7.40-7.96(20H,m)

NMR(16)(CDCl₃)δppm:1.81-2.01(2H,m),2.22(3H,s),2.28-2.68(10H,m),2.79(2H,t,J=6.9Hz),4.37(1H,d,J=24.0Hz),4.76(2H,s),6.79(1H,d,J=8.4Hz),7.33(1H,t,J=8.8Hz),7.40-7.64(10H,m),7.64-7.95(10H,m)

NMR(17)(CDCl₃)δppm:1.7-3.3(16H,m),3.59(2H,m),4.81(2H,s),6.82(1H,d,J=8.5Hz),7.2-8.0(21H,m)

NMR(18)(CDCl₃)δppm: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=8.5Hz),7.2-7.9(21H,m)

NMR(19)(CDCl₃)δppm:1.41-2.31(9H,m),2.24(6H,s),2.46(2H,t,J=7.5Hz),2.77(2H,t,J=7.5Hz),2.93-3.12(2H,m),4.23-4.60(1H,br),4.73(2H,s),6.75(1H,d,J=8.5Hz),7.23-7.92(21H,m)

NMR(20)(CDCl₃)δppm:1.48-2.28(9H,m),2.36-2.61(6H,m),2.77(2H,t,J=7.5Hz),2.92-3.13(2H,m),3.65(4H,t,J=4.5Hz),4.19-4.58(1H,m),4.70(2H,s),6.71(1H,d,J=8.5Hz),7.02-7.94(21H,m)

NMR(21)(CDCl₃)δppm:1.41-2.03(8H,m),2.05-2.80(13H,m),2.77(2H,t,J=7.6Hz),2.88-3.07(2H,m),4.73(2H,s),6.75(1H,d,J=8.5Hz),7.32(1H,t,J=6.4Hz),7.40-7.90(20H,m)

NMR(22)(CDCl₃)δppm:1.62-2.23(8H,m),2.29-2.97(12H,m),3.48-3.93(3H,m),4.22-4.57(1H,br),4.69(2H,s),6.70(1H,d,J=8.5Hz),7.22-8.04(21H,m)

NMR(23)(CDCl₃)δppm:1.69-2.00(3H,m),2.00-2.62(16H,m),2.62-2.87(4H,m),3.50-3.92(3H,m),4.37(1H,d,J=26.8Hz),4.75(2H,s),6.77(1H,d,J=8.4Hz),7.28-7.92(21H,m)

NMR(24)(CDCl₃)δppm:1.82-2.22(4H,m),2.50(3H,s),2.54-3.12(12H,m),4.73(2H,s),6.71(1H,d,J=8.6Hz),7.29-7.88(21H,m)

NMR(25)(CDCl₃)δppm:1.55-1.85(4H,m),2.3-2.5(6H,m),2.7-2.9(2H,m),3.67(4H,t,J=4.5Hz),4.25-4.55(2H,m),4.76(2H,s),6.78(1H,d,J=8.5Hz),7.25-7.95(21H,m)

NMR(26)(DMSO-d₆)δppm:1.37-1.70(4H,m),2.08(3H,s),2.14-2.43(10H,m),2.60-2.77(2H,m),4.33(1H,d,J=26.0Hz),4.96(2H,s),6.80(1H,d,J=10.0Hz),7.27-7.38(1H,m),7.38-7.80(19H,m),7.90-8.03(1H,m)

NMR(27)(CDCl₃)δppm:1.00(3H,t,J=7.0Hz),1.01(3H,t,J=7.0Hz),2.68(2H,t,J=6.9Hz),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=8.5Hz),7.23-7.27(1H,m),7.29-7.57(10H,m),7.68-7.81(9H,m),7.92(1H,brs),11.97(1H,brs)

NMR(28)(CDCl₃)δppm:2.14-2.39(4H,m),2.22(3H,s),2.74(2H,t,J=6.3Hz),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,s),6.67(1H,d,J=8.6Hz),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)δppm:0.89(3H,t,J=7.1Hz),1.00(3H,t,J=7.1Hz),2.35-4.47(15H,m),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)(CDCl₃)δppm:1.01-1.47(2H,m),1.65-1.90(2H,m),2.29(3H,s),2.35-2.65(11H,m),2.65-2.91(2H,m),3.03-3.22(2H,m),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=8.6Hz),7.22-7.63(11H,m),7.63-7.88(9H,m),7.88-8.00(1H,m)

NMR(31)(CDCl₃)δppm:2.18-3.50(20H,m),3.50-3.71(1H,m),3.71-3.95(1H,m),4.20-4.82(4H,m),6.65-6.74(1H,m),7.20-7.63(12H,m),7.63-7.86(9H,m),7.86-7.98(1H,m)

NMR(32)(CDCl₃)δppm:4.09(3H,s),4.42(1H,d,J=22,9Hz),4.85(2H,s),6.93(1H,d,J=8.7Hz),7.00-7.18(1H,m),7.18-7.98(18H,m),8.19(1H,dd,J=2.2Hz,J=8.7Hz),8.60(1H,d,J=2.2Hz),11.55(1H,br)

NMR(33)(CDCl₃)δppm:2.73(2H,t,J=7.4Hz),3.37(2H,t,J=7.4Hz),4.06(1H,d,J=20.6Hz),4.84(2H,s),6.77(1H,d,J=8.6Hz),7.28-7.77(20H,m),10.85(1H,br),12.16(1H,br)

NMR(35)(DMSO-d₆)δppm:2.03-2.46(2H,m),2.67-3.06(2H,m),4.28-4.52(1H,m),4.94-5.24(1H,m),6.83-8.11(22H,m),12.61(1H,brs)

prepared by the same method as described in reference example 2 using a suitable starting compound

The compounds listed in tables 23-31 below.

TABLE 23Reference example 105R¹:H R²:H R⁴:HR⁵:H m:1 A:-CH₂-a crystalline form: white powder state: free NMR (1)

Table 23 shows¹The H-NMR spectrum (NMR (1)) was as follows:

NMR(1)(CDCl₃)δppm:4.81(2H,s),7.05(1H,d,J=3.5Hz),7.25-7.35(2H,m),7.45-7.65(2H,m),7.50(1H,d,J=3.5Hz),10.00(1H,s),10.06(1H,brs)

watch 24Reference example 106R¹:H R²:H R⁴:HR⁵:H m:1 A:-(CH₂)₃-a crystalline form: light yellow particle state: free NMR (1) reference example 107 R⁵:H R⁴:H

m:1 A:-CH₂-a crystalline form: light yellow particle state: free NMR (2) reference example 108R¹:H R²:H R⁴:HR⁵:CH₃(2-and 6-positions) m: 2A: -CH₂-a crystalline form: yellow powder state: free NMR (3)

TABLE 25 reference example 109 R⁵:-CH₂N(C₂H₅)₂(2-position)

R⁴:H m:1 A:-CH₂-a crystalline form: white powder state: free NMR (4) reference example 110

R⁴:H m:1 A:-CH₂-a crystalline form: yellow powder state: free NMR (5) reference example 111 R⁵:-(CH₂)₂N(C₂H₅)₂(2-position)

R⁴:H m:1 A:-CH₂-a crystalline form: brown powder state: HCl NMR (6) reference example 112

R⁴:H m:1 A:-CH₂-a crystalline form: white powder state: 2HCl NMR (7)

TABLE 26 reference example 113 R⁵:-(CH₂)₃OH (2-position) R⁴:H m:1 A:-CH₂-a crystalline form: white powder state: free NMR (8) reference example 114R⁴:H m:1 A:-CH₂-a crystalline form: light yellow powder state: free NMR (9) reference example 115 R⁵:-CH₂N(C₂H₅)₂(2-position) R⁴:H m:1 A:-(CH₂)₅-a crystalline form: yellow oil state: free NMR (10) reference example 116 R⁵:-CH₂N(C₂H₅)2 (2-position) R⁴:H m:1 A:-(CH₂)₃-a crystalline form: yellow amorphous state: free NMR (11)

TABLE 27 reference example 117

R⁴:H m:1 A:-CH₂-a crystalline form: light yellow powder state: free NMR (12) reference example 118

R⁴:H m:1 A:-CH₂-a crystalline form: yellow powder state: 2HCl NMR (13) reference example 119

R⁴:H m:1 A:-CH₂-a crystalline form: light yellow powder state: 2HCl NMR (14) reference example 120 R⁵:H R⁴:Hm:1 A:-CH₂-a crystalline form: yellow powder state: free NMR (15)

TABLE 28 reference example 121R¹:CH₃ R²:H R⁴:HR⁵:H m:1 A:-CH₂-a crystalline form: light brown powder state: free NMR (16) reference example 122R ¹:(CH₃)₃C- R²:H R⁴:HR⁵:H m:1 A:-CH₂-a crystalline form: white powder state: free NMR (17) reference example 123

R²:H R⁴:HR⁵:H m:1 A:-CH₂-a crystalline form: light yellow powder state: free NMR (18) reference example 124R⁴:H m:1 A:-CH₂-a crystalline form: light yellow oil state: free NMR (19)

TABLE 29 reference example 125R⁴:H m:1 A:-CH₂-a crystalline form: yellow amorphous state: free NMR (20) reference example 126R⁴:H m:1 A:-CH₂-a crystalline form: yellow amorphous state: free NMR (21) reference example 127R⁴:H m:1 A:-CH₂-a crystalline form: yellow amorphous state: free NMR (22) reference example 128R⁴:H m:1 A:-CH₂-a crystalline form: yellow amorphous state: free NMR (23)

TABLE 30 reference example 129R⁴:H m:1 A:-CH₂-a crystalline form: light yellow amorphous state: free NMR (24) reference example 130R⁴:H m:1 A:-CH₂-a crystalline form: light yellow amorphous state: free NMR (25) reference example 131R⁴:H m:1 A:-CH₂-a crystalline form: light yellow undefined state: free NMR (26) reference example 132 R⁴:H m:1 A:-CH₂-a crystalline form: yellow amorphous state: 3HCl NMR (27)

TABLE 31 reference example 133R⁴:H m:1 A:-CH₂-a crystalline form: yellow amorphous state: free NMR (28) reference example 134R⁴:H m:1 A:-CH₂-a crystalline form: colorless amorphous state: free NMR (29) reference example 135 R⁵Together with A to formR⁴H m:1 crystalline form: white oil state: free NMR (30)

Tables 24 to 31¹The H-NMR spectra (NMR (1) to NMR (30)) were as follows:

NMR(1)(DMSO-d₆)δppm:2.08(2H,q,J=6.6Hz),2.62(2H,t,J=7.2Hz),4.13(2H,t,J=4.1Hz),7.10(2H,d,J=8.6Hz),7.19(1H,d,J=3.6Hz),7.45(1H,d,J=3.6Hz),7.85(2H,d,J=8.6Hz),9.86(1H,s),12.13(1H,s)

NMR(2)(DMSO-d₆)δppm:5.07(2H,s),7.19(2H,d,J=8.7Hz),7.27-7.40(1H,m),7.40-7.56(1H,m),7.77(1H,d,J=7.5Hz),7.90(2H,d,J=8.8Hz),7.98(1H,d,J=7.1Hz),9.89(1H,s),12.1-13.0(1H,br)

NMR(3)(CDCl₃)δppm:2.38(6H,s),4.57(2H,s),7.06(1H,d,J=3.6Hz),7.51(1H,d,J=3.6Hz),7.61(2H,s),9.92(1H,s),10.10(1H,brs)

NMR(4)(CDCl₃)δppm:1.13(6H,t,J=7.1Hz),2.93(4H,q,J=7.1Hz),3.79(2H,s),5.01(2H,s),7.08(1H,d,J=8.2Hz),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)δppm:2.33(3H,s),2.42-2.88(8H,m),3.71(2H,s),4.92(2H,s),7.02(1H,d,J=8.2Hz),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)δppm:1.29(6H,t,J=7.1Hz),2,98-3.48(8H,m),5.20(2H,s),7.22(1H,d,J=9.0Hz),7.35(1H,d,J=7.6Hz),7.49(1H,d,J=7.6Hz),7.80(1H,d,J=7.8Hz),7.85-7.98(2H,m),8.01(1H,d,J=7.4Hz),9.91(1H,s),10.36(1H,br),12.84(1H,br)

NMR(7)(CDCl₃)δppm:2.86(3H,s),3.14-4.00(12H,m),5.21(2H,s),7.22(1H,d,J=7.8Hz),7.35(1H,t,J=7.6Hz),7.49(1H,t,J=7.6Hz),7.78-7.87(3H,m),8.01(1H,d,J=8.1Hz),9.90(1H,s),11.60(2H,br),12.75(1H,br)

NMR(8)(CDCl₃)δppm:1.83-2.11(2H,m),3.06(2H,t,J=7.3Hz),3.85(2H,t,J=5.2Hz),4.22(1H,br),4.85(2H,s),6.98(1H,d,J=8.2Hz),7.28-7.41(1H,m),7.41-7.49(1H,m),7.74-7.86(4H,m),9.92(1H,s),11.84(1H,br)

NMR(9)(CDCl₃)δppm:1.83-2.06(2H,m),2.25(3H,s),2.32-2.76(10H,m),2.88(2H,t,J=7.7Hz),4.87(2H,s),6.97(1H,d,J=8.3Hz),7.30-7.42(1H,m),7.42-7.51(1H,m),7.72-7.87(4H,m),9.94(1H,s)

NMR(10)(CDCl₃)δppm:0.99(6H,t,J=7.1Hz),1.40-1.61(2H,m),1.70-1.92(4H,m),2.43-2.63(6H,m),3.56(2H,s),3.95(2H,t,J=6.3Hz),6.86(1H,d,J=8.5Hz),7.28-7.40(1H,m),7.40-7.51(1H,m),7.70-7.91(3H,m),7.95(1H,d,J=2.1Hz),9.89(1H,s),10.39-13.00(1H,brs)

NMR(11)(CDCl₃)δppm:0.97(6H,t,J=7.1Hz),2.10-2.40(2H,m),2.40-2.68(6H,m),3.54(2H,s),3.95-4.23(2H,m),6.84(1H,t,J=8.5Hz),7.20-7.40(2H,m),7.58-7.88(3H,m),7.90(1H,d,J=2.1Hz),9.87(1H,s)

NMR(12)(CDCl₃)δppm:1.38-1.76(2H,m),1.76-2.13(6H,m),2.13-2.70(14H,m),2.88(2H,t,J=7.6Hz),2.95-3.18(2H,m),4.86(2H,s),6.97(1H,d,J=8.2Hz),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-d₆)δppm:1.92-2.45(6H,m),2.60-3.21(9H,m),3.21-3.76(4H,m),3.76-4.16(4H,m),5.17(2H,s),7.15(1H,d,J=8.8Hz),7.31(1H,t,J=6.9Hz),7.45(1H,t,J=6.9Hz),7.68-7.92(3H,m),7.99(1H,d,J=7.0Hz),9.87(1H,s),10.73(1H,br),11.78(1H,br),12.80(1H,s)

NMR(14)(DMSO-d₆)δppm:1.28(6H,t,J=7.1Hz),2.00-2.38(6H,m),2.68-2.90(2H,m),2.90-3.25(8H,m),3.47-3.83(3H,m),5.18(2H,s),7.18(1H,d,J=8.7Hz),7.34(1H,t,J=7.7Hz),7.45(1H,t,J=7.7Hz),7.78-7.86(3H,m),8.00(1H,d,J=7.0Hz),9.90(1H,s),10.78(2H,br),12.80(1H,br)

NMR(15)(DMSO-d₆)δppm:2.40(3H,s),5.06(2H,s),7.15-7.40(3H,m),7.65(1H,d,J=8.4Hz),7.77(1H,s),7.89(2H,d,J=8.6Hz),9.88(1H,s),12.61(1H,s)

NMR(16)(DMSO-d₆)δppm:2.27(3H,d,J=0.9Hz),4.98(2H,s),6.79(1H,d,J=1.0Hz),7.12-7.25(2H,m),7.82-7.96(2H,m),9.88(1H,s),12.0-12.7(1H,br)

NMR(17)(DMSO-d₆)δppm:1.26(9H,s),4.98(2H,s),6.78(1H,s),7.15(2H,d,J=8.8Hz),7.90(2H,d,J=8.8Hz),9.88(1H,s),12.42(1H,s)

NMR(18)(DMSO-d₆)δppm:5.05(2H,s),7.19(2H,d,J=8.8Hz),7.25-7.55(3H,m),7.69(1H,s),7.80-8.02(4H,m),9.89(1H,s),12.60(1H,s)

NMR(19)(DMSO-d₆)δppm:1.57-1.84(7H,m),1.84-2.05(3H,m),2.20(1H,q,J=8.5Hz),2.30-2.72(8H,m),2.74-3.12(3H,m),3.16-3.30(1H,m),4.87(2H,s),6.97(1H,d,J=8.3Hz),7.27-7.41(1H, m),7.41-7.53(1H,m),7.70-7.93(4H,m),9.91(1H,s)

NMR(20)(CDCl₃)δppm:1.67-2.95(20H,m),3.55-3.95(3H,m),4.90(2H,s),6.96(1H,d,J=8.3Hz),7.25-7.53(2H,m),7.55-7.95(4H,m),9.90(1H,s)

NMR(21)(CDCl₃)δppm:1.55-3.80(23H,m),4.91(2H,s),6.96(1H,d,J=8.4Hz),7.25-7.52(2H,m),7.65-7.78(4H,m),9.88(1H,s)

NMR(22)(CDCl₃)δppm:1.75-2.95(16H,m),3.55-3.95(7H,m),4.88(2H,s),6.95(1H,d,J=8.3Hz)7.28-7.55(2H,m),7.65-7.95(4H,m),9.90(1H,s)

NMR(23)(CDCl₃)δppm:1.75-3.00(20H,m),2.27(3H,s),3.58-3.98(3H,m),4.88(2H,s),6.95(1H,d,J=8.3Hz),7.30-7.52(2H,m),7.65-7.90(4H,m),9.89(1H,s)

NMR(24)(CDCl₃)δppm:1.5-3.4(15H,m),2.40(4H,t,J=4.5Hz),3.61(4H,t,J=4.5Hz),4.88(2H,s),6.99(1H,d,J=8.5Hz),7.3-7.55(2H,m),7.7-7.9(4H,m),9.92(1H,s)

NMR(25)(CDCl₃)δppm:1.5-3.1(23H,m),2.24(3H,s),4.91(2H,s),7.00(1H,d,J=8Hz),7.3-7.5(2H,m),7.7-7.9(4H,m),9.91(1H,s)

NMR(26)(CDCl₃)δppm:1.7-2.0(4H,m),2.33(3H,s),2.5-3.0(12H,m),4.87(2H,s),6.97(1H,d,J=8Hz),7.3-7.9(6H,m),9.91(1H,s)

NMR(27)(DMSO-d₆)δppm:1.30-3.51(25H,m),3.51-3.75(2H,m),5.16(2H,s),7.09(1H,d,J=8.9Hz),7.27-7.39(1H,m),7.39-7.52(1H,m),7.70-7.84(3H,m),7.98-8.09(1H,m),9.86(1H,s),10.58-11.17(3H,m)

NMR(28)(DMSO-d₆)δppm:1.45(6H,s),2.68-3.01(2H,m),2.77(3H,s),3.21-3.85(10H,m),5.24(2H,s),7.10(1H,d,J=8.3Hz),7.29-7.40(1H,m),7.40-7.52(1H,m),7.74-7.89(3H,m),7.93-8.05(1H,m),9.89(1H,s),11.10-13.00(3H,m)

NMR(29)(CDCl₃)δppm:1.86(2H,quint,J=7.5Hz),2.18-2.63(10H,m),2.30(3H,s),3.05(2H,t,J=7.5Hz),4.82(2H,s),6.24-7.01(2H,m),7.10-7.59(3H,m),7.73-7.93(3H,m),10.17(1H,s)

NMR(30)(CDCl₃)δppm:3.46(1H,dd,J=6.5Hz,J=16.5Hz),3.68(1H,dd,J=10.5Hz,J=16.5Hz),5.67(1H,dd,J=6.5Hz,J=10.5Hz),7.08(1H,d,J=8.5Hz),7.25-7.55(2H,m),7.75-7.85(3H,m),7.99(2H,d,J=8.5Hz),9.84(1H,s)

using a suitable starting compound, the same procedure as described with reference to examples 7, 8 or 9 can be followed

The compounds listed in tables 32-37 below were prepared.

TABLE 32 reference example 136Crystalline form 145 ℃ (0.3 mmHg): colorless oil state: free NMR (1) reference example 137Crystal form: light yellow oil state: free NMR (2) reference example 138Crystal form: colorless oil state: free NMR (3) reference example 139Crystal form: brown oil state: free NMR (4) reference example 140Crystal form: brown oil state: free NMR (5) reference example 141 Crystal form 90-95 ℃ (0.15 mmHg): colorless oil state: free reference example 142(cis-form) b.p. crystal form 90-95 ℃ (0.2 mmHg): colorless oil state: free reference example 143Crystalline form 107 ℃ (0.35 mmHg): colorless oil state: free form

TABLE 33 reference example 144Crystal form: white solid state: free NMR (6) reference example 145B.p. 160-165 ℃ (0.25-0.3mmHg) crystalline form: colorless oil state: free reference example 146B.p. crystalline form at 140 ℃ (0.25-0.3mmHg) 135-: colorless oil state: free NMR (7) reference example 147Crystal form: colorless oil state: free NMR (8) reference example 148Crystal form: colorless oil state: free NMR (9) reference example 149Crystal form: colorless oil state: free NMR (10) reference example 150Crystal form: colorless oil state: free NMR (11) reference example 151Crystal form: brown oil state: free NMR (12)

TABLE 34 REFERENCE EXAMPLE 152B.p. 110-: colorless oil state: free reference example 153Crystal form: light yellow oil state: free NMR (13) reference example 154Crystal form: yellow powder state: free NMR (14) reference example 155 Crystal form at 110 ℃ (0.35 mmHg): colorless oil state: free reference example 156110-: colorless oil state: free reference example 157B.p. crystalline form at 127 ℃ C. (12 mmHg): colorless oil state: free reference example 158113-: colorless oil state: free reference example 159165-170 ℃ (15mmHg) crystalline form: colorless oil state: free NMR (15)

TABLE 35 reference example 160180 ℃ 185 ℃ (15mmHg) crystalline form: colorless oil state: free NMR (16) reference example 161138-143 ℃ (12mmHg) crystalline form: colorless oil state: free reference example 162112 ℃ 116 ℃ (0.23mmHg) M.p.39-41 ℃ crystalline form: colorless oil state: free reference example 163Form 116 ℃ (0.23 mmHg): colorless oil state: free reference example 164Form 108 ℃ (0.3 mmHg): colorless oil state: free reference example 165M.p.73-75.5 ℃ crystalline form: white powder state: free reference example 166B.p. crystal form 134-: colorless oil state: reference example 167B.p. 124-: colorless oil state: free form

TABLE 36 REFERENCE EXAMPLE 168Crystal form: white powder state: 3HClNMR (17) reference example 169The state is as follows: free NMR (18) reference example 170Crystal form: colorless oil state: free NMR (19) reference example 171Crystal form: colorless oil state: free NMR (20) reference example 172110-: colorless oil state: free reference example 173B.p. crystalline form 115-136 ℃ (20 mmHg): colorless oil state: free reference example 174115-: colorless oil state: free reference example 175Crystal form: white powder state: 3HClNMR (21)

TABLE 37 reference example 176165-170 ℃ (18mmHg) crystalline form: yellow oil state: free NMR (22)

The H-NMR spectra (NMR (1) to NMR (22)) shown in tables 32 to 37 are as follows:

NMR(1)(CDCl₃)δppm:1.05(3H,d,J=6Hz),1.25-1.55(2H,m),1.75-3.3(14H,m),2.31(3H,s)

NMR(2)(CDCl₃)δppm:0.89(3H,t,J=7.5Hz),1.17-1.54(3H,m),1.54-1.78(1H,m),1.78-1.94(2H,m),1.94-2.18(3H,m),2.18-2.49(6H,m),2.49-2.72(2H,m),2.72-2.95(3H,m),3.03-3.27(2H,m)

NMR(3)(CDCl₃)δppm:0.91(3H,t,J=7Hz),1.15-1.7(5H,m),1.75-2.15(6H,m),2.28(3H,s),2.15-2.45(3H,m),2.45-2.65(2H,m),2.7-2.95(3H,m),3.05-3.25(2H,m)

NMR(4)(CDCl₃)δppm:0.85-0.94(6H,m),1.23-1.54(2H,m),1.62(1H,br),1.80-1.96(3H,m),1.96-2.18(2H,m),2.18-2.45(6H,m),2.45-2.68(2H,m),2.68-2.92(3H,m),3.00-3.24(2H,m)

NMR(5)(CDCl₃)δppm: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)δppm:1.06(6H,d,J=6.5Hz),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)δppm:1.25-1.6(3H,m),1.6-2.75(14H,m),2.85(1H,dd,J=2Hz,J=11.5Hz),2.9-3.3(5H,m)

NMR(8)(CDCl₃)δppm:1.00(3H,t,J=7.3Hz),1.04(3H,d,J=6.3Hz),1.24-1.51(2H,m),1.70-1.92(3H,m),2.03(1H,t,J=10.7Hz),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)δppm:0.84(3H,t,J=7.3Hz),1.03(3H,d,J=6.2Hz),1.25-1.65(4H,m),1.65-1.93(3H,m),2.02(1H,q,J=10.7Hz),2.19-2.48(5H,m),2.48-2.95(6H,m),3.05-3.21(2H,m)

NMR(10)(CDCl₃)δppm:0.89(3H,d,J=6.5Hz),1.03(6H,dd,J=6.5Hz,J=15.1Hz),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(6H,m),3.13-3.40(3H,m),4.85(1H,br)

NMR(11)(CDCl₃)δppm:1.03(3H,d,J=6.2Hz),1.33-1.52(2H,m),1.72-3.08(16H,m),3.08-3.23(2H,m),3.45-3.80(2H,m)

NMR(12)(CDCl₃)δppm:1.04(3H,d,J=6.2Hz),1.49-1.68(2H,m),1.80-1.99(2H,m),2.06(1H,t,J=10.1Hz),2.24-2.55(5H,m),2.57-2.88(4H,m),2.90-3.10(2H,m),3.15-3.31(3H,m),3.34(3H,s),3.44-3.62(2H,m)

NMR(13)(CDCl₃)δppm:1.07(3H,t,J=7.1Hz),1.40(2H,dq,J=3.8Hz,J=12.0Hz),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)δppm:0.91(3H,t,J=7.1Hz),1.14-1.58(5H,m),1.58-2.13(5H,m),2.22-2.87(13H,m),3.01-3.24(2H,m)

NMR(15)(CDCl₃)δppm:2.0-3.2(17H,m),2.26(3H,s),2.32(3H,s)

NMR(16)(CDCl₃)δppm:1.8-1.9(2H,m),2.0-3.2(17H,m),2.33(3H,s),2.34(3H,s)

NMR(17)(DMSO-d₆)δppm:1.94-2.46(6H,m),2.69(3H,d,J=3.7Hz),2.84-3.16(2H,m),3.16-4.30(11H,m),9.56(1H,br),9.99(1H,br),11.04(1H,br),12.06(1H,br)

NMR(18)(CDCl₃)δppm:1.08(3H,d,J=6.2Hz),1.28-1.55(2H,m),1.55-1.95(5H,m),2.38(3H,s),2.40-2.99(10H,m),3.02-3.22(2H,m)

NMR(19)(CDCl₃)δppm:1.05(3H,d,J=6Hz),1.25-1.55(2H,m),1.75-3.3(14H,m),2.31(3H,s)

NMR(20)(CDCl₃)δppm:1.05(3H,d,J=6Hz),1.25-1.55(2H,m),1.75-3.3(14H,m),2.31(3H,s)

NMR(21)(DMSO-d₆)δppm:1.78-2.47(6H,m),2.68-3.06(2H,m),3.14-4.32(16H,m),5.20-5.78(2H,m),9.1-9.82(2H,m),10.54-11.36(H,m),11.82-12.38(1H,m)

NMR(22)(CDCl₃)δppm:1.3-1.7(6H,m),2.0-3.2(13H,m),2.32(3H,s)

reference example 182

To a solution of tert-butyl propiolate (9.7g) in tetrahydrofuran (300ml) was added dropwise a 1.6M solution of n-butyllithium in n-hexane (48ml) at-70 ℃ and the mixture was allowed to react for 10 minutes. To the mixture was added dropwise a solution of 2- { (2-methoxy-4-formylphenoxy) methylcarbonylamino } benzothiazole (10g) in tetrahydrofuran (200ml) and N, N-dimethylpropyleneurea (20ml) at the same temperature over 20 minutes, the reaction mixture was allowed to react further for 20 minutes, and then the reactor was taken out of the ice bath, and the mixture was stirred further for 20 minutes. To the mixture was added acetic acid (5ml), and the mixture was diluted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, dried over sodium sulfate, concentrated, and the resulting residue was recrystallized from ethyl acetate-n-hexane. The crystals were collected by filtration to give 2- [ 2-methoxy-4- (3-tert-butoxycarbonyl-1-hydroxypropylpropyl) phenoxymethylcarbonylamino ] benzothiazole (13g) as a white powder.

Reference example 183

A solution of sodium hydroxide (4.92g) in water (5ml) was diluted with ethanol (80ml), and the mixture was degassed and then placed under a nitrogen atmosphere. To the mixture was added 3-methoxy-4-dimethylaminocarbonyl benzaldehyde (20g) and the mixture was refluxed for 14 hours. After cooling, ethyl bromoacetate (9.74ml) was added dropwise to the mixture, and the mixture was stirred at room temperature for 3 hours. Ethanol, 1.5N hydrochloric acid and water were added to the mixture, and the mixture was extracted with chloroform. The extract was dried over sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (solvent: n-hexane: ethyl acetate = 9: 1 → 5.6: 1 → 4: 1) to give 3-methoxy-4-ethoxycarbonylmethylthiobenzaldehyde (11.8g), a white solid.

¹H-NMR(CDCl₃)δppm:1.21(3H,t,J=7.1Hz),3.74(2H,s),3.99(3H,s),4.14(2H,q,J=7.1Hz),7.32-7.48(3H,m),9.92(1H,s)

Reference example 184

The following compounds were obtained in the same manner as described in reference example 1 using suitable starting compounds.

α - (2-methoxy-4-formylphenoxymethyl) acetic acid:

yellow powder

¹H-NMR(DMSO-d₆)δppm:3.84(3H,s),4.82(2H,s),7.05(1H,d,J=8Hz),7.41(1H,d,J=2Hz),7.51(1H,dd,J=2Hz,J=8Hz),9.83(1H,s),13.14(1H,br)

Reference example 185

The following compounds were obtained in the same manner as described in reference example 2 using suitable starting compounds.

2- (2-methoxy-4-formylphenoxymethylcarbonylamino) benzimidazole:

yellow powder

¹H-NMR(CDCl₃) δ ppm 4.06(3H, s),4.86(2H, s),7.09(1H, d, J =8.5Hz),7.3-7.55(4H, m),7.8-7.9(2H, m),9.91(1H, s),10.25(1H, br)2- (2-ethoxy-4-formylphenoxymethylcarbonylamino) benzimidazole:

White powder

¹H-NMR(CDCl₃) δ ppm 1.60(3H, t, J =7.0Hz),4.26(2H, q, J =7.0Hz),4.87(2H, s),7.11(1H, d, J =8.3Hz),7.30-7.49(4H, m),7.79-7.88(2H, m),9.90(1H, s),10.34(1H, br)2- [2- (diethylaminocarbonylmethoxy) -4-formylphenoxymethylcarbonylamino]Benzimidazole:

white powder

¹H-NMR(CDCl₃)δppm:1.16(3H,t,J=7Hz),1.30(3H,t,J=7Hz),3.35(2H,q,J=7Hz),3.49(2H,q,J=7Hz),4.92(2H,s),5.00(2H,s),7.09(1H,d,J=8Hz),7.25-7.55(4H,m),7.7-7.85(2H,m),9.86(1H,s)

Reference example 186

The following compounds were obtained in the same manner as described in reference example 5 using suitable starting compounds.

[3- (2-chloroethyl) -4- (2-benzothiazolylaminocarbonylmethoxy) benzoyl ] methyltriphenylphosphonium bromide:

¹H-NMR(DMSO-d₆)δppm:3.16(2H,t,J=7.0Hz),3.92(2H,t,J=7.0Hz),5.18(2H,s),6.12(2H,d,J=13.1Hz),7.14(1H,d,J=9.4Hz),7.31(1H,t,J=6.5Hz),7.44(1H,t,J=6.5Hz),7.60-8.12(19H,m),12.70(1H,br)

[3- (2, 3-diacetoxypropyl) -4- (2-benzothiazolylaminocarbonylmethoxy) benzoyl ] methyltriphenylphosphonium chloride:

¹H-NMR(CDCl₃)δppm:2.00(3H,s),2.05(3H,s),3.0-3.15(2H,m),4.0-4.35(2H,m),4.93,5.05(2H,AB-q,J=16Hz),5.40(1H,m),6.1-6.6(2H,br),6.98(1H,d,J=8Hz),7.2-8.5(21H,m)

reference example 187

To a solution of methyl 2, 4-dihydroxybenzoate (25.1g) in acetone (250ml) were added methyl bromoacetate (14.9ml) and potassium carbonate (21.7g), and the mixture was refluxed for 3 hours. The mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (solvent: n-hexane: ethyl acetate = 3: 1) to give ethyl 2- (3-hydroxy-4-methoxycarbonylphenoxy) acetate (31.5 g).

White powder

¹H-NMR(CDCl₃)δppm:3.81(3H,s),3.91(3H,s),4.65(2H,s),6.39(1H,d,J=2.6Hz),6.45(1H,dd,J=2.6Hz,J=8.8Hz),7.73(1H,d,J=8.8Hz),10.97(1H,s)

Reference example 188

To ethanol (50ml) was added 2- (2-phthalimide) methylbenzothiazole (3.37g) and hydrazine monohydrate (3ml) and the mixture was refluxed for 30 minutes. When it was confirmed that the starting compound had been consumed, the precipitated solid was removed by filtration, and the filtrate was concentrated. To the residue was added an aqueous potassium carbonate solution, and the mixture was extracted with dichloromethane. The extract was dried over magnesium sulfate and concentrated under reduced pressure to remove the solvent, to give 2-aminomethylbenzothiazole (1.42 g).

Yellow powder

¹H-NMR(CDCl₃)δppm:1.83(2H,br),4.30(2H,s),7.33-7.51(2H,m),7.85-7.99(2H,m)

Reference example 189

To dichloromethane (50ml) were added 2-hydroxymethylbenzothiazole (2g) and triethylamine (2.5ml), and methanesulfonyl chloride (1.03ml) was further added thereto under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. After completion of the reaction, the mixture was washed with hydrochloric acid, dried over magnesium sulfate, and concentrated under reduced pressure to remove the solvent. The resulting crude product was dissolved in dimethylformamide (50ml) and potassium phthalimide (5.6g) was added thereto. The mixture was heated at 70 ℃ for 1 hour with stirring. After completion of the reaction, the reaction mixture was poured into water, and the precipitated crystals were collected by filtration. The filtrate was extracted with ethyl acetate, and the extract was concentrated under reduced pressure. The residue was combined with the previously obtained crystals and washed with n-hexane-diethyl ether to give 2- (phthalimide) methylbenzothiazole (3.37 g).

Yellow powder

¹H-NMR(CDCl₃) Delta ppm 5.30(2H, s),7.35-7.47(2H, m),7.74-8.02(6H, m) reference example 190

A solution of methyl p-formylbenzoate (12.33g), malonic acid (16g) and piperidine (1ml) in pyridine (100ml) was refluxed for 2 hours. The reaction mixture was poured into ice water and a white powder precipitated was collected by filtration, washed with water and dried to give 4-methoxycarbonylcinnamic acid (14.7 g).

White powder

¹H-NMR(DMSO-d₆)δppm:3.85(3H,s),6.65(1H,d,J=16Hz),7.63(1H,d,J=16Hz),7.82(2H,d,J=8Hz),8.01(2H,d,J=8Hz),12.57(1H,br)

Reference example 191

To a solution of 4-methoxycarbonylcinnamic acid (4.64g) in acetic acid (300ml) was added 10% palladium-carbon (0.5g) and the mixture was hydrogenated at 70 ℃ under normal pressure for 2 hours. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. Water was added to the residue, and a white powder precipitated was collected by filtration to give 3- (4-methoxycarbonylphenyl) propionic acid (3.87 g).

White powder

¹H-NMR(CDCl₃)δppm:2.71(2H,t,J=7.5Hz),3.02(2H,t,J=7.5Hz),3.91(3H,s),7.29(2H,d,J=8.5Hz),7.97(2H,d,J=8.5Hz)

Reference example 192

To a suspension of 2-carboxybenzothiazole (6.5g) in dry dichloromethane (100ml) were added oxalyl chloride (3.2ml) and one drop of dimethylformamide and the mixture was stirred at room temperature for 3 hours. The mixture was evaporated to remove methylene chloride, and the residue was dissolved in acetone (100ml) and added dropwise to a solution of sodium azide (5g) in water (20ml) under ice-cooling. The mixture was stirred at the same temperature for 3 hours and water was added thereto. The precipitated crystals were collected by filtration, dissolved in methylene chloride (50ml), dried and concentrated under reduced pressure to remove the solvent. Benzene (50ml) was added to the residue and the mixture was refluxed for 4 hours. To the mixture was added ethyl 4-piperidinecarboxylate (5.7g), and the mixture was refluxed for 6 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (solvent: dichloromethane: methanol = 200: 1 → 100: 1) to give 2- (4-ethoxycarbonyl-1-piperidinyl) carbonylaminobenzothiazole (4.0 g).

White powder

¹H-NMR(CDCl₃)δppm:1.25(3H,t,J=7Hz),1.65-2.05(4H,m),2.4-2.6(1H,m),2.95-3.2(2H,m),4.0-4.2(2H,m),4.14(2H,q,J=7Hz),7.15-7.45(2H,m),7.58(1H,d,J=8Hz),7.75(1H,d,J=8Hz),10.11(1H,br)

Reference example 193

To a solution of methyl 2-methoxy-4-trifluoromethanesulfonyloxybenzoate (26.8g), tert-butyl acrylate (62.5ml), triethylamine (25ml) in anhydrous dichloromethane (100ml) under argon atmosphere were added palladium acetate (0.4g) and 1, 3-bis (diphenylphosphino) propane (0.74g) and the mixture was heated at 75 ℃ for 16 hours. The reaction solution was concentrated under reduced pressure to remove the solvent, and water was added thereto. The mixture was extracted with ethyl acetate, and the extracts were washed with water, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent: ethyl acetate: n-hexane = 1: 5) to give tert-butyl 3-methoxy-4-methoxycarbonylcinnamate (23.5 g).

Yellow powder

¹H-NMR(CDCl₃)δppm:1.54(9H,s),3.90(3H,s),3.94(3H,s),6.42(1H,d,J=16Hz),7.07(1H,d,J=1.5Hz),7.13(1H,dd,J=1.5,8Hz),7.55(1H,d,J=16Hz),7.80(1H,d,J=8Hz)

Reference example 194

To a solution of tert-butyl 3-methoxy-4-methoxycarbonylcinnamate (23.5g) in anhydrous dichloromethane (100ml) was added trifluoroacetic acid (50ml) under ice cooling and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was crystallized from ethanol to give 3-methoxy-4-methoxycarbonylcinnamic acid (8.35 g).

White powder

¹H-NMR(CDCl₃+DMSO-d6)δppm:3.88(3H,s),3.94(3H,s),6.50(1H,d,J=16Hz),7.13(1H,s),7.15(1H,d,J=8Hz),7.62(1H,d,J=16Hz),7.78(1H,d,J=8Hz)

Reference example 195

To a suspension of 3-methoxy-4-methoxycarbonylcinnamic acid (8.35g) in acetic acid (200ml) was added 10% palladium-carbon (1.0g), and the mixture was hydrogenated at room temperature. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was crystallized from diethyl ether-n-hexane to give 3- (3-methoxy-4-methoxycarbonylphenyl) propionic acid (7.5 g).

White powder

¹H-NMR(CDCl₃)δppm:2.70(2H,t,J=7.5Hz),2.98(2H,t,J=7.5Hz),3.88(3H,s),3.89(3H,s),5.71(1H,br),6.75-6.9(2H,m),7.75(1H,d,J=8Hz)

Reference example 196

To a solution of dimethyl methylphosphonate (7.7ml) in anhydrous tetrahydrofuran (100ml) was added dropwise a solution of 1.66M n-butyllithium in n-hexane (43ml) at-50 ℃ to-60 ℃. Subsequently, a solution of 2- [2- (3-methoxy-4-methoxycarbonylphenyl) ethyl ] carbonylaminobenzothiazole (8.72g) in anhydrous tetrahydrofuran (50ml) was added dropwise to the reaction solution. A yellow gum-like product was formed in the reaction mixture, to which was further added 1, 3-dimethyl-3, 4,5, 6-tetrahydro-2 (1H) pyrimidinone (10ml) and the mixture was stirred at the same temperature for 2 hours. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the mixture was acidified with dilute hydrochloric acid. The mixture was extracted with ethyl acetate, and the extracts were washed with water, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent: dichloromethane: methanol = 100: 1 → 10: 1) to give dimethyl [ { 3-methoxy-4- [2- (2-benzothiazolyl) aminocarbonyl) ethyl ] benzoyl } methyl ] phosphonate (6.4g), while also recovering the starting compound (3.1 g).

Yellow powder

¹H-NMR(CDCl₃)δppm: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),6.65-6.8(2H,m),7.25-7.45(2H,m),7.60(1H,d,J=8.5Hz),7.64(1H,d,J=7.5Hz),7.82(1H,dd,J=1Hz,J=7.5Hz),11.49(1H,br)

Reference example 197

Dimethyl methylphosphonate (3.9ml), 1.65M n-butyllithium (22ml) and 2- (4-ethoxycarbonyl-1-piperidinyl) carbonylaminobenzothiazole (4.0g) were treated according to the same procedure as described in reference example 196 to give dimethyl [1- (2-benzothiazolyl) aminocarbonyl) -4-piperidinylcarbonylmethyl ] phosphonate (2.5 g).

Pale yellow oil

¹H-NMR(CDCl₃)δppm:1.5-2.05(4H,m),2.75-3.1(3H,m),3.16(2H,d,J=28Hz),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=7.5Hz),7.74(1H,d,J=8Hz),10.04(1H,br)

Using suitable starting compounds, the compounds listed in the following Table 36-1 were obtained in the same manner as described in reference example 1.

TABLE 36-1The compounds listed in the following tables 36-2 to 36-9 can be prepared in the same manner as described in reference example 2 using suitable starting compounds.

TABLE 36-2

TABLE 36-3

TABLE 36-4Reference example 224R⁴:H A:-CH₂- m:1R¹⁹:-OCH₃(4-position)M.p.197.0-197.5 ℃ crystalline form: yellow powder recrystallization solvent: ethyl acetate-dimethylformamide state: reference example 225R⁴:H A:-CH₂- m:1R¹⁹:-OCH₃(4-position) R⁵:-OCH₂CH=CH₂(3-position) m.p.130-132 ℃ crystal form: light yellow powder recrystallization solvent: ethyl acetate-n-hexane state: free reference example 226R⁴:H A:-CH₂- m:1R¹⁹:-OCH₃(4-position)M.p.131.5-132.5 ℃ form: white powder recrystallization solvent: n-hexane-ethyl acetate-dichloromethane status: free reference example 227 R⁴:H A:-CH₂- m:1R¹⁹:-OCH₃(4-position)M.p.169.9-170.3 ℃ crystalline form: light yellow powder recrystallization solvent: ethyl acetate-n-hexane state: free form

TABLE 36-5 reference example 228 R⁴:H A:-CH₂- m:2R¹⁹:-OCH₃(4-position) R⁵:-(CH₂)₂CH₃(2-position)&-OCH₃(3-position) m.p.147.0-147.5 ℃ crystal form: light yellow powder recrystallization solvent: ethyl acetate-n-hexane state: free reference example 229 R⁴:H A:-CH₂- m:1R¹⁹:-OCH₃(4-position)M.p.142.0-143.0 ℃ form: white powder recrystallization solvent: ethyl acetate-n-hexane state: free reference example 230 R⁴:H A:-CH₂- m:1R¹⁹:-OCH₃(4-position) R⁵:-SCH₃(3-position) NMR (22) crystalline form: light yellow powder state: free reference example 231 R⁴:H A:-CH₂- m:2R¹⁹:-OCH₃(4-position) R⁵:-(CH₂)₃CH₃(2-position) & gt-OCH₃(3-position) NMR (27) crystalline form: light yellow powder state: free form

TABLE 36-6 reference example 232 R⁴:H A:-CH₂- m:2R¹⁹:-OCH₃(4-position) R⁵:-CH₃(2-position)&-OCH₃(3-position) NMR (35) crystalline form: orange powder state: free reference example 233 R⁴:H A:-CH₂- m:2R¹⁹:-OCH₃(4-position) R⁵:-CH₂CH₃(2-position)&-OCH₃(3-position) NMR (36) crystalline form: orange powder reference example 234 R⁴:H A:-(CH₂)₃- m:1R¹⁹:-OCH₃(4-position) R⁵:-OCH₃(3-position) m.p.186-188 ℃ crystalline form: orange powder state: free reference example 235 R⁴:H A:-CH₂- m:2R¹⁹:-OCH₃(4-position) R⁵:-CH₂CH=CH₂(2-position)&-OCH₃(5-position) m.p.187-189 ℃ crystalline form: light yellow powder state: free form

Tables 36 to 7 reference example 236 R⁴:H A:-CH₂- m:2R¹⁹:-OCH₃(4-position) R⁵:-OCH₃(2-position)&-N(CH₃)₂(3-position) NMR (46) crystalline form: white powder state: free reference example 237 R⁴:H A:-CH₂- m:1R¹⁹:-OCH₃(4-position) R⁵:-N(CH₃)₂(2-position) NMR (65) crystalline form: white powder state: free form

Tables 36 to 8Reference example 238 R⁴:H A:-CH₂- m:1R¹⁹:-OCH₃(4-position) R⁵:-OCH₃(3-position) T: -CH₂-u: 1NMR (48) crystalline form: white powder state: free form

Tables 36 to 9Reference example 239 R⁴:H A:-(CH₂)₂- m:1R¹⁹:-OCH₃(4-position) R⁵HNMR (73) crystalline form: yellow powder state: free reference example 240 R⁴:H A:-(CH₂)₂- m:1R¹⁹:-OCH₃(4-position) R⁵:-OCH₃(3-position) NMR (75) crystalline form: yellow powder state: compounds listed in the following tables 36-10 to 36-16 can be prepared in the same manner as described in reference example 3 using suitable starting compounds.

Tables 36-10Reference example 241 R⁴:H A:-CH₂- m:1-COCH₂PO(R¹⁸)₂:-COCH₂PO(OCH₃)₂(4-position) R⁵:-OCH₂CH=CH₂(3-position) m.p.134-135 ℃ form: white powder recrystallization solvent: ethyl acetate-n-hexane state: free reference example 242 R⁴:H A:-CH₂- m:1-COCH₂PO(R¹⁸)₂:-COCH₂PO(OCH₃)₂(4-position) NMR (8) crystalline form: yellow oil state: free reference example 243 R⁴:H A:-CH₂- m:1-COCH₂PO(R¹⁸)₂:-COCH₂PO(OCH₃)₂(4-position)NMR (10) crystal form: yellow oil state: free form

Tables 36 to 11 reference example 244 R⁴:H A:-CH₂- m:2-COCH₂PO(R¹⁸)₂:-COCH₂PO(OCH₃)₂(4-position) R⁵:-(CH₂)₂CH₃(2-position)&-OCH₃(3-position) m.p.156.5-157.4 ℃ form: white needle-like recrystallization solvent: ethyl acetate-n-hexane state: free reference example 245 R⁴:H A:-CH₂- m:1-COCH₂PO(R¹⁸)₂:-COCH₂PO(OCH₃)₂(4-position)NMR (16) crystal form: yellow amorphous state: free reference implementationExample 246 R⁴:H A:-CH₂- m:1-COCH₂PO(R¹⁸)₂:-COCH₂PO(OCH₃)₂(4-position) R⁵:-SCH₃(3-position) NMR (23) crystalline form: light brown powder state: free reference example 247 R⁴:H A:-CH₂- m:2-COCH₂PO(R¹⁸)₂:-COCH₂PO(OCH₃)₂(4-position) R⁵:-(CH₂)₃CH₃(2-position)&-OCH₃(3-position) NMR (28) crystalline form: white powder state: free form

Tables 36 to 12 reference example 248R⁴:H A:-CH₂- m:2-COCH₂PO(R¹⁸)₂:-COCH₂PO(OCH₃)₂(4-position) R⁵:-CH₃(2-position)&-OCH₃(3-position) NMR (37) crystalline form: light red powder state: free reference example 249R⁴:H A:-CH₂- m:2-COCH₂PO(R¹⁸)₂:-COCH₂PO(OCH₃)₂(4-position) R⁵:-CH₂CH₃(2-position)&-OCH₃(3-position) NMR (38) crystalline form: light red powder state: free reference example 250R⁴:H A:-(CH₂)₃- m:1-COCH₂PO(R¹⁸)2:-COCH₂PO(OCH₃)₂(4-position) R⁵:-OCH₃(3-position) m.p.140-142 ℃ crystal form: colorless prismatic crystal recrystallization solvent: second step Alcohol state: free reference example 251R⁴:H A:-CH₂- m:2-COCH₂PO(R¹⁸)₂:-COCH₂PO(OCH₃)₂(4-position) R⁵:-CH₂CH=CH₂(2-position)&-OCH₃(5-position) m.p.125-128 ℃ crystal form: light brown prismatic recrystallization solvent: ethanol-n-hexane state: free form

Tables 36 to 13 reference example 252R⁴:H A:-CH₂- m:2-COCH₂PO(R¹⁸)₂:-COCH₂PO(OCH₃)₂(4-position) R⁵:-OCH₃(2-position)&-N(CH₃)₂(3-position) NMR (47) crystalline form: light yellow powder state: free reference example 253R⁴:H A:-CH₂- m:2-COCH₂PO(R¹⁸)₂:-COCH₂PO(OCH₃)₂(4-position) R⁵Br (2-position)&-OCH₃(5-position) m.p.196-199 ℃ crystalline form: white powder recrystallization solvent: ethanol state: free reference example 254R⁴:H A:-CH₂- m:1-COCH₂PO(R¹⁸)₂:-COCH₂PO(OCH₃)₂(4-position) R⁵:-N(CH₃)₂(2-position) NMR (66) crystalline form: yellow oil state: free reference example 254AR⁴:H A:-CH₂- m:1-COCH₂PO(R¹⁸)₂:-COCH₂PO(OCH₃)₂(4-position))R⁵:-OCH₃(2-position) NMR (77) crystalline form: white powder state: free form

Tables 36 to 14Reference example 255R⁴:H A:-CH₂- m:1-COCH₂PO(R¹⁸)₂:-COCH₂PO(OCH₃)₂(4-position) R⁵:-OCH₃(3-position) T: -CH₂-u: 1NMR (49) crystalline form: brown oil state: free form

Tables 36-15Reference example 256R⁴:H A:-(CH₂)₂- m:1-COCH₂PO(R¹⁸)₂:-COCH₂PO(OCH₃)₂(4-position) R⁵HNMR (74) crystalline form: light brown oil state: free reference example 257R⁴:H A:-(CH₂)₂- m:1-COCH₂PO(R¹⁸)₂:-COCH₂PO(OCH₃)₂(4-position) R⁵:-OCH₃(3-position) NMR (76) crystalline form: yellow powder state: the compounds listed in the following tables 36 to 17 can be prepared in the same manner as described in reference example 7, 8 or 9 using an appropriate starting compound.

Tables 36 to 17

Reference example 262Colorless oil state: free NMR (71) reference example 263Light yellow oil state: free NMR (72) Using a suitable starting compound, the compounds listed in the following tables 36-18 to 36-21 were obtained in the same manner as described in reference example 187. Using a suitable starting compound, the compounds listed in the following tables 36 to 16 can be prepared in the same manner as described in reference example 5 or 6.

Tables 36 to 16Reference example 258R⁴:H A:-CH₂- m:2R⁵:-OCH₃(2&3-position) NMR (67) crystalline form; light yellow amorphous state: free reference example 259R⁴:H A:-CH₂- m:1R⁵:-O(CH₂)₃Cl (3-position) NMR (68) crystalline form: colorless amorphous state: free reference example 260R⁴:H A:-CH₂- m:1NMR (69) crystalline form: light yellow amorphous state: free reference example 261R⁴:H A:-CH₂- m:1R⁵:-OCH₃(3-position) NMR (70) crystalline form: dark brown amorphous state: free form

Tables 36-18Reference example 264R⁵OH (3-position) A: -CH₂- m:1-COR¹⁹:-COOCH₃(4-position) R²⁴:-OCH₃NMR (1) crystalline form:white solid state: free reference example 265A:-CH₂- m:1-COR¹⁹:-COOCH₃(4-position) R ²⁴:-OCH₃NMR (2) crystalline form: white solid state: free reference example 266R⁵:-OCH₂CH=CH₂(3-position) A: -CH₂- m:1-COR¹⁹:-COOCH₃(4-position) R²⁴:-OCH₃NMR (4) crystalline form: colorless oil state: free reference example 267 A:-CH₂- m:1-COR¹⁹:-COOCH₃(4-position) R²⁴:-OCH₃NMR (6) crystal form: yellow oil state: free reference example 268 A:-CH₂- m:1-COR¹⁹:-COOCH₃(4-position) R²⁴:-OCH₃NMR (9) crystalline form: colorless oil state: free reference example 269R⁵:-CH₂CH=CH₂(2-position)&-OH (3-position) A: -CH₂- m:2-COR¹⁹:-COOCH₃(4-position) R²⁴:-OCH₃M.p.93.1-93.8 ℃ form: colorless needle-like recrystallization solvent: n-hexane-ethyl acetate state: free reference example 270R⁵:-(CH₂)₂CH₃(2-position)&-OH (3-position) A: -CH₂- m:2-COR¹⁹:-COOCH₃(4-position) R²⁴:-OCH₃NMR (12) crystal form: white solid state: free form

Tables 36 to 19 reference example 271R⁵:-(CH₂)₂CH₃(2-position)&-OCH₃(3-position) A: -CH₂- m:2-COR¹⁹:-COOCH₃(4-position) R²⁴:-OCH₃NMR (13) crystal form: colorless oil state: free reference example 272A:-CH₂- m:1-COR¹⁹:-COOCH₃(4-position) R²⁴:-OCH₃NMR (15) crystal form: colorless oil state: free reference example 273R⁵:-SCH₃(3-position) A: -CH ₂- m:1-COR¹⁹:-COOCH₃(4-position) R²⁴:-OCH₃NMR (20) crystal form: light yellow powder state: free reference example 274R⁵:-(CH₂)₃CH₃(2-position)&-OH (3-position) A: -CH₂- m:2-COR¹⁹:-COOCH₃(4-position) R²⁴:-OCH₃NMR (24) crystal form: light brown powder state: free reference example 275R⁵:-(CH₂)₃CH₃(2-position)&-OCH₃(3-position) A: -CH₂- m:2-COR¹⁹:-COOCH₃(4-position) R²⁴:-OCH₃NMR (25) crystal form: white powder state: free reference example 276R⁵:-CH₂CH₃(2-position)&-OH (3-position) A: -CH₂- m:2-COR¹⁹:-COOCH₃(4-position) R²⁴:-OCH₃NMR (29) crystalline form: white powder state: free form

Reference example 277R⁵:-CH₃(2-position)&-OH (3-position) A: -CH₂- m:2-COR¹⁹:-COOCH₃(4-position) R²⁴:-OCH₃NMR (30) crystal form: white powder state: free form

Tables 36 to 20 reference example 278R⁵:-CH₃(2-position)&-OCH₃(3-position) A: -CH₂- m:2-COR¹⁹:-COOCH₃(4-position) R²⁴:-OCH₃NMR (31) crystalline form: colorless needle-like state: free reference example 279R⁵:-CH₂CH₃(2-position)&-OCH₃(3-position) A: -CH₂- m:2-COR¹⁹:-COOCH₃(4-position) R²⁴:-OCH₃NMR (32) crystal form: colorless oil state: free reference example 280R⁵OH (3-position) A: -CH₂- m:1-COR¹⁹:-COOCH₃(4-position) R²⁴:-OC₂H₅NMR (40) crystal form: colorless oil state: free reference example 281R ⁵:-OCH₃(3-position) A: -CH₂- m:1-COR¹⁹:-COOCH₃(4-position) R²⁴:-OC₂H₅NMR (41) crystal form: light brown powder state: free reference example 282R⁵:-OCH₃(3-position) A: - (CH)₂)₃- m:1-COR¹⁹:-COOCH₃(4-position) R²⁴:-OCH₃M.p.48-50 ℃ crystalline form: white powder recrystallization solvent: ethyl acetate-n-hexane state: free reference example 283R⁵:-OCH₃(2-position)&-NH₂(3-position) A: -CH₂- m:2-COR¹⁹:-COOCH₃(4-position) R²⁴:-OCH₃NMR (44) crystalline form: yellow oil state: free reference example 284R⁵:-OCH₃(2-position)&-N(CH₃)₂(3-position) A: -CH₂- m:2-COR¹⁹:-COOCH₃(4-position) R²⁴:-OCH₃NMR (45) crystalline form: brown oil state: free form

Tables 36 to 21 reference example 285R⁵Br (2-position)&-OH (5-position) A: -CH₂- m:2-COR¹⁹:-COOCH₃(4-position) R²⁴:-OCH₃NMR (56) crystal form: white powder state: swimming deviceReference example 286R⁵Br (2-position)&-OCH₃(5-position) A: -CH₂- m:2-COR¹⁹:-COOCH₃(4-position) R²⁴:-OCH₃NMR (57) crystalline form: white powder state: free reference example 287R⁵:-NH₂(2-position)&-OCH₃(5-position) A: -CH₂- m:2-COR¹⁹:-COOCH₃(4-position) R²⁴:-OC₂H₅NMR (59) crystalline form: white powder state: free reference example 288R⁵:-N(CH₃)₂(2-position) A: -CH₂- m:1-COR¹⁹:-COOCH₃(4-position)NMR (63) crystalline form: yellow oil state: free form

Tables 36-22 Reference example 289A:-CH₂- m:1 -COR¹⁹:-COOCH₃(4-position) NMR (3) crystalline form: white solid state: free reference example 290R⁵:-OCH₂CH=CH₂(3-position) A: -CH₂- m:1 -COR¹⁹:-COOCH₃(4-position) NMR (5) crystalline form: white solid state: free reference example 291A:-CH₂- m:1 -COR¹⁹:-COOCH₃(4-position) NMR (7) crystalline form: light yellow oil state: free reference example 292A:-CH₂- m:1 -COR¹⁹:-COOCH₃(4-position) m.p.124.5-126.0 ℃ crystal form: white powder recrystallization solvent: ethyl acetate state: swimming deviceReference example 293R⁵:-(CH₂)₂CH₃(2-position)&-OCH₃(3-position) A: -CH₂- m:2 -COR¹⁹:-COOCH₃(4-position) NMR (14) crystalline form: white solid state: free reference example 294A:-CH₂- m:1 -COR¹⁹:-COOCH₃(4-position) m.p.131.5-132.0 ℃ form: light yellow powder recrystallization solvent: ethyl acetate state: free reference example 295R⁵:-SCH₃(3-position) A: -CH₂- m:1-COR¹⁹:-COOCH₃(4-position) NMR (21) crystal form: white powder state: free form

Tables 36 to 23

Reference example 296R⁵:-(CH₂)₃CH₃(2-position)&-OCH₃(3-position) A: -CH₂- m:2 -COR¹⁹:-COOCH₃(4-position) NMR (26) crystalline form: white powder state: free reference example 297R⁵:-CH₃(2-position)&-OCH₃(3-position) A: -CH₂- m:2 -COR¹⁹:-COOCH₃(4-position) NMR (33) crystalline form: white powder

Reference example 298R⁵:-CH₂CH₃(2-position) &-OCH₃(3-position) A: -CH₂- m:2 -COR¹⁹:-COOCH₃(4-position) NMR (34) crystalline form: white powder

Reference example 299R⁵:-OCH₃(3-position) A: - (CH)₂)₃- m:1 -COR¹⁹:-COOCH₃(4-position) m.p.89-90 ℃ crystal form: colorless needle-like recrystallization solvent: water-ethanol state: free reference example 300R⁵:-CH₂CH=CH₂(2-position)&-OCH₃(5-position) A: -CH₂- m:2 -COR¹⁹:-COOCH₃(4-position) NMR (43) crystalline form: white powder state: free form

Reference example 301R⁵Br (2-position)&-OCH₃(5-position) A: -CH₂- m:2 -COR¹⁹:-COOCH₃(4-position) NMR (58) crystalline form: white powder state: free form

Reference example 302R⁵:-N(CH₃)₂(2-position) A: -CH₂- m:1 -COR¹⁹Crystalline form-COOCH 3 (4-position) NMR (64): white amorphous state: free form

Reference example 303

Obtained by the same procedure as described in reference example 6 using a suitable starting compound

The following compounds were used. Ethyl α - (2, 3-dihydroxy-4-acetylphenoxy) acetate:

white powder

¹H-NMR(DMSO-d₆)δppm:2.56(3H,s),3.69(3H,s),4.91(2H,s),6.49(1H,d,J=9.1Hz),7.35(1H,d,J=9.1Hz),8.79(1H,s), 12.31(1H,s)

Ethyl α - (2, 3-dimethoxy-4-acetylphenoxy) acetate:

white solid

¹H-NMR(CDCl₃)δppm:2.60(3H,s),3.81(3H,s),3.93(3H,s),3.99(3H,s),4.75(2H,s),6.57(1H,d,J=8.9Hz),7.48(1H,d,J=8.9Hz)

Ethyl α - [2, 3-dimethoxy-4- (2-bromoacetyl) phenoxy ] acetate:

colorless oil

¹H-NMR(CDCl₃)δppm:3.81(3H,s),3.93(3H,s),4.07(3H,s),4.57(2H,s),4.76(2H,s),6.58(1H,d,J=8.9Hz),7.54(1H,d,J=8.9Hz)

(2, 3-dimethoxy-4-methoxycarbonylaminobenzoyl) methylenetriphenylphosphorane:

colorless amorphous form

¹H-NMR(CDCl₃)δppm:3.77(3H,s),3.94(6H,s),4.61(1H,brd,J=27.8Hz),4.70(2H,s),6.56(1H,d,J=8.8Hz),7.38-7.80(16H,m)

Ethyl α - [3- (3-chloropropoxy) -4-acetylphenoxy ] acetate:

Yellow oil

¹H-NMR(CDCl₃)δppm:1.31(3H,t,J=7Hz),2.2-2.5(2H,m),2.57(3H,s),3.77(2H,t,J=6.5Hz),4.30(2H,t,J=7Hz),4.66(2H,s),6.47(1H,dd,J=2H,J=8.5Hz),6.57(1H,d,J=2Hz),7.81(1H,d,J=8.5Hz)

Ethyl α - [3- (3-chloropropyloxy) -4- (2-bromoacetyl) propoxy ] acetate:

colorless oil

¹H-NMR(CDCl₃)δppm:1.31(3H,t,J=7Hz),2.25-2.55(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=2Hz,J=9Hz),6.59(1H,d,J=2Hz),7.89(1H,d,J=9Hz)

[2- (3-chloropropyloxy) -4-ethoxycarbonylmethoxybenzoyl ] methylenetriphenylphosphorane:

light brown amorphous

¹H-NMR(CDCl₃)δppm:1.31(3H,t,J=7Hz),2.2-2.7(2H,m),3.67(2H,d,J=5.5Hz),4.27(2H,q,J=7Hz),4.2-4.4(2H,m),4.66(2H,s),6.20(1H,br),6.47(1H,dd,J=2Hz,J=9Hz),6.57(1H,d,J=2Hz),7.4-8.0(16H,m)

(2, 3-dimethoxy-4-carboxymethoxybenzoyl) methylphenylphosphonium chloride:

colorless prismatic crystal (recrystallization in dilute hydrochloric acid)

M.p.137-151 deg.C (decomposition)

¹H-NMR(DMSO-d₆)δppm:3.78(3H,s),3.81(3H,s),4.69(2H,s),6.63(1H,d,J=8.9Hz),7.28(1H,d,J=8.9Hz),7.50-7.80(15H,m)

[2- (3-Chloropropoxy) -4-carboxymethoxybenzoyl ] methyltriphenylphosphonium chloride:

light yellow amorphous

¹H-NMR(CDCl₃)δppm:2.1-2.45(2H,m),3.63(2H,t,J=6.5Hz),4.04(2H,t,J=5Hz),4.49(2H,s),6.35(1H,dd,J=2Hz,J=7Hz),6.48(1H,d,J=2Hz),7.35-7.9(16H,m)

Tables 36-1 to 36-23¹H-NMR spectra (NMR (1) to NMR (77))

As follows: NMR (1) (CDCl)₃)δppm:3.81(3H,s),3.91(3H,s),4.65(2H,s),6.39(1H,d,J=2.6Hz),6.45(1H,dd,J=2.6Hz,J=8.8Hz),7.73(1H,d,J=8.8Hz),10.97(1H,s)

NMR(2)(CDCl₃)δppm:3.80(3H,s),3.87(3H,s),4.64(2H,s),5.16(2H,s),6.42(1H,dd,J=2.4Hz,J=8.7Hz),6.60(1H,d,J=2.4Hz),7.30-7.43(3H,m),7.49-7.52(2H,m),7.85(1H,d,J=8.7Hz)

NMR(3)(DMSO-d₆)δppm:3.76(3H,s),4.76(2H,s),5.19(2H,s),6.54(1H,dd,J=2.3Hz,J=8.7Hz),6.76(1H,d,J=2.3Hz),7.27-7.44(3H,m),7.49-7.53(2H,m),7.69(1H,d,J=8.7Hz),13.07(1H,brs)

NMR(4)(CDCl₃)δppm:3.82(3H,s),3.86(3H,s),4.58-4.62(2H,m),4.66(2H,s),5.28-5.58(2H,m),5.98-6.19(1H,m),6.41(1H,dd,J=2.4Hz,J=8.7Hz),6.54(1H,d,J=2.4Hz),7.83(1H,d,J=8.7Hz)

NMR(5)(DMSO-d₆)δppm: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=2.3Hz,J=8.7Hz),6.64(1H,d,J=2.3Hz),7.67(1H,d,J=8.7Hz),13.05(1H,brs)

NMR(6)(CDCl₃)δppm: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=8.7Hz),6.53(1H,d,J=2.4Hz),7.79(1H,d,J=8.7Hz)

NMR(7)(CDCl₃)δppm:1.52-2.03(8H,m),3.84(3H,s),4.71(2H,s),4.30-5.20(2H,m),6.40(1H,dd,J=2.4Hz,J=8.7Hz),6.54(1H,d,J=2.4Hz),7.80(1H,d,J=8.7Hz)

NMR(8)(CDCl₃)δppm: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(1H,m),7.79-7.90(3H,m),8.31-10.20(1H,brs)

NMR(9)(CDCl₃)δppm:3.61(3H,s),3.81(3H,s),4.70(2H,s),6.83-6.97(2H,m),7.22-7.33(2H,m),7.33-7,45(3H,m),7.85(1H,d,J=8.8Hz)

NMR(10)(CDCl₃)δppm:3.50-3.70(8H,m),4.79(2H,s),6.77-6.97(2H,m),7.09-7.49(8H,m),7.58-7.89(2H,m),9.97-10.81(1H,brs)

NMR(11)(CDCl₃)δppm:0.88(3H,t,J=7.2Hz),1.26-1.47(2H,m),1.47-1.66(2H,m),2.56(2H,t,J=7.5Hz),3.78(3H,s),4.66(2H,s),6.33(1H,d,J=2.4Hz),6.46(1H,dd,J=2.4Hz,J=8.3Hz),7.05(1H,d,J=8.3Hz)

NMR(12)(CDCl₃)δppm:0.92(3H,t,J=7.4Hz),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=8.9Hz),7.65(1H,d,J=8.9Hz),11.08(1H,s)

NMR(13)(CDCl₃)δppm:0.94(3H,t,J=7.3Hz),1.49-1.71(2H,m),2.63-2.77(2H,m),3.80(3H,s),3.83(3H,s),3.89(3H,s),4.70(2H,s),6.48(1H,d,J=8.8Hz),7.70(1H,d,J=8.8Hz)

NMR(14)(CDCl₃)δppm:0.93(3H,t,J=7.3Hz),1.47-1.70(2H,m),2.62-2.76(2H,m),3.83(3H,s),3.90(3H,s),4.74(2H,s),6.51(1H,d,J=8.8Hz),7.20(1H,brs),7.72(1H,d,J=8.8Hz)

NMR(15)(CDCl₃)δppm:3.77(3H,s),3.79(3H,s),4.59(2H,s),6.45(1H,d,J=2.5Hz),6.65(1H,dd,J=2.5Hz,J=8.8Hz),6.92-7.03(2H,m),7.03-7.17(1H,m),7.26-7.40(2H,m),7.91(1H,d,J=8.8Hz)

NMR(16)(CDCl₃)δppm:3.72(3H,s),3.77(3H,s),3.81(2H,d,J=21.6Hz),4.68(2H,s),6.34(1H,d,J=2.4Hz),6.62(1H,dd,J=2.4Hz,J=8.8Hz),7.04-7.15(2H,m),7.15-7.47(5H,m),7.68-7.83(2H,m),7.86(1H,d,J=8.8Hz),10.65(1H,brs)

NMR(17)(DMSO-d₆)δppm:2.02(3H,s),3.75(3H,s),4.64(2H,s),6.47(1H,d,J=8.3Hz),6.60(1H,d,J=8.3Hz),7.07(1H,t,J=8.3Hz),12.93(1H,brs)

NMR(18)(DMSO-d₆)δppm:0.86(3H,t,J=7.2Hz),1.13-1.51(4H,m),2.59(2H,t,J=7.6Hz),3.74(3H,s),4.63(2H,s),6.46(1H,d,J=8.3Hz),6.59(1H,d,J=8.3Hz),7.06(1H,t,J=8.3Hz),12.89(1H,brs)

NMR(19)(CDCl₃)δppm:0.97(3H,t,J=7.1Hz),1.31-1.68(4H,m),2.77(2H,t,J=7.0Hz),3.84(3H,s),4.75(2H,s),6.51(1H,d,J=8.2Hz),6.64(1H,d,J=8.2Hz),7.14(1H,t,J=8.2Hz),7.26-7.39(1H,m),7.39-7.52(1H,m),7.73-7.90(2H,m),9.70(1H,brs)

NMR(20)(CDCl₃)δppm:2.43(3H,s),3.82(3H,s),3.88(3H,s),4.70(2H,s),6.59(1H,dd,J=8.8Hz,J=2.4Hz),6.81(1H,d,J=2.4Hz),8.00(1H,d,J=8.8Hz)

NMR(21)(DMSO-d₆)δppm:2.39(3H,s),3.77(3H,s),4.81(2H,s),6.62-6.83(2H,m),7.89(1H,d,J=9.1Hz),13.14(1H,brs)

NMR(22)(CDCl₃)δppm:2.48(3H,s),3.90(3H,s),4.82(2H,s),6.69(1H,dd,J=8.7Hz,J=2.4Hz),6.86(1H,d,J=2.4Hz),7.36(1H,dt,J=1.2Hz,J=7.7Hz),7.48(1H,dt,J=1.2Hz,J=7.7Hz),7.84(2H,t,J=7.7Hz),8.05(1H,d,J=8.7Hz),9.91(1H,brs)

NMR(23)(CDCl₃)δppm:2.41(3H,s),3.63(2H,d,J=22.6Hz),3.80(6H,d,J=11.2Hz),4.82(2H,s),6.71(1H,dd,J=8.8Hz,J=2.4Hz),6.85(1H,d,J=2.4Hz),7.34(1H,dt,J=1.3Hz,J=9.2Hz),7.47(1H,dt,J=1.3H,J=9.2Hz),7.82(2H,t,J=9.2Hz),8.01(1H,d,J=8.8Hz)

NMR(24)(CDCl₃)δppm:0.93(3H,t,J=7.0Hz),1.19-1.62(4H,m),2.73(2H,t,J=7.0Hz),3.79(3H,s),3.91(3H,s),4.70(2H,s),6.27(1H,d,J=9.0Hz),7.67(1H,d,J=9.0Hz),11.07(1H,s)

NMR(25)(CDCl₃)δppm:0.94(3H,t,J=7.2Hz),1.29-1.63(4H,m),2.72(2H,t,J=7.1Hz),3.80(3H,s),3.83(3H,s),3.89(3H,s),4.70(2H,s),6.50(1H,d,J=8.8Hz),7.72(1H,d,J=8.8Hz)

NMR(26)(DMSO-d₆)δppm:0.88(3H,t,J=7.1Hz),1.19-1.61(4H,m),2.60(2H,t,J=6.7Hz),3.70(3H,s),3.78(3H,s),4.77(2H,s),6.71(1H,d,J=8.8Hz),7.60(1H,d,J=8.8Hz),13.05(1H,brs)

NMR(27)(CDCl₃)δppm:0.99(3H,t,J=7.1Hz),1.37-1.71(4H,m),2.80(2H,t,J=6.9Hz),3.87(3H,s),3.91(3H,s),4.82(2H,s),6.66(1H,d,J=8.8Hz),7.34(1H,dt,J=1.3Hz,J=7.7Hz),7.46(1H,dt,J=1.3Hz,J=7.7Hz),7.69-7.90(3H,m),9.62(1H,brs)

NMR(28)(CDCl₃)δppm:1.00(3H,t,J=7.0Hz),1.39-1.73(4H,m),2.78(2H,t,J=8.0Hz),3.76(6H,d,J=11.4Hz),3.79(3H,s),3.81(2H,d,J=22.1Hz),4.82(2H,s),6.69(1H,d,J=8.8Hz),7.34(1H,t,J=8.6Hz),7.46(1H,t,J=8.6Hz),7.57(1H,d,J=8.8Hz),7.82(2H,t,J=8.6Hz),9.87(1H,brs)

NMR(29)(CDCl₃)δppm:1.14(3H,t,J=7.5Hz),2.75(2H,q,J=7.5Hz),3.80(3H,s),3.91(3H,s),4.71(2H,s),6.28(1H,d,J=9.0Hz),7.67(1H,d,J=9.0Hz),11.08(1H,s)

NMR(30)(CDCl₃)δppm:2.18(3H,s),3.80(3H,s),3.91(3H,s),4.71(2H,s),6.28(1H,d,J=9.0Hz),7.67(1H,d,J=9.0Hz),11.11(1H,s)

NMR(31)(CDCl₃)δppm:2.34(3H,s),3.81(3H,s),3.82(3H,s),3.89(3H,s),4.70(2H,s),6.51(1H,d,J=8.8Hz),7.71(1H,d,J=8.8Hz)

NMR(32)(CDCl₃)δppm:1.18(3H,t,J=7.5Hz),2.76(2H,q,J=7.5Hz),3.80(3H,s),3.84(3H,s),3.89(3H,s),4.71(2H,s),6.51(1H,d,J=8.8Hz),7.73(1H,d,J=8.8Hz)

NMR(33)(DMSO-d₆)δppm: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=8.9Hz),13.11(1H,brs)

NMR(34)(DMSO-d₆)δppm: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)(CDCl₃)δppm:2.31(3H,s),3.85(3H,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=1.2Hz,J=7.6Hz),7.69-7.89(3H,m),9.79(1H,brs)

NMR(36)(CDCl₃)δppm:1.27(3H,t,J=7.6Hz),2.83(2H,q,J=7.6Hz),3.87(3H,s),3.91(3H,s),4.83(2H,s),6.66(1H,d,J=8.8Hz),7.30(1H,dt,J=1.3Hz,J=7.3Hz),7.46(1H,dt,J=1.3Hz,J=7.3Hz),7.70-7.90(3H,m),9.72(1H,brs)

NMR(37)(CDCl₃)δppm:2.33(3H,s),3.77(6H,d,J=11.1Hz),3.80(3H,s),3.81(2H,d,J=22.0Hz),4.82(2H,s),6.69(1H,d,J=8.8Hz),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),9.87(1H,brs)

NMR(38)(CDCl₃)δppm: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=8.8Hz),7.38(1H,dt,J=1.4Hz,J=8.6Hz),7.47(1H,dt,J=1.4Hz,8.6Hz),7.59(1H,d,J=8.8Hz),7.83(2H,t,J=8.6Hz),9.73(1H,brs)

NMR(39)(CDCl₃)δppm:2.24(3H,s),3.85(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=8.3Hz),7.29-7.40(1H,m),7.40-7.52(1H,m),7.74-7.91(2H,m)

NMR(40)(CDCl₃)δppm:1.30(3H,t,J=7Hz),3.91(3H,s),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)(CDCl₃)δppm:1.30(3H,t,J=7Hz),3.86(3H,s),3.89(3H,s),4.28(2H,q,J=7Hz),6.43(1H,dd,J=2.5Hz,J=8.5Hz),6.58(1H,d,J=2.5Hz),7.84(1H,d,J=8.5Hz)

NMR(42)(CDCl₃)δppm:1.69(3H,d,J=7Hz),3.80(3H,s),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)(CDCl₃)δppm:3.38(2H,d,J=6.5Hz),3.84(3H,s),3.86(3H,s),4.74(2H,s),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)(CDCl₃)δppm:3.80(3H,s),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)(CDCl₃)δppm: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,d,J=8.7Hz)

NMR(46)(CDCl₃)δppm:2.91(6H,s),3.88(3H,s),3.89(3H,s),4.80(2H,s),6.64(1H,d,J=8.7Hz),7.30-7.38(2H,m),7.42-7.51(1H,m),7.80-7.89(2H,m),10.24(1H,br)

NMR(47)(CDCl₃)δppm: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,J=8.6Hz),7.34(1H,t,J=9.1Hz),7.43(1H,t,J=9.1Hz),7.80-7.90(2H,m),10.10(1H,br)

NMR(48)(CDCl₃)δppm: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),7.84-7.89(1H,m),7.98(1H,d,J=7.3Hz)

NMR(49)(CDCl₃)δppm:3.72(3H,s),3.78(3H,s),3.79(2H,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),7.82-7.90(2H,m),7.98(1H,d,J=7.6Hz)

NMR(50)(DMSO-d₆)δppm:1.13(6H,d,J=7.0Hz),3.08-3.35(1H,m),3.69(3H,s),4.66(2H,s),6.38(1H,d,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-d₆)δppm:0.69-1.00(3H,m),1.08-1.62(8H,m),2.32-2.63(2H,m),3.68(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)(CDCl₃)δppm:2.31(3H,s),3.78(3H,s),4.74(2H,s),6.42(1H,d,J=2.4Hz),6.52(1H,dd,J=2.4Hz,J=8.8Hz),7.12(1H,d,J=8.8Hz),7.25-7.53(2H,m),7.72-7.94(2H,m),9.71(1H,s)

NMR(53)(CDCl₃)δppm: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=8.5Hz),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)(CDCl₃)δppm: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)(DMSO-d₆)δppm:2.09(3H,s),3.68(3H,s),4.66(2H,s),6.32-6.52(2H,m),7.02(1H,d,J=8.1Hz),12.95(1H,s)

NMR(56)(CDCl₃)δppm:3.82(3H,s),3.93(3H,s),4.73(2H,s),6.34(1H,s),8.02(1H,s),10.93(1H,s)

NMR(57)(CDCl₃)δppm:3.82,3.86,3.88(each3H,eachs),4.77(2H,s),6.40(1H,s),8.07(1H,d,J=3.1Hz)

NMR(58)(DMSO-d₆)δppm:3.74,3.82(each3H,eachs),4.97(2H,s),6.74(1H,s),7.85(1H,d,J=3.6Hz),12.82-13.44(1H,br)

NMR(59)(DMSO-d₆)δppm:3.73,3.74(each3H,eachs),4.63(2H,s),6.76(1H,s),7.30(1H,s),10.66(1H,brs)

NMR(60)(DMSO-d₆)δppm:3.66(3H,s),3.70(3H,s),4.64,4.73(total 1H,eachs),6.34-6.52(2H,m),6.79-6.96(1H,m),12.88-13.03(1H,m)

NMR(61)(CDCl₃)δppm: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-d₆)δppm: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(1H,m),12.81-13.01(1H,brs)

NMR(63)(CDCl₃)δppm:2.84(6H,s),3.89(3H,s),4.81(2H,s),5.23(2H,s),6.70(1H,d,J=9.0Hz),7.26-7.40(5H,m),7.60-7.64(2H,m)

NMR(64)(CDCl₃)δppm:2.91(6H,s),3.93(3H,s),4.73(2H,s),7.14(1H,d,J=7.8Hz),7.90-7.94(2H,m),9.72(1H,br)

NMR(65)(CDCl₃)δppm: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)(CDCl₃)δppm:3.03(6H,s),3.61(2H,d,J=22.7Hz),3.77(3H,s),3.81(3H,s),4.94(2H,s),7.15(1H,d,J=8.4Hz),7.30(1H,t,J=7.8Hz),7.43(1H,t,J=7.8Hz),7.76-7.86(4H,m)

NMR(67)(CDCl₃)δppm:3.96(3H,s),4.03(3H,s),4.55(1H,brd,J=27.4Hz),4.76(2H,s),6.71(1H,d,J=8.7Hz),7.25-7.38(1H,m),7.39-7.88(19H,m),10.50(1H,brs)

NMR(68)(CDCl₃)δppm:2.10-2.30(2H,m),3.58(2H,t,J=6.6Hz),4.04-4.19(2H,m),4.38-4.72(1H,m),4.65(2H,s),6.39(1H,dd,J=2.3Hz,J=8.6Hz),6.52(1H,d,J=2.3Hz),7.28-7.95(20H,m),10.58(1H,brs)

NMR(69)(CDCl₃)δppm:1.82-2.11(2H,m),2.11-2.38(4H,m),2.3-2.62(2H,m),3.49-3.75(4H,m),4.04(2H,t,J=5.9Hz),4.50-4.93(1H,m),4.68(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,m),7.62-7.96(9H,m),10.37(1H,brs)

NMR(70)(CDCl₃)δppm:3.00(6H,s),3.89(3H,s),4.70(2H,s),6.49(1H,dd,J=2.5Hz,J=8.5Hz),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),8.55-8.65(1H,m),9.90(1H,br)

NMR(71)(CDCl₃)δppm:1.21-1.56(2H,m),1.67(1H,br),1.75-1.94(2H,m),2.01(1H,t,J=10.6Hz),2.01-2.89(14H,m),3.02-3.28(2H,m),3.55-3.78(2H,m),3.85-4.02(1H,m)

NMR(72)(CDCl₃)δppm:1.83(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)(CDCl₃)δppm: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),7.25-7.45(2H,m),7.68(1H,d,J=7.5Hz),7.8-7.95(1H,m),7.90(2H,d,J=8.5Hz)

NMR(74)(CDCl₃)δppm: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)(CDCl₃)δppm: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)δppm: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),6.65-6.8(2H,m),7.25-7.45(2H,m),7.60(1H,d,J=8.5Hz),7.64(1H,d,J=7.5Hz),7.82(1H,dd,J=1Hz,J=7.5Hz),11.49(1H,br)

NMR(77)(CDCl₃) δ ppm 3.62(2H, d, J =22.5Hz),3.77,3.82(6H, both s),4.04(3H, s),4.85(2H, s),7.02(1H, d, J =8.5Hz),7.3-7.55(2H, m),7.6-7.7(2H, m),7.8-7.9(2H, m),10.31(1H, br)

Example 1

A solution of 2- (2-isopropylbenzyloxymethylcarbonylamino) benzothiazole (6.5g), anhydrous maleic acid (3.9g) and aluminum chloride (8.0g) in 1, 2-dichloroethane (50ml) was stirred at room temperature for 7 hours. Water was added to the mixture to decompose aluminum chloride, ethyl acetate was added thereto, and the mixture was stirred. The crystal precipitated was collected by filtration, washed with ethyl acetate and dried to obtain a mixture of a trans-compound and a cis-compound (7.3 g). The resulting mixture was dissolved in dimethylformamide (50ml), concentrated hydrochloric acid (1ml) was added thereto and the mixture was stirred at 60 ℃ for 30 minutes. Water (about 100ml) was added to the mixture, and crystals precipitated were collected by filtration, washed with methanol and dried to give 2- [ 2-isopropyl-4- (trans-3-carboxypropenoyl) phenoxymethylcarbonylamino ] benzothiazole (6.2 g).

¹H-NMR(DMSO-d₆)δppm:1.25(6H,d,J=7Hz),3.40(1H,sept,J=7Hz),5.12(2H,s),6.64(1H,d,J=15.5Hz),7.03(1H,d,J=8.5Hz),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)

Example 2

To a solution of 2- [ 2-isopropyl-4- (3-carboxypropenyl) phenoxymethylcarbonylamino ] benzothiazole (1.0g) and triethylamine (0.4ml) in methylene chloride (20ml) was added dropwise isobutyl chloroformate (0.32ml) under ice-cooling, to the mixture was added N-methylpiperazine (0.27ml) at the same temperature and the mixture was stirred for 2.5 hours. The reaction solution was washed with water, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent: dichloromethane → dichloromethane: methanol = 30: 1) and recrystallized from ethanol to give 2- { 2-isopropyl-4- [3- (4-methyl-1-piperazinylcarbonyl) acryloyl ] phenoxymethylcarbonylamino } benzothiazole (0.80 g).

Light brown powder

M.p.190-192℃

Example 3

A solution of 2- [4- (3-carboxypropenyl) phenoxymethylcarbonylamino ] benzothiazole (1.0g), thionyl chloride (0.23ml) and one drop of dimethylformamide (20ml) in dichloromethane (20ml) was stirred at room temperature for 10 hours. The solution was added dropwise to a solution of 4- (4-methyl-1-piperazinyl) piperidine (0.5g) and pyridine (1ml) in dichloromethane (20ml) under ice-cooling. Water was added to the reaction solution, the mixture was basified with 5% aqueous sodium hydroxide solution, the mixture was extracted with dichloromethane, and the extract was washed, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent: dichloromethane: methanol = 50: 1 → 10: 1). The resulting compound was converted to its hydrochloride by a conventional method and recrystallized from ethanol-diethyl ether to give 2- [4- {3- [4- (4-methyl-1-piperazinyl) -1-piperidinylcarbonyl) acryloyl } phenoxymethylcarbonylamino ] benzothiazole dihydrochloride (0.14 g).

White powder

M.p.202.5-225 deg.C (decomposition)

¹H-NMR(DMSO-d₆)δppm:1.35-1.8(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),5.08(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)

Example 4

To a solution of 2- [ 2-isopropyl-4- (3-carboxypropenoyl) phenoxymethylcarbonylamino ] benzothiazole (0.97g) in dimethylformamide (10ml) were added dropwise 4- (4-methyl-1-piperazinyl) piperidine (0.65g) and diethyl cyanophosphate (0.6ml) at room temperature. To the mixture was added triethylamine (0.5ml), and the mixture was stirred at room temperature for 10 minutes. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (solvent: dichloromethane: methanol = 100: 1 → 10: 1). The resulting compound was converted to its hydrochloride in ethanol by a conventional method and recrystallized from ethanol-diethyl ether to give 2- { 2-isopropyl-4- [3- [4- (4-methyl-1-piperazinyl) -1-piperidinylcarbonyl) acryloyl ] phenoxymethylcarbonylamino } benzothiazole dihydrochloride (0.45 g).

Yellow powder

M.p.186-190 deg.C (decomposition)

Example 5

To a solution of dibutyl tartrate (4.0g) in methanol (100ml) was added a solution of sodium periodate (3.0g) in water (30ml), and the mixture was stirred for 10 minutes and extracted with ethyl acetate. Further, a 5% aqueous solution of sodium hydroxide was added to a suspension of dimethyl { [ 3-methoxy-4- (2-benzothiazolylaminocarbonylmethoxy) benzoyl ] methyl } phosphonate (5.7g) in tetrahydrofuran (100ml) under ice-cooling until the reaction solution became homogeneous, and then a tetrahydrofuran glyoxylate (30ml) solution prepared from dibutyl tartrate in advance was added dropwise thereto under ice-cooling. The mixture was stirred for 30 minutes and acidified with 5% hydrochloric acid and concentrated under reduced pressure to remove tetrahydrofuran. The precipitated crystals were collected by filtration and washed with dichloromethane. The dichloromethane layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (solvent: dichloromethane: methanol = 200: 1) to give 2- [ 2-methoxy-4- (3-butoxycarbonylacryloyl) phenoxymethylcarbonylamino ] benzothiazole (2.85g), which was further stirred in tetrahydrofuran-5% aqueous sodium hydroxide solution at room temperature for 30 minutes to give 2- [ 2-methoxy-4- (3-carboxypropenyl) phenoxymethylcarbonylamino ] benzothiazole (2.9 g).

¹H-NMR(DMSO-d₆)δppm: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),7.7-8.1(4H,m),11.68(1H,br)

Example 6

To a solution of ethyl propiolate (17.7ml) in tetrahydrofuran (450ml) was added dropwise a 1.71M solution of n-butyllithium in n-hexane (102ml) at-78 ℃ and the mixture was stirred for 10 minutes. To the solution were added dropwise a solution of 2- (2-methoxy-4-formylphenoxymethylcarbonylamino) benzothiazole (20g) in tetrahydrofuran (400ml) and N, N-dimethylpropyleneurea (40ml) at the same temperature over 15 minutes, the mixture was further stirred for 10 minutes, and the reaction vessel was taken out in an ice bath and further stirred for 20 minutes. To the mixture was added acetic acid (11ml) and the mixture was diluted with ethyl acetate, and the ethyl acetate layer was washed with a saturated aqueous solution of sodium carbonate, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (solvent: dichloromethane: methanol = 100: 1 → 50: 1) to give 2- [ 2-methoxy-4- (3-methoxycarbonyl-1-hydroxypropargyl) phenoxymethylcarbonylamino ] benzothiazole (33.7g) as a dark brown oil.

To a solution of 2- [ 2-methoxy-4- (3-methoxycarbonyl-1-hydroxypropylpropyl) phenoxymethylcarbonylamino ] benzothiazole (33.7g) in dimethylformamide (150ml) was added tri-n-butylamine (14.3m) and the mixture was stirred at room temperature for 1.5 hours. The mixture was diluted with ethyl acetate, washed with 0.15N hydrochloric acid and dried over sodium sulfate. The mixture was concentrated under reduced pressure to remove the solvent, and the precipitated crystals were collected by filtration to give 2- [ 2-methoxy-4- (trans-3-methoxycarbonylacryloyl) phenoxymethylcarbonylamino ] benzothiazole (compound a,5.5g) as a pale yellow powder. Further, the filtrate was concentrated under reduced pressure, and crystallized from ethanol-diethyl ether to give 2- [ 2-methoxy-4- (cis-3-methoxycarbonylacryloyl) phenoxymethylcarbonylamino ] benzothiazole (compound B,6.0g) as a pale yellow powder.

A compound A:

¹H-NMR(DMSO-d₆)δppm:1.26(3H,t,J=7.1Hz),3.92(3H,s),4.21(2H,q,J=7.1Hz),5.11(2H,s),6.71(1H,d,J=15.5Hz),7.08(1H,d,J=8.6Hz),7.31-7.37(1H,m),7.44-7.50(1H,m),7.59(1H,d,J=2.0Hz),7.75-7.81(2H,m),7.98(1H,d,J=15.5Hz),8.00-8.02(1H,m),12.67(1H,brs)

compound B:

¹H-NMR(DMSO-d₆)δppm:1.05(3H,t,J=7.1Hz),3.89(3H,s),3.97(2H,q,J=7.1Hz),5.11(2H,s),6.35(1H,d,J=12.3Hz),7.05(1H,d,J=8.8Hz),7.21(1H,d,J=12.3Hz),7.31-7.37(1H,m),7.44-7.50(3H,m),7.78-7.81(1H,m),7.99-8.02(1H,m),12.62(1H,brs)

example 7

A solution of 2- { 2-isopropyl-4- [ trans-3- (4-methyl-1-piperazinyl) carbonylacryloyl ] phenoxymethylcarbonylamino } benzothiazole (100mg) in dimethylformamide (10ml) was allowed to stand for 6.5 hours through a window with direct exposure to sunlight. Water was added to the mixture, and crystals precipitated were collected by filtration and recrystallized from ethanol to give 2- { 2-isopropyl-4- [ cis-3- (4-methyl-1-piperazinyl) carbonylacryloyl ] phenoxymethylcarbonylamino } benzothiazole (45 mg).

Light yellow powder

M.p.114-115℃

Example 8

To a solution of dimethyl { [ 3-methoxy-4- (2-benzothiazolylaminocarbonylmethoxy) benzoyl ] methyl } phosphonate (1.7g) and pyridine-4-carbaldehyde (0.5g) in tetrahydrofuran (30ml) was added a 5% aqueous sodium hydroxide solution (6ml) under ice-cooling, and the mixture was stirred for 5 hours. The mixture was neutralized with acetic acid, and the precipitated crystals were collected by filtration and then recrystallized from methylene chloride-ethanol-ethyl ether to give 2- { 2-methoxy-4- [3- (4-pyridyl) acryloyl ] phenoxymethylcarbonylamino } benzothiazole (1.3 g).

Light yellow powder

M.p.206-207℃

Example 9

To a solution of 2- [ 2-methoxy-4- (3-tert-butoxycarbonyl-1-hydroxypropylpropyl) phenoxymethylcarbonylamino ] benzothiazole (1g) in chloroform (50ml) was added activated manganese dioxide (1g) and the mixture was refluxed for 2 hours. To the mixture was further added active manganese dioxide (1g) and the mixture was refluxed for 1.5 hours. The mixture was filtered through a layer of celite and the filtrate was concentrated. The residue was recrystallized from ethanol to give 2- [ 2-methoxy-4- (3-tert-butoxycarbonylpropynoyl) phenoxymethylcarbonylamino ] benzothiazole (0.5 g).

Example 10

To a solution of 2- [ 2-methoxy-4- (3-tert-butoxycarbonylpropynoyl) phenoxymethylcarbonylamino ] benzothiazole (0.5g) in dichloromethane (30ml) was added trifluoroacetic acid (10ml), and the mixture was stirred at room temperature for 4 hours. The mixture was concentrated, and methylene chloride was added to the residue. The mixture was stirred, and crystals precipitated were collected by filtration and recrystallized from methylene chloride-trifluoroacetic acid to give 2- [ 2-methoxy-4- (3-carboxypropynoyl) phenoxymethylcarbonylamino ] benzothiazole (0.26g) as a yellow powder.

M.p.174-176℃

The following compounds were obtained in the same manner as in example 1 or 5 using suitable starting compounds.

Watch 38Example 11

R⁴:H A:-CH₂- Z:O

R⁵:CH₃(2-position) m:1

M.p.261-262 ℃ crystalline form: grayish brown powder

Recrystallization solvent: dimethylformamide methanol

The state is as follows: free example 12

R⁴:H A:-CH₂- Z:O

R⁵:C₂H₅(2-position) m:1

M.p.245-246 ℃ crystalline form: grayish brown powder

Recrystallization solvent: dimethylformamide methanol

The state is as follows: free example 13

R⁴:H A:-CH₂- Z:O

R⁵: n-propyl (2-position) m:1

Crystal form: yellow powder state: free form

NMR(1)

Watch 39

Example 14R4:H A:-CH2- Z:OR5: isopropyl (2-position) m:1m.p.225-240 ℃ (decomposition) crystalline form: yellow powder recrystallization solvent: dimethylformamide-methanol state: free form	NMR(2)
		Example 15R4:H A:-CH2- Z:OR5: n-butyl (2-position) m:1M.p.187.5-190 ℃ crystalline form: light yellow powder recrystallization solvent: chloroform-dimethylformamide state: free form
Example 16R4:H A:-CH2- Z:OR5H m:1M.p.250-275 ℃ (decomposition) crystalline form: white powder recrystallization solvent: dimethylformamide-methanol state: free form	NMR(3)
		Example 17R4:H A:-CH2- Z:OR5: n-pentyl (2-position) m:1M.p.139-163 ℃ crystal form: light yellow powder recrystallization solvent: dimethylformamide-dichloromethane status: free form	NMR(4)

Watch 40

Example 18R4:H A:-CH2-R5F (2-position) M.p.233-234 ℃ crystal form: light brown powder recrystallization solvent: dimethylformamide-methanol state: free form	Z:Om:1
		Example 19R4:H A:-CH2-R5Crystalline form of Cl (2-position): yellow powder state: free form	Z:Om:1NMR(5)
Example 20R4:H A:-CH2-R5:-(CH2)4(2-and 3-together) crystalline form: yellow powder state: free form	Z:Om:2NMR(6)
		Example 21R 4:H A:-CH2-R5:CH3(2-and 3-position) crystalline form: yellow powder state: free form	Z:Om:2NMR(7)

TABLE 41 example 22

R⁴:H A:-CH₂- Z:O

R⁵:CH₃(2-and 6-positions) m:2

Crystal form: light brown powder NMR (8)

Recrystallization solvent: dimethylformamide methanol

The state is as follows: free example 23

R⁴:H A:-CH₂- Z:O

R⁵:CH₃(3-and 5-positions) m:2

Crystal form: yellow powder state: free form

NMR(9)24

R⁴:H A:-CH₂- Z:O

R⁵:-(CH₂)₂CO₂C₂H₅(2-position) m:1

M.p.199.6-203.8 ℃ crystalline form: light yellow powder

Recrystallization solvent: chloroform-dimethylformamide

The state is as follows: free example 25

R⁴:H A:-CH₂- Z:O

R⁵:-(CH₂)₄OCOCH₃(2-position) m:1

M.p.176-177.5 ℃ crystalline form: light yellow powder

Recrystallization solvent: chloroform state: free form

TABLE 42 example 26

R⁴:H A:-CH₂- Z:O

R⁵:C₂H₅O (2-position) m:1

Crystal form: yellow powder NMR (10)

The state is as follows: free example 27

R⁴:H A:-CH₂- Z:O

R⁵:CH₃(3-position) m:1

M.p.290 ℃ (decomposition.) crystalline form: white needle NMR (11)

Recrystallization solvent: dimethylformamide state: free example 28

R⁴:H A:-CH₂- Z:O

R⁵:C₂H₅(3-position) m:1

Crystal form: yellow powder NMR (12)

The state is as follows: free example 29

R⁴:H A:-CH₂- Z:O

R⁵: is justPropyl (3-position) m:1

M.p.282 ℃ (decomposition.) crystalline form: light brown needle-like

Recrystallization solvent: dimethylformamide-dichloromethane

The state is as follows: free form

Table 43 example 3

R⁴:H A:-CH₂- Z:O

R⁵: n-butyl (3-position) m:1

M.p.267-279 ℃ (decomposition.) crystalline form: pink powder

The state is as follows: free NMR (14) example 32

R⁴:H A:-CH₂- Z:O

R⁵: isopropyl (3-position) m:1

M.p.262.5-265.5 ℃ form: yellow powder

Recrystallization solvent: dimethylformamide-dichloromethane

The state is as follows: free example 33

R⁴:H A:-CH₂- Z:O

R⁵Cl (3-position) m:1

Crystal form: light yellow powder NMR (15)

The state is as follows: free form

TABLE 44 example 34

R⁴:H A:-CH₂- Z:O

R⁵F (3-position) m:1

Crystal form: light yellow powder NMR (16)

The state is as follows: free example 35

R⁴:H A:-CH₂- Z:O

R⁵:CH₃O (3-position) m:1

Crystal form: yellow powder NMR (17)

The state is as follows: free example 36

R⁴:H A:-CH₂- Z:O

R⁵:C₂H₅O (3-position) m:1

Crystal form: yellow powder NMR (18)

The state is as follows: free example 37

R⁴:H m:1 Z:O

R⁵And A together form:

m.p.294-295 ℃ (split.) crystalline form: white powder

Recrystallization solvent: dimethylformamide state: free form

TABLE 45 example 38

R⁴:H A:-CH₂- Z:O

R⁵:CH₃O (2-position) m:1

Crystal form: yellow powder NMR (19)

The state is as follows: free example 39

R⁴:H A:-CH₂- Z:O

R⁵:(CH₃)₂CHO- (3-position) m:1

Crystal form: light yellow powder NMR (20)

The state is as follows: free example 40

R⁴:H A:-CH₂- Z:O

R⁵:CF₃CH₂O- (3-position) m:1

Crystal form: light yellow powder NMR (21)

The state is as follows: free example 41

R⁴:H A:-CH₂- Z:O

R⁵:CF₃(2-position) m:1

Crystal form: colorless powder NMR (22)

The state is as follows: free form

TABLE 46 example 42

R⁴:H A:-CH₂- Z:O

R⁵:-OCH₂CON(C₂H₅)₂(2-position) m:1

Crystal form: yellow powder NMR (23)

The state is as follows: free example 43

R⁴:H A:-CH₂- Z:O

R⁵:-COOCH₃(2-position) m:1

Crystal form: light yellow powder NMR (24)

The state is as follows: free example 44

R⁴:H A:-CH₂- Z:O

R⁵:-(CH₂)₂-CONH- (2-and 3-together) m:2

Crystal form: yellow powder NMR (25)

The state is as follows: free example 45

R⁴:H A:-CH₂- Z:O

R⁵:(CH₃)₃C- (2-position) m:1

M.p.263-266 ℃ (split.) crystalline form: yellow powder

Recrystallization solvent: dimethylformamide-dichloromethane

The state is as follows: free form

TABLE 47 example 46

R⁴:H A:-CH₂- Z:O

R⁵:-(CH₂)₂COOCH₃(2-position) m:1

Crystal form: yellow powder NMR (26)

The state is as follows: free example 47

R⁴:H A:-CH₂- Z:O

R⁵:-(CH₂)₂CON(CH₃)₂(2-position) m:1

Crystal form: light yellow powder NMR (27)

The state is as follows: free example 48

R⁴:H A:-CH₂- Z:O

R⁵:-(CH₂)₂CON(C₂H₅)₂(2-position) m:1

Crystal form: yellow amorphous NMR (28)

The state is as follows: free example 49

R⁴:H A:-CH₂- Z:O

R⁵Cl (2-position) m:1

M.p.235.5-237 ℃ crystalline form: yellow powder

Recrystallization solvent: dimethylformamide-water

The state is as follows: free form

TABLE 48 example 50

R⁴:H A:-CH₂- Z:O

R⁵:-(CH₂)₂COOC₂H₅(2-position) m:1

M.p.199.6-203.8 ℃ crystalline form: light yellow powder

Recrystallization solvent: chloroform-dimethylformamide

The state is as follows: free NMR (29) example 51

R⁴:H A:-CH₂- Z:O

R⁵n-Butyl (2-position) m:1

-m.p.187.5-190 ℃ crystalline form: light yellow powder

Recrystallization solvent: chloroform-dimethylformamide

The state is as follows: free example 52

R⁴:H A:-CH₂- Z:O

R⁵:-(CH₂)₄OCOCH₃(2-position) m:1

M.p.176-177.5 ℃ crystalline form: light yellow powder

Recrystallization solvent: chloroform state: free form

Table 4953

R⁴:H m:1 Z:O

R⁵Together with A to form

M.p.285-287 ℃ (decomposition.) crystalline form: white powder

Recrystallization solvent: dimethylformamide-water

The state is as follows: free example 54

R⁴:H A:-CH₂- Z:O

R⁵: n-heptyl (2-position) m:1

M.p.187-188.5 ℃ crystalline form: light yellow powder

Recrystallization solvent: dichloromethane-dimethylformamide

The state is as follows: free example 55

R⁴:H A:-CH₂- Z:S

R⁵:CH₃O (2-position) m:1

M.p.241-244 ℃ crystalline form: yellow powder

The state is as follows: free form

Tables 38 to 49¹The H-NMR spectra (NMR (1) to NMR (29)) are as follows:

NMR(1)(DMSO-d₆)δppm:0.92(3H,t,J=7.4Hz),1.58-1.69(2H,m),2.69(2H,t,J=7.4Hz),5.12(2H,s),6.65(1H,d,J=15.4Hz),7.03(1H,d,J=8.6Hz),7.31(1H,t,J=7.6Hz),7.44(1H,t,J=7.7Hz),7.76(1H,d,J=7.7Hz),7.87-7.99(4H,m)

NMR(2)(DMSO-d₆)δppm:1.25(6H,d,J=7Hz),3.40(1H,sept,J=7Hz),5.12(2H,s),6.64(1H,d,J=15.5Hz),7.03(1H,d,J=8.5Hz),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)

NMR(3)(DMSO-d₆)δppm:5.07(2H,s),6.65(1H,d,J=15.5Hz),7.15(2H,d,J=9Hz),7.1-7.5(2H,m),7.76(1H,d,J=7Hz),7.89(1H,d,J=15.5Hz),7.99(1H,d,J=7Hz),8.05(2H,d,J=9Hz),12.70(1H,br),13.04(1H,br)

NMR(4)(DMSO-d₆)δppm:0.89(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(1H,d,J=15.5Hz),7.04(1H,d,J=8.5Hz),7.30-7.38(1H,m),7.43-7.51(1H,m),7.78-7.82(1H,d,J=7.9Hz),7.85-8.10(4H,m)

NMR(5)(DMSO-d₆)δppm:5.22(2H,s),6.67(1H,d,J=15.5Hz),7.24-7.49(3H,m),7.77(1H,d,J=7.6Hz),7.89(1H,d,J=15.5Hz),7.96-8.12(3H,m),12.83(1H,br)

NMR(6)(DMSO-d₆)δppm:1.6-1.9(4H,m),2.65-3.0(4H,m),5.06(2H,s),6.45(1H,d,J=16Hz),6.82(1H,d,J=8.5Hz),7.25-7.65(4H,m),7.75(1H,d,J=8Hz),7.97(1H,d,J=8Hz),12.85(1H,br)

NMR(7)(DMSO-d₆)δppm:2.22(3H,s),2.31(3H,s),5.05(2H,s),6.44(1H,d,J=15.5Hz),6.85(1H,d,J=8.5Hz),7.25-7.6(4H,m),7.76(1H,d,J=8Hz),7.98(1H,d,J=8Hz),12.83(1H,br)

NMR(8)(DMSO-d₆)δppm:2.36(6H,s),4.75(2H,s),6.67(1H,d,J=15.5Hz),7.30-7.53(2H,m),7.77(1H,d,J=8.9Hz),7.79(2H,s),7.91(1H,d,J=15.5Hz),8.00(1H,d,J=7.00Hz),12.09-13.2(2H,br)

NMR(9)(DMSO-d₆)δppm:2.10(6H,s),4.95(2H,s),6.22(1H,d,J=16Hz),6.78(2H,s),7.02(1H,d,J=16Hz),7.25-7.5(2H,m),7.76(1H,d,J=8Hz),7.98(1H,d,J=7.5Hz),12.9(2H,br)

NMR(10)(CDCl₃)δppm:1.37(3H,d,J=7.0Hz),4.14(2H,q,J=7.0Hz),5.09(2H,s),6.65(1H,d,J=15.5Hz),7.06(1H,d,J=8.6Hz),7.31(1H,d,J=7.4Hz),7.44(1H,t,J=7.4Hz),7.55(1H,s),7.67-7.78(2H,m),7.90(1H,d,J=15.5Hz),7.98(1H,d,J=7.4Hz),12.74(2H,br)

NMR(11)(DMSO-d₆)δppm:2.45(3H,s),5.03(2H,s),6.45(1H,d,J=15.6Hz),6.90-7.06(2H,m),7.28-7.35(1H,m),7.41-7.48(1H,m),7.56(1H,d,J=15.6Hz),7.75(2H,t,J=7.4Hz),7.97-8.00(1H,m),12.80(2H,brs)

NMR(12)(DMSO-d₆)δppm:1.13(3H,t,J=7.4Hz).2.80(2H,q,J=7.4Hz),5.03(2H,s),6.47(1H,d,J=15.6Hz),6.94(1H,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),7.68-7.81(2H,m),7.92-8.03(1H,m),12.86(2H,br)

NMR(14)(DMSO-d₆)δppm:0.82(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(1H,d,J=15.7Hz).6.91-7.07(2H,m),7.30-7.41(1H,m),7.41-7.54(1H,m),7.51(1H,d,J=15.7Hz),7.74-7.82(2H,m),8.00-8.04(1H,m)

NMR(15)(DMSO-d₆)δppm:5.08(2H,s),6.50(1H,d,=15.7Hz),7.13(1H,dd,J=2.5Hz,J=8.7Hz),7.27-7.49(4H,m),7.71(1H,d,J=8.7Hz),7.76(1H,d,J=7.0Hz),7.99(1H,d,J=7.0Hz),12.85(1H,br)

NMR(16)(DMSO-d₆)δppm:5.09(2H,s),6.61(1H,d,J=15.6Hz),6.98-7.13(2H,m),7.30(1H,t,J=7.1Hz),7.44(1H,t,J=7.1Hz),7.63(1H,dd,J=3.4Hz,J=15.6Hz),7.74-7.90(2H,m),7.97(1H,d,J=7.1Hz),12.88(1H,br)

NMR(17)(DMSO-d₆)δppm:3.89(3H,s),5.06(2H,s),6.51(1H,d,J=15.5Hz),6.71(1H,d,J=2.2Hz,J=8.7Hz),6.82(1H,d,J=2.2Hz),7.25-7.50(2H,m),7.66(1H,d,J=8.7Hz),7.70(1H,d,J=15.5Hz),7.74-7.81(1H, m),7.94-8.03(1H,m),12.80(2H,br)

NMR(18)(DMSO-d₆)δppm:1.34(3H,t,J=6.9Hz),4.15(2H,q,J=6.9Hz),5.05(2H,s),6.45(1H,d,J=15.5Hz),6.68(1H,dd,J=2.0Hz,J=8.7Hz),6.77(1H,d,J=2.0Hz),7.26-7.50(2H,m),7.66(1H,d,J=8.7Hz),7.72-7.81(1H,m),7.79(1H,d,J=15.5Hz),7.91-8.05(1H,m),12.77(2H,br)

NMR(19)(DMSO-d₆)δppm: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),7.7-8.1(4H,m),11.68(1H,br)

NMR(20)(DMSO-d₆)δppm:1.29(6H,d,J=6.0Hz),4.82(1H,sept,J=6.0Hz),5.05(2H,s),6.43(1H,d,J=15.5Hz),6.89(1H,dd,J=2.3Hz,J=8.7Hz),6.78(1H,d,J=2.3Hz),7.31(1H,t,J=7.0Hz),7.45(1H,t,J=7.0Hz),7.66(1H,d,J=8.7Hz),7.78(1H,d,J=15.5Hz),7.80(1H,d,J=7.0Hz),7.99(1H,d,J=7.0Hz),12.76(1H,br)

NMR(21)(DMSO-d₆)δppm:4.92(2H,q,J=8.7Hz),5.07(2H,s),6.48(1H,d,J=15.5Hz),6.81(1H,dd,J=2.3Hz,J=8.8Hz),6.93(1H,d,J=2.3Hz),7.32(1H,t,J=7.0Hz),7.45(1H,t,J=7.0Hz),7.62-7.79(3H,m),7.99(1H,d,J=7.0Hz),12.78(1H,br)

NMR(22)(DMSO-d₆)δppm: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(1H,d,J=7.5Hz),8.15-8.45(2H,m),12.88(1H,br)

NMR(23)(DMSO-d₆)δppm: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(1H,d,J=15.5Hz),7.10(1H,d,J=8.5Hz),7.25-7.55(3H,m),7.7-7.85(2H,m),7.86(1H,d,J=15.5Hz),7.98(1H,d,J=7.5Hz),12.66(1H,br)

NMR(24)(DMSO-d₆)δppm:3.90(3H,s),5.18(2H,s),6.67(1H,d,J=15.5Hz),7.28-7.36(2H,m),7.46(1H,t,J=7.6Hz),7.78(1H,d,J=7.6Hz),7.89(1H,d,J=15.5Hz),7.99(1H,t,J=7.6Hz),8.25(1H,dd,J=2.3Hz,J=8.9Hz)8.38(1H,d,J=2.3Hz)

NMR(25)(DMSO-d₆)δppm:2.48(2H,t,J=7.5Hz),3.12(2H,t,J=7.5Hz),5.04(2H,s),6.52(1H,d,J=15.7Hz),7.13(1H,d,J=8.7Hz),7.34(1H,t,J=7.2Hz),7.42-7.63(3H,m),7.80(1H,d,J=7.6Hz),8.02(1H,d,J=7.2Hz),10.33(1H,br),12.98(1H,br)

NMR(26)(DMSO-d₆)δppm:2.71(2H,t,J=7.6Hz),2.98(2H,t,J=7.6Hz),3.59(3H,s),5.13(2H,s),6.60-6.75(1H,m),7.04-7.08(1H,m),7.27-7.38(1H,m),7.38-7.51(1H,m),7.55-7.78(1H,m),7.84-7.99(4H,m),9.40(2H,brs)

NMR(27)(DMSO-d₆+CDCl₃)δppm:2.66(2H,t,J=8.8Hz),2.84(3H,s),2.89-3.06(5H,m),5.01(2H,s),6.57-6.75(1H,m),6.90-7.10(1H,m),7.18-7.30(1H,m),7.30-7.41(1H,m),7.63-7.72(1H,m),7.72-7.90(3H,m),7.96(1H,s),11.50-13.00(2H,brs)

NMR(28)(DMSO-d₆)δppm:1.00(3H,t,J=7.0Hz),1.07(3H,t,J=7.0Hz),2.68(2H,t,J=7.4Hz),3.01(2H,t,J=7.4Hz),3.15-3.46(4H,m),5.06(2H,s),6.78(2H,d,J=15.4Hz),6.95-6.99(1H,m),7.25-7.30(1H,m),7.38-7.43(1H,m),7.72-7.85(5H,m)

NMR(29)(DMSO-d₆)δppm:1.12(3H,t,J=7.1Hz),2.69(2H,t,J=7.8Hz),2.98(2H,t,J=7.8Hz),4.00(2H,q,J=7.1Hz),5.13(2H,s),6.61(1H,d,J=15.4Hz),7.04(1H,d,J=8.8Hz),7.30-7.40(1H,m),7.55(1H,m),7.75(1H,d,J=7.3Hz),7.86(1H,d,J=15.4Hz),7.91-8.10(3H,m),12.40-13.30(2H,m)

using suitable starting compounds, the following table was prepared in the same manner as described in example 3 or 4

50-125.

Watch 50 Example 56R⁴:H A:-CH₂- m:1

R^11b:H R⁵:H

M.p.175-185 ℃ crystalline form: white powder

Recrystallization solvent: ethanol state: free NMR (1) example 57R⁴:H A:-CH₂- m:1

R^11b:H R⁵: isopropyl (2-position)

M.p.190-192 ℃ crystalline form: light brown powder

Recrystallization solvent: ethanol state: free trans form

TABLE 51 example 58R⁴:H A:-CH₂- m:1

R^11b:H R⁵:H

M.p.202.5-225 ℃ (decomposition.) crystalline form: white powder NMR (2)

Recrystallization solvent: ethanol-ether state: 2HCl EXAMPLE 59R⁴:H A:-CH₂- m:1

R^11b:H R⁵: isopropyl (2-position)

M.p.186-190 ℃ (decomposition.) crystalline form: yellow powder

Recrystallization solvent: ethanol-ether state: 2HCl EXAMPLE 60R⁴:H A:-CH₂- m:1

R^11b:H R⁵:H

M.p.202-206 ℃ (split.) crystalline form: yellow powder state: 2HCl

Recrystallization solvent: ethanol-ethyl ether

TABLE 52 example 61R⁴:H A:-CH₂- m:1

R^11b:H R⁵: isopropyl (2-position)

M.p.114-115 ℃ crystalline form: light yellow powder cis

Recrystallization solvent: ethanol-water state: free example 62R⁴:H A:-CH₂- m:1

R^11b:H R⁵Cl (2-position)

M.p206.5-209 ℃ crystalline form: white powder

Recrystallization solvent: ethanol-water state: free example 63

R¹:CH₃ R⁴:H A:-CH₂- m:1

R²:H

R^11b:H R⁵:H

M.p.138.5-141.5 ℃ form: white powder

The state is as follows: free form

TABLE 53 example 64R⁴:H A:-CH₂- m:1

R^11b:H R⁵:H

M.p.221-222.5 ℃ crystalline form: light yellow powder

The state is as follows: free example 65R⁴:H A:-CH₂- m:1

R^11b:H R⁵Cl (2-position)

M.p.181-183 ℃ crystalline form: white powder

Recrystallization solvent: ethanol-ether state: free example 66R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃(2-position)

M.p.261-262 ℃ crystalline form: yellow powder

Recrystallization solvent: ethanol state: 2HCl

TABLE 54 example 67R⁴:H A:-CH₂- m:1

R^11b:H R⁵:C₂H₅(2-position)

M.p.227-229 ℃ crystalline form: light yellow powder

Recrystallization solvent ethanol state: 2HCl EXAMPLE 68R⁴:H A:-CH₂- m:1

R^11b:H R⁵F (2-position)

M.p.226-227 ℃ crystalline form: brown powder

Recrystallization solvent: ethanol state: 2HCl EXAMPLE 69R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃(2-position)

Recrystallization solvent: ethanol crystal form: light yellow powder

The state is as follows: 3HCl NMR (3)

TABLE 55 example 70R⁴:H A:-CH₂- m:1

R^11b:H R⁵:C₂H₅(2-position)

M.p.157-160 ℃ crystalline form: light yellow powder

Recrystallization solvent: ethanol state: 3HCl EXAMPLE 71R⁴:H A:-CH₂- m:1

R^11b:H R⁵F (2-position)

Recrystallization solvent: ethanol crystal form: brown powder

The state is as follows: 3HCl NMR (4) example 72R⁴:H A:-CH₂- m:1

R^11b:H R⁵: n-propyl (2-position)

Crystal form: yellow powder state: 3HCl NMR (5)

TABLE 56 example 73R⁴:H A:-CH₂- m:1

R^11b:H R⁵Cl (2-position)

M.p.200 ℃ crystalline form: yellow powder

Recrystallization solvent: ethanol-water state: 2HCl example 74R⁴:H A:-CH₂- m:1

R^11b:H R⁵:C₂H₅(2-position)

M.p.115-118 ℃ crystalline form: light brown powder

Recrystallization solvent: ethanol state: 2HCl EXAMPLE 75R⁴:H A:-CH₂- m:1

R^11b:H R⁵: isopropyl (2-position)

M.p.188-191 ℃ crystalline form: white powder state: 2HCl

Recrystallization solvent: ethanol-water-ethyl ether

TABLE 57 EXAMPLE 76R⁴:H A:-CH₂- m:1

R^11b:H R⁵: n-propyl (2-position)

Crystal form: light yellow powder state: 3HCl NMR (6) example 77R⁴:H A:-CH₂- m:1

R^11b:H R⁵:C₂H₅(2-position)

Crystalline form at-m.p.228-230 ℃: light yellow powder

Recrystallization solvent: ethanol state: 2HCl EXAMPLE 78R⁴:H m:1

R5 and a together form:

R^11b:H

m.p.203-205 ℃ crystalline form: white powder state: 3HCl

Recrystallization solvent: methanol-Ether

TABLE 58 example 79R⁴:H A:-CH₂- m:1

R^11b:H R⁵: n-propyl (2-position)

M.p.202-204 ℃ crystalline form: white powder

Recrystallization solvent: ethyl acetate-n-hexane state: 3HCl EXAMPLE 80R⁴:H A:-C₂H₂- m:1

R^11b:H R⁵: n-propyl (2-position)

Crystal form: yellow powder state: 2HCl NMR (9) example 81R⁴:H A:-CH₂- m:1

R^11b:H R⁵Cl (2-position)

M.p.171 ℃ crystalline form: light yellow powder state: 2HCl

Recrystallization solvent: ethanol-water

TABLE 59 example 82R⁴:H A:-CH₂- m:2

R^11b:H R⁵:CH₃(2-and 6-position)

M.p.233-235 ℃ crystalline form: light yellow powder

Recrystallization solvent: ethanol state: free example 83R⁴:H A:-CH₂- m:2

R^11b:H R⁵:CH₃(2-and 6-position)

M.p.206-210 ℃ crystalline form: light yellow powder

Recrystallization solvent: ethanol state: free example 84R⁴:H A:-CH₂- m:1

R^11b:H R⁵F (2-position)

M.p.205-208 ℃ crystalline form: white powder

Recrystallization solvent: ethanol-water state: 2HCl

TABLE 60 example 85R⁴:H A:-CH₂- m:1

R^11b:H R⁵F (2-position)

M.p.173-175 ℃ crystalline form: light yellow powder

Recrystallization solvent: ethanol-water-ether state: 2HCl EXAMPLE 86R⁴:H A:-CH₂- m:1

R⁵:C₂H₅OOC(CH₂)₂- (2-position)

R^11b:H

M.p.152.4-156.3 ℃ form: white powder

Recrystallization solvent: ethanol-water-ether state: 3HCl EXAMPLE 87R⁴:H A:-CH₂- m:1

R^11b:H R⁵F (2-position)

M.p.150-153 ℃ crystalline form: light yellow powder

Recrystallization solvent: dichloromethane-ether state: free form

TABLE 61 example 88R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (2-position)

Crystal form: light yellow powder state: 2HCl

Recrystallization solvent: ethanolWater NMR (11) example 89R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (2-position)

M.p.203-206 ℃ crystalline form: light yellow powder

Recrystallization solvent: ethanol-water-ether state: 2HCl EXAMPLE 90R⁴:H A:-CH₂- m:1

R^11b:H R⁵: n-butyl (2-position)

M.p.161.7-165 ℃ crystalline form: light yellow powder

Recrystallization solvent: ethanol-water-ether state: 3HCl

TABLE 62 example 91R⁴:H A:-CH₂- m:1

R^11b:H R⁵N-butyl (2-position)

M.p.153-155.5 ℃ crystalline form: light yellow powder

Recrystallization solvent: ethanol-water-ether state: 3HCl EXAMPLE 92R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CF₃(2-position)

M.p.185-187 ℃ crystalline form: light yellow powder

Recrystallization solvent: isopropyl alcohol-water state: 2HCl EXAMPLE 93R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CF₃(2-position)

M.p.175-178 ℃ crystalline form: light yellow powder

Recrystallization solvent: ethanol-water state: 2HCl

TABLE 63 example 94R⁴:H A:-CH₂- m:1

R⁵:CH₃COO(CH₂)₄- (2-position)

R^11b:H M.p.151-154 ℃ crystalline form: white powder

Recrystallization solvent: ethanol-water-ether state: 3HCl EXAMPLE 95R⁴:H A:-CH₂- m:1

R^11b:H R⁵: n-butyl (2-position)

M.p.167-168 ℃ crystalline form: white powder

Recrystallization solvent: ethanol-water state: 3HCl EXAMPLE 96R⁴:H A:-CH₂- m:1

R^11b:H R⁵: n-butyl (2-position)

M.p.135-137 ℃ crystalline form: light yellow powder

Recrystallization solvent: ethanol-water-ether state: 3HCl

TABLE 64 EXAMPLE 97R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (2-position)

M.p.183.5-186 ℃ crystalline form: yellow powder

Recrystallization solvent: ethanol-water state: 2HCl EXAMPLE 98R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (2-position)

M.p.174-176 ℃ crystalline form: light yellow powder

Recrystallization solvent: ethanol-water state: 2HCl EXAMPLE 99R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (2-position)

M.p.153-154 ℃ crystalline form: yellow powder

Recrystallization solvent: ethanol-water state: 2HCl

TABLE 65 example 100R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (2-position)

M.p.177.5-179.5 ℃ form: light yellow powder

Recrystallization solvent: ethanol-water state: 3HCl EXAMPLE 101R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (2-position)

M.p.165-168 ℃ crystalline form: light yellow powder

Recrystallization solutionPreparation: ethanol-water-ether state: 3HCl EXAMPLE 102R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (2-position)

M.p.161.5-164 ℃ crystalline form: yellow powder

Recrystallization solvent: ethanol-water state: HCl

TABLE 66 example 103R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (2-position)

M.p.181-183 ℃ crystalline form: white powder

Recrystallization solvent: ethanol-water state: 2HCl example 104R⁴:H A:-CH₂- m:1

R^11b:H R⁵:C₂H₅O- (2-position)

M.p.174-177 ℃ crystalline form: light yellow powder state: 2HCl

Recrystallization solvent: ethanol-water-isopropanol-diethyl ether example 105R⁴:H A:-CH₂- m:1

R^11b:H R⁵:C₂H₅O- (2-position)

M.p.194-196 ℃ crystalline form: yellow powder state: 2HCl

Recrystallization solvent: ethanol-water-isopropanol-ethyl ether

TABLE 67 example 106R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (2-position)

M.p.200-203 ℃ crystalline form: light yellow powder

Recrystallization solvent: ethanol-water state: 2HCl EXAMPLE 107R⁴:H A:-CH(CH₃)- m:1

R^11b:H R⁵:CH₃O (2-position)

M.p.169-170 ℃ crystalline form: light yellow powder

Recrystallization solvent: ethanol state: 2HCl example 108R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (2-position)

M.p.181-189 ℃ crystalline form: light yellow powder

Recrystallization solvent: ethanol-water state: 3HCl NMR (12)

TABLE 68 example 109R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (2-position)

M.p.158-160 ℃ crystalline form: light yellow powder

Recrystallization solvent: ethanol-water state: 3HCl example 110R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (2-position)

M.p.176.5-181.5 ℃ form: yellow powder

Recrystallization solvent: ethanol-water state: 3HCl NMR (13) example 111R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (2-position)

M.p.141-142 ℃ crystalline form: white powder

Recrystallization solvent: ethanol-dichloromethane state: free form

TABLE 69 example 112R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (2-position)

M.p.131.5-133 ℃ crystalline form: light yellow powder

Recrystallization solvent: ethanol-dichloromethane state: free example 113 R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (2-position)

Crystal form: light yellow amorphous state: free NMR (14)

114R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (2-position)

M.p.140-142 ℃ state: methanesulfonic acid salt

Recrystallization solvent: ethanol-isopropyl ether

Crystal form: light yellow powder

TABLE 70 example 115R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (2-position)

M.p.168.5-169 ℃ crystalline form: white powder

Recrystallization solvent: ethanol-dichloromethane state: free example 116R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (2-position)

M.p.128.2-131.5 ℃ form: yellow powder state: free form

Recrystallization solvent: ethanol-Ether-Dichloromethane example 117R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (2-position)

M.p.144-146 ℃ crystalline form: light yellow powder

Recrystallization solvent: ethanol state: methanesulfonic acid salt

TABLE 71 example 118R⁴:H A:-CH₂- m:1

R^11b:H R⁵:C₂H₅O- (2-position)

M.p.190-192 ℃ crystalline form: yellow powder

The state is as follows: methanesulfonic acid salt

Recrystallization solvent: ethanol-isopropanol-diethyl ether-water example 119R⁴:H A:-CH₂- m:1

R⁵:CH₃OOC(CH₂)₂- (2-position)

R^11b:H

M.p.110-111 ℃ crystalline form: light yellow powder

Recrystallization solvent: ethanol state: free example 120R⁴:H A:-CH₂- m:1

R⁵:(CH₃)₂NOC(CH₂)₂- (2-position)

R^11b:H

M.p.162.5-164 ℃ crystalline form: yellow powder

Recrystallization solvent: ethanol-water state: HCl

TABLE 72 example 121R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (2-position)

M.p.205-207.5 ℃ crystalline form: light yellow powder

Recrystallization solvent: ethanol-water state: 2HCl example 122R⁴:H A:-CH₂- m:1

R⁵:(C₂H₅)₂NOCCH₂O- (2-position)

R^11b:H

M.p.167-169 ℃ crystalline form: white powder

Recrystallization solvent: ethanol-water state: 2HCl EXAMPLE 123R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O- (2-position)

M.p.190.5-192.5 ℃ crystalline form: yellow powder state: free form

Recrystallization solvent: ethanol-dichloromethane-diethyl ether

TABLE 73 example 124R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O- (2-position)

M.p.148.2-149 ℃ form: light yellow powder state: free form

Recrystallization solvent: ethanol-dichloromethane-diethyl ether example 125R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O- (2-position)

M.p.211-211.5 ℃ crystalline form: light yellow powder

Recrystallization solvent: ethanol-dichloromethane state: free example 126R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O- (2-position)

M.p.204-206 ℃ crystalline form: white needle-like shape

Recrystallization solvent: ethanol-dichloromethane state: free form

TABLE 74 example 127R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O- (2-position)

M.p.168-170.4 ℃ crystalline form: white needle-like state: free form

Recrystallization solvent: ethanol dichloromethane diethyl ether example 128R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O- (2-position)

M.p.175.8-177.2 ℃ crystalline form: white powder

Recrystallization solvent: ethanol-dichloromethane state: free example 129R⁴:H A:-CH₂- m:1

R^11b:H R⁵:C₂H₅(2-position)

M.p.130-132.5 ℃ state: dimethyl sulfonate

Recrystallization solvent: ethanol-ethyl ether

Crystal form: yellow powder

TABLE 75 example 130R⁴:H A:-CH₂- m:1

R^11b:H R⁵:C₂H₅O- (2-position)

M.p.225-226 ℃ crystalline form: light yellow powder

Recrystallization solvent: dichloromethane-ethanol state: free example 131R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (2-position)

M.p.222-223 ℃ crystalline form: white powder

Recrystallization solvent: methanol-dichloromethane state: free example 132R⁴:H A:-CH₂- m:1

R^11b:H R⁵:C₂H₅O- (2-position)

M.p.122.5-125 ℃ crystalline form: light yellow powder

Recrystallization solvent: ethanol-dichloromethane state: free form

TABLE 76 example 133R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (2-position)

M.p.162-163 ℃ crystalline form: white powder

Recrystallization solvent: ethanol-dichloromethane state: free example 134 R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (2-position)

M.p.177.2-178 ℃ crystalline form: light yellow powder

Recrystallization solvent: ethanol-dichloromethane state: free form

135R⁴:H A:-CH₂- m:1

R^11b:H R⁵:C₂H₅(2-position)

M.p.140-155 ℃ (split.) crystalline form: white powder NMR (27)

Recrystallization solvent: ethanol-dichloromethane-diethyl ether state: free form

TABLE 77 EXAMPLE 136R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (2-position)

M.p.171-172.2 ℃ crystalline form: white needle-like state: free form

Recrystallization solvent: ethanol dichloromethane-diethyl ether example 137R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (2-position)

M.p.232.5-233 ℃ crystalline form: yellow powder

Recrystallization solvent: dichloromethane-ethanol state: free example 138R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (2-position)

Crystal form: light yellow amorphous NMR (28)

The state is as follows: 3HCl

TABLE 78 example 139R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (2-position)

M.p.192-194 ℃ crystalline form: yellow powder

Recrystallization solvent: ethanol-dichloromethane state: free example 140R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (2-position)

M.p.201-204 ℃ crystalline form: yellow powder

Recrystallization solvent: ethanol-dichloromethane state: free example 141 R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (2-position)

M.p.172-175 ℃ crystalline form: yellow powder

Recrystallization solvent: ethanol-dichloromethane state: free form

TABLE 79 example 142R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (2-position)

M.p.146.5-148 ℃ form: yellow powder

Recrystallization solvent: ethanol-dichloromethane state: free example 143R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (2-position)

M.p.114-117 ℃ crystalline form: light yellow powder

Recrystallization solvent: ethanol-dichloromethane state: free example 144R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (2-position)

M.p.176-181 ℃ crystalline form: light yellow powder state: 2HCl

Recrystallization solvent: ethanol-Water-Ether NMR (29)

TABLE 80 example 145R⁴:-CH₂OCOC(CH₃)₃ A:-CH₂- m:1

R^11b:H R⁵:CH₃O (2-position)

M.p.106.5-108.2 ℃ form: light yellow powder

Recrystallization solvent: ethanol-ether-n-hexane state: free example 146R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (2-position)

M.p.189-190 ℃ crystalline form: white powder

Recrystallization solvent: ethanol-dichloromethane state: free example 147 R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (2-position)

M.p.151-153 ℃ crystalline form: white powder

Recrystallization solvent: ethyl acetate-ether state: free form

TABLE 81 EXAMPLE 148R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (2-position)

M.p.145-147 ℃ crystalline form: white powder state: free form

Recrystallization solvent: ethyl acetate-chloroform example 149R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (2-position)

M.p.189-190.5 ℃ crystalline form: light yellow powder

Recrystallization solvent: ethyl acetate-chloroform state: free example 150R⁴:H A:-CH₂- m:1

R^11b:H R⁵: isopropyl (2-position)

M.p.196-199 ℃ (split.) crystalline form: light yellow powder

Recrystallization solvent: ethanol-dichloromethane state: free form

TABLE 82 example 151R⁴:H A:-CH₂- m:1

R^11b:H R⁵:C₂H₅O- (2-position)

M.p.155-158 ℃ (decomposition.) crystalline form: yellow powder state: free form

Recrystallization solvent: ethanol dichloromethane diethyl ether example 152R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (2-position))

M.p.162-164 ℃ crystalline form: white powder

Recrystallization solvent: ethyl acetate-ether state: free example 153 R⁴:H A:-CH₂- m:1

R^11b:H R⁵: n-propyl (2-position)

M.p.137-139 ℃ (decomposition.) crystalline form: light yellow powder

Recrystallization solvent: ethanol-dichloromethane state: free form

TABLE 83 example 154R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (2-position)

M.p.158-159 ℃ crystalline form: white powder state: free form

Recrystallization solvent: ethanol dichloromethane diethyl ether example 155R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (2-position)

M.p.154-154.5 ℃ crystalline form: white powder state: free form

Recrystallization solvent: ethanol dichloromethane diethyl ether example 156R⁴:H A:-CH₂- m:1

R^11b:-CH₃R⁵:CH₃O (2-position)

M.p.180-181.5 ℃ crystalline form: dark yellow powder state: free form

Recrystallization solvent: ethanol-dichloromethane-diethyl ether

TABLE 84 example 157R⁴:H A:-CH₂- m:1

R^11b:H R⁵:C₂H₅(2-position)

p.165-175 ℃ (split.) crystalline form: yellow powder NMR (30)

Crystallization solvent: dichloromethane-ethanol-ether state: free example 158R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (2-position)

M.p.125-128 ℃ crystalline form: yellow powder state: free form

Recrystallization solvent: ethanol-dichloromethane example159R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃(2-position)

M.p.195-195.5 ℃ crystalline form: light yellow powder state: free form

Recrystallization solvent: ethanol-dichloromethane

TABLE 85 example 160R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CF₃(2-position)

M.p.188-190 ℃ crystalline form: light yellow powder state: free form

Recrystallization solvent: ethanol-dichloromethane example 161R⁴:H A:-CH₂- m:1

R^11b:H R⁵F (2-position)

M.p.197-200 ℃ crystalline form: light yellow powder state: free form

Recrystallization solvent: ethanol-dichloromethane example 162R⁴:H m:1

R⁵And A together form:R^11b:H

m.p.138-141 ℃ crystalline form: white powder state: free form

TABLE 86 example 163R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (2-position)

M.p.155.5-158 ℃ crystalline form: light brown powder-like note: free form

Recrystallization solvent: ethanol-dichloromethane example 164R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃(2-position)

M.p.163-166 ℃ crystalline form: brown powder state: free form

Heavy solvent condensation: dichloromethane-ethanol-diethyl ether example 165R⁴:H A:-CH₂- m:1

R^11b:H R⁵: n-butyl (2-position)

M.p.161-163.4 ℃ crystalline form: yellow powder state: 2HCl

Recrystallization solvent: ethanol-dichloromethane-water

TABLE 87 example 166R⁴:H A:-CH₂- m:1

R^11b:H R⁵: n-butyl (2-position)

M.p.137-139 ℃ crystalline form: light brown powder state: free form

Recrystallization solvent: ethanol-dichloromethane-water example 167R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃(2-position)

M.p.215-217 ℃ crystalline form: light yellow powder state: free form

Recrystallization solvent: ethanol-dichloromethane example 168R⁴:H A:-CH₂- m:1

R^11b:H R⁵: n-heptyl (2-position)

M.p.146.5-149 ℃ crystalline form: light yellow powder

Recrystallization solvent: ethanol-dichloromethane-water state: 2HCl

TABLE 88 example 169R⁴:H A:-CH₂- m:1

R^11b:H R⁵: n-heptyl (2-position)

M.p.152-153.5 ℃ crystalline form: white powder

Recrystallization solvent: ethanol-dichloromethane-water state: free example 170R⁴:H A:-CH₂- m:1

R^11b:H R⁵: n-heptyl (2-position)

M.p.166.5-169.3 ℃ crystalline form: yellow powder

Recrystallization solvent: ethanol-dichloromethane state: free example 171R⁴:H A:-CH₂- m:1

R^11b:H R⁵: n-heptyl (2-position)

M.p.155-165 ℃ crystalline form: light yellow powder state: 2HCl

Recrystallization solvent: ethanol-dichloromethane-water NMR (31)

TABLE 89 example 172R⁴:H A:-(CH₂)₃- m:1

R^11b:H R⁵:CH₃O (2-position)

M.p.219-220 ℃ crystalline form: dark yellow powder state: free form

Recrystallization solvent: ethanol-dichloromethane

173R⁴:H A:-(CH₂)₃- m:1

R^11b:H R⁵:CH₃O (2-position)

M.p.177-185 ℃ crystalline form: dark yellow powder state: 3HCl

Recrystallization solvent: ethanol-dichloromethane-water NMR (32)

TABLE 90 example 175R⁴:H A:-CH₂- m:1

R^11b:H R⁵:C₂H₅O (2-position)

M.p.182-184 ℃ crystalline form: light yellow powder state: 2HCl

Recrystallization solvent: ethanol-water-ethyl ether

176R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃(2-position)

M.p.265-270 ℃ crystalline form: light yellow powder-like material: 2HCl

Recrystallization solvent: ethanol-Water-Ether NMR (33) example 177R⁴:H A:-CH₂- m:1

R^11b:H R⁵: isopropyl (2-position)

M.p.203-207 ℃ crystalline form: light yellow powder state: 2HCl

Recrystallization solvent: ethanol-water-ethyl ether

TABLE 91 EXAMPLE 178R⁴:H A:-CH₂- m:2

R⁵:CH₃(2-and 6-position)

R^11b:H

M.p.234-238 ℃ crystalline form: light yellow powder state: 2HCl

Recrystallization solvent: ethanol-Water-Ether EXAMPLE 179R⁴:H A:-CH₂- m:1

R^11b:H R⁵F (2-position)

M.p.214-217 ℃ crystalline form: light yellow powder state: 2HCl

Recrystallization solvent: ethanol-Water example 180R⁴:H A:-CH₂- m:1

R^11b:H R⁵:C₂H₅(2-position)

M.p.188-190 ℃ crystalline form: light yellow powder state: 2HCl

Recrystallization solvent: ethanol-water

TABLE 92 example 181R⁴:H A:-CH₂- m:1

R^11b:H R⁵: n-propyl (2-position)

M.p.164-167 ℃ crystalline form: yellow powder state: 2HCl

Recrystallization solvent: ethanol-Water example 182R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (3-position)

M.p.165-168 ℃ crystalline form: light yellow powder-like material: 2HCl

Recrystallization solvent: ethanol-Water NMR (56) example 183R⁴:H A:-CH₂- m:1

R⁵:CH₃O (2-position)

R^11b:H

M.p.143-145 ℃ crystalline form: light yellow powder state: free form

Recrystallization solvent: ethanol-dichloromethane

TABLE 93 EXAMPLE 184R⁴:H A:-CH₂- m:1

R^11b:H R⁵:H

M.p.215-218.5 ℃ (split.) crystalline form: white powder

Recrystallization solvent: ethanol-water-ether state: 2HCl example 185R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CF₃(2-position)

M.p.101-106 ℃ crystalline form: white powder state: 2HCl

RecrystallizationSolvent: Ether-ethanol-Water NMR (34) example 186R⁴:H A:-CH₂- m:1

R⁵:CH₃O (2-position)

R^11b:H

M.p.179-183 ℃ crystalline form: white powder state: 2HCl

Recrystallization solvent: ethanol-water-ethyl ether

TABLE 94 example 187R⁴:H A:-CH₂- m:1

R⁵:C₂H₅CH(CH₃) - (2-position)

R^11b:H

M.p.129-131 ℃ crystalline form: light yellow powder

Recrystallization solvent: isopropyl alcohol-water column: hydrogen oxalate EXAMPLE 188R⁴:H A:-CH₂- m:1

R^11b:H R⁵:C₂H₅(3-position)

M.p.163-165 ℃ crystalline form: light yellow powder state: 2HCl

Heavy knotCrystal solvent: water-ethanol-dichloromethane example 189R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃(CH₂)₄- (2-position)

M.p.161-162 ℃ crystalline form: white powder state: 2HCl

Recrystallization solvent: isopropyl alcohol-water

Watch 95Example 190R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (4-position)

M.p.166-168 ℃ crystalline form: yellow powder state: 2HCl

Recrystallization solvent: water-ethanol-dichloromethane

Watch 96Example 191R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (2-position)

M.p.175-177 ℃ crystalline form: white powder state: 2HCl

Recrystallization solvent: ethanol-Water-Ether example 192R⁴:H A:-CH₂- m:2

R⁵:CH₃(2-and 3-position)

R^11b:H

M.p.158-162 ℃ crystalline form: light yellow powder state: succinic acid salt

Recrystallization solvent: ethanol-isopropyl ether example 193R⁴:H A:-CH₂- m:2

R⁵:CH₃(2-and 3-position)

R^11b:H

M.p.126-128.5 ℃ crystalline form: yellow powder state: succinic acid salt

Recrystallization solvent: ethanol-ethyl ether

TABLE 97 example 194R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CF₃(2-position)

M.p.166-171 ℃ crystalline form: light yellow powder state: HCl

Recrystallization solvent: isopropanol-ethanol NMR (35) example 195R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (3-position)

M.p.175-178 ℃ crystalline form: yellow powder state: free form

Recrystallization solvent: methanol example 196R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (3-position)

M.p.240-245 ℃ crystalline form: light yellow powder free: HCl

Recrystallization solvent: ethanol-water

TABLE 98 EXAMPLE 197R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃(3-position)

M.p.212-215 ℃ crystalline form: white powder state: 2HCl

Recrystallization solvent: ethanol-Water example 198R⁴:H A:-CH₂- m:2

R⁵:-(CH₂)₄- (2-and 3-together)

R^11b:H

M.p.180-190 ℃ crystalline form: yellow powder state: 2HCl

Recrystallization solvent: ethanol-Ether NMR (36) example 199R⁴:H A:-CH₂- m:2

R^11b:H R⁵:CH₃(3-and 5-position)

M.p.210-216 ℃ crystalline form: white powder state: 2HCl

Recrystallization solvent: ethanol-Water-Ether NMR (37)

TABLE 99 example 200R⁴:H A:-CH₂- m:1

R^11b:H R⁵: isopropyl (3-position)

M.p.177.5-180.5 ℃ crystalline form: light yellow powder

Crystal form: ethanol-water state: 2HCl example 201R⁴：H A:-CH₂- m:2

R^11b:H R⁵:CH₃(3-and 5-position)

M.p.119-122.5 ℃ crystalline form: white powder

Recrystallization solvent: ethanol-isopropyl ether state: mesylate salt example 202R⁴:H A:-CH₂- m:1

R^11b:H R⁵:-COOCH₃(2-position)

M.p.169-172 ℃ crystalline form: white powder

Recrystallization solvent: ethanol-water state: dimethyl sulfonate

TABLE 100 example 203R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (3-position)

M.p.214-220 ℃ crystalline form: light yellow powder state: free form

Recrystallization solvent: methanol example 204R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (3-position)

M.p.195-197 ℃ crystalline form: yellow powder state: free form

Recrystallization solvent: methylene chloride methanol example 205R⁴:H A:-CH₂- m:2

R⁵- (CH2)4- (2-and 3-position together)

R^11b:H

M.p.151-153 ℃ crystalline form: light yellow powder

Recrystallization solvent: the water state: free form

Table 101 example 206R⁴:H A:-CH₂- m:1

R^11b:H R⁵: n-butyl (3-position)

M.p.148-150.4 ℃ crystalline form: light yellow powder state: 2HCl

Recrystallization solvent: isopropyl alcohol-water-ethyl ether example 207R⁴:H A:-CH₂- m:1

R^11b:H R⁵:(CH₃)₃C- (2-position)

M.p.142-144.5 ℃ crystalline form: light yellow powder state: oxalate salt

Recrystallization solvent: isopropyl alcohol-Water example 208R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃(3-position)

M.p.139.2-140.8 ℃ crystalline form: light yellow powder

Recrystallization solvent: ethanol-water state: methanesulfonic acid salt

Table 102 example 209R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O- (3-position)

M.p.158-163 ℃ crystalline form: light yellow powder state: 2HCl

Recrystallization solvent: ethanol-Water-Ether NMR (38) example 210R⁴:H A:-CH₂- m:1

R^11b:H R⁵: n-butyl (3-position)

M.p.84-86 ℃ crystalline form: yellow amorphous state: free example 211R⁴:H A:-CH₂- m:1

R^11b:H R⁵: n-propyl (3-position)

M.p.121-124 ℃ crystalline form: light yellow powder state: oxalic acid hydrogen salt

Recrystallization solvent: isopropyl alcohol-water

Table 103 example 212R⁴:H A:-CH₂- m:2

R⁵:CH₃(2-and 3-position)

R^11b:H

M.p.140-150 ℃ crystalline form: yellow powder NMR (39)

Recrystallization solvent: acetone-water state: mesylate salt example 213R⁴:H A:-CH₂- m:1

R⁵:-(CH₂)₂-CONH- (2-and 3-together)

R^11b:H

M.p.173-175 ℃ state: dimethyl sulfonate

Recrystallization solvent: ether-ethanol-water

Crystal form: yellow powder example 214R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (3-position)

M.p.168-172 ℃ (split.) crystalline form: yellow powder

Recrystallization solvent: ethanol-ether state: 2HCl

Table 104 example 215R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (3-position)

M.p.155-160℃ NMR(40)

Crystal form: light yellow powder state: 2HCl

Recrystallization solvent: ethanol-Water-Isopropanol-Ether example 216R⁴:H A:-CH₂- m:1

R⁵:CH₃O (3-position)

R^11b:H

M.p.163-165 ℃ crystalline form: light yellow powder

Recrystallization solvent: ethanol-water state: 2HCl example 217

R¹:CH₃ R⁴:H A:-CH₂- m:1

R²:CH₃ R⁵:CH₃O (3-position)

R^11b:H

M.p.190-193 ℃ (decomposition.) crystalline form: yellow powder

Recrystallization solvent: ethanol-water state: 2HCl

Watch 105Example 218R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (2-position)

M.p.174.4-176.5 ℃ form: yellow powder

Recrystallization solvent: ethanol-water-ether state: 2HCl

Table 106Example 219R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O- (3-position)

M.p.162-165 ℃ crystalline form: light yellow powder

Recrystallization solvent: diethyl ether-water-Ethanol state: 2HCl example 220R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O- (3-position)

M.p.206-211 ℃ crystalline form: light yellow powder state: 2HCl

Recrystallization solvent: ethanol-water-ethyl ether-isopropanol

NMR (41) example 221R⁴:H A:-CH₂- m:1

R^11b:H R⁵:(CH₃)₂CHO- (3-position)

M.p.168-172 ℃ crystalline form: yellow powder state: 2HCl

Recrystallization solvent: ethanol-water-isopropanol-ethyl ether

TABLE 107 example 222R⁴:H A:-CH₂- m:1

R⁵:(CH₃)₂CHO- (3-position)

R^11b:H

M.p.203-208 ℃ crystalline form: light yellow powder state: 2HCl

Recrystallization solvent: ethanol-water-isopropanol-ethyl ether

NMR (42) example 223R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (3-position)

M.p.180-185 ℃ crystalline form: white powder state: 2HCl

Recrystallization solvent: ethanol-Water NMR (43) example 224R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (3-position)

M.p.180-190 ℃ crystalline form: yellow powder state: 2HCl

Recrystallization solvent: ethanol NMR (44)

Table 108 example 225R⁴:H A:-CH₂- m:1

R⁵:CH₃O (3-position)

R^11b:H

M.p.157-160 ℃ crystalline form: light yellow powder state: 2HCl

Recrystallization solvent: ethanol-Water example226R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (3-position)

M.p.171-174 ℃ crystalline form: light yellow powder state: 2HCl

Recrystallization solvent: ethanol-Water example 227R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (3-position)

M.p.236-238 ℃ crystalline form: light yellow powder state: HCl

Recrystallization solvent: ethanol-water

Watch 109

228R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (3-position)

M.p.161-165 ℃ crystalline form: light yellow powder state: 2HCl

Recrystallization solvent: ethanol-Water-Ether-Isopropanol example 229 R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (3-position)

M.p.191-194 ℃ crystalline form: light yellow powder state: 2HCl

Recrystallization solvent: ethanol-Water example 230R⁴:H A:-CH₂- m:1

R⁵:CH₃O (3-position)

R^11b:H

M.p.200-210 ℃ (decomposition.) crystalline form: yellow powder NMR (45)

Recrystallization solvent: ethanol-water-ether state: 2HCl

Table 110 example 231R⁴:H A:-CH₂- m:1

R⁵:CH₃O (3-position)

R^11b:H

M.p.165-170 ℃ crystalline form: yellow powder state: 2HCl

Recrystallization solvent: ether-ethanol-isopropanol-water

NMR (46) example 232R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (3-position)

M.p.150-170 ℃ crystalline form: yellow powder NMR (47)

Recrystallization solvent: isopropyl alcohol state: dimethanesulfonate salt of example 233R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (3-position)

M.p.166-169 ℃ crystalline form: light yellow powder

Recrystallization solvent: ethanol-water state: 2HCl

TABLE 111 example 234R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (3-position)

M.p.186-200 ℃ (decomposition.) crystalline form: yellow powder state: 3HCl

Recrystallization solvent: isopropanol NMR (48) example 235

R¹:CH₃ R⁴:H A:-CH₂- m:1

R²:CH₃ R⁵:CH₃O (3-position)

R^11b:H

M.p.204-210 ℃ (split.) crystalline form: yellow powder state: HCl

Recrystallization solvent: ethanol-Water-Ether NMR (49) example 236

R¹:H R⁴:H A:-CH₂- m:1

R²:H R⁵:CH₃O (3-position)

R^11b:H

M.p.157-160 ℃ crystalline form: yellow powder

Recrystallization solvent: ethanol-water state: 2HCl

Table 112 example 237

R¹:H R⁴:H A:-CH₂- m:1

R²:H R⁵:CH₃O (3-position)

R^11b:H

M.p.83.1-85.5 ℃ form: yellow powder state: free form

Recrystallization solvent: ethanol-Ether-Hexane example 238R⁴:H A:-CH₂- m:1

R^11b:H R⁵F (3-position)

M.p.215-220 ℃ crystalline form: white powder state: 2HCl

Recrystallization solvent: ethanol-isopropanol-diethyl ether-water

NMR (50) example 239R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (3-position)

M.p.149-154 ℃ crystalline form: light yellow powder state: 2HCl

Recrystallization solvent: ethanol-water-isopropanol-ethyl ether

NMR(51)

TABLE 113 example 240R⁴:H A:-CH₂- m:1

R^11b:H R⁵Cl (3-position)

M.p.126-129 ℃ crystalline form: light yellow powder state: free form

Recrystallization solvent: ethanol-Isopropanol example 241R⁴:H A:-CH₂- m:1

R^11b:H R⁵:(CH₃)₃C- (2-position)

M.p.181-183.8 ℃ crystalline form: light yellow powder state: 2HCl

Recrystallization solvent: ethanol-Water-Ether example 242

R¹:CH₃ R⁴:H A:-CH₂- m:1

R²:CH₃ R⁵:CH₃O (3-position)

R^11b:H

M.p.192-197 ℃ (decomposition.) crystalline form: yellow powder state: 2HCl

Recrystallization solvent: ethanol-Water NMR (52)

TABLE 114 example 243R⁴:H A:-CH₂- m:1

R^11b:H R⁵:C₂H₅O (3-position)

M.p.166-170 ℃ crystalline form: light yellow powder state: 2HCl

Recrystallization solvent: ethanol-Water example 244R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CF₃CH₂O (3-position)

Crystal form: light yellow powder state: dimethanesulfonate NMR (53)

Recrystallization solvent: ethanol-Water-Ether-Isopropanol example 245R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CF₃CH₂O (3-position)

M.p.179-183 ℃ crystalline form: light yellow powder state: 2HCl

Recrystallization solvent: isopropyl alcohol-ethanol-water-ethyl ether

Watch 115Example 246R⁴:H A:-CH₂- m:2

R⁵:CH₃O (3-and 5-position)

R^11b:H

M.p.182-185 ℃ crystalline form: light yellow powder

Recrystallization solvent: ethanol-water state: 2HCl, trans example 247R⁴:H A:-CH₂- m:2

R⁵:CH₃O (3-and 5-position)

R^11b:H

M.p.177-183 ℃ crystalline form: light yellow powder

Recrystallization solvent: ethanol-water state: 2HCl, cis form

Watch 116Example 248R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (3-position)

M.p.158-162 ℃ crystalline form: light yellow powder state: 2HCl

Recrystallization solvent: ethanol-Water-Ether example 249 R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (3-position)

M.p.167-171 ℃ (split.) crystalline form: yellow powder

Recrystallization solvent: ethanol-water state: 3HCl EXAMPLE 250

R¹:CH₃ R⁴:H A:-CH₂- m:1

R²:CH₃ R⁵:CH₃O (3-position)

R^11b:H

M.p.137-140 ℃ crystalline form: yellow powder

Recrystallization solvent: ethanol-water state: methanesulfonic acid salt

TABLE 117 example 251

R¹:(CH₃)₃C- (3-position) R⁴:H A:-CH₂- m:1

R²:H R⁵:CH₃O (3-position)

R^11b:H

M.p.129-131 ℃ crystalline form: light yellow powder

Recrystallization solvent: ethanol-water-ethyl ether-isopropanol

The state is as follows: bis-mesylate salt example 252R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (3-position)

M.p.230-231 ℃ crystalline form: light yellow powder

Recrystallization solvent: ethanol-water state: bis-mesylate salt example 253R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (3-position)

M.p.159-164 ℃ (decomposition.) crystalline form: light yellow powder

Recrystallization solvent: ethanol-water state: 2HCl NMR (54)

TABLE 118 example 254R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (3-position)

M.p.202-205 ℃ (split.) crystalline form: white powder

Recrystallization solvent: ethanol-water state: 2HCl EXAMPLE 255R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (3-position)

M.p.115-120 ℃ crystalline form: light brown powder NMR (55)

Recrystallization solvent: ethanol-water-isopropanol-ethyl ether

The state is as follows: mesylate salt example 256R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (3-position)

M.p.168.5-171.5 ℃ form: white powder

Recrystallization solvent: ethanol-water state: 2HCl

TABLE 119 example 257R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (3-position)

M.p.163-166 ℃ crystalline form: white powder

Recrystallization solvent: ethanol-water state: 2HCl example 258R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (3-position)

M.p.177.5-179 ℃ crystalline form: white powder

Recrystallization solvent: ethanol-water state: 2HCl example 259R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (3-position)

M.p.165-168.5 ℃ crystalline form: light yellow powder state: 2HCl

Recrystallization solvent: ethanol-water-ethyl ether

Table 120 example 260R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (3-position)

M.p.159-160 ℃ crystalline form: light yellow powder

Recrystallization solvent: ethanol-water state: 2HCl example 261R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (3-position)

M.p.177-178.2 ℃ crystalline form: light yellow powder

Recrystallization solvent: ethanol-water state: 2HCl

S- (-) -Compound: [ alpha ] to]_D ²²Example 262 at-5.75 ° (c =2, water) R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (3-position)

M.p.173-175 ℃ crystalline form: light yellow powder

Recrystallization solvent: ethanol-water state: 2HCl

R- (+) -compound: [ alpha ] to]_D ²²+4.35 ° (c =2, water)

TABLE 121 example 263R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (3-position)

M.p.168-170.5 ℃ crystalline form: white powder

Recrystallization solvent: ethanol-water state: 2HCl EXAMPLE 264R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (3-position)

M.p.156-159 ℃ crystalline form: light yellow powder

Recrystallization solvent: ethanol-water state: 2HCl EXAMPLE 265R⁴:H A:-CH₂- m:1

R⁵:CH₃O (3-position)

R^11b:H

M.p.176-179 ℃ crystalline form: light yellow powder

Recrystallization solvent: ethanol-water state: 2HCl

Table 122 example 266R⁴:H A:-CH₂- m:1

R⁵:C₂H₅O (3-position)

R^11b:H

M.p.159-161 ℃ crystalline form: yellow powder state: 2HCl

Recrystallization solvent: ethanol-Water-Isopropanol-Ether example 267R⁴:H A:-CH₂- m:1

R²:CH₃ R⁵:CH₃O (3-position)

R^11b:H

M.p.166-169 ℃ crystalline form: yellow powder state: 2HCl

Recrystallization solvent: ethanol-Water-Ether-Isopropanol example 268R⁴:H A:-CH₂- m:1

R⁵:C₂H₅O (3-position)

R^11b:H

M.p.215-217 ℃ crystalline form: white powder

Recrystallization solvent: ethanol-water state: 2HCl

Table 123 example 269R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (3-position)

M.p.174-177 ℃ crystalline form: yellow powder state: free form

Recrystallization solvent: ethanol-Water example 270R⁴:H A:-CH₂- m:1

R⁵:CH₃O (3-position)

R^11b:H

M.p.202.5-205 ℃ crystalline form: white powder state: 2HCl

Recrystallization solvent: ethanol-Water example 271R⁴:H A:-CH₂- m:1

R⁵:CH₃O (3-position)

R^11b:H

M.p.155-158 ℃ crystalline form: yellow powder state: 2HCl

Recrystallization solvent: ethanol-water-isopropanol-ethyl ether

TABLE 124 example 272R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (3-position)

M.p.202-204 ℃ crystalline form: light yellow powder state: 2HCl

Recrystallization solvent: ethanol-Water example 273R⁴:H A:-CH₂- m:1

R⁵:CH₃O (3-position)

R^11b:H

M.p.163-165 ℃ crystalline form: light brown powder state: 2HCl

Recrystallization solvent: ethanol-Water example 274R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (3-position)

M.p.160-162 ℃ crystalline form: light yellow powder

Recrystallization solvent: ethanol-water state: 2HCl

Table 125 example 275R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (3-position)

M.p.158-160 ℃ crystalline form: light yellow powder state: 2HCl

Recrystallization solvent: Ethanol-Ether-Water example 276R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (3-position)

M.p.164-166 ℃ crystalline form: light yellow powder state: 2HCl

Recrystallization solvent: ethanol-Water Using suitable starting compounds, the compounds listed in the following Table 126-128 were obtained in the same manner as described in example 5.

Table 126Example 277R⁴:H A:-CH₂- m:1

R^16a:C₂H₅ R^11b:H R⁵:H

M.p.130.5-132 ℃ crystalline form: light orange powdery state: free form

Recrystallization solvent: dimethylformamide methanol

Watch 127Example 278R⁴:H A:-CH₂- m:1

R^16a:C₂H₅ Z:O

R^11b:H R⁵:H

M.p.183.5-184 ℃ crystalline form: white powder

Recrystallization solvent: dichloromethane-ethanol state: free example 279R⁴:H A:-CH₂- m:1

R^16a:C₂H₅ Z:O

R^11b:H (2-position) m.p.221 ℃ (crystalline form: light yellow powder

Recrystallization solvent: ether-ethanol state: 2HCl

Table 128 example 280R⁴:H A:-CH₂- m:1

R^16a:CH₃ Z:O

R^11b:CH₃ R⁵:CH₃O (2-position)

M.p.124-126.5 ℃ crystalline form: light yellow powder

Recrystallization solvent: ethyl acetate-n-hexane example 281R⁴:H A:-CH₂- m:1

R^16a:C₂H₅ Z:S

R^11b:H R⁵:CH₃O (2-position)

M.p.156-159 ℃ crystalline form: yellow powder

Recrystallization solvent: ethanol-dichloromethane state: free form

Using suitable starting compounds, the following procedure was carried out in the same manner as described in example 8

The compounds listed in tables 129-149.

TABLE 129Example 282R⁴:H A:-CH₂- m:1

R⁵: isopropyl (2-position)

R^11b:H

M.p.137-138 ℃ crystalline form: light yellow powder state: free example 283R⁴:H A:-CH₂- m:1

R⁵: isopropyl (2-position)

R^11b:H

M.p.197-198 ℃ crystalline form: white powder state: free form

Recrystallization solvent: dichloromethane-ethanol

Watch 130

284R⁴:H A:-CH₂- m:1

R^11b:H (2-position)

M.p.240 ℃ (decomposition.) crystalline form: light yellow powder state: 2HCl

Recrystallization solvent: ethanol-Water example 285R⁴:H A:-CH₂- m:1

R^11b:H R⁵: isopropyl (2-position)

M.p.169.5-170 ℃ crystalline form: white powder state: free form

Recrystallization solvent: ethanol example 286R⁴:H A:-CH₂- m:1

R^11b:H R⁵: isopropyl (2-position)

Crystal form: light brown powder state: HCl NMR (7)

TABLE 131 example 287R⁴:H A:-CH₂- m:1

R^11b:H R⁵:-(CH₂)₄OH (2-position)

M.p.170.5-175.5 ℃ crystalline form: light yellow powder state: free form

Recrystallization solvent: ethyl acetate-n-Hexane NMR (8) example 288R⁴:H A:-CH₂- m:1

R^11b:H R⁵:H

M.p.201.5-202.5 ℃ (decomposition.) crystalline form: light yellow powder

Recrystallization solvent: ethanol-dichloromethane state: free example 289 R⁴:H A:-CH₂- m:1

R^11b:H (2-position)

M.p.195-198 ℃ crystalline form: yellow powder

Recrystallization solvent: ethanol-water state: 3HCl

Table 132 example 290R⁴:H A:-CH₂- m:1

R^11b:H R⁵: isopropyl (2-position)

M.p.101-103.5 ℃ crystalline form: yellow amorphous state: free example 291R⁴:H A:-CH₂- m:1

R^11b:H (2-position)

M.p.148.2-153 ℃ crystalline form: light brown powder state: 3HCl

Recrystallization solvent: ethanol-Ether NMR (10) example 292R⁴:H A:-CH₂- m:1

R^11b:H (2-position)

M.p.184-187 ℃ crystalline form: light yellow powder

Recrystallization solvent: ethanol-water-ether state: 2HCl

TABLE 133 example 293R⁴:H A:-CH₂- m:1

R^11b:H R⁵F (2-position)

M.p.151-154 ℃ crystalline form: white powder state: HCl

Recrystallization solvent: ethanol-Water-Ether-Isopropanol example 294R⁴:H A:-CH₂- m:1

R^11b:H R⁵Cl (2-position)

M.p.207-209 ℃ crystalline form: white powder state: free form

Recrystallization solvent: ethyl acetate-n-Hexane EXAMPLE 295R⁴:H A:-CH₂- m:1

R^11b:H R⁵Cl (2-position)

M.p.164-166 ℃ crystalline form: light yellow powder

Recrystallization solvent: methanol-ether state: HCl

Table 134 example 296R⁴:H A:-CH₂- m:1

R^11b:H R⁵F (2-position)

M.p.141-141.5 ℃ crystalline form: white powder state: free form

Recrystallization solvent: dichloromethane-diethyl ether example 297R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (2-position)

M.p.186.5-191 ℃ (decomposition) crystalline form: light yellow powder

Recrystallization solvent: ethanol-ether state: mesylate salt example 298R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃(2-position)

Crystal form: light yellow amorphous state: free NMR (15)

TABLE 135 EXAMPLE 299R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃(2-position)

Crystal form: light yellow amorphous state: free NMR (16) example 300R⁴:H A:-CH₂- m:1

R^11b:H R⁵:C₂H₅O (2-position)

M.p.202.5-203 ℃ crystalline form: grey powder

Recrystallization solvent: ethanol-isopropanol-water-ethyl ether

The state is as follows: mesylate salt example 301R⁴:H A:-CH₂- m:1

R^11b:H (2-position)

M.p.186-189 ℃ crystalline form: light yellow powder

Recrystallization solvent: water-ethanol-ether state: 3HCl

TABLE 136 example 302R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O(3-)

M.p.135.145 ℃ crystalline form: white powder state: free form

Recrystallization solvent: ethanol-dichloromethane NMR (17) example 303 R⁴:H m:1

R^11b:H R⁵Cl (2-position)

Crystal form: light yellow amorphous state: free NMR (18) example 304R⁴:H A:-CH₂- m:1

R^11b:H (2-position)

M.p.146.5-150 ℃ crystalline form: white powder

Recrystallization solvent: ethanol-water state: 2HCl

TABLE 137 example 305R⁴:H A:-CH₂- m:2

R^11b:H R⁵:CH₃O (2-and 6-position)

M.p.115-120 ℃ crystalline form: light yellow powder NMR (19)

Recrystallization solvent: ethanol-ether state: mesylate salt example 306R⁴:H A:-CH₂- m:1

R^11b:H (2-position))

M.p.207-208.5 ℃ form: white powder

Recrystallization solvent: ether-ethanol state: mesylate salt example 307R⁴:H A:-CH₂- m:1

R^11b:H (2-position)

Crystal form: light yellow amorphous state: free NMR (20)

TABLE 138 EXAMPLE 308R⁴:H A:-CH₂- m:1

R^11b:H (2-position)

M.p.139-141 ℃ crystalline form: yellow powder

Recrystallization solvent: ethanol state: mesylate salt example 309R⁴:H A:-CH₂- m:1

R^11b:H (2-position)

M.p.194-197 ℃ crystalline form: white powder

Recrystallization solvent: ethanol-water state: dimethanesulfonate salt of example 310R⁴:H A:-CH₂- m:1

R^11b:H (2-position)

M.p.218-220 ℃ crystalline form: light yellow powder

Recrystallization solvent: ethanol-water state: dimethyl sulfonate

TABLE 139 example 311R⁴:H A:-CH₂- m:1

R^11b:H (2-position)

M.p.182.5-186 ℃ crystalline form: yellow powder

Recrystallization solvent: ethanol-ether state: 2HCl example 312

R¹:CH₃ R⁴:H A:-CH₂- m:1

R²:CH₃

R^11b:H (2-position)

Crystal form: white powder state: methanesulfonic acid salt

Recrystallization solvent: ethanol-Ether NMR (21) example 313R⁴:H A:-CH₂- m:1

R^11b:H (2-position)

M.p.140-141 ℃ crystalline form: white powder state: methanesulfonic acid salt

Recrystallization solvent: ethanol-isopropanol-ethyl ether

Table 140 example 314R⁴:H A:-CH₂- m:1

R^11b:H (2-position)

M.p.166-177 ℃ crystalline form: white powder NMR (22)

Recrystallization solvent: ethanol-ether state: 2HCl example 315R⁴:H A:-CH₂- m:1

R^11b:H (2-position)

M.p.156-157 ℃ crystalline form: white powder

Recrystallization solvent: ethanol state: free example 316R⁴:H A:-CH₂- m:1

R^11b:H (2-position)

M.p.191-192 ℃ crystalline form: white powder state: 3HCl

Recrystallization solvent: ethanol-water-isopropanol

TABLE 141 example 317R⁴:H A:-CH₂- m:1

R^11b:H (2-position)

Crystal form: light yellow amorphous state: free NMR (23) example 318R⁴:H A:-CH₂- m:1

R^11b:H (2-position)

Crystal form: colorless amorphous state: free NMR (24) example 319 R⁴:H A:-CH₂- m:1

R^11b:H (2-position)

M.p.178-180 ℃ crystalline form: white powder state: 3HCl

Recrystallization solvent: ethanol-isopropanol-diethyl ether-water

Table 142 embodiment 320R⁴:H A:-CH₂- m:1

R^11b:H (2-position)

Crystal form: light yellow amorphous state: free NMR (25) example 321R⁴:H A:-CH₂- m:1

R^11b:H (2-position)

M.p.198-201 ℃ crystalline form: light yellow powder state: 2HCl

Recrystallization solvent: ethanol-Water example 322R⁴:H A:-CH₂- m:1

R^11b:H (2-position)

M.p.177-178 ℃ crystalline form: white powder state: free form

Recrystallization solvent: ether-ethanol-dichloromethane

TABLE 143 example 323R⁴:H m:1

R^11b:H R⁵Together with A to form

M.p.234-235 ℃ crystalline form: white powder state: free form

Recrystallization solvent: ethyl acetate-n-Hexane EXAMPLE 324R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (2-position)

M.p.206-207 ℃ crystalline form: light yellow powder state: free form

Recrystallization solvent: dichloromethane-ethanol-Ether example 325R⁴:H A:-CH₂- m:1

R^11b:H R⁵n-Butyl (2-position)

M.p.195.5-196.5 ℃ form: light yellow needle-shaped

Recrystallization solvent: ethanol-dichloromethane state: free form

TABLE 144 example 326 R⁴:H A:-CH₂- m:1

R^11b:H (2-position)

M.p.134-136 ℃ (decomposition) crystalline form: yellow powder state: free form

Recrystallization solvent: methylene chloride-isopropyl ether example 327R⁴:H A:-CH₂- m:1

R^11b:H (2-position)

M.p.207.6-214 ℃ (split.) crystalline form: white powder

Recrystallization solvent: dichloromethane NMR (26) state: free embodiment 328R⁴:H A:-CH₂- m:1

R^11b:H R⁵: n-butyl (2-position)

M.p.191-193 ℃ crystalline form: light yellow powder

Recrystallization solvent: ethanol-dichloromethane state: free form

Table 145 example 329R⁴:H A:-CH₂- m:1

R^11b:H (2-position)

M.p.112-114 ℃ crystalline form: light yellow powder state: free form

Recrystallization solvent: ethyl acetate-diethyl ether example 330R⁴:H A:-CH₂- m:1

R^11b:H (2-position)

M.p.209-211 ℃ crystalline form: yellow powder

Recrystallization solvent: ethanol-water state: 3HCl EXAMPLE 331R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (2-position)

M.p.208-210 ℃ crystalline form: light yellow powder

Recrystallization solvent: ethanol-dichloromethane state: free form

Table 146 example 332R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (2-position)

M.p.200-203 ℃ crystalline form: yellow powder state: free form

Recrystallization solvent: ethanol-isopropanol-dichloromethane example 333 R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (2-position)

M.p.196-197 ℃ crystalline form: white powder state: free form

Recrystallization solvent: ethanol-dichloromethane example 334R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (2-position)

M.p.203-204 ℃ crystalline form: white powder state: free form

Recrystallization solvent: dichloromethane-ethanol-isopropanol

TABLE 147 example 335R⁴:H A:-CH₂- m:1

R^11b:H R⁵:C₂H₅O (2-position)

M.p.206-208 ℃ crystalline form: light yellow powder state: free form

Recrystallization solvent: dichloromethane-n-hexane example 336R⁴:H A:-CH₂- m:1

R^11b:H R⁵:C₂H₅O (2-position)

M.p.190-192 ℃ crystalline form: light yellow needle state: free form

Recrystallization solvent: chloroform-Ethyl acetate example 337R⁴:H A:-CH₂- m:1

R^11b:H R⁵:C₂H₅O (2-position)

M.p.207-209 ℃ crystalline form: light yellow powder state: free form

Recrystallization solvent: ethyl acetate-isopropyl ether

Table 148 example 338R⁴:H A:-CH₂- m:1

R^11b:H R⁵: isopropyl (2-position)

M.p.199.5-200.5 ℃ crystalline form: white powder

Recrystallization solvent: methanol-dimethylformamide state: free example 339R⁴:H A:-CH₂- m:1

R^11b:H R⁵:C₂H₅O (2-position)

M.p.204-206 ℃ crystalline form: light yellow powder state: free form

Recrystallization solvent: ethanol-dichloromethane example 340R⁴:H A:-CH₂- m:1

R^11b:H R⁵:C₂H₅O (2-position)

M.p.115-117 ℃ crystalline form: light yellow powder state: free form

Recrystallization solvent: ethyl acetate-isopropyl ether

TABLE 149 example 341R⁴:H A:-CH₂- m:1

R^11b:H R⁵:C₂H₅O (2-position)

M.p.225-227 ℃ crystalline form: light yellow powder state: free form

Recrystallization solvent: ethyl acetate-isopropyl ether example 342R⁴:H A:-CH₂- m:1

R^11b:H R⁵:C₂H₅O (2-position)

M.p.196.5-198 ℃ crystalline form: light yellow powder

Recrystallization solvent: chloroform-ethyl acetate state: free example 343R⁴:H A:-CH₂- m:1

R^11b:H R⁵:CH₃O (2-position)

M.p.192-194 ℃ crystalline form: light yellow powder

Recrystallization solvent: ethyl acetate-isopropyl ether state: as described in free tables 50-149¹The H-NMR spectra (NMR (1) to NMR (55)) are as follows:

NMR(1)(CDCl₃)δppm:2.33(3H,s),2.45(4H,t,J=5Hz),3.6-3.8(4H,m),4.85(2H,s),7.09(2H,d,J=9Hz),7.3-7.55(2H,m),7.50(1H,d,J=15Hz),7.8-7.95(2H,m),7.93(1H,d,J=15Hz),8.10(2H,d,J=9Hz),9.88(1H,br)

NMR(2)(DMSO-d₆)δppm:1.35-1.8(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),5.08(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)

NMR(3)(DMSO-d₆)δppm:2.32(3H,s),2.45-4.50(20H,m,2.50(s)),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-d₆)δppm: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-d₆)δppm: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,m),7.74-7.99(4H,m),7.91(1H,d,J=15Hz),11.5-13.0(3H,br)

NMR(6)(DMSO-d₆)δppm:0.93(3H,t,J=7.4Hz),1.55-1.75(2H,m),2.6-2.8(4H,m),2.79(3H,s),3.0-4.15(14H,m),4.2-4.4(1H,m),5.12(2H,s),7.03(1H,d,J=8.5Hz),7.25-7.55(2H,m),7.45(1H,s),7.75-7.9(4H,m),7.79(1H,d,J=8.5Hz)

NMR(7)(DMSO-d₆)δppm:1.25(6H,d,J=7Hz),1.3-2.0(4H,m),2.6-3.5(6H,m),5.12(2H,s),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)(CDCl₃)δppm:1.62(3H,t,J=7.3Hz),1.76-2.03(4H,m),2.85-3.09(2H,m),3.95-4.11(2H,m),4.52(2H,q,J=7.3Hz),4.88(2H,s),5.28(1H,brs),6.98(1H,d,J=7.5Hz),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)(DMSO-d₆)δppm:0.93(3H,t,J=7.4Hz),1.5-1.8(2H,m),1.8-2.2(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-d₆)δppm:1.56-1.91(4H,m),2.70-2.90(7H,m),3.10-3.52(8H,m),5.14(2H,s),6.65-6.75(1H,m),6.99-7.15(2H,m),7.28-7.40(1H,m),7.40-7.52(1H,m),7.52-7.60(2H,m),7.72-7.85(1H,m),7.90-8.08(4H,m),10.90-13.18(3H,m)

NMR(11)(DMSO-d₆)δppm: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,s),4.06-4.34(1H,m),4.42-4.71(1H,m),5.08(2H,s),7.07(1H,d,J=8.5Hz),7.31(1H,t,J=7.0Hz),7.38-7.69(3H,m),7.69-7.92(3H,m),7.98(1H,d,J=8.5Hz),11.76(2H,br),12.71(1H,br),

NMR(12)(DMSO-d₆)δppm:1.40-1.85(2H,m),2.00-2.23(2H,m),2.40(3H,s),2.60-2.88(1H,m),2.81(3H,s),3.00-3.80(10H,m),3.89(3H,s),4.10-4.30(1H,m),4.48-4.78(1H,m),5.06(2H,s),7.04(1H,d,J=8.5Hz),7.21-7.31(1H,m),7.40(1H,d,J=15.2Hz),7.52-7.60(1H,m),7.60-7.88(4H,m),11.02-12.33(2H,m),12.33-12.80(1H,m)

NMR(13)(DMSO-d₆)δppm:2.40(3H,s),2.81(3H,s),2.90-4.35(15H,m),3.89(3H,s),5.07(2H,s),6.99-7.12(1H,m),7.12-7.35(2H,m),7.52-7.60(1H,m),7.60-7.91(4H,m),11.00-13.28(3H,m)

NMR(14)(CDCl₃)δppm:1.31-1.64(2H,m),1.77-2.07(2H,m),2.21-2.87(10H,m),2.29(3H,s),2.67(3H,s),3.06-3.26(1H,m),3.96-4.28(1H,m),4.10(3H,s),4.62-4.78(1H,m),4.87(2H,s),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)(CDCl₃)δppm:1.20-2.16(4H,m),2.31-2.72(3H,m),2.44(3H,s),2.72-3.34(2H,m),4.85(2H,s),6.76-7.06(3H,m),7.21-7.58(2H,m),7.72-8.00(4H,m)

NMR(16)(CDCl₃)δppm:1.43-2.13(4H,m),2.28(6H,s),2.45(3H,s),2.53-3.28(5H,m),3.56-4.56(2H,m),4.86(2H,s),6.80-7.11(3H,m),7.28-7.53(2H,m),7.74-7.93(4H,m)

NMR(17)(CDCl₃)δppm:1.3-1.5(2H,m),1.7-1.9(2H,m),2.6-2.8(2H,m),2.8-3.3(2H,m),3.90(3H,s),4.80(2H,s),6.5-6.65(2H,m),6.73(1H,d,J=15.5Hz),6.87(1H,dd,J=15.5Hz,J=6Hz),7.3-7.55(2H,m),7.6-7.95(4H,m)

NMR(18)(CDCl₃)δppm:1.12(3H,t,J=5.9Hz),1.28-3.78(11H,m),4.97(1H,t,J=5.3Hz),6.68-7.53(5H,m),7.70-8.14(4H,m)

NMR(19)(DMSO-d₆)δppm:1.29-2.11(4H,m),2.32(3H,s),2.60-3.08(3H,m),3.08-3.56(3H,m),3.91(6H,s),4.85(2H,s),6.73-6.93(1H,m),7.19-7.54(5H,m),7.71-7.83(1H,m),7.93-8.05(1H,m),8.29-8.80(1H,m),12.14(1H,brs)

NMR(20)(CDCl₃)δppm:1.86-2.13(2H,m),2.39(3H,s),2.48-3.06(12H,m),3.82(3H,s),4.87(2H,s),6.82-8.09(9H,m),7.04(1H,s),7.21(1H,s)

NMR(21)(DMSO-d₆)δppm:1.4-2.2(6H,m),2.35(3H,s),2.65-2.85(2H,m),2.95-4.05(14H,m),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),7.8-8.0(2H,m),9.58(1H,br),12.45(1H,br)

NMR(22)(DMSO-d₆)δppm:1.33-1.71(5H,m),1.80-2.00(1H,m),2.00-2.21(2H,m),2.65-2.77(2H,m),2.80(3H,s),2.88-3.10(4H,m),3.10-4.00(14H,m),4.00-4.23(1H,m),4.47-4.66(1H,m),5.13(2H,s),6.71-6.87(1H,m),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)(CDCl₃)δppm: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,m),7.22-7.53(2H,m),7.70-7.97(4H,m)

NMR(24)(CDCl₃)δppm:1.43-2.18(12H,m),2.37-2.68(8H,m),2.86(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(3H,m),7.22-7.53(2H,m),7.68-7.93(4H,m)

NMR(25)(CDCl₃)δppm:1.48-3.22(19H,m),1.62(3H,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),7.92-8.09(1H,m),8.36(1H,d,J=15.2Hz)

NMR(26)(DMSO-d₆)δppm:2.65-2.8(1H,m),2.9-3.05(1H,m),3.3-3.45(2H,m),3.8(1H,m),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(3H,m),7.95-8.2(4H,m),8.66(2H,br),12.58(1H,br)

NMR(27)(CDCl₃)δppm:1.36(3H,t,J=7.5Hz),2.6-3.6(6H,m),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-d₆)δppm:1.67-1.97(2H,m),2.80(3H,s),2.88-4.35(17H,m),3.90(3H,s),5.10(2H,s),7.08(1H,d,J=8.6Hz),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)(DMSO-d₆)δppm: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(3H,m),7.98(1H,d,J=7.1 Hz),11.52(2H,br),12.55(1H,br)

NMR(30)(CDCl₃)δppm:1.1-1.4(3H,m),1.37(3H,t,J=7.5Hz),2.5-2.8(2H,m),2.86(2H,q,J=7.5Hz),2.9-3.1(1H,m),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,m),9.60(1H,br)

NMR(31)(DMSO-d₆)δppm:0.74-0.91(3H,m),1.12-1.44(6H,m),1.50-1.71(2H,m),2.55-2.90(3H,m),2.79(3H,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=8.7Hz),7.27-7.51(3H,m),7.71-8.02(5H,m),11.00-13.00(3H,m)

NMR(32)(DMSO-d₆)δppm: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(3H,m),7.67-7.89(3H,m),7.89-8.03(1H,m),11.06-12.62(3H,m)

NMR(33)(DMSO-d₆)δppm:1.40-1.92(2H,m),1.92-2.30(4H,m),2.31(3H,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),7.86-8.05(3H,m),10.88-12.00(2H,m),12.70(1H,br)

NMR(34)(DMSO-d₆)δppm: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),8.32(1H,d,J=8.7Hz),10.89-12.06(2H,m),12.76(1H,br)

NMR(35)(DMSO-d₆)δppm: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(3H,m),7.75-7.85(2H,m),7.97(1H,d,J=7.1Hz),8.23(1H,s),8.33(1H,d,J=8.7Hz),9.37(2H,br),12.78(1H,br)

NMR(36)(DMSO-d₆)δppm:1.2-1.5(2H,m),1.6-1.85(8H,m),2.31(3H,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=8.5Hz),7.20(1H,d,J=15.5Hz),7.25-7.5(3H,m),7.55(1H,d,J=8.5Hz),7.75(1H,d,J=7.5Hz),7.97(1H,d,J=7Hz)

NMR(37)(DMSO-d₆)δppm: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=8Hz),11.24,12.04(all1H,br),11.74(1H,br),12.64(1H,br)

NMR(38)(DMSO-d₆)δppm:2.54-2.93(5H,m),2.93-3.78(10H,m),3.78-4.17(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),12.68(1H,br)

NMR(39)(DMSO-d₆)δppm:2.22(3H,s),2.33(3H,s),2.36(3H,s),2.80(3H,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(3H,m),7.76(1H,d,J=7Hz),7.98(1H,d,J=7Hz),9.76(1H,br),12.60(1H,br)

NMR(40)(DMSO-d₆)δppm:2.05-2.35(2H,m),2.54-2.98(5H,m),2.98-3.85(10H,m),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),8.00(1H,d,J=7.8Hz),11.22(2H,br),12.68(1H,br)

NMR(41)(DMSO-d₆)δppm:1.89-2.44(4H,m),2.53-3.78(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=7.8Hz),7.98(1H,d,J=7.0Hz),10.61(1H,br),11.27(1H,br),12.71(1H,br)

NMR(42)(DMSO-d₆)δppm:1.30(6H,d,J=5.9Hz),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(3H,m),7.64(1H,d,J=8.7Hz),7.71-7.90(2H,m),7.98(1H,d,J=7.1Hz),11.81(2H,br),12.58(1H,br)

NMR(43)(DMSO-d₆)δppm:1.35(3H,d,J=6Hz),1.5-2.2(4H,m),2.5-3.8(13H,m),3.88(3H,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(3H,br)

NMR(44)(DMSO-d₆)δppm:1.30(3H,d,J=6.5Hz),1.5-2.3(4H,m),2.55-2.8(1H,m),3.0-4.7(13H,m),3.88(3H,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,m),7.56(1H,d,J=15.5Hz),7.64(1H,d,J=8.5Hz),7.77(1H,d,J=8Hz),7.98(1H,d,J=7.5Hz),9.85(1H,br),10.01(1H,br),12.25(1H,br)

NMR(45)(DMSO-d₆)δppm:2.05-2.20(2H,m),2.5-4.0(18H,m),3.88(3H,s),4.1-4.25(1H,m),4.5-4.65(1H,m),5.06(2H,s),6.70(1H,d,J=8.5Hz),6.81(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=8.5Hz),7.77(1H,d,J=8Hz),7.99(1H,d,J=7.5Hz),10.78(1H,br),11.94(1H,br),12.66(1H,br)

NMR(46)(DMSO-d₆)δppm:1.43-1.85(2H,m),1.97-2.42(4H,m),2.58-2.82(1H,m),2.82-4.08(18H,m),4.08-4.30(1H,m),4.42-4.72(1H,m),5.06(2H,s),5.22-5.68(2H,m),6.62-6.78(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)(DMSO-d₆)δppm:1.3-2.0(6H,m),2.37(6H,s),2.8-4.2(16H,m),3.88(3H,s),5.07(2H,s),6.71(1H,dd,J=7H,J=2Hz),6.81(1H,d,J=2Hz),7.25(1H,d,J=15Hz),7.25-7.5(3H,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-d₆)δppm:2.4-4.5(23H,m),3.88(3H,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),11.58(1H,br),12.71(1H,br)

NMR(49)(DMSO-d₆)δppm:2.16(3H,s),2.23(3H,s),2.74(3H,d,J=4Hz),2.85-3.7(6H,m),3.86(3H,s),4.15-4.6(2H,m),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)(DMSO-d₆)δppm:1.39-1.90(2H,m),1.98-2.37(4H,m),2.58-2.90(4H,m),2.98-3.99(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-d₆)δppm:1.67-2.03(2H,m),2.80(3H,s),2.99-4.35(20H,m),5.07(2H,s),6.70(1H,dd,J=2.2Hz,J=8.7Hz),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-d₆)δppm:2.15(3H,s),2.22(3H,s),2.83(3H,s),2.5-4.4(17H,m),3.86(3H,s),4.94(2H,s),6.65(1H,d,J=8.5Hz),6.78(1H,s),7.2-7.7(3H,m),12.05(1H,br)

NMR(53)(DMSO-d₆)δppm:2.36(6H,s),2.55-4.45(20H,m),4.92(2H,q,J=8.9Hz),5.08(2H,s),6.80(1H,dd,J=2.3Hz,J=8.9Hz),6.94(1H,d,J=2.3Hz),7.21-7.75(5H,m),7.77(1H,d,J=8.1Hz),7.98(1H,d,J=7.1Hz),9.95(2H,br),12.63(1H,br)

NMR(54)(DMSO-d₆)δppm:1.40(6H,d,J=6.0Hz),1.51-1.86(2H,m),2.05-2.30(2H,m),2.57-2.73(1H,m),2.79(3H,s),2.98-3.87(8H,m),3.88(3H,s),4.14-4.25(1H,m),4.40-4.70(1H,m),5.06(2H,s),6.70(1H,dd,J=2.2Hz,J=8.8Hz),6.81(1H,d,J=2.2Hz),7.23-7.66(5H,m),7.77(1H,d,J=7.6Hz),8.00(1H,d,J=7.0Hz),11.40-1.3.10(3H,m)

NMR(55)(DMSO-d₆)δppm:1.4-2.4(4H,m),2.34(3H,s),2.7-5.0(9H,m),3.88(3H,s),5.06(2H,s),6.71(1H,dd,J=2Hz,J=9Hz),6.82(1H,d,J=2Hz),7.2-7.5(3H,m),7.55-7.8(3H,m),7.99(1H,d,J=7Hz),9.6-10.2(1H,m),12.60(1H,br)

NMR(56)(DMSO-d₆)δppm:1.40-1.84(2H,m),2.00-2.42(4H,m),2.67(1H,t,J=12.5Hz),2.77(3H,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,m),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=8.6Hz),7.77(1H,d,J=8.1Hz),7.99(1H,d,J=7.9Hz),11.05-12.10(2H,m),12.68(1H,br)

example 344

2- { 3-allyloxy-4- [3- (1-piperidinyl) carbonylacryloyl ] phenoxymethylcarbonylamino } benzothiazole (0.55g) was dissolved in methanol (70ml) and dioxane (40ml), and 10% palladium-carbon (0.15g), p-toluenesulfonic acid monohydrate (70mg) and water (3ml) were added thereto, and the mixture was degassed and refluxed overnight under a nitrogen atmosphere. The mixture was filtered through a layer of celite, water-dichloromethane was added to the filtrate, and the mixture was separated and dried over sodium sulfate. The residue was crystallized from ethanol-dichloromethane and recrystallized from dichloromethane-ethanol to give 2- { 3-hydroxy-4- [3- (1-piperidinyl) carbonylacryloyl ] phenoxymethylcarbonylamino } benzothiazole (120 mg).

Yellow powder

M.p.207.3-210℃

Example 345

Under ice-cooling, 40% glyoxylic acid (7.7ml) was added to a tetrahydrofuran (100ml) solution of dimethyl [ { 2-methoxy-4- [2- (2-benzothiazoylaminocarbonyl) ethyl ] benzoyl } methyl ] phosphonate (6.4g) and further a 5% aqueous sodium hydroxide solution (70ml) was added dropwise thereto. The mixture was stirred for 30 minutes, acidified with 5% hydrochloric acid and the precipitated yellow powder collected by filtration, washed with ethanol, dried and then recrystallized from dimethylformamide-ethanol to give 2- {2- [ 3-methoxy-4- (trans-3-carboxypropenyl) phenyl ] ethylcarbonylamino } benzothiazole (4.0 g).

Yellow powder

M.p.260-261℃

Example 346

Under ice-cooling, to tetrahydrofuran (50ml) was added dimethyl [ { 2-dimethylamino-4- [ (2-benzothiazolyl) aminocarbonylmethoxy ] benzoyl } methyl ] phosphonate (4.70g), and 5% aqueous sodium hydroxide solution (40ml) and glyoxylic acid (3.5ml) were added thereto, and the mixture was stirred at the same temperature for 10 minutes. After confirming that the starting compound had been consumed, the mixture was acidified with hydrochloric acid and concentrated under reduced pressure to remove the solvent. The precipitated crystals were collected by filtration and dissolved in methylene chloride (100ml) and the mixture was heated with stirring at 100 ℃ for 30 minutes. After cooling, isopropanol was added to the reaction solution, and the precipitated crystals were collected by filtration. The crystals were recrystallized from dimethylformamide-isopropanol to give 1, 1-dimethyl-2-carboxy-4-oxo-7- [ (2-benzothiazolyl) aminocarbonylmethoxy ] -1,2,3, 4-tetrahydroquinolinium chloride (2.46 g).

Light green powder

M.p.184.5-186.5℃

The following compounds were obtained in the same manner as in example 1 or 5 using suitable starting compounds.

Watch 150Example 347

R⁵:H A:-CH₂CH₂- m:1 s:0

Z:- R^A:H R⁴:H

At the position-COCH = CHCOOH: 4-position

M.p.253.5-255 ℃ crystalline form: white powder

Recrystallization solvent: dimethylformamide-ethanol

The state is as follows: free example 348

R⁵:-OCH₃(3-position) A: -CH₂CH₂- m:1 s:0

Z:- R^A:H R⁴:H

At the position-COCH = CHCOOH: 4-position

M.p.260-261 ℃ crystalline form: yellow powder

Recrystallization solvent: dimethylformamide-ethanol

The state is as follows: dissociative example 349(5-position) A: -CH₂- m:1 s:1

Z:O R^A:H R⁴:H

At the position-COCH = CHCOOH: 4-position

M.p.184-186 ℃ crystalline form: light yellow powder

Recrystallization solvent: dimethylformamide-ethanol-water

The state is as follows: HCl

TABLE 151 example 350

R⁵:-OCH₃(3-position) A: -CH₂- m:1 s:1

Z:O R^A:-N(CH₃)₂(6-position) R⁴:H

At the position-COCH = CHCOOH: 4-position

M.p.263-264 ℃ (decomposition.) crystalline form: light brown powder

Recrystallization solvent: dimethylformamide-ethanol-water

The state is as follows: hydrate example 351(3-position) A: -CH₂- m:1 s:1

Z:O R^A:H R⁴:H

At the position-COCH = CHCOOH: 4-position

M.p.294-297 ℃ crystalline form: yellow powder

Recrystallization solvent: dimethyl formamide

The state is as follows: free example 352

R⁵:-OCH₂CH=CH₂(3-position) A: -CH₂- m:1 s:1

Z:O R^A:H R⁴:H

At the position-COCH = CHCOOH: 4-position

M.p.248-254 ℃ crystalline form: light yellow powder

Recrystallization solvent: dilute hydrochloric acid

NMR (36) State: free form

Watch 152Example 353(3-position) A:-CH₂- m:1 s:1

Z:O R⁴:H

At the position-COCH = CHCOOH: 4-position

M.p.270.0-271.5 ℃ form: light yellow powder

Recrystallization solvent: dimethylformamide-dichloromethane

The state is as follows: free example 354(3-position) A: -CH₂- m:1 s:1

Z:O R⁴:H

At the position-COCH = CHCOOH: 4-position

M.p.270.5-273.3 ℃ form: yellow powder

Recrystallization solvent: dimethylformamide-dichloromethane

The state is as follows: free example 355

R⁵:-(CH₂)₃CH₃(2-position) OCH₃(5-position)

A:-CH₂- m:2 s:1 Z:O R⁴:H

At the position-COCH = CHCOOH: 4-position

M.p.203-206 ℃ crystalline form: yellow powder

Recrystallization solvent: dimethylformamide-dichloromethane

The state is as follows: free form

TABLE 153 example 356

R⁵:-(CH₂)₂CH₃(2-position)&-OCH₃(3-position)

A:-CH₂- m:2 s:1 Z:O R⁴:H

At the position-COCH = CHCOOH: 4-position

M.p.232-234 ℃ crystalline form: yellow powder

Recrystallization solvent: tetrahydrofuran water

The state is as follows: free example 357(3-position) A: -CH₂- m:1 s:1

Z:O R⁴:H

At the position-COCH = CHCOOH: 4-position

M.p.237-245 ℃ (decomposition) crystalline form: white powder

Recrystallization solvent: tetrahydrofuran water

NMR (37) state: free example 358

R⁵:-CH₂CH₃(2-position)&-OCH₃(5-position)

A:-CH₂- m:2 s:1 Z:O R⁴:H

At the position-COCH = CHCOOH: 4-position

M.p.127-138 ℃ (decomposition) crystalline form: yellow powder

Recrystallization solvent: dimethylformamide acetonitrile

NMR (38) State: free form

Table 154 example 359

R⁵:-OCH₃(2-&6-position)

A:-CH₂- m:2 s:1 Z:O R⁴:H

At the position-COCH = CHCOOH: 4-position

M.p.137-138 ℃ crystalline form: yellow powder

Recrystallization solvent: dimethylformamide-ethanol-diethyl ether-n-hexane

The state is as follows: free example 360

R⁵:-OCH₃(2-&3-position)

A:-CH₂- m:2 s:1 Z:O R⁴:H

At the position-COCH = CHCOOH: 4-position

M.p.235-237 ℃ crystalline form: yellow powder

Recrystallization solvent: dichloromethane-dimethylformamide

The state is as follows: free example 361

R⁵:-CH₃(2-position)&-OCH₃(3-position)

A:-CH₂- m:2 s:1 Z:O R⁴:H

At the position-COCH = CHCOOH: 4-position

Crystal form: NMR (39) state of pale yellow powder: free example 362

R⁵:-CH₃(2-position)&-OCH₃(3-position)

A:-CH₂- m:2 s:1 Z:O R⁴:H

At the position-COCH = CHCOOH: 6-position

Crystal form: light brown powder NMR (40) state: free form

TABLE 155 example 363

R⁵:-(CH₂)₃CH₃(2-position)&-OCH₃(3-position)

A:-CH₂- m:2 s:1 Z:O R⁴:H

At the position-COCH = CHCOOH: 4-position

Crystal form: yellow powder NMR (41) state: free examples 364

R⁵:-SCH₃(3-position)

A:-CH₂- m:1 s:1 Z:O R⁴:H

At the position-COCH = CHCOOH: 4-position

Crystal form: yellow powder NMR (42) state: free example 365

R⁵:-CH₂CH₃(2-position)&-OCH₃(3-position)

A:-CH₂- m:2 s:1 Z:O R⁴:H

At the position-COCH = CHCOOH: 4-position

Crystal form: light brown powder NMR (43) state: free example 366

R⁵:-OCH₃(3-position)

A:-CH(CH₃)- m:1 s:1 Z:O R⁴:H

At the position-COCH = CHCOOH: 4-position

M.p.225-228 ℃ (split) crystalline form: light brown powder

Recrystallization solvent: dimethylformamide-ethanol-diethyl ether-water

The state is as follows: free form

TABLE 156 example 367(2-&3-position)

A:-CH₂- m:2 s:1 Z:O R⁴:H

At the position-COCH = CHCOOH: 4-position

M.p.255-256 ℃ (decomposition) crystalline form: yellow powder

Recrystallization solvent: dimethylformamide-acetonitrile status: free examples 368

R⁵:-OCH₃(3-position)

A:-(CH₂)₃- m:1 s:1 Z:O R⁴:H

At the position-COCH = CHCOOH: 4-position

M.p.239-241 ℃ (decomposition) crystalline form: light yellow powder

Recrystallization solvent: dimethylformamide-acetonitrile status: free example 369

R⁵:-(CH₂)₂CH₃(2-position)&-OCH₃(5-position)

A:-CH₂- m:2 s:1 Z:O R⁴:H

At the position-COCH = CHCOOH: 4-position

M.p.222-224 ℃ (decomposition) crystalline form: light yellow powder

Recrystallization solvent: dimethylformamide-acetonitrile status: free example 370

R⁵:-CH₂CH=CH₂(2-position)&-OCH₃(5-position)

A:-CH₂- m:2 s:1 Z:O R⁴:H

At the position-COCH = CHCOOH: 4-position

M.p.224-225 ℃ (decomposition) crystalline form: yellow powder

Recrystallization solvent: dimethylformamide-acetonitrile status: free form

Watch 157Example 371

R⁵:-OCH₃(2-&5-position)

A:-CH₂- m:2 R⁴:H

At the position-COCH = CHCOOH: 4-position

NMR (44) crystalline form: yellow powder state: free example 372

R⁵:-CH₃(2-position)&-OCH₃(5-position)

A:-CH₂- m:2 R⁴:H

At the position-COCH = CHCOOH: 4-position

NMR (45) crystalline form: yellow powder example 373

R⁵:-OC₂H₅(2-position)&-OCH₃(5-position)

A:-CH₂- m:2 R⁴:H

At the position-COCH = CHCOOH: 4-position

M.p.202-204 ℃ (split) crystalline form: yellow powder

Recrystallization solvent: dimethylformamide-acetonitrile status: free form

Table 158 example 374

R⁵Br (2-position)&-OCH₃(5-position)

A:-CH₂- m:2 R⁴:H

At the position-COCH = CHCOOH: 4-position

M.p.238-239 ℃ (decomposition) crystalline form: yellow powder

Recrystallization solvent: dimethylformamide-acetonitrile status: free example 375

R⁵:-CH(CH₃)₂(2-position)&-OCH₃(5-position)

A:-CH₂- m:2 R⁴:H

At the position-COCH = CHCOOH: 4-position

NMR (46) crystal form: yellow powder state: free embodiment 376

R⁵:-(CH₂)₅CH₃(2-position)&-OCH₃(5-position)

A:-CH₂- m:2 R⁴:H

At the position-COCH = CHCOOH: 4-position

NMR (47) crystal form: yellow powder state: free example 377

R⁵:-N(CH₃)₂(2-position)

A:-CH₂- m:1 R⁴:H

At the position-COCH = CHCOOH: 4-position

NMR (48) crystal form: light yellow powder state: free form

Watch 159Example 378

R⁵:-OCH₃(3-position)

A:-CH₂- m:1 R⁴:H T:-CH₂- u:1

At the position-COCH = CHCOOH: 4-position

NMR (49) crystalline form: yellow powder state: free form

Watch 160Example 379

R⁴:H

M.p.211.5-213 ℃ crystalline form: white powder state: free form

Recrystallization solvent: dimethylformamide methanol

The compounds listed in the following tables 161-193 can be prepared in the same manner as described in example 3 or 4 using suitable starting compounds.

Table 161Example 380R⁴:H

M.p.187.5-188.5 ℃ crystalline form: white powder

Recrystallization solvent: ethanol-ether state: free example 381R⁴:H

M.p.164-166 ℃ crystalline form: white powder

Recrystallization solvent: ethanol-ether state: 2HCl

TABLE 162 example 382

R⁴H M.p.148.4-151.2 ℃ crystal form: yellow powder

Recrystallization solvent: ethanol-ether state: 2HCl example 383

R⁴H M.p.200-210 ℃ (decomposition) crystalline form: light brown powder

Recrystallization solvent: ethanol-water-ether state: 2HCl-H2O

NMR (1) example 384

R⁴H M.p.160.2-162.3 ℃ crystal form: light yellow powder

Recrystallization solvent: ethanol-ether state: 2HCl

TABLE 163 example 385

R⁴H M.p.156-166 ℃ (decomposition) crystalline form: light brown powder

Recrystallization solvent: ethanol-water-ether state: 3HCl-3H₂O

NMR (2) example 386

R⁴:H M.p.178-179 ℃ crystalline form: light yellow powder

Recrystallization solvent: ethanol state: free example 387

R⁴H M.p.252-253.5 ℃ crystal form: white powder

Recrystallization solvent: ethanol-water-ether state: free form

TABLE 164 example 388

R⁴H m.p.244-246 ℃ (decomposed) crystalline form: light brown powder

Recrystallization solvent: ethanol-chloroform state: free example 389

R⁴H M.p.173-176 ℃ crystal form: light yellow powder

Recrystallization solvent: ethanol-water-ether state: 2HCl example 390

R⁴H M.p.161.2-163.0 ℃ crystal form: light yellow powder

Recrystallization solvent: ethanol-water-ether state: 2HCl

TABLE 165 example 391

R⁴H M.p.172-176 ℃ crystal form: white powder

Recrystallization solvent: ethanol-water-ether state: free example 392

R⁴H M.p.234.5-236.5 ℃ crystal form: yellow powder

Recrystallization solvent: ethanol-water state: mesylate salt example 393

R⁴H M.p.114-117 ℃ crystal form: light yellow powder

Recrystallization solvent: ethanol-ether state: dimethyl sulfonate

Watch 166 example 394

R⁴H M.p.167.0-168.5 ℃ crystal form: light yellow powder

Recrystallization solvent: ethanol-water state: 2HCl example 395

R⁴H M.p.183-183.5 ℃ crystal form: light brown powder

Recrystallization solvent: ethanol state: free example 396

R⁴H M.p.237.5-238.5 ℃ crystal form: yellow powder

Recrystallization solvent: ethanol-water state: 2HCl

TABLE 167 examples 397

R⁴H M.p.158.0-161.0 ℃ crystal form: yellow powder

Recrystallization solvent: ethanol-water state: 2HCl example 398

R⁴H M.p.162.0-164.3 ℃ crystal form: light yellow powder

Recrystallization solvent: ethanol-water state: 2HCl example 399

R⁴H M.p.133-136 ℃ crystal form: yellow powder

Recrystallization solvent: ethanol-water state: methanesulfonic acid salt

Table 168 example 400

R⁴H M.p.207.3-210.0 ℃ crystal form: yellow powder

Recrystallization solvent: dimethylformamide-ethanol status: free example 401

R⁴H m.p.220-240 ℃ (decomposition) crystalline form: light yellow powder

Recrystallization solvent: ethanol-ether state: 2HCl

NMR (3) example 402

R⁴H m.p.170-180 ℃ (decomposition) crystalline form: light yellow powder

Recrystallization solvent: ethanol-ether state: HCl

NMR(4)

TABLE 169 example 403

R⁴H M.p.190-220 ℃ (decomposition) crystalline form: clear orange powder

Recrystallization solvent: ethanol-ether state: 2HCl

NMR (5) example 404

R⁴H M.p.138.5-140.3 ℃ crystal form: yellow powder

Recrystallization solvent: ethanol-water-ethyl ether

The state is as follows: mesylate salt example 405

R⁴H M.p.217.4-219.0 ℃ crystal form: yellow powder

Recrystallization solvent: ethanol-diethyl ether-dichloromethane

The state is as follows: methanesulfonic acid salt

Table 170 example 406

R⁴H M.p.138.2-139.5 deg.C crystalShape: light yellow powder

Recrystallization solvent: ethanol-water-ethyl ether

The state is as follows: mesylate salt example 407

R⁴H M.p.168.5-171.0 ℃ crystal form: yellow powder

Recrystallization solvent: ethanol-water-ether state: 2HCl example 408

R⁴H M.p.132-134 ℃ crystal form: white powder

Recrystallization solvent: ethanol-ethyl ether

The state is as follows: methanesulfonic acid salt

Table 171 example 409

R⁴H M.p.190-193 ℃ crystal form: yellow powder

Recrystallization solvent: ethanol-acetone-ethyl ether

The state is as follows: 2HCl example 410

R⁴H m.p.110-150 ℃ (decomposed) crystalline form: light yellow powder

Recrystallization solvent: ethanol-dichloromethane-diethyl ether

The state is as follows: dimethanesulfonate NMR (6) example 411

R⁴H M.p.190-240 deg.c (decomposition)) Crystal form: light yellow powder

Recrystallization solvent: ethanol-ethyl ether

The state is as follows: 2HCl NMR (7)

Table 172 example 412

R⁴H M.p.190-210 ℃ (decomposition) crystalline form: light yellow powder

Recrystallization solvent: ethanol-ethyl ether

The state is as follows: 2HCl NMR (8) example 413

R⁴H M.p.167.0-169.0 ℃ crystal form: yellow powder

Recrystallization solvent: ethanol state: 2HCl EXAMPLE 414

R⁴H M.p.200-220 ℃ (decomposition) crystalline form: light yellow powder

Recrystallization solvent: ethanol-water-ethyl ether

The state is as follows: 2HCl NMR (9)

TABLE 173 example 415

R⁴H M.p.177-180 ℃ crystal form: yellow powder

Recrystallization solvent: methylene chloride-isopropyl ether

The state is as follows: 2HCl EXAMPLE 416

R⁴:H M.p.179-182 ℃ crystalline form: yellow powder

Recrystallization solvent: methylene chloride-isopropyl ether

The state is as follows: 2HCl example 417

R⁴H M.p.158-159 ℃ crystal form: yellow powder

Recrystallization solvent: methylene chloride-isopropyl ether

The state is as follows: 2HCl

Table 174 example 418

R⁴H M.p.230-232 ℃ crystal form: yellow powder

Recrystallization solvent: methanol-Ether

The state is as follows: 2HCl example 419

R⁴H M.p.221-224 ℃ crystal form: yellow powder

Recrystallization solvent: methanol-Ether

The state is as follows: 2HCl example 420

R⁴H M.p.179-182 ℃ crystal form: yellow powder

Recrystallization solvent: methanol-Ether

The state is as follows: 2HCl

Table 175 example 421

R⁴:H M.pForm 146.2-148.5 ℃: grey powder

Recrystallization solvent: ethanol

The state is as follows: HCl example 422

R⁴H M.p.153-155 ℃ crystal form: yellow powder

Recrystallization solvent: dichloromethane state: 2HCl example 423

R⁴H M.p.225-228 ℃ crystal form: light yellow powder

Recrystallization solvent: ethanol state: methanesulfonic acid salt

TABLE 176 examples 424

R⁴H NMR (10) crystalline form: light yellow amorphous

The state is as follows: mesylate salt example 425

R⁴H M.p.140-143 ℃ crystal form: light yellow powder

Recrystallization solvent: ethanol state: mesylate salt example 426

R⁴H M.p.152.4-154.8 ℃ crystal form: light yellow powder

Recrystallization solvent: acetone-dichloromethane-water

The state is as follows: 2HCl

TABLE 177 example 427

R⁴H M.p.154-155 ℃ crystal form: yellow powder

Recrystallization solvent: ethanol-ether state: mesylate salt example 428

R⁴H M.p.165-168 ℃ crystal form: yellow powder

Recrystallization solvent: dichloromethane-diethyl ether

The state is as follows: mesylate salt example 429

R⁴H M.p.234-235 ℃ crystal form: yellow powder

Recrystallization solvent: dichloromethane-diethyl ether

The state is as follows: methanesulfonic acid salt

TABLE 178 example 430

R⁴H M.p.195-200 ℃ (decomposition) crystalline form: light yellow powder

Recrystallization solvent: acetone-water-ethyl ether

NMR (11) State: mesylate salt example 431

R⁴H m.p.183-220 ℃ (decomposition) crystalline form: white powder

Recrystallization solvent: acetone-ethanol-ethyl ether

NMR (12) State: 2HCl example 432

R⁴H M.p.159-161 ℃ crystal form: yellow powder

Recrystallization solvent: ethanol-acetone-ethyl ether

The state is as follows: 2HCl

TABLE 179 example 433

R⁴H M.p.177-180 ℃ crystal form: yellow amorphous

Recrystallization solvent: ethanol-water-ether state: 2HCl example 434

R⁴H M.p.178-181 ℃ crystal form: yellow powder

Recrystallization solvent: ethanol-water state: 2HCl example 435

R⁴H M.p.199-202 ℃ crystal form: light orange powder

Recrystallization solvent: ethanol-water state: methanesulfonic acid salt

TABLE 180 example 436

R⁴H NMR (13) crystalline form: yellow amorphous state: 2HCl example 437

R⁴H M.p.151-154 ℃ crystal form: yellow powder

Recrystallization solvent: ethanol-ether state: mesylate salt example 438

R⁴H M.p.114-116 ℃ crystal form: yellow powder

Recrystallization solvent: acetone-water state: methanesulfonic acid salt

TABLE 181 example 439

R⁴H M.p.205-208 ℃ crystal form: yellow powder

Recrystallization solvent: acetone-water state: 2HCl example 440

R⁴H m.p.185-190 ℃ (decomposition.) crystalline form: light yellow powder

Recrystallization solvent: ethanol-dichloromethane-diethyl ether

NMR (14) State: mesylate salt example 441

R⁴H M.p.160-180 ℃ (decomposition) crystalline form: light yellow powder

Recrystallization solvent: ethanol-dichloromethane-diethyl ether

NMR (15) State: 2HCl

TABLE 182 example 442

R⁴H M.p.170-190 ℃ crystal form: light yellow powder

Recrystallization solvent: ethanol-dichloromethane-diethyl ether

NMR (16) State: 2HCl example 443

R⁴H m.p.178-183 ℃ (decomposed) crystalline form: light yellow powder

Recrystallization solvent: ethanol-dichloromethane-diethyl ether

NMR (17) State: 2HCl example 445

R⁴H M.p.138-150 ℃ (decomposition) crystalline form: light brown powder

Recrystallization solvent: ethanol-dichloromethane-diethyl ether

NMR (18) State: methanesulfonic acid salt

TABLE 183 examples 446

R⁴H m.p.120-160 ℃ (decomposed) crystalline form: light brown powder

Recrystallization solvent: ethanol-dichloromethane-diethyl ether-acetone

NMR (19) State: mesylate salt example 447

R⁴:H MCrystalline form at p.169-171 ℃: light yellow powder

Recrystallization solvent: ethanol-water state: 2HCl example 448

R⁴H M.p.178-180 ℃ crystal form: light yellow powder

Recrystallization solvent: ethanol-water-ether state: 2HCl

TABLE 184 EXAMPLE 449

R⁴H M.p.162-164 ℃ crystal form: light yellow powder

Recrystallization solvent: ethanol-water-ethyl ether

The state is as follows: 2HCl example 450

R⁴H M.p.172-175 ℃ crystal form: light yellow powder

Recrystallization solvent: ethanol-water state: 2HCl example 451

R⁴H M.p.167-170 ℃ crystal form: light yellow powder

Recrystallization solvent: ethanol-water state: 2HCl

Table 185 example 452

R⁴H M.p.208-209 ℃ crystal form: light yellow powder

Recrystallization solvent: ethanol-water

The state is as follows: mesylate salt example 453

R⁴H M.p.246-249 ℃ crystal form: yellow powder

Recrystallization solvent: ethanol-water state: 2HCl example 454

R⁴H M.p.188-190 ℃ crystal form: light yellow powder

Recrystallization solvent: ethanol-water state: 2HCl

Table 186 example 455

R⁴H M.p.167-169 ℃ crystal form: light yellow powder

Recrystallization solvent: ethanol-water state: 2HCl example 456

R⁴H M.p.170-173 ℃ crystal form: light yellow powder

Recrystallization solvent: ethanol-water state: 2HCl example 457

R⁴H M.p.225-228 ℃ crystal form: light yellow powder

Recrystallization solvent: ethanol-dichloromethane state: 2HCl

Table 187 example 458

R⁴H M.p.162.0-163.5 ℃ crystal form: yellow powder

Recrystallization solvent: ethanol-water state: mesylate salt example 459

R⁴H M.p.209.5-212.5 ℃ crystal form: white powder

Recrystallization solvent: ethanol-water state: 3HCl example 460

R⁴H M.p.155-185 ℃ (decomposed) crystalline form: light yellow powder

Recrystallization solvent: ethanol-dichloromethane-diethyl ether

NMR (20) State: methanesulfonic acid salt

Table 188 example 461

R⁴H M.p.180-215 ℃ (decomposition) crystalline form: light yellow powder

Recrystallization solvent: ethanol-dichloromethane-diethyl ether

NMR (21) State: 2HCl example 462

R⁴H m.p.220-225 ℃ (decomposition) crystalline form: light yellow powder

Recrystallization solvent: ethanol-dichloromethane-diethyl ether

NMR (22) State: 2HCl example 463

R⁴H M.p.180-215 ℃ (decomposition) crystalline form: light yellow powder

Recrystallization solvent: ethanol-dichloromethane-diethyl ether

NMR (23) state: 2HCl

Table 189 example 464

R⁴H M.p.185.5-192 ℃ crystal form: yellow powder

Recrystallization solvent: ethanol-water

NMR (24) State: 2HCl example 465

R⁴H M.p.159.5-161.2 ℃ crystal form: light yellow powder

Recrystallization solvent: ethanol-ether-water state: 2HCl EXAMPLE 466

R⁴H m.p.150-158 ℃ (decomposed) crystalline form: light yellow powder

Recrystallization solvent: ethanol-dichloromethane-diethyl ether

NMR (25) State: methanesulfonic acid salt

TABLE 190 example 467

R⁴H M.p.193-204 deg.C (decomposition)

Crystal form: light yellow powder

Recrystallization solvent: ethanol-dichloromethane-diethyl ether

NMR (26) State: 2HCl example 468

R⁴H M.p.205-213 deg.C (decomposition)

Crystal form: light yellow powder

Recrystallization solvent: ethanol-dichloromethane-diethyl ether

NMR (27) state: 2HCl example 469

R⁴H m.p.205-213 ℃ (decomposed) crystalline form: light yellow powder

Recrystallization solvent: ethanol-dichloromethane-diethyl ether

NMR (28) State: 2HCl

Table 191 example 470

R⁴H M.p.131-160 deg.C (decomposition)

Crystal form: light yellow powder

Recrystallization solvent: dichloromethane-ethanol-ethyl ether

NMR (29) State: mesylate salt example 471

R⁴H m.p.180-210 ℃ (decomposition) crystalline form: light brown powder

Recrystallization solvent: dichloromethane-ethanol-ethyl ether

NMR (30) State: 2HCl example 472

R⁴H m.p.231-235 ℃ (decomposed) crystalline form: light yellow powder

Recrystallization solvent: dichloromethane-ethanol-ethyl ether

The state is as follows: 2HCl

TABLE 192 example 473

R⁴H M.p.216-221 deg.C (decomposition)

Crystal form: light yellow powder

Recrystallization solvent: dichloromethane-ethanol-ethyl ether

NMR (31) state: 2HCl example 474

R⁴H m.p.175-205 ℃ (decomposed) crystalline form: light yellow powder

Recrystallization solvent: dichloromethane-ethanol-ethyl ether

NMR (32) State: mesylate salt example 475

R⁴H m.p.185-230 ℃ (decomposed) crystalline form: light yellow powder

Recrystallization solvent: dichloromethane-ethanol-ethyl ether

NMR (33) State: 2HCl

TABLE 193 example 476

R⁴:H M.p.160-170℃

Crystal form: light yellow powder

Recrystallization solvent: ethanol-water

NMR (34) State: bis-mesylate salt example 477

R⁴H M.p.172-178 ℃ crystal form: light yellow powder

Recrystallization solvent: ethanol-water NMR (35) state: 3HCl example 478

R⁴H M.p.185.2-186.0 ℃ crystal form: white powder

Recrystallization solvent: ethanol state: free form

Using suitable starting compounds, the same procedures as described in example 8 were carried out to obtain the compounds listed in the following Table 194

Watch 194Example 479

R⁴:H M.p.171.5-173.0℃

Crystal form: light yellow powder

Recrystallization solvent: ethanol-diethyl ether-dichloromethane

The state is as follows: 2HCl EXAMPLE 480

R⁴H M.p.111.5-114.5 ℃ crystal form: light yellow powder

Recrystallization solvent: ethanol-water-isopropanol state: 2HCl

Using suitable starting compounds, the compounds listed in the following Table 195 can be prepared in the same manner as described in example 3 or 4.

Watch 195Example 481

R⁴:H T:-CH₂- u:1

M.p.147-150 ℃ crystalline form: light yellow powder

Recrystallization solvent: ethanol-water-ethyl ether-isopropanol

The state is as follows: 2HCl

TABLE 150 SUMMARY OF 195¹H-NMR spectra (NMR (1) to NMR (49)) were as follows 195:

NMR(1)(DMSO-d₆)δppm:2.65-2.8(4H,m),3.06(9H,s),3.87(3H,s),4.15-4.65(4H,m),5.07(2H,s),6.70(1H,dd,J=2Hz,J=8.5Hz),6.81(1H,d,J=2Hz),7.29(1H,d,J=15Hz),7.48(1H,br),7.62(1H,d,J=15Hz),7.65(1H,d,J=8.5Hz),7.77(1H,d,J=9Hz),7.93(1H,br),11.0(1H,br),12.7(1H,br)

NMR(2)(DMSO-d₆)δppm:1.65(2H,br),2.05-2.40(4H,m),2.55-2.9(4H,m),3.13(6H,s),3.25-4.8(15H,m),5.10(2H,s),6.70(1H,dd,J=2Hz,J=9Hz),6.81(1H,d,J=2Hz),7.26(1H,d,J=15Hz),7.55(1H,d,J=15Hz),7.64(1H,d,J=8.5Hz),7.7-7.8(1H,m),7.88(1H,d,J=9Hz),8.31(1H,br),11.2-12.2(2H,m)

NMR(3)(DMSO-d₆)δppm:1.61(3H,d,J=6.5Hz),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=6.5Hz),6.63(1H,dd,J=2Hz,9Hz),6.77(1H,d,J=2Hz),7.15-7.7(4H,m),7.69(1H,d,J=9Hz),7.76(1H,d,J=7.5Hz),7.98(1H,d,J=7.5Hz),11.1-13.1(3H,m)

NMR(4)(DMSO-d₆)δppm:1.61(3H,d,J=6.5Hz),2.73(3H,d,J=4Hz),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=6.5Hz),6.63(1H,dd,J=2Hz,9Hz),6.78(1H,d,J=2Hz),7.26(1H,d,J=15Hz),7.25-7.5(2H,m),7.59(1H,d,J=15Hz),7.63(1H,d,J=9Hz),7.76(1H,d,J=7.5Hz),7.97(1H,d,J=7Hz),11.40(1H,br),12.9(1H,br)

NMR(5)(DMSO-d₆)δppm:1.61(3H,d,J=6.5Hz),2.35-4.4(23H,m),5.37(1H,q,J=6.5Hz),6.63(1H,dd,J=2Hz,J=8.5Hz),6.78(1H,d,J=2Hz),7.1-7.7(5H,m),7.76(1H,d,J=7.5Hz),7.98(1H,d,J=7Hz),11.85(2H,br)12.90(1H,br)

NMR(6)(DMSO-d₆)δppm:2.42(6H,s),2.82(3H,d,J=4Hz),2.9-3.25(3H,m),3.3-3.6(3H,m),4.15-4.6(6H,m),5.03(2H,s),6.68(1H,d,J=9Hz),7.23(1H,d,J=9Hz),7.31(1H,d,J=15Hz),7.15-7.5(2H,m),7.61(1H,d,J=15Hz),7.76(1H,d,J=7.5Hz),7.98(1H,d,J=7Hz),9.85(1H,br)

NMR(7)(DMSO-d₆)δppm: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=9Hz),7.22(1H,d,J=9Hz),7.25-7.6(4H,m),7.76(1H,d,J=7.5Hz),7.98(1H,d,J=7.5Hz),11.1-12.2(2H,m),12.65(1H,br)

NMR(8)(DMSO-d₆)δppm:2.55-2.7(1H,m),2.79(3H,s),2.85-4.5(20H,m),5.04(2H,s),6.68(1H,d,J=8.5Hz),7.15-7.7(5H,m),7.76(1H,d,J=7.5Hz),7.98(1H,d,J=7Hz),11.4-13.1(2H,m)

NMR(9)(DMSO-d₆)δppm:1.35(3H,d,J=5.5Hz),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=9Hz),7.22(1H,d,J=9Hz),7.29(1H,d,J=15.5Hz),4.05-4.7(6H,m),5.03(2H,s),7.4-7.5(1H,m),7.53(1H,d,J=15.5Hz),7.76(1H,d,J=7.5Hz),7.98(1H,d,J=7Hz),11.5-13.0(2H,m)

NMR(10)(DMSO-d₆)δppm；2.16(3H,s),2.37(3H,s),2.77(3H,d,J=4.2Hz),2.83-3.19(3H,m),3.29-3.58(3H,m),3.88(3H,s),4.12-4.57(2H,m),4.65(2H,s),6.95(1H,d,J=8.8Hz),7.19-7.37(2H,m),7.37-7.50(1H,m),7.50-7.66(2H,m),7.75(1H,d,J=7.9Hz),7.99(1H,d,J=7.9Hz),9.82(1H,brs),11.95-12.71(1H,m)

NMR(11)(DMSO-d₆)δppm；2.17(2H,br),2.34(3H,s),2.82(3H,s),3.05(4H,br),3.4(2H,br),4.05-4.4(5H,m),4.49(1H,br),5.05(2H,s),6.83(1H,d,J=9Hz),7.28(1H,d,J=15Hz),7.29(1H,d,J=9Hz),7.25-7.35(1H,m),7.35-7.5(1H,m),7.52(1H,d,J=15Hz),7.76(1H,d,J=7.5Hz),7.98(1H,d,J=7Hz),9.81(1H,br),12.6(1H,br)

NMR(12)(DMSO-d₆)δppm；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=2.5Hz,J=8.5Hz),7.25-7.41(4H,m),7.4-7.5(1H,m),7.69(1H,d,J=8.5Hz),7.77(1H,d,J=7.5Hz),7.99(1H,d,J=7Hz),11.0-12.2(2H,m)

NMR(13)(DMSO-d₆)δppm；0.91(3H,t,J=7.2Hz),1.20-1.86(6H,m),1.93-2.39(4H,m),2.58-2.89(4H,m),2.76(3H,s),2.95-3.98(9H,m),3.64(3H,s),4.07-4.31(1H,m),4.41-4.69(1H,m),5.09(2H,s),6.83(1H,d,J=8.9Hz),7.20-7.64(5H,m),7.76(1H,d,J=7.9Hz),7.97(1H,d,J=7.9Hz),11.11-12.29(2H,m),12.72(1H,brs)

NMR(14)(DMSO-d₆)δppm；2.0-2.2(2H,m),2.34(3H,s),2.68(2H,t,J=7Hz),2.81(3H,d,J=3Hz),2.9-3.2(2H,m),3.3-3.65(4H,m),3.79(3H,s),4.15(2H,t,J=6Hz),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=15Hz),7.35-7.5(1H,m),7.63(1H,d,J=9.5Hz),7.63(1H,d,J=15Hz),7.72(1H,d,J=7.5Hz),7.9-8.0(1H,m),9.79(1H,br),12.38(1H,br)

NMR(15)(DMSO-d₆)δppm；1.64(2H,br),2.0-2.4(6H,m),2.55-2.9(6H,m),2.95-4.0(3H,m),4.0-4.35(3H,m),4.4-4.7(1H,m),6.55-6.75(2H,m),7.0(1H,br),7.2-7.35(2H,m),7.35-7.45(1H,m),7.5-7.65(2H,m),7.65-7.75(1H,m),7.9-8.0(1H,m),11.2-12.6(2H,m)

NMR(16)(DMSO-d₆)δppm；2.0-2.2(2H,m),2.69(2H,t,J=7Hz),2.80(3H,s),2.9-4.4(22H,m),6.4-6.75(2H,m),7.15-7.5(3H,m),7.5-7.8(3H,m),7.96(1H,d,J=7Hz),11.95(1H,br),12.41(1H,br)

NMR(17)(DMSO-d₆)δppm；1.45-1.9(2H,m),2.0-2.35(4H,m),2.55-2.95(6H,m),2.95-3.25(1H,m),3.3-3.95(12H,m),4.0-4.35(3H,m),4.4-4.65(1H,m),6.4-6.75(2H,m),7.25(1H,d,J=15Hz),7.2-7.5(2H,m),7.55(1H,d,J=15Hz),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)(DMSO-d₆)δppm；1.16(3H,t,J=7.5Hz),1.9-2.2(2H,m),2.48(3H,s),2.62(2H,q,J=7.5Hz),2.82(3H,d,J=4.5Hz),3.0-3.8(5H,m),3.84(3H,s),3.9-4.3(3H,m),5.16(2H,s),6.71(1H,s),7.22(1H,d,J=15Hz),7.25-7.35(1H,m),7.4-7.5(1H,m),7.51(1H,s),7.66(1H,dd,J=5.5Hz,J=15Hz),7.77(1H,d,J=7.5Hz),7.98(1H,d,J=7Hz),9.55(1H,br),11.7(1H,br)

NMR(19)(DMSO-d₆)δppm；1.15(3H,t,J=7.5Hz),1.35-1.7(2H,m),1.9-2.1(2H,m),2.36(3H,s),2.5-2.7(3H,m),2.73(3H,s),2.75(3H,s),3.0-3.2(1H,m),3.3-3.55(1H,m),3.84(3H,s),4.05-4.25(1H,m),4.45-4.65(1H,m),5.16(2H,s),6.71(1H,s),7.26(1H,d,J=15Hz),7.25-7.35(1H,m),7.4-7.5(1H,m),7.50(1H,s),7.58(1H,d,J=15Hz),7.77(1H,d,J=7.5Hz),7.98(1H,d,J=7Hz),9.58(1H,br)

NMR(20)(DMSO-d₆)δppm；0.90(3H,t,J=7.5Hz),1.57(2H,tq,J=7.5Hz,J=8Hz),2.35(3H,s),2.57(2H,t,J=8Hz),2.81(3H,d,J=3.5Hz),2.9-3.25(3H,m),3.3-3.7(3H,m),3.83(3H,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=15Hz),7.25-7.4(1H,m),7.4-7.5(1H,m),7.49(1H,s),7.66(1H,d,J=15Hz),7.77(1H,d,J=8Hz),7.98(1H,d,J=7.5Hz),9.85(1H,br),12.6(1H,br)

NMR(21)(DMSO-d₆)δppm；0.89(3H,t,7.5Hz),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),4.45-4.7(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=15Hz),7.77(1H,d,J=7.5Hz),7.98(1H,d,J=7Hz),11.1-13.2(2H,m)

NMR(22)(DMSO-d₆)δppm；0.90(3H,t,J=7.5Hz),1.4-1.8(4H,m),1.95-2.25(2H,m),2.57(2H,t,J=8Hz),2.6-2.9(1H,m),2.81(3H,s),2.95-4.0(10H,m),3.84(3H,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=15Hz),7.25-7.35(1H,m),7.35-7.5(1H,m),7.48(1H,s),7.58(1H,d,J=15Hz),7.77(1H,d,J=7.5Hz),7.98(1H,d,J=7Hz),11.4-13.0(3H,m)

NMR(23)(DMSO-d₆)δppm；0.90(3H,t,J=7.5Hz),1.57(2H,tq,J=7.5Hz,J=8Hz),2.57(2H,t,J=8Hz),2.65-4.4(17H,m),2.79(3H,s),3.84(3H,s),5.18(2H,s),6.71(1H,s),7.15-7.5(3H,m),7.48(1H,s),7.5-7.8(2H,m),7.98(1H,d,J=7Hz),11.0-13.0(3H,m)

NMR(24)(DMSO-d₆)δppm；1.11(3H,t,J=7.4Hz),2.53-4.17(16H,m),2.59(2H,q,J=7.4Hz),2.79(3H,s),3.84(3H,s),4.17-4.40(1H,m),5.20(2H,s),6.73(1H,s),7.18-7.38(2H,m),7.38-7.54(2H,m),7.54-7.74(1H,m),7.74-7.81(1H,m),7.92-8.05(1H,m),11.32-13.11(3H,m)

NMR(25)(DMSO-d₆)δppm；2.35(3H,s),2.80(3H,d,J=3.5Hz),2.85-3.6(6H,m),3.85(3H,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=15Hz),7.25-7.55(2H,m),7.48(1H,s),7.65(1H,d,J=15Hz),7.77(1H,d,J=7.5Hz),7.98(1H,d,J=7Hz),9.99(1H,br),12.6(1H,br)

NMR(26)(DMSO-d₆)δppm；1.65(2H,br),2.0-2.4(4H,m),2.55-2.95(4H,m),3.0-3.25(1H,m),3.25-4.05(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=8Hz),7.98(1H,d,J=7.5Hz),11.1-13.0(3H,m)

NMR(27)(DMSO-d₆)δppm；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(3H,s),4.1-4.3(1H,m),4.45-4.7(1H,m),4.95-5.25(4H,m),5.86-6.1(1H,m),6.74(1H,s),7.26(1H,d,J=15Hz),7.25-7.55(3H,m),7.56(1H,d,J=15Hz),7.77(1H,d,J=7.5Hz),7.98(1H,d,J=7Hz),11.3-13.2(3H,m)

NMR(28)(DMSO-d₆)δppm；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,m),7.98(1H,d,J=7Hz),11.0-13.3(3H,m)

NMR(29)(DMSO-d₆)δppm；1.32(3H,t,J=7Hz),2.33(3H,s),2.80(3H,s),2.9-3.2(3H,m),3.3-3.5(3H,m),3.81(3H,s),4.03(2H,q,J=7Hz),4.2-4.65(2H,m),5.15(2H,s),6.83(1H,s),7.2-7.4(3H,m),7.44(1H,t,J=8Hz),7.69(1H,d,J=15Hz),7.77(1H,d,J=8Hz),7.98(1H,d,J=8Hz),9.83(1H,br),12.60(1H,br)

NMR(30)(DMSO-d₆)δppm；1.32(3H,t,J=7Hz),1.4-1.9(2H,m),2.05-2.4(4H,m),2.6-3.9(4H,m),3.05-3.95(13H,m),4.03(2H,q,J=7Hz),4.1-4.3(1H,m),4.5-4.7(1H,m),5.17(2H,s),6.83(1H,s),7.2-7.4(3H,m),7.44(1H,t,J=8Hz),7.60(1H,d,J=15.5Hz),7.76(1H,d,J=8Hz),7.98(1H,d,J=8Hz),11.25-12.2(2H,m)

NMR(31)(DMSO-d₆)δppm；1.32(3H,t,J=7Hz),2.55-4.5(19H,m),2.80(3H,s),3.82(3H,s),5.17(2H,s),6.84(1H,s),7.2-7.4(3H,m),7.44(1H,t,J=8Hz),7.64(1H,d,J=15.5Hz),7.76(1H,d,J=8Hz),7.98(1H,d,J=8Hz),11.5-12.5(2H,m)

NMR(32)(DMSO-d₆)δppm；2.32(3H,s),2.81(3H,s),3.4-3.7(4H,m),3.25-3.6(2H,m),3.86(3H,s),4.15-4.65(2H,m),5.26(2H,s),6.89(1H,s),7.32(1H,d,J=15Hz),7.32(1H,t,J=7.5Hz),7.45(1H,t,J=8Hz),7.61(1H,d,J=15Hz),7.77(1H,d,J=8Hz),7.83(1H,s),7.98(1H,d,J=7.5Hz),9.78(1H,br),12.65(1H,br)

NMR(33)(DMSO-d₆)δppm；1.4-1.85(2H,m),2.1-2.4(4H,m),2.6-3.9(4H,m),3.05-4.5(14H,m),4.5-4.65(1H,m),5.27(2H,s),6.89(1H,s),7.2-7.4(2H,m),7.4-7.6(2H,m),7.77(1H,d,J=8Hz),7.81(1H,s),7.98(1H,d,J=8Hz),11.1-12.1(2H,m)

NMR(34)(DMSO-d₆)δppm；2.35(s,6H),2.82(s,3H),2.92-3.27(m,9H),3.30-3.59(m,3H),4.18(br,1H),4.19-4.34(m,1H),4.47-4.65(m,1H),5.24(s,2H),7.33(t,J=7.6Hz,2H),7.44(d,J=7.3Hz,1H),7.46(d,J=15.1Hz,1H),7.78(d,J=8.0Hz,1H),7.84(d,J=15.1Hz,1H),7.96-8.15(m,3H),9.82(br,1H),12.66(br,1H)

NMR(35)(DMSO-d₆)δppm；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,1H),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,1H),11.35-12.13(m,2H)

NMR(36)(DMSO-d₆)δppm；4.61-4.78(2H,m),5.05(2H,s),5.18-5.50(2H,m),5.91-6.17(1H,m),6.46(1H,d,J=15.5Hz),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=15.5Hz),7.92-8.05(1H,m),12.72(2H,brs)

NMR(37)(DMSO-d₆)δppm；4.97(2H,s),6.40-6.58(2H,m),6.91(1H,dd,J=2.4Hz,J=8.8Hz),7.00-7.22(3H,m),7.22-7.51(4H,m),7.61-7.89(3H,m),7.89-8.04(1H,m),12.75(2H,brs)

NMR(38)(DMSO-d₆)δppm；1.12(3H,t,J=7.4Hz),2.60(2H,q,J=7.4Hz),3.85(3H,s),5.15(2H,s),6.46(1H,d,J=15.5Hz),6.71(1H,s),7.26-7.39(1H,m),7.39-7.50(1H,m),7.51(1H,s),7.68(1H,d,J=15.5Hz),7.72-7.81(1H,m),7.91-8.03(1H,m),12.75(2H,brs)

NMR(39)(DMSO-d₆)δppm；2.19(3H,s),3.64(3H,s),5.07(2H,s),6.54(1H,d,J=15.6Hz),6.85(1H,d,J=8.7Hz),7.25-7.40(1H,m),7.40-7.51(1H,m),7.54(1H,d,J=8.8Hz),7.68(1H,d,J=15.6Hz),7.76(1H,d,J=7.5Hz),7.98(1H,d,J=7.5Hz),12.41-13.16(2H,m)

NMR(40)(DMSO-d₆)δppm；2.16(3H,s),3.88(3H,s),4.64(2H,s),6.52(1H,d,J=15.6Hz),6.95(1H,d,J=8.8Hz),7.21-7.38(1H,m),7.38-7.51(1H,m),7.55-7.80(3H,m),7.98(1H,d,J=7.1Hz)

NMR(41)(DMSO-d₆)δppm；0.91(3H,t,J=7.3Hz),1.20-1.65(4H,m),2.54-2.78(2H,m),3.63(3H,s),5.07(2H,s),6.58(1H,d,J=15.6Hz),6.84(1H,d,J=8.7Hz),7.21-7.39(1H,m),7.39-7.51(1H,m),7.55(1H,d,J=8.7Hz),7.67(1H,d,J=15.6Hz),7.76(1H,d,J=7.8Hz),7.97(1H,d,J=7.8Hz),12.05-13.51(2H,m)

NMR(42)(DMSO-d₆)δppm；2.41(3H,s),5.10(2H,s),6.56(1H,d,J=15.5Hz),6.90(1H,dd,J=8.8Hz,J=2.2Hz),6.98(1H,d,J=2.2Hz),7.32(1H,t,J=7.2Hz),7.45(1H,t,J=7.2Hz),7.65-7.85(2H,m),7.99(1H,d,J=7.7Hz),8.05(1H,d,J=8.8Hz),12.06-13.45(2H,m)

NMR(43)(DMSO-d₆)δppm；1.17(3H,t,J=7.5Hz),2.70(2H,q,J=7.5Hz),3.65(3H,s),5.09(2H,s),6.57(1H,d,J=15.6Hz),6.85(1H,d,J=8.9Hz),7.30(1H,dt,J=1.2Hz,J=7.1Hz),7.43(1H,dt,J=1.2Hz,J=7.1Hz),7.56(1H,d,J=8.9Hz),7.67(1H,d,J=15.6Hz),7.76(1H,d,J=7.1Hz),7.97(1H,d,J=7.1Hz),12.51-13.12(2H,m)

NMR(44)(DMSO-d₆)δppm；3.79(3H,s),3.83(3H,s),5.12(2H,s),6.51(1H,d,J=15.5Hz),6.84(1H,s),7.15-7.54(3H,m with 1H sat7.26),7.61-7.86(2H,m with 1H,dat7.76J=15.5Hz),7.99(1H,d,J=7.1Hz),12.20-13.25(2H,m)

NMR(45)(DMSO-d₆)δppm；2.19(3H,s),3.85(3H,s),5.14(2H,s),6.49(1H,d,J=15.5Hz),6.70(1H,s),7.20-7.56(3H,m,with 1H sat7.52),7.60-7.82(2H,m,with 1H dat7.71J=15.5Hz),7.98(1H,d,J=7.0Hz),12.41-13.17(2H,m)

NMR(46)(DMSO-d₆)δppm；1.19(6H,d,J=6.9Hz),3.10-3.42(1H,m),3.86(3H,s),5.16(2H,s),6.50(1H,d,J=15.5Hz),6.70(1H,s),7.21-7.60(3H,mwith 1H sat7.55),7.65-7.82(2H,m with 1H dat7.73J=15.5Hz),7.89-8.08(1H,m),12.42-13.12(2H,m)

NMR(47)(DMSO-d₆)δppm；0.68-0.92(3H,m),1.08-1.64(8H,m),2.38-2.68(2H,m),3.85(3H,s),5.14(2H,s),6.49(1H,d,J=15.5Hz),6.71(1H,s),7.20-7.57(3H,m),7.62-7.85(2H,m with 1H dat7.72J=15.5Hz),7.88-8.05(1H,m),12.45-13.12(2H,m)

NMR(48)(DMSO-d₆)δppm；3.17(s,6H),5.28(s,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),8.25(s,1H)

NMR(49)(DMSO-d₆)δppm；3.87(s,3H),4.75(d,J=5Hz,2H),4.77(s,2H),6.50(d,J=15.5Hz,1H),6.72(dd,J=2.2HzJ=8.6Hz,1H),6.78(d,J=2.2Hz,1H),7.33-7.57(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 (PKC) inhibitory Activity

PKC activity assay method:

PKC purification was performed using murine brain soluble fractions as described by Kikkawa et al (see Ushio Kikkawa, Yoshimi Takai, Ryoji Minakuchi, Sinichi Inohara and Yasutomi Nishizuka: The Journal of Biological Chemistry, vol.257, No.22, pp13341-13348 (1982)). In 20mM Tris-HCl buffer (pH7.5), calf thymus-derived H1 histone (200. mu.g/ml), 10. mu.M [ gamma. ]³²P]ATP, 5mM magnesium acetate, 8. mu.g/ml phosphatidylserine, 2. mu.g/ml diacyl-glycerol and 0.3mM Ca²⁺In the presence of a catalyst prepared by measuring the molecular weight of [ gamma ]³²P]The transfer of Adenosine Triphosphate (ATP) to calf thymus-derived H1 histone determines PKC activity. The test mixture was dissolved in dimethylformamide and the test compound solution was added to the test system so that its final concentration was adjusted to 0.8%. The reaction mixture was incubated at 30 ℃ for 30 minutes and the reaction was stopped with 25% trichloroacetic acid. The acid-insoluble protein was collected on nitrocellulose membrane by suction filtration. Measurement by scintillation counting ³²The radioactivity of p. IC for PKC inhibitory Activity of said test Compounds₅₀Indicating a concentration of test compound required to reduce PKC activity by 50%. The test results are shown in Table 196.

Results

Watch 196

Test compounds	PKC inhibitory Activity (IC)50,μM)
		The compound of example 71	0.8
Practice ofThe compound of example 88	0.1
		The compound of example 89	0.3
The compound of example 100	0.3
		The compound of example 160	0.6
A compound of example 182	0.08
		The compound of example 192	0.8
The compound of example 197	0.3

(2) Collagen arthritis test in mice

Bovine type ii-Collagen (supplied by Collagen Gijyutsu kennyukai) (0.1%) was emulsified with Complete Freund's Adjuvant (CFA) (50%) (produced by DIFCO, ltd.) and the resulting emulsifier was injected subcutaneously from the tail of mice (first sensitization). Three weeks later, mice were again injected intraperitoneally with bovine type ii collagen (0.1%) (secondary sensitization). After three weeks, mice were observed for swelling of the limbs and evaluated on four scales of 0-3 for each limb. The grades (0-3) for each limb were added and the result was used as a score for arthritis, i.e. the highest grade was 12 (grade 3 x 4 limb). Two weeks after the first sensitization, mice were orally administered the test compound once a day.

Mice treated with the compound of example 182 at a dose of 50mg/kg had a significantly lower arthritis score than control mice.

Treatment of mice with 50mg/kg of the compound of example 160, 192 or 197 also resulted in a significant reduction in the arthritis score compared to control mice.

(3) Mouse cGVHD (chronic graft versus host disease model)

A female mouse (DBA/2NCrj) was subjected to cervical dislocation and dislocation surgery, and the spleen was isolated to prepare a spleen cell preparation. The formulation was adjusted to 37.5X 10⁷Cells/ml and were administered from the tail vein of BDF1 female mice at a dose of 200 μ l per mouse. After two weeks, blood was collected in the absence of heparin and assayed for anti-DNA antibodies by ELISA.

Mice were orally administered the compound of example 182 at a once daily dose of 30-50mg/kg for two weeks and the effect of the test compound on cGVHD was determined.

The amount of anti-DNA antibody in blood was determined by OD 405. In the control group, the amount of the anti-DNA antibody was 0.348. + -. 0.111 (mean. + -. s.e.), the amount of the anti-DNA antibody in the treatment group with the compound of example 182 at a dose of 30mg/kg was 0.255. + -. 0.062 (mean. + -. s.e.), and the amount of the anti-DNA antibody in the treatment group with the compound of example 182 at a dose of 50mg/kg was 0.094. + -. 0.026 (mean. + -. s.e.). From the results, it can be demonstrated that the compound of example 182 can reduce anti-DNA antibodies in blood depending on the dose, compared to the control group.

In addition, the compound of example 100 was orally administered to mice at a once-daily dose of 30mg/kg for two weeks, and the effect of the test compound on cGVHD was determined.

The amount of anti-DNA antibody in blood was determined by OD 405. In the control group, the amount of anti-DNA antibody was 0.258. + -. 0.084 (mean. + -. s.e.), and in the treatment group with the compound of example 100 at a dose of 30mg/kg, it was 0.177. + -. 0.061 (mean. + -. s.e.). From the results, it can be confirmed that the compound of example 100 can reduce anti-DNA antibodies in blood, as compared to the control group.

(4) Mouse kidney ischemia-reperfusion model

The right kidney of SD male mice was excised, and the left renal artery was agglomerated and then perfused to obtain a renal ischemia-reperfusion model. The effect of the compounds of examples 71, 89 and 100 on the renal ischemia-reperfusion model was evaluated.

The compound of example 71 was administered intravenously to mice at a dose of 3mg/kg 5 minutes prior to ischemia. After 24 hours, blood was taken from the tail vein and creatine and urinary nitrogen content were determined. Control group, creatine content in blood 2.19 ± 0.21 (mean ± s.e.); the treatment group with the compound of example 71 was 1.4 ± 0.11 (mean ± s.e.), whereas the control group had a urinary nitrogen content of 78.8 ± 5.6 (mean ± s.e.) in blood and the treatment group with the compound of example 71 was 54.1 ± 5.0 (mean ± s.e.). That is, the compound of example 71 significantly reduced both creatine and urinary nitrogen levels compared to the control.

The compound of example 89 was administered intravenously to mice at a dose of 3mg/kg 5 minutes prior to ischemia and reperfusion. After 48 hours, blood was taken from the tail vein and creatine and urinary nitrogen content were determined. Control group, creatine content in blood was 4.31 ± 0.53 (mean ± s.e.); the treatment group with the compound of example 89 was 2.34 ± 0.46 (mean ± s.e.), whereas the control group had a urinary nitrogen content of 155.1 ± 15.4 (mean ± s.e.) in blood and the treatment group with the compound of example 89 was 99.1 ± 16.0 (mean ± s.e.). That is, the compound of example 89 can significantly reduce both creatine and urinary nitrogen levels compared to the control group.

The compound of example 100 was administered intravenously to mice at a dose of 30mg/kg 1 hour prior to ischemia. After 48 hours, blood was taken from the tail vein and creatine and urinary nitrogen content were determined. Control group, creatine content in blood was 2.48 ± 0.59 (mean ± s.e.); the treatment group with the compound of example 100 was 1.53 ± 0.20 (mean ± s.e.), whereas the control group had a urinary nitrogen content of 91.3 ± 20.1 (mean ± s.e.) in blood and the treatment group with the compound of example 100 was 63.1 ± 10.3 (mean ± s.e.). That is, it was demonstrated that the compound of example 100 can reduce both creatine and urinary nitrogen content compared to the control group.

(5) Phorbol ester (TPA) -induced mouse auricle edema and acanthosis model

Female mice (ICR) were dosed with 200. mu.g/ml phorbol ester (TPA) (10. mu.l) in one ear. After 24 hours, the thickness of the mouse pinna was measured with a graduated thickness ruler and the thickness growth of the pinna was calculated. The test compound was dissolved in acetone and the test compound solution was applied to both ears 30 minutes prior to TPA application.

A 0.3% or 1% solution of the compound of example 88 was applied to the ear at a dose of 20 μ l. After 24 hours, the pinna thickness had increased to 215. + -.40 μm (mean. + -. s.e.) for the control group, 87. + -.53 μm (mean. + -. s.e.) for the treatment group with 0.3% of the compound of example 88 and 67. + -.23 μm (mean. + -. s.e.) for the treatment group with 1% of the compound of example 88. That is, the compound of example 88 significantly reduced the increase in the thickness of the auricle as compared with the control group.

(6) Mouse model of atopic dermatitis

Female mice (Balb/c) were administered 1% Trinitrobenzene (TNCB) (10. mu.l) to each ear once every two days for a total of 24 days. After 24 days, the mice were divided into groups, and the thickness of the auricle of the mouse was measured using a graduated thickness ruler and the growth of the thickness of the auricle was calculated. The compounds described in examples 88 and 89 were dissolved in acetone at a concentration of 1%. The compound of example 182 was dissolved in acetone: the concentration in the methanol mixture was 0.75%. On day 24 after the start of the test, the test compound solution was administered to each lateral ear once daily for two weeks before and 30 minutes after TNCB administration. The compound of example 88 inhibits the growth of pinna thickness by up to 25-30%, whereas the compounds of examples 89 and 182 inhibit the growth of pinna thickness by up to about 25%. That is, the compounds of the present invention are demonstrated to be useful in the treatment of acanthosis caused by TNCB administration.

Claims (34)

1. A thiazole compound of the formula:

wherein T is lower alkylene;

u is 0 or 1;

R¹and R²May be the same or different and are each a hydrogen atom or a lower alkyl group, or together form- (CH) in which n is 4 or 5₂)_nA group or form an amino or halogen atom which may be substituted by a substituent selected from lower alkyl, lower alkoxy, nitro, optionally lower alkylOptionally substituted benzene ring;

R³is a group of the formula:

wherein R is^11b、p、R^11aAs defined below; a is lower alkylene; z is O or S; s is 0 or 1; m is 1 or 2;

R⁴is hydrogen or lower alkanoyloxy-lower alkyl;

each R⁵May be the same or different and are each selected from (a) a hydrogen atom; (b) alkyl optionally substituted with hydroxy; (c) a halogen atom; (d) a group of the formula: - (O)_t-A-(CO)_l-NR⁷R⁸Wherein t is 0 or 1, A is lower alkylene, l is 0 or 1, and R⁷And R⁸Which may be the same or different and are each a hydrogen atom or a lower alkyl group, or together with the nitrogen atom to which they are attached form a 5-or 7-membered saturated heterocyclic group which may be interrupted by a nitrogen atom or an oxygen atom, said heterocyclic group being optionally substituted by a group selected from the group consisting of: - (A)_l-NR⁹R¹⁰Wherein A and l are as defined above, and R⁹And R¹⁰May be the same or different and are each a hydrogen atom or a lower alkyl group, or form, together with the nitrogen atom to which they are attached, a 5-or 7-membered saturated heterocyclic group which may be interrupted by a nitrogen atom or an oxygen atom, said heterocyclic group optionally carrying a lower alkyl substituent; lower alkyl optionally substituted with hydroxy; hydroxy and lower alkanoyl; (e) lower alkoxycarbonyl-lower alkyl; (f) lower alkanoyloxy-lower alkyl; (g) lower alkoxy optionally substituted by halogen; (h) lower alkyl substituted by halogen; (i) lower alkyl substituted with carboxyl; (j) a lower alkoxycarbonyl group; (k) lower alkenyloxy; (l) Phenyl-lower alkoxy; (m) a cycloalkoxy group; (n) phenyl; (o) a phenoxy group; (p) a hydroxyl group; (q) lower alkylthio; (r) lower alkenyl; or(s) amino optionally substituted with lower alkyl;

R⁶Is a group of the formula:

(1)-CO-CH=CR^11b-(CO)_p-R^11aor (2) -CO-C ≡ C-COR¹⁴

p is 0 or 1;

R^11bis hydrogen or lower alkyl;

R^11ais hydroxy, lower alkoxy or a 5-to 10-membered mono-or bicyclic, saturated or unsaturated heterocyclyl group containing 1 to 4 heteroatoms as ring atoms, selected from nitrogen, oxygen or sulfur atoms, said heterocyclyl group optionally carrying 1 to 3 substituents selected from: lower alkyl; (ii) a group of the formula: - (B)_l-NR¹²R¹³Wherein l is as defined above, B is-CO-A-, carbonyl or lower alkylene, A is as defined above, and R¹²And R¹³Which may be the same or different and are each a hydrogen atom, a lower alkyl group or a lower alkyl group substituted by an amino group optionally having a lower alkyl substituent, or together with the nitrogen atom to which they are attached form a 5-to 12-membered saturated, monocyclic, bicyclic or spirocyclic heterocyclic group which may be interrupted by a nitrogen or oxygen atom, said heterocyclic group optionally having a substituent selected from the group consisting of: lower alkyl, lower alkoxycarbonyl, lower alkyl substituted by lower alkoxy, amino optionally substituted by lower alkyl, and lower alkyl substituted by hydroxy; (iii) a lower alkoxycarbonyl group; (iv) hydroxy-substituted lower alkyl; (v) pyridyl optionally substituted on the pyridyl ring by lower alkyl optionally substituted by halogen; (vi) halo-substituted lower alkyl; (vii) lower alkoxy; (viii) a cycloalkyl group; (ix) hydroxy; (x) a tetrahydropyranyloxy-substituted lower alkyl group; (xi) a pyrimidinyl group; (xii) lower alkyl substituted by lower alkoxy; (xiii) carboxyl; (xiv) phenyl-lower alkoxy; (xv) phenyl-lower alkyl optionally bearing a lower alkylenedioxy group on the phenyl ring; (xvi) lower alkanoyloxy groups; and (xvii) piperidinyl optionally bearing a lower alkyl substituent on the piperidine ring;

R¹⁴Is hydroxy or lower alkoxy; and

when m is 1, the groups A and R⁵Together may form a group of the formula:wherein R is⁶As defined above, and r is 0, 1 or 2; or when m is 2, twoR is⁵The radicals together forming a lower alkylenedioxy group, a lower alkylene group or a radical- (CH)₂)₂-CONH-, or a group R⁵And R⁶Together may form a group of the formula: -CO-CH (R)²⁸)-CH(R^28’) -W-wherein R²⁸And R^28’Is a hydrogen atom or a carboxyl group, with the proviso that R²⁸And R^28′Not both being carboxyl, and W is-N (R)^29a) -orWherein R is^29aIs hydrogen or lower alkyl, R^29bIs lower alkyl and X is as defined above.

2. The thiazole compound or salt thereof according to claim 1, wherein u is 0; r¹And R²Identical or different and are each a hydrogen atom or a lower alkyl group, R³Is a group of the formula:wherein R is^11b、R^11aAnd p is as defined in claim 1.

3. The thiazole compound or salt thereof according to claim 1, wherein u is 0; r¹And R²Identical or different and are each a hydrogen atom or a lower alkyl group, R³Is a group of the formula:a, R therein⁵、R⁶And m is as defined in claim 1, and s is 0.

4. The thiazole compound or salt thereof according to claim 1, wherein u is 0; r¹And R²Identical or different and are each a hydrogen atom or a lower alkyl group, R ³Is a group of the formula:a, R therein⁵、R⁶And m is as defined in claim 1, s is 1, and Z is O.

5. The thiazole compound or salt thereof according to claim 1, wherein u is 0; r¹And R²Identical or different and are each a hydrogen atom or a lower alkyl group, R³Is a group of the formula:a, R therein⁵、R⁶And m is as defined in claim 1, S is 1, and Z is S.

6. The thiazole compound or salt thereof according to claim 1, wherein u is 0; r¹And R²Together form a radical- (CH)₂)_n-, where n is 4; r³Is a group of the formula:wherein R is^11b、R^11aAnd p is as defined in claim 1.

7. The thiazole compound or salt thereof according to claim 1, wherein u is 0; r¹And R²Together form a radical- (CH)₂)_n-, where n is 4; r³Is a group of the formula:a, R therein⁵、R⁶And m is as defined in claim 1, and s is 0.

8. The thiazole compound or salt thereof according to claim 1, wherein u is 0; r¹And R²Together form a radical- (CH)₂)_n-, where n is 4; r³Is a group of the formula:a, R therein⁵、R⁶And m is as defined in claim 1, s is 1, and Z is O.

9. The thiazole compound or salt thereof according to claim 1, wherein u is 0; r¹And R²Together form a radical- (CH)₂)_n-, where n is 4; r³Is a base of the following formulaAnd (3) clustering:a, R therein ⁵、R⁶And m is as defined in claim 1, S is 1, and Z is S.

10. The thiazole compound or salt thereof according to claim 1, wherein u is 0; r¹And R²Together form a radical- (CH)₂)_n-, where n is 5; r³Is a group of the formula:wherein R is^11b、R^11aAnd p is as defined in claim 1.

11. The thiazole compound or salt thereof according to claim 1, wherein u is 0; r¹And R²Together form a radical- (CH)₂)_n-, where n is 5; r³Is a group of the formula:a, R therein⁵、R⁶And m is as defined in claim 1, and s is 0.

12. The thiazole compound or salt thereof according to claim 1, wherein u is 0; r¹And R²Together form a radical- (CH)₂)_n-, where n is 5; r³Is a group of the formula:a, R therein⁵、R⁶And m is as defined in claim 1, s is 1, and Z is O.

13. The thiazole compound or salt thereof according to claim 1, wherein u is 0; r¹And R²Together form a radical- (CH)₂)_n-, where n is 5; r³Is a group of the formula:a, R therein⁵、R⁶And m is as defined in claim 1, S is 1, and Z is S。

14. The thiazole compound or salt thereof according to claim 1, wherein u is 0; r¹And R²Together form a benzene ring which may optionally have a substituent selected from the group consisting of lower alkyl, lower alkoxy, nitro, amino optionally having a lower alkyl substituent, or a halogen atom; r ³Is a group of the formula:wherein R is^11b、R^11aAnd p is as defined in claim 1.

15. The thiazole compound or salt thereof according to claim 1, wherein u is 0; r¹And R²Together form a benzene ring which may optionally have a substituent selected from the group consisting of lower alkyl, lower alkoxy, nitro, amino optionally having a lower alkyl substituent, or a halogen atom; r³Is a group of the formula:a, R therein⁵、R⁶And m is as defined in claim 1, and s is 0.

16. The thiazole compound or salt thereof according to claim 1, wherein u is 0; r¹And R²-form a benzene ring optionally having a substituent selected from the group consisting of lower alkyl, lower alkoxy, nitro, amino optionally having a lower alkyl substituent, or a halogen atom; r³Is a group of the formula:a, R therein⁵、R⁶And m is as defined in claim 1, s is 1, and Z is O.

17. The thiazole compound or salt thereof according to claim 1, wherein u is 0; r¹And R²Together form a benzene ring optionally bearing a substituent selected from the group consisting of lower alkylLower alkoxy, nitro, amino optionally substituted with lower alkyl, or halogen; r³Is a group of the formula: A, R therein⁵、R⁶And m is as defined in claim 1, S is 1, and Z is S.

18. A thiazole compound or a salt thereof according to claim 4 wherein R⁶Is a group of the formula: -CO-CH = CR^11b-(CO)_p-R^11aWherein R is^11bAnd p is as defined in claim 1, R^11aIs hydroxy or lower alkoxy.

19. A thiazole compound or a salt thereof according to claim 4 wherein R⁶Is a group of the formula: -CO-CH = CR^11b-(CO)_p-R^11aWherein R is^11bAs defined in claim 1, p is 1 and R is^11aIs a 5-to 10-membered monocyclic or bicyclic, saturated or unsaturated heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen, oxygen or sulfur atoms as ring atoms, said heterocyclic group optionally carrying 1 to 3 substituents selected from the group consisting of: lower alkyl; (ii) a group of the formula: - (B)_l-NR¹²R¹³Wherein l is as defined above; b is-CO-A-, carbonyl or lower alkylene, wherein A is as defined above; and R¹²And R¹³Which may be the same or different and are each a hydrogen atom, a lower alkyl group or a lower alkyl group substituted by an amino group optionally having a lower alkyl substituent, or together with the nitrogen atom to which they are attached form a 5-to 12-membered saturated, monocyclic, bicyclic or spirocyclic heterocyclic group which may be interrupted by a nitrogen or oxygen atom, said heterocyclic group optionally having a substituent selected from the group consisting of: lower alkyl, lower alkoxycarbonyl, lower alkyl substituted by lower alkoxy, amino optionally substituted by lower alkyl, and lower alkyl substituted by hydroxy; (iii) a lower alkoxycarbonyl group; (iv) hydroxy-substituted lower alkyl; (v) pyridyl optionally substituted on the pyridyl ring by lower alkyl optionally substituted by halogen; (vi) halo-substituted lower alkyl; (vii) lower stage An alkoxy group; (viii) a cycloalkyl group; (ix) hydroxy; (x) a tetrahydropyranyloxy-substituted lower alkyl group; (xi) a pyrimidinyl group; (xii) lower alkyl substituted by lower alkoxy; (xiii) carboxyl; (xiv) phenyl-lower alkoxy; (xv) phenyl-lower alkyl optionally bearing a lower alkylenedioxy group on the phenyl ring; (xvi) lower alkanoyloxy groups; and (xvii) piperidinyl optionally bearing a lower alkyl substituent on the piperidine ring.

20. A thiazole compound or a salt thereof according to claim 4 wherein R⁶Is a group of the formula: -CO-CH = CR^11b-(CO)_p-R^11aWherein R is^11bAs defined in claim 1, p is 0 and R is^11aAs defined in claim 19.

21. A thiazole compound or a salt thereof according to claim 4 wherein R⁶Is a group of the formula: -CO-C ≡ C-COR¹⁴Wherein R is¹⁴As defined in claim 1.

22. A thiazole compound or salt thereof according to claim 16 wherein R⁶Is a group of the formula: -CO-CH = CR^11b-(CO)_p-R^11aWherein R is^11bAnd p is as defined in claim 1, R^11aIs hydroxy or lower alkoxy.

23. A thiazole compound or salt thereof according to claim 16 wherein R⁶Is a group of the formula: -CO-CH = CR^11b-(CO)_p-R^11aWherein R is^11bAs defined in claim 1, p is 1 and R is ^11aAs defined in claim 19.

24. A thiazole compound or salt thereof according to claim 16 wherein R⁶Is a group of the formula: -CO-CH = CR^11b-(CO)_p-R^11aWherein R is^11bAs defined in claim 1, p is 0 and R is^11aAs defined in claim 19.

25. A thiazole compound or salt thereof according to claim 16 wherein R⁶Is a group of the formula: -CO-C ≡ C-COR¹⁴,R¹⁴As defined in claim 1.

26. The thiazole compound or salt thereof according to claim 1, wherein u is 1; r³Is a group of the formula:wherein R is^11b、R^11aAnd p is as defined in claim 1.

27. The thiazole compound or salt thereof according to claim 1, wherein u is 1; r¹And R²Are the same or different and are each a hydrogen atom or a lower alkyl group; r³Is a group of the formula:wherein A, Z, s, R⁵、R⁶And m is as defined in claim 1.

28. The thiazole compound or salt thereof according to claim 1, wherein u is 1; r¹And R²Together form a radical- (CH)₂)_n-, where n is 4; r³Is a group of the formula:wherein A, Z, s, R⁵、R⁶And m is as defined in claim 1.

29. The thiazole compound or salt thereof according to claim 1, wherein u is 1; r¹And R²Together form a radical- (CH)₂)_n-wherein n is 5; r³Is a group of the formula:wherein A, Z, s, R⁵、R⁶And m is as defined in claim 1.

30. The thiazole compound or salt thereof according to claim 1, wherein u is 1; r¹And R²Together form a benzene ring optionally having a substituent selected from the group consisting of lower alkyl, lower alkoxy, nitro, amino optionally having a lower alkyl substituent, and halogen, R³Is a group of the formula:wherein A, Z, s, R⁵、R⁶And m is as defined in claim 1.

31. The thiazole compound or salt thereof according to any of claims 2,3, 6 to 15 and 17 to 30, wherein R^11aThe heterocyclic group is selected from the following groups: pyrrolidinyl, piperidinyl, piperazinyl, morpholino, 1-azacyclooctyl, homopiperazinyl, homomorpholino, 1, 4-diazabicyclo [4.3.0]Nonyl, 1, 4-diazabicyclo [4.4.0 ]]Decyl, pyridyl, 1,2,5, 6-tetrahydropyridinyl, thienyl, 1,2, 4-triazolyl, 1,2,3, 4-tetrazolyl, 1,3, 4-triazolyl, quinolyl, 1, 4-dihydroquinolyl, benzothiazolyl, pyrazolyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrrolinyl, quinolone, 1, 3-dioxolanyl, thiomorpholinyl, 3, 4-dihydroquinolone, 1,2,3, 4-tetrahydroquinolyl, 2,3,4, 5-tetrahydrofuryl, indolyl, isoindolyl, 3H-indolyl, indolinyl, perhydroindolyl, indazolyl, benzimidazolyl, benzoxazolyl, imidazolinyl, imidazolidinyl, isoquinolyl, perhydronaphthyl, perhydrom-diazanaphthyl, quinoxalyl, 1, 2-diazanaphthyl, 2, 3-diazanaphthyl, chromanyl, isoindolinyl, isochromanoyl, pyrazolyl, 1,3, 4-oxadiazolyl, 1,3, 4-thiadiazolyl, thienyl, imidazolyl, pyrazolidinyl, benzofuranyl, 2, 3-dihydrobenzo [ b ]Furyl, benzothienyl, tetrahydropyranyl, 4H-benzopyranyl, 1H-indazolyl, isoindolinyl, 2-imidazolinyl2-pyrrolinyl, furyl, oxazolyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, pyranyl, pyrazolidinyl, 2-pyrazolinyl, quinuclidinyl, 1, 4-benzoxazinyl, 3, 4-dihydro-2H-1, 4-benzothiazinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 1,2,3, 4-tetrahydroquinoxalinyl, 1, 3-dithia-2, 4-dihydronaphthyl, 1, 4-dithianyl, 2, 5-dihydrofuro [3,4-c ] naphtyl]Pyridyl, 2,3,4,5,6, 7-hexahydro-1H-azepine, 1,2,3,4,5,6,7, 8-octahydroazocinyl, 1,2,3,4,5, 6-hexahydroheptylene, 1, 3-dioxolanyl, 3,4,5, 6-tetrahydro-2H-pyranyl and 5, 6-dihydro-2H-pyranyl.

32. A compound according to claim 1, selected from the group consisting of the following thiazole compounds or salts thereof:

(1)2- { (3-methoxy-4- (3- (4- (4-methyl-1-homopiperazinyl) -1-piperidinylcarbonyl) acryloyl) phenoxy) methylcarbonylamino } benzothiazole,

(2)2- { (2-isopropyl-4- (3- (4- (4-methyl-1-piperazinyl) -1-piperidinylcarbonyl) acryloyl) phenoxy) methylcarbonylamino } benzothiazole,

(3)2- { (2-methoxy-4- (3- (2- (4-methyl-1-piperazinyl) methyl-4-morpholinocarbonyl) acryloyl) phenoxy) methylcarbonylamino } benzothiazole,

(4)2- { (2-ethoxy-4- (3- (4- (4-methyl-1-piperazinyl) -1-piperidinylcarbonyl) acryloyl) phenoxy) methylcarbonylamino } benzothiazole,

(5)2- { (3-methyl-4- (3- (4- (4-methyl-1-homopiperazinyl) -1-piperidinylcarbonyl) acryloyl) phenoxy) methylcarbonylamino } benzothiazole,

(6)2- { (3-methoxy-6-ethyl-4- (3- (4- (4-methyl-1-homopiperazinyl) -1-piperidinylcarbonyl) acryloyl) phenoxy) methylcarbonylamino } benzothiazole,

(7)2- { (3-methoxy-6-ethyl-4- (3- (4-methyl-1-piperazinyl) acryloyl) phenoxy) methylcarbonylamino } benzothiazole,

(8)2- { (2-trifluoromethyl-4- (3- (4-hydroxy-1-piperazinyl) acryloyl) phenoxy) methylcarbonylamino } benzothiazole,

(9)2- { (2-fluoro-4- (3- (2- (4-methyl-1-piperazinyl) methyl-4-morpholinocarbonyl) acryloyl) phenoxy) methylcarbonylamino } benzothiazole,

(10)2- { (2-methoxy-4- (3- (4- (4-methyl-1-piperazinyl) -1-piperidinylcarbonyl) acryloyl) phenoxy) methylcarbonylamino } benzothiazole,

(11)2- { (2, 3-dimethyl-4- (3- (4- (4-methyl-1-homopiperazinyl) -1-piperidinylcarbonyl) acryloyl) phenoxy) methylcarbonylamino } benzothiazole,

(12)2- { (3-methoxy-4- (3- (4- (3, 4-dimethyl-1-piperazinyl) -1-piperidinylcarbonyl) acryloyl) phenoxy) methylcarbonylamino } benzothiazole,

(13)2- { (3-methoxy-6-isopropyl-4- (3- (4-methyl-1-piperazinyl) carbonyl) acryloyl) phenoxy) methylcarbonylamino } benzothiazole,

(14)2- { (2-methoxy-4- (3- (4- (4-methyl-1-homopiperazinyl) -1-piperidinylcarbonyl) acryloyl) phenoxy) methylcarbonylamino } benzothiazole, and

(15)2- { (2-n-butyl-4- (3- (4- (4-methyl-1-homopiperazinyl) -1-piperidinylcarbonyl) acryloyl) phenoxy) methylcarbonylamino } benzothiazole.

33. A protein kinase C inhibitor comprising the thiazole compound according to any one of claims 1 to 32 or a salt thereof as an active ingredient.

34. A process for the preparation of a thiazole compound according to any of claims 1 to 32 comprising the steps of:

(a) reacting a compound of the following formula (2) with a compound of the formula (3) or a compound of the formula (4) to give a compound of the formula (1a),wherein R is¹、R²、R⁴、R⁵Z, m, s, T, u and A are as defined in claim 1,wherein R is^11bAs defined in claim 1, wherein the first and second substrates are,wherein R is¹⁵Is the group: -CH = C (R)^11b)(COR¹⁶) Wherein R is^11bAs defined in claim 1, and R ¹⁶Is hydroxy or lower alkoxy; or is the group: -C ≡ C-COR¹⁴Wherein R is¹⁴As defined in claim 1; and X is a halogen atom;wherein R is¹、R²、R⁴、R⁵Z, m, s, T, u and A are as defined in claim 1, and R¹⁵As defined above;

(b) reacting a compound of the following formula (1b) with a compound of the formula (5) to give a compound of the formula (1c),wherein R is¹、R²、R⁴、R⁵、R^11bZ, m, s, T, u and A are as defined in claim 1,

R¹⁷h (5) wherein R¹⁷Is R^11aSaid heterocyclic group containing only at least one-N <,wherein R is¹、R²、R⁴、R⁵、R^11bZ, m, s, T, u and A are as defined in claim 1, and R¹⁷As defined above;

(c) reacting a compound of the following formula (10) with a compound of the formula (12) to give a compound of the formula (1d),wherein R is¹、R²、R⁴、R⁵Z, m, s, T, u and A are as defined in claim 1, and R¹⁸Is a lower alkoxy group, and is,wherein R is¹⁶As defined above, the above-mentioned,wherein R is¹、R²、R⁴、R⁵Z, m, s, T, u and A are as defined in claim 1, and R¹⁶As defined above;

(d) reacting a compound of the following formula (10) with a compound of the formula (20) to give a compound of the formula (1h),wherein R is¹、R²、R⁴、R⁵Z, m, s, T, u and A are as defined in claim 1, and R¹⁸As defined above, the above-mentioned,

R²²CHO (20) wherein R ²²Is a 5-to 10-membered saturated or unsaturated heteromonocyclic, heterobicyclic group (said heterocyclic group optionally having 1 to 3 substituents selected from the group consisting of (i) a lower alkyl group, (ii) a group- (B)_l-NR¹²R¹³Wherein l is as defined above; b is A group-CO-A-, carbonyl or lower alkylene, A is as defined above, R¹²And R¹³Which may be the same or different and are each hydrogen atom, lower alkyl substituted by amino optionally bearing a lower alkyl substituent, or together with the adjacent nitrogen atom to which they are attached form a 5-to 12-membered saturated heteromonocyclic, heterobicyclic or heterospirocyclic heterocycle, which may optionally bear substituents selected from the group consisting of: lower alkyl, lower alkoxycarbonyl, lower alkyl substituted by lower alkoxy, amino optionally substituted by lower alkyl, and lower alkyl substituted by hydroxy; (iii) a lower alkoxycarbonyl group; (iv) hydroxy-substituted lower alkyl; (v) pyridyl optionally substituted on the pyridyl ring by lower alkyl optionally substituted by halogen; (vi) halo-substituted lower alkyl; (vii) lower alkoxy; (viii) a cycloalkyl group; (ix) hydroxy; (x) a tetrahydropyranyloxy-substituted lower alkyl group; (xi) a pyrimidinyl group; (xii) lower alkyl substituted by lower alkoxy; (xiii) carboxyl; (xiv) phenyl-lower alkoxy; (xv) phenyl-lower alkyl optionally bearing a lower alkylenedioxy group on the phenyl ring; (xvi) lower alkanoyloxy groups; and (xvii) optionally on the piperidine ring Piperidinyl having a lower alkyl substituent,wherein R is¹、R²、R⁴、R⁵Z, m, s, T, u and A are as defined in claim 1, R¹⁸And R²²As defined above;

(e) converting a compound of the following formula (11) into a compound of the formula (1 d') in the presence of a basic compound,wherein R is¹、R²、R⁴、R⁵Z, m, s, T, u and A are as defined in claim 1, and R²⁰Is a lower alkoxy group, and is,wherein R is¹、R²、R⁴、R⁵Z, m, s, T, u and A are as defined in claim 1, and R^16aIs a lower alkoxy group, and is,

optionally, converting said compound of formula (1 d') in the presence of an acid or basic compound to a compound of formula (1 e):wherein R is¹、R²、R⁴、R⁵Z, m, s, T, u and A are as defined in claim 1;

(f) converting a compound of the following formula (11) into a compound of the formula (1f) in the presence of an oxidizing agent,wherein R is¹、R²、R⁴、R⁵Z, m, s, T, u and A are as defined in claim 1, and R²⁰Is a lower alkoxy group, and is,wherein R is¹、R²、R⁴、R⁵Z, m, s, T, u and A are as defined in claim 1, and R²⁰As defined above, the above-mentioned,

optionally, converting said compound of formula (1f) in the presence of an acid or basic compound to a compound of formula (1 g):wherein R is¹、R²、R⁴、R⁵Z, m, s, T, u and A are as defined in claim 1;

(g) reacting a compound of the following formula (19) with a compound of the formula (20) to give a compound of the formula (1h), Wherein R is¹、R²、R⁴、R⁵Z, m, s, T, u and A are as defined in claim 1, and R²¹Is a phenyl group, and the phenyl group,

R²²CHO (20)R²²as defined above, the above-mentioned,wherein R is¹、R²、R⁴、R⁵Z, m, s, T, u and A are as defined in claim 1, and R²²As defined above;

(h) reacting a compound of the following formula (23) with a compound of the formula (24) to obtain a compound of the formula (1),wherein R is³As defined in claim 1, wherein the first and second substrates are,wherein R is¹、R²、R⁴T and u are as defined in claim 1,wherein R is¹、R²、R³、R⁴T and u are as defined in claim 1;

(i) reacting a compound of the following formula (19a) with a compound of the formula (44) to give a compound of the formula (1q),wherein T, u, R¹、R²、R⁴、Z、R⁵And m is as defined in claim 1, and R²¹As defined above, A' is lower alkylene,

OHC·COOH (44)wherein T, u, R¹、R²、R⁴、A’、Z、R⁵And m is as defined in claim 1, and R²¹As defined above;

(j) reacting a compound of the following formula (54) with a compound of the formula (12) to give a compound of the formula (1s),wherein R is¹、R²T, u and R⁴As defined in claim 1, and R¹⁸As defined above, the above-mentioned,wherein R is¹⁶As defined above, the above-mentioned,wherein R is¹、R²T, u and R⁴As defined in claim 1, and R¹⁶As defined above, the above-mentioned,

optionally, converting said compound of formula (1s) to a compound of formula (1 t):wherein R is¹、R²T, u and R⁴As defined in claim 1;

(k) reacting a compound of the following formula (1u) with a compound of the formula (5) to obtain a compound of the formula (1v), Wherein R is¹、R²、T、u、R⁴And R^11bAs defined in claim 1, wherein the first and second substrates are,

R¹⁷h (5) wherein R¹⁷As defined above, the above-mentioned,wherein R is¹、R²、T、u、R⁴And R^11bAs defined in claim 1; or

(1) Reacting a compound of the following formula (54) with a compound of the formula (20) to give a compound of the formula (1w),wherein R is¹、R²、T、u、R⁴And R¹⁸As defined above, the above-mentioned,

R²²CHO (20) wherein R²²As defined above, the above-mentioned,wherein R is¹、R²T, u and R⁴As defined in claim 1, and R²²As defined above.