D E S C RI PT I ON

THIAZOLE DERIVATIVE AS PROTEIN KINASE C INHIBITORS

TECHNICAL HELD The present invention relates to a novel thiazole derivative.

BACKGROUND ART

There have hitherto been known various thiazole derivatives, among which some compounds having a somewhat similar substituents to those of the present invention are disclosed in the following literatures. JP-A-2-306916 discloses inhibitors for platelet adhesion comprising a benzazole compound of the following formula:

wherein X is S or >N-R3 (R3 is H, lower alkyl, etc.); Rl is halogen, cyano, cyano- substituted lower alkoxy, phenyl-alkyl having a substituent on benzene ring, substituted furyl-alkoxy, substituted pyrrolidinyl-alkyl, substituted amino, substituted amino-alkyl or -alkoxy, etc.; R2 is pyrrolyl having optionally alkyl substituent, thienyl, pyridylthio-lower alkyl, phenyl group which has optionally 1 to 3 substituents selected from lower alkoxy, lower alkyl, OH, halogen, or -O- Y-NR8R9 (Y is lower alkylene, R8 and R9 are each H, lower alkyl, cycloalkyl, or both combine to form a nitrogen-containing 5- or 6-membered saturated hetero¬ cyclic group, or -NRlORH (Rio and RU are each H, lower alkyl, substituted phenyl, or both combine to form a heterocyclic group). However, the benzazole

compounds of this literature are significantly different from the thiazole compounds of the present invention in the substituents at 2-position of the thiazole nucleus. Besides, this literature does not disclose any compounds having protein kinase C inhibitory activities as in the present invention.

European Patent 318 084 (= U.S. Patent 4,957,932 and 5,037,840) discloses that the benzoheterazoles of the following formula are leukotriene antagonists and inhibitors of leukotriene biosynthesis and are useful as antiasthmetic, antiallergic, anti-inflammatory and cytoprotective agents.

wherein Rl is H, halogen, alkyl, etc.; R2 is alkyl, alkenyl, etc.; R3 is H or R2; R4 i _s H, halogen, -NO ₂ , etc.; R5 is H, halogen, -N0 ₂ , etc.; R7 is H or alkyl; X2 and X3

are O, S, S(O), etc.; X is NR3, O or S; Zl and Z are -CONR3- or -HET(-R3,-R5). _; and Qi and Q2 are -COOR3, -CONHS(0) ₂ R!3, -CN, etc. However, these

benzoheterazoles of this literature are essentially different from the thiazole compounds of the present invention in the substituent at 2-position of the azole nucleus. Besides, this literature does not disclose any compounds having protein kinase C inhibitory activity.

Some thiazole or benzothiazole compounds having similar chemical structure to the benzoheterazoles of the above European Patent 318084 are also disclosed in PCT publications WO 93/21168 and WO 93/21169 and therein

it is mentioned that those compounds are useful as leukotriene antagonist, but these thiazole or benzothiazole compounds of these literatures are clearly different from the thiazole compounds of the present invention in the substituent at 2-position likewise, and further these literatures do not disclose any compound having protein kinase C inhibitory activity, either. DISCLOSURE OF INVENTION

The thiazole derivatives of the present invention are novel compounds, and have not been disclosed in any literature, and have the following formula (1).

wherein T is a lower alkylene; u is 0 or 1 ; R ¹ and R ² are the same or different and are each a hydrogen atom or a lower alkyl, or both combine to form a group: -(CH ₂ ) _n - (n is 4 or 5) or to form a

benzene ring which may optionally be substituted by a member selected from a lower alkyl, a lower alkoxy, a nitro, an amino having optionally a lower alkyl substituent, or a halogen atom; R ³ is a group of the formula:

wherein R ^{1 lb} , p, R ^{l la} are defined hereinafter; A is a lower alkylene; Z is O or S; s

is 0 or 1 ; m is 1 or 2;

R ⁴ is a hydrogen atom or a lower alkanoyloxy-lower alkyl;

R ⁵ s are the same or different and are each a member selected from (a) a hydrogen atom, (b) an alkyl having optionally a hydroxy substituent, (c) a halogen atom, (d) a group of the formula: -(O) _t -A-(CO) NR ⁷ R ⁸ (wherein t is 0 or

1, A is a lower alkylene, I is 0 or 1 , and R ⁷ and R ⁸ are the same or different and are each a hydrogen atom or a lower alkyl, or both combine together with the nitrogen atom to which they bond to form a 5- to 7-membered saturated heterocyclic group which may be intervened with a nitrogen or oxygen atom, said heterocyclic group being optionally substituted by a member selected from a group of the formula: -(A)^-NR ⁹ R ¹⁰ (wherein A and £ are as defined above,

and R ⁹ and R ¹⁰ are the same or different and are each a hydrogen atom or a lower alkyl, or both combine together with the nitrogen atom to which they bond to form a 5- to 7-membered saturated heterocyclic group which may be intervened with a nitrogen or oxygen atom, said heterocyclic group having optionally a lower alkyl substituent), a lower alkyl having optionally a hydroxy substituent, a hydroxy group, and a lower alkanoyl), (e) a lower alkoxy- carbonyl-lower alkyl, (f) a lower alkanoyloxy-lower alkyl, (g) a lower alkoxy having optionally a halogen substituent, (h) a halogen-substituted lower alkyl, (i) a carboxyl-substituted lower alkyl, (j) a lower alkoxy carbonyl, (k) a lower alkenyloxy, (1) a phenyl-lower alkoxy, (m) a cycloalkyloxy, (n) a phenyl, (o) a phenyloxy, (p) a hydroxy, (q) a lower alkylthio, (r) a lower alkenyl, or (s) an amino having optionally a lower alkyl substituent; R ⁶ is a group of the formula:

(1) or (2) -CO-C≡C-CORl*;

p is 0 or 1 ;

R ^{1 lb} is a hydrogen atom or a lower alkyl;

R ^{i ]a} is a hydroxy, a lower alkoxy, or a 5- to 10-membered, monocyclic or dicyclic, saturated or unsaturated heterocyclic group which contains 1 to 4 hetero atoms selected from a nitrogen, oxygen or sulfur atom as a ring member, said heterocyclic group having optionally 1 to 3 substituents selected from the group consisting of (i) a lower alkyl, (ii) a group of the formula: -(B)ι-NR ¹² R ¹³

(wherein 1 is as defined above, B is -CO-A- (A is as defined above), a carbonyl, or a lower alkylene, and R ¹² and R ¹³ are the same or different and are each a hydrogen atom, a lower alkyl, or a lower alkyl substituted by an amino having optionally a lower alkyl substituent, or both combine together with the nitrogen atom to which they bond to form a 5- to 12-membered saturated, monocyclic, dicyclic or spirocyclic heterocyclic group which may be intervened with a nitrogen or oxygen atom, said heterocyclic group having optionally a substituent selected from a lower alkyl, a lower alkoxycarbonyl, a lower alkoxy- substituted lower alkyl, an amino having optionally a lower alkyl substituent, and a hydroxy-substituted lower alkyl), (iii) a lower alkoxycarbonyl, (iv) a hydroxy-substituted lower alkyl, (v) a pyridyl being optionally substituted by a lower alkyl having optionally a halogen substituent on the pyridine ring, (vi) a halogen-substituted lower alkyl, (vii) a lower alkoxy, (viii) a cycloalkyl, (ix) a hydroxy, (x) a tetrahydropyranyloxy-substituted lower alkyl, (xi) a pyrimidyl, (xii) a lower alkoxy-substituted lower alkyl, (xiii) a carboxyl, (xiv) a phenyl- lower alkoxy, (xv) a phenyl-lower alkyl having optionally a lower alkylene-

dioxy on the phenyl ring, (xvi) a lower alkanoyloxy, and (xvii) a piperidinyl having optionally a lower alkyl substituent on the piperidine ring;

R ^l4 is a hydroxy or a lower alkoxy; and

when m is 1 , the groups A and R ⁵ may combine to form a group of the formula:

(wherein R ⁶ is as defined above, and r is 0, 1 or 2), or when m is 2, two R ⁵ groups may combine to form a lower alkylenedioxy, a lower alkylene, or a group of the formula: -(CH ₂ ) ₂ -CONH-, or the groups R ⁵ and R ⁶ may combine to form a

group of the formula: -CO-CH(R ²⁸ )-CH(R ^28' )-W- (wherein R ² « and R28' are a

hydrogen atom or a carboxyl group, provided that both R ²⁸ and R ²⁸ are not

simultaneously a carboxyl group, and W is -N(R ^29a )- or . χ~ (wherein R ^29a is a hydrogen atom or a lower alkyl, R ^{2 b} is a lower alkyl, and X is a halogen atom)), or a salt thereof.

The thiazole derivatives of the formula (1) show inhibitory activity on protein kinase C (PKC, Ca ²⁺ /phospholipid-depending serine/threonine protein phosphatase), and are useful as a protein kinase C inhibitor.

It has been proved that PKC plays an important role in the regulation of various biological functions such as the metabolism regulation, the cell prolification, the cell differentiation, the release reaction of neurotransmitter,etc.

Therefore, it is indicated that a PKC inhibitor may be useful in the prophylaxis or treatment of various diseases caused by the hyperaction of the above- mentioned biological functions being participated by PKC.

More particularly, the protein kinase C inhibitors containing as an active ingredient the present thiazole derivative are useful as an agent for treatment of autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis, etc., various allergic diseases such as Crohn's disease, colitis ulcerosa, asthma, atopic dermatitis; an agent for protection of rejection in organ transplant, GVHD reaction, etc.; an agent for prophylaxis or treatment of various ischemic diseases in the organs such as heart, liver, kidney, brain, etc., acute pancreatitis, sepsis, multiple organs failure introduced by burn, ARDS, by inhibiting the production of cytokinin derived from T-cell such as IL- 2, or inflammatory cytokinin such as TNF-α.

Further, by other biological functions such as cell prolification, hormone secretion, regulation of metabolism, etc. which are concerned with PKC, the protein kinase C inhibitors of the present invention are useful in the prophylaxis or treatment of cancer, diabetes, Alzheimer disease, arteriosclerosis, HIV infection, nephritis, angiitis, etc.

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

The lower alkyl group includes a straight chain or branched chain C _r C ₆

alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, etc.

The lower alkoxy group includes a straight chain or branched chain C _r

Cg alkoxy group, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy,

tert-butoxy, pentyloxy, hexyloxy, etc.

The halogen atom is fluorine atom, chlorine atom, bromine atom or iodine atom. The lower alkanoyloxy-substituted lower alkyl group includes a straight chain or branched chain Cι-C ₆ alkyl group which is substituted by 1 or 2

straight chain or branched chain C ₂ -C ₆ alkanoyloxy groups, for example,

acetyloxymethyl, 2-propionyloxyethyl, 1-butyryloxyethyl, 3-acetyloxypropyl, 4-acetyloxybutyl, 4-isobutyryloxybutyl, 5-pentanoyloxypentyl, 6-acetyloxy- hexyl, 6-tert-butylcarbonyloxyhexyl, l,l-dimethyl-2-hexanoyloxyethyl, 2- methyl-3-acetyloxypropyl, diacetyloxymethyl, 1,3-diacetyloxypropyl, etc. The alkyl group having optionally a hydroxy substituent includes a straight chain or branched chain C C ₈ alkyl group which may optionally have

1 to 3 hydroxy substituents, for example, 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 ,1- dimethyl-2-hydroxyethyl, 1,3-dihydroxypropyl, 5,5,4-trihydroxypentyl, 5- hydroxypentyl, 6-hydroxyhexyl, 1-hydroxyisopropyl, 2-methyl-3-hydroxy- propyl, 7-hydroxyheptyl, 8-hydroxyoctyl, etc. The lower alkylene group includes a straight chain or branched chain C _j -

C ₆ alkylene group, for example, methylene, ethylene, trimethylene, 2-methyl-

trimethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene, pentamethylene, hexamethylene, etc.

The 5- to 7-membered saturated heterocyclic group which is formed by

combining R ⁷ and R ⁸ , or R ⁹ and R ¹⁰ together with the adjacent nitrogen atom with or without being intervening with another nitrogen atom or an oxygen atom, for example, pyrrolidinyl, piperidinyl, piperazinyl, morpholino, homo- piperazinyl, homomorpholino, etc. The lower alkyl group having optionally a hydroxy substituent includes, in addition to the above lower alkyl groups, a straight chain or branched chain C _r C ₆ alkyl group which may optionally have 1 to 3 hydroxy substituents, for

example, hydroxymethyl, 2-hydroxy ethyl, 1 -hydroxy ethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl, l,l-dimethyl-2-hydroxyethyl, 5,5,4- trihydroxypentyl, 5-hydroxy pentyl, 6-hydroxyhexyl, 1 -hydroxy isopropyl, 2- methyl-3-hydroxypropyl, etc.

The lower alkanoyl group includes a straight chain or branched chain C _\ -

C alkanoyl group, for example, formyl, acetyl, propionyl, butyryl, isobutyfyl,

pentanoyl, t-butylcarbonyl, hexanoyl, etc. The above heterocyclic group which is substituted by a group of the formula: -(A) _/ -NR ⁹ N ¹⁰ (A is a lower alkylene group, I is 0 or 1, R ⁹ an R ¹⁰ are the

same or different and each are a hydrogen atom or a lower alkyl group, or R ⁹

and R ⁱ ° combine together with the nitrogen atom to which they bond to form a 5- or 7-membered saturated heterocyclic group with or without being intervened with another nitrogen atom or an oxygen atom, and said hetero¬ cyclic group having optionally a lower alkyl substituent), a lower alkyl group having optionally a hydroxy substituent, a hydroxy group and a lower alkanoyl group includes the above mentioned heterocyclic groups having 1 to 3

sustituents selected from a group of the formula: -(A) _/ -NR ⁹ N ¹⁰ (A is a straight

chain or branched chain Cι-C ₆ alkylene group, I is 0 or 1, R ⁹ an Ri° are the same

or different and each are a hydrogen atom or a straight chain or branched chain C Cg alkyl group, or R ⁹ and R ¹⁰ combine together with the nitrogen atom to

which they bond to form a 5- or 7-membered saturated heterocyclic group with or without being intervened with another nitrogen atom or an oxygen atom, and said heterocyclic group having optionally 1 to 3 straight chain or branched chain Cι-C ₆ alkyl substituents), a straight chain or branched chain alkyl group

having optionally 1 to 3 hydroxy substituents, a hydroxy group and a straight chain or branched chain C _r C ₆ alkanoyl group, for example, 4-methyl-

piperazinyl, 2-(4-methyl- 1 -piperazinyl)methylmorpholino, 4-(4-methyl- 1 - piperazinyl)piperidinyl, 4-methylhomopiperazinyl, 4-(2-hydroxyethyl)- piperazinyl, 4-morpholinopiperidinyl, 2-[(l-pyrrolidinyl)methyl]morpholino, 4- hydroxypiperidinyl, 4-acetylpiperazinyl, 4-dimethylaminopiperidinyl, 4-(4- methyl- 1 -homopiperazinyl)piperidinyl, 4-(4,5-dimethyl- 1 -homopiperaziny 1)- piperidinyl, 4-(3-methyl-4-ethyl-l-piperazinyl)piperidnyl, 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, 3-ethylpyrrolidinyl, 2,3-dimethylpyrrolidinyl, 2,3,4-trimethylpyrrolidinyl, 2-propylmoφholino, 3-(l-pyrrolidinyl)pyrrolidinyl, 3- isopropylmoφholino, 2,3-dimethylmoφholino, 4-n-butylpiperidinyl, 3,4,5- trimethylpiperidinyl, 3-pentylpiperidinyl, 4-methylhomopiperazinyl, 4,5- dimethylhomopiperazinyl, 4-hexylhomopiperazinyl, 3-methyl-4-ethyl-

piperazinyl, 3-methyl-4-n-propyl-l -piperazinyl, 3,4-dimethylpiperazinyl, 4- isopropyl-3-methylpiperazinyl, 4-methyl-3-isopropylpiperazinyl, 4-methyl- homomoφholino, 3-propionylpyrrolidinyl, 4-butyrylpiperidinyl, 4-pentanoyl- piperazinyl, 3-hexanoylmoφholino, 4-acetylhomopiperazinyl, 3-hydroxy- moφholino, 4-hydroxyhomopiperazinyl, 4-hydroxy piperazinyl, 3-hydroxy- pyrrolidinyl, 3-hydroxymethylpyrrolidinyl, 3-(3-hydroxypropyl)moφholino, 2- hydroxymethylhomomoφholino, 2-(4-methyl- 1 -piperazinyl)methylhomo- moφholino, 4-(l,3-dihydroxy-2-propyl)piperazinyl, 4-ethylhomopiperazinyI, 3- (4-methyl-l-homopiperazinyl)pyrrolidinyl, 4-methyl-3-(l-piperidinyl)methyl- piperazinyl, 4-methyl-3-(4-methyl-l-homopiperazinyl)methylpiperazinyl, 4- methyl-3-(4-methyl- 1 -piperazinyl)methylpiperazinyl, etc.

The above heterocyclic group substituted by a lower alkyl group includes the above heterocyclic groups substituted by 1 to 3 straight chain or branched chain Cι-C ₆ alkyl groups, for example, 4-methylpiperazinyl, 3,4-

dimethylpiperazinyl, 3-ethylpyrrolidinyl, 2-propylpyrrolidinyl, 1-methyl- pyrrolidinyl, 3,4,5-trimethylpiperidinyl, 4-butylpiperidinyl, 3-pentylmoφholino, 4-ethylhomopiperazinyl, 4-methylhomopiperazinyl, 4-hexylpiperazinyl, 4- methylhomopiperazinyl, 4,5-dimethylhomopiperazinyl, 3-methyl-4-ethyl- piperazinyl, 3-methyl-4-n-propylpiperazinyl, 4-isopropyl-3-methylpiperazinyl, 4- methyl-3-isopropylpiperazinyl, 4-methylhomomoφholino, etc.

The lower alkoxycarbonyl-substituted lower alkyl group includes a straight chain or branched chain Cj-C ₆ alkyl group which is substituted by a

straight chain or branched chain alkoxycarbonyl group having 1 to 6 carbon atoms, for example, methoxycarbonylmethyl, 3-methoxycarbonylpropyl, ethoxy-

carbonylmethyl, 3-ethoxycarbonylpropyl, 4-ethoxycarbonylbutyl, 5-iso- propoxycarbonylpentyl, 6-propoxycarbonylhexyl, 1 , 1 -dimethyl-2-butoxy- carbonylethyl, 2-methyl-3-tert-butoxycarbonylpropyl, 2-pentyloxycarbonyl- ethyl, hexyloxycarbonylmethyl, etc. The lower alkanoyloxy-substituted lower alkyl group includes a straight chain or branched chain Cj-Cg alkyl group which is substituted by a straight

chain or branched chain C ₂ -C ₆ alkanoyloxy group, for example, acetyloxy-

methyl, 2-propionyloxy ethyl, 1-butyryloxyethyl, 3-acetyloxypropyl, 4-acetyl- oxybutyl, 4-isobutyryloxybutyl, 5-pentanoyloxypentyl, 6-acetyloxyhexyl, 6- tert-butylcarbonyloxyhexyl, l ,l-dimethyl-2-hexanoyloxyethyl, 2-methyl-3- acetyloxypropyl, etc.

The lower alkoxy group having optionally a halogen substituent includes a straight chain or branched chain Cj- alkoxy group which

optionally has 1 to 3 halogen substituents, for example, in addition to the above lower alkoxy groups, trifluoromethoxy, trichloromethoxy, chloromethoxy, bromomethoxy, fluoromethoxy, iodomethoxy, difluoromethoxy, dibromo- methoxy, 2-chloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, 3-chloro- propoxy, 2,3-dichloropropoxy, 4,4,4-trichlorobutoxy, 4-fluorobutoxy, 5-chloro- pentyloxy, 3-chloro-2-methylpropoxy, 6-bromohexyloxy, 5,6-dichlorohexyl- oxy, etc.

The halogen-substituted lower alkyl group includes a straight chain or branched chain Cι-C ₆ alkyl group, which has 1 to 3 halogen substituents, for

example, trifluoromethyl, trichloromethyl, chloromethyl, bromomethyl, fluoro- methyl, iodomethyl, difluoromethyl, dibromomethyl, 2-chloroethyl, 2,2,2-trifluoro-

ethyl, 2,2,2-trichloroethyl, 3-chloropropyl, 2,3-dichloropropyl, 4,4,4-trichloro- butyl, 4-fluorobutyl, 5-chloropentyl, 3-chloro-2-methylpropyl, 6-bromohexyl, 5,6-dichlorohexyl, etc.

The carboxy-substituted lower alkyl group includes a carboxyalkyl group wherein the alkyl moiety is a straight chain or branched chain C _r C ₆ alkyl

group, for example, carboxymethyl, 2-carboxy ethyl, 1-carboxyethyl, 3-carboxy- propyl, 4-carboxybutyl, 5-carboxypentyl, 6-carboxyhexyl, l ,l-dimethyl-2- carboxyethyl, 2-methyl-3-carboxypropyl, etc.

The lower alkoxycarbonyl group includes a straight chain or branched chain alkoxycarbonyl group having 1 to 6 carbon atoms in the alkoxy moiety, for example, methoxycarbonyl, ethoxycarbonyl, propoxy carbonyl, isopropoxy- carbonyl, butoxy carbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxy- carbonyl, etc.

The aminocarbonyl-substituted lower alkoxy group having optionally a lower alkyl group includes a straight chain or branched chain Cj- alkoxy

group, which has an aminocarbonyl group having optionally 1 to 2 straight chain or branched chain Cι-C ₆ alkyl group, for example, aminocarbonyl-

methoxy, 2-aminocarbonylethoxy, 1-aminocarbonylethoxy, 3-aminocarbonyl- propoxy, 4-aminocarbonylbutoxy, 5-aminocarbonylpentyloxy, 6-amino- carbonylhexyloxy, l,l-dimethyl-2-aminocarbonylethoxy, 2-methyl-3-amino- carbonylpropoxy, methylaminocarbonylmethoxy, 1-ethylaminocarbonylethoxy, 2-propylaminocarbonylethoxy , 1 -ethylaminocarbonylethoxy , 2-propylamino- carbonylethoxy, 3-isopropylaminocarbonylpropoxy, 4-butylaminocarbonyl- butoxy, 5-pentylaminocarbonylpentyloxy, 6-hexylaminocarbonylhexyloxy,

dimethylaminocarbonylmethoxy, 2-diethylaminocarbonylethoxy, 2-dimethyl- aminocarbonylethoxy, (N-ethyl-N-propylamino)carbonylmethoxy, 2-(N-methyl- N-hexylamino)carbonylethoxy, etc.

The amino-substituted lower alkyl group having optionally a lower alkyl substituent includes a straight chain or branched chain Cj-C ₆ alkyl group which

is substituted by an amino group having optionally 1 to 2 Cι-C ₆ alkyl

substituents, for example, aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-amino- propyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl, l ,l-dimethyl-2-aminoethyl, 2-methyl-3-aminopropyl, methylaminomethyl, 1-ethylaminoethyl, 2-propylamino- ethyl, 3-isopropylaminopropyl, 4-butylaminobutyl 5-pentylaminopentyl, 6-hexyl- aminohexyl, dimethylaminomethyl, (N-ethyl-N-propylamino)methyl, 2-(N- methyl-N-hexylamino)ethyl, etc.

The 5- to 12-membered saturated heteromonocyclic, heterobicyclic or heterospirocyclic group which is formed by combining R ¹² and R ¹³ together with the adjacent nitrogen atom to which they bond with or without being intervened with another nitrogen atom or an oxygen atom includes, for example, pyrrolidinyl, piperidinyl, piperazinyl, moφholino, homopiperazinyl, homo- moφholino, l,4-diazabicyclo[4.3.0]nonyl, l ,4-diazabicyclo[4.4.0]decyl, 1,4- diazaspiro[5.5]undecyl, etc. The lower alkoxy-substituted lower alkyl group includes a straight chain or branched chain C _r C ₆ alkyl group which has 1 to 3 straight chain or

branched chain Cι-C ₆ alkoxy groups, for example, methoxymethyl 3-methoxy-

propyl, ethoxymethyl, 2-methoxyethyl, 3-ethoxypropyl, 4-ethoxybutyl, 5- isopropoxypentyl, 6-propoxyhexyl, l ,l-dimethyl-2-butoxyethyl, 2-methyl-3-

tert-butoxypropyl, 2-pentyloxy ethyl, hexyloxymethyl, etc.

The amino group having optionally a lower alkyl substituent includes an amino group having optionally 1 to 2 straight chain or branched chain Cι-C ₆

alkyl groups, for example, amino, methylamino, ethylamino, propylamino, isopropylamino, butylamino, tert-butylamino, pentylamino, hexylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, dipentylamino, dihexylamino, N-methyl-N-ethylamino, N-ethyl-N-propylamino, N-methyl-N- butylamino, N-methyl-N-hexylamino, etc.

The above heterocyclic group having a substituent selected from a lower alkyl group, a lower alkoxy-substituted lower alkyl group, a lower alkoxy¬ carbonyl group, an amino group having optionally a lower alkyl substituent and a hydroxy-substituted lower alkyl group includes the above mentioned hetero¬ cyclic groups having 1 to 3 substituents selected from a straight chain or branched chain C _j -C ₆ alkyl group, a straight chain or branched chain C _r C ₆

alkyl group which has 1 to 3 straight chain or branched chain C _r C ₆ alkoxy

group, a straight chain or branched chain alkoxycarbonyl group having 1 to 6 carbon atoms in the alkoxy moiety, an amino group having optionally 1 to 2 straight chain or branched chain Ci-Cg alkyl groups and a straight chain or

branched chain Cι-C ₆ alkyl group which has 1 to 3 hydroxy substituents, for

example, 4-methylpiperazinyl, 3,4-dimethylpiperazinyl, 4-ethylpiperazinyl, 4- methylhomopiperazinyl, 4-dimethylaminopiperidinyl, 4-tert-butoxycarbonyl- homopiperazinyl, 4-n-butylhomopiperazinyl, 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,

3,3,4-trimethylpiperazinyl, 4,5-dimethylhomopiperazinyl, 3-methyl-4-ethyl- piperazinyl, 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-l,4-diazasprio[5.5]undecyl, 3-amino- 1 ,4-diazabicyclo[4.4.0]decyl, 5-hydroxymethyl-l,4-diazabicyclo[4.3.0]nonyl, 3- ethoxycarbonylhomomoφholino, 3-diethylaminomoφholino, 3-methoxy- methylpyrrolidinyl, etc.

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

The pyridyl group having optionally a lower alkyl substituent which may optionally have a halogen substituent on the pyridine ring includes a pyridyl group having 1 to 3 straight chain or branched chain C]-C ₆ alkyl groups which

may optionally 1 to 3 halogen substituents on the pyridine ring, for example, 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, etc.

The cycloalkyl group includes a C ₃ -C ₈ cycloalkyl group, for example,

cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.

The tetrahydropyranyloxy-substituted lower alkyl group includes a tetrahydropyranyloxy-substituted alkyl group wherein the alkyl moiety is a

straight chain or branched chain Cj-C ₆ alkyl group, for example, (2-tetrahydro-

pyranyl)oxymethyl, 2-(3-tetrahydropyranyl)oxyethyl, l-(4-tetrahydropyranyl)- oxyethyl, 3-(2-tetrahydropyranyl)oxypropyl, 4-(3-tetrahydropyranyl)oxybutyl, 5-(4-tetrahydropyranyl)oxypentyl, 6-(2-tetrahydropyranyl)oxyhexyl, 1,1- dimethyl-2-(3-tetrahydropyranyl)oxyethyl, 2-methyl-3-(4-tetrahydropyranyl)- oxypropyl, etc.

The phenyl-lower alkyl group includes a phenylalkyl group wherein the alkyl moiety is a straight chain or branched chain Cj-Cg alkyl group, for

example, benzyl, 2-phenylethyl, 1 -pheny lethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl, l,l-dimethyl-2-:phenylethyl, 2-methyl-3-phenyl- propyl, etc.

The phenyl-lower alkoxy group includes a phenylalkoxy group wherein the alkoxy moiety is a straight chain or branched chain Cι -C ₆ alkoxy group, for

example, benzyloxy, 2-phenylethoxy, 1-phenylethoxy, 3-phenylpropoxy, 4- pheny Ibutoxy, 5-phenylpentyloxy, 6-phenylhexyloxy, l ,l-dimethyl-2-phenyl- ethoxy, 2-methyl-3-phenylpropoxy, etc.

The lower alkanoyloxy group includes a straight chain or branched chain Cι-C ₆ alkanoyloxy group, for example, formyloxy, acetyloxy, propionyloxy,

butyryloxy, isobutyryloxy, pentanoyloxy, tert-butylcarbonyloxy, hexanoyloxy, etc.

The piperidinyl group having optionally a lower alkyl substituent on the piperidine ring includes a piperidinyl group having optionally a straight chain or branched chain Cι-C ₆ alkyl group, for example, piperidinyl, l-methyl-4-

piperidinyl, l-ethyl-3-piperidinyl, l-ethyl-2-piperidinyl, l-propyl-4-piperidinyl, 1-

butyl-4-piperidinyl, l-pentyl-4-piperidinyl, l-hexyl-4-piperidinyl, l-isobutyl-3- piperidinyl, l-tert-butyl-2-piperidinyl, etc.

The phenyl-lower alkyl group having optionally a lower alkylenedioxy substituent on the phenyl ring includes a phenylalkyl group having optionally a straight chain or branched chain Cj-C ₄ alkylenedioxy group on the phenyl ring

wherein the alkyl moiety is a straight chain or branched chain C _j -Cg alkyl

group, in addition to the above phenyl-lower alkyl groups, for example, 3,4- methylenedioxybenzyl, 2-(3,4-ethylenedioxyphenyl)ethyl, 1 -(3,4-ethylene- dioxyphenyl)ethyl, 3-(2,3-trimethylenedioxyphenyl)propyl, 4-(3,4-tetra- methylenedioxyphenyl)butyl, 5-(3,4-methylenedioxyphenyl)pentyl, 6-(2,3- trimethylenedioxyphenyl)hexyl, etc.

The lower alkylenedioxy group includes a straight chain or branched chain Cj-C alkylenedioxy group, for example, methylenedioxy, ethylenedioxy,

trimethylenedioxy, tetramethylenedioxy, etc. The 5- to 10-membered, saturated or unsaturated heteromonocyclic or heterobi cyclic residue having 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom includes, for example, pyrrolidinyl, piperidinyl, piperazinyl, moφholino, 1-azabicyclooctyl, homopiperazinyl, homo- moφholino, l,4-diazabicyclo[4.3.0]nonyl, l,4-diazabicyclo[4.4.0]decyl, pyridyl, 1,2,5,6-tetrahydropyridyl, thienyl, 1,2,4-triazolyl, 1,2,3,4-tetrazolyl, 1,3,4-triazoly, quinolyl, 1,4-dihydroquinolyl, benzothiazolyl, pyrazyl, pyrimidyl, pyridazinyl, pyrrolyl, pyrrolinyl, carbostyril, 1 ,3-dioxolanyl, thiomoφholino, 3,4-dihydro- carbostyril, 1,2,3,4-tetrahydroquinolyl, 2,3,4,5-tetrahydrofuryl, indolyl, isoindolyl, 3H-indolyl, indolinyl, indolidinyl, indazolyl, benzimidazolyl, benzoxazolyl,

imidazolinyl, imidazolidinyl, isoquinolyl, naphthylidinyl, quinazolidinyl, quinoxalinyl, cinnolinyl, phthalazinyl, chromanyl, isoindolinyl, isochromanyl, pyrazolyl, 1 ,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, thienyl, imidazolyl, pyrazolidinyl, benzofuryl, 2,3-dihydrobenzo[b]furyl, benzothienyl, tetrahydropyranyl, 4H- chromenyl, IH-indazolyl, 2-imidazolinyl, 2-pyrrolinyl, furyl, oxazolyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, pyranyl, pyrazolidinyl, 2-pyrazolinyl, quinuclidinyl, 1 ,4-benzoxazinyl, 3,4-dihydro-2H-l,4-benzoxazinyl, 3,4-dihydro- 2H-l,4-benzothiazinyl, 1,4-benzothiazinyl, 1,2,3,4-tetrahydroisoquinolyl, 1,2,3,4- tetrahydroquinoxalinyl, l,3-dithia-2,4-dihydronaphthalenyl, 1 ,4-dithia- naphthalenyl, 2,5-dihydrofurano[3.4-c]pyridyl, 2,3,4,5,6,7-hexahydro-lH- azepinyl, 1,2,3,4,5,6,7,8-octahydroazocinyl, 1,2,3,4,5,6,-tetrahydrooxepinyl, 1,3- dioxolanyl, 3,4,5,6-tetrahydro-2H-pyranyl, 5,6-dihydro-2H-pyranyl, etc.

The above heterocyclic groups having 1 to 3 substituents selected from (i) a lower alkyl group; (ii) a group: -(B)^-NR12R1 ³ (£ i _s the same as defined

above, B is a group: -CO-A- (A is the same as defined above), a carbonyl group or a lower alkylene group, R ¹² and R ¹³ are the same or different, and each are a hydrogen atom, a lower alkyl group, an amino-substituted lower alkyl group having optionally a lower alkyl substituent, or combine together with the adjacent nitrogen atom to which they bond to form a 5- to 12-membered saturated heteromonocyclic, heterobicyclic or spiro-cyclic hetero ring with or without being intervened with another nitrogen atom or an oxygen atom, said heterocyclic group may optionally have a substituent selected from a lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxy-substituted lower alkyl group, an amino group having optionally a lower alkyl substituent and a

hydroxy-substituted lower alkyl group); (iii) a lower alkoxycarbonyl group; (iv) a hydroxy-substituted lower alkyl group; (v) a pyridyl group being optionally substituted by a lower alkyl group having optionally a halogen substituent on the pyridine ring; (vi) a halogen-substituted lower alkyl group; (vii) a lower alkoxy group; (viii) a cycloalkyl group; (ix) a hydroxy group; (x) a tetrahydro- pyranyloxy-substituted lower alkyl group; (xi) a pyrimidyl group; (xii) a lower alkoxy-substituted lower alkyl group; (xiii) a carboxyl group; (xiv) a phenyl- lower alkoxy group; (xv) a phenyl-lower alkyl group having optionally a lower alkylenedioxy substituent on the phenyl ring; (xvi) a lower alkanoyloxy group; and (xvii) a piperidinyl group having optionally a lower alkyl substituent on the piperidine ring includes the above heterocyclic groups having 1 to 3 substituents selected from (i) a straight chain or branched chain Ci-Cg alkyl

group; (ii) a group: -(B) -NR ¹² R ^]3 (£ is the same as defined above, B is a group:

-CO-A- (A is the same as defined above), a carbonyl group or a straight chain or branched chain _\ -C^ alkylene group, R ² and R ⁱ³ are the same or different,

and each are a hydrogen atom, a straight chain or branched chain C _r C ₆ alkyl

group, or a straight chain or branched chain Cj-C ₆ alkyl group which has an

amino group having optionally 1 to 2 straight chain or branched chain alkyl substituents, or both combine together with the adjacent nitrogen atom to which they bond to form a 5- to 12-membered saturated heteromonocyclic, heterobicyclic or sprio-cyclic hetero ring with or without being intervened with another nitrogen atom or an oxygen atom, said heterocyclic group may optionally have 1 to 3 substituents selected from a straight chain or branched chain C Ce alkyl group, a straight chain or branched chain C _\ -C ₆ alkyl group

which has 1 to 3 straight chain or branched chain C _r C ₆ alkoxy substituents, a

straight chain or branched chain alkoxycarbonyl group having 1 to 6 carbon atoms in the alkoxy moiety, an amino group having optionally 1 to 2 straight chain or branched chain Cj- alkyl substituent and a straight chain or

branched chain Cj-Cg alkyl group having 1 to 3 hydroxy substituents); (iii) an

alkoxycarbonyl group having 1 to 6 carbon atoms in the alkoxy moiety; (iv) a straight chain or branched chain Cj-Cg alkyl group having 1 to 3 hydroxy

substituents; (v) a pyridyl group having optionally 1 to 3 straight chain or branched chain C _r C ₆ alkyl groups which have optionally 1 to 3 halogen

substituents on the pyridine ring; (vi) a straight chain or branched chain Cι-C ₆

alkyl group having 1 to 3 halogen substituents; (vii) a straight chain or branched chain Cj-Cg alkoxy group; (viii) a C ₃ -C ₈ cycloalkyl group; (ix) a

hydroxy group; (x) a tetrahydropyranyloxy-substituted alkyl group wherein the alkyl moiety is a straight chain or branched chain C _r C ₆ alkyl group; (xi) a

pyrimidyl group; (xii) a straight chain or branched chain Cι-C ₆ alkyl group

having 1 to 3 straight chain or branched chain C _r C ₆ alkoxy substituents; (xiii)

a carboxyl group; (xiv) a phenyl alkoxy group wherein the alkoxy moiety is a straight chain or branched chain Cj-Cg alkoxy group; (xv) a phenylalkyl group

having optionally a straight chain or branched chain C ₁ -C ₄ alkylenedioxy

substituent on the phenyl ring, wherein the alkyl moiety is a straight chain or branched chain Cj-Cg alkyl group; (xvi) a straight chain or branched chain C _r

C ₆ alkanoyloxy group; and (xvii) a piperidinyl group having optionally 1 to 3

straight chain or branched chain C]-C ₆ alkyl substituents on the piperidine ring,

for example, 4-methylpiperazinyl, 4-(4-methyl-l-piperazinyl)piperidinyl, 2-(4- methyl- 1 -piperazinylmethyl)moφholino, 2-(4-methyl- 1 -piperazinylmethyl)- pyrrolidinyl, 3-(4-methyl-l-piperazinyl)pyrrolidinyl, 1 -ethyl- 1,2,3,4-tetrazolyl, 1- tert-butoxycarbonylpiperidinyl, 1-methylpiperidinyl, 2,2-dimethyl-l,3- dioxolanyl, 4-(3,4-dimethyl-l-piperazinyl)piperidinyl, 4-(4-ethyl-l-piperazinyl)- piperidinyl, 4-[N-(2-diethylaminoethyl)-N-methylamino]piperidinyl, 4-(4-methyl- 1 -homopiperazinyl)piperidinyl, 2-(4-ethyl- 1 -piperazinylmethyl)moφholino, 4- dimethylaminopiperidinyl, 2-moφholinomethylpyrrolidinyl, 4-(l-pyrrolidinyl)- piperdinyl, 4-isopentylpiperazinyl, 4-(2-hydroxyethyl)piperazinyl, 2-(l- pyrrolidinylmethyl)moφholino, 4-moφholinopiperidinyl, 2-aminomethyl- moφhlino, 1-dimethylaminomethylcarbonylpiperidinyl, 1 -methylimidazolyl, 4-(2- pyridyl)piperazinyl, 4-(3,4-methylenedioxybenzyl)piperazinyl, l-(4-chloro- butyl)- 1,2,3,4-tetrazolyl, 2-methoxycarbonylpyridyl, 2-carboxypyridyl, 4- isopropylpyridyl, 4-hydroxypiperidinyl, 2-methyl-3-hydroxy-2,5-dihydrofuran- [3,4-c]pyridyl, 1 -cyclohexyl-1 ,2,34-tetrazolyl, 3-(4-methyl- 1 -piperazinyl)- pyrrolidinyl, l-[(3-3,4,5,6-tetrahydro-2H-pyranyl)methyl]-l,2,3,4-tetrazol yl, l-(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-l-piperazinyl)homomoφholino, 2-methyl- moφholino, 2-methoxymethylmoφholino, 2-chloromethylmoφholino, 2- hydroxymethylmoφholino, 2-n-butoxymethylmoφholino, 2-(4-methyl-l - homopiperazinylmethyl)moφholino, 6,7-dimethoxy-l,2,3,4-tetrahydro- isoquinolyl, 2-(4-methyl- 1 -homopiperazinylmethyl)homomoφholino, 2- chloromethylhomomoφholino, 2-hydroxymethylhomomoφholino, 4-hydroxy-

piperazinyl, 2-methoxymethyl-l ,2,3,4,5,6-hexahydrooxepinyl, 4-(2-phenyl- ethoxy)piperidinyl, 4-benzyloxypiperidinyl, 4-hydroxy-3- methylpiperazinyl, 4- methylhomopiperazinyl, 4-acetyloxypiperazinyl, 4-methoxypiperazinyl, 4-(4- tert-butoxycarbonyl-l-homopiperazinyl)piperidnyl, 4-(4-n-butyl-l-homo- piperazinyl)piperidinyl, 4-(l-methyl-4-piperidinyl)homopiperazinyl, 3-(4-methyl- 1 -homopiperazinyl)piperidinyl, 2-(4-dimethylamino-l -piperidinylmethyl)- moφholino, 2-(4-methyl- 1 -piperazinylmethyl)homomoφholino, 2- [4-(2- hydroxyethyl)- 1 -piperazinylmethyl]moφholino, 4-(3-methyl- 1 -piperazinyl)- piperidinyl, 4-(4-ethyl-l-homopiperazinyl)piperidinyl, 3-(4-methyl-l-homo- piperazinyl)py rrolidiny 1 , 4- [4-( 1 ,3-dihydroxy-2-propyl)- 1 -piperazinyl] - piperidinyl, 4-[4-(l,3-dihydoxy-2-propyl)-l-homopiperazinyl]piperidnyl, 4- methyl-3-(l-piperidinylmethyl)piperazinyl, 4-methyl-3-(4-methyl-l-piperazinyl- methyl)piperazinyl, 4-methyl-3-(4-methyl-l-homopiperazinylmethyl)piperazinyl, 3,4,5-trimethoxypiperazinyl, 4-isopropylpiperazinyl, 4-(l ,4-diazabicyclo[4.3.0]- nony piperidinyl, (3,3,4-trimethyl-l-piperazinyl)piperidinyl, 4-(l,4-diazabicyclo- [4.4.0]decyl)piperidinyl, 4-(3-methyl-4-ethyl-l-piperazinyl)piperidinyl, 4-(3- methyl-4-propyl-l-piperazinyl)piperidinyl, 4-(3-propyl-4-methyl-l-piperazinyl)- piperidinyl, 4-(3-methyl-4-isopropyl-l -piperazinyl)piperidinyl, 4-(3-ethyl-4- methyl-l-piperazinyl)piperidinyl, 4-[3-methyl-4-(2-methoxyethyl)-l-piperazinyl]- piperidinyl, 4-[3-methyl-4-(2-hydroxyethyl)-l-piperazinyl]piperidinyl, 4-(4- methyl-l-l,4-diazaspiro[5.5]undecyl)piperidinyl, 4-(4-methyl-3-isopropyl-l- piperazinyl)piperidinyl, 4-(2-pyrimidyl)piperazinyl, etc.

The lower alkenyloxy group includes a ₂ - straight chain or branched

chain alkenyloxy group, for example, vinyloxy, 1-methylvinyloxy, 2,2-dimethyl- vinyloxy, 1 ,2-dimethylvinyloxy, 1-propylvinyloxy, allyloxy, 2-butenyloxy, 3-

butenyloxy, 1-ethylvinyloxy, 1-methylallyloxyl, 1-pentenyloxy, 2-pentenyloxy, 2-hexenyloxy, 3-methyl-l -butenyloxy, 1 -butenyloxy, etc.

The cycloalkyloxy group includes a C ₃ -C ₈ cycloalkyloxy group, for

example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy, etc.

The lower alkylthio group includes a Cι-C ₆ straight chain or branched

chain alkylthio group, for example, methylthio, ethylthio, propylthio, isopropyl- thio, butylthio, isobutylthio, tert-butylthio, pentylthio, hexylthio, etc.

The lower alkenyl group includes a C ₂ -C ₆ straight chain or branched

chain alkenyl group, for example, vinyl, 1 -methyl vintyl, 2,2-dimethyl vinyl, 1,2- dimethylvinyl, 1-propenylvinyl, allyl, 2-butenyl, 3-butenyl, 1-ethylvinyl, 1-methyl- allyl, 1-pentenyl, 2-pentenyl, 2-hexenyl, 3-methyl-l -butenyl, 1-butenyl, etc. The present invention specifically includes the following compounds.

(1) A thiazole derivative of the formula (1) wherein R ^l and R ² are the

same or different and each are a hydrogen atom or a lower alkyl group, R ³ is a

group of the formula: (R ^{l lb} , p and RH ^a are the same as defined in the formula (1)), R ⁴ is a hydrogen atom, and u is 0, or a salt thereof.

(2) A thiazole derivative of the formula (1) wherein Rl and R ² are the

same or different and each are a hydrogen atom or a lower alkyl group, R ³ is a

group of t (R ^{l lb} , p and R ^{i J} are the same as defined in the formula (1)), R ⁴ is a lower alkanoyloxy-lower alkyl group,

and u is 0, or a salt thereof.

(3) A thiazole derivative of the formula (1) wherein R ¹ and R ² are the

same or different and each are a hydrogen atom or a lower alkyl group, R ³ is a

_/ CO-CH=CR ^{l lb} -(CO)p-R ^{l la} _{/τ 1 1} , group of the formula: r ^~~ χ ^v (R ^{l l} , p and R ^{] ]a} are the

same as defined in the formula (1)), R ⁴ is a hydrogen atom, and u is 1, or a salt thereof.

(4) A thiazole derivative of the formula (1) wherein R ^l and R ² are the

same or different and each are a hydrogen atom or a lower alkyl group, R ³ is a

, , , , ^lb -(CO)p-R ^{l la} _m . .. , „ „ group of the formula: ( ^R ♦ P ^{and R are} the same as defined in the formula (1)), R ⁴ is a lower alkanoyloxy-lower alkyl group, and u is 1 , or a salt thereof.

(5) A thiazole derivative of the formula (1) wherein R ^l and R ²

combine to form a group: -(CH ₂ ) _n - (n is 4), R ³ is a group of the formula:

( fRR ^l l ^lb , p and R ^{1 la} are the same as defined in the formula (1)), R ⁴ is a hydrogen atom, and u is 0, or a salt thereof.

(6) A thiazole derivative of the formula (1) wherein Rl and R ²

combine to form a group: -(CH ₂ ) _n - (n is 4), R ³ is a group of the formula:

, p and R ^{l la} are the same as defined in the formula (1)), R ⁴ is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof.

(7) A thiazole derivative of the formula (1) wherein R ^l and R ²

combine to form a group: -(CH ₂ ) _n - (n is 4), R ³ is a group of the formula:

_{/rι l l} , _{J n 1} , , , ,. , . (R ^πb , p and R ^{1 la} are the same as defined in the formula (1)), R ⁴ is a hydrogen atom, and u is 1, or a salt thereof.

(8) A thiazole derivative of the formula (1) wherein R ¹ and R ²

combine to form a group: -(CH ₂ ) _n - (n is 4), R ³ is a group of the formula:

in the formula (1)), R ⁴ is a lower alkanoyloxy-lower alkyl group and u is 1, or a salt thereof. (9) A thiazole derivative of the formula (1) wherein R ^l and R ²

combine to form a group: -(CH ₂ ) _n - (n is 5), R ³ is a group of the formula:

n the formula (1)), R ⁴ is a hydrogen atom, and u is 0, or a salt thereof.

(10) A thiazole derivative of the formula (1) wherein R ^l and R ²

combine to form a group: -(CH ₂ ) _n - (n is 5), R ³ is a group of the formula:

^lb -(CO)p-R ^{l la} _{m t t} . _{Λ n Λ} . , , „. , (R ¹ ' ^b , p and R ^{1 la} are the same as defined in the formula (1)), R ⁴ is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof.

(11) A thiazole derivative of the formula (1) wherein R ^l and R ²

combine to form a group: -(CH2) _n - (n is 5), R ³ is a group of the formula:

the formula (1)), R ⁴ is a hydrogen atom, and u is 1, or a salt thereof.

(12) A thiazole derivative of the formula (1) wherein R ^l and R ²

combine to form a group: -(CH ₂ ) _n - (n is 5), R ³ is a group of the formula:

_/ CO-CH=CR ^llb -(CO) _p -R ^{l la} „, , .. , „ , , , , „. , .

/ ^~~~ >C (R ^{l I} , p and R ^{1 la} are the same as defined in

the formula (1)), R ⁴ is a lower alkanoyloxy-lower alkyl group and u is 1, or a salt thereof.

(13) A thiazole derivative of the formula (1) wherein R ¹ and R ² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R ³ is a

, . _{e ι} ^lb -(CO) _p -R ^{l la} ... _{Λ n Λ Λ} group of the formula: (R ^llb » P and R ^{1 ia} are the same as defined in the formula (1)), R ⁴ is a hydrogen atom, and u is 0, or a salt thereof.

(14) A thiazole derivative of the formula (1) wherein R ^l and R ² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom.R ³ is a

group of the formula: (R ^{l lb} , p and RH ^a are

the same as defined in the formula (1)), R ⁴ is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof.

(15) A thiazole derivative of the formula (1) wherein Rl and R ² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R ³ is a

group o , p and R ^la are the same as defined in the formula (1)), R ⁴ is a hydrogen atom, and u is 1, or a salt thereof. (16) A thiazole derivative of the formula (1) wherein R ¹ and R ² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R ³ is a

group of the formula: (R ^{l lb} , p and Ri ^l are the same as defined in the formula (1)), R ⁴ is a lower alkanoyloxy-lower alkyl group and u is 1, or a salt thereof.

(17) A thiazole derivative of the formula (1) wherein Rl and R ² are the

same or different and each are a hydrogen atom or a lower alkyl group, R ³ is a

group of the formula: (s is 0, R ⁶ is a group: -CO-CH=CR ^{i ib} -(CO) _p -R ^{i ia} (R ^] ι ^b , p and R ^{1 la} are the same as defined in the

formula (1)), R ⁵ , m, A and Z are the same as defined in the formula (1)), R ⁴ is a

hydrogen atom, and u is 0, or a salt thereof.

(18) A thiazole derivative of the formula (1) wherein R ^l and R ² are the

same or different and each are a hydrogen atom or a lower alkyl group, R ³ is a

group of the formula: ( ^{s 1S} 0» ^{R6 ls a} g ^rou P ^:

-CO-CH=CR ^Hb -(CO) _p -R ^{l la} (R ^Ub , p and R ^Ha are the same as defined in the

formula (1)), R ⁵ , m, A and Z are the same as defined in the formula (1)), R ⁴ is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof.

(19) A thiazole derivative of the formula (1) wherein R and R ² are the

same or different and each are a hydrogen atom or a lower alkyl group, R ³ is a

group of the formula: * ^{s a} S ^rou P ^:

-CO-CH=CRl ^ib -(CO) _p -R ^{l la} (R ^{l lb} , p and R ^{] la} are the same as defined in the

formula (1)), R ⁵ , m, A and Z are the same as defined in the formula (1)), R ⁴ is a hydrogen atom, and u is 1 , or a salt thereof.

(20) A thiazole derivative of the formula (1) wherein R ^] and R ² are the

same or different and each are a hydrogen atom or a lower alkyl group, R ³ is a

group of the formula: ( ^s * ^s 0» ^R6 * ^{s a} group:

-CO-CH=CR ⁱ -(CO) _p -R ^{l la} (R ^{l lb} , p and R ^l ' ^a are the same as defined in the

formula (1)), R ⁵ , m, A and Z are the same as defined in the formula (1)), R ⁴ is a lower alkanoyloxy-lower alkyl group and u is 1, or a salt thereof. (21) A thiazole derivative of the formula (1) wherein R ^l and R ²

combine to form a group: -(CH2) _n - (n is 4), R ³ is a group of the formula:

(s is 0, R ⁶ is a group: -CO-CH=CR ^{l l} -(CO) _D -R l

(R ^{l lb} , p and R ^{1 Ja} are the same as defined in the formula (1)), R ⁵ , m, A and Z are

the same as defined in the formula (1)), R ⁴ is a hydrogen atom, and u is 0, or a salt thereof.

(22) A thiazole derivative of the formula (1) wherein R ^l and R ²

combine to form a group: -(CH2) _n - (n is 4), R ³ is a group of the formula:

ⁱ -(CO) _p -R ^{l la}

(R ^{l lb} , p and R ^Ha are the same as defined in the formula (1)), R ⁵ , m, A and Z are

the same as defined in the formula (1)), R ⁴ is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof.

(23) A thiazole derivative of the formula (1) wherein R and R ²

combine to form a group: -(CH2) _n - (n is 4), R ³ is a group of the formula:

ⁱ t>-(CO) -R ^{l ia} (R ^llb , p and R ^{l la} are the same as defined in the formula (1)), R ⁵ , m, A and Z are

the same as defined in the formula (1)), R ⁴ is a hydrogen atom, and u is 1, or a salt thereof.

(24) A thiazole derivative of the formula (1) wherein R ^l and R ²

combine to form a group: -(CH ₂ ) _n - (n is 4), R ³ is a group of the formula:

33

group of the formula: (s is 0, R ⁶ is a group: (R ^nb , p and R" ^a are the same as defined in the

formula (1)), R ⁵ , m, A and Z are the same as defined in the formula (1)), R ⁴ is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof.

(31) A thiazole derivative of the formula (1 ) wherein R ¹ and R ² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R ³ is a

group of the formula: (s is 0, R ⁶ is a group: -CO-CH=CR ^{! lb} -(CO) _p -R ^{1 la} (R ^{1 lb} , p and R ^{1 la} are the same as defined in the

formula (1)), R ⁵ , m, A and Z are the same as defined in the formula (1)), R ⁴ is a hydrogen atom, and u is 1 , or a salt thereof.

(32) A thiazole derivative of the formula (1) wherein R ^l and R ² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R ³ is a

group of the formula: (s is 0, R ⁶ is a group:

-CO-CH=CR ^{i lb} -(CO) _p -R ^{l la} (R ^{l lb} , p and RH ^a are the same as defined in the

formula (1)), R ⁵ , m, A and Z are the same as defined in the formula (1)), R ⁴ is a lower alkanoyloxy-lower alkyl group and u is 1, or a salt thereof.

34

(33) A thiazole derivative of the formula (1) wherein R ^l and R ² are the

same or different, and each are a hyrogen atom or a lower alkyl group, R ³ is a

group of the formula: (s is 1, Z is an oxygen atom, R ⁶ is a group: -CO-CH=CR ^{1 lb} -(CO) _p -R ^{i la} (R ^πb , p and R ^Ha are the same as defined

in the formula (1)), R ⁵ , m and A are the same as defined in me formula (1)), R ⁴ is a hydrogen atom, and u is 0, or a salt thereof.

(34) A thiazole derivative of the formula (1) wherein R ¹ and R ² are the

same or different, and each are a hyrogen atom or a lower alkyl group, R ³ is a

group of the formula: ( ^{s s} 1» Z is an oxygen atom, R ⁶ is a group: -CO-CH=CR ^{l lb} -(CO) _p -R ^{1 la} (R ^{l lb} , p and R^ are the same as defined

in the formula (1)), R ⁵ , m and A are the same as defined in the formula (1)), R ⁴ is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof.

(35) A thiazole derivative of the formula (1) wherein R ^l and R ² are the

same or different, and each are a hydrogen atom or a lower alkyl group, R ³ is a

group of the formula: (s is 1 , Z is an oxygen atom, R ⁶ is a group: -CO-CH=CR ⁱ ι -(CO) _p -R ^na (R ^{l lb} , p and R ^]a are the same as defined

in the formula (1)), R ⁵ , m and A are the same as defined in the formula (1)), R ⁴ is a hydrogen atom, and u is 1, or a salt thereof.

(36) A thiazole derivative of the formula (1) wherein R ¹ and R ² are the

same or different, and each are a hydrogen atom or a lower alkyl group, R ³ is a

31

(Rl ^lb , p and R ^{l ]a} are the same as defined in the formula (1)), R ⁵ , m, A and Z are

the same as defined in the formula (1)), R ⁴ is a lower alkanoyloxy-lower alkyl group and u is 1, or a salt thereof. (25) A thiazole derivative of the formula (1) wherein R ¹ and R ²

combine to form a group: -(CH ₂ ) _n - (n is 5), R ³ is a group of the formula:

_ lζ ^m (s is 0, R ⁶ is a group: -CO-CH=CR ^{i i} -(CO) _p -R ^Ha

(R lb, p and R ^{l la} are the same as defined in the formula (1)), R ⁵ , m, A and Z are

the same as defined in the formula (1)), R ⁴ is a hydrogen atom, and u is 0, or a salt thereof.

(26) A thiazole derivative of the formula (1) wherein R ¹ and R ²

combine to form a group: -(CH ₂ ) _n - (n is 5), R ³ is a group of the formula:

(s is O, R ⁶ is a group: -CO-CH=CR ^{i b} -(CO) _p -RH ^a

(R ^{l lb} , p and RH ^a are the same as defined in the formula (1)), R ⁵ , m, A and Z are

the same as defined in the formula (1)), R ⁴ is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof.

(27) A thiazole derivative of the formula (1) wherein R ¹ and R ²

combine to form a group: -(CH2) _n - (n is 5), R ³ is a group of the formula:

^lb -(CO) _p -R ^{i la}

32

(R ^{1 b} , p and R ^{1 Ja} are the same as defined in the formula (1)), R ⁵ , m, A and Z are

the same as defined in the formula (1)), R ⁴ is a hydrogen atom, and u is 1, or a salt thereof.

(28) A thiazole derivative of the formula (1) wherein Rl and R ²

combine to form a group: -(CH ₂ ) _n - (n is 5), R ³ is a group of the formula:

^ib -(CO)p-RH

(R ^{1 lb} , p and R ^{] la} are the same as defined in the formula (1)), R ⁵ , m, A and Z are

the same as defined in the formula (1)), R ⁴ is a lower alkanoyloxy-lower alkyl group and u is 1 , or a salt thereof. (29) A thiazole derivative of the formula (1) wherein Rl and R ² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R ³ is a

group of the formula: ' ^{s a} S ^rou P ^: -CO-CH=CR ^{l lb} -(CO)p-R ^{l la} (RH ^b , p and RH ^a are the same as defined in the

formula (1)), R ⁵ , m, A and Z are the same as defined in the formula (1)), R ⁴ is a hydrogen atom, and u is 0, or a salt thereof.

(30) A thiazole derivative of the formula (1) wherein Rl and R ² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R ³ is a

group of the formula: (s is 1, Z is an oxygen atom, R ⁶ is a group: -CO-CH=CRH ^b -(CO) _p -RH (R ^{l lb} , p and R" ³ are the same as defined

in the formula (1)), R ⁵ , m and A are the same as defined in the formula (1)), R ⁴ is a lower alkanoyloxy-lower alkyl group and u is 1, or a salt thereof. (37) A thiazole derivative of the formula (1) wherein R ¹ and R ²

combine to form a group: -(CH ₂ ) _n - (n is 4), R ³ is a group of the formula:

' ^v (s is 1, Z is an oxygen atom, R ⁶ is a group:

R ⁶

-CO-CH=CR ^Hb -(CO) _p -R ^{l la} (R ^{l lb} , p and R ^Ha are the same as defined in the

formula (1)), R ⁵ , m and A are the same as defined in the formula (1)), R ⁴ is a hydrogen atom, and u is 0, or a salt thereof.

(38) A thiazole derivative of the formula (1) wherein R ¹ and R ²

combine to form a group: -(CH ₂ ) _n - (n is 4), R ³ is a group of the formula:

(s is 1, Z is an oxygen atom, R ⁶ is a group:

-CO-CH=CR ^{1 ib} -(CO) _p -R ^{l la} (R ^{l lb} , p and R ^{l la} are the same as defined in the

formula (1)), R ⁵ , m and A are the same as defined in the formula (1)), R ⁴ is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof.

(39) A thiazole derivative of the formula (1) wherein R ¹ and R ²

combine to form a group: -(CH ₂ ) _n - (n is 4), R ³ is a group of the formula:

(s is 1, Z is an oxygen atom, R ⁶ is a group: -CO-CH=CR ^{l lb} -(CO) _p -R ^{l la} (RH ^b , p and RH are the same as defined in the

formula (1)), R ⁵ , m and A are the same as defined in the formula (1)), R ⁴ is a hydrogen atom, and u is 1 , or a salt thereof. (40) A thiazole derivative of the formula (1) wherein R ^l and R ²

combine to form a group: -(CH ₂ ) _n - (n is 4), R ³ is a group of the formula:

(s is 1, Z is an oxygen atom, R ⁶ is a group:

-CO-CH=CR ^{l lb} -(CO) _p -R ^{i la} (R ^Hb , p and R ^{l Ja} are the same as defined in the

formula (1)), R ⁵ , m and A are the same as defined in the formula (1)), R ⁴ is a lower alkanoyloxy-lower alkyl group and u is 1 , or a salt thereof.

(41) A thiazole derivative of the formula (1) wherein R ^l and R ²

combine to form a group: -(CH ₂ ) _n - (n is 5), R ³ is a group of the formula:

(s is 1, Z is an oxygen atom, R ⁶ is a group:

-CO-CH=CR ^{l lb} -(CO) _p -R ^{l la} (RH ^b , p and R" ⁸ are the same as defined in the

formula (1)), R ⁵ , m and A are the same as defined in the formula (1)), R ⁴ is a hydrogen atom, and u is 0, or a salt thereof.

(42) A thiazole derivative of the formula (1) wherein R ^l and R ²

combine to form a group: -(CH ₂ ) _n - (n is 5), R ³ is a group of the formula:

(s is 1, Z is an oxygen atom, R ⁶ is a group:

-CO-CH=CR ^πb -(CO) _p -R ¹ i ^a (Rllb, _{p an} d Riia ar _{e t} he same as defined in the

formula (1)), R ⁵ , m and A are the same as defined in the formula (1)), R ⁴ is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof. (43) A thiazole derivative of the formula (1) wherein R ^l and R ²

combine to form a group: -(CH ₂ ) _n - (n is 5), R ³ is a group of the formula:

(s is 1, Z is an oxygen atom, R ⁶ is a group:

-CO-CH=CR ^{i ib} -(CO) _p -R ^{i ia} (R ^nb , p and R ^{l l} are the same as defined in the

formula (1)), R ⁵ , m and A are the same as defined in the formula (1)), R ⁴ is a hydrogen atom, and u is 1, or a salt thereof.

(44) A thiazole derivative of the formula (1) wherein R ^l and R ²

combine to form a group: -(CH ₂ ) _n - (n is 5), R ³ is a group of the formula:

(s is 1 , Z is an oxygen atom, R ⁶ is a group:

-CO-CH=CR ^{l lb} -(CO) _p -R ^{l la} (R ^{l lb} , p and R ^{l la} are the same as defined in the

formula (1)), R ⁵ , m and A are the same as defined in the formula (1)), R ⁴ is a lower alkanoyloxy-lower alkyl group and u is 1 , or a salt thereof.

(45) A thiazole derivative of the formula (1) wherein R ^l and R ² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R ³ is a

group of the formula: (s is 1 , Z is an oxygen atom, R ⁶ is a group: -CO-CH=CRH ^b -(CO) _p -RH ^a (RH ^b , p and R ¹ ' ³ are the same as defined

in the formula (1)), R ⁵ , m and A are the same as defined in the formula (1)), R ⁴ is a hydrogen atom, and u is 0, or a salt thereof. (46) A thiazole derivative of the formula (1) wherein Rl and R ² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R ³ is a

group of the formula: (s is 1 , Z is an oxygen atom, R ⁶ is a group: -CO-CH=CR ^Hb -(CO) _p -RH ^a (R ^{i 1b} , p and R" ³ are the same as defined

in the formula (1)), R ⁵ , m and A are the same as defined in the formula (1)), R ⁴ is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof. (47) A thiazole derivative of the formula (1) wherein R ¹ and R ² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R ³ is a

group of the formula: (s is 1 , Z is an oxygen atom, R ⁶ is a group: -CO-CH=CRH ^b -(CO) _p -RH ^a (RH , p and R ^U * are the same as defined

in the formula (1)), R ⁵ , m and A are the same as defined in the formula (1)), R ⁴ is a hydrogen atom, and u is 1, or a salt thereof.

(48) A thiazole derivative of the formula (1) wherein R ¹ and R ² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R ³ is a

group of the formula: (s is 1 , Z is an oxygen atom, R ⁶ is a group: -CO-CH=CRH ^b -(CO) _p -R ^{l la} (R ^{l lb} , p and R ^la are the same as defined

in the formula (1)), R ⁵ , m and A are the same as defined in the formula (1)), R ⁴ is a lower alkanoyloxy-lower alkyl group and u is 1, or a salt thereof.

(49) A thiazole derivative of the formula (1) wherein R ^l and R ² are the

same or different and each are a hydrogen atom or a lower alkyl group, R ³ is a

group of the formula: (s is 1 , Z is a sulfur atom, R ⁶ is a group: -CO-CH=CRH ^b -(CO) _p -RH ^a (R ^{l lb} , p and R ^{i Ja} are the same as defined

in the formula (1)), R ⁵ , m and A are the same as defined in the formula (1)), R ⁴ is a hydrogen atom, and u is 0, or a salt thereof. (50) A thiazole derivative of the formula (1) wherein Rl and R ² are the

same or different and each are a hydrogen atom or a lower alkyl group, R ³ is a

group of the formula: (s is 1, Z is a sulfur atom, R ⁶ is a group: -CO-CH=CRH -(CO) _p -RH (RH ^b , p and R ^{i a} are the same as defined

in the formula (1)), R ⁵ , m and A are the same as defined in the formula (1)), R ⁴ is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof.

(51) A thiazole derivative of the formula (1) wherein R ¹ and R ² are the

same or different and each are a hydrogen atom or a lower alkyl group, R ³ is a

group of the formula: (s is 1, Z is a sulfur atom, R ⁶ is a group: -CO-CH=CR ^{i lb} -(CO) _p -RH ^a (R ^{i lb} , p and R ^{n a} are the same as defined

in the formula (1)), R ⁵ , m and A are the same as defined in the formula (1)), R ⁴ is a hydrogen atom, and u is 1 , or a salt thereof.

(52) A thiazole derivative of the formula (1) wherein R and R ² are the

same or different and each are a hydrogen atom or a lower alkyl group, R ³ is

a group of the formula: (s is 1 , Z is a sulfur atom, R ⁶ is a group: -CO-CH=CRH ^b -(CO) _p -R ^ia (R ^{l lb} , p and R ¹¹ * are the same as defined

in the formula (1)), R ⁵ , m and A are the same as defined in the formula (1)), R ⁴ is a lower alkanoyloxy-lower alkyl group and u is 1 , or a salt thereof.

(53) A thiazole derivative of the formula (1) wherein R and R ²

combine to form a group: -(CH ₂ ) _n - (n is 4), R ³ is a group of the formula:

(s is 1 , Z is a sulfur atom, R ⁶ is a group:

-CO-CH=CR ^{l lb} -(CO) _p -RH ^a (RH ^b , p and R ^Ha are the same as defined in the

formula (1)), R ⁵ , m and A are the same as defined in the formula (1)), R ⁴ is a hydrogen atom, and u is 0, or a salt thereof.

(54) A thiazole derivative of the formula (1 ) wherein R ¹ and R ²

combine to form a group: -(CH ₂ ) _n - (n is 4), R ³ is a group of the formula:

(s is 1 , Z is a sulfur atom, R ⁶ is a group: -CO-CH=CR ^{l lb} -(CO)p-R ^{l la} (R ^{l lb} , p and R ^{l la} are the same as defined in the

formula (1)), R ⁵ , m and A are the same as defined in the formula (1)), R ⁴ is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof.

(55) A thiazole derivative of the formula (1) wherein R ¹ and R ²

combine to form a group: -(CH ₂ ) _n - (n is 4), R ³ is a group of the formula:

(s is 1, Z is a sulfur atom, R ⁶ is a group:

-CO-CH=CR ^Hb -(CO)p-R ^{i ia} (R ^Hb , p and R ^{l la} are the same as defined in the

formula (1)), R ⁵ , m and A are the same as defined in the formula (1)), R ⁴ is a hydrogen atom, and u is 1 , or a salt thereof.

(56) A thiazole derivative of the formula (1) wherein R ^l and R ²

combine to form a group: -(CH ₂ ) _n - (n is 4), R ³ is a group of the formula:

is 1, Z is a sulfur atom, R ⁶ is a group:

^la (RH ^b , p and R ^{l la} are the same as defined in the

formula (1)), R ⁵ , m and A are the same as defined in the formula (1)), R ⁴ is a lower alkanoyloxy-lower alkyl group and u is 1 , or a salt thereof.

(57) A thiazole derivative of the formula (1) wherein Rl and R ²

combine to form a group: -(CH ₂ ) _n - (n is 5), R ³ is a group of the formula:

(s is 1, Z is a sulfur atom, R ⁶ is a group:

-CO-CH=CR ^b -(CO) _p -RH ^a (RH ^b , p and RH ^a are the same as defined in the

formula (1)), R ⁵ , m and A are the same as defined in the formula (1)), R ⁴ is a hydrogen atom, and u is 0, or a salt thereof. (58) A thiazole derivative of the formula (1) wherein R ¹ and R ²

combine to form a group: -(CH ₂ ) _n - (n is 5), R ³ is a group of the formula:

(s is 1, Z is a sulfur atom, R ⁶ is a group:

-CO-CH=CR ^H -(CO) _p -R ^{l la} (R ^{i ]b} , p and R ^{1 Ja} are the same as defined in the

formula (1)), R ⁵ , m and A are the same as defined in the formula (1)), R ⁴ is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof.

(59) A thiazole derivative of the formula (1) wherein Rl and R ²

combine to form a group: -(CH ₂ ) _n - (n is 5), R ³ is a group of the formula:

(s is 1 , Z is a sulfur atom, R ⁶ is a group:

-CO-CH=CR ^1ib -(CO) _p -RH ^a (RH ^b , p and R ^Ha are the same as defined in the

formula (1)), R ⁵ , m and A are the same as defined in the formula (1)), R ⁴ is a hydrogen atom, and u is 1, or a salt thereof.

(60) A thiazole derivative of the formula (1) wherein R ^l and R ²

combine to form a group: -(CH ₂ ) _n - (n is 5), R ³ is a group of the formula:

(s is 1, Z is a sulfur atom, R ⁶ is a group: -CO-CH=CR ^{l lh} -(CO) _p -R»a (Rl lb, _p and R ^{ϊ la} are the same as defined in the

formula (1)), R ⁵ , m and A are the same as defined in the formula (1)), R ⁴ is a lower alkanoyloxy-lower alkyl group and u is 1, or a salt thereof. (61) A thiazole derivative of the formula (1) wherein R ¹ and R ² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R ³ is a

group of the formula: (s is 1, Z is a sulfur atom, R ⁶ is a group: -CO-CH=CR ^lb -(CO) _p -R ^la (R ^b , p and R ^{l la} are the same as defined

in the formula (1)), R ⁵ , m and A are the same as defined in the formula (1)), R ⁴ is a

hydrogen atom, and u is 0, or a salt thereof.

(62) A thiazole derivative of the formula (1) wherein R ^l and R ² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R ³ is a

group of the formula: (s is 1 , Z is a sulfur atom, R ⁶ is a group: -CO-CH=CR ^πb -(CO) _p -R ^{l la} (RH ^b , p and RH ^a are the same as defined

in the formula (1)), R ⁵ , m and A are the same as defined in the formula (1)), R ⁴ is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof.

(63) A thiazole derivative of the formula ( 1 ) wherein R ^l and R ² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R ³ is a

group of the formula: (s is 1 , Z is a sulfur atom, R ⁶ is a group: -CO-CH=CR ^{i lb} -(CO) _p -R ^H (RH ^b , p and R ^H are the same as defined

in the formula (1)), R ⁵ , m and A are the same as defined in the formula (1)), R ⁴ is a hydrogen atom, and u is 1, or a salt thereof.

(64) A thiazole derivative of the formula (1) wherein R ¹ and R ² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R ³ is a

group of the formula: (s is 1 , Z is a sulfur atom, R ⁶ is a group: -CO-CH=CR ^{i ib} -(CO) _p -R ^Ha (R ^{i lb} , p and R ^{1 3} are the same as defined

in the formula (1)), R ⁵ , m and A are the same as defined in the formula (1)), R ⁴ is a lower alkanoyloxy-lower alkyl group and u is 1 , or a salt thereof.

(65) A thiazole derivative of the formula (1) wherein R ^l and R ² are the

same or different and each are a hydrogen atom or a lower alkyl group, R ³ is a

group of the formula: * ^{s a} S ^rou P ^: -CO-C≡C-COR ⁱ⁴ (R ¹⁴ is the same as defined in the formula ( 1 )), R ⁵ , Z, m and A

are the same as defined in the formula (1)), R ⁴ is a hydrogen atom, and u is 0, or a

salt thereof.

(66) A thiazole derivative of the formula (1) wherein R ^l and R ² are the

same or different and each are a hydrogen atom or a lower alkyl group, R ³ is a

group of the formula: ( ^s 0> ^R6 i ^a g ^rou P ^:

-CO-C≡C-COR ¹⁴ (R ¹⁴ is the same as defined in the formula (1)), R ⁵ , Z, m and A

are the same as defined in the formula (1)), R ⁴ is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof.

(67) A thiazole derivative of the formula (1) wherein R ^l and R ² are the

same or different and each are a hydrogen atom or a lower alkyl group, R ³ is a

group of the formula: ^R6 * ^{s a} g ^rou P ^:

-CO-C≡C-CORi ⁴ (R14 i _{s m} e same as defined in the formula (1)), R5, Z, m and A

are the same as defined in the formula (1)), R ⁴ is a hydrogen atom, and u is 1 , or a salt thereof. (68) A thiazole derivative of the formula (1) wherein R ¹ and R ² are the

same or different and each are a hydrogen atom or a lower alkyl group, R ³ is a

group of the formula: ( ^s i ®> ^R6 is ^a group:

-CO-C≡C-COR ⁱ⁴ (R ¹⁴ is the same as defined in the formula (1)), R5, Z, m and A

are the same as defined in the formula (1)), R ⁴ is a lower alkanoyloxy-lower alkyl group and u is 1 , or a salt thereof.

(69) A thiazole derivative of the formula (1) wherein R ^l and R ²

combine to form a group: -(CH ₂ ) _n - (n is 4), R ³ is a group of the formula:

^{(S iS} ° ^{* R6 iS a gr} ° ^Up: - ^C °- ^C≡C - ^C0R14 ( ^{RM is} Λe same as defined in the formula (1)), R ⁵ , Z, m and A are the same as defined in the

formula (1)), R ⁴ is a hydrogen atom, and u is 0, or a salt thereof.

(70) A thiazole derivative of the formula (1) wherein R ¹ and R ²

combine to form a group: -(CH ₂ ) _n - (n is 4), R ³ is a group of the formula:

R ⁶ is a group: -CO-C≡C-COR ¹⁴ (R ¹⁴ is the same as defined in the formula (1)), R ⁵ , Z, m and A are the same as defined in the

formula (1)), R ⁴ is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof.

(71) A thiazole derivative of the formula (1) wherein R ^l and R ²

combine to form a group: -(CH ₂ ) _n - (n is 4), R ³ is a group of the formula:

(s is 0, R ⁶ is a group: -CO-C≡C-COR ⁱ⁴ (R ^l4 is the same as defined in the formula (1)), R ⁵ , Z, m and A are the same as defined in the

formula (1)), R ⁴ is a hydrogen atom, and u is 1, or a salt thereof.

(72) A thiazole derivative of the formula (1) wherein R ¹ and R ²

combine to form a group: -(CH ₂ ) _n - (n is 4), R ³ is a group of the formula:

(s is 0, R ⁶ is a group: -CO-C≡C-COR ⁱ⁴ (R ^l4 is the same as defined in the formula (1)), R ⁵ , Z, m and A are the same as defined in the

formula (1)), R ⁴ is a lower alkanoyloxy-lower alkyl group and u is 1 , or a salt thereof. (73) A thiazole derivative of the formula (1) wherein R ^l and R ²

combine to form a group: -(CH ₂ ) _π - (n is 5), R ³ is a group of the formula:

^a g ^rou P ^: -CO-C≡C-COR ⁴ (R is the same as defined in the formula (1)), R ⁵ , Z, m and A are the same as defined in the

formula (1)), R ⁴ is a hydrogen atom, and u is 0, or a salt thereof.

(74) A thiazole derivative of the formula (1) wherein R ^] and R ²

combine to form a group: -(CH ₂ ) _n - (n is 5), R ³ is a group of the formula:

(s is 0, R ⁶ is a group: -CO-C≡C-COR ⁱ⁴ (R ^l4 is the same as defined in the formula (1)), R ⁵ , Z, m and A are the same as defined in the

formula (1)), R ⁴ is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof.

(75) A thiazole derivative of the formula (1) wherein R ^l and R ²

combine to form a group: -(CH ₂ ) _n - (n is 5), R ³ is a group of the formula:

^{(s is} °' ^{R6 is a} S ^rou P ^: -CO-C≡C-COR ⁱ⁴ (RI ⁴ is the same as defined in the formula (1)), R ⁵ , Z, m and A are the same as defined in the

formula (1)), R ⁴ is a hydrogen atom, and u is 1, or a salt thereof.

(76) A thiazole derivative of the formula (1) wherein Rl and R ²

combine to form a group: -(CH ₂ ) _n - (n is 5), R ³ is a group of the formula:

^{(s is} °' ^{R6 is a group:} - ^C °- ^C≡C - ^{C0R14 (Rl4 is Λe} same as defined in the formula (1)), R ⁵ , Z, m and A are the same as defined in the

formula (1)), R ⁴ is a lower alkanoyloxy-lower alkyl group and u is 1, or a salt thereof.

(77) A thiazole derivative of the formula (1) wherein R ^l and R ² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R ³ is a

group of the formula: ^R6 * ^{s a} g ^rou P ^:

-CO-C≡C-COR ⁱ⁴ (R ¹⁴ is the same as defined in the formula (1)), R ⁵ , Z, m and A

are the same as defined in the formula (1)), R ⁴ is a hydrogen atom, and u is 0, or a salt thereof.

(78) A thiazole derivative of the formula (1) wherein R ¹ and R ² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R ³ is a

group of the formula: ( ^{s s} ®> ^{R6 iS a} g ^rou P ^:

-CO-C≡C-COR ¹⁴ (R ¹⁴ is the same as defined in the formula (1)), R ⁵ , Z, m and A

are the same as defined in the formula (1)), R ⁴ is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof.

(79) A thiazole derivative of the formula (1) wherein R ^l and R ² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R ³ is a

group of the formula: ( ^s i 0> ^R6 i ^a g ^rou P ^:

-CO-C≡C-CORl ⁴ (R ¹⁴ is the same as defined in the formula (1)), R ⁵ , Z, m and A

are the same as defined in the formula (1)), R ⁴ is a hydrogen atom, and u is 1, or a

salt thereof.

(80) A thiazole derivative of the formula (1) wherein R ^l and R ² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R ³ is a

group of the formula: ( ^s is 0, R ⁶ is a group:

-CO-C≡C-COR ^l4 (R ¹⁴ i _{s m} e same as defined in the formula (1)), R ⁵ , Z, m and A

are the same as defined in the formula (1)), R ⁴ is a lower alkanoyloxy-lower alkyl group and u is 1, or a salt thereof. (81) A thiazole derivative of the formula (1) wherein R ¹ and R ² are the

same or different and each are a hydrogen atom or a lower alkyl group, R ³ is a

group of the formula: (s is 1 , Z is an oxygen atom, R ⁶ is a group: -CO-C≡C-CORl ⁴ (R14 J _S the same as defined in the formula (1)), R ⁵ , m

and A are the same as defined in the formula (1)), R ⁴ is a hydrogen atom, and u is

0, or a salt thereof. (82) A thiazole derivative of the formula (1) wherein R ¹ and R ² are the

same or different and each are a hydrogen atom or a lower alkyl group, R ³ is a

group of the formula: ' ^s 1, Z is an oxygen atom, R ⁶ is a group: -CO-C≡C-COR ¹⁴ (R ¹⁴ is the same as defined in the formula (1)), R ⁵ , m

and A are the same as defined in the formula (1)), R ⁴ is a lower alkanoyloxy- lower alkyl group and u is 0, or a salt thereof.

(83) A thiazole derivative of the formula (1) wherein R ¹ and R ² are the

same or different and each are a hydrogen atom or a lower alkyl group, R ³ is a

group of the formula: (s is 1 , Z is an oxygen atom, R ⁶ is a group: -CO-C≡C-COR ¹⁴ (R ¹⁴ is the same as defined in the formula (1)), R ⁵ , m

and A are the same as defined in the formula (1)), R ⁴ is a hydrogen atom, and u is

1, or a salt thereof.

(84) A thiazole derivative of the formula (1) wherein R ¹ and R ² are the

same or different and each are a hydrogen atom or a lower alkyl group, R ³ is a

group of the formula: (s is 1 , Z is an oxygen atom, R ⁶ is

a group: -CO-C≡C-COR ¹⁴ (R ¹⁴ is the same as defined in the formula (1)), R ⁵ , m

and A are the same as defined in the formula (1)), R ⁴ is a lower alkanoyloxy- lower alkyl group and u is 1, or a salt thereof.

(85) A thiazole derivative of the formula (1) wherein R ¹ and R ²

combine to form a group: -(CH ₂ ) _n - (n is 4), R ³ is a group of the formula:

is a group:

-CO-C≡C-COR ¹⁴ (R ¹⁴ is the same as defined in the formula (1)), R ⁵ , m and A

are the same as defined in the formula (1)), R ⁴ is a hydrogen atom, and u is 0, or a salt thereof. (86) A thiazole derivative of the formula (1) wherein R ¹ and R ²

combine to form a group: -(CH ₂ ) _n - (n is 4), R ³ is a group of the formula:

s a group:

-CO-C≡C-CORl ⁴ (R1 ⁴ i _{s t} e same as defined in the formula (1)), R ⁵ , m and A

are the same as defined in the formula (1)), R ⁴ is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof.

(87) A thiazole derivative of the formula (1) wherein R ¹ and R ²

combine to form a group: -(CH ₂ ) _n - (n is 4), R ³ is a group of the formula:

(s is 1, Z is an oxygen atom, R ⁶ is a group:

-CO-C≡C-COR ¹⁴ (R ¹⁴ is the same as defined in the formula (1)), R ⁵ , m and A

are the same as defined in the formula (1)), R ⁴ is a hydrogen atom, and u is 1, or a salt thereof.

(88) A thiazole derivative of the formula (1) wherein R ¹ and R ²

combine to form a group: -(CH2) _n - (n is 4), R ³ is a group of the formula:

(s is 1, Z is an oxygen atom, R ⁶ is a group:

-CO-C≡C-COR ¹⁴ (R ¹⁴ is the same as defined in the formula (1)), R ⁵ , m and A

are the same as defined in the formula (1)), R ⁴ is a lower alkanoyloxy-lower alkyl group and u is 1, or a salt thereof.

(89) A thiazole derivative of the formula (1) wherein R ¹ and R ²

combine to form a group: -(CH ₂ ) _n - (n is 5), R ³ is a group of the formula:

(s is 1, Z is an oxygen atom, R ⁶ is a group:

-CO-C≡C-COR ¹⁴ (R ^l4 is the same as defined in the formula (1)), R ⁵ , m and A

are the same as defined in the formula (1)), R ⁴ is a hydrogen atom, and u is 0, or a salt thereof. (90) A thiazole derivative of the formula (1) wherein R ¹ and R ²

combine to form a group: -(CH ₂ ) _n - (n is 5), R ³ is a group of the formula:

(s is 1 , Z is an oxygen atom, R ⁶ is a group:

-CO-C≡C-COR ^l4 (R ^I4 is the same as defined in the formula (1)), R ⁵ , m and A

are the same as defined in the formula (1)), R ⁴ is a lower alkanoyloxy-lower alkyl

group and u is 0, or a salt thereof.

(91) A thiazole derivative of the formula (1) wherein R ¹ and R ²

combine to form a group: -(CH ₂ ) _n - (n is 5), R ³ is a group of the formula:

(s is 1, Z is an oxygen atom, R ⁶ is a group: -CO-C≡C-COR ¹⁴ (R ¹⁴ is the same as defined in the formula (1)), R ⁵ , m and A

are the same as defined in the formula (1)), R ⁴ is a hydrogen atom, and u is 1, or a salt thereof.

(92) A thiazole derivative of the formula (1) wherein R ¹ and R ²

combine to form a group: -(CH ₂ ) _n - (n is 5), R ³ is a group of the formula:

(s is 1, Z is an oxygen atom, R ⁶ is a group:

-CO-C≡C-COR ¹⁴ (R ¹⁴ is the same as defined in the formula (1)), R ⁵ , m and A

are the same as defined in the formula (1)), R ⁴ is a lower alkanoyloxy-lower alkyl group and u is 1 , or a salt thereof.

(93) A thiazole derivative of the formula (1) wherein R ^l and R ² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R ³ is a

group of the formula: ' ^{Z ιs an oχ} y ^en atom, R ⁶ is a group: -CO-C≡C-COR ¹⁴ (R ¹⁴ is the same as defined in the formula (1)), R5, m

and A are the same as defined in the formula (1)), R ⁴ is a hydrogen atom, and u is

0, or a salt thereof.

(94) A thiazole derivative of the formula (1) wherein R ^l and R ² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R ³ is a

group of the formula: (s is 1 , Z is an oxygen atom, R ⁶ is a group: -CO-C≡C-COR ¹⁴ (R ¹⁴ is the same as defined in the formula (1)), R ⁵ , m

and A are the same as defined in the formula (1)), R ⁴ is a lower alkanoyloxy- lower alkyl group and u is 0, or a salt thereof. (95) A thiazole derivative of the formula (1) wherein R ¹ and R ² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R ³ is a

group of the formula: (s is 1 , Z is an oxygen atom, R ⁶ is a group: -CO-C≡C-COR ¹⁴ (R ¹⁴ is the same as defined in the formula (1)), R ⁵ , m

and A are the same as defined in the formula (1)), R ⁴ is a hydrogen atom, and u is

1 , or a salt thereof.

(96) A thiazole derivative of the formula (1) wherein R ^l and R ² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R ³ is a

group of the formula: (s is 1 , Z is an oxygen atom, R ⁶ is a group: -CO-C≡C-COR ¹⁴ (R ¹⁴ is the same as defined in the formula (1)), R ⁵ , m

and A are the same as defined in the formula (1)), R ⁴ is a lower alkanoyloxy-

lower alkyl group and u is 1, or a salt thereof. (97) A thiazole derivative of the formula (1) wherein R ¹ and R ² are the

same or different and each are a hydrogen atom or a lower alkyl group, R ³ is a

group of the formula: (s is 1 , Z is a sulfur atom, R ⁶ is a group: -CO-C≡C-COR ¹⁴ (R ¹⁴ is the same as defined in the formula (1)), R ⁵ , m

and A are the same as defined in the formula (1)), R ⁴ is a hydrogen atom, and u is 0, or a salt thereof.

(98) A thiazole derivative of the formula (1) wherein R ¹ and R ² are the

same or different and each are a hydrogen atom or a lower alkyl group, R ³ is a

group of the formula: (s is 1 , Z is a sulfur atom, R ⁶ is a group: -CO-C≡C-COR ¹⁴ (R ¹⁴ is the same as defined in the formula (1)), R ⁵ , m

and A are the same as defined in the formula (1)), R ⁴ is a lower alkanoyloxy- lower alkyl group and u is 0, or a salt thereof.

(99) A thiazole derivative of the formula (1) wherein R ¹ and R ² are the

same or different and each are a hydrogen atom or a lower alkyl group, R ³ is a

a group: -CO-C≡C-COR ¹⁴ (R ¹⁴ is the same as defined in the formula (1)), R ⁵ , m

and A are the same as defined in the formula (1)), R ⁴ is a hydrogen atom, and u is

1 , or a salt thereof.

(100) A thiazole derivative of the formula (1) wherein R ¹ and R ² are the

same or different and each are a hydrogen atom or a lower alkyl group, R ³ is a

group of the formula: (s is 1 , Z is a sulfur atom, R ⁶ is a group: -CO-C≡C-COR ¹⁴ (R ¹⁴ is the same as defined in the formula (1)), R ⁵ , m

and A are the same as defined in the formula (1)), R ⁴ is a lower alkanoyloxy- lower alkyl group and u is 1, or a salt thereof. (101) A thiazole derivative of the formula (1) wherein R ¹ and R ²

combine to form a group: -(CH ₂ ) _n - (n is 4), R ³ is a group of the formula:

(s is 1, Z is a sulfur atom, R ⁶ is a group:

-CO-C≡C-COR ¹⁴ (R ¹⁴ is the same as defined in the formula (1)), R ⁵ , m and A

are the same as defined in the formula (1)), R ⁴ is a hydrogen atom, and u is 0, or a salt thereof.

(102) A thiazole derivative of the formula (1) wherein R ¹ and R ²

combine to form a group: -(CH ₂ ) _n - (n is 4), R ³ is a group of the formula:

(s is 1 , Z is a sulfur atom, R ⁶ is a group:

-CO-C≡C-COR ¹⁴ (R ¹⁴ is the same as defined in the formula (1)), R ⁵ , m and A

are the same as defined in the formula (1)), R ⁴ is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof.

(103) A thiazole derivative of the formula (1) wherein R ¹ and R ²

combine to form a group: -(CH ₂ ) _n - (n is 4), R ³ is a group of the formula:

( ^{s 1S} 1 » Z is a sulfur atom, R ⁶ is a group:

-CO-C≡C-COR ¹⁴ (R ¹⁴ is the same as defined in the formula (1)), R ⁵ , m and A

are the same as defined in the formula (1)), R ⁴ is a hydrogen atom, and u is 1, or a salt thereof.

(104) A thiazole derivative of the formula (1) wherein R ¹ and R ²

combine to form a group: -(CH ₂ ) _n - (n is 4), R ³ is a group of the formula:

(s is 1 , Z is a sulfur atom, R ⁶ is a group:

-CO-C≡C-COR ¹⁴ (R ¹⁴ is the same as defined in the formula (1)), R ⁵ , m and A

are the same as defined in the formula (1)), R ⁴ is a lower alkanoyloxy-lower alkyl group and u is 1 , or a salt thereof. (105) A thiazole derivative of the formula (1) wherein R ¹ and R ²

combine to form a group: -(CH ₂ ) _n - (n is 5), R ³ is a group of the formula:

(s is 1, Z is a sulfur atom, R ⁶ is a group:

-CO-C≡C-COR ¹⁴ (R ¹⁴ is the same as defined in the formula (1)), R ⁵ , m and A

are the same as defined in the formula (1)), R ⁴ is a hydrogen atom, and u is 0, or a

salt thereof.

(106) A thiazole derivative of the formula (1) wherein R ¹ and R ²

combine to form a group: -(CH ₂ ) _n - (n is 5), R ³ is a group of the formula:

(s is 1 , Z is a sulfur atom, R ⁶ is a group: -CO-C≡C-COR ¹⁴ (R ¹⁴ is the same as defined in the formula (1)), R ⁵ , m and A

are the same as defined in the formula (1)), R ⁴ is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof.

(107) A thiazole derivative of the formula (1) wherein R ¹ and R ²

combine to form a group: -(CH ₂ ) _n - (n is 5), R ³ is a group of the formula:

^s * ^s 11 Z is a sulfur atom, R ⁶ is a group:

-CO-C≡C-COR ^l4 (R ^l4 is the same as defined in the formula (1)), R ⁵ , m and A

are the same as defined in the formula (1)), R ⁴ is a hydrogen atom, and u is 1, or a salt thereof.

(108) A thiazole derivative of the formula (1) wherein R ¹ and R ²

combine to form a group: -(CH ₂ ) _n - (n is 5), R ³ is a group of the formula:

(s is 1, Z is a sulfur atom, R ⁶ is a group:

-CO-C≡C-COR ¹⁴ (R ¹⁴ is the same as defined in the formula (1)), R5, m and A

are the same as defined in the formula (1)), R ⁴ is a lower alkanoyloxy-lower alkyl group and u is 1 , or a salt thereof. (109) A thiazole derivative of the formula (1) wherein R ¹ and R ²

combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R ³ is a

group of the formula: (s is 1 , Z is a sulfur atom, R ⁶ is a group: -CO-C≡C-COR ¹⁴ (R ¹⁴ is the same as defined in the formula (1)), R ⁵ , m

and A are the same as defined in the formula (1)), R ⁴ is a hydrogen atom, and u is 0, or a salt thereof.

(110) A thiazole derivative of the formula (1) wherein R ¹ and R ² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R ³ is a

group of the formula: (s is 1 , Z is a sulfur atom, R ⁶ is a group: -CO-C≡C-CORi ⁴ (R14 i _s the same as defined in the formula (1)), R ⁵ , m

and A are the same as defined in the formula (1)), R ⁴ is a lower alkanoyloxy- lower alkyl group and u is 0, or a salt thereof.

(111) A thiazole derivative of the formula (1) wherein Rl and R ² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R ³ is a

group of the formula: (s is 1 , Z is a sulfur atom, R ⁶ is a group: -CO-C≡C-COR ^l4 (R ^J4 is the same as defined in the formula (1)), R5, m

and A are the same as defined in the formula (1)), R ⁴ is a hydrogen atom, and u is

1 , or a salt thereof.

(112) A thiazole derivative of the formula (1) wherein R ¹ and R ² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R ³ is a

group of the formula: (s is 1 , Z is a sulfur atom, R ⁶ is a group: -CO-C≡C-COR ¹⁴ (R ¹⁴ is the same as defined in the formula (1)), R ⁵ , m

and A are the same as defined in the formula (1)), R ⁴ is a lower alkanoyloxy- lower alkyl group and u is 1, or a salt thereof.

The compounds of the present invention of the formula (1) may be prepared by various processes, but preferably prepared by the following processes. Reaction Scheme- 1

wherein R ¹ , R ² , R ⁴ , R ⁵ , Z, m, s, T, u and A are the same as defined above, R ¹⁵ is a

group: -CH=C(R ^{l lb} )(COR ⁱ⁶ ) (R ^{l lb} is the same as defined above, and R ¹⁶ is a

hydroxy group or a lower alkoxy group), or a group: -C≡C-COR ¹⁴ (R ¹⁴ is the

same as defined above), and X is a halogen atom.

The reaction between the compound (2) and the compound (3) or the compound (4) is called Friedel-Crafts Reaction, and carried out in the presence of a Lewis acid in a suitable solvent. The Lewis acid may be any conventional Lewis acids which are used in mis kind of Friedel-Crafts Reaction, and is, for example, aluminum chloride, zinc chloride, iron chloride, stannous chloride, boron tribromide, boron trifluoride, cone, sulfuric acid, etc. The solvent may be, for example, carbon disulfide, aromatic hydrocarbons such as nitrobenzene, chlorobenzene, halogenated hydrocarbons such as dichloromethane, dichloro- ethane, carbon tetrachloride, tetrachloroethane, aliphatic nitro compounds such as nitroethane, nitromethane, or a mixture of these solvents. The compound (3) and the compound (4) are used each at least in an equimolar amount, preferably in an amount of 1 to 5 moles, to 1 mole of the compound (2). The Lewis acid is usually used in an amount of 1 to 6 moles, to 1 mole of the compound (2). The reaction is usually carried out at 0 to 120 ^β C, preferably at 0 to 70°C, for about 0.5 to 24 hours.

The compound wherein R ¹⁵ is a group: -CH=C(R ^{l lb} )(COR ¹⁶ ), and the double bond thereof shows a cis-configuration can be isomerized into the compound wherein the double bond shows a trans-configuration by heating it at about 50°C to 100°C in dimethylformamide.

The compound (la) wherein R ¹⁵ is a group: -CH=C(R ^{l lb} )(COR ¹⁶ ) or a

group: -C≡C-COR ¹⁴ , and R ¹⁶ and R ¹⁴ are both a lower alkoxy group may be

converted into a compound (l a) wherein a corresponding R ¹⁶ and R ¹⁴ are a

hydroxy group, by treating it under the same conditions as in the reaction of converting the compound (Id) into the compound (le) in Reaction Scheme 4, described hereinbelow. Reaction Scheme-2

(lb) (lc)

wherein R ¹ , R ² , R ⁴ , R ⁵ , R ^{l lb} , Z, m, s, T, u and A are the same as defined above,

R ¹⁷ is the heterocyclic residues as defined for R ^Ha but having at least one -^

in the heterocyclic nucleus.

The process of Reaction Scheme-2 is a conventional amido bond producing reaction, and is carried out by reacting the thiazole compound (lb) and the amine compound (5). The amido bond producing reaction can be carried out under the same conditions as those of the conventional amino bond producing reaction, for example,

(a) a mixed acid anhydride process, i.e. a process of reacting the carboxylic acid compound (lb) with an alkyl halocarbonate to form a mixed acid anhydride and reacting the resultant with the amine compound (5);

(b) an activated ester process, i.e. a process of converting the carboxylic acid compound (lb) into an activated ester such as p-nitrophenyl ester, N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester, etc., and

reacting the resultant with the amine compound (5);

(c) a carbodiimide process, i.e. a process of condensing the carboxylic acid compound (lb) and the amine compound (5) in the presence of an activating agent such as dicyclohexylcarbodiimide, carbonyldiimidazole, etc.; (d) other processes, i.e. a process of converting the carboxylic acid compound (lb) into a carboxylic anhydride by treating it with a dehydrating agent such as acetic anhydride, and reacting the resultant with the amine compound (5); a process of reacting an ester of the carboxylic acid compound (lb) with a lower alcohol and the amine compound (5) at high temperature under high pressure; a process of reacting an acid halide compound of the carboxylic acid compound (lb), i.e. a carboxylic acid halide, with the amine compound (5).

The mixed acid anhydride used in the above mixed acid anhydride process (a) is obtained by the known Schδtten-Baumann reaction, and the reaction product is used without isolating from the reaction mixture for the reaction with the amine compound (5) to give the desired compound (1) of the present invention. The Schδtten-Baumann reaction is usually carried out in the presence of a basic compound. The basic compound is any conventional compounds used for the Schδtten-Baumann reaction and includes, for example, organic basic compounds such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmoφholine, 4-dimethylaminopyridine, 1,5-diazabicyclo- [4.3.0]nonene-5 (DBN), l ,8-diazabicyclo[5.4.0]undecene-7 (DBU), 1,4-diaza- bicyclo[2.2.2]octane (DABCO), etc., and inorganic basic compounds such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, etc. The reaction is usually carried out at a temperature

from about -20°C to about 100°C, preferably at a temperature of -20°C to about 50°C, for about 5 minutes to about 10 hours, preferably for 5 minutes to about 2 hours.

The reaction between the mixed acid anhydride thus obtained and the amine compound (5) is usually carried out at a temperature of -20 ^β C to about 150 ^β C, preferably at a temperature of -20°C to about 50°C, for about 5 minutes to about 35 hours, preferably for about 5 minutes to 30 hours. The mixed acid anhydride process is usually carried out in a solvent in the presence of a basic compound. The basic compounds may be any basic compounds used in the above Schδtten-Baumann reaction. The solvent may be any conventional solvents which are usually used in the mixed acid anhydride process and includes, for example, halogenated hydrocarbons (e.g. chloroform, dichloro¬ methane, dichloroethane, etc.), aromatic hydrocarbons (e.g. benzene, p-chloro- benzene, toluene, xylene, etc.), ethers (e.g. diethyl ether, diisopropyl ether, tetrahydrofuran, dimethoxyethane, etc.), esters (e.g. methyl acetate, ethyl acetate, etc.), aprotic polar solvents (e.g. N,N-dimethylformamide, dimethyl- sulfoxide, acetonitrile, hexamethylphosphoric triamide, l-methyl-2-pyrrolidinone (NMP), etc.), or a mixture of these solvents. The alkyl halocarbonate used in the mixed acid anhydride process includes, for example, methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, isobutyl chloroformate, and the like. In said process, the carboxylic acid compound (lb), the alkyl halocarbonate ester and the amine compound (5) are usually used in equimolar amount each, but preferably the alkyl halocarbonate ester and the amine compound (5) are used in an amount of about 1 to 1.5 mole, to 1 mole of the carboxylic acid (lb).

Among the above other processes (d), in case of the process of reacting the carboxylic acid halide with the amine compound (5), the reaction is usually carried out in the presence of a basic compound in a suitable solvent. The basic compound is any conventional basic compounds and includes, for example, in addition to the basic compounds used in the above mentioned Schδtten- Baumann reaction, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, and the like. The solvent includes, for example, in addition to the solvents used in the mixed acid anhydride process, alcohols (e.g. methanol, ethanol, propanol, butanol, 3-methoxy-l-butanol, ethylcellosolve, methylcellosolve, etc.), pyridine, acetone, water, or a mixture of two or more these solvents, and the like. The amount of the amine compound (5) and the carboxylic acid halide is not critical, but the amine compound (5) is usually used at least in equimolar amount, preferably in an amount of about 1 to 5 moles, to 1 mole of the carboxylic acid halide. The reaction is usually carried out at a temperature of about -70°C to about 180°C, preferably at a temperature of about -50°C to about 150°C, for about 5 minutes to about 30 hours.

Besides, the amido bond producing reaction of Reaction Scheme-2 may also be carried out by reacting the carboxylic acid compound (lb) and the amine compound (5) in the presence of a condensing agent such as phosphorus compounds (e.g. phenylphosphine-2,2'-dithiopyridine, diphenylphosphinyl chloride, phenyl-N-phenylphosphoramide chloridate, diethyl cyanophosphate, diethyl cyanophosphate, diphenylphosphoryl azide, N,N'-bis(2-oxo-3-oxa- zolidinyl)phosphinic chloride, etc.).

The reaction is usually carried out in the presence of the same solvent and the same basic compound which can be used in the above reaction of the

carboxylic acid halide compound and the amine compound (5). The reaction is usually carried out at a temperature of -20 ^β C to about 150°C, preferably at a temperature of 0 ^β C to about 100 ^β C, for about 5 minutes to about 30 hours. The condensing agent and the amine compound (5) are used at least in equimolar amount, preferably in an amount of about 1 to 2 moles, to 1 mole of the carboxylic acid compound (lb).

Reaction Scheme-3

wherein R ^l , R2, R ³ , R ⁴ , 5 _? Z, m, s, T, u, R ⁱ⁶ and A are the same as defined above,

R ¹⁸ and R ¹⁹ are a lower alkoxy group, and R ²² is the same as defined below.

The reaction of the compound (6) and the compound (7) is carried out in the presence of a basic compound in a suitable solvent. The basic compound includes inorganic basic compounds such as metal sodium, metal potassium, sodium hydride, sodium amide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, etc., organic basic compounds such as alkali metal alkoxide (e.g., sodium methylate, sodium ethylate, potassium t-butoxide), an alkyl lithium, aryl lithium or lithium amide (e.g., methyl lithium, n-butyl lithium, phenyl lithium, lithium diisopropylamide), pyridine, piperidine, quinohne, triethylamine, N,N-dimethylaniline, etc. The solvent may be any one which does not disturb the reaction, for example, water, ethers (e.g., diethyl ether, dioxane, tetrahydrofuran, monoglyme, diglyme, etc.), aromatic hydrocarbons (e.g., benzene, toluene, xylene, etc.), aliphatic hydro¬ carbons (e.g., n-hexane, heptane, cyclohexane, etc.), amines (e.g., pyridine, N,N- dimethylaniline, etc), aprotic polar solvents (e.g., N,N-dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, etc.), halogenated hydro¬ carbons (e.g., dichloromethane, chloroform, carbon tetrachloride, etc.), alcohols (e.g., methanol, ethanol, isopropyl alcohol, etc.), ureas (e.g., N,N'-dimethyl- propylene urea (DMPU), etc.), l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)- pyrimidinone, or a mixture of these solvents. The reaction is usually carried out at -80°C to 150°C, preferably at about -80° to 120°C, for 0.5 to about 15 hours.

The compound (7) is usually used at least in an equimolar amount, preferably in an amount of 1 to 5 moles, to 1 mole of the compound (6). The reaction of converting the compound (8) into the compound (10) is

carried out in the presence of an oxidizing agent in a suitable solvent. The oxidizing agent includes, for example, benzoquinones (e.g., 2,3-dichloro-5,6- dicyano-l,4-benzoquinone (DDQ ), pyridinium chromates (e.g., pyridinium chlorochromate, pyridium dichlorochromate, etc.), dimethylsulfoxide-oxazolyl chloride, dichromic acid, dichromates (e.g. sodium dichromate, potassium dichromate, etc.), permanganic acid, permanganates (e.g. potassium permanganate, sodium permanganate, etc.), manganese dioxide, etc. The solvent includes, for example, water, organic acids (e.g. formic acid, acetic acid, trifluoroacetic acid, etc.), alcohols (e.g. methanol, ethanol, etc.), halogenated hydrocarbons (e.g. chloroform, dichloromethane, etc.), ethers (e.g., tetrahydro¬ furan, diethyl ether, dioxane, etc.), dimethylsulfoxide, dimethylformamide, or a mixture of these solvents. The oxidizing agent is preferably used in an excess amount to the amount of the starting compound. The above reaction is usually carried out at 0°C to 200°C, preferably at 0°C to about 150°C, for 1 hour to about 10 hours.

The reaction of the compound (9) and the compound (7) is carried out under the same conditions as those in the reaction of the compound (6) and the compound (7).

The reaction of the compound (10) and the compound (12) is carried out under the same conditions as those in the reaction of the compound (6) and the compound (7).

The reaction of the compound (10) and the compound (20) is carried out under the same conditions as mose in the reaction of the compound (6) and the compound (7).

Reaction Scheme-4

wherein R ¹ , R ² , R ⁴ , R ⁵ , Z, m, s, T, u and A are the same as defined above, R ²⁰ is a lower alkoxy group, M is an alkali metal such as lithium, sodium, potassium, etc.,

and R ^16a is a lower alkoxy group.

The reaction of the compound (6) and the compound (13) is carried out in the presence of a basic compound in a suitable solvent, at -80°C to room temperature, for 5 minutes to 6 hours. The solvent may be, for example, ethers (e.g., diethyl ether, dioxane, tetrahydrofuran, etc.), aromatic hydrocarbons (e.g., benzene, toluene, etc.), saturated hydrocarbons (e.g., hexane, heptane, pentane, cyclohexane, etc.), ureas (e.g., N,N'-dimethylpropyleneurea (DMPU), etc.). The basic compounds are the same ones which are used in the reaction of the compound (6) and the compound (7) in the above Reaction Scheme-3. The compound (13) is usually used at least in equimolar amount, preferably in an amount of 1 to 5 moles, to 1 mole of the compound (6).

The reaction of converting the compound (11) into the compound (Id') is carried out in the presence of a basic compound in a suitable solvent. The basic compound may be organic basic compound such as triethylamine, trimethyl- amine, diisopropylamine, tri-n-butylamine, ethylamine, pyridine, dimethylaniline, N-methylmoφholine, 4-dimethylaminopyridine, DBN, DBU, DABCO, etc. The solvent includes, for example, water, alcohols (e.g., ethanol, methanol, isopropanol, etc.), dimethylformamide, diemthylsulfoxide, hexamethylphosphoric triamide, or a mixture of these solvents. The reaction is usually carried out at room temperature to 150°C, preferably at room temperature to 100°C, for about 1 to 5 hours.

The reaction of converting the compound (11) into the compound (If) is carried out under the same conditions as those in the reaction of converting the compound (8) into the compound (10) in the above Reaction Scheme-3. The reaction of converting the compound (Id') into the compound (le) is

carried out in the presence of an acid or a basic compound in a suitable solvent, or without a solvent. The solvent includes, for example, water, lower alcohols (e.g., ethanol, methanol, 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.), fatty acids (e.g., acetic acid, formic acid, etc.), or a mixture of these solvents. The acid includes, for example, mineral acids (e.g., hydrochloric acid, sulfuric acid, hydrobromic acid, etc.), organic acids (e.g., formic acid, acetic acid, trifluoric acid, aromatic sulfuric acids, etc.). The basic compound includes, for example, an alkali metal carbonate (e.g., sodium carbonate, potassium carbonate, etc.), an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, etc.), etc. The reaction is usually carried out at room temperature to about 200°C, preferably at room temperature to 150°C, for about 10 minutes to 25 hours. The reaction of converting the compound (If) into the compound (lg) is carried out under the same conditions as those in the reaction of converting the compound (Id') into the compound (le) as mentioned above.

Reaction Scheme-5

wherein R ¹ , R ² , R ⁴ , R ⁵ , Z, m, s, T, u and A are the same as defined above, X ¹ is a

halogen atom, R ²¹ is a phenyl group, R ²² is a 5- to 10-membered, saturated or unsaturated heteromonocyclic, heterobicyclic residue (said heterocyclic residue optionally having 1 to 3 substituents selected from (i) a lower alkyl group; (ii) a group: -(B)^-NR ¹² R ¹³ (£ is the same as defined above, B is a group: -CO-A- (A

is the same as defined above), a carbonyl group or a lower alkylene group, R ¹²

and R ¹³ are the same or different, and each are a hydrogen atom, a lower alkyl

group, an amino-substituted lower alkyl group having optionally a lower alkyl substituent, or combine together with the adjacent nitrogen atom to which they bond to form a 5- to 12-membered saturated heteromonocyclic, heterobicyclic or hetero-sprio ring with or without being intervened with another nitrogen atom or an oxygen atom, said heterocyclic group may optionally have a substituent selected from a lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxy-substituted lower alkyl group, an amino group having optionally a lower alkyl substituent and a hydroxy-substituted lower alkyl group); (iii) a lower alkoxycarbonyl group; (iv) a hydroxy-substituted lower alkyl group; (v) a pyridyl group being optionally substituted by a lower alkyl group having optionally a halogen substituent on the pyridine ring; (vi) a halogen-substituted lower alkyl group; (vii) a lower alkoxy group; (viii) a cycloalkyl group; (ix) a hydroxy group; (x) a tetrahydropyranyloxy-substituted lower alkyl group; (xi) a pyrimidyl group; (xii) a lower alkoxy-substituted lower alkyl group; (xiii) a carboxyl group; (xiv) a phenyl-lower alkoxy group; (xv) a phenyl-lower alkyl group having optionally a lower alkylenedioxy substituent on the phenyl ring; (xvi) a lower alkanoyloxy group; and (xvii) a piperidinyl group having optionally a lower alkyl substituent on the piperidine ring.

The reaction of the compound (2) and the compound (14), and the reaction of the compound (2) and the compound (15)are carried out under the same conditions as those in the reaction of the compound (2) and the compound (3) or the compound (4) in the above Reaction Scheme- 1.

The halogenating reaction of the compound (16) is carried out in the presence of a halogenating agent in a suitable solvent. The halogenating agent may be, for example, halogen molecules (e.g., bromine, chlorine, etc.), iodine chloride, sulfuryl chloride, copper compounds (e.g., copper (II) bromide, etc.), N- halogenated succinimides (e.g., N-bromosuccinimide, N-chlorosuccinimide, etc.). The solvent may be, for example, halogenated hydrocarbons (e.g., dichloro¬ methane, dichloroethane, chloroform, carbon tetrachloride, etc.), fatty acids (e.g., acetic acid, propionic acid, etc.), carbon disulfide, etc. The halogenating agent is usually used in an amount of 1 to 10 moles, preferably in an amount of 1 to 5 moles, to 1 mole of the compound (16). The reaction is usually carried out at 0°C to a boiling point of the solvent to be used, preferably at 0°C to 100°C, for about 5 minutes to 20 hours.

The reaction of the compound (17) and the compound (18) is carried out in a suitable solvent at room temperature to 150°C, preferably at room temperature to about 100°C, for about 1 hour to 10 hours. The solvent may be the same solvents used in the reaction of the carboxylic halide and the amine compound (5) among the reactions between the compound (lb) and the compound (5) in the above Reaction Scheme-2. The compound (18) is used at least in equimolar amount, preferably in an amount of 1 to 1.5 moles, to 1 mole of the compound (17).

In the above process, there is obtained a compound of the formula (21):

wherein R ¹ , R ² , R ⁴ , R ⁵ , Z, m, A, R ²¹ , s, T, u and X are the same as defined above, which is further treated in the presence of a basic compound in a suitable solvent to give the compound (19). The solvent and the basic compound are the same ones which are used in the reaction of the carboxylic halide and the amine compound (5) in the reaction of the compound (lb) and the compound (5) in the Reaction Scheme-2. The reaction is usually carried out at 0°C to 100°C, preferably at 0°C to about 70°C, for about 1 hour to 5 hours.

The reaction of the compound (19) and the compound (20) is carried out under the same conditions as those in the reaction of the compound (6) and the compound (7) in the above Reaction Scheme-3.

Alternatively, the reaction of the compound (19) and the compound (20) is usually carried out in a suitable solvent at 0°C to 150°C, preferably at room temperature to about 100°C, for about 0.5 hour to 8 hours. The solvent may be any one which does not disturb 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 polar solvents (e.g., N,N-dimethyl- formamide, dimethylsulfoxide, hexamethylphosphoric triamide, etc.), etc. The compound (20) is usually used at least in equimolar amount, preferably in an

amount of 1 to 5 moles, to 1 mole of the compound (19). The reaction is promoted when a para-aldehyde is added into the reaction system. Reaction Scheme-6

wherein R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , Z, s, T, u and A are the same as defined above, q is 1 ,

R ^5a is a halogen-substituted lower alkyl group, R ^5b is a group: -A-NR ⁷ R ⁸ (A,

R ⁷ , R ⁸ are the same as defined above) or a lower alkanoyloxy-lower alkyl group,

R ²³ is a group: -NR ⁷ R ⁸ (R ⁷ and R ⁸ are the same as defined above), or a lower alkanoyloxy group.

The reaction of the compound (If) and the compound (22) is carried out in the presence or absence of a basic compound in a suitable inert solvent, or without a solvent. The inert solvent includes, for example, aromatic hydro¬ carbons (e.g., benzene, toluene, xylene, etc.), ethers (e.g., tetrahydrofuran, dioxane, diethylene glycol dimethyl ether, etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, etc.), lower alcohols (e.g., methanol, ethanol, isopropanol, butanol, tert-butanol, etc.), water, acetic acid, ethyl acetate, acetone, acetonitrile, pyridine, dimethylsulfoxide, dimethyl- formamide, hexamethylphosphoric triamide, 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 hydrogen carbonate (e.g.,

sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.), sodium hydride, potassium, sodium, sodium amide, an alkali metal alkoxide (e.g., sodium methoxide, etc.), organic basic compounds (e.g., pyridine, N-ethyldiisopropyl- amine, dimethylaminopyridine, triethylamine, l,5-diazabicyclo[4.3.0]nonen-5- (DBN), l ,8-diazabicyclo[5.4.0]undecen-7 (DBU), 1 ,4-diazabicyclo[2.2.2]octane (DABCO), etc. The amount of the compound (li) and the compound (22) is not critical, but the compound (22) is usually used at least in equimolar amount, preferably in an amount of 1 to 10 moles, to 1 mole of the compound (li). The reaction is usually carried out at 0°C to 200°C, preferably at 0°C to 170°C, for about 30 minutes to 75 hours. Into the reaction system, an alkali metal halide such as sodium iodide, potassium iodide or a copper powder may be added. Reaction Scheme-7

(23)

(1) wherein R ¹ , R ² , R ³ , R ⁴ , T and u are the same as defined above. The reaction of the compound (23) and the compound (24) is carried out under the same conditions as those in the reaction of the compound (lb) and the compound (5) in the above Reaction Scheme-2.

Reaction Scheme-8

(Ik) ( )

wherein R ¹ , R ² , R ³ , T, X and u are the same as defined above, and R ^4a is a lower alkanoyloxy-lower alkyl group.

The reaction of the compound (Ik) and the compound (25) is carried out under the same conditions as those in the reaction of the compound (li) and the compound (22) in the above Reaction Scheme-6. Reaction Scheme-9

wherein R ¹ , R ² , R ⁴ , R5, R , R7 _? R8 _? Z, S, T, u and q are the same as defined above,

and R ^5c is a carboxy-substituted lower alkyl group, R ^5d is a group: -A-CO-

NR ⁷ R ⁸ (R ⁷ and R ⁸ are the same as defined above).

The reaction of the compound (lm) and the compound (26) is carried out under the same conditions as those in the reaction of the compound (lb) and the compound (5) in the above Reaction Scheme-2.

The starting compounds (2), (6) and (23) in the above Reaction Schemes

are prepared by the following processes. Reaction Scheme- 10

(2a)

wherein R ¹ , R ² , R ⁴ , R5, X, Z, T, u and m are the same as defined above, and R ²⁴ is a hydroxy group, a lower alkoxy group or a phenyl-lower alkoxy group, and A' is a lower alkylene group. The reaction of the compound (27) and the compound (28) is carried out under the same conditions as those in the reaction of the compound (li) and the compound (22) in the above Reaction Scheme-6.

The reaction of converting the compound (29) wherein R ²⁴ is a lower alkoxy group into the compound (30) is carried out under the same conditions as those in the reaction of converting the compound (Id) into the compound (le) in the above Reaction Scheme-4.

The reaction of converting the compound (29) wherein R ²⁴ is a phenyl- lower alkoxy group into the compound (30) is carried out under the same conditions as those in the reaction of converting the compound (5b) into the

compound (5c) in Reaction Scheme- 13, which is described hereinbelow.

The reaction of the compound (30) and the compound (24) is carried out under the same conditions as those in the reaction of the compound (lb) and the compound (5) in the above Reaction Scheme-2. Reaction Scheme- 11

(6a)

wherein R ¹ , R ² , R ⁴ , R ⁵ , A', Z, R ²⁴ , T, u and m are the same as defined above.

The reaction of the compound (31) and the compound (28) is carried out under the same conditions as those in the reaction of the compound (27) and the compound (28) in the above Reaction Scheme- 10.

The reaction of converting the compound (32) wherein R ²⁴ is a lower alkoxy group into the compound (33) is carried out under the same conditions as those in the reaction of converting the compound (29) wherein R ²⁴ is a lower alkoxy group into the compound (30) in the above Reaction Scheme- 10.

The reaction of converting the compound (32) wherein R ²⁴ is a phenyl- lower alkoxy group into the compound (33) is carried out under the same

conditions as those in the reaction of converting the compound (5b) into the compound (5c) in Reaction Scheme- 13, which is described hereinbelow.

The reaction of the compound (33) and the compound (24) is carried out under the same conditions as those in the reaction of the compound (30) and the compound (24) in the above Reaction Scheme- 10. Reaction Scheme- 12

(34) (35) (23a)

wherein R ⁵ , R ⁶ , m, A', X, Z and R ²⁴ are the same as defined above.

The reaction of the compound (34) and the compound (28) is carried out under the same conditions as those in the reaction of the compound (27) and the compound (28) in the above Reaction Scheme- 10.

The reaction of converting the compound (35) wherein R ²⁴ is a lower alkoxy group into the compound (23a) is carried out under the same conditions as those in the reaction of converting the compound (29) wherein R ²⁴ is a lower alkoxy group into the compound (30) in the above Reaction Scheme-10. The reaction of converting the compound (35) wherein R ²⁴ is a phenyl- lower alkoxy group into the compound (23a) is carried out under the same conditions as those in the reaction of converting the compound (5b) into the compound (5c) in Reaction Scheme-13, which is described hereinbelow.

The starting compound (5) is prepared by the following processes.

Reaction Scheme-13

R ¹² R ¹³ NH (36) ,„ _{C ] 7h R} 17a_ _R 25 — — R ^17b -R ²⁵ - R ^17b H

(5a) (5b) ( ^5c >

wherein R ¹² , R ¹ 3 are the same as defined above, R ^17a is the same groups for R ¹⁷

having at least one oxo group on the heterocyclic group, R ^17b is the same

groups for R ¹⁷ having at least one group: -N-R ¹² R ¹³ (R ^!2 and R ¹³ are the same

as defined above) on the heterocyclic group, and R ²⁵ is a phenyl-lower alkyl

group. The reaction of the compound (5a) and the compound (36) is carried out in the presence of a reducing agent in a suitable solvent or without a solvent. The solvent may be, for example, water, alcohols (e.g., methanol, ethanol, isopropanol, etc.), acetonitrile, formic acid, acetic acid, ethers (e.g., dioxane, diethyl ether, diglyme, tetrahydrorfuran, etc.), aromatic hydrocarbons (e.g., benzene, toluene, xylene, etc.), or a mixture of these solvents. The reducing agent may be, for example, formic acid, an alkali metal salt of fatty acid (e.g., sodium formate, etc.), hydrogenating agent (e.g., sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, etc.), catalysts (e.g., palladium- black, palladium-carbon, platinum oxide, platinum black, Raney-nickel, etc.). When formic acid is used as a reducing agent, the reaction is usually carried out at room temperature to about 200°C, preferably at 50 to 150°C, for one to about 10 hours. The formic acid is used in an excess amount to the amount of the compound (5 a).

When a hydrogenating agent is used as a reducing agent, the reaction is

usually carried out at -30°C to about 100 ^β C, preferably at 0°C to 70°C, for 30 minutes to about 12 hours. The hydrogenating agent is used in an amount of 1 to 20 moles, preferably in an amount of 1 to 6 moles, to 1 mole of the compound (5a). Especially, when lithium aluminum hydride is used as a hydrogenating agent, the solvent may be ethers (e.g., diethyl ether, dioxane, tetrahydrofuran, diglyme, etc.), or aromatic hydrogen carbonates (e.g., benzene, toluene, xylene, etc.).

When a catalyst is used as a reducing agent, the reaction is usually carried out under a pressure of atmospheric pressure to 20 atms, preferably under atmospheric pressure to 10 atom of hydrogen gas, in the presence of a hydrogen donor such as formic acid, ammonium formate, cyclohexene, hydrazine hydrate, etc. at a temperature of -30"C to about 100°C, preferably at a temperature of 0°C to 60°C, for about one to 12 hours. The catalyst is used in an amount of 0.1 to 40 % by weight, preferably in an amount of 0.1 to 20 % by weight, to the weight of the compound (5a).

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

The reaction of converting the compound (5b) into the compound (5c) is carried out by hydrogenation in the presence of a catalyst in a suitable solvent. The solvent may be, for example, water, acetic acid, alcohols (e.g., methanol, ethanol, isopropanol, etc.), hydrocarbons (e.g., hexane, cyclohexane, etc.), ethers (e.g., dioxane, tetrahydrorfuran, diethyl ether, ethylene glycol dimethyl ether, etc.), esters (e.g., ethyl acetate, methyl acetate, etc.), aprotic polar solvents (e.g., dimethylformamide, etc.), or a mixture of these solvents. The catalyst may be, for example, palladium, palladium black, palladium hydroxide, palladium hydroxide-

carbon, palladium-carbon, platinum, platinum oxide, copper cromite, Raney nickel, etc. The catalyst is used usually in an amount of 0.02 to 1 time of the amount of the compound (5b). The reaction is usually carried out at a temperature of -20°C to about 100°C, preferably at a temperature of 0 ^β C to about 70°C, under 1 to 10 atms of hydrogen gas, for about 0.5 to about 20 hours.

Reaction Scheme- 14

R 17c_ -R 25 17d_ _R 25 - R ^17d H

(5e) (50 < ^5d )

_R 17e_ _R 25 - R ^17c H

(5g) (5h)

wherein R ¹² , R ¹³ and R ²⁵ are the same as defined above, R ^17c is the same groups

for R ¹⁷ but having at least one carboxyl group on the heterocyclic group, R ^17d

is the same groups for R ¹⁷ but having at least one -CONR ¹² R ¹³ (R ^l2 and R ¹³

are the same as defined above) on the heterocyclic group, and R ^17e is the same

groups for R ¹⁷ but having at least one -CH ₂ NR ¹² R ¹³ (R12 and R ¹³ are the same

as defined above) on the heterocyclic group. The reaction of the compound (5d) and the compound (36) is carried out under the same conditions as those in the reaction of the compound (lb) and the compound (5) in the above Reaction Scheme-2.

The reactions of converting the compound (5e) into the compound (50, and converting the compound (5g) into the compound (5h), are carried out

under the same conditions as those in the reaction of converting the compound (5b) into the compound (5c) in the above Reaction Scheme-13.

The reaction of converting the compound (5e) into the compound (5g) is carried out by reduction with using a hydrogenation agent. The hydrogenation agent may be, for example, lithium aluminum hydride, sodium borohydride, diboran, etc., and is used at least in an equimolar amount, preferably in an amount of 1 to 15 moles, to 1 mole of the starting compound. The reduction is carried out in a suitable solvent such as water, a lower alcohol (e.g., methanol, ethanol, isopropanol, etc.), ethers (e.g., tetrahydrofuran, diethyl ether, diisopropyl ether, diglyme, etc.), or a mixture of these solvents. The reaction is usually carried out at a temperature of -60°C top 150°C, preferably at a temperature of -30°C to 100°C, for about 10 minutes to 5 hours. When lithium aluminum hydride or diboran is used as a hydrogenating agent, an anhydrous solvent such as tetrahydrofuran, diethyl ether, diisopropyl ether, diglyme, etc. may be preferably used. Reaction Scheme- 15

R ¹² R ¹³ NH (36) ,„ „ _{β 17o R} 17f_ _R 25 -— R ¹⁷ ε-R ²⁵ - R ^17β H

(5i) (5j) < ^5k )

wherein R ¹² , R ¹³ and R ²⁵ are the same as defined above, R ^17f is the same groups

for R ¹⁷ but having at least one halogen-substituted lower alkyl group on the

heterocyclic group, and R ¹⁷ 8 is the same groups for R ¹⁷ but having at least one

-B'-NR ¹² R ¹³ (B' is a lower alkylene group, R ¹² , R ¹³ are the same as defined above) on the heterocyclic group.

The reaction of the compound (5i) and the compound (36) is carried out under the same conditions as those in the reaction of the compound (li) and the compound (22) in the above Reaction Scheme-6.

The reaction of converting the compound (5j) into the compound (5k) is carried out under the same conditions as those in the reaction of converting the compound (5b) into the compound (5c) in the above Reaction Scheme- 13.

The compound of the formula (1) wherein R ⁶ is a group of the formula:

wherein R ^{l lb} , p and RH ^a are the same as defined above, and showing a trans- configuration at the double bond of the above formula may be isomerized into a cis-compound at the corresponding double bond by being exposed to sunlight, a suitable solvent. The solvent may be the same solvents used in the reaction of the carboxylic halide and the amine compound (5) in the reactions of the compound (lb) and the compound (5) in the above Reaction Scheme-2. The reaction is carried out at a temperature of 0°C to 70°C, preferably at 0°C to room temperature, for about 1 to 10 hours.

Among the starting compounds (32) used in the Reaction Scheme-11 , some compounds (32) are prepared by the following process.

Reaction Scheme- 16

(28)

(37) (38) (32a)

wherein R ⁵ , m, A', M and R ²⁴ are the same as defined above, and R ²⁶ and R ²⁷ are the same or different and each are a lower alkyl group.

The compound of converting the compound (37) into the compound (38) is carried out in the presence of a basic compound in a suitable solvent. The solvent may be, for example, water, lower alcohols (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 a mixture 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.), etc. The reaction is usually carried out at room temperature to about 200°C, preferably at room temperature to about 150°C, for about 10 minutes to about 25 hours.

The reaction of the compound (38) and the compound (28) is carried out under the same conditions as those in the reaction of the compound (27) and the compound (28) in the above Reaction Scheme-10.

The each step of the above Reaction Scheme- 16 can be carried out in one-pot system without isolating the compound (38) from the reaction system.

Reaction Scheme- 17

wherein R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , s, T, u, q, Z and A are me same as defined above, R ^5e

is a lower alkenyloxy group, and R ^5f is a hydroxy group.

The reaction of converting the compound (lo) into the compound (lp) is carried out in the presence of a catalyst and an acid in a suitable solvent. The solvent may be, for example, water, acetic acid, alcohols (e.g., methanol, ethanol, isopropanol, etc.), hydrocarbons (e.g., hexane, cyclohexane, etc.), ethers (e.g., dioxane, tetrahydrorfuran, diethyl ether, ethylene glycol dimethyl ether, etc.), esters (e.g., ethyl acetate, methyl acetate, etc.), aprotic polar solvents (e.g., dimethylformamide, etc.), or a mixture of these solvents. The catalyst may be, for example, palladium, palladium black, palladium hydroxide, palladium hydroxide- carbon, palladium-carbon, platinum, platinum oxide, copper cromite, Raney nickel, etc. The acid includes, for example, organic acids such as p-toluene- sulfonic acid, etc. The catalyst is used in an amount of 0.02 to 1 time of the amount of the compound (lo). The acid is usually used in a catalytic amount. The reaction is usually carried out at a temperature of -20°C to about 150°C, preferably at a temperature of 0 ^β C to about 120°C, for about 0.5 to about 20 hours.

Reaction Scheme- 18

(39) (40) ₍₄₁₎

(42) (43)

(lq) wherein T, u, R ¹ , R ² , R ⁴ , A', Z, R ⁵ , m, R ²¹ , R ²⁴ and X are the same as defined above.

The reaction of the compound (39) and the compound (28) is carried out under the same, conditions as those in the reaction of the compound (li) and the compound (22) in the above Reaction Scheme-6.

The reaction of converting the compound (40) into the compound (41) is carried out under the same conditions as those in the reaction of converting the compound (16) into the compound (17) in the above Reaction Scheme-5. The reaction of the compound (41) and the compound (18) is carried out

under the same conditions as those in the reaction of the compound (17) and the compound (18) in the above Reaction Scheme-5.

The reaction of converting the compound (42) wherein R ²⁴ is a lower alkoxy group into the compound (43) is carried out under the same conditions as those in the reaction of converting the compound (Id) into the compound (le) in the above Reaction Scheme-4.

The reaction of converting the compound (42) wherein R ²⁴ is a phenyl- lower alkoxy group into the compound (43) is carried out under the same conditions as those in the reaction of converting the compound (5b) into the compound (5c) in the above Reaction Scheme-13.

The reaction of the compound (43) and the compound (24) is carried out under the same conditions as those in the reaction of the compound (lb) and the compound (5) in the above Reaction Scheme-2.

The reaction of the compound (19a) and the compound (44) is carried out in a suitable solvent in the presence of a basic compound, at 0°C to lSO'C, preferably at room temperature to about 100°C, for about 0.5 to 8 hours. The solvent may be any solvent which does not disturb the reaction, and may be water, alcohols (e.g., methanol, ethanol, isopropanol, etc.), aromatic hydro¬ carbons (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.), polar solvents (e.g., dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, etc.), or a mixture of these solvents. The compound (44) is usually used at least in an equimolar amount, preferably in an amount of 1 to 5 moles, to 1 mole of the

compound (19a). The basic compound may be the same basic compounds which are used in the reaction of the compound (6) and the compound (7) in the above Reaction Scheme-3. The starting compound (9) can be prepared, for example, by the process in Reaction Scheme- 19 or -20, as explained below. Reaction Scheme- 19

wherein T, u, Rl, R ² , R ⁴ , A', Z, R ⁵ , m, X, R ²⁴ and Rl9 are the same as defined above.

The reaction of the compound (45) and the compound (28) is carried out under the same conditions as those in the reaction of the compound (li) and the compound (22) in the above Reaction Scheme-6.

The reaction of converting the compound (46) wherein R ²⁴ is a lower alkoxy group into the compound (47) is carried out under the same conditions as those in the reaction of converting the compound (Id) into the compound (le) in the above Reaction Scheme-4.

The reaction of converting the compound (46) wherein R ²⁴ is a phenyl- lower alkoxy group into the compound (47) is carried out under the same

conditions as those in the reaction of converting the compound (5b) into the compound (5c) in the above Reaction Scheme-13.

The reaction of the compound (47) and the compound (24) is carried out under the same conditions as those in the reaction of the compound (lb) and the compound (5) in the above Reaction Scheme-2. Reaction Scheme-20

wherein R ¹⁹ , R ⁵ and m are the same as defined above, R ^19a is a lower alkoxy group.

The reaction of the compound (48) and the compound (49) is carried out in a suitable solvent in the presence of a basic compound. The solvents and the basic compounds are the same ones which are used in the reaction of the compound (6) and the compound (7) in the above Reaction Scheme-3. The compound (49) is usually used at least in an equimolar amount, preferably in an amount of 1 to 3 moles, to 1 mole of the compound (48). The reaction is usually carried out at room temperature to 200°C, preferably at room temperature to

about 150°C, for about 1 to about 60 hours.

The reaction of converting the compound (50) into the compound (9b) is carried out under the same conditions as those in the reaction of converting the compound (5b) into the compound (5c) in the above Reaction Scheme-13. The reaction of the compound (51) and the compound (52) is carried out in a suitable solvent in the presence of a basic compound 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, cyclo- hexane, etc.), dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, or a mixture of these solvents. The basic compound may be the same ones which are used in the reaction of the compound (lb) and the compound (5) using a carboxylic halide in the above Reaction Scheme-2. The catalyst includes, for example, palladium chloride, tetrakis(triphenylphosphine)palladium, palladium acetate, l,3-bis(diphenylphosphino)propane, or a mixture of these solvents. The reaction is usually carried out at 0°C to 200°C, preferably at room temperature to about 150°C, for about 1 to about 20 hours. The compound (52) is usually used at least in an equimolar amount, preferably in an amount of 1 to 10 moles, to 1 mole of the compound (51), The basic compound is usually used at least in an equimolar amount, preferably in an amount of 1 to 3 moles, to 1 mole of the compound (51). The catalyst is used at least in an excess amount of the compound (51).

The reaction of converting the compound (53) into the compound (50) is carried out under the same conditions as those in the reaction of converting the compound (Id) into the compound (l e) in the above Reaction Scheme-4.

Reaction Scheme-21

(10a)

(lr) wherein T, u, R ⁵ , q, R ^l8 , R ¹ , R ² , R ⁴ , A, Z, s and W are the same as defined above,

R ^5c J is an amino group having optionally a lower alkyl substituent, and a group:

-C(0)CH ₂ -P(0)(R ^l8 ) ₂ and a group: -R ⁵ l are positioned each other at ortho-

position.

The reaction of the compound (10a) and the compound (44) is carried out under the same conditions as those in the reaction of the compound (10) and the compound (12) in the above Reaction Scheme-3. The compound (lr) wherein W is a group of the formula: _{+ R} 9b

- _R 29b ^X_ wherein R ^29b and X- are the same as defined above) can be obtained by treating with a hydrohalogenic acid such as hydrochloric acid, hydrobromic acid, etc., after the reaction is complete.

Reaction Scheme-22

R ²² CHO (20)

(lw) (It)

wherein R ^l , R ² , T, u, R ⁴ R ¹⁶ , R ¹⁸ and R ²² are the same as defined above.

The reaction of the compound (54) and the compound (12) is carried out under the same conditions as those in the reaction of the compound (10) and the compound (12) in the above Reaction Scheme-3.

The reaction of converting the compound (Is) wherein R ¹⁶ is a lower alkoxy group into the compound (It) is carried out under the same conditions as those in the reaction of converting the compound (Id) into the compound (le) in the above Reaction Scheme-4. The reaction of the compound (54) and the compound (20) is carried out under the same conditions as those in the reaction of the compound (10) and the compound (20) in the above Reaction Scheme-3.

The starting compound (54) is prepared, for example, by the following process.

Reaction Scheme-23

(58) (58a)

wherein R ¹ , R ² , M, R ¹⁹ and R ¹⁸ are the same as defined above.

The halogenation reaction of the compound (58) is carried out under conventional halogenation conditions which are employed in the halogenation reaction of a carboxylic acid. The reaction of the carboxylic acid halide compound of the compound (58) and the compound (55) is carried out in the presence or absence of a basic compound in a suitable solvent. The solvent includes, for example, halogenated hydrocarbons (e.g., methylene chloride, 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 polar solvents (e.g., N,N-dimethyl- formamide, dimethylsulfoxide, hexamethylphosphoric triamide, etc.), alcohols (e.g., methanol, ethanol, propanol, butanol, 3-methoxy-l -butanol, ethyl- cellosolve, methylcellosolve, et.), pyridine, acetone, acetonitrile, water, or a mixture of these solvents. The basic compound includes, for example, organic basic compounds such as triethylamine, trimethylamine, pyridine, dimethyl- aniline, N-methylmo holine, DBN, DBU, DABCO, etc., or inorganic basic

compounds such as potassium carbonate, sodium carbonate, potassium hydride, sodium hydride, potassium hydroxide, sodium hydroxide, silver carbonate, sodium methoxide, sodium ethoxide, etc. The compound (55) is used at least in an equimolar amount, preferably in an amount of 1 to 3 moles, to 1 mole of the carboxylic acid halide compound of the compound (58). The reaction is usually carried out at -30°C to about 180°C, preferably at 0°C to about 150°C, for about 5 minutes to about 30 hours.

The reaction of the compound (58a) and the compound (56) is carried out in a suitable solvent, or without a solvent, at 0°C to about 200°C, preferably at room temperature to about 150°C. The solvent may be the same solvents used in the above reaction of the carboxylic halide of the compound (58) and the compound (55). The compound (56) is used at least in an equimolar amount, preferably in an amount of 1 to 1.5 mole, to 1 mole of the compound (58a). The reaction is carried out for about 1 hour to about 5 hours. The reaction of the compound (58b) and the compound (7) is carried out under the same conditions as those in the reaction of the compound (9) and the compound (7) in the above Reaction Scheme-3. ' Reaction Scheme-24

(lv)

wherein R ¹ , R ² , R ⁴ , R ^{l lb} , T, u and R ¹⁷ are the same as defined above.

The reaction of the compound (lu) and the compound (5) is carried out under the same conditions as those in the reaction of the compound (lb) and the compound (5) in the above Reaction Scheme-2. The starting compound (24) can be prepared, for example, by the method of Reaction Scheme-25, as explained below. Reaction Scheme-25

(24a) wherein R ¹ , R ² , M, X and T are the same as defined above, and R ³⁰ is a lower alkylsulfonyl group.

The reaction of the compound (59) and the compound (60) is carried out under the same conditions as those in the reaction of the compound (li) and the compound (22) in the above Reaction Scheme-6. The reaction of the compound (61) and the compound (62) is carried out under the same conditions as those in the reaction of the compound (li) and the compound (22) in the above Reaction Scheme-6.

The reaction of converting the compound (63) into the compound (24a) is carried out by treating the compound (63) with hydrazine in a suitable

solvent, or hydrolyzing the compound (63). The solvent used in the reaction with hydrazine may be, in addition to water, the same solvents used in the reaction using a carboxylic acid halide in the reaction of the compound (lb) and the compound (5) in Reaction Scheme-2. The reaction is usually carried out at room temperature to about 120°C, preferably at 0°C to about 100°C, for about 0.5 hour to about 5 hours. The hydrazine is usually used at least in an equimolar amount, preferably in an amount of 1 to 6 moles, to 1 mole of the compound (63).

The hydrolysis is carried out in a suitable solvent or without a solvent in the presence of an acid or a basic compound. The solvent includes, for example, water, lower alcohols (e.g., methanol, ethanol, isopropanol, etc.), ketones (e.g., acetone, methyl ethyl ketone, etc.), ethers (e.g., diethyl ether, dioxane, tetra¬ hydrofuran, ethylene glycol dimethyl ether, etc.), fatty acids (e.g., acetic acid, formic acid, etc.), or a mixture of these solvents. The acid includes, for example, mineral 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, an alkali metal carbonate (e.g., sodium carbonate, potassium carbonate, etc.), an alkali metal or alkaline earth metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, calcium hydroxide, etc.). The reaction is usually carried out at room temperature to about 200°C, preferably at room temperature to about 150°C, for about 10 minutes to about 25 hours.

Among the desired compounds (1) of the present invention, the compounds having an acidic group can easily be converted into salts by treating them with a pharmaceutically acceptable basic compound. The basic compound includes, for example, an alkali metal hydroxide such as sodium

hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, etc., an alkali metal carbonate such as sodium carbonate, etc., an alkali metal hydrogen carbonate such as potassium hydrogen carbonate, an alkali metal alkoxide such as sodium methylate, potassium ethylate, and the like. Besides, among the desired compounds (1) of the present invention, the compounds having a basic group can easily be converted into acid addition salts thereof by treating them 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-toluene- sulfonic acid, ethanesulfonic acid, oxalic acid, maleic acid, fumaric acid, citric acid, succinic acid, benzoic acid, etc.). These salts can be also used as an active ingredient of the pharmaceutical composition of the present invention as well as the compound (1) in a free form. In addition, the compounds of the present invention also include stereoisomers and optical isomers, and these isomers are also used as an active ingredient.

The desired compound obtained in the above Reaction Schemes can easily be isolated and purified by conventional isolation methods from the reaction system. The isolation methods are, for example, distillation method, recrystallization method, column chromatography, ion exchange chromato- graphy, gel chromatography, affinity chromatography, preparative thin layer chromatography, extraction with solvent, dilution method, and the like.

The compounds (1) of the present invention are useful as a protein kinase inhibitor, and can be used in the form of a conventional pharmaceutical preparation. The preparation is prepared by using conventional diluents or carriers such as fillers, thickening agents, binders, wetting agent, disintegrators,

surfactants, lubricants, and the like. The pharmaceutical preparations can be selected from various forms in accordance with the desired utilities, and the representative forms are tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (solutions, suspensions, etc.), and the like. In order to form in tablets, there are used carriers such as vehicles (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, polyvinylpyrrohdone, etc.), disintegrators (e.g. dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium laurylsulfate, stearic monoglyceride, starches, lactose, etc.), disintegration inhibitors (e.g. white sugar, stearin, cacao butter, hydrogenated oils, etc.), absorption promoters (e.g. quaternary ammonium base, sodium laurylsulfate, etc.), wetting agents (e.g. glycerin, starches, etc.), adsorbents (e.g. starches, lactose, kaolin, bentonite, colloidal silicates, etc.), lubricants (e.g. purified talc, stearates, boric acid powder, polyethylene glycol, etc.), and the like. Moreover, the tablets may also be in the form of a conventional coated tablet, such as sugar-coated tablets, gelatin- coated tablets, enteric coated tablets, film coating tablets, or double or multiple layer tablets. In the preparation of pills, the carriers may be conventional ones, and include, for example, vehicles (e.g. glucose, lactose, starches, cacao butter, hydrogenated vegetable oils, kaolin, talc, etc.), binders (e.g. gum arabic powder, tragacanth powder, gelatin, edianol, etc.), disintegrators (e.g. laminaran, agar, etc.), and the like. In the preparation of suppositories, the carriers may be

conventional ones, and include, for example, polyethylene glycol, cacao butter, higher alcohols, higher alcohol esters, gelatin, semi-synthetic glycerides, and the like. The capsules are prepared by mixing the active compound with a conventional carrier, and fulfilling the mixture into hard gelatin capsules or soft capsules. In the preparation of injections, the solutions and suspensions are sterilized and are preferably made isotonic with the blood. In the preparation of these solutions, emulsions and suspensions, there are used conventional diluents, such as water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and the like. In this case, the pharmaceutical preparations may also be incorporated with sodium chloride, glucose, or glycerin in an amount sufficient to make them isotonic, and may also be incorporated with conventional solubilizers, buffers, anesthetizing agents. Besides, the pharmaceutical preparations may optionally be incorporated with coloring agents, preservatives, perfumes, flavors, sweetening agents, and other medicaments, if required.

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

The pharmaceutical preparation of the present invention may be administered in any method, and the suitable method for administration may be determined in accordance with various forms of preparations, ages, sexes and other conditions of the patients, the degree of severity of diseases, and the like.

For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered orally. Injections are intravenously administered alone or together with a conventional auxiliary liquid (e.g. glucose, amino acid solutions), and further are optionally administered alone in intramuscular, intracutaneous, subcutaneous, or intraperitoneal route, if required. Suppositories are administered in intrarectal route.

The dosage of the pharmaceutical preparation of the present invention may be selected in accordance with the usage, ages, sexes and other conditions of the patients, the degree of severity of the diseases, and the like, but it is usually in the range of about 0.6 to 50 mg of the compound (1) or a salt thereof per 1 kg of body weight of the patient per day. The active compound is contained in an amount of about 10 to 1000 mg per one unit of the dosage form.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is illustrated in more detail by the following

Preparations of pharmaceutical composition, Reference Examples of processes for preparing the starting compounds to be used for preparing the desired compounds of the present invention, and Examples of processes for preparing the desired compounds, and Experiment of the activities of the desired compounds of the present invention.

Preparation 1

Film coated tablets are prepared from the following components. Components Amount

2- [2-Methoxy-4- { 3-[4-(4-methyl- 1 -piperazinyl)- 1 -piperidiny lcarbony 1] aery loyl } phenoxymethyl - carbonylaminojbenzothiazole 150 g

Avicel (trade mark of microcrystalline cellulose manufactured by Asahi Chemical Industry, Co., Ltd.) 40 g

Corn starch 30 g

Magnesium stearate 2 g

Hydroxypropyl methylcellulose 10 g

Polyethylene glycol-6000 3 g Castor oil 40 g

Ethanol 40 g

The active compound of the present invention, Avicel, corn starch and magnesium stearate are mixed and kneaded, and the mixture is tabletted by using a conventional pounder (R 10 mm) for sugar coating. The tablets thus obtained are coated with a film coating agent consisting of hydroxypropyl

methylcellulose, polyethylene glycol-6000, castor oil and ethanol to give film coated tablets. Preparation 2

Tablets are prepared from the following components.

Components Amount

2-[3-Methoxy-4-{3-[4-(3,4-dimethyl-l-piperazinyl)- l-piperidinylcarbonyl]acryloyl}phenoxymethyl- carbonylaminojbenzimidazole 150 g

Citric acid 1.0 g Lactose 33.5 g

Dicalcium phosphate 70.0 g

Pullonic F-68 30.0 g

Sodium laurylsulfate 15.0 g

Polyvinylpyrrohdone 15.0 g Polyethylene glycol (Carbowax 1500) 4.5 g

Polyethylene glycol (Carbowax 6000) 45.0 g

Corn starch 30.0 g

Dry sodium stearate 3.0 g

Dry magnesium stearate 3.0 g Ethanol q.s.

The active compound of the present invention, citric acid, lactose, dicalcium phosphate, Pullonic F-68 and sodium laurylsulfate are mixed.

The mixture is screened with No. 60 screen and is granulated with an alcohol solution containing polyvinylpyrrohdone, Carbowax 1500 and 6000. If required, an alcohol is added thereto so that the powder mixture is made a paste-

like mass. Corn starch is added to the mixture and the mixture is continuously mixed to form uniform particles. The resulting particles are passed through No. 10 screen and entered into a tray and then dried in an oven at 100°C for 12 to 14 hours. The dried particles are screened with No. 16 screen and thereto are added dry sodium laurylsulfate and dry magnesium stearate, and the mixture is tabletted to form the desired shape.

The core tablets thus prepared are vanished and dusted with talc in order to guard from wetting. Undercoating is applied to the core tablets. In order to administer the tablets orally, the core tablets are vanished several times. In order to give round shape and smooth surface to the tablets, further undercoating and coating with lubricant are applied thereto. The tablets are further coated with a coloring coating material until the desired colored tablets are obtained. After drying, the coated tablets are polished to obtain the desired tablets having uniform gloss. Preparation 3

An injection preparation is prepared from the following components.

Components A ount

2-{2-(3-Moφholinopropyl)-4-[3-(4-pyridyl)acryloyl}- phenoxymethylcarbonylamino}benzothiazole 5 g Polyethylene glycol (molecular weight: 4000) 0.3 g

Sodium chloride 0.9 g

Polyoxyethylene sorbitan monooleate 0.4 g

Sodium metabisulfite 0.1 g

Methyl-paraben 0.18 g Propyl-paraben 0.02 g

Distilled water for injection 10.0 ml

The above parabens, sodium metabisulfite and sodium chloride are dissolved with stirring in distilled water of half volume of the above at 80°C. The solution thus obtained is cooled to 40°C, and the active compound of the present invention and further polyethylene glycol and polyoxyethylene sorbitan monooleate are dissolved in the above solution. To the solution is added distilled water for injection to adjust to the desired volume, and the solution is sterilized by filtering with an appropriate filter paper to give an injection preparation. Reference Example 1

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

^! H-NMR (CDC1 ₃ ) δppm: 1.24 (6H, d, J=7Hz), 3.39 (IH, sept, J=7Hz), 4.69

(2H, s), 6.75 (IH, dd, J=lHz, J=8Hz), 6.95-7.3 (3H, m) Reference Example 2

A solution of α-(2-isopropylphenoxy)acetic acid (13.1 g) in thionyl

chloride (30 ml) is refluxed for 30 minutes. The mixture is concentrated under reduce pressure to remove the excess thionyl chloride, and the resultant is dissolved in dichloromethane (50 ml). The mixture is added dropwise into a solution of 2-aminobenzothiazole (9.1 g) and pyridine (7.2 ml) in dichloro- methane (100 ml) under ice-cooling. The mixture is stirred at the same temperature for five hours, and then washed with water, dried, and concentrated under reduced pressure. To the residue is added ethanol to give 2-(2-isopropyl- phenoxymethylcarbonylamino)benzothiazole (16.66 g). Yellow powder Η-NMR (CDC1 ₃ ) δppm: 1.32 (6H, d, J=7Hz) 3.43 (IH, sept, J=7Hz), 4.78

(2H, s), 6.85 (IH, dd, J=lHz, J=8Hz), 7.0-7.55 (5H, m), 7.8-7.9 (2H, m), 9.74 (IH, br)

Reference Example 3

To a solution of dimethyl methylphosphonate (19.5 ml) in anhydrous tetrahydrofuran (300 ml) is added a 1.72 M solution of n-butyl lithium in n- hexane (107 ml) at -50°C. Thirty minutes later, to the mixture is added in portions 2-(2-methoxy-4-formylphenoxymethylcarbonylamino)benzothiazol e (20.5 g) under nitrogen atmosphere. The mixture is stirred at -50°C for one hour, and thereto is added water. The mixture is acidified with cone, hydro- chloric acid, and extracted with ethyl acetate. The extract is washed with water, dried and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; dichloromethane:memanol = 200: 1 → 30:1) to give dimethyl {2-[3-methoxy-4-(2-benzothiazolylaminocarbonyl- methoxy)phenyl]-2-hydroxyethyl}phosphonate (19.0 g).

^! H-NMR (CDCI ₃ ) δppm: 2.05-2.35 (2H, m), 3.73, 3.76, 3.78 and 3.81 (6H,

each s), 3.98 (2H, d, J=2.5Hz), 4.01 (3H, s), 4.77 (2H, s), 5.0-5.15 (IH, m), 6.90 (IH, dd, J=2Hz, J=8Hz), 6.98 (IH, d, J=8Hz), 7.07 (IH, d, J=2Hz), 7.25-7.5 (2H, m), 7.8-7.9 (2H, m), 10.66 (IH, br) To a solution of dimethyl {2-[3-methoxy-4-(2-benzothiazolylamino- carbonylmethoxy)phenyl]-2-hydroxyethyl}phosphonate (19.0 g) in chloroform (300 ml) is added active manganese dioxide (17.7 g), and the mixture is refluxed for three hours. To the mixture is additionally added active manganese dioxide (18 g), and the mixture is refluxed for three hours. To the mixture is further added active manganese dioxide (20 g), and the mixture is refluxed for three hours. The manganese dioxide is collected by filtration, and washed with chloroform. The filtrate and the washings are combined and concentrated under reduced pressure to remove the chloroform. The residue is purified by silica gel column chromatography (solvent; dichloromethane :methanol = 200: 1 — 50: 1) to give dimethyl {[3-methoxy-4-(2-benzothiazolylaminocarbonylmethoxy)- benzoyl]methyl}phosphonate (7.76 g). White powder ¹ H-NMR (CDCI ₃ ) δppm: 3.62 (2H, d, J=22.5Hz), 3.79 (6H, d, J=l 1.2Hz),

4.04 (3H, s), 4.85 (2H, s), 7.02 (IH, d, J=8.5Hz), 7.3-7.55 (2H, m), 7.6-7.7 (2H, m), 7.8-7.9 (2H, m), 10.31 (IH, br) Reference Example 4

To a solution of chloroacetyl chloride (10.0 ml) in anhydrous 1,2-dichloro- ethane (250 ml) is added aluminum chloride (12 g) at room temperature, and the mixture is stirred for 20 minutes. To the mixture is added at once 2-(2-isopropyl-

phenoxymethylcarbonylamino)benzothiazole (20 g), and the mixture is stirred at room temperature for one hour. The reaction mixture is poured into water, and thereto is added n-hexane. The precipitates are collected by filtration, washed with water, and dried to give 2-[2-isopropyl-4-(2-chloroacetyl)phenoxy- methylcarbonylaminojbenzothiazole (25.9 g). White powder

^! H-NMR (DMSO-dt _f ) δppm: 1.24 (6H, d, J=7Hz), 3.38 (IH, m), 5.12 (4H, s),

7.01 (IH, d, J=9Hz), 7.25-7.55 (2H, m), 7.7-7.95 (3H, m), 7.97 (IH, d, J=8Hz), 13.00 (lH, br) Reference Example 5

A suspension of 2-[2-isopropyl-4-(2-chloroacetyl)phenoxymethyl- carbonylamino]benzimidazole (4.0 g) and triphenylphosphine (2.8 g) in chloroform (100 ml) is refluxed for 7 hours. The reaction mixture is concentrated under reduced pressure, and the residue is crystallized from dichloromethane-diethyl ether to give [3-isopropyl-4-(2-benzothiazolyl- aminocarbonylmethoxy)benzoyl]methyltriphenylphosphonium chloride (3.8 g). Η-NMR (DMSO-α δppm: 1.23 (6H, d, J=7Hz), 3.40 (IH, m), 5.18 (2H, s),

6.19 (2H, d, J=13.5Hz), 7.09 (IH, d, J=9Hz), 7.25-7.5 (2H, m), 7.6-8.05 (19H, m), 12.77 (IH, s) To a solution of [3-isopropyl-4-(2-benzothiazolylaminocarbonyl- methoxy)benzoyl]methyltriphenylphosphonium chloride (3.3 g) in methanol (50 ml) is added DBU (1 ml), and the mixture is stirred at room temperature for two hours. The precipitated crystals are collected by filtration, washed with methanol, and dried to give [3-isopropyl-4-(2-benzothiazolylaminocarbonyl-

methoxy)benzoyl]methylenetriphenylphosphorane (2.27 g). White powder 1H-NMR (CDC1 ₃ ) δppm: 1.32 (6H, d, J=7Hz), 3.42 (IH, sept, J=7Hz), 4.2-

4.6 (IH, m), 4.73 (2H, s), 6.75 (IH, d, =8.5Hz), 7.25-8.0 (21H, m), 10.01 (IH, br) Using the suitable starting compounds, the following compound is obtained in the same manner as in Reference Example 5. [3-(3-chloropropyl)-4-(2-benzothiazolylaminocarbonylmethoxy) benzoyl]- methylenetriphenylphosphonium chloride: White powder ^! H-NMR (CDCI ₃ ) 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 (IH, d, J=8.7Hz), 7.34 (IH, t, J=7.5Hz), 7.48 (IH, t, J=7.0 Hz), 7.76-8.02 (19H, m), 12.75 (lH, br)

Reference Example 6 To dimethylformamide (200 ml) are added 2-methoxy-4-acetylphenol (20 g), ethyl α-bromoacetate (15 ml) and potassium carbonate (18.3 g), and the mixture is stirred at room temperature overnight. After the reaction is complete, water is added to the mixture, and the mixture is extracted with ethyl acetate. The extract is washed with aqueous sodium hydrogen carbonate solution, and dried over magnesium sulfate, and concentrated under reduced pressure to remove the solvent. The resulting crystals are collected, and washed with n- hexane-diethyl ether to give ethyl oc-(2-methoxy-4-acetylphenoxy)acetate

(23.86 g).

To chloroform (230 ml) are added ethyl oc-(2-methoxy-4-acetylphenoxy)-

acetate (23 g) and copper (II) bromide (55 g), and the mixture is refluxed for 3.5 hours. After the reaction is complete, the mixture is filtered through a cerite pad to remove the precipitates, and washed with sodium hypochlorite. The filtrate is dried over magnesium sulfate, and concentrated under reduced pressure to remove the solvent, and then crystallized to give ethyl α-[2-methoxy-4-(2- bromoacetyl)phenoxy] acetate (21.28 g).

To chloroform (200 ml) are added ethyl α-[2-methoxy-4-(2-bromoacetyl)- phenoxy] acetate (20 g) and triphenylphosphine (20.6 g) in an ice-bath, and the mixture is stirred for one hour. After confirming that the starting compounds are well consumed, the mixture is washed with an aqueous potassium carbonate solution. The mixture is dried over magnesium sulfate, and concentrated under reduced pressure to remove the solvent. To the residue is added methanol (200 ml), and thereto is added dropwise sodium hydroxide in an ice-bath. After confirming that the starting compounds are well consumed, to the mixture is added cone, hydrochloric acid. The precipitated crystals are washed with water and diethyl ether, and dried to give (3-methoxy-4-carboxymethoxybenzoyl)- methylenetriphenylphosphorane (25 g).

To dichloromethane (50 ml) are added (3-methoxy-4-carboxymethoxy- benzoyl)methylenetriphenylphosphorane (5 g), 2-aminobenzothiazole (1.9 g), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (2.93 g) and triethylamine (3.3 ml), and the mixture is stirred overnight. After the reaction is complete, the mixture is washed with an aqueous sodium hydrogen carbonate solution, and dried over magnesium sulfate to remove the solvent, and further recrystallized from toluene to give [3-methoxy-4-(2-benzothiazolylaminocarbonylmethoxy)- benzoy 1] methy lenetriphenylphosphorane (5.17 g) .

Pale yellow powder

*H-NMR (CDCI ₃ ) δppm: 4.03 (3H, s), 4.12-4.62 (IH, m), 4.79 (2H, s), 6.96

(IH, d, J=8.3Hz), 7.25-7.90 (22H, m) Reference Example 7 To a solution of N-benzyl-4-piperidone (8.0 g) and 3,4-dimethyl- piperazine (9.5 g) in ethanol (100 ml) are added 5 % platinum-carbon (2 g) and acetic acid (14.4 ml), and the mixture is subjected to catalytic hydrogenation at room temperature under atmospheric pressure. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. Water is added to the resultant, and the mixture is basified with a 5% aqueous sodium hydroxide solution, and the mixture is extracted with diethyl ether. The extract is washed with water, dried and concentrated under reduced pressure to remove the solvent. The residue is dissolved in ethanol, and thereto is added to cone, hydrochloric acid to give a hydrochioride. The resulting white powder is collected by filtration, dissolved in water, and basified with a 5% aqueous sodium hydroxide solution. The mixture is extracted with diethyl ether, washed with water, dried, and concentrated under reduced pressure to give 4-(3,4- dimethyl-1 -piperazinyl)- 1-benzylpiperidine (4.2 g).

Η-NMR (CDCI ₃ ) 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-l -piperazinyl)- 1-benzylpiperidine (4.2 g) in ethanol (50 ml) is added 20 % palladium hydroxide-carbon (0.4 g), and the mixture is subjected to catalytic hydrogenation at 50°C under atmospheric pressure. The catalyst is removed by filtration, and the filtrate is concentrated

under reduced pressure. The residue is evaporated to give 4-(3,4-dimethyl-l- piperazinyl)piperidine (1.65 g).

Colorless oil b.p. 145°C (0.3 mmHg) Η-NMR (CDC1 ₃ ) 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 (50 g) in dichloromethane (300 ml) is cooled with ice. To the solution is added N-methylmorpholine (22.5 g), and then further thereto is added dropwise isobutyl chloroformate (30 g). The mixture is stirred at the same temperature for about one hour, and thereto is added dropwise pyrrolidine (18.8 ml) at the same temperature. The mixture is warmed to room temperature, and stirred for two days. The mixture is washed twice with water (250 ml), and dried over magnesium sulfate. The mixture is concentrated under reduced pressure, and the residue is recrystalhzed from ethyl acetate-n-hexane to give 2-(l-pyrrolidinyl)carbonyl-l-benzylpyrrolidine (31 g), as white powder.

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

Lithium aluminum hydride (9 g) is suspended in dry tetrahydrofuran (100

ml) under ice-cooling, and thereto is added dropwise a solution of 2-(l- pyrrolidinyl)carbonylpyrrolidine (33 g) in dry tetrahydrofuran (80 ml). The mixture is refluxed under nitrogen atmosphere for four hours. The mixture is cooled with ice, and thereto is added a saturated aqueous sodium sulfate solution (about 15 ml), and then mixture is further stirred at room temperature for three hours. The precipitated sodium sulfate is removed by filtration, washed well with chloroform. The filtrate and the washings are combined, concentrated under reduced pressure, and evaporated to give 2-(l-pyrrolidinyl)methyl- pyrrolidine (22 g). Colorless oil

B.p. 99-101 °C (20 mmHg) Reference Example 9

4-Benzyl-2-chloromethylmorpholine (15 g) and 4-(2-hydroxyethyl)- piperazine (25 ml) are mixed, and the mixture is heated with stirring at 130°C for five hours. After the reaction is complete, the mixture is extracted with chloro¬ form, and the extract is dried over magnesium sulfate. The residue thus obtained is concentrated under reduced pressure to give 4-benzyl-2-[4-(2-hydroxyethyl)- l-piperazinyl]methylmoφholine (16 g).

Η-NMR (CDC1 ₃ ) δppm: 1.86 (IH, 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-B enzyl-2- [4- (2-hydroxyethyl)- 1 -piperazinyl] methy lmoφholine ( 16 g) is dissolved in ethanol (160 ml), and thereto is added palladium hydroxide (1.6 g). The mixture is subjected to de-benzylation at 50°C under hydrogen atmosphere. Five hours later, the mixture is filtered through a cerite pad, and the

filtrate is concentrated under reduced pressure. The resulting crystals are washed with diethyl ether-n-hexane to give 2-[4-(2-hydroxyethyl)-l- piperazinyl]methylmoφholine (9.09 g).

M.p. 73-75.5°C

White powder

Η-NMR (CDC1 ₃ ) δppm: 2.25 (IH, 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 (IH, m)

Using the suitable starting compounds, the compounds as listed in Tables 1 to 4 are obtained in the same manner as in Reference Example 1.

Table 1

Reference Example 13

R ⁵ : -(CH ₂ ) ₃ CH ₃ (2-position) m: 1 A: -CH ₂ -

M.p. 102- 104°C Solvent for recrystallization: Ethanol-water

Crystalline form: White powder Form: Free

Table 2

Reference Example 14

R ⁵ _: -(CH ₂ ) ₄ CH ₃ (2-position) m: l A: -CH.-

M.p. 71.4-74.4'C Solvent for recrystallization: Ethanol-water Crystalline form: White powder Form: Free

Reference Example 17

R ⁵ : -(CH ₂ ) ₄ - (combined at 2- and 3-positions) m: 2 ' A: -CH ₂ -

Crystalline form: White powder Form: Free NMR (6)

Table 3

Reference Example 22

R ⁵ : C ₂ H ₅ (3-position) m: 1 A: -CH ₂ -

M.p. 102-104°C Solvent for recrystallization: Ethanol-water

Crystalline form: White powder Form: Free

Reference Example 23

R ⁵ : -(CH ₂ ) ₂ CH ₃ (3-position) m: 1 A: -CH ₂ -

M.p. 63.5-66.0°C Solvent for recrystallization: Ethanol-water

Crystalline form: White powder Form: Free

Table 4

Reference Example 24

R ⁵ : -(CH ₂ ) ₃ CH ₃ (3-position) m: 1 A: -CH ₂ -

M.p. 69.0-72.5°C Solvent for recrystallization: Ethanol-water

Crystalline form: Colorless prisms Form: Free NMR (11)

Η-NMR spectrum (NMR (1) to NMR (17)) as described in Tables 1 to 4 are as follows:

NMR (1) (DMSO-dg) 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 (IH, s) NMR (2) (DMSO-d ₆ ) 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 (IH, s)

NMR (3) (CDC1 ₃ ) 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 (IH, d, J=8.3Hz), 6.9-7.05 (IH, m), 7.15 (2H, t, J=7.2Hz), 9.4-10.1 (lH, m) NMR (4) (DMSO-d ₆ ) δppm: 4.77 (2H, s), 6.88-7.30 (4H, m), 13.09 (IH, s)

NMR (5) (CDCI ₃ ) δppm: 4.76 (2H, s), 6.89 (IH, dd, J=1.5Hz, J=8.0Hz),

6.99 (IH, dt, J=1.5Hz, J=7.6Hz), 7.23 (IH, dt, J=1.5Hz, J=7.6Hz), 7.41 (IH, dd, J=1.5Hz, J=8.0Hz), 8.16 (IH, br)

NMR (6) (DMSO-d ₆ ) δppm: 1.6-1.85 (4H, m), 2.55-2.75 (4H, m), 4.63 (2H,

s), 6.57 (IH, d, J=8Hz), 6.65 (IH, d, J=7.5Hz), 6.9-7.05 (IH, m), 12.94 (IH, br) NMR (7) (DMSO-d ₆ ) δppm: 2.10 (3H, s), 2.20 (3H, s), 4.63 (2H, s), 6.64

(IH, d, J=8Hz), 6.75 (IH, d, J=7.5Hz), 6.95-7.1 (IH, m), 12.9 (IH, br)

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

12.87 (IH, s) NMR (9) (DMSO-d ₆ ) δppm: 2.22 (6H, s), 4.48 (2H, s), 6.48 (2H, s), 6.60

(lH, s)

NMR (10) (DMSO-d ₆ ) δppm: 2.26 (3H, s), 4.62 (2H, s), 6.60-6.80 (3H, m),

7.11-7.18 (lH. m)

NMR (11) (DMSO-d ₆ ) 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 (lH, m), 13.00 (lH, br)

NMR (12) (CDC1 ₃ ) δppm: 1.22 (6H, d, J=6.9Hz), 2.77-3.00 (IH, m), 4.68

(2H, s), 6.66-6.76 (IH, m), 6.81-6.95 (2H, m), 7.17-7.29 (IH, m), 8.65 (IH, brs)

NMR (13) (CDCI ₃ ) δppm: 4.69 (2H, s), 6.79-6.85 (IH, m), 6.85-7.04 (2H,

m), 7.19-7.28 (IH, m), 8.00 (IH, br)

NMR (14) (CDCI ₃ ) δppm: 4.69 (2H, s), 6.62-6.79 (3H, m), 7.20-7.32 (IH,

m), 9.07 (lH, br) NMR (15) (CDCI ₃ ) δppm: 3.79 (3H, s), 4.67 (2H, s), 6.47-6.61 (3H, m),

7.16-7.26 (IH, m), 9.12 (IH, br)

NMR (16) (CDCI ₃ ) 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 (IH, m), 8.34 (IH, br)

Using the suitable starting compounds, the compounds as listed in Tables 5-9 are obtained in the same manner as Reference Example 2.

Table 5

Table 6

Reference Example 36

R ⁵ : F (2-position) m: 1 A: -CH ₂ - R ⁴ : H

Crystalline form: Pale yellow powder Form: Free NMR (7)

Reference Example 37

R ⁵ : Cl (2-position) m: 1 A: -CH ₂ - R ⁴ : H

Crystalline form: Yellow powder Form: Free NMR (8)

Reference Example 38

R ⁵ : -(CH ₂ ) ₄ - (combined at 2- and 3-positions) : 2 A: -CH ₂ - R ⁴ : H

Crystalline form: White powder Form: Free NMR (9)

Table 7

Reference Example 39

R ⁵ : CH ₃ (2- and 3-positions) m: 2 A: -CH ₂ - R ⁴ : H

Crystalline form: Yellow powder Form: Free NMR (10)

Reference Example 40

R ⁵ : CH ₃ (2- and 6-positions) m: 2 A: -CH ₂ - R : H

Crystalline form: Yellow powder Form: Free NMR (11)

Reference Example 41

R ⁵ : CH ₃ (3- and 5-positions)

Table 8

Reference Example 44

R ⁵ : CH ₃ (3-position) m: 1 A: -CH ₂ - R ⁴ : H

Solvent for recrystallization: Ethyl acetate-n-hexane Crystalline form: Pale brown powder Form: Free NMR (15)

Reference Example 45

R ⁵ : C ₂ H ₅ (3-position) m: 1 A: -CH ₂ - R ⁴ : H

Crystalline form: Beige needles Form: Free NMR (16)

Reference Example 46

R ⁵ _: -(CH ₂ ) ₂ CH ₃ (3-position) m: 1 A: -CH ₂ - R ⁴ : H

M.p. 110.0-111.0°C Solvent for recrystallization: Ethyl acetate-n-hexane

Crystalline form: Pale yellow needles Form: Free

Reference Example 47

R ⁵ _: -(CH ₂ ) ₃ CH ₃ (3-position) m: 1 A: -CH ₂ - R ⁴ : H

M.p. 110.5-111.0°C Solvent for recrystallization: Ethyl acetate-n-hexane

Crystalline form: Pale yellow needles Form: Free

Reference Example 48

R5 _: (3-position) m: 1 A: -CH ₂ - R ⁴ : H

M.p. 93.7-94.0°C Solvent for recrystallization: Ethyl acetate-n-hexane

Crystalline form: Pink powder Form: Free

Table 9

^! H-NMR spectrum (NMR (1) to NMR (20)) as described in Tables 5 to 9 are as follows:

NMR (1) (DMSO-dg) δppm: 2.45 (3H, s), 4. 95 (2H, s), 6.81-6.95 (2H, m),

7.10-7.22 (2H, m), 7.32 (IH, t, J=6.1Hz), 7.45 (IH, t, J=6.4Hz), 7.77 (IH, d, J=6.4Hz), 7.99 (IH, d, J=6.3Hz), 12.60 (IH, s)

NMR (2) (DMSO-d ₆ ) 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 (IH, m), 7.40-7.52 (IH, m), 7.77 (IH, d, J=8.0Hz), 7.98 (IH, d, J=7.8Hz), 12.58 (IH, s)

NMR (3) (CDC1 ₃ ) 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 (IH, d, J=8.0Hz), 7.01-7.50 (5H, m), 7.79-7.86 (2H, m), 9.6-9.8 (lH, s)

NMR (4) (CDCI ₃ ) δppm: 0.95 (3H, t J=7.2Hz), 1.37-1.55 (2H, m), 1.59-

1.74 (2H, m), 2.71 (2H, d, J=7.2Hz), 4.77 (2H, s), 6.82 (IH, d, J=8.1Hz), 6.98-7.06 (IH, m), 7.16-7.26 (2H, m), 7.30-7.38 (IH, m), 7.41-7.50 (IH, m), 7.79-7.86 (2H, m), 9.78 (IH, brs)

NMR (5) (CDCI ₃ ) 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 (IH, br) NMR (6) (CDCI ₃ ) 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 (IH, d, J=8.0Hz), 6.98-7.05 (IH, m), 7.17-7.26 (2H, m), 7.31-7.38 (IH, m), 7.42-7.50 (IH, m), 7.79-7.87 (2H, m), 9.73 (IH, brs)

NMR (7) (DMSO-d ₆ ) δppm: 5.03 (2H, s), 6.90-7.07 (IH, m), 7.07-7.20

(2H, m), 7.20-7.50 (2H, m), 7.45 (IH, dt, J=1.3Hz, J=7.3Hz), 7.77 (IH, d, J=7.8Hz), 7.99 (IH, dd, J=0.7Hz, J=7.7Hz), 12.63 (IH, s)

NMR (8) (CDCI ₃ ) δppm: 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 (IH, br)

NMR (9) (CDCI3) δppm: 1.75-2.0 (4H, m), 2.75-2.9 (4H, m), 4.74 (2H, s),

6.63 (IH, d, J=8Hz), 6.82 (IH, d, J=8Hz), 7.05-7.15 (IH, m), 7.3-7.5 (2H, m), 7.75- 7.9 (2H, m), 9.73 (IH, br)

NMR (10) (CDCI ₃ ) δppm: 2.29 (3H, s), 2.32 (3H, s), 4.75 (2H, s), 6.70 (IH,

d, J=8Hz), 6.90 (IH, d, J=7.5Hz), 7.05-7.15 (IH, m), 7.3-7.5 (2H, m), 7.75-7.9 (2H,

m), 9.76 (lH, br)

NMR (11) (DMSO-dg) δppm: 2.27 (6H, s), 4.63 (2H, s), 6.90-7.12 (3H, s),

7.29-7.40 (IH, m), 7.42-7.52 (IH, s), 7.76 (IH, d, J=7.8Hz), 8.02 (IH, d, J=7.4 Hz), 12.49 (IH, s) NMR (12) (CDC1 ₃ ) δppm: 2.32 (6H, s), 4.73 (2H, s), 6.61 (2H, s), 6.72 (IH,

s), 7.3-7.55 (2H, m), 7.8-7.95 (2H, m), 9.86 (IH, br)

NMR (13) (CDCI3) 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 (IH, d, J=8.5Hz), 7.04 (IH, t, J=7.2Hz), 7.15-7.29 (2H, m), 7.34 (IH, t, J=8.9Hz), 7.43 (IH, t, J=8.0Hz), 7.79- 7.87 (2H, m), 9.73 (lH, br)

NMR (14) (CDCI ₃ ) δppm: 3.22 (2H, t, J=7.0Hz), 3.82 (2H, t, J=7.0Hz),

4.81 (2H, s), 6.86 (IH, d, J=8.2Hz), 7.05 (IH, t, J=7.2Hz), 7.15-7.52 (4H, m), 7.81 (2H, t, J=8.4Hz), 9.78 (lH, br)

NMR (15) (CDCI ₃ ) δppm: 2.37 (3H, s), 4.74 (2H, s), 6.74-6.85 (2H, m),

6.85 (IH, d, J=7.3Hz), 7.17-7.30 (IH, m), 7.30-7.40 (IH, m), 7.40-7.54 (IH, m), 7.77-7.90 (2H, m), 9.88 (IH, brs)

NMR (16) (CDCI ₃ ) 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 (IH, m), 7.21-7.50 (3H, m), 7.79-7.86 (2H, m), 9.94 (lH, br) NMR (17) (CDCI ₃ ) δppm: 4.73 (2H, s), 6.75-6.84 (IH, m), 6.84-6.98 (IH,

m), 7.01-7.08 (IH, m), 7.21-7.46 (3H, m), 7.82 (2H, t, J=8.4Hz), 10.09 (IH, br) NMR (18) (DMSO-cL,) δppm: 4.94 (2H, s), 6.75-6.92 (3H, m), 7.27-7.47

(3H, m), 7.75 (IH, d, J=8.0Hz), 7.97 (IH, d, J=8.0Hz)

NMR (19) (CDC1 ₃ ) 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 (IH, br)

NMR (20) (CDCI ₃ ) 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 (IH, br)

Using the suitable starting compounds, the compounds as listed in Table 10 are obtained in the same manner as in Reference Example 3.

Table 10

Reference Example 53

R ⁵ : C ₂ H ₅ O (2-position) m: 1 A: -CH ₂ - R ⁴ : H R ¹⁸ : CH ₃ O

Crystalline form: Pale yellow powder Form: Free NMR (1)

Reference Example 54

R5 _: sition) m: 1 A: -CH _? - R ⁴ : H R ¹ 8 _: CH ₃ O

Crystalline form: White powder Form: Free NMR (2)

Reference Example 55

R ⁵ : CF ₃ CH ₂ O (3-position) m: 1 A: -CH ₂ -

R ⁴ : H R ¹⁸ : CH ₃ O

Crystalline form: White powder Form: Free NMR (3)

Reference Example 56

R ⁵ : CF ₃ (2-position) m: 1 A: -CH,- R : H R ¹⁸ : CH ₃ O

Crystalline form: White powder Form: Free NMR (4)

Reference Example 57

R5-. CH ₃ O (3-position) m: 1 A: -CH ₂ - R ⁴ : H R ⁱ «: CH ₃ O

Crystalline form: White powder Form: Free NMR (5)

ϊH-NMR spectrum (NMR (1) to NMR (5)) as described in Table 10 are as follows:

NMR (1) (CDC1 ₃ ) 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 (IH, d, J=8.6Hz), 7.33 (IH, t, J=7.5Hz), 7.46 (IH, t, J=7.5Hz), 7.60-7.65 (2H, m), 7.79- 7.86 (2H, m), 10.28 (lH. br)

NMR (2) (CDCI ₃ ) 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 (IH, sept, J=6.0Hz), 4.79 (2H, s), 6.51-6.56 (2H, m), 7.36 (IH, t, J=7.0Hz), 7.49 (IH, t, J=7.0Hz), 7.79-7.88 (3H, m), 9.98 (IH, br) NMR (3) (CDCI ₃ ) 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 (IH, d, J=2.2Hz), 6.60 (IH, dd, J=2.2Hz, J=8.8Hz), 7.34 (IH, dt, J=1.3Hz, J=7.3Hz), 7.45 (IH, dt, J=1.3Hz, J=7.3Hz), 7.75-

7.86 (3H, m)

NMR (4) (DMSO-d ₆ ) 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 (IH, d, J=8Hz), 7.98 (IH, d, J=8Hz), 8.2-8.35 (2H, m), 12.68 (IH, br)

NMR (5) (CDCI ₃ ) 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 (IH, s) Using the suitable starting compounds, the compounds as listed in Tables

11-13 are obtained in the same manner as in Reference Example 4.

Table 11

Reference Example 61

R ⁵ : -(CH ₂ ) ₃ CH ₃ (2-position) m l A: -CH.-

R ⁴ : H X: Cl

Crystalline form: White powder Form: Free NMR (4)

Table 12

Reference Example 62

R ⁵ : Cl (2-position) m: 1 A: -CH ₂ - R ⁴ : H X: C1

Solvent for recrystallization: 1,2-Dichloroethane-n -hexane

Crystalline form: White powder Form: Free

Reference Example 63

R ⁵ : -(CH ₂ ) ₂ C1 (2-position) m: 1 A: -CH ₂ -

R ⁴ : H X: Br

Crystalline form: Pale yellow powder Form: Free NMR (5)

Reference Example 64

R ⁵ : -(CH ₂ ) ₃ C1 (2-position) m: 1 A: -CH ₂ -

R ⁴ : H X: Br

Crystalline form: Pale yellow powder Form: Free NMR (6)

Reference Example 65

R ⁵ : -(CH ₂ ) ₄ C1 (2-position) m: 1 A: -CH ₂ -

R ⁴ : H X: Cl

M.p. 146.5-149°C Solvent for recrystallization: Ethyl acetate-n-hexane

Crystalline form: White powder Form: Free

Table 13

Reference Example 66

R ⁵ : -(CH ₂ ) ₂ CO ₂ C ₂ H ₅ (2-position) m: 1 A: -CH ₂ -

R ⁴ : H X: Cl

M.p. 131.0-133.0°C

Solvent for recrystallization: Ethyl acetate-n-hexane

Crystalline form: White powder Form: Free

Reference Example 67

R ⁵ : -(CH ₂ ) ₂ CO ₂ CH ₃ (2-position) m: l A: -CH ₂ -

R ⁴ : H X: Cl

Crystalline form: White powder Form: Free NMR (7)

Reference Example 68

R5 _: OCOCH ₃ (2-position) m: 1 A: -CH,-

I

— CH ₂ CHCH ₂ OCOCH ₃ R ⁴ : H X: Cl

Crystalline form: White powder Form: Free NMR (8)

Reference Example 69

R ⁵ and A combine to form: m: 1 R ⁴ : H X: C1

M.p. 206-208°C

Solvent for recrystallization: Dimethylformamide-ethanol

Crystalline form: White powder Form: Free

Η-NMR spectrum (NMR (1) to NMR (8)) as described in Tables 11-13 are as follows:

NMR (1) (CDC1 ₃ ) δppm: 4.41 (2H, s), 4.84 (2H, s), 7.07 (2H, d, J=9.0Hz),

7.36 (IH, t, J=7.3Hz), 7.45 (IH, t, J=7.3Hz), 7.88 (2H, t, J=8.5Hz), 8.03 (2H, d, J=9.0Hz)

NMR (2) (DMSO-d ₆ ) δppm: 2.30 (3H, s), 5.11 (4H, s), 7.00-7.10 (IH, m),

7.28-7.40 (IH, m), 7.40-7.55 (IH, m), 7.70-7.93 (3H, m), 7.98 (IH, d, J=7.1Hz), 12.68 (IH, s)

NMR (3) (DMSO-d ₆ ) δppm: 1.21 (3H, t, J=7.4Hz), 2.72 (2H, q, J=7.4Hz),

5.12, 5.13 (4H, each s), 7.02 (IH, d, J=8.6Hz), 7.31 (IH, dt, J=1.2Hz, J=7.3Hz), 7.45 (IH, dt, J=1.3Hz, J=7.3Hz), 7.75-7.92 (3H, m), 7.95-8.00 (IH, m), 12.68 (IH, brs)

NMR (4) (CDCI ₃ ) 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 (IH, d, J=8.6Hz), 7.32-7.39 (IH, m), 7.43-7.51 (IH, m), 7.79-7.87 (4H, m), 9.10-10.01 (lH, brs)

NMR (5) (CDCI ₃ ) 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 (IH, d, J=9.4Hz), 7.31 (IH, t, J=6.9Hz), 7.45 (IH, t, J=8.3Hz), 7.76 (IH, d, J=7.9Hz), 7.82-8.06 (3H, m) NMR (6) (CDCI ₃ ) 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 (IH, d, J=9.3Hz), 7.35 (IH, t, J=6.8Hz), 7.47 (IH, t, J=9.4Hz), 7.80-7.94 (4H, m), 9.68 (IH, br)

NMR (7) (CDCI ₃ ) 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 (IH, d, J=8.4Hz), 7.30-7.37 (IH, m), 7.41- 7.48 (IH, m), 7.78-7.89 (4H, m), 9.00-11.30 (IH, brs)

NMR (8) (CDC1 ₃ ) δppm: 2.00 (3H, s), 2.09 (3H, s), 3.08 (IH, dd, J=8Hz,

J=14Hz), 3.23 (IH, dd, J=6Hz, J=14Hz), 4.14 (IH, dd, J=5.5Hz, J=12Hz), 4.33 (IH, dd, J=3Hz, J=12Hz), 4.64 (2H, s), 4.5 (2H, s), 5.49 (IH, m), 6.90 (IH, d, J=9Hz), 7.3-8.0 (6H, m), 8.79 (IH, br)

Using the suitable starting compounds, the compounds as listed in Tables 14-22 are obtained in the same manner as in Reference Example 5 or 6.

Table 14

Reference Example 70

R ⁵ : H m: 1 A: -CH ₂ - R ⁴ : H

Crystalline form: Pale yellow amoφhous Form: Free NMR (1)

Reference Example 71

R ⁵ : CH ₃ (2-position) m: 1 A: -CH ₂ - R ⁴ : H

Crystalline form: Pale yellow amoφhous Form: Free NMR (2)

Reference Example 72

R ⁵ : C ₂ H ₅ (2-position) m: 1 A: -CH ₂ - R ⁴ : H Crystalline form: White powder Form: Free NMR (3)

Reference Example 73

R ⁵ _: (3-position) m: 1 A: -CH ₂ - R ⁴ : H

Crystalline form: White powder Form: Free NMR (4)

Table 15

Reference Example 74

R ⁵ : -(CH ₂ ) ₃ CH ₃ (2-position) m: 1 A: -CH ₂ - R ⁴ : H

Crystalline form: Pale yellow powder Form: Free NMR (5)

Reference Example 75

R ⁵ _: Cl (2-position) m: 1 A: -CH ₂ - R ⁴ : H

Crystalline form: Pale yellow amoφhous Form: Free NMR (6)

Reference Example 76 R ⁵ : F (2-position) m: 1 A: -CH ₂ - R ⁴ : H Crystalline form: White powder Form: Free NMR (7)

Reference Example 77

R ⁵ : -(CH ₂ ) ₂ C1 (2-position) m: 1 A: -CH ₂ - R ⁴ : H Crystalline form: White powder Form: Free NMR (8)

Reference Example 78

R ⁵ : -(CH ₂ ) ₄ C1 (2-position) m: 1 A: -CH ₂ - R ⁴ : H Crystalline form: White needles Form: Free NMR (9)

Table 16

Reference Example 79

R ⁵ : -(CH ₂ ) ₂ CO ₂ C ₂ H ₅ (2-position) m: l

A: -CH ₂ - R ⁴ : H Crystalline form: White powder Form: Free NMR (10)

Reference Example 80

R ⁵ _: OCOCH ₃ (2-position) m: 1

— CH ₂ CHCH ₂ OCOCH ₃ A: -CH ₂ - R ⁴ : H

Crystalline form: White powder Form: Free NMR (11)

Reference Example 81 R5 _: (2-position) m: l

-(CH^-N^O A: -CH ₂ - R ⁴ : H Crystalline form: White powder Form: Free NMR (12)

Reference Example 82

R5; (2-position) m: 1

— (CH ₂ ) ₂ -N^^N-CH ₃

A: -CH ₂ - R ⁴ : H

Crystalline form: Pale yellow amoφhous Form: Free NMR (13)

Table 17

Reference Example 83

R ⁵ : -(CH ₂ ) ₃ N(C ₂ H ₅ ) ₂ (2-position) m: l

A: -CH ₂ - R ⁴ : H Crystalline form: White powder Form: Free NMR (14)

Reference Example 84 R5 _: (2-position) m: l A: -CH ₂ - R ⁴ : H Crystalline form: White powder Form: Free NMR (15)

Reference Example 85

R ⁵ : / \ (2-position) m: l

— (CH ₂ ) ₃ -N N-CH ₃

A: -CH ₂ - R ⁴ : H

Crystalline form: White powder Form: Free NMR (16) .

Reference Example 86 R5 _: (2-position) m: l

(CH ₂ ) ₃ -N N- COCH ₃ A: -CH ₂ - R ⁴ : H

M.p. 153- 155°C Solvent for recrystallization: Ethyl acetate

Crystalline form: White powder Form: Free

Table 18

Reference Example 87

R ⁵ : \ (2-position) m: 1

— (CH ₂ ) ₃ -N N-(CH ₂ ) ₂ OH

A: -CH ₂ - R ⁴ : H

Crystalline form: White amoφhous Form: Free NMR (17)

Reference Example 88

R ⁵ : (2-position) m: 1

A: -CH ₂ - R ⁴ : H

Crystalline form: White amoφhous Form: Free NMR (18)

Reference Example 89

R ⁵ : (2-position) m: 1

A: -CH ₂ - R ⁴ : H

Crystalline form: Colorless amoφhous Form: Free NMR (19)

Reference Example 90

R ⁵ : (2-position) m: 1

A: -CH ₂ - R ⁴ : H

Crystalline form: Colorless amoφhous Form: Free NMR (20)

Table 19

Reference Example 91

R ⁵ : (2-position) m: 1 A: -CH ₂ - R ⁴ : H

Crystalline form: Yellow amoφhous Form: Free NMR (21)

Reference Example 92

R5-. (2-position) m: 1

A: -CH ₂ - R ⁴ : H

Crystalline form: Colorless amoφhous Form: Free NMR (22)

Reference Example 93

R ⁵ : (2-position)

m: 1 A: -CH ₂ - R ⁴ : H

Crystalline form: Yellow amoφhous Form: Free NMR (23)

Reference Example 94

R ⁵ : / \ (2-position) m: 1

— (CH^-N ^N-CH,

A: -CH ₂ - R ⁴ : H

Crystalline form: Yellow amoφhous Form: Free NMR (24)

Table 20

Reference Example 95 R5 _: (2-position)

-(CH ₂ ) ₄ -N O m: 1 A: -CH ₂ - R ⁴ : H

Crystalline form: White powder Form: Free NMR (25)

Reference Example 96 R5 _: (2-position)

-(CH ₂ ) ₄ -N N-CH ₃ m: 1 A: -CH ₂ - R ⁴ : H

CrystalUne form: Pale yellow powder Form: Free NMR (26)

Reference Example 97

R ⁵ ; (2-position) m: l A: -CH ₂ - R ⁴ : H

Crystalline form: White amoφhous Form: Free NMR (27)

Reference Example 98

R ⁵ : (2-position)

m: 1 A: -CH ₂ - R ⁴ : H

Crystalline form: White amoφhous Form: Free NMR (28)

Table 21

Reference Example 99

^R5: r τi ' ^CH 3 (2-position ⁾

O m: 1 A: -CH ₂ - R ⁴ : H

Crystalline form: White amoφhous Form: Free NMR (29)

Reference Example 100

R ⁵ : (2-position)

m: 1 A: -CH ₂ - R ⁴ : H

Crystalline form: White amoφhous Form: Free NMR (30)

Reference Example 101

R ⁵ : (2-position)

m: 1 A: -CH ₂ - R ⁴ : H

Crystalline form: Yellow amoφhous Form: Free NMR (31)

Reference Example 102

R ⁵ : -COOCH ₃ (2-position) m: 1 A: -CH ₂ - R ⁴ : H

Crystalline form: Pale yellow amoφhous Form: Free NMR (32)

Table 22

Reference Example 103

R ⁵ : -(CH ₂ ) ₂ CONH- (combined at 2- and 3-positions) m: 2 A: -CH ₂ - R ⁴ : H

Crystalline form: Yellow amoφhous Form: Free NMR (33)

Reference Example 104

R ⁵ and A combine to form: m: 1 R ⁴ : H

Crystalline form: White powder Form: Free NMR (35)

Η-NMR spectrum (NMR (1) to NMR (35)) as described in Tables 14-22 are as follows:

NMR (1) (CDC1 ₃ ) δppm: 4.37 (IH, d, J=24Hz), 4.77 (2H, s), 6.91 (2H, d,

J=8.8Hz), 7.16 (IH, t, J=7.3Hz), 7.32 (IH, t, J=7.3Hz), 7.38-7.82 (17H, m), 7.89 (2H, d, J=8.8Hz)

NMR (2) (CDCI ₃ ) δppm: 2.35 (3H, s), 4.41 (IH, brs), 4.70 (2H, s), 6.70 (IH,

d, J=8.2Hz), 7.20-8.00 (21 H, m)

NMR (3) (DMSO-d ₆ ) δppm: 1.19 (3H, t, J=7.4Hz), 2.69 (2H, q, J=7.4Hz),

4.43 (IH, d, J=2.5Hz), 5.00 (2H, s), 6.83 (IH, d, J=8.9Hz), 7.25-7.38 (IH, m), 7.38-7.85 (19H, m), 7.98 (IH, d, J=7.1Hz), 12.65 (IH, brs)

NMR (4) (CDCI ₃ ) δppm: 1.32 (6H, d, J=7Hz), 3.42 (IH, sept, J=7Hz), 4.2-

4.6 (IH, m), 4.73 (2H, s), 7.25-8.0 (21H, m), 10.01 (IH, br)

NMR (5) (CDC1 ₃ ) 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 (IH, br-d, J=24.7Hz), 4.66 (2H, s), 5.98 (IH, br-s), 6.66 (IH, d, J=8.3Hz), 6.99-7.10 (IH, m), 7.19-7.31 (IH, m), 7.38-7.60 (11H, m), 7.60-7.87 (8H, m) NMR (6) (DMSO-d ₆ ) δppm: 4.52 (IH, d, J=23Hz), 5.12 (2H, s), 7.07 (IH,

d, J=8.4Hz), 7.31 (IH, td, J=7.6Hz, J=1.0Hz), 7.45 (IH, td, J=7.6Hz, J=1.4Hz), 7.45-8.15 (19H, m), 12.68 (IH, s)

NMR (7) (CDCI ₃ ) δppm: 4.34 (IH, d, J=22Hz), 4.79 (2H, s), 6.97 (IH, t,

J=8.4Hz), 7.30-7.38 (2H, m), 7.38-7.92 (19H, m), 9.97 (IH, br) NMR (8) (DMSO-dg) 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 (IH, d, J=9.4Hz), 7.34 (IH, t, J=6.5Hz), 7.44 (IH, t, J=6.5Hz), 7.60-8.12 (19H, m), 12.70 (IH, br)

NMR (9) (CDCI ₃ ) δppm: 1.67-1.90 (4H, m), 2.64-2.82 (2H, m), 3.68 (IH, bt,

J=6.0Hz), 5.19 (2H, s), 6.12 (2H, d, J=14.0Hz), 7.10 (IH, d, J=10.0Hz), 7.29-7.41 (IH, m), 7.41-7.52 (IH, m), 7.69-7.95 (17H, m), 7.95-8.06 (2H, m), 12.74 (IH, br-s) NMR (10) (DMSO-dg) 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 (IH, d, J=30.0Hz), 5.01 (2H, s), 6.82 (IH, d, J=14.0Hz), 7.29-7.38 (IH, m), 7.40-7.50 (IH, m), 7.50-7.80 (18H, m), 8.00-8.02 (IH, d, J=4.0Hz), 12.61 (IH, brs) NMR (11) (CDCI ₃ ) 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 (IH, m), 6.1-6.6 (2H, br), 6.98 (IH, d, J=8Hz), 7.2-8.5 (2H, m)

NMR (12) (CDCI ₃ ) δppm: 2.54-2.78 (6H, m), 2.87-3.12 (2H, m), 3.69-3.90

(4H, m), 4.36 (I H, d, J=24.0Hz), 4.78 (2H, s), 6.77 (IH, d, J=8.5Hz), 7.27-7.88 (21H, m)

NMR (13) (CDC1 ₃ ) δppm: 2.27 (3H, s), 2.32-2.76 (10H, m), 2.76-3.05 (2H,

m), 4.36 (IH, d, J=26.0Hz), 4.71 (2H, s), 6.77 (IH, d, J=8.3Hz), 7.27-8.02 (21H, m) NMR (14) (CDCI ₃ ) 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 (IH, d, J=24.4Hz), 4.76 (2H, s), 6.80 (IH, d, J=6.8Hz), 7.32 (IH, t, J=7.3Hz), 7.39-7.93 (20H, m)

NMR (15) (CDCI ₃ ) 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 (IH, d, J=28.0Hz), 4.74 (2H, s), 6.77 (IH, d, J=8.3Hz), 7.33 (IH, t, J=7.3Hz), 7.40-7.96 (20H, m)

NMR (16) (CDCI ₃ ) 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 (IH, d, J=24.0Hz), 4.76 (2H, s), 6.79 (IH, d, J=8.4Hz), 7.33 (IH, t, J=8.8Hz), 7.40-7.64 (10H, m), 7.64-7.95 (10H, m)

NMR (17) (CDCI ₃ ) δppm: 1.7-3.3 (16H, m), 3.59 (2H, m), 4.81 (2H, s), 6.82

(lH, d, J=8.5Hz), 7.2-8.0 (21 H, m)

NMR (18) (CDCI ₃ ) 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 (IH, m), 4.1-4.8 (2H, br), 4.68 (2H, s), 6.70 (IH, d, J=8.5Hz), 7.2-7.9 (21H, m)

NMR (19) (CDCI ₃ ) 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 (IH, br), 4.73 (2H, s), 6.75 (IH, d, J=8.5Hz), 7.23-7.92 (21H, m)

NMR (20) (CDCI ₃ ) 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 (IH, m), 4.70 (2H,

s), 6.71 (IH, d, J=8.5Hz), 7.02-7.94 (21H, m)

NMR (21) (CDC1 ₃ ) 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 (IH, d, J=8.5Hz), 7.32 (IH, t, J=6.4Hz), 7.40-7.90 (20H, m) NMR (22) (CDCI ₃ ) δppm: 1.62-2.23 (8H, m), 2.29-2.97 (12H, m), 3.48-

3.93 (3H, m), 4.22-4.57 (IH, br), 4.69 (2H, s), 6.70 (IH, d, J=8.5Hz), 7.22-8.04 (21H, m)

NMR (23) (CDCI ₃ ) 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 (IH, d, J=26.8Hz), 4.75 (2H, s), 6.77 (IH, d, J=8.4Hz), 7.28-7.92 (21H, m)

NMR (24) (CDCI ₃ ) δppm: 1.82-2.22 (4H, m), 2.50 (3H, s), 2.54-3.12 (12H,

m), 4.73 (2H, s), 6.71 (IH, d, J=8.6Hz), 7.29-7.88 (21H, m)

NMR (25) (CDCI ₃ ) 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 (IH, d, J=8.5Hz), 7.25-7.95 (21 H, m)

NMR (26) (DMSO-d ₆ ) 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 (IH, d, J=26.0Hz), 4.96 (2H, s), 6.80 (IH, d, J=10.0Hz), 7.27-7.38 (IH, m), 7.38-7.80 (19H, m), 7.90-8.03 (IH, m)

NMR (27) (CDCI ₃ ) 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 (IH, m), 4.96 (2H, s), 6.67 (IH, d, J=8.5Hz), 7.23-7.27 (IH, m), 7.29-7.57 (10H, m), 7.68- 7.81 (9H, m), 7.92 (IH, brs), 11.97 (IH, brs)

NMR (28) (CDCI ₃ ) 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 (IH, m), 4.73 (2H, s), 6.67 (IH, d, J=8.6Hz), 7.26-7.33 (IH, m), 7.33-7.62 (10H, m), 7.62-7.85 (9H, m), 7.90 (IH, brs)

NMR (29) (CDC1 ₃ ) 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 (IH, m), 7.20-7.61 (1 IH, m), 7.61-7.85 (9H, m), 7.85-7.93 (lH, m)

NMR (30) (CDCI ₃ ) δppm: 1.01-1.47 (2H, m), 1.65-1.90 (2H, m), 2.29 (3H,

s), 2.35-2.65 (1 IH, m), 2.65-2.91 (2H, m), 3.03-3.22 (2H, m), 3.73-3.91 (IH, m), 4.22-4.54 (IH, m), 4.73 (2H, s), 4.75-4.92 (IH, m), 6.69 (IH, d, J=8.6Hz), 7.22- 7.63 (1 IH, m), 7.63-7.88 (9H, m), 7.88-8.00 (ΪH, m)

NMR (31) (CDCI ₃ ) δppm: 2.18-3.50 (20H, m), 3.50-3.71 (IH, m), 3.71-

3.95 (IH, m), 4.20-4.82 (4H, m), 6.65-6.74 (IH, m), 7.20-7.63 (12H, m), 7.63-7.86 (9H, m), 7.86-7.98 (lH, m)

NMR (32) (CDCI ₃ ) δppm: 4.09 (3H, s), 4.42 (IH, d, J=22.9Hz), 4.85 (2H,

s), 6.93 (IH, d, J=8.7Hz), 7.00-7.18 (IH, m), 7.18-7.98 (18H, m), 8.19 (IH, dd, J=2.2Hz, J=8.7Hz), 8.60 (IH, d, J=2.2Hz), 11.55 (IH, br)

NMR (33) (CDCI ₃ ) δppm: 2.73 (2H, t, J=7.4Hz), 3.37 (2H, t, J=7.4Hz),

4.06 (IH, d, J=20.6Hz), 4.84 (2H, s), 6.77 (IH, d, J=8.6Hz), 7.28-7.77 (20H, m), 10.85 (lH, br), 12.16 (lH. br) NMR (35) (DMSO-d ₆ ) δppm: 2.03-2.46 (2H, m), 2.67-3.06 (2H, m), 4.28-

4.52 (IH, m), 4.94-5.24 (IH, m), 6.83-8.11 (22H, m), 12.61 (IH, brs)

Using the suitable starting compounds, the compounds as listed in Tables 23-31 are obtained in the same manner as in Reference Example 2.

Table 23

-NMR spectrum (NMR (1)) as described in Table 23 are as follows: NMR (1) (CDC1 ₃ ) δppm: 4.81 (2H, s), 7.05 (IH, d, J=3.5Hz), 7.25-7.35

(2H, m), 7.45-7.65 (2H, m), 7.50 (IH, d, J=3.5Hz), 10.00 (IH, s), 10.06 (IH, brs)

Table 24

Reference Example 107

Table 25

Reference Example 109

R ⁵ _: -CH ₂ N(C ₂ H ₅ ) ₂ (2-position)

R ⁴ : H m: 1 A: -CH ₂ -

Crystalline form: White powder Form: Free NMR (4)

Reference Example 110

(2-position)

R ⁴ : H m: l A: -CH ₂ -

Crystalline form: Yellow powder Form: Free NMR (5)

Reference Example 111

R ⁵ _: -(CH ₂ ) ₂ N(C ₂ H ₅ ) ₂ (2-position)

R ⁴ : H m: l A: -CH ₂ -

Crystalline form: Brown powder Form: HCl NMR (6)

Reference Example 112

(2-position)

R ⁴ : H m: 1 A: -CH ₂ -

Crystalline form: White powder Form: 2HC1 NMR (7)

Table 26

Reference Example 113

R ⁵ _: -(CH ₂ ) ₃ OH (2-position)

R ⁴ : H m: 1 A: -CH ₂ -

Crystalline form: White powder Form: Free NMR (8)

Reference Example 1 14

(2-position)

R ⁴ : H m: 1 A: -CH ₂ -

CrystaUine form: Pale yellow powder Form: Free NMR (9)

Reference Example 115

R5 _: -CH ₂ N(C ₂ H ₅ ) ₂ (2-position)

R ⁴ : H m: 1 A: -(CH ₂ )r-

CrystaUine form: Yellow oil Form: Free NMR (10)

Reference Example 116

R ⁵ : -CH ₂ N(C ₂ H ₅ ) ₂ (2-position)

R ⁴ : H m: 1 A: -(CH ₂ ) ₃ -

CrystaUine form: Yellow amoφhous Form: Free NMR (11)

Table 27

Reference Example 117

CH ₃ (2-position)

R ⁴ : H m: 1 A: -CH ₂ -

Crystalline form: Pale yellow powder Form: Free NMR (12)

Reference Example 118

N 0 (2-position)

R ⁴ : H m: 1 A: -CH ₂ -

Crystalline form: Yellow powder Form: 2HC1 NMR (13)

Reference Example 119

(2-position)

R ⁴ : H m: 1 A: -CH ₂ -

Crystalline form: Pale yellow powder Form: 2HC1 NMR (14)

Reference Example 120

R ¹ R ⁵ _: H R ⁴ : H

R ² m: 1 A: -CH ₂ -

Crystalline form: Yellow powder Form: Free NMR (15)

Table 28

Reference Example 124 (2-position)

R ⁴ : H m: 1 A: -CH ₂ -

CrystaUine form: Pale yellow oil Form: Free NMR (19)

Table 29

Reference Example 125

on) H m: 1 A: -CH ₂ -

Crystalline form: YeUow amoφhous Form: Free NMR (20)

Reference Example 126

R ⁴ : H m: 1 A: -CH ₂ -

CrystalUne form: Yellow amoφhous Form: Free NMR (21)

Table 30

Reference Example 129

(2-position)

R ⁴ : H m: 1 A: -CH ₂ -

Crystalline form: Pale yellow amoφhous Form: Free NMR (24)

Reference Example 130

(2-position)

R ⁴ : H m: 1 A: -CH ₂ -

Crystalline form: Pale yellow amoφhous Form: Free NMR (25)

Reference Example 131

R ⁵ : — (CH ₂ ) ₃ -N Λ N-CH ₃ (2-position)

R ⁴ : H m: 1 A: -CH ₂ -

Crystalline form: Pale yellow amoφhous Form: Free NMR (26)

Table 31

Reference Example 133

₂ ) ₂ -N N-CH ₃ (2-position)

R ⁴ : H m: 1 A: -CH ₂ - Crystalline form: Yellow amoφhous Form: Free NMR (28)

Reference Example 134

R »5°.: _— (CH ₂ ) ₃ -N N-CH ₃ (3-position)

R ⁴ : H m: 1 A: -CH ₂ -

Crystalline form: Colorless amoφhous Form: Free NMR (29)

Reference Example 135

R ⁴ : H m: l

CrystaUine form: White oil Form: Free NMR (30)

Η-NMR spectrum (NMR (1) to NMR (30)) as described in Tables 24-31 are as follows:

NMR (1) (DMSO-de) 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 (IH, d, J=3.6Hz), 7.45 (IH, d, J=3.6Hz), 7.85 (2H, d, J=8.6Hz), 9.86 (IH, s), 12.13 (IH, s)

NMR (2) (DMSO-d ₆ ) δppm: 5.07 (2H, s), 7.19 (2H, d, J=8.7Hz), 7.27-7.40

(IH, m), 7.40-7.56 (IH, m), 7.77 (IH, d, J=7.5Hz), 7.90 (2H, d, J=8.8Hz), 7.98 (IH, d, J=7.1Hz), 9.89 (IH, s), 12.1-13.0 (IH, br)

NMR (3) (CDC1 ₃ ) δppm: 2.38 (6H, s), 4.57 (2H, s), 7.06 (IH, d, J=3.6Hz),

7.51 (IH, d, J=3.6Hz), 7.61 (2H, s), 9.92 (IH, s), 10.10 (IH, brs)

NMR (4) (CDCI ₃ ) 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 (IH, d, J=8.2Hz), 7.23-7.35 (IH, m), 7.35-7.45 (IH, m), 7.74-7.87 (4H, m), 9.92 (IH, s), 10.71 (IH, s)

NMR (5) (CDCI ₃ ) δppm: 2.33 (3H, s), 2.42-2.88 (8H, m), 3.71 (2H, s), 4.92

(2H, s), 7.02 (IH, d, J=8.2Hz), 7.27-7.40 (IH, m), 7.40-7.59 (IH, m), 7.67-7.93 (lH, m), 9.93 (lH, s)

NMR (6) (CDCI ₃ ) δppm: 1.29 (6H, t, J=7.1Hz), 2.98-3.48 (8H, m), 5.20

(2H, s), 7.22 (IH, d, J=9.0Hz), 7.35 (IH, d, J=7.6Hz), 7.49 (IH, d, J=7.6Hz), 7.80 (IH, d, J=7.8Hz), 7.85 -7.98 (2H, m), 8.01 (IH, d, J=7.4Hz), 9.91 (IH, s), 10.36 (IH, br), 12.84 (IH, br)

NMR (7) (CDC1 ₃ ) δppm: 2.86 (3H, s), 3.14-4.00 (12H, m), 5.21 (2H, s),

7.22 (IH, d, J=7.8Hz), 7.35 (IH, t, J=7.6Hz), 7.49 (IH, t, J=7.6Hz), 7.78-7.87 (3H, m), 8.01 (IH, d, J=8.1Hz), 9.90 (IH, s), 11.60 (2H, br), 12.75 (IH, br)

NMR (8) (CDC1 ₃ ) δppm: 1.83-2.11 (2H, m), 3.06 (2H, t, J=7.3Hz), 3.85

(2H, t, J=5.2Hz), 4.22 (IH, br), 4.85 (2H, s), 6.98 (IH, d, J=8.2Hz), 7.28-7.41 (IH, m), 7.41-7.49 (IH, m), 7.74-7.86 (4H, m), 9.92 (IH, s), 11.84 (IH, br)

NMR (9) (CDCI ₃ ) 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 (IH, d, J=8.3Hz), 7.30-7.42 (IH, m), 7.42-7.51 (IH, m), 7.72-7.87 (4H, m), 9.94 (IH, s)

NMR (10) (CDCI ₃ ) 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 (IH, d, J=8.5Hz), 7.28-7.40 (IH, m), 7.40-7.51 (IH, m), 7.70-7.91 (3H, m), 7.95 (IH, d, J=2.1Hz), 9.89 (IH, s). 10.39-13.00 (IH, brs)

NMR (11) (CDCI ₃ ) 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 (IH, t, J=8.5Hz), 7.20-7.40 (2H, m), 7.58-7.88 (3H, m), 7.90 (IH, d, J=2.1Hz), 9.87 (IH, s)

NMR (12) (CDCI ₃ ) 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 (IH, d,

J=8.2Hz), 7.31-7.42 (IH, m), 7.42-7.57 (IH, m), 7.73-7.87 (4H, m), 9.91 (IH, s) NMR (13) (DMSO-de) 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 (IH, d, J=8.8Hz), 7.31 (IH, t, J=6.9Hz), 7.45 (IH, t, J=6.9Hz), 7.68-7.92 (3H, m), 7.99 (IH, d, J=7.0Hz), 9.87 (IH, s), 10.73 (IH, br), 11.78 (IH, br), 12.80 (IH, s)

NMR (14) (DMSO-d ₆ ) 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 (IH, d, J=8.7Hz), 7.34 (IH, t, J=7.7Hz), 7.45 (IH, t, J=7.7Hz), 7.78-7.86 (3H, m), 8.00 (IH, d, J=7.0Hz), 9.90 (IH, s), 10.78 (2H, br), 12.80 (IH, br) ^'

NMR (15) (DMSO-d ₆ ) δppm: 2.40 (3H, s), 5.06 (2H, s), 7.15-7.40 (3H, m),

7.65 (IH, d, J=8.4Hz), 7.77 (IH, s), 7.89 (2H, d, J=8.6Hz), 9.88 (IH, s), 12.61 (IH, s)

NMR (16) (DMSO-de) δppm: 2.27 (3H, d, J=0.9Hz), 4.98 (2H, s), 6.79 (IH,

d, J=1.0Hz), 7.12-7.25 (2H, m), 7.82-7.96 (2H, m), 9.88 (IH, s), 12.0-12.7 (IH, br) NMR (17) (DMSO-d _fj ) δppm: 1.26 (9H, s), 4.98 (2H, s), 6.78 (IH, s), 7.15

(2H, d, J=8.8Hz), 7.90 (2H, d, J=8.8Hz), 9.88 (IH, s), 12.42 (IH, s)

NMR (18) (DMSO-d ₆ ) δppm: 5.05 (2H, s), 7.19 (2H, d, J=8.8Hz), 7.25-

7.55 (3H, m), 7.69 (IH, s), 7.80-8.02 (4H, m), 9.89 (IH, s), 12.60 (IH, s) NMR (19) (DMSO-dg) δppm: 1.57-1.84 (7H, m), 1.84-2.05 (3H, m), 2.20

(IH, q, J=8.5Hz), 2.30-2.72 (8H, m), 2.74-3.12 (3H, m), 3.16-3.30 (IH, m), 4.87 (2H, s), 6.97 (IH, d, J=8.3Hz), 7.27-7.41 (IH, m), 7.41-7.53 (IH, m), 7.70-7.93 (4H, m), 9.91 (lH, s)

NMR (20) (CDC1 ₃ ) δppm: 1.67-2.95 (20H, m), 3.55-3.95 (3H, m), 4.90

(2H, s), 6.96 (IH, d, J=8.3Hz), 7.25-7.53 (2H, m), 7.55-7.95 (4H, m), 9.90 (IH, s) NMR (21) (CDCI ₃ ) δppm: 1.55-3.80 (23H, m), 4.91 (2H, s). 6.96 (IH, d,

J=8.4Hz), 7.25-7.52 (2H, m), 7.65-7.78 (4H, m), 9.88 (IH, s)

NMR (22) (CDCI ₃ ) δppm: 1.75-2.95 (16H, m), 3.55-3.95 (7H, m), 4.88

(2H, s), 6.95 (IH, d, J=8.3Hz) 7.28-7.55 (2H, m), 7.65-7.95 (4H, m), 9.90 (IH, s) NMR (23) (CDCI ₃ ) δppm: 1.75-3.00 (20H, m), 2.27 (3H, s), 3.58-3.98 (3H,

m), 4.88 (2H, s), 6.95 (IH, d, J=8.3Hz), 7.30-7.52 (2H, m), 7.65-7.90 (4H, m), 9.89 (lH, s)

NMR (24) (CDCI ₃ ) 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 (IH, d, J=8.5Hz), 7.3-7.55 (2H, m), 7.7-7.9 (4H, m), 9.92 (IH, s)

NMR (25) (CDC1 ₃ ) δppm: 1.5-3.1 (23H, m), 2.24 (3H, s), 4.91 (2H, s), 7.00

(IH, d, J=8Hz), 7.3-7.5 (2H, m), 7.7-7.9 (4H, m), 9.91 (IH, s) NMR (26) (CDCI3) δppm: 1.7-2.0 (4H, m), 2.33 (3H, s), 2.5-3.0 (12H, m),

4.87 (2H, s), 6.97 (IH, d, J=8Hz), 7.3-7.9 (6H, m), 9.91 (IH, s)

NMR (27) (DMSO-c δppm: 1.30-3.51 (25H, m), 3.51-3.75 (2H, m), 5.16

(2H, s), 7.09 (IH, d, J=8.9Hz), 7.27-7.39 (IH, m), 7.39-7.52 (IH, m), 7.70-7.84 (3H, m), 7.98-8.09 (IH, m), 9.86 (IH, s), 10.58-11.17 (3H, m) NMR (28) (DMSO-dg) 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 (IH, d, J=8.3Hz), 7.29-7.40 (IH, m), 7.40- 7.52 (IH, m), 7.74-7.89 (3H, m), 7.93-8.05 (IH, m), 9.89 (IH, s), 11.10-13.00 (3H, m)

NMR (29) (CDCI ₃ ) 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 (IH, s)

NMR (30) (CDCI ₃ ) δppm: 3.46 (IH, dd, J=6.5Hz, J=16.5Hz), 3.68 (IH, dd,

J=10.5Hz, J=16.5Hz), 5.67 (IH, dd, J=6.5Hz, J=10.5Hz), 7.08 (IH, 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 (IH, s) Using the suitable starting compounds, the compounds as listed in Tables

32-37 are obtained in the same manner as in Reference Examples 7, 8 or 9.

Table 32

Reference Example 136 Reference Example 137

B.p.: 145°C (0.3 mmHg) CrystaUine form: Pale yellow oil Crystalline form: Colorless oil Form: Free Form: Free NMR (2)

NMR (l)

Reference Example 138 Reference Example 139

CrystalUne form: Colorless oil CrystalUne form: Brown oil Form: Free Form: Free NMR (3) NMR (4)

Reference Example 140 Reference Example 141

Crystalline form: Brown oil B.p.: 90-95 °C (0.15 mmHg) Form: Free Crystalline form: Colorless oil NMR (5) Form: Free

Reference Example 142 Reference Example 143

(cis-form) B.p.: 107°C (0.35 mmHg) B.p.: 90-95°C (0.2 mmHg) Crystalline form: Colorless oil Crystalline form: Colorless oil Form: Free Form: Free

Table 33

Reference Example 144 Reference Example 145

Crystalline form: White soUd B.p.: 160-165°C (0.25-0.3 mmHg) Form: Free Crystalline form: Colorless oil NMR (6) Form: Free

Reference Example 146 Reference Example 147

B.p.: 135-140°C (0.25-0.3 mmHg) Crystalline form: Colorless oil Crystalline form: Colorless oil Form: Free Form: Free NMR (8) NMR (7)

Reference Example 148 Reference Example 149

Crystalline form: Colorless oU Crystalline form: White amoφhous Form: Free Form: Free NMR (9) NMR (10)

Reference Example 150 Reference Example 151

Crystalline form: Colorless oU Crystalline form: Brown oil

Form: Free Form: Free NMR (11) NMR (12)

Table 34

Reference Example 152 Reference Example 153

^CH3 - v ^r H ^NH C2H5 -"w ^H

B.p.: 110-115°C (0.22 mmHg) CrystaUine form: Pale yellow oil Crystalline form: Colorless oil Form: Free Form: Free NMR (13)

Reference Example 154 Reference Example 155

Crystalline form: Yellow powder B.p.: 110'C (0.35 mmHg) Form: Free Crystalline form: Colorless oil NMR (14) Form: Free

Reference Example 156 Reference Example 157

B.p.: 1 10-115°C (0.28 mmHg) B.p.: 120-127°C (12 mmHg) Crystalline form: Colorless oil Crystalline form: Colorless oil Form: Free Form: Free

Reference Example 158 Reference Example 159

B.p.: 113-130°C (18 mmHg) B.p.: 165-170°C (15 mmHg) Crystalline form: Colorless oil Crystalline form: Colorless oil Form: Free Form: Free NMR (15)

Table 35

Reference Example 160 Reference Example 161

B.p.: 180-185^ (15 mmHg) B.p.: 138-143°C (12 mmHg)

Crystalline form: Colorless oil Crystalline form: Colorless oil

Form: Free Form: Free

NMR (16)

Reference Example 162 Reference Example 163

B.p.: 112-116°C (0.23 mmHg) B.p.: 116'C (0.23 mmHg)

M.p. 39-41 °C Crystalline form: Colorless oil

Crystalline form: Colorless oil Form: Free

Form: Free

Reference Example 164 Reference Example 165

B.p.: 108°C (0.3 mmHg) M.p. 73-75.5°C Crystalline form: Colorless oil Crystalline form: White powder Form: Free Form: Free Reference Example 166 Reference Example 167

B.p.: 134-137°C (2.5 mmHg) B.p.: 124-130°C (0.7 mmHg) Crystalline form: Colorless oil Crystalline form: Colorless oil Form: Free Form: Free

Table 36

Reference Example 168 Reference Example 169

Crystalline form: White powder Form: Free

Form: 3HC1 NMR (18)

NMR (17)

Reference Example 170 Reference Example 171

Crystalline form: Colorless oil Crystalline form: Colorless oil

Form: Free Form: Free

NMR (19) NMR (20)

Reference Example 172 Reference Example 173

B.p.: 110-128 ^β C (20 mmHg) B.p.: 115-136°C (20 mmHg) Crystalline form: Colorless oil CrystaUine form: Colorless oil Form: Free Form: Free Reference Example 174 Reference Example 175

B.p.: 115-133°C (20 mmHg) Crystalline form: White powder Crystalline form: Colorless oil Form: 3HC1 Form: Free NMR (21)

Table 37

Reference Example 176

B.p.: 165-170 ^o C (18 mmHg)

<O ^c CrystaUine form: Yellow oil Form: Free

CH ₃ -N NH NMR (22)

^! H-NMR spectrum (NMR (1) to NMR (22)) as described in Tables 32-37 are as follows: NMR (1) (CDC1 ₃ ) 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) (CDCI ₃ ) δppm: 0.89 (3H, t, J=7.5Hz), 1.17-1.54 (3H, m), 1.54-

1.78 (IH, 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) (CDCI ₃ ) 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) (CDCI ₃ ) δppm: 0.85-0.94 (6H, m), 1.23-1.54 (2H, m), 1.62 (IH,

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) (CDCI ₃ ) δppm: 1.06-1.98 (15H, m), 2.20-2.47 (5H, m), 2.47-2.61

(IH, m), 2.61-2.90 (6H, m), 3.09-3.33 (2H, m)

NMR (6) (CDCI ₃ ) δppm: 1.06 (6H, d, J=6.5Hz), 1.25-1.55 (2H, m), 1.75-

1.95 (2H, m), 2.2-2.4 (IH, m), 2.45-2.75 (1 IH, m), 3.05-3.2 (2H, m) NMR (7) (CDCI ₃ ) δppm: 1.25-1.6 (3H, m), 1.6-2.75 (14H, m), 2.85 (IH, dd,

J=2Hz, J=l 1.5Hz), 2.9-3.3 (5H, m)

NMR (8) (CDC1 ₃ ) 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 (IH, 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) (CDCI ₃ ) 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 (IH, q, J=10.7Hz), 2.19-2.48 (5H, m), 2.48-2.95 (6H, m), 3.05-3.21 (2H, m)

NMR (10) (CDCI ₃ ) 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 (IH, br)

NMR (11) (CDCI ₃ ) 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) (CDCI ₃ ) δppm: 1.04 (3H, d, J=6.2Hz), 1.49-1.68 (2H, m), 1.80-

1.99 (2H, m), 2.06 (IH, 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) (CDCI ₃ ) δppm: 1.07 (3H, t, J=7.1Hz), 1.40 (2H, dq, J=3.8Hz,

J=l 2.0Hz), 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) (CDCI ₃ ) 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) (CDCI ₃ ) δppm: 2.0-3.2 (17H, m), 2.26 (3H, s), 2.32 (3H, s)

NMR (16) (CDC1 ₃ ) δppm: 1.8-1.9 (2H, m), 2.0-3.2 (17H, m), 2.33 (3H, s),

2.34 (3H, s)

NMR (17) (DMSO-d ₆ ) 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 (IH, br), 9.99 (IH, br), 11.04 (IH, br), 12.06 (IH, br)

NMR (18) (CDC1 ₃ ) 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) (CDCI ₃ ) 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) (CDCI ₃ ) 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-c^) 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 (IH, m), 11.82- 12.38 (lH, m)

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

Reference Example 182 To a solution of t-butyl propiolate (9.7 g) in tetrahydrofuran (300 ml) is added dropwise a 1.6M solution of n-butyl lithium in n-hexane (48 ml) at -70°C, and the mixture is reacted for 10 minutes. To the mixture is added dropwise a solution of 2-{(2-methoxy-4-formylphenoxy)methylcarbonylamino}- benzothiazole (10 g) in tetrahydrofuran (200 ml) and N,N-dimethylpropylene urea (20 ml) at the same temperature over a period of 20 minutes. The reaction mixture is further reacted for 20 minutes, and then the reaction vessel is taken out from the iced bath, and the mixture is further stirred for 20 minutes. To the

mixture is added acetic acid (5 ml), and the mixture is diluted with ethyl acetate. The organic layer is washed with a saturated aqueous sodium hydrogen carbonate solution, dried over sodium sulfate, concentrated, and the residue thus obtained is recrystalhzed from ethyl acetate-n-hexane. The crystals are collected by filtration to give 2-[2-methoxy-4-(3-t-butoxycarbonyl-l- hydroxypropargyl)phenoxymethylcarbonylamino]benzothiazole (13 g) as white power. Reference Example 183

A solution of sodium hydroxide (4.92 g) in water (5 ml) is diluted with ethanol (80 ml), and the mixture is subjected to deaeration, and then put under nitrogen atmosphere. To the mixture is added 3-methoxy-4-dimethylamino- carbonylthiobenzaldehyde (20 g), and the mixture is refluxed for 14 hours. After cooling, to the mixture is added dropwise ethyl bromoacetate (9.74 ml), and the mixture is stirred at room temperature for three hours. To the mixture are added ethanol, 1.5N hydrochloric acid and water, and the mixture is extracted with chloroform. The extract is dried over sodium sulfate and concentrated, and the residue is purified by silica gel column chromatography (solvent; n-hexane:ethyl acetate = 9:1 — > 5.6:1 — >4: 1) to give 3-methoxy-4- ethoxycarbonylmethylthiobenzaldehyde (11.8 g) as white solid. Η-NMR (CDC1 ₃ ) 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 (IH, s) Reference Example 184

Using the suitable starting compounds, the following compound is obtained in the same manner as in Reference Example 1.

α-(2-Methoxy-4-formylphenoxymethyl)acetic acid: Yellow powder Η-NMR (DMSO-c^) δppm: 3.84 (3H, s), 4.82 (2H, s), 7.05 (IH, d, J=8Hz),

7.41 (IH, d, J=2Hz), 7.51 (IH, dd, J=2Hz, J=8Hz), 9.83 (IH, s), 13.14 (IH, br) Reference Example 185

Using the suitable starting compounds, the following compounds are obtained in the same manner as in Reference Example 2. 2-(2-Methoxy-4-formylphenoxymethylcarbonylamino)benzimidazol e: Yellow powder Η-NMR (CDC1 ₃ ) δppm: 4.06 (3H, s), 4.86 (2H, s), 7.09 (IH, d, J=8.5Hz),

7.3-7.55 (4H, m), 7.8-7.9 (2H, m), 9.91 (IH, s), 10.25 (IH, br) 2-(2-Ethoxy-4-formylphenoxymethylcarbonylamino)benzimidazole :

White powder

Η-NMR (CDCI ₃ ) δppm: 1.60 (3H, t, J=7.0Hz), 4.26 (2H, q, J=7.0Hz), 4.87

(2H, s), 7.11 (IH, d, J=8.3Hz), 7.30-7.49 (4H, m), 7.79-7.88 (2H, m), 9.90 (IH, s),

10.34 (lH, br)

2-[2-(Diethylaminocarbonylmethoxy)-4-formylphenoxymethylc arbonylamino]- benzimidazole:

White powder ϊH-NMR (CDCI ₃ ) 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 (IH, d, J=8Hz), 7.25-7.55 (4H, m), 7.7-7.85 (2H, m), 9.86 (IH, s) Reference Example 186

Using the suitable starting compounds, the following compounds are obtained in the same manner in Reference Example 5.

[3-(2-Chloroethyl)-4-(2-benzothiazolylaminocarbonylmethox y)benzoyl]methyl- triphenylphosphonium bromide: Η-NMR (DMSO-d ₆ ) 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 (IH, d, J=9.4Hz), 7.31 (IH, t, J=6.5Hz), 7.44 (IH, t, J=6.5Hz), 7.60-8.12 (19H, m), 12.70 (IH, br) [3-(2,3-Diacetyloxypropyl)-4-(2-benzothiazolylaminocarbonylm ethoxy)- benzoyl]methyltriphenylphosphonium chloride: Η-NMR (CDC1 ₃ ) 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 (IH, m), 6.1-6.6 (2H, br), 6.98 (IH, d, J=8Hz), 7.2-8.5 (21H, m) Reference Example 187

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

*H-NMR (CDCI3) δppm: 3.81 (3H, s), 3.91 (3H, s), 4.65 (2H, s), 6.39 (IH, d,

J=2.6Hz), 6.45 (IH, dd, J=2.6Hz, J=8.8Hz), 7.73 (IH, d, J=8.8Hz), 10.97 (IH, s) Reference Example 188

To ethanol (50 ml) are added 2-(2-phthalimide)methylbenzothiazole

(3.37 g) and hydrazine monohydrate (3 ml), and the mixture is refluxed for 30 minutes. After confirming that the starting compounds are consumed, the precipitated solid is removed by filtration, and the filtrate is concentrated. To the residue is added aqueous potassium carbonate solution, and the mixture is extracted with dichloromethane. The extract is dried over magnesium sulfate, and concentrated under reduced pressure to remove the solvent to give 2- aminomethylbenzothiazole (1.42 g).

Yellow powder

¹ H-NMR (CDC1 ₃ ) 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 (50 ml) are added 2-hydroxymethylbenzothiazole (2 g) and triethylamine (2.5 ml), and further tiTereto is added methanesulfonyl chloride (1.03 ml) under ice-cooling, and the mixture is stirred at the same temperature for one hour. After the reaction is complete, the mixture is washed with hydrochloric acid, dried over magnesium sulfate, and concentrated under reduced pressure to the remove the solvent. The resulting crude product is dissolved in dimethylformamide (50 ml), and thereto is added potassium phthalimide (5.6 g). The mixture is heated witfi stirring at 70°C for one hour. After the reaction is complete, the reaction mixture is poured into water, and the precipitated crystals are collected by filtration. Separately, the filtrate is extracted with ethyl acetate, and the extract is concentrated under reduced pressure. The residue and the crystals obtained before are combined, and washed with n-hexane-diethyl ether to give 2-(2-phthalimide)methylbenzo-

thiazole (3.37 g).

Yellow powder

Η-NMR (CDC1 ₃ ) δppm: 5.30 (2H, s), 1.35-1 Al (2H, m), 7.74-8.02 (6H,

m) Reference Example 190

A solution of methyl p-formylbenzoate (12.33 g), malonic acid (16 g) and piperidine (1 ml) in pyridine (100 ml) is refluxed for two hours. The reaction mixture is poured into ice-water, and the precipitated white powder is collected by filtration, and washed with water, and dried to give 4-methoxycarbonyl cinnamic acid (14.7 g). White powder Η-NMR (DMSO-dg) δppm: 3.85 (3H, s), 6.65 (IH, d, J=16Hz), 7.63 (IH,

d, J=16Hz), 7.82 (2H, d, J=8Hz), 8.01 (2H, d, J=8Hz), 12.57 (IH, br) Reference Example 191 To a solution of 4-methoxycarbonylcinnamic acid (4.64 g) in acetic acid

(300 ml) is added 10 % palladium-carbon (0.5 g), and the mixture is subjected to hydrogenation at 70 ^β C under atmospheric pressure for two hours. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. To the residue is added water, and the precipitated white powder is collected by filtration to give 3-(4-methoxycarbonylphenyl)propionic acid (3.87 g). White powder

*H-NMR (CDCI ₃ ) 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 (6.5 g) in anhydrous dichloromethane (100 ml) are added oxalyl chloride (3.2 ml) and a drop of dimethylformamide, and the mixture is stirred at room temperature for three hours. The mixture is evaporated to remove the dichloromethane, and the residue is dissolved in acetone (100 ml), and added dropwise into an aqueous solution of sodium azide (5 g) in water (20 ml) under ice-cooling. The mixture is stirred at the same temperature for three hours, and thereto is added water. The precipitated crystals are collected by filtration, dissolved in dichloromethane (50 ml), dried, and concentrated under reduced pressure to remove the solvent. To the residue is added benzene (50 ml), and the mixture is refluxed for four hours. To the mixture is added ethyl 4-piperidinecarboxylate (5.7 g), and the mixture is refluxed for 6 hours. To the reaction solution is added water, and the mixture is extracted with ethyl acetate. The extract is washed with water, dried, and concentrated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography (solvent; dichloromethane: methanol = 200: 1 — > 100: 1) to give 2-(4-ethoxycarbonyl-l-piperidinyl)- carbonylaminobenzothiazole (4.0 g).

White powder

Η-NMR (CDC1 ₃ ) δppm: 1.25 (3H, t, J=7Hz), 1.65-2.05 (4H, m), 2.4-2.6

(IH, 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 (IH, d, J=8Hz), 7.75 (IH, d, J=8Hz), 10.11 (IH, br) Reference Example 193

To a solution of methyl 2-methoxy-4-trifluoromethanesulfonyloxy- benzoate (26.8 g), t-butyl acrylate (62.5 ml), triethylamine (25 ml) in anhydrous

dimethylformamide (100 ml) are added palladium acetate (0.4 g) and 1,3- bis(diphenylphosphino)propane (0.74 g) under argon atmosphere, and the mixture is heated with stirring at 75°C for 16 hours. The reaction solution is concentrated under reduced pressure to remove the solvent, and thereto is added water. The mixture is extracted with ethyl acetate, and the extract is washed with water, dried, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; ethyl acetate: n-hexane = 1 :5) to give t-butyl 3-methoxy-4-methoxycarbonylcinnamate (23.5

g). Yellow powder

Η-NMR (CDC1 ₃ ) δppm: 1.54 (9H, s), 3.90 (3H, s), 3.94 (3H, s), 6.42 (IH,

d, J=16Hz), 7.07 (IH, d, J=1.5Hz), 7.13 (IH, dd, J=1.5, 8Hz), 7.55 (IH, d, J=16Hz),

7.80 (lH, d, J=8Hz)

Reference Example 194 To a solution of t-butyl 3-methoxy-4-methoxycarbonylcinnamate (23.5 g) in anhydrous dichloromethane (100 ml) is added trifluoroacetic acid (50 ml) under ice-cooling, and the mixture is stirred at room temperature overnight. The reaction solution is concentrated under reduced pressure to remove the solvent, and the residue is crystallized from ethanol to give 3-methoxy-4-methoxy- carbonylcinnamic acid (8.35 g). White powder

Η-NMR (CDCl ₃ +DMSO-d ₆ ) δppm: 3.88 (3H, s), 3.94 (3H, s), 6.50 (IH, d,

J=16Hz), 7.13 (IH, s), 7.15 (IH, d, J=8Hz), 7.62 (IH, d, J=16Hz), 7.78 (IH, d, J=8Hz)

Reference Example 195

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

White powder

Η-NMR (CDC1 ₃ ) 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 (IH, br), 6.75-6.9 (2H, m), 7.75 (IH, d, J=8Hz) Reference Example 196

To a solution of dimethyl methylphosphonate (7.7 ml) in anhydrous tetrahydrofuran (100 ml) is added dropwise a 1.66M solution of n-butyl lithium in n-hexane (43 ml) at -50°C to -60°C. Subsequently, a solution of 2-[2-(3- methoxy-4-methoxycarbonylphenyl)ethyl]carbonylaminobenzothia zole (8.72 g) in anhydrous tetrahydrofuran (50 ml) is added dropwise to the reaction solution. A yellow gummy material generates in the reaction mixture, and thereto is further added l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)pyrimidinone (10 ml), and the mixture is stirred at the same temperature for two hours. To the reaction mixture is added a saturated aqueous ammonium chloride solution, and the mixture is acidified with diluted hydrochloric acid. The mixture is extracted with ethyl acetate, and the extract is washed with water, dried, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; dichloro- methane:methanol = 100: 1 — > 10: 1) to give dimethyl [{3-methoxy-4-[2-(2-benzo-

thiazolyl)aminocarbonyl)ethyl]benzoyl }methyl]phosphonate (6.4 g), whereby the starting compound (3.1 g) is also recovered.

Yellow powder m-NMR (CDC1 ₃ ) 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 (IH, d, J=8.5Hz), 7.64 (IH, d, J=7.5Hz), 7.82 (IH, dd, J=lHz, J=7.5Hz), 11.49 (lH, br) Reference Example 197

Dimethyl methylphosphonate (3.9 ml), 1.65M n-butyl lithium (22 ml) and 2-(4-ethoxycarbonyl-l-piperidinyl)carbonylaminobenzothiazole (4.0 g) are treated in the same manner as in Reference Example 196 to give dimethyl [l-(2- benzothiazolyl)aminocarbonyl)-4-piperidinylcarbonylmethyl]ph osphonate (2.5

g).

Pale yellow oil Η-NMR (CDCI ₃ ) 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 (IH, d, J=7.5Hz), 7.74 (IH, d, J=8Hz), 10.04 (IH, br)

Using the suitable starting compounds, the compounds as listed in Table 36-1 are obtained in the same manner as in Reference Example 1.

Table 36-1

Using the suitable starting compounds, the compounds as listed in Tables -2 to 36-9 are obtained in the same manner as Reference Example 2.

Table 36-2

Table 36-3

Table 36-4

Reference Example 224

R ¹⁹ : -OCH ₃ (4-position) R ⁵ : _ _0CH2 _ ~~ (3-position)

M.p. 197.0-197.5°C Crystalline form: Yellow powder

Solvent for recrystalUzation: Ethyl acetate-dimethylformamide Form: Free

Reference Example 225

R ¹⁹ : -OCH ₃ (4-position) R ⁵ : -OCH ₂ CH=CH ₂ (3-position) M.p. 130- 132°C CrystaUine form: Pale yellow powder

Solvent for recrystaUization: Ethyl acetate-n-hexane Form: Free

Reference Example 226

R ¹⁹ : -OCH ₃ (4-position) R ⁵ : o~ ( ³ -P ^osition )

M.p. 131.5-132.5°C Crystalline form: White powder

Solvent for recrystalUzation: n-Hexane-ethyl acetate-dichloromethane Form: Free

Reference Example 227

R ¹

" j R ^: H A: -CH ₂ - m: 1

R ²

R ¹⁹ : -OCH ₃ (4-position) R ⁵ : __ ~Λ (3-position)

M.p. 169.9-170.3°C Crystalline form: Pale yellow powder

Solvent for recrystaUization: Ethyl acetate-n-hexane Form: Free

Table 36-5

Reference Example 228

R ¹⁹ : -OCH ₃ (4-position)

R ⁵ : -(CH ₂ ) ₂ CH ₃ (2-position) & -OCH ₃ (3-position)

M.p. 147.0-147.5°C Crystalline form: Pale yellow powder

Solvent for recrystaUization: Ethyl acetate-n-hexane Form: Free

Reference Example 229

R ¹⁹ : -OCH ₃ (4-position) R5 _: _ _Q _ ^~ (3-position)

M.p. 142.0-143.0°C Crystalline form: White powder

Solvent for recrystaUization: Ethyl acetate-n-hexane Form: Free

Reference Example 230

R ¹⁹ : -OCH ₃ (4-position) R ⁵ : -SCH ₃ (3-position)

NMR (22) Crystalline form: Pale yellow powder

Form: Free

Reference Example 231

R ¹⁹ : -OCH ₃ (4-position)

R ⁵ : -(CH ₂ ) ₃ CH ₃ (2-position) & -OCH ₃ (3-position) NMR (27) Crystalline form: Pale yellow powder

Form: Free

Table 36-6

Reference Example 232

R ¹⁹ : -OCH ₃ (4-position)

R ⁵ : -CH ₃ (2-position) & -OCH ₃ (3-position)

NMR (35) Crystalline form: Orange powder

Form: Free

Reference Example 233

R ¹⁹ : -OCH ₃ (4-position)

R ⁵ : -CH ₂ CH ₃ (2-position) & -OCH ₃ (3-position)

NMR (36) CrystalUne form: Orange powder

Reference Example 234

R ¹⁹ : -OCH ₃ (4-position) R ⁵ _: -OCH ₃ (3-position)

M.p. 186- 188°C CrystaUine form: White powder

Form: Free

Reference Example 235

^Rl ^ CH,- m: 2

R^ _^ R ^4: H A: -

R ¹⁹ : -OCH ₃ (4-position)

R ⁵ : -CH ₂ CH=CH ₂ (2-position) & -OCH ₃ (5-position)

M.p. 187-189°C Crystalline form: Pale yellow powder

Form: Free

Table 36-7

Reference Example 236

R ¹⁹ : -OCH ₃ (4-position)

R ⁵ : -OCH ₃ (2-position) & -N(CH ₃ ) ₂ (3-ρosition)

NMR (46) Crystalline form: White powder

Form: Free

Reference Example 237

R ⁹ : -OCH ₃ (4-position)

R ⁵ : -N(CH ₃ ) ₂ (2-position)

NMR (65) Crystalline form: White powder

Form: Free

Table 36-8

Reference Example 238

R ¹⁹ : -OCH ₃ (4-position) R ⁵ ; -OCH ₃ (3-position) T: -CH ₂ - u: 1

NMR (48) Crystalline form: White powder

Form: Free

Table 36-9

Reference Example 239

R ¹⁹ : -OCH ₃ (4-position) R ⁵ : H

NMR (73) Crystalline form: Yellow powder

Form: Free

Using the suitable starting compounds, the compounds as listed in Table 36-10 to 36-16 are obtained in the same manner as in Reference Example 3.

Table 36-10

Reference Example 241

-COCH ₂ PO(R ¹⁸ ) ₂ : -COCH ₂ PO(OCH ₃ ) ₂ (4-position)

R ⁵ : -OCH ₂ CH=CH ₂ (3-position)

M.p. 134- 135°C Crystalline form: White powder

Solvent for recrystaUization: Ethyl acetate-n-hexane Form: Free

Reference Example 242

^Rl : ^ J R H A: -CH ₂ - m: 1

R ²

-COCH ₂ PO(R ¹⁸ ) ₂ : -COCH ₂ PO(OCH ₃ ) ₂ (4-position)

R ⁵ : _ ₀ _/ ^~ (3-position)

NMR (8) CrystaUine form: Yellow oil

Form: Free

Reference Example 243

-COCH ₂ PO(R ¹⁸ ) ₂ : -COCH ₂ PO(OCH ₃ ) ₂ (4-position)

R ⁵ : ^~ (3-position)

NMR ( 10) CrystaUine form: Yellow oil

Form: Free

Table 36- 1 1

Reference Example 244

-COCH ₂ PO(R ¹⁸ ) ₂ : -COCH ₂ PO(OCH ₃ ) ₂ (4-position) R ⁵ : -(CH ₂ ) ₂ CH ₃ (2-position) & -OCH ₃ (3-position)

M.p. 156.5-157.4 °C CrystalUne form: White needles

Solvent for recrystaUization: Ethyl acetate-n-hexane Form: Free

Reference Example 245

-COCH ₂ PO(R ¹⁸ ) ₂ : -COCH ₂ PO(OCH ₃ ) ₂ (4-position) R ⁵ : - _Q -ζ^ (3-position)

NMR (16) Crystalline form: Yellow amoφhous Form: Free

Reference Example 246

-COCH ₂ PO(R ¹⁸ ) ₂ : -COCH ₂ PO(OCH ₃ ) ₂ (4-position)

R ⁵ : -SCH ₃ (3-position)

NMR (23) Crystalline form: Pale brown powder Form: Free

Reference Example 247

-COCH ₂ PO(R ¹⁸ ) ₂ : -COCH ₂ PO(OCH ₃ ) ₂ (4-position)

R ⁵ : -(CH ₂ ) ₃ CH ₃ (2-position) & -OCH ₃ (3-position)

NMR (28) Crystalline form: White powder Form: Free

Table 36-12 Reference Example 248

: J R ^4: H A: -CH ₂ - m: 2

R ²

-COCH ₂ PO(R ¹⁸ ) ₂ : -COCH ₂ PO(OCH ₃ ) ₂ (4-position)

R ⁵ : -CH ₃ (2-position) & -OCH ₃ (3-position)

NMR (37) Crystalline form: Pale red powder Form: Free

Reference Example 249

R , ι ¹

^ R ^4: H A: -CH, m: 2

^

R ²

-COCH ₂ PO(R ¹⁸ ) ₂ : -COCH ₂ PO(OCH ₃ ) ₂ (4-position)

R ⁵ : -CH ₂ CH ₃ (2-position) & -OCH ₃ (3-position)

NMR (38) Crystalline form: Pale red powder Form: Free

Reference Example 250

-COCH ₂ PO(R ¹⁸ ) ₂ : -COCH ₂ PO(OCH ₃ ) ₂ (4-position)

R ⁵ : -OCH ₃ (3-position)

M.p. 140-142°C Crystalline form: Colorless prisms

Solvent for recrystalUzation: Ethanol Form: Free

Reference Example 251

-COCH ₂ PO(R ¹⁸ ) ₂ : -COCH ₂ PO(OCH ₃ ) ₂ (4-position)

R ⁵ : -CH ₂ CH=CH ₂ (2-position) & -OCH ₃ (5-position)

M.p. 125-128"C Crystalline form: Pale brown prisms

Solvent for recrystalUzation: Ethanol-n-hexane Form: Free

Table 36-13

Reference Example 252

-COCH ₂ PO(R ¹⁸ ) ₂ : -COCH ₂ PO(OCH ₃ ) ₂ (4-position)

R ⁵ : -OCH ₃ (2-position) & -N(CH ₃ ) ₂ (3-position)

NMR (47) Crystalline form: Pale yellow powder Form: Free

Reference Example 253

-COCH ₂ PO(R ¹⁸ ) ₂ : -COCH ₂ PO(OCH ₃ ) ₂ (4-position) R ⁵ : -Br (2-position) & -OCH ₃ (5-position) M.p. 196-199°C CrystaUine form: White powder

Solvent for recrystalUzation: Ethanol Form: Free

Reference Example 254

-COCH ₂ PO(R ¹⁸ ) ₂ : -COCH ₂ PO(OCH ₃ ) ₂ (4-position)

R ⁵ : -N(CH ₃ ) ₂ (2-position)

NMR (66) CrystaUine form: Yellow oil Form: Free

Reference Example 254A

-COCH ₂ PO(R ¹⁸ ) ₂ : -COCH ₂ PO(OCH ₃ ) ₂ (4-position)

R ⁵ : -OCH ₃ (2-position)

NMR (77) Crystalline form: White powder Form: Free

Table 36-14

Reference Example 255

-COCH ₂ PO(R ¹⁸ ) ₂ : -COCH ₂ PO(OCH ₃ ) ₂ (4-position) R ⁵ : -OCH ₃ (3-position) T: -CH ₂ - u: 1

NMR (49) Crystalline form: Brown oil Form: Free

Table 36-15

Reference Example 256

-COCH ₂ PO(R ¹⁸ ) ₂ : -COCH ₂ PO(OCH ₃ ) ₂ (4-position)

R ⁵ : H

NMR (74) CrystaUine form: Pale brown oil Form: Free

Reference Example 257

-COCH ₂ PO(R ¹⁸ ) ₂ : -COCH ₂ PO(OCH ₃ ) ₂ (4-position)

R ⁵ : -OCH ₃ (3-position)

NMR (76) Crystalline form: Yellow powder Form: Free

Using the suitable starting compounds, the compounds as listed in Table 36-16 are obtained in the same manner as in Reference Example 5 or 6.

Table 36-16

Reference Example 258

R ⁵ : -OCH ₃ (2 & 3-positions)

NMR (67) Crystalline form: Pale yellow amoφhous Form: Free

Reference Example 259

R ⁵ ; -O(CH ₂ ) ₃ Cl (3-position)

NMR (68) Crystalline form: Colorless amoφhous Form: Free

Reference Example 260

/ \

^R5; -0(CH ₂ ) ₃ N O (3-position)

NMR (69) Crystalline form: Pale yellow amoφhous Form: Free

Reference Example 261

R ^J

R ^4: H A: -CH ₂ - m: l

R 2 ^Jj! ^ N(CH ₃ )2

R ⁵ : -OCH ₃ (3-position) NMR (70) Crystalline form: Dark brown amoφhous Form: Free

Using the suitable starting compounds, the compounds as listed in Table 36-17 are obtained in the same manner as in Reference Example 7, 8 or 9.

Table 36-17 Reference Example 262

Colorless oil

Form: Free

NMR (71)

Reference Example 263

Pale yellow oil Form: Free NMR (72)

Using the suitable starting compounds, the compounds as listed in Tables 36-18 to 36-21 are obtained in the same manner as in Reference Example 187.

Table 36-18

Reference Example 264

R ⁵ : -OH (3-position) A: -CH ₂ - m: 1

-COR ¹⁹ : -COOCH ₃ (4-position) R ²⁴ : -OCH ₃

NMR (l) Crystalline form: White soUd Form: Free

Reference Example 265

R ⁵ : _ _0CH2 - ^~ Λ (3-position) A: -CH ₂ - m: 1

-COR ¹⁹ : -COOCH ₃ (4-position) R ²⁴ : -OCH ₃

NMR (2) Crystalline form: White soUd Form: Free

Reference Example 266

R5 _: -OCH ₂ CH=CH ₂ (3-position) A: -CH ₂ - m: 1

-COR ¹⁹ : -COOCH ₃ (4-position) R ²⁴ : -OCH ₃

NMR (4) Crystalline form: Colorless oil Form: Free

Reference Example 267

R ⁵ : o- ⁽³ "P ^{osiuon) A:} "CH ₂ - m: 1

-COR ¹⁹ : -COOCH ₃ (4-position) R ²⁴ : -OCH ₃

NMR (6) CrystaUine form: Yellow oil Form: Free

Reference Example 268

R ⁵ : _ ^~ (3-position) A: -CH ₂ - m: 1

-COR ¹⁹ : -COOCH ₃ (4-position) R ²⁴ : -OCH ₃

NMR (9) Crystalline form: Colorless oil Form: Free

Reference Example 269

R ⁵ : -CH ₂ CH=CH ₂ (2-position) & -OH (3-position) A: -CH ₂ - m: 2

-COR ¹⁹ : -COOCH ₃ (4-position) R ²⁴ : -OCH ₃

M.p. 93.1-93.8°C CrystaUine form: Colorless needles Solvent for recrystallization: n-Hexane-ethyl acetate Form: Free

Reference Example 270

R ⁵ _: -(CH ₂ ) ₂ CH ₃ (2-position) & -OH (3-position)

A: -CH ₂ - m: 2

-COR ¹⁹ : -COOCH ₃ (4-position) R ²⁴ : -OCH ₃

NMR (12) Crystalline form: White soUd Form: Free

Table 36-19

Reference Example 271

R ⁵ : -(CH ₂ ) ₂ CH ₃ (2-position) & -OCH ₃ (3-position)

A: -CH ₂ - m: 2

-COR ¹⁹ : -COOCH ₃ (4-position) R ²⁴ : -OCH ₃

NMR (13) Crystalline form: Colorless oil Form: Free

Reference Example 272

R ⁵ : — _Q -Z^X (3-position) A: -CH ₂ - m: 1

-COR ¹⁹ : -COOCH ₃ (4-position) R ²⁴ : -OCH ₃

NMR (15) CrystalUne form: Colorless oil Form: Free

Reference Example 273

R ⁵ : -SCH ₃ (3-position) A: -CH ₂ - m: 1

-COR ¹⁹ : -COOCH ₃ (4-position) R ²⁴ : -OCH ₃

NMR (20) Crystalline form: Pale yellow powder Form: Free

Reference Example 274

R ⁵ : -(CH ₂ ) ₃ CH ₃ (2-position) & -OH (3-position)

A: -CH ₂ - m: 2

-COR ¹⁹ : -COOCH, (4-position) R ²⁴ : -OCH ₃

NMR (24) CrystalUne form: Pale brown powder Form: Free

Reference Example 275

R ⁵ : -(CH ₂ ) ₃ CH ₃ (2-position) & -OCH ₃ (3-position)

A: -CH ₂ - m: 2

-COR ¹⁹ : -COOCH ₃ (4-position) R ²⁴ : -OCH ₃

NMR (25) Crystalline form: White powder Form: Free

Reference Example 276

R ⁵ : -CH ₂ CH ₃ (2-position) & -OH (3-position) A: -CH ₂ - m: 2

-COR ¹⁹ : -COOCH ₃ (4-position) R ²⁴ : -OCH ₃

NMR (29) Crystalline form: White powder Form: Free

Reference Example 277

R ⁵ : -CH ₃ (2-position) & -OH (3-position)

A: -CH ₂ - m: 2

-COR ¹⁹ : -COOCH ₃ (4-position) R ²⁴ : -OCH ₃

NMR (30) Crystalline form: White powder Form: Free

Table 36-20

Reference Example 278

R ⁵ : -CH ₃ (2-position) & -OCH ₃ (3-position)

A: -CH ₂ - m: 2

-COR ¹⁹ : -COOCH ₃ (4-position) R ²⁴ : -OCH ₃

NMR (31) CrystaUine form: Colorless needles Form: Free

Reference Example 279

R ⁵ : -CH ₂ CH ₃ (2-position) & -OCH ₃ (3-position)

A: -CH ₂ - m: 2

-COR ¹⁹ : -COOCH3 (4-position) R ²⁴ : -OCH ₃

NMR (32) CrystaUine form: Colorless oil Form: Free

Reference Example 280 R ⁵ :-OH (3-position) A: -CH ₂ - m: 1

-COR ¹⁹ : -COOCH ₃ (4-position) R ²⁴ : -OC ₂ H ₅

NMR (40) CrystaUine form: Colorless oil Form: Free

Reference Example 281

R ⁵ ;-OCH ₃ (3-position)

A: -CH ₂ - m: 1

-COR ¹⁹ : -COOCH ₃ (4-position) R ²⁴ : -OC ₂ H ₅

NMR (41) Crystalline form: Pale brown powder Form: Free

Reference Example 282

R ⁵ :-OCH ₃ (3-position) A: -(CH ₂ ) ₃ - m: 1

-COR ¹⁹ : -COOCH ₃ (4-position) R ²⁴ : -OCH ₃

M.p. 48-50°C Crystalline form: White powder

Solvent for recrystaUization: Ethyl acetate-n-hexane Form: Free

Reference Example 283

R ⁵ : -OCH ₃ (2-position) & -NH ₂ (3-position)

A: -CH ₂ - m: 2

-COR ¹⁹ : -COOCH ₃ (4-position) R ²⁴ : -OCH ₃

NMR (44) CrystaUine form: Yellow oil Form: Free

Reference Example 284

R ⁵ _: -OCH ₃ (2-position) & -N(CH ₃ ) ₂ (3-position)

A: -CH ₂ - m: 2

-COR ¹⁹ : -COOCH ₃ (4-position) R ²⁴ : -OCH ₃

NMR (45) Crystalline form: Brown oil Form: Free

Table 36-21

Reference Example 285

R ⁵ : -Br (2-position) & -OH (5-position)

A: -CH ₂ - m: 2

-COR ¹⁹ : -COOCH ₃ (4-position) R ²⁴ : -OCH ₃

NMR (56) Crystalline form: White powder Form: Free

Reference Example 286

R ⁵ : -Br (2-position) & -OCH ₃ (5-position)

A: -CH ₂ - m: 2

-COR ¹⁹ : -COOCH ₃ (4-position) R ²⁴ : -OCH ₃

NMR (57) Crystalline form: White powder Form: Free

Reference Example 287

R ⁵ : -NH ₂ (2-position) & -OCH ₃ (5-position)

A: -CH ₂ - m: 2

-COR ¹⁹ : -COOCH ₃ (4-position) R ²⁴ : -OC ₂ H ₅

NMR (59) Crystalline form: White powder Form: Free

Reference Example 288

R ⁵ _: -N(CH ₃ ) ₂ (2-position) A: -CH ₂ - m: 1

-COR ¹⁹ : -COOCH ₃ (4-position) R ²⁴ :

NMR (63) CrystaUine form: YeUow oil Form: Free

Using the suitable starting compounds, the compounds as listed in Tables 36-22 to 36-23 are obtained in the same manner as in Reference Example 1 or 194.

Table 36-22

Reference Example 289

^R5: (3-position)

A: -CH ₂ - m: 1 -COR ¹⁹ : -COOCH ₃ (4-position)

NMR (3) Crystalline form: White soUd Form: Free

Reference Example 290

R5; -OCH ₂ CH=CH ₂ (3-position)

A: -CH ₂ - m: 1 -COR ¹⁹ : -COOCH ₃ (4-position)

NMR (5) Crystalline form: White soUd Form: Free

Reference Example 291

R ⁵ : _{^ Q} TΛ (3-position)

A: -CH ₂ - m: 1 -COR ¹⁹ : -COOCH ₃ (4-position)

NMR (7) CrystaUine form: Pale yellow oil Form: Free

Reference Example 292

R ⁵ : ^ (3-position)

A: -CH ₂ - m: 1 -COR ¹⁹ : -COOCH, (4-position)

M.p. 124.5-126.0°C Crystalline form: White powder Solvent for recrystalUzation: Ethyl acetate Form: Free

Reference Example 293

R ⁵ : -(CH ₂ ) ₂ CH ₃ (2-position) & -OCH ₃ (3-position)

A: -CH ₂ - m: 2 -COR ¹⁹ : -COOCH ₃ (4-position)

NMR (14) Crystalline form: White soUd Form: Free

Reference Example 294

R ⁵ : _Q _/ ^~ \ (3-position)

A: -CH ₂ - m: 1 -COR ¹⁹ : -COOCH ₃ (4-position)

M.p. I31.5-132.0°C CrystalUne form: Pale yellow powder Solvent for recrystalUzation: Ethyl acetate Form: Free

Reference Example 295

R ⁵ : -SCH ₃ (3-position) A: -CH ₂ - m: 1

-COR ¹⁹ : -COOCH ₃ (4-position) NMR (21) Crystalline form: White powder Form: Free

Table 36-23

Reference Example 296

R ⁵ : -(CH ₂ ) ₃ CH ₃ (2-position) & -OCH ₃ (3-position)

A: -CH ₂ - m: 2 -COR ¹⁹ : -COOCH ₃ (4-position)

NMR (26) Crystalline form: White powder Form: Free

Reference Example 297

R ⁵ : -CH ₃ (2-position) & -OCH ₃ (3-position)

A: -CH ₂ - m: 2 -COR ¹⁹ : -COOCH ₃ (4-position)

NMR (33) Crystalline form: White powder

Reference Example 298

R ⁵ : -CH ₂ CH ₃ (2-position) & -OCH ₃ (3-position)

A: -CH ₂ - m: 2 -COR ¹⁹ : -COOCH ₃ (4-position)

NMR (34) Crystalline form: White powder

Reference Example 299

R ⁵ : -OCH ₃ (3-position)

A: -(CH ₂ ) ₃ - m: 1 -COR ¹⁹ : -COOCH ₃ (4-position)

M.p. 89-90°C CrystaUine form: Colorless needles

Solvent for recrystalUzation: Water-ethanol Form: Free

Reference Example 300

R ⁵ : -CH ₂ CH=CH ₂ (2-position) & -OCH ₃ (5-position)

A: -CH ₂ - m: 2 -COR ¹⁹ : -COOCH ₃ (4-position)

NMR (43) Crystalline form: White powder Form: Free

Reference Example 301

R ⁵ : -Br (2-position) & -OCH ₃ (5-position)

A: -CH ₂ - m: 2 -COR ¹⁹ : -COOCH ₃ (4-position)

NMR (58) Crystalline form: White powder Form: Free

Reference Example 302

R ⁵ : -N(CH ₃ ) ₂ (2-position)

A: -CH ₂ - m: 1 -COR ¹⁹ : -COOCH ₃ (4-position)

NMR (64) Crystalline form: White amoφhous Form: Free

Reference Example 303

Using the suitable starting compounds, the following compounds are obtained in the same manner as in Reference Example 6. Methyl α-(2,3-dihydroxy-4-acetylphenoxy)acetate:

White powder

*H-NMR (DMSO-de) δppm: 2.56 (3H, s), 3.69 (3H, s), 4.91 (2H, s), 6.49 (IH,

d, J=9.1Hz), 7.35 (IH, d, J=9.1Hz), 8.79 (IH, s), 12.31 (IH, s) Methyl α-(2,3-dimethoxy-4-acetylphenoxy)acetate: White solid Η-NMR (CDC1 ₃ ) δppm: 2.60 (3H, s), 3.81 (3H, s), 3.93 (3H, s), 3.99 (3H, s),

4.75 (2H, s), 6.57 (IH, d, J=8.9Hz), 7.48 (IH, d, J=8.9Hz) Methyl α-[2,3-dimethoxy-4-(2-bromoacetyl)phenoxy]acetate:

Colorless oil

Η-NMR (CDCI3) δppm: 3.81 (3H, s), 3.93 (3H, s), 4.07 (3H, s), 4.57 (2H, s),

4.76 (2H, s), 6.58 (IH, d, J=8.9Hz), 7.54 (IH, d, J=8.9Hz)

(2,3-Dimethoxy-4-methoxycarbonylmethoxybenzoyl)methylenet riphenyl- phosphorane:

Colorless amoφhous

Η-NMR (CDCI ₃ ) δppm: 3.77 (3H, s), 3.94 (6H, s), 4.61 (IH, brd, J=27.8Hz),

4.70 (2H, s), 6.56 (IH, d, J=8.8Hz), 7.38-7.80 (16H, m)

Ethyl α- [3 - ( 3 -chloropropoxy )-4-acety lphenoxy )acetate : Yellow oil Η-NMR (CDCI ₃ ) 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 (IH, dd, J=2H, J=8.5Hz), 6.57 (IH, d, J=2Hz), 7.81 (IH, d, J=8.5Hz)

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

Colorless oil

*H-NMR (CDCI ₃ ) 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 (IH, dd, J=2Hz, J=9Hz), 6.59 (IH, d, J=2Hz), 7.89 (IH, d, J=9Hz)

[2-(3-Chloropropoxy)-4-ethoxycarbonylmethoxybenzoyl]methy lenetriphenyl- phosphorane: Pale brown amoφhous ϊH-NMR (CDC1 ₃ ) 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 (IH, br), 6.47 (IH, dd, J=2Hz, J=9Hz), 6.57 (IH, d, J=2Hz), 7.4-8.0 (16H, m) (2,3-Dimethoxy-4-carboxymethoxybenzoyl)methyltriphenylphosph onium chloride:

Colorless prisms (recrystalhzed from diluted hydrochloric acid)

M.p. 137-151 °C (decomposed)

Η-NMR (DMSO-d _δ ) δppm: 3.78 (3H, s), 3.81 (3H, s), 4.69 (2H, s), 6.63 (IH,

d, J=8.9Hz), 7.28 (IH, d, J=8.9Hz), 7.50-7.80 (15H, m) [2-(3-Chloropropoxy)-4-carboxymethoxybenzoyl]methyltriphenyl phosphonium chloride:

Pale yellow amoφhous

Η-NMR (CDCI ₃ ) 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 (IH, dd, J=2Hz, J=7Hz), 6.48 (IH, d, J=2Hz), 7.35-7.9 (16H, m)

^J H-NMR spectrum (NMR (1) to NMR (77)) as described in Tables 36-1 to 36-23 are as follows:

NMR (1) (CDCI ₃ ) δppm: 3.81 (3H, s), 3.91 (3H, s), 4.65 (2H, s), 6.39 (IH, d,

J=2.6Hz), 6.45 (IH, dd, J=2.6Hz, J=8.8Hz), 7.73 (IH, d, J=8.8Hz), 10.97 (IH, s)

NMR (2) (CDC1 ₃ ) δppm: 3.80 (3H, s), 3.87 (3H, s), 4.64 (2H, s), 5.16 (2H, s),

6.42 (IH, dd, J=2.4Hz, J=8.7Hz), 6.60 (IH, d, J=2.4Hz), 7.30-7.43 (3H, m), 7.49- 7.52 (2H, m), 7.85 (IH, d, J=8.7Hz) NMR (3) (DMSO-de) δppm: 3.76 (3H, s), 4.76 (2H, s), 5.19 (2H, s), 6.54 (IH,

dd, J=2.3Hz, J=8.7Hz), 6.76 (IH, d, J=2.3Hz), 7.27-7.44 (3H, m), 7.49-7.53 (2H, m), 7.69 (IH, d, J=8.7Hz), 13.07 (IH, brs)

NMR (4) (CDCI ₃ ) 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 (IH, m), 6.41 (IH, dd, J=2.4Hz, J=8.7Hz), 6.54 (IH, d, J=2.4Hz), 7.83 (IH, d, J=8.7Hz)

NMR (5) (DMSO-dg) 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 (IH, m), 6.52 (IH, dd, J=2.3Hz, J=8.7Hz), 6.64 (IH, d, J=2.3Hz), 7.67 (IH, d, J=8.7Hz), 13.05 (IH, brs)

NMR (6) (CDCI ₃ ) δppm: 1.52-2.00 (8H, m), 3.82 (3H, s), 3.84 (3H, s), 4.66

(2H, s), 4.73-4.84 (IH, m), 6.37 (IH, dd, J=2.4Hz, J=8.7Hz), 6.53 (IH, d, J=2.4Hz), 7.79 (IH, d, J=8.7Hz)

NMR (7) (CDCI ₃ ) δppm: 1.52-2.03 (8H, m), 3.84 (3H, s), 4.71 (2H, s), 4.30-

5.20 (2H, m), 6.40 (IH, dd, J=2.4Hz, J=8.7Hz), 6.54 (IH, d, J=2.4Hz), 7.80 (IH, d, J=8.7Hz) NMR (8) (CDCI ₃ ) 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 (IH, m), 6.40-6.62 (2H, m), 7.32-7.42 (IH, m), 7.44-7.52 (IH, m), 7.79-7.90 (3H, m), 8.31-10.20 (IH, brs)

NMR (9) (CDCI ₃ ) 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 (IH, d, J=8.8Hz)

NMR (10) (CDC1 ₃ ) 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 (IH, brs)

NMR (11) (CDCI ₃ ) 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 (IH, d, J=2.4Hz), 6.46 (IH, dd, J=2.4Hz, J=8.3Hz), 7.05 (IH, d, J=8.3Hz)

NMR (12) (CDCI ₃ ) 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 (IH, d, J=8.9Hz), 7.65 (IH, d, J=8.9Hz), 11.08 (1 H, s) NMR (13) (CDCI ₃ ) 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 (IH, d, J=8.8Hz), 7.70 (IH, d, J=8.8Hz)

NMR (14) (CDC1 ₃ ) 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 (IH, d, J=8.8Hz), 7.20 (IH, brs), 7.72 (IH, d, J=8.8Hz)

NMR (15) (CDCI ₃ ) δppm: 3.77 (3H, s), 3.79 (3H, s), 4.59 (2H, s), 6.45 (IH, d,

J=2.5Hz), 6.65 (IH, dd, J=2.5Hz, J=8.8Hz), 6.92-7.03 (2H, m), 7.03-7.17 (IH, m), 7.26-7.40 (2H, m), 7.91 (IH, d, J=8.8Hz)

NMR (16) (CDCI ₃ ) δppm: 3.72 (3H, s), 3.77 (3H, s), 3.81 (2H, d, J=21.6Hz),

4.68 (2H, s), 6.34 (IH, d, J=2.4Hz), 6.62 (IH, 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 (IH, d, J=8.8Hz), 10.65 (IH, brs) NMR (17) (DMSO-d ₆ ) δppm: 2.02 (3H, s), 3.75 (3H, s), 4.64 (2H, s), 6.47

(IH, d, J=8.3Hz), 6.60 (IH, d, J=8.3Hz), 7.07 (IH, t, J=8.3Hz), 12.93 (IH, brs)

NMR (18) (DMSO-cy 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 (IH, d, J=8.3Hz), 6.59 (IH, d, J=8.3Hz), 7.06 (IH, t, J=8.3Hz), 12.89 (IH, brs)

NMR (19) (CDC1 ₃ ) 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 (IH, d, J=8.2Hz), 6.64 (IH, d, J=8.2Hz), 7.14 (IH, t, J=8.2Hz), 7.26-7.39 (IH, m), 7.39-7.52 (IH, m), 7.73-7.90 (2H, m), 9.70 (lH, brs)

NMR (20) (CDCI ₃ ) δppm: 2.43 (3H, s), 3.82 (3H, s), 3.88 (3H, s), 4.70 (2H,

s), 6.59 (IH, dd, J=8.8Hz, J=2.4Hz), 6.81 (IH, d, J=2.4Hz), 8.00 (IH, d, J=8.8Hz) NMR (21) (DMSO-dg) δppm: 2.39 (3H, s), 3.77 (3H, s), 4.81 (2H, s), 6.62-

6.83 (2H, m), 7.89 (IH, d, J=9.1Hz), 13.14 (IH, brs)

NMR (22) (CDCI ₃ ) δppm: 2.48 (3H, s), 3.90 (3H, s), 4.82 (2H, s), 6.69 (IH,

dd, J=8.7Hz, J=2.4Hz), 6.86 (IH, d, J=2.4Hz), 7.36 (IH, dt, J=1.2Hz, J=7.7Hz), 7.48 (IH, dt, J=1.2Hz, J=7.7Hz), 7.84 (2H, t, J=7.7Hz), 8.05 (IH, d, J=8.7Hz), 9.91 (lH. brs)

NMR (23) (CDCI ₃ ) 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 (IH, dd, J=8.8Hz, J=2.4Hz), 6.85 (IH, d, J=2 Hz), 7.34 (IH, dt, J=1.3Hz, J=9.2Hz), 7.47 (IH, dt, J=l .3H, J=9.2Hz), 7.82 (2H, t, J=9.2Hz), 8.01 (IH, d, J=8.8Hz) NMR (24) (CDCI ₃ ) 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 (IH, d, J=9.0Hz), 7.67 (lH, d, J=9.0Hz), 11.07 (lH, s)

NMR (25) (CDCI ₃ ) 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 (IH, d, J=8.8Hz), 7.72 (IH, d, J=8.8Hz)

NMR (26) (DMSO-d ₆ ) 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 (IH, d, J=8.8Hz), 7.60 (IH, d, J=8.8Hz), 13.05 (IH, brs)

NMR (27) (CDC1 ₃ ) 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 (IH, d, J=8.8Hz), 7.34 (IH, dt, J=1.3Hz, J=7.7Hz), 7.46 (IH, dt, J=1.3Hz, J=7.7Hz), 7.69-7.90 (3H, m), 9.62 (IH, brs) NMR (28) (CDCI ₃ ) 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=l 1.4Hz), 3.79 (3H, s), 3.81 (2H, d, J=22.1Hz), 4.82 (2H, s), 6.69 (IH, d, J=8.8Hz), 7.34 (IH, t, J=8.6Hz), 7.46 (IH, t, J=8.6Hz), 7.57 (IH, d, J=8.8Hz), 7.82 (2H, t, J=8.6Hz), 9.87 (IH, brs)

NMR (29) (CDCI ₃ ) 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 (IH, d, J=9.0Hz), 7.67 (IH, d, J=9.0Hz), 11.08 (IH, s)

NMR (30) (CDCI ₃ ) δppm: 2.18 (3H, s), 3.80 (3H, s), 3.91 (3H, s), 4.71 (2H, s),

6.28 (IH, d, J=9.0Hz), 7.67 (IH, d, J=9.0Hz), 11.11 (IH, s)

NMR (31) (CDCI ₃ ) δppm: 2.34 (3H, s), 3.81 (3H, s), 3.82 (3H, s), 3.89 (3H,

s), 4.70 (2H, s), 6.51 (IH, d, J=8.8Hz), 7.71 (IH, d, J=8.8Hz)

NMR (32) (CDCI3) 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 (IH, d, J=8.8Hz), 7.73 (IH, d, J=8.8Hz)

NMR (33) (DMSO-d ₆ ) δppm: 2.10 (3H, s), 3.70 (3H, s), 3.78 (3H, s), 4.78

(2H, s), 6.72 (IH, d, J=8.9Hz), 7.59 (IH, d, J=8.9Hz), 13.11 (IH, brs)

NMR (34) (DMSO-d ₆ ) 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 (IH, d, J=8.9Hz), 7.60 (IH, d, J=8.9Hz), 13.09 (IH, brs) NMR (35) (CDC1 ₃ ) δppm: 2.31 (3H, s), 3.85 (3H, s), 3.90 (3H, s), 4.82 (2H,

s), 6.65 (IH, d, J=8.8Hz), 7.34 (IH, dt, J=1.2Hz, J=7.6Hz), 7.46 (IH, dt, J=1.2Hz, J=7.6Hz), 7.69-7.89 (3H, m), 9.79 (IH, brs)

NMR (36) (CDCI ₃ ) 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 (IH, d, J=8.8Hz), 7.30 (IH, dt, J=1.3Hz, J=7.3Hz), 7.46 (IH, dt, J=l .3Hz, J=7.3Hz), 7.70-7.90 (3H, m), 9.72 (IH, brs)

NMR (37) (CDCI ₃ ) δppm: 2.33 (3H, s), 3.77 (6H, d, J=l 1.1Hz), 3.80 (3H, s),

3.81 (2H, d, J=22.0Hz), 4.82 (2H, s), 6.69 (IH, d, J=8.8Hz), 7.35 (IH, dt, J=1.3Hz, J=7.9Hz), 7.47 (IH, dt, J=1.3Hz, J=7.9Hz), 7.61 (IH, d, J=8.8Hz), 7.82 (2H, t, J=7.9Hz), 9.87 (IH, brs) NMR (38) (CDCI3) 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 (IH, d, J=8.8Hz), 7.38 (IH, dt, J=1.4Hz, J=8.6Hz), 7.47 (IH, dt, J=1.4Hz, 8.6Hz), 7.59 (IH, d, J=8.8Hz), 7.83 (2H, t, J=8.6Hz), 9.73 (IH, brs)

NMR (39) (CDCI ₃ ) δppm: 2.24 (3H, s), 3.85 (3H, s), 4.75 (2H, s), 6.51 (IH, d,

J=8.3Hz), 6.63 (IH, d, J=8.3Hz), 7.14 (IH, t, J=8.3Hz), 7.29-7.40 (IH, m), 7.40-7.52 (IH, m), 7.74-7.91 (2H, m)

NMR (40) (CDCI ₃ ) δppm: 1.30 (3H, t, J=7Hz), 3.91 (3H, s), 4.27 (2H, q,

J=7Hz), 4.63 (2H, s), 6.41 (IH, d, J=2.5Hz), 6.48 (IH, dd, J=2.5Hz, J=9Hz), 7.75 (lH, d, J=9Hz), 10.96 (lH, s)

NMR (41) (CDC1 ₃ ) δppm: 1.30 (3H, t, J=7Hz), 3.86 (3H, s), 3.89 (3H, s),

4.28 (2H, q, J=7Hz), 6.43 (IH, dd, J=2.5Hz, J=8.5Hz), 6.58 (IH, d, J=2.5Hz), 7.84 (IH, d, J=8.5Hz)

NMR (42) (CDC1 ₃ ) δppm: 1.69 (3H, d, J=7Hz), 3.80 (3H, s), 4.95 (IH, q,

J=7Hz), 6.45-6.7 (3H, m), 7.15-7.5 (3H, m), 7.7-7.9 (2H, m), 9.77 (IH, br)

NMR (43) (CDCI ₃ ) 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 (IH, m), 6.34 (IH, s), 7.69 (IH, s), 9.28 (IH, br)

NMR (44) (CDC1 ₃ ) δppm: 3.80 (3H, s), 3.84 (3H, s), 3.88 (3H, s), 4.73 (2H,

s), 5.98 (2H, br), 6.12 (IH, d, J=9Hz), 7.59 (IH, d, J=9.1Hz)

NMR (45) (CDCI ₃ ) δppm: 2.88 (6H, s), 3.80 (3H, s), 3.83 (3H, s), 3.87 (3H,

s), 4.71 (2H, s), 6.48 ( IH, d, J=8.7Hz), 7.29 (IH, d, J=8.7Hz)

NMR (46) (CDCI3) δppm: 2.91 (6H, s), 3.88 (3H, s), 3.89 (3H, s), 4.80 (2H,

s), 6.64 (IH, d, J=8.7Hz), 7.30-7.38 (2H, m), 7.42-7.51 (IH, m), 7.80-7.89 (2H, m), 10.24 (IH, br)

NMR (47) (CDCI ₃ ) 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 (IH, d, J=8.6Hz), 7.26 (IH, d, J=8.6Hz), 7.34 (IH, t, J=9.1Hz), 7.43 (IH, t, J=9.1Hz), 7.80-7.90 (2H, m), 10.10 (IH, br)

NMR (48) (CDCI ₃ ) δppm: 3.86 (3H, s), 3.89 (3H, s), 4.65 (2H, s), 4.97 (IH, d,

J=5.9Hz), 6.49-6.55 (2H, m), 7.34-7.54 (3H, m), 7.84-7.89 (IH, m), 7.98 (IH, d, J=7.3Hz)

NMR (49) (CDCI ₃ ) 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 (IH, d, J=7.6Hz)

NMR (50) (DMSO-d ₆ ) δppm: 1.13 (6H, d, J=7.0Hz), 3.08-3.35 (IH, m), 3.69

(3H, s), 4.66 (2H, s), 6.38 (IH, d, J=2.4Hz), 6.48 (IH, d, J=2.4Hz, J=8.4Hz), 7.07 (lH, d, J=8.4Hz), 12.93 (lH, s) NMR (51) (DMSO-d ₆ ) 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 (IH, d, J=8.2Hz), 12.92 (lH, s)

NMR (52) (CDC1 ₃ ) δppm: 2.31 (3H, s), 3.78 (3H, s), 4.74 (2H, s), 6.42 (IH, d,

J=2.4Hz), 6.52 (IH, dd, J=2.4Hz, J=8.8Hz), 7.12 (IH, d, J=8.8Hz), 7.25-7.53 (2H, m), 7.72-7.94 (2H, m), 9.71 (IH, s)

NMR (53) (CDCI ₃ ) δppm: 1.30 (6H, d, J=6.9Hz), 3.19-3.46 (IH, m), 3.79

(3H, s), 4.75 (2H, s), 6.44 (IH, d, J=2.4Hz), 6.60 (IH, dd, J=2.4Hz, J=8.5Hz), 7.20 (IH, d, J=8.5Hz), 7.24-7.53 (2H, m), 7.72-7.94 (2H, m), 9.51-9.82 (IH, brs)

NMR (54) (CDCI ₃ ) 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 (IH, d, J=2.4Hz), 6.55 (IH, dd, J=2.4Hz, J=8.3Hz), 7.12 (IH, d, J=8.3Hz), 7.23-7.52 (2H, m), 7.75-7.92 (2H, m), 9.56-9.80 (lH, brs)

NMR (55) (DMSO-dg) δppm: 2.09 (3H, s), 3.68 (3H, s), 4.66 (2H, s), 6.32-

6.52 (2H, m), 7.02 (IH, d, J=8.1Hz), 12.95 (IH, s) NMR (56) (CDCI ₃ ) δppm: 3.82 (3H, s), 3.93 (3H, s), 4.73 (2H, s), 6.34 (IH,

s), 8.02 (IH, s), 10.93 (IH, s)

NMR (57) (CDCI ₃ ) δppm: 3.82, 3.86, 3.88 (each 3H, each s), 4.77 (2H, s),

6.40 (IH, s), 8.07 (IH, d, J=3.1Hz)

NMR (58) (DMSO-d ₆ ) δppm: 3.74, 3.82 (each 3H, each s), 4.97 (2H, s),

6.74 (IH, s), 7.85 (IH, d, J=3.6Hz), 12.82-13.44 (IH, br)

NMR (59) (DMSO-d ₆ ) δppm: 3.73, 3.74 (each 3H, each s), 4.63 (2H, s),

6.76 (IH, s), 7.30 (IH, s), 10.66 (IH, brs) NMR (60) (DMSO-d ₆ ) δppm: 3.66 (3H, s), 3.70 (3H, s), 4.64, 4.73 (total IH,

each s), 6.34-6.52 (2H, m), 6.79-6.96 (IH, m), 12.88-13.03 (IH, m)

NMR (61) (CDC1 ₃ ) δppm: 3.77 (3H, s), 3.97 (3H, s), 4.78 (2H, s), 6.51-6.72

(2H, m), 6.89 (IH, d, J=8.8Hz), 7.21-7.56 (2H, m), 7.73-7.92 (2H, m)

NMR (62) (DMSO-c 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 (IH, m), 12.81-13.01 (IH, brs)

NMR (63) (CDCI ₃ ) δppm: 2.84 (6H, s), 3.89 (3H, s), 4.81 (2H, s), 5.23 (2H,

s), 6.70 (IH, d, J=9.0Hz), 7.26-7.40 (5H, m), 7.60-7.64 (2H, m)

NMR (64) (CDCI ₃ ) δppm: 2.91 (6H, s), 3.93 (3H, s), 4.73 (2H, s), 7.14 (IH, d,

J=7.8Hz), 7.90-7.94 (2H, m), 9.72 (IH, br)

NMR (65) (CDCI ₃ ) δppm: 3.03 (6H, s), 3.91 (3H, s), 4.92 (2H, s), 7.12 (IH, d,

J=8.3Hz), 7.29 (IH, dt, J=1.2Hz, J=7.8Hz), 7.43 (IH, dt, J=1.2Hz, J=7.8Hz), 7.78- 7.86 (4H, m), 13.22 (lH, br)

NMR (66) (CDCI ₃ ) 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 (IH, d, J=8.4Hz), 7.30 (IH, t, J=7.8Hz), 7.43 (IH, t, J=7.8Hz), 7.76-7.86 (4H, m)

NMR (67) (CDCI ₃ ) δppm: 3.96 (3H, s), 4.03 (3H, s), 4.55 (IH, brd,

J=27.4Hz), 4.76 (2H, s), 6.71 (IH, d, J=8.7Hz), 7.25-7.38 (IH, m), 7.39-7.88 (19H,

m), 10.50 (IH, brs)

NMR (68) (CDC1 ₃ ) δppm: 2.10-2.30 (2H, m), 3.58 (2H, t, J=6.6Hz), 4.04-

4.19 (2H, m), 4.38-4.72 (IH, m), 4.65 (2H, s), 6.39 (IH, dd, J=2.3Hz, J=8.6Hz), 6.52 (IH, d, J=2.3Hz), 7.28-7.95 (20H, m), 10.58 (IH, brs) NMR (69) (CDCI3) 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 (IH, m), 4.68 (2H, s), 6.40 (IH, dd, J=2.2Hz, J=8.6Hz), 6.54 (IH, d, J=2.2Hz), 7.23-7.37 (IH, m), 7.37- 7.62 (10H, m), 7.62-7.96 (9H, m), 10.37 (IH, brs)

NMR (70) (CDCI ₃ ) δppm: 3.00 (6H, s), 3.89 (3H, s), 4.70 (2H, s), 6.49 (IH,

dd, J=2.5Hz, J=8.5Hz), 6.57 (IH, d, J=2.5Hz), 6.93 (IH, dd, J=2.5Hz, J=9Hz), 7.08 (IH, d, J=2.5Hz), 7.20-8.05 (16H, m), 8.55-8.65 (IH, m), 9.90 (IH, br)

NMR (71) (CDCI ₃ ) δppm: 1.21-1.56 (2H, m), 1.67 (IH, br), 1.75-1.94 (2H, m),

2.01 (IH, 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 (IH, m) NMR (72) (CDCI ₃ ) δppm: 1.83 (IH, br), 2.15 (IH, dd, J=4.1Hz, J=12.8Hz),

2.26 (6H, s), 2.43 (IH, dd, J=7.8Hz, J=12.8Hz), 2.53 (IH, dd, J=10.2Hz, J=12.1Hz), 2.68-2.98 (3H, m), 3.50-3.72 (2H, m), 3.78-3.99 (IH, m)

NMR (73) (CDCI ₃ ) 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 (IH, d, J=7.5Hz), 7.8-7.95 (IH, m), 7.90 (2H, d, J=8.5Hz)

NMR (74) (CDC1 ₃ ) 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 (IH, m), 7.81-7.90 (3H, m)

NMR (75) (CDC1 ₃ ) 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 (IH, d, J=8Hz), 6.72 (IH, s), 7.25-7.5 (2H, m), 7.6-7.75 (2H, m), 7.85 (IH, d, J=7.5Hz), 11.40 (IH, br)

NMR (76) (CDC1 ₃ ) 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 (IH, d, J=8.5Hz), 7.64 (IH, d, J=7.5Hz), 7.82 (IH, dd, J=lHz, J=7.5Hz), 11.49 (lH, br)

NMR (77) (CDC1 ₃ ) δppm: 3.62 (2H, d, J=22.5Hz), 3.77, 3.82 (6H, each s),

4.04 (3H, s), 4.85 (2H, s), 7.02 (IH, d, J=8.5Hz), 7.3-7.55 (2H, m), 7.6-7.7 (2H, m), 7.8-7.9 (2H, m), 10.31 (lH, br) Example 1

A solution of 2-(2-isopropylphenoxymethylcarbonylamino)benzothiazole (6.5 g), anhydrous maleic acid (3.9 g) and aluminum chloride (8.0 g) in 1,2- dichloroethane (50 ml) is stirred at room temperature for 7 hours. To the mixture is added water in order to decompose the aluminum chloride, and thereto is added ethyl acetate, and the mixture is stirred. The precipitated crystals are collected by filtration, washed with ethyl acetate, and dried to give a mixture (7.3 g) of a trans- compound and a cis-compound. The mixture thus obtained is dissolved in dimethylformamide (50 ml), and thereto is added cone, hydrochloric acid (1 ml), and the mixture is stirred at 60°C for 30 minutes. To the mixture is added water (about 100 ml), and the precipitated crystals are collected by filtration, washed with methanol, and dried to give 2-[2-isopropyl-4-(trans-3- carboxyacryloyl)phenoxymethylcarbonylamino]benzothiazole (6.2 g).

^J H-NMR (DMSO-d _f s) δppm: 1.25 (6H, d, J=7Hz), 3.40 (IH, sept, J=7Hz),

5.12 (2H, s), 6.64 (IH, d, J=15.5Hz), 7.03 (IH, d, J=8.5Hz), 7.25-7.5 (2H, m), 7.77

(IH, d, J=7.5Hz), 7.85-8.05 (4H, m), 12.70 (IH, br), 13.10 (IH, br) Example 2

To a solution of 2-[2-isopropyl-4-(3-carboxyacryloyl)phenoxymethyl- carbonylamino]benzothiazole (1.0 g) and triethylamine (0.4 ml) in dichloro- methane (20 ml) is added dropwise isobutyl chloroformate (0.32 ml) under ice- cooling. To the mixture is added N-methylpiperazine (0.27 ml) at the same temperature, and the mixture is stirred for 2.5 hours. The reaction solution is washed with water, dried and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; dichloromethane — > dichloromethane:methanol = 30: 1), and recrystalhzed from ethanol to give 2-{2- isopropyl-4-[3-(4-methyl-l-piperazinylcarbonyl)acryloyl]phen oxy- methylcarbonylamino}benzothiazole (0.80 g). Pale brown powder M.p. 190-192°C Example 3

A solution of 2-[4-(3-carboxyacryloyl)phenoxymethylcarbonyamino]- benzothiazole (1.0 g), thionyl chloride (0.23 ml) and a drop of dimethylformamide (20 ml) in dichloromethane (20 ml) is stirred at room temperature for 10 hours. The solution is added dropwise into a solution of 4-(4-methyl-l- piperazinyl)piperidine (0.5 g) and pyridine (1 ml) in dichloromethane (20 ml) under ice-cooling. To the reaction solution is added water, and the mixture is basified with 5 % aqueous sodium hydroxide solution. The mixture is extracted with dichloromethane, and the extract is washed, dried, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; dichloromethane:methanol = 50:1 — > 10: 1). The compound thus

obtained is converted into a hydrochioride thereof by a conventional method and recrystalhzed from ethanol-diethyl ether to give 2-[4-{3-[4-(4-methyl-l- piperazinyl)-l-piperidinylcarbonyl)acryloyl}phenoxymethylcar bonylamino]- benzothiazole dihydrochloride (0.14 g). White powder

M.p. 202.5-225°C (decomposed)

1H-NMR (DMSO-dg) 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 (IH, m), 4.5-4.7 (IH, m), 5.08 (2H, s), 7.15 (2H, d, J=9Hz), 7.3-7.55 (3H, m), 7.76 (IH, d, J=14Hz), 7.77 (IH, d, J=8.5Hz), 7.98 (IH, d, J=8Hz), 8.05 (2H, d, J=9Hz), 12.67 (1 H, br) Example 4

To a solution of 2-[2-isopropyl-4-(3-carboxyacryloyl)phenoxymethyl- carbonylaminojbenzothiazole (0.97 g) in dimethylformamide (10 ml) are added dropwise 4-(4-methyl-l-piperazinyl)piperidine (0.65 g) and diethyl cyano- phosphate (0.6 ml) at room temperature. To the mixture is added triethylamine (0.5 ml), and the mixture is stirred at room temperature for 10 minutes. To the mixture is added water, and the mixture is extracted with ethyl acetate. The extract is washed with water, dried, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; dichloro- methane:methanol = 100: 1 → 10:1). The compound thus obtained is converted into a hydrochioride thereof in ethanol by a conventional method, and recrystalhzed 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°C (decomposed) Example 5

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

Η-NMR (DMSO-dβ) δppm: 3.89 (3H, s), 5.09 (2H, s), 6.67 (IH, d,

J=15.5Hz), 7.08 (IH, d, J=8.5Hz), 7.25-7.55 (2H, m), 7.57 (IH, m), 7.7-8.1 (4H, m), 11.68 (lH, br)

Example 6

To a solution of ethyl propiolate (17.7 ml) in tetrahydrofuran (450 ml) is added dropwise a 1.71 M solution of n-butyl lithium in n-hexane (102 ml) at -78°C, and the mixture is stirred for 10 minutes. To the solution is added dropwise a solution of 2-(2-methoxy-4-formylphenoxymethylcarbonylamino)- benzothiazole (20 g) in tetrahydrofuran (400 ml) and N,N-dimethylpropylene urea (40 ml) at the same temperature over a period of 15 minutes. The mixture is further stirred for 10 minutes, and the reaction vessel is taken out from an iced bath, and further stirred for 20 minutes. To the mixture is added acetic acid (11 ml), and the mixture is diluted with ethyl acetate. The ethyl acetate layer is washed with a saturated aqueous sodium carbonate solution, dried over sodium sulfate, and concentrated. The residue is purified by silica gel column chromatography (solvent; dichloromethane : methanol = 100: 1 — » 50: 1) to give 2- [2-methoxy-4-(3-methoxycarbonyl-l-hydroxypropargyl)phenoxyme thyl- carbonylamino]benzothiazole (33.7 g) as a dark brown oil.

To a solution of 2- [2-methoxy-4- (3 -methoxy carbonyl- 1-hydroxy- propargyl)phenoxymethylcarbonylamino]benzothiazole (33.7 g) in dimethyl¬ formamide (150 ml) is added tri-n-butylamine (14.3 ml), and the mixture is stirred at room temperature for 1.5 hour. The mixture is diluted with ethyl acetate, and washed with 0.15N hydrochloric acid, and dried over sodium sulfate. The mixture is concentrated under reduced pressure to remove the solvent, and the precipitated crystals are collected by filtration to give 2-[2-methoxy-4-(trans-3- methoxycarbonylacryloyl)phenoxymethylcarbonylamino]benzothia zole (Compound A, 5.5 g) as pale yellow powder. On the other hand, the filtrate is concentrated under reduced pressure, and crystallized from ethanol-diethyl ether

to give 2-[2-methoxy-4-(cis-3-methoxycarbonylacryloyl)phenoxy- methylcarbonylamino]benzothiazole (Compound B, 6.0 g) as pale yellow powder. Compound A: ϊH-NMR (DMSO-d ₆ ) 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 (IH, d, J=15.5Hz), 7.08 (IH, d, J=8.6Hz), 7.31-7.37 (IH, m), 7.44-7.50 (IH, m), 7.59 (IH, d, J=2.0Hz), 7.75-7.81 (2H, m), 7.98 (IH, d, J=15.5Hz), 8.00-8.02 (IH, m), 12.67 (IH, brs) Compound B: Η-NMR (DMSO-dg) 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 (IH, d, J=12.3Hz), 7.05 (IH, d, J=8.8Hz), 7.21 (IH, d, J=12.3Hz), 7.31-7.37 (IH, m), 7.44-7.50 (3H, m), 7.78-7.81 (IH, m), 7.99-8.02 (IH, m), 12.62 (IH, brs) Example 7 A solution of 2-{2-isopropyl-4-[trans-3-(4-methyl-l-piperazinyl)- carbonylacryloyl]phenoxymethylcarbonylamino}benzothiazole (100 mg) in dimethylformamide (10 ml) is allowed to stand for 6.5 hours by a window in order to be exposed to direct sunlight. To the mixture is added water, the precipitated crystals are collected by filtration, and recrystalhzed from ethanol to give 2-{2- isopropyl-4-[cis-3-(4-methyl-l-piperazinyl)carbonylacryloyl] phenoxy- methylcarbonylamino}benzothiazole (45 mg).

Pale yellow powder

M.p. 114-115°C Example 8

To a solution of dimethyl { [3-methoxy-4-(2-benzothiazolylaminocarbonyl- methoxy)benzoyl]methyl}phosphonate (1.7 g) and pyridine-4-aldehyde (0.5 g) in tetrahydrofuran (30 ml) is added a 5% aqueous sodium hydroxide solution (6 ml) under ice-cooling, and the mixture is stirred for 5 hours. The mixture is neutralized with acetic acid, and the precipitated crystals are collected by filtration, and then recrystalhzed from dichloromethane-ethanol-diethyl ether to give 2-{ 2-methoxy-4-[3-(4-pyridyl)acryloyl]phenoxymethylcarbonylamin o}- benzothi azole (1.3 g).

Pale yellow powder M.p. 206-207°C

Example 9

To a solution of 2-[2-methoxy-4-(3-t-butoxycarbonyl-l-hydoxypropargyl)- phenoxymethylcarbonylamino]benzothiazole (1 g) in chloroform (50 ml) is added active manganese dioxide (1 g), and the mixture is refluxed for two hours. To the mixture is further added active manganese dioxide (1 g), and the mixture is refluxed for 1.5 hour. The mixture is filtered through a cerite pad, and the filtrate is concentrated. The residue is recrystalhzed from ethanol to give 2-[2-methoxy- 4-(3-t-butoxycarbonylpropiolyl)phenoxymethylcarbonylamino]be nzothiazole (0.5 g). Example 10

To a solution of 2-[2-methoxy-4-(3-t-butoxycarbonylpropioloyl)phenoxy- methylcarbonylaminojbenzothiazole (0.5 g) in methylene chloride (30 ml) is added trifluoroacetic acid (10 ml), and the mixture is stirred at room temperature for 4 hours. The mixture is concentrated, and to the residue is added methylene chloride. The mixture is stirred, and the precipitated crystals are collected by

filtration, and recrystalhzed from dichloromethane-trifluoroacetic acid to give 2- [2-methoxy-4-(3-carboxypropioloyl)phenoxymethylcarbonylamino ]- benzothiazole (0.26 g) as brown powder.

M.p. 174-176°C

Using the suitable starting compounds, the following compounds are obtained in the same manner as in Example 1 or 5.

Table 38

Example 11

R ⁴ : H A: -CH ₂ - Z: O

R ⁵ : CH ₃ (2-position) m: 1

M.p. 261-262 ⁰ C Crystalline form: Beige powder

Solvent for recrystalUzation: Dimethylformamide-methanol Form: Free

Example 12

R ⁴ : H A: -CH ₂ - Z: O

R ⁵ : C ₂ H ₅ (2-position) m: 1

M.p. 245-246°C Crystalline form: Beige powder

Solvent for recrystalUzation: Dimethylformamide-methanol Form: Free

Table 39

Example 14 R ⁴ : H A: -CH, Z: O

R ⁵ : Isopropyl (2-position) m: 1

M.p. 225-240°C (decomp.) Crystalline form: Yellow powder NMR (2) Solvent for recrystalUzation: Dimethylformamide-methanol Form: Free

Example 15 R : H A: -CH ₂ - Z: O

R ⁵ : n-Butyl (2-position) m: 1

M.p. 187.5-190°C Crystalline form: Pale yellow powder

Solvent for recrystallization: Chloroform-dimethylformamide Form: Free

Example 16 R ⁴ : H A: -CH,- Z: O

R ⁵ : H m: 1

M.p. 250-275°C (decomp.) Crystalline form: White powder NMR (3) Solvent for recrystalUzation: Dimethylformamide-methanol Form: Free

Example 17 R ⁴ : H A: -CH,- Z: O

R ⁵ : n-Pentyl (2-position) m: 1

M.p. 139- 163°C CrystaUine form: Pale yellow powder NMR (4)

Solvent for recrystaUization: Dimethylformamide-dichloromethane

Form: Free

Table 40

Example 20

R ⁴ : H A: -CH ₂ - Z: O

R ⁵ : -(CH ₂ ) (combined at 2- and 3-positions) m: 2

CrystaUine form: Yellow powder NMR (6)

Form: Free

Table 41

Example 22

R ⁴ : H A: -CH ₂ - Z: O

R ⁵ : CH ₃ (2- and 6-positions) m: 2

CrystaUine form: Beige powder NMR (8)

Solvent for recrystalUzation: Dimethylformamide-methanol Form: Free

Example 23

R ⁴ : H A: -CH ₂ - Z: O

R ⁵ : CH ₃ (3- and 5-positions) m: 2

Crystalline form: Yellow powder Form: Free

NMR (9)

Example 24

R ⁴ : H A: -CH ₂ - Z: O

R ⁵ : -(CH ₂ ) ₂ CO ₂ C ₂ H ₅ (2-position) m: 1

M.p. 199.6-203.8°C Crystalline form: Pale yellow powder

Solvent for recrystallization: CWoroform-dimethylformamide Form: Free

Example 25

R ⁴ : H A: -CH ₂ - Z: O

R ⁵ : -(CH ₂ ) ₄ OCOCH ₃ (2-position) m: 1

M.p. 176-177.5°C CrystaUine form: Pale yellow powder

Solvent for recrystallization: Chloroform Form: Free

M.p. 290°C (decomp.) CrystalUne form: White needles NMR (11)

Solvent for recrystalUzation: Dimethylformamide Form: Free

M.p. 282°C (decomp.) Crystalline form: Pale brown needles

Solvent for recrystaUization: Dimethylformamide-dichloromethane Form: Free

Table 43

Example 31

R ⁴ : H A: -CH ₂ - Z: O

R ⁵ : n-Butyl (3-position) m: 1

M.p. 267-279°C (decomp.) Crystalline form: Pink powder

Form: Free NMR (14)

Table 44

Example 37

R ⁴ : H m: 1 Z: O

R ⁵ and A combine to form:

M.p. 294-295°C (decomp.) K Crystalline form: White powder

Solvent for recrystalUzation: Dimethylformamide Form: Free

Table 45

Table 46

Example 44 R : H A: -CH ₂ - Z: O

R ⁵ : -(CH ₂ ) ₂ -CONH- (combined at 2- and 3-positions) m: 2

CrystaUine form: Yellow powder NMR (25)

Form: Free

Example 45 R ⁴ : H A: -CH ₂ - Z: O R ⁵ : (CH ₃ ) ₃ C- (2-position) m: l

M.p. 263-266°C (decomp.) Crystalline form: Yellow powder

Solvent for recrystaUization: Dimethylformamide-dichloromethane Form: Free

Table 47

Example 49

R ⁴ : H A: -CH ₂ - Z: O

R ⁵ : Cl (2-position) m: 1

M.p. 235.5-237 ^β C Crystalline form: Yellow powder

Solvent for recrystalUzation: Dimethylformamide- water

Form: Free

Table 48

Example 50

R ⁴ : H A: -CH ₂ - Z: O

R ⁵ : -(CH ₂ ) ₂ COOC ₂ H ₅ (2-position) m: 1

M.p. 199.6-203.8°C Crystalline form: Pale yellow powder

Solvent for recrystaUization: Chloroform-dimethylformamide Form: Free NMR (29)

Example 51

R ⁴ : H A: -CH ₂ - Z: O

R ⁵ : n-Butyl (2-position) m: 1

M.p. 187.5-190°C Crystalline form: Pale yellow powder

Solvent for recrystalUzation: Chloroform-dimethylformamide

Form: Free

Example 52

R ⁴ : H A: -CH ₂ - Z: O

R ⁵ : -(CH ₂ ) ₄ OCOCH ₃ (2-position) m: 1

M.p. 176-177.5°C CrystalUne form: Pale yellow powder

Solvent for recrystalUzation: Chloroform Form: Free

Table 49

Example 53

R ⁴ : H m: 1 Z: O

R ⁵ and A combine to form:

M.p. 285-287°C (decomp.) Crystalline form: White powder

Solvent for recrystalUzation: Dimethylformamide-water Form: Free

Example 54

R ⁴ : H A: -CH ₂ - Z: O

R ⁵ : n-Heptyl (2-position) m: 1

M.p. 187-188.5°C CrystalUne form: Pale yellow powder

Solvent for recrystaUization: Dichloromethane-dimethylformamide Form: Free

Example 55

R ⁴ : H A: -CH ₂ - Z: S

R ⁵ : CH ₃ O (2-position) m: 1

M.p. 241-244"C Crystalline form: Yellow powder

Form: Free

Η-NMR spectrum (NMR (1) to NMR (29)) as described in Tables 38-49 are as follows:

NMR (1) (DMSO-d ₆ ) 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 (IH, d, J=15.4Hz), 7.03 (IH, d, J=8.6Hz), 7.31 (IH, t, J=7.6Hz), 7.44 (IH, t, J=7.7Hz), 7.76 (IH, d, J=7.7Hz), 7.87-7.99 (4H, m) NMR (2) (DMSO-d ₆ ) δppm: 1.25 (6H, d, J=7Hz), 3.40 (IH, sept, J=7Hz),

5.12 (2H, s), 6.64 (IH, d, J=15.5Hz), 7.03 (IH, d, J=8.5Hz), 7.25-7.5 (2H, m), 7.77 (IH, d, J=7.5Hz), 7.85-8.05 (4H, m), 12.70 (IH, br), 13.10 (IH, br)

NMR (3) (DMSO-dg) δppm: 5.07 (2H, s), 6.65 (IH, d, J=15.5Hz), 7.15 (2H,

d, J=9Hz), 7.1-7.5 (2H, m), 7.76 (IH, d, J=7Hz), 7.89 (IH, d, J=15.5Hz), 7.99 (IH, d, J=7Hz), 8.05 (2H, d, J=9Hz), 12.70 (IH, br), 13.04 (IH, br)

NMR (4) (DMSO-d ₆ ) 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 (IH, d, J=15.5Hz), 7.04 (IH, d, J=8.5Hz), 7.30-7.38 (IH, m), 7.43-7.51 (IH, m), 7.78-7.82 (IH, d, J=7.9Hz), 7.85- 8.10 (4H, m)

NMR (5) (DMSO-dg) δppm: 5.22 (2H, s), 6.67 (IH, d, J=15.5Hz), 7.24-7.49

(3H, m), 7.77 (IH, d, J=7.6Hz), 7.89 (IH, d, J=15.5Hz), 7.96-8.12 (3H, m), 12.83 (lH, br)

NMR (6) (DMSO-d ₆ ) δppm: 1.6-1.9 (4H, m), 2.65-3.0 (4H, m), 5.06 (2H, s),

6.45 (IH, d, J=16Hz), 6.82 (IH, d, J=8.5Hz), 7.25-7.65 (4H, m), 7.75 (IH, d, J=8Hz), 7.97 (IH, d, J=8Hz), 12.85 (IH, br)

NMR (7) (DMSO-d ₆ ) δppm: 2.22 (3H, s), 2.31 (3H, s), 5.05 (2H, s), 6.44 (IH,

d, J=15.5Hz), 6.85 (IH, d, J=8.5Hz), 7.25-7.6 (4H, m), 7.76 (IH, d, J=8Hz), 7.98

(lH, d, J=8Hz), 12.83 (lH, br)

NMR (8) (DMSO- ;) δppm: 2.36 (6H, s), 4.75 (2H, s), 6.67 (IH, d,

J=15.5Hz), 7.30-7.53 (2H, m), 7.77 (IH, d, J=8.9Hz), 7.79 (2H, s), 7.91 (IH, d, J=15.5Hz), 8.00 (IH, d, J=7.00Hz), 12.09-13.2 (2H, br) NMR (9) (DMSO-d ₆ ) δppm: 2.10 (6H, s), 4.95 (2H, s), 6.22 (IH, d, J=16Hz),

6.78 (2H, s), 7.02 (IH, d, J=16Hz), 7.25-7.5 (2H, m), 7.76 (IH, d, J=8Hz), 7.98 (IH, d, J=7.5Hz), 12.9 (2H, br)

NMR (10) (CDC1 ₃ ) δppm: 1.37 (3H, d, J=7.0Hz), 4.14 (2H, q, J=7.0Hz), 5.09

(2H, s), 6.65 (IH, d, J=15.5Hz), 7.06 (IH, d, J=8.6Hz), 7.31 (IH, d, J=7.4Hz), 7.44 (IH, t, J=7.4Hz), 7.55 (IH, s), 7.67-7.78 (2H, m), 7.90 (IH, d, J=15.5Hz), 7.98 (IH, d, J=7.4Hz), 12.74 (2H, br)

NMR (11) (DMSO-dg) δppm: 2.45 (3H, s), 5.03 (2H, s), 6.45 (IH, d,

J=15.6Hz), 6.90-7.06 (2H, m), 7.28-7.35 (IH, m), 7.41-7.48 (IH, m), 7.56 (IH, d, J=15.6Hz), 7.75 (2H, t, J=7.4Hz), 7.97-8.00 (IH, m), 12.80 (2H, brs) NMR (12) (DMSO-dg) δppm: 1.13 (3H, t, J=7.4Hz). 2.80 (2H, q, J=7.4Hz),

5.03 (2H, s), 6.47 (IH, d, J=15.6Hz), 6.94 (IH, dd, J=2.5Hz, J=8.6Hz), 7.01 (IH, d, J=2.5Hz), 7.27-7.50 (2H, m), 7.53 (IH, t, J=15.6Hz), 7.68-7.81 (2H, m), 7.92-8.03 (lH, m), 12.86 (2H, br)

NMR (14) (DMSO-dg) 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 (IH, d, J=15.7Hz). 6.91-7.07 (2H, m), 7.30-7.41 (IH, m), 7.41-7.54 (IH, m), 7.51 (IH, d, J=15.7Hz), 7.74-7.82 (2H, m), 8.00-8.04 (lH, m)

NMR (15) (DMSO-de) δppm: 5.08 (2H, s), 6.50 (IH, d, =15.7Hz), 7.13 (IH,

dd, J=2.5Hz, J=8.7Hz), 7.27-7.49 (4H, m), 7.71 (IH, d, J=8.7Hz), 7.76 (IH, d,

J=7.0Hz), 7.99 (IH, d, J=7.0Hz), 12.85 (IH, br)

NMR (16) (DMSO-d ₆ ) δppm: 5.09 (2H, s), 6.61 (IH, d, J=15.6Hz), 6.98-7.13

(2H, m), 7.30 (IH, t, J=7.1Hz), 7.44 (IH, t, J=7.1Hz), 7.63 (IH, dd, J=3.4Hz, J=15.6Hz), 7.74-7.90 (2H, m), 7.97 (IH, d, J=7.1Hz), 12.88 (IH, br) NMR (17) (DMSO-dg) δppm: 3.89 (3H, s), 5.06 (2H, s), 6.51 (lH,d,

J=15.5Hz), 6.71 (IH, d, J=2.2Hz, J=8.7Hz), 6.82 (IH, d, J=2.2Hz), 7.25-7.50 (2H, m), 7.66 (IH, d, J=8.7Hz), 7.70 (IH, d, J=15.5Hz), 7.74-7.81 (IH, m), 7.94-8.03 (IH, m), 12.80 (2H, br)

NMR (18) (DMSO-d ₆ ) δppm: 1.34 (3H, t, J=6.9Hz), 4.15 (2H, q, J=6.9Hz),

5.05 (2H, s), 6.45 (IH, d, J=15.5Hz), 6.68 (IH, dd, J=2.0Hz, J=8.7Hz), 6.77 (IH, d, J=2.0Hz), 7.26-7.50 (2H, m), 7.66 (IH, d, J=8.7Hz), 7.72-7.81 (IH, m), 7.79 (IH, d, J=15.5Hz), 7.91-8.05 (IH, m), 12.77 (2H, br)

NMR (19) (DMSO-dg) δppm: 3.89 (3H, s), 5.09 (2H, s), 6.67 (IH, d,

J=15.5Hz), 7.08 (IH, d, J=8.5Hz), 7.25-7.55 (2H, m), 7.57 (IH, m), 7.7-8.1 (4H, m), 11.68 (lH, br)

NMR (20) (DMSO-d ₆ ) δppm: 1.29 (6H, d, J=6.0Hz), 4.82 (IH, sept,

J=6.0Hz), 5.05 (2H, s), 6.43 (IH, d, J=15.5Hz), 6.89 (IH, dd, J=2.3Hz, J=8.7Hz), 6.78 (IH, d, J=2.3Hz), 7.31 (IH, t, J=7.0Hz), 7.45 (IH, t, J=7.0Hz), 7.66 (IH, d, J=8.7Hz), 7.78 (IH, d, J=15.5Hz), 7.80 (IH, d, J=7.0Hz), 7.99 (IH, d, J=7.0Hz), 12.76 (lH, br)

NMR (21) (DMSO-d ₆ ) δppm: 4.92 (2H, q, J=8.7Hz), 5.07 (2H, s), 6.48 (IH,

d, J=15.5Hz), 6.81 (IH, dd, J=2.3Hz, J=8.8Hz), 6.93 (IH, d, J=2.3Hz), 7.32 (IH, t, J=7.0Hz), 7.45 (IH, t, J=7.0Hz), 7.62-7.79 (3H, m), 7.99 (IH, d, J=7.0Hz), 12.78 (lH, br)

NMR (22) (DMSO-d ₆ ) δppm: 5.28 (2H, s), 6.69 (IH, d, J=15.5Hz), 7.25-

7.55 (3H, m), 7.77 (IH, d, J=8Hz), 7.92 (IH, d, J=15.5Hz), 7.98 (IH, d, J=7.5Hz), 8.15-8.45 (2H, m), 12.88 (IH, br)

NMR (23) (DMSO-d ₆ ) 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 (IH, d, J=15.5Hz), 7.10 (IH, d, J=8.5Hz), 7.25-7.55 (3H, m), 7.7-7.85 (2H, m), 7.86 (IH, d, J=15.5Hz), 7.98 (IH, d, J=7.5Hz), 12.66 (lH, br)

NMR (24) (DMSO-d ₆ ) δppm: 3.90 (3H, s), 5.18 (2H, s), 6.67 (IH, d,

J=15.5Hz), 7.28-7.36 (2H, m), 7.46 (IH, t, J=7.6Hz), 7.78 (IH, d, J=7.6Hz), 7.89 (IH, d, J=15.5Hz), 7.99 (IH, t, J=7.6Hz), 8.25 (IH, dd, J=2.3Hz, J=8.9Hz) 8.38 (IH, d, J=2.3Hz)

NMR (25) (DMSO-d ₆ ) δppm: 2.48 (2H, t, J=7.5Hz), 3.12 (2H, t, J=7.5Hz),

5.04 (2H, s), 6.52 (IH, d, J=15.7Hz), 7.13 (IH, d, J=8.7Hz), 7.34 (IH, t, J=7.2Hz), 7.42-7.63 (3H, m), 7.80 (IH, d, J=7.6Hz), 8.02 (IH, d, J=7.2Hz), 10.33 (IH, br), 12.98 (lH. br)

NMR (26) (DMSO-d ₆ ) 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 (IH, m), 7.04-7.08 (IH, m), 7.27-7.38 (IH, m), 7.38-7.51 (IH, m), 7.55-7.78 (IH, m), 7.84-7.99 (4H, m), 9.40 (2H, brs)

NMR (27) (DMSO-d ₆ + CDC1 ₃ ) 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 (IH, m), 6.90-7.10 (IH, m), 7.18-7.30 (IH, m), 7.30-7.41 (IH, m), 7.63-7.72 (IH, m), 7.72-7.90 (3H, m), 7.96 (IH, s), 11.50- 13.00 (2H, brs)

NMR (28) (DMSO-d ₆ ) 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 (IH, m), 7.25-7.30 (IH, m), 7.38-7.43 (IH, m), 7.72- 7.85 (5H, m)

NMR (29) (DMSO-d ₆ ) 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 (IH, d, J=15.4Hz), 7.04 (IH, d, J=8.8Hz), 7.30-7.40 (IH, m), 7.55 (IH, m), 7.75 (IH, d, J=7.3Hz), 7.86 (IH, d, J=15.4Hz), 7.91-8.10 (3H, m), 12.40-13.30 (2H, m)

Using the suitable starting compounds, the compounds as listed in Tables 50-125 are obtained in the same manner as in Example 3 or 4.

Table 50

Example 56

R ^Hb :H R": _ ' ^~ _cH3 R ⁵ _: H

M.p.175-185°C Crystalline form: White powder

Solvent for recrystalUzation: Ethanol Form: Free NMR(l)

Example 57

R ^llb :H R ¹⁷ : _ cH ₃ R ⁵ : Isopropyl (2-position)

M.p.190-192°C Crystalline form: Pale brown powder

Solvent for recrystalUzation: Ethanol Form: Free Trans-form

Table 51

Example 58

M.p. 202.5-225°C (decomp.) Crystalline form: White powder NMR (2)

Solvent for recrystaUization: Ethanol-diethyl ether Form: 2HC1

Example 59

, ι

^ R ^4: H A: -CH ₂ - m: 1

R ²

R ^{i ib} _: H R ⁱ⁷ _: ' \ _N ' cH ₃ R ⁵ : Isopropyl (2-position)

M.p. 186-190°C (decomp.) Crystalline form: Yellow powder

Solvent for recrystaUization: Ethanol-diethyl ether Form: 2HC1

Example 60

M.p. 202-206°C (decomp.) Crystalline form: Yellow powder Form: 2HC1 Solvent for recrystaUization: Ethanol-diethyl ether

Table 52

Example 61

R ^llb :H R ¹⁷ : / — \ R ⁵ : Isopropyl (2-position)

— N N-CH ₃

M.p.114-115°C Crystalline form: Pale yellow powder Cis-form

Solvent for recrystaUization: Ethanol-water Form: Free

Example 62

R ^llb :H R ¹⁷ : R ⁵ : Cl (2-position)

—

M.p.206.5-209°C Crystalline form: White powder

Solvent for recrystaUization: Ethanol-water Form: Free

Example 63

R^CH;, R ^: H A:-CH ₂ - m: 1

R ² :H

M.p.138.5-141.5°C Crystalline form: White powder

Form: Free

Table 53

Example 64

R ^{l l} : H R ¹⁷ : / — \ R ⁵ : H -r N~CH ₃

M.p. 221-222.5°C Crystalline form: Pale yellow powder Form: Free

Example 65

R ^{l lb} : H R ¹⁷ : R ⁵ : Cl (2-position)

-N — N . N-CH ₃

M.p. 181-183 ^β C CrystaUine form: White powder

Solvent for recrystaUization: Ethanol-diethyl ether Form: Free

Example 66

R ^{l lb} : H R ¹⁷ : R ⁵ : CH ₃ (2-position)

M.p. 261-262°C Crystalline form: Yellow powder

Solvent for recrystalUzation: Ethanol Form: 2HC1

Table 54

Example 67

R ^{l lb} : H R ¹⁷ : — /— R ⁵ : C ₂ H ₅ (2-position)

— N V-N N-CH ₃

M.p. 227-229°C Crystalline form: Pale yellow powder

Solvent for recrystalUzation: Ethanol Form: 2HC1

M.p. 226-227°C Crystalline form: Brown powder Solvent for recrystalUzation: Ethanol Form: 2HC1

Example 69

R ^{l lb} : H R ⁷ : ^C^l^N-C^ R5 _{: C} H ₃ (2-position)

— N O

Solvent for recrystalUzation: Ethanol Crystalline form: Pale yellow powder Form: 3HC1 NMR (3)

Table 55

Example 70

R ^{l l} : H R ¹⁷ : R5 _: C ₂ H ₅ (2-position)

M.p. 157- 160"C Crystalline form: Pale yellow powder

Solvent for recrystalUzation: Ethanol Form: 3HC1

Example 71

CH ₂ N N-CH ₃ Rllb- H Ri7 _: / ^^ R5; F (2-position)

Solvent for recrystalUzation: Ethanol CrystalUne form: Brown powder

Table 56

Example 73

R ^{l l} : H R": ^_^CH ₂ ϊ^N-CH _{3 R} 5 _{: C} l (2-position)

— N O

M.p. 200°C Crystalline form: Yellow powder

Solvent for recrystaUization: Ethanol-water Form: 2HC1

Example 74

R ^{l l} : H R ¹⁷ : R* _: C ₂ H ₅ (2-position)

M.p. 115-118°C Crystalline form: Pale beige powder

Solvent for recrystalUzation: Ethanol Form: 2HC1

Example 75

R ^{l l} : H R": _R 5 _{: Isopropy} i ₍₂ .position)

M.p. 188- 191°C Crystalline form: White powder Form: 2HC1

Solvent for recrystaUization: Ethanol-water-diethyl ether

Table 57

Example 76

/ — ^ R ^llb :H R ¹⁷ : ^£H ₂ r^N-CH ₃ R5 _{: n} .p _r0 p _y l (2-position)

— N O CrystaUine form: Pale yellow powder Form: 3HC1 NMR (6)

Example 77

R" ^i> :H R": _/ - - ^CH2 ' J ^N"CH3 R ⁵ : C ₂ H ₅ (2-position)

M.p.228-230°C Crystalline form: Pale yellow powder

Solvent for recrystalUzation: Ethanol Form: 2HC1

Example 78

R ,ι ¹ R ²

R ⁵ and A combine to form:

Cς

R ^llb :H Ri7 _: - - N N-CH ₃

M.p.203-205°C Crystalline form: White powder Form: 3HC1

Solvent for recrystallization: Methanol-diethyl ether

Table 58

Example 79

/ \

R ^llb :H R ⁱ ': _/ ~ _ ^Cti3 R ⁵ : n-Propyl (2-position)

M.p.202-204°C -Ό Crystalline form: White powder

Solvent for recrystaUization: Ethyl acetate-n-hexane Form: 3 HCl

R ^llb :H R ⁷ : _R 5 _{: α (} 2-position)

M.p.171°C Crystalline form: Pale yellow powder Form: 2HC1

Solvent for recrystaUization: Ethanol-water

Table 59

Example 82

R ^{l lb} : H R ¹⁷ : / — \ / \ R ⁵ : CH, (2- and 6-positions)

N-CH ₃

M.p. 233-235°C Crystalline form: Pale yellow powder

Solvent for recrystalUzation: Ethanol Form: Free

Example 83

R ^{l lb} : H R ¹⁷ : R ⁵ : CH ₃ (2- and 6-positions)

M.p. 206-210°C Crystalline form: Pale yellow powder

Solvent for recrystalUzation: Ethanol Form: Free

Example 84

R ^{l l} : H -' -σ N N-CH ₃ R ⁵ : F (2-position)

M.p. 205-208°C Crystalline form: White powder

Solvent for recrystallization: Ethanol-water Form: 2HC1

Table 60

Example 85

Ri ^lb : H R ^l7 : R5 _: F (2-position)

M.p. 173-175°C Crystalline form: Pale yellow powder

Solvent for recrystallization: Ethanol-water-diethyl ether Form: 2HC1

Example 86

R ⁵ : C ₂ H ₅ OOC(CH ₂ ) ₂ - (2-position)

M.p. 152.4-156.3°C Crystalline form: White powder

Solvent for recrystallization: Ethanol-water-diethyl ether Form: 3HC1

Example 87

R ^{l l} : H R ¹⁷ : _/ __^ ⁱ² _J ⁾ R5 _{: F} (2-position)

— N O

M.p. 150-153 "C CrystaUine form: Pale yellow powder

Solvent for recrystalUzation: Dichloromethane-diethyl ether Form: Free

Table 61

Example 88

R ^{l l} : H R ¹⁷ : R ⁵ : CH ₃ O (2-position)

Crystalline form: Pale yellow powder Form: 2HC1 Solvent for recrystaUization: Ethanol-water NMR (11)

Example 89

R^ H R ¹⁷ : ^CH ₂ f^N-CH _{3 R} 5 _{: C} H ₃ O (2-position)

— N O

M.p. 203-206°C Crystalline form: Pale yellow powder

Solvent for recrystallization: Ethanol-water-diethyl et her Form: 2HC1

Example 90

R'

R H A: -CH,- m: l

R ^{l lb} : H R ⁵ : n-Butyl (2-position)

M.p. 161.7- 165°C Crystalline form: Pale yellow powder

Solvent for recrystallization: Ethanol-water-diethyl et her Form: 3HC1

Table 62

Example 91

R ^{l l} : H R ⁷ : ^_^CH ₂ I ^> ^N-CH _{3 R} 5 _{: n} . _Bu tyl (2-position)

— N O M.p. 153-155.5°C Crystalline form: Pale yellow powder

Solvent for recrystallization: Ethanol-water-diethyl et her Form: 3HC1

Example 92

R ^{l lb} : H R ¹⁷ : — _/ —\ R5 _: CF ₃ (2-position)

— N V-N N-CH ₃

M.p. 185- 187"C CrystalUne form: Pale yellow powder

Solvent for recrystallization: Isopropyl alcohol-water Form: 2HC1

Example 93

^Rl : ^ J R ^4: H A: -CH ₂ - m: 1

R ²

/ — \

R ^{l l} : H R ¹⁷ : ^CH ₂ ^N-CH _{3 R5} ^ _(2.position)

-l^O

M.p. 175-178°C Crystalline form: Pale yellow powder

Solvent for recrystaUization: Ethanol-water Form: 2HC1

Table 63

Example 94

R ⁵ : CH ₃ COO(CH ₂ ) ₄ - (2-position)

M.p. 151-154°C Crystalline form: White powder

Solvent for recrystallization: Ethanol-water-diethyl ether Form: 3HC1

Example 95

R ^{l l} : H R ¹⁷ : R ⁵ : n-Butyl (2-position)

M.p. 167-168°C Crystalline form: White powder

Solvent for recrystaUization: Ethanol-water Form: 3HC1

Example 96

^Rl : ^ J R ^4: H A: -CH ₂ - : 1

R ²

R ^{l lb} : H R ¹⁷ : R ⁵ _: n-Butyl (2-position)

M.p. 135-137°C CrystaUine form: Pale yellow powder

Solvent for recrystallization: Ethanol-water-diethyl ether Form: 3HC1

Table 64

Example 97

R ^{l lb} : H R ⁵ : CH ₃ O (2-position)

M.p. 183.5-186°C Crystalline form: Yellow powder

Solvent for recrystaUization: Ethanol-water Form: 2HC1

Example 98

R ^{l lb} : H R ¹⁷ : R ⁵ : CH ₃ O (2-position)

M.p. 174-176°C Crystalline form: Pale yellow powder

Solvent for recrystaUization: Ethanol-water Form: 2HC1

Example 99

R ^{l lb} : H R ¹⁷ : R ⁵ : CH ₃ O (2-position)

M.p. 153-154°C Crystalline form: Yellow powder

Solvent for recrystaUization: Ethanol-water Form: 2HC1

Table 65

Example 100

R ^{l l} : H R ¹⁷ : " " -N .-CH ₃ ^{R5: CH} 3° (2-position)

M.p. 111.5-119.5'C Crystalline form: Pale yellow powder

Solvent for recrystaUization: Ethanol-water Form: 3HC1

Example 101

R ^{l lb} : H R ¹⁷ : _R 5 _{: C} H ₃ O (2-position)

M.p. 165-168°C Crystalline form: Pale yellow powder

Solvent for recrystallization: Ethanol-water-diethyl et her Form: 3HC1

Example 102

R ^{l lb} : H R ¹⁷ : R ⁵ : CH ₃ O (2-position)

-r4 N"CH ₃

M.p. 161.5-164°C Crystalline form: Yellow powder

Solvent for recrystaUization: Ethanol-water Form: HCl

Table 66

Example 103

R ¹

' R ^4: H A:-CH ₂ - m: 1

R^

R ^llb :H R ¹⁷ : R ⁵ : CH ₃ O (2-position)

M.p.181 - 183 °C Crystalline form: White powder

Solvent for recrystaUization: Ethanol-water Form: 2HC1

Example 104

^Rl : ^ J R ^4: H A:-CH ₂ - m: 1

R ²

R ⁱⁱ b _: H Rl : — . /-^ R ⁵ _: C ₂ H ₅ O- (2-position)

— V-N N-CH ₃

M.p.174-177°C Crystalline form: Pale yellow powder Form: 2HC1

Solvent for recrystaUization: Ethanol-water-isopropyl alcohol-diethyl ether

Example 105

^Rl : ^ J R ^4: H A:-CH ₂ - m: 1

R

/ — v

R ^llb :H R ¹⁷ : ^/ CH ₂ ^N-CH ₃ R5 _: c ₂ H ₅ O- (2-position)

— N O

M.p.194- 196"C Crystalline form: Yellow powder Form: 2HC1

Solvent for recrystaUization: Ethanol-water-isopropyl alcohol-diethyl ether

Table 67

Example 106

R ^{l lb} : H R ¹⁷ : R ⁵ : CH ₃ O (2-position)

M.p. 200-203°C Crystalline form: Pale yellow powder

Solvent for recrystaUization: Ethanol-water Form: 2HC1

Example 107

R ^{l lb} : H R ⁱ⁷ : _/ — — \ R ⁵ _: CH ₃ O (2-position)

— N V- N N-CH ₃

M.p. 169-170°C Crystalline form: Pale yellow powder

Solvent for recrystalUzation: Ethanol Form: 2HC1

M.p. 181-189°C Crystalline form: Pale yellow powder

Solvent for recrystaUization: Ethanol-water Form: 3HC1 NMR (12)

Table 68

Example 109

CH ₂ N -CH ₃ R ^{l lb} : H R ¹⁷ : / -J R ⁵ : CH ₃ O (2-position)

^"N ° M.p. 158-160°C Crystalline form: Pale yellow powder

Solvent for recrystaUization: Ethanol-water Form: 3HC1

Example 110

R ^{l lb} : H R ¹⁷ :

M.p. 176.5-181.5° CrystaUine form: Yellow powder

Solvent for recrystaUization: Ethanol-water Form: 3HC1 NMR (13)

M.p. 141-142°C Crystalline form: White powder

Solvent for recrystaUization: Ethanol-dichloromethane Form: Free

M.p.131.5-133 "C Crystalline form: Pale yellow powder

Solvent for recrystaUization: Ethanol-dichloromethane Form: Free

Example 113

R ^llb :H R ¹⁷ : — \ /—\ R ⁵ : CH ₃ O (2-position)

— N V-N N-CH ₃

Crystalline form: Pale yellow amorphous Form: Free NMR (14)

Example 114

R ¹

: ^{^} J R H A:-CH ₂ - m: 1

R^

R ^llb :H R ¹⁷ : — \ _/ - _^ , R5; CH ₃ O (2-position)

- -O

M.p.140-142°C Form: Methanesulfonate

Solvent for recrystallization: Ethanol-diisopropyl ether Crystalline form: Pale yellow powder

Table 70

Example 115

CH ₃

R ^H : H R ¹⁷ : _ _N ' (CHH, ₂ ), ₂ CCRH^ R : CH ₃ O (2-position)

\ CH ₃

M.p. 168.5-169°C Crystalline form: White powder

Solvent for recrystaUization: Ethanol-dichloromethane Form: Free

Example 116

R ^{l l} : H R ¹⁷ : / ^Cn S R5 _: CH ₃ O (2-position)

— N O

M.p. 128.2-131.5°C Crystalline form: Yellow powder Form: Free

Solvent for recrystallization: Ethanol-diethyl ether-dichloromethane

M.p. 144-146°C Crystalline form: Pale yellow powder

Solvent for recrystalUzation: Ethanol Form: Methanesulfonate

Table 71

R ⁵ : C ₂ H ₅ O- (2-position)

M.p. 190- 192°C Crystalline form: YeUow powder

Form: Methanesulfonate

Solvent for recrystaUization: Ethanol-isopropyl alcohol-diethyl ether-water

Example 119

R ¹¹ /^

^1 R ^: H A: -CH ₂ - m: 1

R ⁵ : CH ₃ OOC(CH ₂ ) ₂ - (2-position)

R"': H RΠ _: ^CH^^CH,

— N O

M.p. 110- 111 "C Crystalline form: Pale yeUow powder

Solvent for recrystalUzation: Ethanol Form: Free

Example 120

R ⁵ : (CH ₃ ) ₂ NOC(CH ₂ ) ₂ - (2-position)

M.p. 162.5-164'C Crystalline form: Yellow powder

Solvent for recrystallization: Ethanol-water Form: HCl

Table 72

Example 121

R ^{l lb} : H R ¹⁷ : R5 _{: C} H ₃ O (2-position) M.p. 205-207.5°C Crystalline form: Pale yellow powder

Solvent for recrystaUization: Ethanol-water Form: 2HC1

Example 122

R ⁵ : (C ₂ H ₅ ) ₂ NOCCH ₂ O- (2-position)

M.p. 167-169°C Crystalline form: White powder

Solvent for recrystaUization: Ethanol-water Form: 2HC1

Example 123

R ^{i ib} . H ^Rl?: R ⁵ : CH ₃ O- (2-position)

M.p. 190.5-192.5°C Crystalline form: Yellow powder Form: Free Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether

Table 73

Example 124

Ri ^ib _: H Rl ⁷ : O- (2-position)

M.p. 148.2-149°C Crystalline form: Pale yellow powder Form: Free

Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether

M.p. 211 -211.5°C Crystalline form: Pale yellow powder

Solvent for recrystaUization: Ethanol-dichloromethane Form: Free

R ⁵ : CH ₃ O- (2-position)

M.p. 204-206'C CrystalUne form: White needles

Solvent for recrystaUization: Ethanol-dichloromeuiane Form: Free

Table 74

Example 127

R ^{l lb} : H R ¹⁷ : -o r ^~ R ⁵ : CH ₃ O- (2-position)

M.p. 168-170.4°C CrystalUne form: White needles Form: Free

Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether

Example 128

iib _: H Rl ⁷ : /—-, R ⁵ ; CH ₃ O- (2-position)

- > -<OH

M.p. 175.8-177.2'C Crystalline form: White powder

Solvent for recrystaUization: Ethanol-dichloromethane Form: Free

Example 129

R ^{l lb} : H R ¹⁷ : -^ R5 _: C ₂ H ₅ (2-position)

— 1 NH

M.p. 130-132.5 Form: Dimethanesulfonate

Solvent for recrystaUization: Ethanol-diethyl ether CrystaUine form: Yellow powder

Table 75

R ⁵ : C ₂ H ₅ O- (2-position)

M.p. 225-226°C Crystalline form: Pale yellow powder

Solvent for recrystalUzation: Dichloromethane-ethanol Form: Free

Example 131

ii ^b - H Rl?: R ⁵ : CH ₃ O (2-position)

M.p. 222-223 °C Crystalline form: White powder

Solvent for recrystallization: Methanol-dichloromethane Form: Free

Example 132

R ^{l lb} ; H R ¹⁷ _: R ⁵ : C ₂ H ₅ O- (2-position)

M.p. 122.5-125°C Crystalline form: Pale yellow powder

Solvent for recrystaUization: Ethanol-dichloromethane Form: Free

Table 76

Example 133

Rl lb- _{H R} i7; —^ - » _R 5; cH ₃ O (2-position)

- ^• 0- ^c *-0

M.p. 162-163°C CrystalUne form: White powder

Solvent for recrystaUization: Ethanol-dichloromethane Form: Free

Example 134

R ^l

^ R ^4: H A: -CH,- m: 1

R ²

R ^{l lb} : H R ⁷ : R ⁵ : CH ₃ O (2-ρosition)

M.p. 177.2-178'C Crystalline form: Pale yellow powder

Solvent for recrystaUization: Ethanol-dichloromethane Form: Free

M.p. 140-155°C (decomp.) CrystalUne form: White powder NMR (27)

Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether Form: Free

Table 77

Example 136

R ^{i lb} : H R ¹⁷ : R ⁵ : CH ₃ O (2-position)

M.p. 171-172.2'C CrystalUne form: White needles Form: Free

Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether

Example 137 R ¹

R H A: -CH ₂ - m: l ²

R ^l : H R ¹⁷ : R ⁵ : CH ₃ O (2-position)

M.p. 232.5-233°C Crystalline form: Yellow powder

Solvent for recrystalUzation: Dichloromethane-ethanol Form: Free

Example 138

R ¹

R H A: -CH,- m: l

R

Ri ⁱ b- H RΠ _: R5; _C H ₃ O (2-position)

Crystalline form: Pale yellow amoφhous NMR (28)

Form: 3HC1

Table 78

Example 139

R ^{l l} : H R ¹⁷ : ^{1 3} R ⁵ : CH ₃ O (2-position)

M.p. 192-194°C CrystalUne form: Yellow powder

Solvent for recrystaUization: Ethanol-dichloromethane Form: Free

Example 140

R ^{l l b} : H R ¹⁷ : ,CH ₂ OCH ₃ R5 _: CH ₃ O (2-position)

— N O

M.p. 201 -204 °C Crystalline form: Yellow powder

Solvent for recrystaUization: Ethanol-dichloromethane Form: Free

Example 141

R ^{l lb} : H R ¹⁷ : , ^CH2 C1 R5 _: CH ₃ O (2-position)

-N^O

M.p. 172-175°C Crystalline form: YeUow powder

Solvent for recrystaUization: Ethanol-dichloromethane Form: Free

Table 79

Example 142

CH ₂ OH

R ^{l l} : H R ¹⁷ : r-i R ⁵ : CH ₃ O (2-position)

— N O

M.p. 146.5-148°C Crystalline form: Yellow powder

Solvent for recrystaUization: Ethanol-dichloromethane Form: Free

R ⁵ : CH ₃ O (2-position)

M .p . 114- 117 °C Crystalline form: Pale yeUow powder

Solvent for recrystaUization: Ethanol-dichloromethane Form: Free

Example 144

,CH ₂ N N- CH ₃

R ^{l l} : H R ¹⁷ : / \^J R ⁵ : CH ₃ O (2-position)

- N O

M.p. 176- 181 °C CrystaUine form: Pale yellow powder Form: 2HC1

Solvent for recrystalUzation: Ethanol-water-diethyl ether NMR (29)

Table 80

Example 145

R ^: -CH ₂ OCOC(CH ₃ ) ₃ A: -CH ₂ - m: 1

_R ι ⁱ b; H R ⁱ : / — v, R ⁵ _: CH ₃ O (2-position)

M.p. 106.5-108.2°C Crystalline form: Pale yellow powder

Solvent for recrystallization: Ethanol-diethyl ether-n-hexane Form: Free

Example 146

R ^{l l} : H R ¹⁷ : R ⁵ : CH ₃ O (2-position)

M.p. 189-190°C Crystalline form: White powder

Solvent for recrystaUization: Ethanol-dichloromethane Form: Free

Example 147

R ¹

: " R ^: H A: -CH ₂ - m: 1

R ²

R ^{l lb} : H R ¹⁷ : R ⁵ _: CH ₃ O (2-position)

M.p. 151-153"C Crystalline form: White powder

Solvent for recrystaUization: Ethyl acetate-diethyl ether Form: Free

Table 81

Example 148

_R ^{i ib} ; H R ¹⁷ : R ⁵ : CH ₃ O (2-position)

M.p. 145-147°C CrystaUine form: White powder Form: Free

Solvent for recrystallization: Ethyl acetate-chloroform

Example 149

R ^{l lb} - H ¹⁷ : R ⁵ : CH ₃ O (2-position)

M.p. 189-190.5°C Crystalline form: Pale yellow powder

Solvent for recrystallization: Ethyl acetate-chloroform Form: Free

M.p. 196-199°C (decomp.) Crystalline form: Pale yellow powder

Solvent for recrystaUization: Ethanol-dichloromethane Form: Free

Table 82

R ⁵ : C ₂ H ₅ O- (2-position)

M.p. 155-158°C (decomp.) Crystalline form: YeUow powder Form: Free Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether

Example 152

R ^{l lb} : H R ¹⁷ : R ⁵ : CH ₃ O (2-position)

M.p. 162- 164°C Crystalline form: White powder

Solvent for recrystaUization: Ethyl acetate-diethyl ether Form: Free

n-Propyl (2-position)

M.p. 137-139°C (decomp.) Crystalline form: Pale yellow powder

Solvent for recrystaUization: Ethanol-dichloromethane Form: Free

Table 83

Example 154

R ^ll :H R ¹⁷ : R ⁵ : CH ₃ O (2-position)

M.p.158-159°C Crystalline form: White powder Form: Free

Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether

Example 155

^Rl ^ ] R ^4: H A:-CH ₂ - m: 1

R R ^llb :H R ¹⁷ : : / \ =\ R ⁵ : CH ₃ O (2-position)

M.p.154-154.5°C Crystalline form: White powder Form: Free

Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether

Example 156

R ¹

" j R ^: H A:-CH ₂ - m: 1

R ²

R ^ll :-CH ₃ R ¹⁷ : R ⁵ _: CH ₃ O (2-position)

M.p.180-181.5°C Crystalline form: Dark yellow powder Form: HCl

Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether

Table 84

Example 157

,CH ₃ R ^{l lb} : H R ¹⁷ : — < R ⁵ : C ₂ H ₅ (2-position)

-N l*— OH ⁵

M.p. 165-175°C (decomp.) Crystalline form: Yellow powder NMR (30) Solvent for recrystalUzation: Dichloromethane-ethanol-diethyl ether Form: Free

Example 158

R ^{l lb} : H R ¹⁷ : _ ^QH R ⁵ : CH ₃ O (2-position)

M.p. 125-128°C Crystalline form: Yellow powder Form: Free

Solvent for recrystaUization: Ethanol-dichloromethane

Example 159

^Rl ^ i R ^4: H A: -CH ₂ - m: 1

R ²

R ^{l lb} : H R ¹⁷ : _ _N V-OH R ⁵ : CH ₃ (2-position)

M.p. 195-195.5°C Crystalline form: Pale yellow powder Form: Free

Solvent for recrystaUization: Ethanol-dichloromethane

Table 85

Example 160

_R iib; H R ^l ; _ _I ^_Λ _N _ _OH R5 _: CF ₃ (2-position)

M.p. 188-190"C CrystaUine form: Pale yellow powder Form: Free

Solvent for recrystaUization: Ethanol-dichloromethane

R ⁵ : F (2-position)

M.p. 197-200°C CrystalUne form: Pale yellow powder Form: Free

Solvent for recrystaUization: Ethanol-dichloromethane

Example 162

R ⁵ and A combine to form: f f ) R ^{1 lb} : H

R ¹⁷ : .jT _f l

M.p. 138-141°C Crystalline form: White powder Form: Free

Table 86

Example 163

_R i ib; H Ri7 _: — N N-CH ₃ R5 _: CH ₃ O (2-position)

M.p. 155.5-158°C Crystalline form: Pale brown powder Form: Free

Solvent for recrystaUization: Ethanol-dichloromethane

Example 164

R ^lb : H R ^l7 : -isf ^~ V-OCOCH ₃ R ⁵ : CH ₃ (2-position)

M.p. 163-166"C Crystalline form: Brown powder Form: Free

Solvent for recrystalUzation: Dichloromethane-ethanol-diethyl ether

Example 165

R ^{l lb} : H R ¹⁷ : ^R5; n-Butyl (2-position)

M.p. 161-163.4°C Crystalline form: Yellow powder Form: 2HC1

Solvent for recrystalUzation: Ethanol-dichloromethane-water

Table 87

Example 167

R ^{l b} : H R ¹⁷ : R ⁵ : CH ₃ (2-position)

M.p. 215-217°C CrystaUine form: Pale yellow powder Form: Free

Solvent for recrystaUization: Ethanol-dichloromethane

Example 168

R ^{l lb} : H R ¹⁷ : R ⁵ : n-Heptyl (2-position)

M.p. 146.5-149°C Crystalline form: Pale yellow powder

Solvent for recrystallization: Ethanol-dichloromethane-water Form: 2HC1

Table 88

Example 169

_R ^iib ;H R ^l : _J ~ ^Λ _N _OH R ⁵ : n-Heptyl (2-position)

M.p.152-153.5°C Crystalline form: White powder

Solvent for recrystallization: Ethanol-dichloromethane-water Form: Free

Example 170

^Rl ^

: J R ^4: H A:-CH ₂ - m: 1

R ² iib H RI : _ _Q R5 _: n-Heptyl (2-position)

M.p.166.5-169.3°C Crystalline form: YeUow powder

Solvent for recrystaUization: Ethanol-dichloromethane Form: Free

Example 171

^Rl ^

: J R ^4: H A: -CH ₂ - m: 1

R ²

^CH 2 N-CH _{3 R} ^iib H RΠ _: / ^ R5; n-Heptyl (2-position)

— N O

M.p.155- 165"C Crystalline form: Pale yellow powder Form: 2HC1

Solvent for recrystalUzation: Ethanol-dichloromethane-water NMR (31 )

Table 89

Example 172

R ^{l lb} : H R ¹⁷ : R ⁵ : CH ₃ O (2-position)

M.p. 219-220 ^< 'C CrystalUne form: Dark yellow powder Form: Free

Solvent for recrystaUization: Ethanol-dichloromethane

Example 173

^Rl : ^ J R* H A: -(CH ₂ ) ₃ - m: 1

R ²

_R iib H Rl ⁷ : R ⁵ _: CH ₃ O (2-position)

M.p. 177-185°C Crystalline form: Dark yellow powder Form: 3HC1

Solvent for recrystallization: Ethanol-dichloromethane-water NMR (32)

Table 90

Example 175

R ^{l lb} . H R ^l7 : _ S- ^* . _CH3 ⁵ : C ₂ H ₅ O (2-position)

M.p. 182-184°C Crystalline form: Pale yellow powder Form: 2HC1

Solvent for recrystallization: Ethanol-water-diethyl ether

Example 176

^Rl : ^ J R ^4: H A: -CH ₂ - m: 1

R ²

R ^{l lb;} H R ^I7 : ^{R5: CH} 3 (2-position)

M.p. 265-270°C Crystalline form: Pale yellow powder Form: 2HC1

Solvent for recrystaUization: Ethanol-water-diethyl ether NMR (33)

Example 177

_R ^{i ib} ; H R ^I7 : R ⁵ : Isopropyl (2-position)

M.p. 203-207°C CrystalUne form: Pale yellow powder Form: 2HC1

Solvent for recrystallization: Ethanol-water-diethyl ether

Table 91

_Rllb: H

M.p. 234-238°C Crystalline form: Pale yellow powder Form: 2HC1

Solvent for recrystaUization: Ethanol-water-diethyl ether

Example 179

R ^lb : H R ¹⁷ : _^Q^ _N ^ _CH3 R*: F (2-position)

M.p. 214-217°C CrystaUine form: Pale yellow powder Form: 2HC1

Solvent for recrystaUization: Ethanol-water

Example 180

R ^lb : H R ¹⁷ : _ ₁ jΛ_ _f ^~ _CH3 R ⁵ : C ₂ H ₅ (2-position)

M.p. 188-190°C Crystalline form: Pale yellow powder Form: 2HC1

Solvent for recrystaUization: Ethanol-water

Table 92

Example 18

R ^{l lb} : H R ¹⁷ : _ _N ^— \_ _r ~ ^~N _N _ _CH3 R*: n-Propyl (2-position)

M.p. 164-167°C Crystalline form: Yellow powder Form: 2HC1

Solvent for recrystaUization: Ethanol-water

Example 182

R ^b : H R ^l7 : _ _N ^A_^~ _CH3 ^{R5: CH} ₃ ° (3-position)

M.p. 165-168°C Crystalline form: Pale yellow powder Form: 2HC1

Solvent for recrystaUization: Ethanol-water NMR (56)

Example 183

R ⁵ : CH ₃ O (2-position)

M.p. 143-145°C Crystalline form: Pale yellow powder Form: Free

Solvent for recrystaUization: Ethanol-dichloromethane

Table 93

Example 184

R ^{l lb} : H R ¹⁷ : ^Q^^^.^ R ⁵ : H

M.p. 215-218.5°C (decomp.) Crystalline form: White powder

Solvent for recrystallization: Ethanol-water-diethyl ether Form: 2HC1

Example 185

R ^{l lb} : H R ¹⁷ : R ⁵ : CF ₃ (2-position)

M.p. 101 - 106°C CrystaUine form: White powder Form: 2HC1

Solvent for recrystaUization: Diethyl ether-ethanol-water NMR (34)

Example 186

R ⁵ : CH ₃ O (2-position)

M.p. 179-183'C CrystalUne form: White powder Form: 2HC1

Solvent for recrystallization: Ethanol-water-diethyl ether

Table 94

Example 187

R ⁵ : C ₂ H ₅ CH(CH ₃ )- (2-position)

R ^{l l} : H R ¹⁷ :

-CH w N-CH ₃

M .p. 129- 131°C Crystalline form: Pale yellow powder

Solvent for recrystallization: Isopropyl alcohol-water Form: Dioxalate

Example 188

Ri ib; H Ri , — . _f — ^ R5 _: C ₂ H ₅ (3-position)

^~N v_ Vv ^N - ^CH3

M.p. 163-165°C Crystalline form: Pale yellow powder Form: 2HC1

Solvent for recrystalUzation: Water-ethanol-dichloromethane

Example 189

R ^{l l b} : H R ^l7 : /—^ r~ R ⁵ : CH ₃ (CH ₂ ) ₄ - (2-position)

^{_r " N} - ^CH3

M.p. 161-162°C CrystalUne form: White powder Form: 2HC1

Solvent for recrystallization: Isopropyl alcohol-water

Table 95

Example 190

R ^{l lb} : H R ⁵ : CH ₃ O (4-position)

M.p. 166-168°C Crystalline form: Yellow powder Form: 2HC1

Solvent for recrystaUization: Water-ethanol-dichloromethane

Table 96

Example 191

Riib; H Rl ⁷ R5 _: CH ₃ O (2-ρosition)

M.p. 175- 177°C Crystalline form: White powder Form: 2HC1 Solvent for recrystallization: Ethanol-water-diethyl ether

Example 192

R ⁵ : CH ₃ (2- and 3-positions) R ^l : H R ¹⁷ : _^ _^ _N _ _C H ₃

M.p. 158- 162°C Crystalline form: Pale yellow powder Form: Succinate

Solvent for recrystallization: Ethanol-diisopropyl ether

Example 193

R ⁵ : CH ₃ (2- and 3-positions)

M.p. 126- 128.5°C Crystalline form: Yellow powder Form: Succinate Solvent for recrystaUization: Ethanol-diethyl ether

Table 97

Example 194

R ^ll :H ^R17 : — N NH R ⁵ : CF ₃ (2-position)

M.p.166-17 C CrystaUine form: Pale yellow powder Form: HCl

Solvent for recrystallization: Isopropyl alcohol-ethanol NMR (35)

Example 196

^Rl : ^ J R ^: H A:-CH ₂ - m: 1

R ²

R ^llb :H ^Rl7 : R ⁵ : CH ₃ O (3-position)

M.p.240-245°C Crystalline form: Pale yellow powder Form: HCl

Solvent for recrystaUization: Ethanol-water

Table 98

Example 197

R ^{l lb} : H R ¹⁷ : R ⁵ : CH ₃ (3-position)

M.p. 212-215°C CrystalUne form: White powder Form: 2HC1

Solvent for recrystallization: Ethanol-water

Example 198

R ⁵ : -(CH ₂ ) ₄ - (combined at 2- and 3-positions)

R ^{l lb} : H R ¹⁷ :

^■ w ^∞3

M.p. 180- 190 ^β C Crystalline form: Yellow powder Form: 2HC1

Solvent for recrystaUization: Ethanol-diethyl ether NMR (36)

Example 199

R ^{l lb} : H R ¹⁷ : R5 _: CH ₃ (3- and 5-positions)

M.p. 210-216°C CrystaUine form: White powder Form: 2HC1

Solvent for recrystallization: Ethanol-water-diethyl ether NMR (37)

Table 99

Example 200

R ^{i ib} - H R ¹⁷ : -tc — -i / — v, R ⁵ : Isopropyl (3-position)

N-CH ₃

M.p. 177.5-180.5°C Crystalline form: Pale yellow powder

Solvent for recrystaUization: Ethanol-water Form: 2HC1

M.p. 119-122.5°C Crystalline form: White powder

Solvent for recrystallization: Ethanol-diisopropyl ether Form: Methanesulfonate

Example 202 R ^{1 "} j R ^: H A: -CH ₂ - m: 1

R ^{l lb} : H R ¹⁷ : R5 _: -COOCH ₃ (2-position)

M.p. 169-172°C Crystalline form: White powder

Solvent for recrystalUzation: Ethanol-water Form: Dimethanesulfonate

Table 100

Example 203

Ri ib H R ^l7 : — — _\ R5 _: CH ₃ O (3-position)

→O- N-CH ₃

M.p. 214-220°C Crystalline form: Pale yellow powder Form: Free

Solvent for recrystallization: Methanol

Example 204

R ^{l lb} : H R ¹⁷ : /— r~ _\ R ⁵ : CH ₃ O (3-position)

M.p. 195-197°C CrystalUne form: Yellow powder Form: Free

Solvent for recrystaUization: Dichloromethane-methanol

Example 205

^Rl : ^ J R ^4: H A: -CH ₂ - m: 2

R ²

R ⁵ : -(CH ₂ ) ₄ - (combined at 2- and 3-positions)

M.p. 151-153 ^β C Crystalline form: Pale yellow powder

Solvent for recrystalUzation: Water Form: Free

Table 101

Example 206

i ⁱ b H Rl ⁷ : R ⁵ _: n-Butyl (3-position)

M.p. 148-150.4°C Crystalline form: Pale yellow powder Form: 2HC1

Solvent for recrystalUzation: Isopropyl alcohol-water-diethyl ether

Example 207

, ι

^ R H A: -CH,- m: 1

R ²

_R ^{i ib} H RI ⁷ : — — Λ R ⁵ : (CH ₃ ) ₃ C- (2-position)

^" _ Vv ^N~CH3

M.p. 142-144.5 ^* C Crystalline form: Pale yellow powder Form: Oxalate Solvent for recrystallization: Isopropyl alcohol-water

M.p. 139.2-140.8 ^β C Crystalline form: Pale yellow powder

Solvent for recrystallization: Ethanol-water Form: Methanesulfonate

Table 102

Example 209

R ^lb : H R ⁷ : ^{R5; CH} 3°- ⁽ 3-position ⁾

M.p. 158-163°C Crystalline form: Pale yellow powder Form: 2HC1

Solvent for recrystalUzation: Ethanol-water-diethyl ether NMR (38)

Example 211

R ¹

" R ^4: H A: -CH ₂ - m: 1

R ²

R ^{l lb} : H R ¹⁷ : R ⁵ : n-Propyl (3-position)

M.p. 121-124°C Crystalline form: Pale yellow powder Form: Dioxalate

Solvent for recrystallization: Isopropyl alcohol- water

Table 103

M.p. 140-150°C Crystalline form: Yellow powder NMR (39)

Solvent for recrystalUzation: Acetone-water Form: Methanesulfonate

Example 213

,ι

^R : ^ J R = H A: -CH ₂ - m: 1

R^

R ⁵ : -(CH ₂ ) ₂ -CONH- (combined at 2- and 3-positions)

M.p. 173-175°C Form: Dimethanesulfonate

Solvent for recrystalUzation: Diethyl ether-ethanol-water Crystalline form: Yellow powder

Example 214

_R ^{i ib} ; H R ^l7 : ⁰ " ³ R5; CH ₃ O (3-position)

M.p. 168-172°C (decomp.) Crystalline form: Yellow powder

Solvent for recrystaUization: Ethanol-diethyl ether Form: 2HC1

Table 104

Example 215

R ^{l lb} : H R ¹⁷ : ^{R5: CH} 3θ (3-position)

M.p. 155-160°C NMR (40)

CrystaUine form: Pale yellow powder Form: 2HC1

Solvent for recrystaUization: Ethanol-water-isopropyl alcohol-diethyl ether

m: l

R ^{l b} : H R ¹⁷ :

-N^^N^N-C ₂ H ₅

M.p. 163-165 ^β C CrystaUine form: Pale yellow powder

Solvent for recrystaUization: Ethanol-water Form: 2HC1

Example 217

R»: CH ₃ R ^4: H A: -CH ₂ - m: 1

R ² : CH ₃ R ⁵ _: CH ₃ O (3-position)

M.p. 190-193°C (decomp.) Crystalline form:Yellow powder Solvent for recrystaUization: Ethanol-water Form: 2HC1

Riib. _{H R} 17. R5 CH ₃ O (2-position)

M.p. 174.4-176.5"C Crystalline form: Yellow powder

Solvent for recrystalUzation: Ethanol-water-diethyl ether Form: 2HC1

Example 219

R ^{l b} : H R ¹⁷ : _R 5 _{: C} H ₃ O- (3-position)

M.p. 162- 165°C CrystaUine form: Pale yellow powder

Solvent for recrystalUzation: Diethyl ether-water-ethanol Form: 2HC1

Example 220

R ^{l l} : H R ¹⁷ : R ⁵ : CH ₃ O- (3-position)

M.p. 206-211 °C CrystalUne form: Pale yellow powder Form: 2HC1

Solvent for recrystaUization: Ethanol-water-diethyl ether-isopropyl alcohol NMR (41)

Example 221

^ R* H A: -CH ₂ - m: 1

R ²

R ^{l lb} : H R ⁵ : (CH ₃ ) ₂ CHO- (3-position)

M.p. 168-172°C Crystalline form: YeUow powder Form: 2HC1

Solvent for recrystaUization: Ethanol-water-isopropyl alcohol-diethyl ether

Table 107

Example 222

R5 _: (CH ₃ ) ₂ CHO- (3-position)

CH ₂ N N— CH ₃

R ^{l l} : H R ¹⁷ :

— N 0

M.p. 203-208°C Crystalline form: Pale yellow powder Form: 2HC1

Solvent for recrystaUization: Ethanol-water-isopropyl alcohol-diethyl ether NMR (42)

Example 223

CH ₃ R ^{l lb} : H R ¹⁷ : r-< R ⁵ : CH ₃ O (3-position)

^~ _ Y ^J Y ^{r CH} 3 M.p. 180- 185°C Crystalline form: White powder Form: 2HC1

Solvent for recrystaUization: Ethanol-water NMR (43)

Example 224

R ^{l lb} : H R ¹⁷ : R ⁵ : CH ₃ O (3-position)

M.p. 180-190°C Crystalline form: Yellow powder Form: 2HC1

Solvent for recrystalUzation: Ethanol NMR (44)

Table 108

Example 225

R ⁵ : CH ₃ O (3 -position)

M.p. 157-160°C CrystalUne form: Pale yellow powder Form: 2HC1

Solvent for recrystaUization: Ethanol-water

Example 226

R ^{l l} : H R ⁱ⁷ : ^CH3 R5 _: CH ₃ O (3-position)

M.p. 171-174°C Crystalline form: Pale yellow powder Form: 2HC1

Solvent for recrystaUization: Ethanol-water

M.p. 236-238 °C Crystalline form: Pale yellow powder Form: HCl

Solvent for recrystaUization: Ethanol-water

Table 109

Example 228

Riib; H Rl ⁷ : _/ —\ - R ⁵ _: CH ₃ O (3-position)

M.p. 161 - 165°C Crystalline form: Pale yellow powder Form: 2HC1

Solvent for recrystaUization: Ethanol-water-diethyl ether-isopropyl alcohol

Example 229

R _{; H} R. ⁷ : R ⁵ : CH ₃ 0 (3-posi.io _n)

M.p. 191- 194°C Crystalline form: Pale yellow powder Form: 2HC1

Solvent for recrystaUization: Ethanol-water

Example 230

^Rl : ^ J R ^4: H A: -CH ₂ - m: 1

R ²

R ⁵ : CH ₃ O (3-ρosition)

M.p. 200-210°C (decomp.) Crystalline form: Yellow powder NMR (45) Solvent for recrystallization: Ethanol-water-diethyl ether Form: 2HC1

Table 110

Example 231

R ⁵ : CH ₃ O (3-position)

M.p. 165-170°C Crystalline form: Yellow powder Form: 2HC1

Solvent for recrystalUzation: Diethyl ether-ethanol-isopropyl alcohol-water NMR (46)

Example 232

R ^{l lb} : H R ¹⁷ : _/ -→ ₍ ^CH2 _^ R*: CH ₃ O (3-position)

-N^ N-CH ₃

M.p. 150- 170°C Crystalline form: Yellow powder NMR (47)

Solvent for recrystaUization: Isopropyl alcohol Form: Dimethanesulfonate

Example 233

R ^{l lb} : H R ¹⁷ : R ⁵ : CH ₃ O (3-position)

M.p. 166-169'C Crystalline form: Pale yellow powder

Solvent for recrystaUization: Ethanol-water Form: 2HC1

Table 111

Example 234

R ^{l lb} : H R ¹⁷ : _r ^ ^CU2 _J ^{i CHz} R ⁵ _: CH ₃ O (3-position)

M.p. 186-200°C (decomp.) Crystalline form: Yellow powder Form: 3HC1 Solvent for recrystaUization: Isopropyl alcohol NMR (48)

m: l

M.p. 204-210°C (decomp.) Crystalline form: Yellow powder Form: HCl Solvent for recrystallization: Ethanol-water-diethyl ether NMR (49)

Example 236

R^ H R ^: H A: -CH ₂ - m: 1

R ² : H R ⁵ : CH ₃ O (3-position)

M.p. 157-160°C Crystalline form: Yellow powder Solvent for recrystaUization: Ethanol-water Form: 2HC1

Table 112

m: l

M.p. 83.1-85.5°C - Crystalline form: Yellow powder Form: Free

Solvent for recrystallization: Ethanol-diethyl ether-n-hexane

Example 238

_R i ib; H RΠ _: R5 _: F (3-position)

M.p. 215-220°C Crystalline form: White powder Form: 2HC1

Solvent for recrystaUization: Ethanol-isopropyl alcohol-diethyl ether-water NMR (50)

R ⁵ : CH ₃ O (3-position)

CH ₂ N N-CH

M.p. 149-154"C Crystalline form: Pale yellow powder Form: 2HC1

Solvent for recrystaUization: Ethanol-water-isopropyl alcohol-diethyl ether NMR (51)

Table 113

Example 240 R ¹

R ^: H A: -CH ₂ - m:l

R^

R ^llb :H R ¹⁷ : ^γCH ₂ ^ ^N -CH ₃ R5 _: cl (3-position)

M.p.126-129°C Crystalline form: Pale yellow powder Form: Free

Solvent for recrystallization: Ethanol-isopropyl alcohol

Example 241

^Rl ^ J R ^4: H A: -CH ₂ - : 1

R ²

R ^ll :H R ¹⁷ : _/ _^ ^{CH N} _V ^{N C} " ³ R ⁵ : (CH ₃ ) ₃ C- (2-position)

M.p.181 - 183.8 ^β C Crystalline form: Pale yellow powder Form: 2HC1

Solvent for recrystallization: Ethanol-water-diethyl ether

Example 242

R»:CH ₃ R ^4: H A:-CH ₂ - m: 1

R ² : CH ₃ R ⁵ : CH ₃ O (3-position)

M.p.192-197°C (decomp.) Crystalline form: Yellow powder Form: 2HC1 Solvent for recrystaUization: Ethanol-water NMR (52)

Table 114

Example 244

R ^l : H R ⁷ : R ⁵ : CF ₃ CH ₂ O (3-position)

Crystalline form: Pale yellow powder Form: Dimethanesulfonate NMR (53) Solvent for recrystaUization: Ethanol-water-diethyl ether-isopropyl alcohol

Example 245 R ¹

' j R ^4: H A: -CH ₂ - m: 1

R^

R ^{l lb} : H R ¹⁷ : /— /-^ R5 _: CF ₃ CH ₂ O (3-position)

M.p. 179- 183°C Crystalline form: Pale yellow powder Form: 2HC1

Solvent for recrystalUzation: Isopropyl alcohol-ethanol-water-diethyl ether

Table 115

Example 246

R ⁵ : CH ₃ O (3- and 5-positions)

M.p. 182-185°C Crystalline form: Pale yellow powder

Solvent for recrystaUization: Ethanol-water Form: 2HC1, trans-form

Example 247

R ⁵ : CH ₃ O (3- and 5-positions)

M.p. 177-183°C CrystaUine form: Pale yellow powder

JSρlvent for recrystaUization: Ethanol-water Form: 2HC1, cis-form

Table 116

Example 248

R ^{l lb} : H R ¹⁷ : _R5: CH ₃ 0 (3-position)

M.p. 158-162 "C Crystalline form: Pale yellow powder Form: 2HC1

Solvent for recrystallization: Ethanol-water-diethyl ether

Example 249

RH ^b : H R ¹⁷ : ^ CH ₂ ^Ϊ ^N— CH _{3 R} 5 _{: C} H ₃ O (3-position)

- ^ -CH ₃

M.p. 167-171 °C (decomp.) Crystalline form: Yellow powder Solvent for recrystaUization: Ethanol-water Form: 3HC1

Example 250

R ¹ : ^ R ⁴ H A: -CH ₂ - m: 1

R ² : CH ₃ R ⁵ : CH ₃ O (3-position)

M.p. 137-140°C Crystalline form: Yellow powder

Solvent for recrystaUization: Ethanol-water Form: Methanesulfonate

Table 117

Example 251

R ¹ : (CH ₃ ) ₃ C- (3-position) R ^4: H A: -CH ₂ - m: 1

R ² : H R ⁵ ; CH ₃ O (3-position)

M.p. 129- 131 °C Crystalline form: Pale yellow powder

Solvent for recrystaUization: Ethanol-water-diethyl ether-isopropyl alcohol

Form: Dimethanesulfonate

M.p. 230-231 °C Crystalline form: Pale yellow powder

Solvent for recrystaUization: Ethanol-water Form: Dimethanesulfonate

Example 253

R ¹

R ^: H A: -CH,- m: 1

R^

R ^{l lb} : H R ⁱ : R ⁵ ; CH ₃ O (3-position)

M.p. 159-164°C (decomp.) Crystalline form: Pale yellow powder

Solvent for recrystaUization: Ethanol-water Form: 2HC1 NMR (54)

Table 118

Example 254

R ^{l lb} : H R ¹⁷ : R ⁵ : CH ₃ O (3-position)

M.p. 202-205 ^<> C (decomp.) CrystaUine form: White powder

Solvent for recrystaUization: Ethanol-water Form: 2HC1

Example 255

R ^lb : H R ⁷ : R ⁵ : CH ₃ O (3-position)

^~ J^

M.p. 115-120°C Crystalline form: Pale brown powder NMR (55)

Solvent for recrystaUization: Ethanol-water-isopropyl alcohol-diethyl ether Form: Methanesulfonate

Example 256

_R ^{i ib} H R ⁱ⁷ _: R ⁵ : CH ₃ O (3-position)

M.p. 168.5-171.5°C Crystalline form: White powder

Solvent for recrystaUization: Ethanol-water Form: 2HC1

Table 119

Example 257 R ¹

R H A: -CH ₂ - m: l

R^

R ^{l lb} : H R ¹⁷ : R ⁵ _: CH ₃ O (3-position)

M.p. 163-166°C Crystalline form: White powder

Solvent for recrystaUization: Ethanol-water Form: 2HC1

Example 258

Riib; _H Rl ⁷ : R5 _: CH ₃ O (3-position)

M.p. 177.5-179°C CrystaUine form: White powder

Solvent for recrystaUization: Ethanol-water Form: 2HC1

Example 259

R ^{l lb} : H R ¹⁷ : /— v Λ Λ R ⁵ : CH ₃ O (3-position)

— ^ ) N ^v N-CH ₃

M.p. 165-168.5°C Crystalline form: Pale yellow powder Form: 2HC1

Solvent for recrystallization: Ethanol-water-diethyl ether

Table 120

Example 260

R ¹

R ^: H A: -CH ₂ - m: l

R

R ⁵ : CH ₃ O (3-position)

M.p. 159-160°C Crystalline form: Pale yellow powder

Solvent for recrystaUization: Ethanol-water Form: 2HC1

Example 261

R ^lb : H R ¹⁷ : R ⁵ : CH ₃ O (3-position)

M.p. 177- 178.2'C Crystalline form: Pale yellow powder

Solvent for recrystaUization: Ethanol-water Form: 2HC1

S-(-)-compound: [α] _D ²² : -5.75° (c=2, water)

Example 262

R ^H : H R ^l : R ⁵ : CH ₃ O (3-position)

M.p. 173-175°C Crystalline form: Pale yellow powder

Solvent for recrystaUization: Ethanol-water Form: 2HC1

R-(+)-compound: [α] _D ²² : +4.35° (c=2, water)

M.p. 168-170.5°C Crystalline form: White powder

Solvent for recrystaUization: Ethanol-water Form: 2HC1

R ⁵ : CH ₃ O (3-position)

M.p. 156-159°C Crystalline form: Pale yeUow powder

Solvent for recrystaUization: Ethanol-water Form: 2HC1

Example 265

R ⁵ : CH ₃ O (3-position)

_R iib; H Rl ⁷ :

M.p. 176-179°C Crystalline form: Pale yellow powder Solvent for recrystaUization: Ethanol-water Form: 2HC1

Table 122

Example 266

R ⁵ : C ₂ H ₅ O (3-position)

M.p. 159-161 °C CrystalUne form: Yellow powder Foπn: 2HC1 Solvent for recrystaUization: Ethanol-water-isopropyl alcohol-diethyl ether

- _^-N _Λ/ ^CH ₃

M.p. 166- 169°C Crystalline form: Yellow powder Form: 2HC1

Solvent for recrystaUization: Ethanol-water-diethyl ether-isopropyl alcohol

Example 268

R ⁵ : C ₂ H ₅ O (3-position)

M.p. 215-217°C CrystalUne form: White powder

Solvent for recrystaUization: Ethanol-water Form: 2HC1

Table 123

R ⁵ : CH ₃ O (3-position)

M.p. 174-177°C Crystalline form: YeUow powder Form: Free

Solvent for recrystaUization: Ethanol-water

Example 270

R ⁵ : CH ₃ O (3-position)

Form: 2HC1 Solvent for recrystaUization: Ethanol-water

Example 271

R ⁵ : CH ₃ O (3-position)

155- 158 ^β C Crystalline form: YeUo ³ w powder Form: 2HC1

Solvent for recrystaUization: Ethanol-water-diisopropyl alcohol-diethyl ether

Table 124

Example 272

R ^{l lb} : H R ¹⁷ : / — \ / — \ R ⁵ : CH ₃ O (3-position)

-^N- ^;N-CH ₃

M.p. 202-204°C Crystalline form: Pale yellow powder Form: 2HC1

Solvent for recrystaUization: Ethanol-water

M.p. 163-165°C Crystalline form: Pale brown powder Form: 2HC1

Solvent for recrystaUization: Ethanol-water

Example 274

R ^{l lb} : H R ⁵ : CH ₃ O (3-position)

M.p. 160-162°C Crystalline form: Pale yellow powder Solvent for recrystaUization: Ethanol-water Form: 2HC1

Table 125

Example 275

R ^{l lb} : H R ¹⁷ : R ⁵ : CH ₃ O (3-position)

M.p. 158-160°C CrystalUne form: Pale yellow powder Form: 2HC1

Solvent for recrystaUization: Ethanol-diethyl ether-water

Example 276

R ^{l l} : H R ⁵ : CH ₃ O (3-position)

M.p. 164-166°C Crystalline form: Pale yellow powder Form: 2HC1

Solvent for recrystaUization: Ethanol-water

Using the suitable starting compounds, the compounds as listed in Tables 126-128 are obtained in the same manner as in Example 5.

Table 126

Example 277

R ^16a : C ₂ H ₅ R ^{l lb} : H R ⁵ : H

M.p. 130.5-132°C Crystalline form: Pale orange powder Form: Free

Solvent for recrystalUzation: Dimethylformamide-methanol

Table 127

Example 279

R ^16a : C ₂ H ₅ Z: O

R ^{l lb} : H R ⁵ : — s (2-position) (CH ₂ ) ₃ N N-CH ₃

M.p. 22TC (decomp.) Crystalline form: Pale yellow powder

Solvent for recrystalUzation: Diethyl ether-ethanol Form: 2HC1

Table 128

Using the suitable starting compounds, the compounds as listed in Tables 129-149 are obtained in die same manner as in Example 8.

Table 129

Example 282

R ⁵ : Isopropyl (2-position)

H

R ^{l lb} : H R ²² :

N- -N

M.p. 137-138°C Crystalline form: Pale yellow powder Form: Free

Example 283

R ⁵ : Isopropyl (2-position)

C ₂ H ₅

R ^{l l} : H R22

N N

M.p. 197- 198°C Crystalline form: White powder Form: Free

Solvent for recrystalUzation: Dichloromethane-ethanol

Table 130

Example 284

_R i ib; H R22; C ₂ H _{5 R} 5; ^_^ (2-position) ,/* — (CH ₂ ) ₃ Γ^N-CH ₃

N N

M.p. 240°C (decomp.) Crystalline form: Pale yellow powder Form: 2HC1 Solvent for recrystaUization: Ethanol-water

Example 285

R ¹ j R ^: H A: -CH ₂ - m: 1

R^

R ^{i ib} H R ²² : J R ⁵ : Isopropyl (2-position)

COOC(CH ₃ ) ₃ M.p. 169.5-170°C Crystalline form: White powder Form: Free

Solvent for recrystalUzation: Ethanol

Table 131

Example 287

_R ^{i i} b H R ²² : F ² " ⁵ R5 _: -(CH ₂ ) ₄ OH (2-position)

-if P

N N

M.p. 170.5-175.5°C Crystalline form: Pale yellow powder Form: Free

Solvent for recrystaUization: Ethyl acetate-n-hexane NMR (8)

Example 288

_R ^{i ib} H R ²² : π π R ⁵ : H

M.p. 201.5-202.5°C (decomp.) CrystalUne form: Pale yellow powder

Solvent for recrystaUization: Ethanol-dichloromethane Form: Free

Example 289

R ^{i i} b; H R ²² : (2-position)

M.p. 195-198°C Crystalline form: Yellow powder

Solvent for recrystaUization: Ethanol-water Form: 3 HCl

Table 132

Example 290

Ri ib; H R22 >, R5; isopropyl (2-position)

M.p. 101-103.5°C CrystaUine form: Yellow amorphous Form: Free

Example 291

Rllb; H R22; [j n R5. /—\ (2-position)

_^ jl — (CH ₂ ) ₄ N^^N— CH ₃ ^v

M.p. 148.2-153 ^β C CrystaUine form: Pale brown powder Form: 3HC1

Solvent for recrystaUization: Ethanol-diethyl ether NMR (10)

Example 292

^{R l} ^ J R ^4: H A: -CH ₂ - m: 1

R ²

R ^{l lb} : H R ²² : (2-position)

M.p. 184-187"C Crystalline form: Pale yellow powder

Solvent for recrystallization: Ethanol-water-diethyl ether Form: 2HC1

Table 133

Example 293

_R ιib; H R22 ,X L. J R5; _F (2-position)

I CH ₃

M.p. 151 -154°C Crystalline form: White powder Form: HCl

Solvent for recrystaUization: Ethanol-water-diethyl ether-isopropyl alcohol

Example 294

_R ι ib; H R22 R5 ci (2-position)

M.p. 207-209°C CrystaUine form: White powder Form: Free

Solvent for recrystaUization: Ethyl acetate-n-hexane

Example 295

^{R l} /^

: J R ^4: H A: -CH ₂ - m: 1

R ²

_R i ib H R22; R5; (2-position) M.p. 164-166°C Crystalline form: Pale yellow powder

Solvent for recrystallization: Methanol-diethyl ether Form: HCl

Table 134

Example 296

R ^{l lb} : H R22; R ⁵ : F (2-position)

M.p. 141-141.5°C Crystalline form: White powder Form: Free

Solvent for recrystalUzation: Dichloromethane-diethyl ether

Example 297

R ^{l lb} : H R22 _: R ⁵ : CH ₃ O (2-position)

M.p. 186.5-19TC (decomp.) Crystalline form: Pale yellow powder

Solvent for recrystaUization: Ethanol-diethyl ether Form: Methanesulfonate

Example 298

R ^{l l} : H R22; R ⁵ : CH ₃ (2-position)

Crystalline form: Pale yellow amoφhous Form: Free NMR (15)

Table 135

Example 299

R ^l :H R ⁵ : CH ₃ (2-position)

CrystaUine orm: ae ye ow amoφ ous Form: Free NMR (16)

Example 300

R ^llb :H R22; R ⁵ : C ₂ H ₅ O (2-position)

M.p.202.5-203°C CrystalUne form: Pale powder

Solvent for recrystaUization: Ethanol-isopropyl alcohol-water-diethyl ether

Form: Methanesulfonate

Example 301

R ^llb :H R ²² : R5 _: (CH ₂ ) ₃ N N— CH ₃ (2-position)

M.p.186-189°C CrystaUine form: Pale yellow powder

Solvent for recrystalUzation: Water-ethanol-diethyl ether Form: 3HC1

Table 136

Example 302

R ^{l lb} : H R ²² : R ⁵ : CH ₃ O (3-position)

NH

M.p. 135-145 ⁰ C Crystalline form: White powder Form: Free

Solvent for recrystaUization: Ethanol-dichloromethane NMR (17)

Example 303

R ^{l l} : H R22 _: R ⁵ : Cl (2-position)

CrystaUine form: Pale yellow amoφhous Form: Free NMR (18)

Example 304

R ^{l lb} : H R ²² : ^R5; — ₍ CH ₂ ) N ^~Λ 0 (2-position)

M.p. 146.5- 150°C Crystalline form: White powder

Solvent for recrystaUization: Ethanol-water Form: 2HC1

Table 137

Example 305

Solvent for recrystaUization: Ethanol-diethyl ether Form: Methanesulfonate

_R i ib; H R22; N-Λ 5; (2-position)

N — (CH ₂ ) ₃ N^_ _/ N- CH ₃

CH ₃

CrystalUne form: Pale yellow amoφhous Form: Free NMR (20)

Table 138

Example 308

_R i ib H R ²² : - — -, R K5 ^J _f —^ (2-position)

- (CH ₂ ) ₂ COIv^N-CH ₃ or

M.p. 139- 141 °C Crystalline form: YeUow powder

Solvent for recrystaUization: Ethanol Form: Methanesulfonate

Example 309

_R i ib H R ²² : (2-position)

M.p. 194- 197°C Crystalline form: White powder

Solvent for recrystaUization: Ethanol-water Form: Dimethanesulfonate

Example 310

R ¹

: ^' R H A: -CH ₂ - m: 1

R ²

R ^{l lb} : H R ² 2 _: (2-position)

M.p. 218-220°C Crystalline form: Pale yellow powder

Solvent for recrystaUization: Ethanol-water Form: Dimethanesulfonate

Table 139

Example 313

^Rl : ^ J R H A:-CH ₂ - m: 1

R ²

R ^ll :H R 2; R5; „C ₂ H ₅ (2-position)

[ J -(CH ₂ ) ₃ <

O C ₂ H ₅

M.p.140-141°C Crystalline form: White powder Form: Methanesulfonate

Solvent for recrystallization: Ethanol-isopropyl alcohol-diethyl ether

Table 140

Example 314

R ^lb : H R ^5; — ₍ CH ₂ ) ₂ CON^ -N^^N-CH ₃ (2-position)

M.p. 166- 177°C Crystalline form: White powder NMR (22)

Solvent for recrystaUization: Ethanol-diethyl ether Form: 2HC1

Example 315

R ^l : H R ² _: ^ ^ R ⁵ : — (CH ₂₎₂ CON^N-CH ₃ (2-position)

M.p. 156- 157°C CrystalUne form: White powder

Solvent for recrystalUzation: Ethanol Form: Free

Example 316

R ^{l lb} : H R ⁵ _: (2-position)

M.p. 191-192°C Crystalline form: White powder Form: 3HC1

Solvent for recrystallization: Ethanol-water-isopropyl alcohol

Table 141

Example 317

R ^{l lb} : H R ⁵ : (2-position)

Crystalline form: Pale yellow amoφhous Form: Free NMR (23)

Example 318

^ R ^4: H A: -CH,- m: 1

R ²

R ^l : H R ⁵ : _ _(CH2)3j . _ϊ Q _D (2-position)

CrystalUne form: Colorless amoφhous Form: Free NMR (24)

m: l

H ₂ N N-CH ₃

N — / (2-position)

M.p. 178-180°C CrystaUine form: White powder Form: 3HC1

Solvent for recrystallization: Ethanol-isopropanol-diethyl ether-water

Table 142

Example 320

R ^l : H R ⁵ : (2-position)

CrystaUine form: Pale yellow amoφhous Form: Free NMR (25)

Example 321

R ^l :H R ⁵ : — ₍ CH ₂₎₃ N N-CH ₃ (2-position) _R ²² _:

M.p.198-201 °C Crystalline form: Pale yellow powder Form: 2HC1 Solvent for recrystaUization: Ethanol-water

Example 322

" ^■ 0 R ^4: H A: -CH,- m:l

R^

R ^llb :H ^R5; — (CH ₂ ) _{3 ^} O ⁽ 2-position ⁾

M.p.177-178°C Crystalline form: White powder Form: Free

Solvent for recrystalUzation: Diethyl ether-ethanol-dichloromethane

Table 143

Example 323

R ^{11 b} : H R ⁵ and A combine to form

M.p. 234-235°C Crystalline form: Wh oite poawder Form: Free

Solvent for recrystaUization: Ethyl acetate-n-hexane

R ²² :

M.p. 206-207"C Crystalline form: Pale yellow powder Form: Free

Solvent for recrystalUzation: Dichloromethane-ethanol-diethyl ether

Example 325

R ^{1 "} J R^ H A: -CH ₂ - m: 1

R ²

R ^{l lb} : H R ⁵ ; n-Butyl (2-position) R ²² : — ^x

M.p. 195.5- 196.5 ^β C CrystalUne form: Pale yellow needles

Solvent for recrystaUization: Ethanol-dichloromethane Form: Free

Table 144

Example 326

R ^{l lb} : H R5 _: OCOCH ₃ ( ₂ -position) R ²² :

— CH ₂ CHCH ₂ OCOCH ₃ M.p. 134-136°C (decomp.) Crystalline form: Yellow powder Form: Free

Solvent for recrystaUization: Dichloromethane-diisopropyl ether

Example 327

R ^{l lb} : H R ⁵ _: ^0H (2-position) R ²² : _ ^ _N

— CH ₂ CHCH ₂ OH v-

M.p. 207.6-214°C (decomp.) CrystalUne form: White powder

Solvent for recrystalUzation: Dichloromethane NMR (26) Form: Free

Example 328

R ¹

" j R ^4: H A: -CH ₂ - m: 1

R ²

R ^{l lb} : H R ⁵ : n-Butyl (2-position) R ²² : M.p. 191-193°C CrystaUine form: Pale yeUow powder

Solvent for recrystalUzation: Ethanol-dichloromethane Form: Free

Table 145

Example 329

N N

II

R ^Hb ; _H R ⁵ : _ ₍ CH ₂ ) ₄ N o (2-position) R ²² : ^ ^N

(CH ₂ ) ₃ C1 M.p. 112-114°C Crystalline form: Pale yellow powder Form: Free

Solvent for recrystaUization: Ethyl acetate-diethyl ether

Example 330

^{R l} ^

: J R H A: -CH ₂ - m: 1

R ²

R ^b : H R ⁵ : _ _(C H ₂ ) ₃ Γ N-CH ₃ (2-position) R ²² : _^ _N

M.p. 209-211 °C Crystalline form: Yellow powder

Solvent for recrystaUization: Ethanol-water Form: 3HC1

Example 331

R ^{l l} : H R ⁵ : CH ₃ O (2-position) R ²² : M.p. 208-210°C Crystalline form: Pale yellow powder

Solvent for recrystaUization: Edianol-dichloromethane Form: Free

Table 146

Example 332

R ^{l lb} : H R ⁵ : CH ₃ O (2-position) R ²² :

M.p. 200-203°C Crystalline form: Yellow powder Form: Free

Solvent for recrystalUzation: Ethanol-isopropyl alcohol-dichloromethane

Example 333

R ^{l lb} : H R ⁵ : CH ₃ O (2-position) R ²² : M.p. 196-197 °C CrystaUine form: White powder Form: Free

Solvent for recrystaUization: Ethanol-dichloromethane

Example 334

^Rl : ^ J R ^: H A: -CH ₂ - m: 1

R ²

R ^{l lb} : H R ⁵ : CH ₃ O (2-position) R ²² :

M.p. 203-204 ^β C Crystalline form: White powder Form: Free Solvent for recrystallization: Dichloromethane-ethanol-isopropyl alcohol

Table 147

Example 335

M.p. 206-208°C Crystalline form: Pale yeUow powder Form: Free

Solvent for recrystallization: Dichloromethane-n-hexane

Example 336

^R1 /^

R ^: H A: -CH,- m: l

R ¹

N N

R ^{l lb} : H R ⁵ : C ₂ H ₅ O (2-position) R ²² : ^ _N - N 2H5 M.p. 190-192°C Crystalline form: Pale yellow needles Form: Free

Solvent for recrystalUzation: Chloroform-ethyl acetate

Example 337

N N

J] " R ^{l lb} : H R ⁵ -. C ₂ H ₅ O (2-position) R ²² : -^N' ^N

M.p. 207-209°C Crystalline form: Pale yellow powder Form: Free

Solvent for recrystalUzation: Ethyl acetate-dusopropyl ether

Table 148

Example 338

R ^{l lb} : H R ⁵ : Isopropyl (2-position) R ²² : M.p. 199.5-200.5°C Crystalline form: White powder

Solvent for recrystaUization: Methanol-dimethylformamide Form: Free

Example 339

R ^{l lb} : H R ⁵ : C ₂ H ₅ O (2-position) R ²² : ^_ _T ll

M.p. 204-206°C Crystalline form: Pale yellow powder Form: Free

Solvent for recrystaUization: Ethanol-dichloromethane

Example 340

R ^{l lb} : H R ⁵ : C ₂ H ₅ O (2-position) R ²² : _TH

O M.p. 115-117°C CrystaUine form: Pale yellow powder Form: Free

Solvent for recrystalUzation: Ethyl acetate-dusopropyl ether

Table 149

Example 341

R ^{l lb} : H R ⁵ : C ₂ H ₅ O (2-position) R ²² :

M.p. 225-227°C Crystalline form: Pale yellow powder Form: Free

Solvent for recrystalUzation: Ethyl acetate-dusopropyl ether

Example 342

R ¹

" R ^4: H A: -CH ₂ - m: 1

R ²

R ^πb : H R ⁵ _: C ₂ H ₅ O (2-position) R ²² :

M.p. 196.5-198°C CrystalUne form: Pale yellow powder

Solvent for recrystalUzation: Chloroform-ethyl acetate Form: Free

Example 343

^Rl ^

: J R ^4: H A: -CH ₂ - m: 1

R ²

R ^{l lb} : H R ⁵ _: CH ₃ O (2-position) R ²² :

M.p. 192-194 ^β C Crystalline form: Pale yellow powder

Solvent for recrystalUzation: Ethyl acetate-dusopropyl ether Form: Free

^J H-NMR spectrum (NMR (1) to NMR (55)) as described in Tables 50-149

are as follows:

NMR (1) (CDC1 ₃ ) 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 (IH, d, J=15Hz), 7.8-7.95 (2H, m), 7.93 (IH, d, J=15Hz), 8.10 (2H, d, J=9Hz), 9.88 (IH, br)

NMR (2) (DMSO-d ₆ ) 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 (IH, m), 4.5-4.7 (IH, m), 5.08 (2H, s), 7.15 (2H, d, J=9Hz), 7.3-7.55 (3H, m), 7.76 (IH, d, J=14Hz), 7.77 (IH, d, J=8.5Hz), 7.98 (IH, d, J=8Hz), 8.05 (2H, d, J=9Hz), 12.67 (IH, br) NMR (3) (DMSO-d ₆ ) δppm: 2.32 (3H, s), 2.45-4.50 (20H, m, 2.50 (s)),

5.14 (2H, s), 7.04 (IH, 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-dg) 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-dg) 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 (IH, m), 3.3-3.9 (9H, m), 4.15- 4.35 (IH, m), 4.5-4.8 (IH, m), 5.12 (2H, s), 7.02 (IH, d, J=8.6Hz), 7.27-7.47 (3H, m), 7.74-7.99 (4H, m), 7.91 (IH, d, J=15Hz), 11.5-13.0 (3H, br)

NMR (6) (DMSO-d ₆ ) 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 (IH, m), 5.12 (2H, s), 7.03 (IH, d, J=8.5Hz), 7.25-7.55 (2H, m), 7.45 (IH, s), 7.75-7.9 (4H, m), 7.79 (IH, d, J=8.5Hz)

NMR (7) (DMSO-d _f i) 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 (IH, dd, J=6Hz, J=15.5Hz), 7.00 (IH, d, J=8.5Hz), 7.17 (IH, d, J=15.5Hz), 7.25-7.5 (2H, m), 7.7-8.05 (4H, m), 9.14 (2H, br), 12.73 (IH, br) NMR (8) (CDC1 ₃ ) 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 (IH, brs), 6.98 (IH, d, J=7.5Hz), 7.32-7.43 (IH, m), 7.43-7.55 (IH, m), 7.56 (IH, d,

J=15.2Hz), 7.77-7.93 (2H, m), 8.00-8.12 (2H, m), 8.35 (IH, d, J=15.2Hz), 10.85 (IH, brs)

NMR (9) (DMSO-d ₆ ) 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 (IH, m), 5.13 (2H, s), 7.03 (IH, d, J=8.6Hz), 7.17 (IH, d, J=15.1Hz), 7.30 (IH, t, J=7Hz), 7.74- 7.99 (5H, m), 11.5-12.3 (IH, br), 12.3-13.3 (IH, br)

NMR (10) (DMSO-dg) 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 (IH, m), 6.99-7.15 (2H, m), 7.28-7.40 (IH, m), 7.40-7.52 (IH, m), 7.52-7.60 (2H, m), 7.72-7.85 (IH, m), 7.90-8.08 (4H, m), 10.90- 13.18 (3H, m)

NMR (11) (DMSO-d ₆ ) 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 (IH, m), 4.42-4.71 (IH, m), 5.08 (2H, s), 7.07 (IH, d, J=8.5Hz), 7.31 (IH, t, J=7.0Hz), 7.38-7.69 (3H, m), 7.69-7.92 (3H, m), 7.98 (IH, d, J=8.5Hz), 11.76 (2H, br), 12.71 (IH, br), NMR (12) (DMSO-d ₆ ) δppm: 1.40-1.85 (2H, m), 2.00-2.23 (2H, m), 2.40

(3H, s), 2.60-2.88 (IH, m), 2.81 (3H, s), 3.00-3.80 (10H, m), 3.89 (3H, s), 4.10-4.30 (IH, m), 4.48-4.78 (IH, m), 5.06 (2H, s), 7.04 (IH, d, J=8.5Hz), 7.21-7.31 (IH, m), 7.40 (IH, d, J=15.2Hz), 7.52-7.60 (IH, m), 7.60-7.88 (4H, m), 11.02-12.33 (2H, m), 12.33-12.80 (lH, m)

NMR (13) (DMSO-d ₆ ) 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 (IH, m), 7.12-7.35 (2H, m), 7.52-7.60 (IH, m), 7.60-7.91 (4H, m), 11.00-13.28 (3H, m)

NMR (14) (CDC1 ₃ ) 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 (IH, m), 3.96-4.28 (IH, m), 4.10 (3H, s), 4.62-4.78 (IH, m), 4.87 (2H, s), 7.07 (IH, d, J=8.1Hz), 7.14-7.32 (2H, m), 7.52 (IH, d, J=14.9Hz), 7.61-7.77 (3H, m), 7.91 (IH, d, J=14.9Hz)

NMR (15) (CDCI ₃ ) 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) (CDCI ₃ ) 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) (CDCI ₃ ) 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 (IH, d,

J=15.5Hz), 6.87 (IH, dd, J=15.5Hz, J=6Hz), 7.3-7.55 (2H, m), 7.6-7.95 (4H, m) NMR (18) (CDCI ₃ ) δppm: 1.12 (3H, t, J=5.9Hz), 1.28-3.78 (1 IH, m), 4.97

(IH, t, J=5.3Hz), 6.68-7.53 (5H, m), ^' 7.70-8.14 (4H, m)

NMR (19) (DMSO-d ₆ ) 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 (IH, m), 7.19-7.54 (5H, m), 7.71-7.83 (IH, m), 7.93-8.05 (IH, m), 8.29-8.80 (IH, m), 12.14 (IH, brs)

NMR (20) (CDCI ₃ ) 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 (IH, s), 7.21 (IH, s)

NMR (21) (DMSO-d ₆ ) 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 (IH, dd, J=7Hz, J=15.5Hz), 7.02 (IH, d, J=8.5Hz), 7.16 (IH, d, J=15.5Hz), 7.26 (IH, d, J=3.5Hz), 7.50 (IH, d, J=3.5Hz), 7.8-8.0 (2H, m), 9.58 (IH, br), 12.45 (IH, br) NMR (22) (DMSO-d ₆ ) δppm: 1.33-1.71 (5H, m), 1.80-2.00 (IH, 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 (IH, m), 4.47-4.66 (IH, m), 5.13 (2H, s), 6.71-6.87 (IH, m), 6.98- 7.09 (IH, m), 7.09-7.22 (IH, m), 7.26-7.40 (IH, m), 7.40-7.52 (IH, m), 7.72-7.83 (IH, m), 7.83-7.97 (2H, m), 7.97-8.08 (IH, m), 11.32-12.55 (2H, m), 12.70 (IH, brs) NMR (23) (CDC1 ₃ ) 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) (CDCI ₃ ) 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) (CDCI ₃ ) 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 (IH, d, J=8.5Hz), 7.22-7.53 (3H, m), 7.59 (IH, d, J=15.2Hz), 7.76-7.90 (2H, m), 7.92-8.09 (IH, m), 8.36 (IH, d, J=15.2Hz) NMR (26) (DMSO-d ₆ ) δppm: 2.65-2.8 (IH, m), 2.9-3.05 (IH, m), 3.3-3.45

(2H, m), 3.8 (IH, m), 4.65 (2H, br), 5.11 (2H, s), 7.06 (IH, d, J=8.5Hz), 7.25-7.5 (2H, m), 7.64 (IH, d, J=15.5Hz), 7.75-7.9 (3H, m), 7.95-8.2 (4H, m), 8.66 (2H, br), 12.58 (lH. br)

NMR (27) (CDCI ₃ ) δppm: 1.36 (3H, t, J=7.5Hz), 2.6-3.6 (6H, m), 2.86 (2H,

q, J=7.5Hz), 4.05 (IH, m), 4.50 (IH, m), 4.87 (2H, s), 6.93 (IH, d, J=8Hz), 7.3-7.55 (3H, m), 7.8-8.0 (5H, m), 9.66 (IH, br)

NMR (28) (DMSO-d ₆ ) 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 (IH, d, J=8.6Hz), 7.20-7.66 (4H, m), 7.66- 7.95 (3H, m), 7.99 (IH, d, J=7.1Hz), 12.70 (IH, s)

NMR (29) (DMSO-d ₆ ) δppm: 2.05-2.35 (2H, m), 2.55-4.18 (22H, m), 4.18-

4.42 (IH, m), 5.09 (2H, s), 7.07 (IH, d, J=8.6Hz), 7.27-7.57 (4H, m), 7.74-7.77 (3H, m), 7.98 (IH, d, J=7.1Hz), 11.52 (2H, br), 12.55 (IH, br)

NMR (30) (CDC1 ₃ ) 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 (IH, m), 3.2-3.6 (2H, m), 3.84.1 (IH, m), 4.5-4.8 (IH, m), 4.87 (2H, s), 5.35 (IH, br), 6.93 (IH, d, J=9Hz), 7.25-7.6 (3H, m), 7.75-8.05 (5H, m), 9.60 (IH, br)

NMR (31) (DMSO-dg) 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 (IH, m), 5.11 (2H, s), 7.01 (IH, 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-d ₆ ) δppm: 1.45-1.89 (2H, m), 2.00-2.38 (6H, m), 2.55-

2.86 (6H, m), 3.01-3.22 (IH, m), 3.22-3.94 (9H, m), 3.77 (3H, s), 3.99-4.50 (3H, m), 4.50-4.70 (IH, m), 7.07-7.20 (IH, m), 7.20-7.37 (IH, m), 7.37-7.54 (3H, m), 7.67-7.89 (3H, m), 7.89-8.03 (IH, m), 11.06-12.62 (3H, m)

NMR (33) (DMSO-dg) 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 (IH, m), 4.44-4.73 (IH, m), 5.11 (2H, s), 7.23 (IH, d, J=9.3H), 7.31 (IH, 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 (IH, br)

NMR (34) (DMSO-d ₆ ) 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 (IH, m), 4.48-4.71 (IH, m), 5.29 (2H, s), 7.21-7.57 (4H, m), 7.75-7.83 (2H, m), 7.98 (IH, d, J=7.4Hz), 8.23 (IH, s), 8.32 (IH, d, J=8.7Hz), 10.89-12.06 (2H, m), 12.76 (IH, br) NMR (35) (DMSO-d ₆ ) δppm: 2.88-3.28 (4H, m), 3.73-4.31 (4H, m), 5.30

(2H, s), 7.31 (IH, t, J=6.9Hz), 7.35-7.48 (3H, m), 7.75-7.85 (2H, m), 7.97 (IH, d, J=7.1Hz), 8.23 (IH, s), 8.33 (IH, d, J=8.7Hz), 9.37 (2H, br), 12.78 (IH, br)

NMR (36) (DMSO-d ₆ ) 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 (IH, ), 4.4-4.5 (IH, m), 5.04 (2H, s), 6.81 (IH, d, J=8.5Hz), 7.20 (IH, d, J=15.5Hz), 7.25-7.5 (3H, m), 7.55 (IH, d, J=8.5Hz), 7.75 (IH, d, J=7.5Hz), 7.97 (IH, d, J=7Hz)

NMR (37) (DMSO-dg) δppm: 1.4-1.9 (2H, m), 2.12 (6H, s), 2.0-4.0 (19H,

m), 4.45-4.6 (IH, m), 4.95 (2H, s), 6.77 (2H, s), 6.88 (IH, d, J=16Hz), 7.03 (IH, d, J=16Hz), 7.35-7.5 (2H, m), 7.76 (IH, d, J=7.5Hz), 7.99 (IH, d, J=8Hz), 11.24, 12.04 (all lH, br), 11.74 (lH. br), 12.64 (lH, br)

NMR (38) (DMSO-d ₆ ) δppm: 2.54-2.93 (5H, m), 2.93-3.78 (10H, m), 3.78-

4.17 (7H, m), 4.17-4.44 (IH, m), 5.07 (2H, s), 6.65-6.78 (IH, m), 6.78-6.90 (IH, m), 7.18-7.71 (5H, m), 7.76 (IH, d, J=7.5Hz), 7.98 (IH, d, J=7.1Hz), 11.28 (2H, br), 12.68 (lH, br) NMR (39) (DMSO-d ₆ ) 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 (IH, m), 4.4-4.55 (IH, m), 5.06 (2H, s), 6.85 (IH, d, J=9Hz), 7.24 (IH, d, J=15.5Hz), 7.37 (IH, d, J=15.5Hz), 7.25-7.55 (3H, m), 7.76 (IH, d, J=7Hz), 7.98 (IH, d, J=7Hz), 9.76 (IH, br), 12.60 (IH, br)

NMR (40) (DMSO-d ₆ ) 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 (IH, m), 5.07 (2H, s), 6.65-6.79 (IH, m), 6.79-6.90 (IH, m), 7.18-7.71 (5H, m), 7.77 (IH, d, J=7.7Hz), 8.00 (IH, d, J=7.8Hz), 11.22 (2H, br), 12.68 (IH, br)

NMR (41) (DMSO-d ₆ ) δppm: 1.89-2.44 (4H, m), 2.53-3.78 (16H, m), 3.78-

4.13 (6H, m), 4.13-4.42 (IH, m), 5.07 (2H, s), 6.70 (IH, dd, J=2.2Hz, J=8.7Hz). 6.81 (IH, d, J=2.2Hz), 7.19-7.73 (5H, m), 7.76 (IH, d, J=7.8Hz), 7.98 (IH, d, J=7.0Hz), 10.61 (IH, br), 11.27 (IH, br), 12.71 (IH, br)

NMR (42) (DMSO-dg) δppm: 1.30 (6H, d, J=5.9Hz), 2.55-4.19 (19H, m),

4.19-4.41 (IH, m), 4.82 (IH, sept, J=5.9Hz), 5.07 (2H, s), 6.60-6.71 (IH, m), 6.76- 6.79 (IH, m), 7.22-7.49 (3H, m), 7.64 (IH, d, J=8.7Hz), 7.71-7.90 (2H, m), 7.98 (IH, d, J=7.1Hz), 11.81 (2H, br), 12.58 (IH, br)

NMR (43) (DMSO-dg) 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 (IH, m), 4.45-4.65 (IH, m), 5.06 (2H, s), 6.70 (IH, d, J=9Hz), 6.81 (IH, s), 7.27 (IH, d, J=15.5Hz), 7.25-7.5 (2H, m), 7.56 (IH, d, J=15.5Hz), 7.64 (IH, d, J=8.5Hz), 7.77 (IH, d, J=8Hz), 7.99 (IH, d, J=8Hz), 1 S¬ IS (3H, br)

NMR (44) (DMSO-dg) δppm: 1.30 (3H, d, J=6.5Hz), 1.5-2.3 (4H, m), 2.55-

2.8 (IH, m), 3.0-4.7 (13H, m), 3.88 (3H, s), 5.07 (2H, s), 6.70 (IH, d, J=9Hz), 6.81 (IH, m), 7.27 (IH, d, J=15.5Hz), 7.25-7.5 (2H, m), 7.56 (IH, d, J=15.5Hz), 7.64 (IH, d, J=8.5Hz), 7.77 (IH, d, J=8Hz), 7.98 (IH, d, J=7.5Hz), 9.85 (IH, br), 10.01 (IH, br), 12.25 (IH, br)

NMR (45) (DMSO-d ₆ ) δppm: 2.05-2.20 (2H, m), 2.5-4.0 (18H, m), 3.88

(3H, s), 4.1-4.25 (IH, m), 4.5-4.65 (IH, m), 5.06 (2H, s), 6.70 (IH, d, J=8.5Hz), 6.81 (IH, m), 7.28 (IH, d, J=15Hz), 7.25-7.5 (2H, m), 7.56 (IH, d, J=15Hz), 7.64 (IH, d,

J=8.5Hz), 7.77 (IH, d, J=8Hz), 7.99 (IH, d, J=7.5Hz), 10.78 (IH, br), 11.94 (IH, br), 12.66 (lH, br)

NMR (46) (DMSO-d ₆ ) δppm: 1.43-1.85 (2H, m), 1.97-2.42 (4H, m), 2.58-

2.82 (IH, m), 2.82-4.08 (18H, m), 4.08-4.30 (IH, m), 4.42-4.72 (IH, m), 5.06 (2H, s), 5.22-5.68 (2H, m), 6.62-6.78 (IH, m), 6.78-6.95 (IH, m), 7.24-7.70 (5H, m), 7.77 (IH, d, J=6.2Hz), 7.99 (IH, d, J=5.8Hz), 10.35 (2H, br), 11.48 (IH, br)

NMR (47) (DMSO-dg) 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 (IH, dd, J=7H, J=2Hz), 6.81 (IH, d, J=2Hz), 7.25 (IH, d, J=15Hz), 7.25-7.5 (3H, m), 7.65-7.75 (2H, m), 7.77 (IH, d, J=7Hz), 7.98 (IH, d, J=6Hz), 9.40 (IH, br)

NMR (48) (DMSO-d ₆ ) δppm: 2.4-4.5 (23H, m), 3.88 (3H, s), 5.09 (2H, s),

6.71 (IH, d, J=9Hz), 6.82 (IH, s), 7.2-7.75 (5H, m), 7.77 (IH, d, J=8Hz), 7.98 (IH, d, J=7Hz), 10.98 (IH, br), 11.58 (IH, br), 12.71 (IH, br)

NMR (49) (DMSO-dg) 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 (IH, d, J=8.5Hz), 6.79 (IH, m), 7.27 (IH, d, J=15Hz), 7.61 (IH, d, J=15Hz), 7.63 (IH, d, J=8.5Hz), 11.42 (lH, br)

NMR (50) (DMSO-dg) 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 (IH, m), 4.48-4.70 (IH, 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 (IH, d, J=7.3Hz), 10.80-11.95 (2H, m), 12.68 (IH, br)

NMR (51) (DMSO-d ₆ ) δppm: 1.67-2.03 (2H, m), 2.80 (3H, s), 2.99-4.35

(20H, m), 5.07 (2H, s), 6.70 (IH, dd, J=2.2Hz, J=8.7Hz), 6.82 (IH, d, J=2.2Hz), 7.19-7.74 (5H, m), 7.77 (IH, d, J=7.5Hz), 7.99 (IH, d, J=7.9Hz), 10.80-12.32 (2H,

br), 12.69 (IH, br)

NMR (52) (DMSO-d ₆ ) 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 (IH, d, J=8.5Hz), 6.78 (IH, s), 7.2-7.7 (3H, m), 12.05 (lH, br) NMR (53) (DMSO-d ₆ ) δppm: 2.36 (6H, s), 2.55-4.45 (20H, m), 4.92 (2H,

q, J=8.9Hz), 5.08 (2H, s), 6.80 (IH, dd, J=2.3Hz, J=8.9Hz), 6.94 (IH, d, J=2.3Hz), 7.21-7.75 (5H, m), 7.77 (IH, d, J=8.1Hz), 7.98 (IH, d, J=7.1Hz), 9.95 (2H, br), 12.63 (IH, br)

NMR (54) (DMSO-d _fj ) δppm: 1.40 (6H, d, J=6.0Hz), 1.51-1.86 (2H, m),

2.05-2.30 (2H, m), 2.57-2.73 (IH, m), 2.79 (3H, s), 2.98-3.87 (8H, m), 3.88 (3H, s), 4.14-4.25 (IH, m), 4.40-4.70 (IH, m), 5.06 (2H, s), 6.70 (IH, dd, J=2.2Hz, J=8.8Hz), 6.81 (IH, d, J=2.2Hz), 7.23-7.66 (5H, m), 7.77 (IH, d, J=7.6Hz), 8.00 (IH, d, J=7.0Hz), 11.40-13.10 (3H, m)

NMR (55) (DMSO-d ₆ ) 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 (IH, dd, J=2Hz, J=9Hz), 6.82 (IH, d, J=2Hz), 7.2-

7.5 (3H, m), 7.55-7.8 (3H, m), 7.99 (IH, d, J=7Hz), 9.6-10.2 (IH, m), 12.60 (IH, br)

NMR (56) (DMSO-dg) δppm: 1.40-1.84 (2H, m), 2.00-2.42 (4H, m), 2.67

(IH, t, J=12.5Hz), 2.77 (3H, s), 3.12 (IH, t, J=12.5Hz), 3.24-4.05 (12H, m), 4.10- 4.31 (IH, m), 4.48-4.71 (IH, m), 5.07 (2H, s), 6.70 (IH, dd, J=2.1Hz, J=8.7Hz), 6.82 (IH, d, J=2.1Hz), 7.19-7.62 (4H, m), 7.64 (IH, d, J=8.6Hz), 7.77 (IH, d, J=8.1Hz), 7.99 (IH, d, J=7.9Hz), 11.05-12.10 (2H, m), 12.68 (IH, br) Example 344

2-{3-Allyloxy-4-[3-(l-piperidinyl)carbonylacryloyl]phenox ymethyl- carbonylaminojbenzothiazole (0.55 g) is dissolved in methanol (70 ml) and

dioxane (40 ml), and thereto are added 10 % palladium-carbon (0.15 g), p- toluenesulfonic acid monohydrate (70 mg) and water (3 ml). The mixture is subjected to deaeration, and the mixture is refluxed under nitrogen atmosphere overnight. The mixture is filtered through a cerite pad, and to the filtrate is added water-methylene chloride, and the mixture is separated, and dried over sodium sulfate. The residue is crystallized from ethanol-methylene chloride, and recrystalhzed from dimethylformamide-ethanol to give 2-{3-hydroxy-4-[3-(l- piperidinyl)carbonylacryloyl]phenoxymethylcarbonylamino}benz othiazole (120 mg). Yellow powder

M.p. 207.3-210°C Example 345

To a solution of dimethyl [{2-methoxy-4-[2-(2-benzothiazolylamino- carbonyl)ethyl]benzoyl}methyl]phosphonate (6.4 g) in tetrahydrofuran (100 ml) is added 40 % glyoxylic acid (7.7 ml), and further thereto is added dropwise a 5 % aqueous sodium hydroxide solution (70 ml) under ice-cooling. The mixture is stirred for 30 minutes, and the mixture is acidified with 5 % hydro¬ chloric acid. The precipitated yellow powder is collected by filtration, washed with ethanol, dried, and then recrystallized from dimethylformamide-ethanol to give 2-{2-[3-methoxy-4-(trans-3-carboxyacryloyl)phenyl]ethylcarbo nylamino}- benzothiazole (4.0 g). Yellow powder M.p. 260-261°C Example 346 To tetrahydrofuran (50 ml) is added dimethyl [{2-dimethylamino-4-[(2-

benzothiazolyl)aminocarbonylmethoxy]benzoyl }methyl]phosphonate (4.70 g), and thereto are added 5 % aqueous sodium hydroxide solution (40 ml) and glyoxylic acid (3.5 ml) under ice-cooling, and the mixture is stirred at the same temperature for 10 minutes. After confirming that the starting compounds are consumed, the mixture is acidified with hydrochloric acid, and concentrated under reduced pressure to remove the solvent. The precipitated crystals are collected by filtration, dissolved in dimethylformamide (100 ml), and the mixture is heated with stirring at 100°C for 30 minutes. After cooling, to the reaction solution is added isopropyl alcohol, and the precipitated crystals are collected by filtration. The crystals are recrystalhzed from dimethylformamide-isopropyl alcohol to give l,l-dimethyl-2-carboxy-4-oxo-7-[(2-benzothiazolyl)- aminocarbonylmethoxy]-l,2,3,4-tetrahydroquinolinium chloride (2.46 g). Pale green powder M.p. 184.5-186.5°C Using the suitable starting compounds, the compounds as listed in Table

150-160 are obtained in the same manner as in Example 1 or 5.

Table 150

s: 0

Position of -COCH=CHCOOH: 4-position M.p. 253.5-255°C Crystalline form: White powder Solvent for recrystallization: Dimethylformamide-ethanol Form: Free

Example 348

R ⁵ : -OCH ₃ (3-position) A: -CH ₂ CH ₂ - m: l s: 0

Z: - R ^A : H R ⁴ : H

Position of -COCH=CHCOOH: 4-position M.p. 260-261°C Crystalline form: Yellow powder

Solvent for recrystallization: Dimethylformamide-ethanol Form: Free

Example 349 R5 _: (5-position) A: -CH, m: 1 s: 1

-0(CH ₂ ) ₃ N p

Z: O R ^A : H R ⁴ : H

Position of-COCH=CHCOOH: 4-position M.p. 184-186 ^β C CrystaUine form: Pale yellow powder

Solvent for recrystalUzation: Dimethylformamide-etiianol- water Form: HCl

Table 151

Example 350

R ⁵ : -OCH ₃ (3-position) A: -CH ₂ - m: 1 s: 1

Z: O R ^A : -N(CH ₃ ) ₂ (6-position) R ⁴ : H

Position of-COCH=CHCOOH: 4-position M.p. 263-264°C (decomp.) Crystalline form: Pale brown powder Solvent for recrystalUzation: Dimethylformamide-ethanol-water Form: Hydrate

Example 351

R ⁵ : -0CH ₂ - ^~ (3-position) A: -CH ₂ - m: 1 s: 1

Z: O R ^A : H R ⁴ : H

Position of-COCH=CHCOOH: 4-position M.p. 294-297°C Crystalline form: Yellow powder

Solvent for recrystalUzation: Dimethylformamide Form: Free

Example 352

R ⁵ : -OCH ₂ CH=CH ₂ (3-position) A: -CH ₂ - m: 1 s: 1

Z: O R ^A : H R ⁴ : H

Position of-COCH=CHCOOH: 4-position

M.p. 248-254°C CrystaUine form: Pale yellow powder

Solvent for recrystallization: Diluted hydrochloric acid

NMR (36) Form: Free

Table 152

Example 353

R ⁵ : -- _j — , (3-ρosition) A: -CH ₂ - m: 1 s: 1

Z: O R ⁴ : H

Position of -COCH=CHCOOH: 4-position

M.p. 270.0-271.5°C CrystaUine form: Pale yellow powder

Solvent for recrystaUization: Dimethylformamide-dichloromethane

Form: Free

Example 354

R ⁵ : __ ^" Λ (3-position) A: -CH ₂ - m: 1 s: 1

Z: O R ⁴ : H

Position of -COCH=CHCOOH: 4-position

M.p. 270.5-273.3 °C Crystalline form: Yellow powder

Solvent for recrystaUization: Dimethylforrnamide-dichloromethane

Form: Free

Example 355

R ⁵ : -(CH ₂ ) ₃ CH ₃ (2-position) & -OCH ₃ (5-position)

A: -CH ₂ - m: 2 s: 1 Z: O R ⁴ : H

Position of -COCH=CHCOOH: 4-position M.p. 203-206°C Crystalline form: Yellow powder

Solvent for recrystaUization: Dimethylformamide-dichloromethane Form: Free

Table 153

Example 356

R ⁵ : -(CH ₂ ) ₂ CH ₃ (2-ρosition) & -OCH ₃ (3-position)

A: -CH ₂ - m: 2 s: 1 Z: O R ⁴ : H

Position of -COCH=CHCOOH: 4-position

M.p. 232-234°C Crystalline form: Yellow powder

Solvent for recrystaUization: Tetrahydrofuran-water

Form: Free

Example 357

R5; __ _Q _^ ^~ \ (3-position) A: -CH ₂ - m: 1 s: 1

Z: O R ⁴ : H

Position of -COCH=CHCOOH: 4-position

M.p. 237-245°C (decomp.) Crystalline form: White powder

Solvent for recrystaUization: Tetrahydrofuran-water

NMR (37) Form: Free

Example 358

R ⁵ : -CH ₂ CH ₃ (2-position) & -OCH ₃ (5-position)

A: -CH ₂ - m: 2 s: 1 Z: O R ⁴ : H

Position of-COCH=CHCOOH: 4-position

M.p. 127-138°C (decomp.) Crystalline form: Yellow powder

Solvent for recrystalUzation: Dimethylformamide-acetonitrile

NMR (38) Form: Free

Table 154

Example 359

R ⁵ : -OCH ₃ (2- & 6-positions)

A: -CH ₂ - m: 2 s: 1 Z: O R ⁴ : H

Position of -COCH=CHCOOH: 4-position

M.p. 137- 138°C Crystalline form: Yellow powder

Solvent for recrystaUization: Dimethylformamide-ethanol-diethyl ether-n-hexane

Form: Free

Example 360

R ⁵ : -OCH ₃ (2- & 3-positions)

A: -CH ₂ - m: 2 s: 1 Z: O R ⁴ : H

Position of-COCH=CHCOOH: 4-position

M.p. 235-237°C CrystaUine form: Yellow powder

Solvent for recrystaUization: Dichloromethane-dimethylformamide

Form: Free

Example 361

R ⁵ : -CH ₃ (2-position) & -OCH ₃ (3-position)

A: -CH ₂ - m: 2 s: 1 Z: O R ⁴ : H

Position of -COCH=CHCOOH: 4-position

Crystalline form: Pale yellow powder NMR (39) Form: Free

Example 362

R ⁵ : -CH ₃ (2-position) & -OCH ₃ (3-position)

A: -CH ₂ - m: 2 s: 1 Z: O R ⁴ : H

Position of -COCH=CHCOOH: 6-position

Crystalline form: Pale brown powder NMR (40) Form: Free

Table 155

Example 363

R ⁵ : -(CH ₂ ) ₃ CH ₃ (2-position) & -OCH ₃ (3-position)

A: -CH ₂ - m: 2 s: 1 Z: O R ⁴ : H

Position of-COCH=CHCOOH: 4-position

Crystalline form: Yellow powder NMR (41) Form: Free

Example 364

R ⁵ : -SCH ₃ (3-position)

A: -CH ₂ - m: 1 s: 1 Z: O R ⁴ : H

Position of-COCH=CHCOOH: 4-position

Crystalline form: Yellow powder NMR (42) Form: Free

Example 365

R ⁵ : -CH ₂ CH ₃ (2-position) & -OCH ₃ (3-position)

A: -CH ₂ - m: 2 s: 1 Z: O R ⁴ : H

Position of-COCH=CHCOOH: 4-position

Crystalline form: Pale brown powder NMR (43) Form: Free

Example 366

R ⁵ : -OCH ₃ (3-position)

A: -CH(CH ₃ )- m: 1 s: 1 Z: O R ⁴ : H

Position of-COCH=CHCOOH: 4-position M.p. 225-228°C (decomp.) Crystalline form: Pale brown powder Solvent for recrystallization: Dimethylformamide-ethanol-diethyl ether-water Form: Free

Table 156

Example 367

R ⁵ : / — \ (2- & 3-positions)

\ P

A: -CH ₂ - m: 2 s: 1 Z: O R ⁴ : H

Position of -COCH=CHCOOH: 4-position

M.p. 255-256°C (decomp.) Crystalline form: Yellow powder

Solvent for recrystalUzation: Dimethylformamide-acetonitrile Form: Free

Example 368

R ⁵ : -OCH ₃ (3-position)

A: -(CH ₂ ) ₃ - m: 1 s: 1 Z: O R ⁴ : H

Position of -COCH=CHCOOH: 4-position

M.p. 239-241 °C (decomp.) Crystalline form: Pale yellow powder

Solvent for recrystaUization: Dimethylformamide-acetonitrile Form: Free

Example 369

R ⁵ : -(CH ₂ ) ₂ CH ₃ (2-position) & -OCH ₃ (5-position)

A: -CH ₂ - m: 2 s: 1 Z: O R ⁴ : H

Position of -COCH=CHCOOH: 4-position

M.p. 222-224°C (decomp.) Crystalline form: Pale yellow powder

Solvent for recrystalUzation: Dimethylformamide-acetonitrile Form: Free

Example 370

R ⁵ : -CH ₂ CH=CH ₂ (2-position) & -OCH ₃ (5-position)

A: -CH ₂ - m: 2 s: 1 Z: O R ⁴ : H

Position of-COCH=CHCOOH: 4-position

M.p. 224-225°C (decomp.) Crystalline form: Yellow powder

Solvent for recrystalUzation: Dimethylformamide-acetonitrile Form: Free

Table 157

Example 371

R ⁵ : -OCH ₃ (2- & 5-positions)

A: -CH ₂ - m: 2 R ⁴ : H

Position of -COCH=CHCOOH: 4-position

NMR (44) Crystalline form: Yellow powder Form: Free

Example 372

R ⁵ : -CH ₃ (2-position) & -OCH ₃ (5-position)

A: -CH ₂ - m: 2 R ⁴ : H

Position of -COCH=CHCOOH: 4-position NMR (45) CrystaUine form: Yellow powder

Example 373

R ⁵ : -OC ₂ H ₅ (2-position) & -OCH ₃ (5-position) A: -CH ₂ - m: 2 R ⁴ : H

Position of-COCH=CHCOOH: 4-position

M.p. 202-204°C (decomp.) Crystalline form: Yellow powder

Solvent for recrystalUzation: Dimethylformamide-acetonitrile Form: Free

Table 158

Example 374

R ⁵ : -Br (2-position) & -OCH ₃ (5-position)

A: -CH ₂ - m: 2 R ⁴ : H

Position of-COCH=CHCOOH: 4-position

M.p. 238-239°C (decomp.) Crystalline form: Yellow powder

Solvent for recrystalUzation: Dimethylformamide-acetonitrile Form: Free

Example 375

R ⁵ : -CH(CH ₃ ) ₂ (2-position) & -OCH ₃ (5-position)

A: -CH ₂ - m: 2 R ⁴ : H

Position of-COCH=CHCOOH: 4-position

NMR (46) CrystalUne form: Yellow powder Form: Free

Example 376

R ⁵ : -(CH ₂ ) ₅ CH ₃ (2-position) & -OCH ₃ (5-position)

A: -CH ₂ - m: 2 R ⁴ : H

Position of -COCH=CHCOOH: 4-position

NMR (47) CrystaUine form: Yellow powder Form: Free

Example 377

R ⁵ : -N(CH ₃ ) ₂ (2-position)

A: -CH ₂ - m: 1 R ⁴ : H

Position of -COCH=CHCOOH: 4-position

NMR (48) Crystalline form: Pale yellow powder Form: Free

Table 159

Example 378

R ⁵ : -OCH ₃ (3-position)

A: -CH ₂ - m: 1 R ⁴ : H T: -CH ₂ - u: 1

Position of -COCH=CHCOOH: 4-position

NMR (49) CrystalUne form: Yellow powder Form: Free

Table 160

Example 379

M.p. 211.5-213'C rysta ne orm: te pow er Form: Free

Solvent for recrystalUzation: Dimethylformamide-methanol

Using the suitable starting compounds, the compounds as listed in Tables 161-193 are obtained in the same manner as in Example 3 or 4.

Table 161

Example 380

M.p. 187.5-188.5°C Crystalline form: White powder

Solvent for recrystaUization: Ethanol-diethyl ether Form: Free

Example 381

M.p. 164-166°C Crystalline form: White powder

Solvent for recrystaUization: Ethanol-dietiiyl ether Form: 2HC1

Table 162

Example 382

R ^4: H M.p. 148.4-151.2°C Crystalline form: Yellow powder

Solvent for recrystaUization: Ethanol-diethyl ether Form: 2HC1

Example 383

R ^: H M.p. 200-210°C (decomp.) Crystalline form: Pale brown powder Solvent for recrystaUization: Ethanol-water-diethyl ether Form: 2HCl-H ₂ O

NMR (l)

Example 384

R* H M.p. 160.2-162.3°C Crystalline form: Pale yellow powder

Solvent for recrystaUization: Ethanol-diethyl ether Form: 2HC1

Table 163

Example 385

R ^4: H M.p. 156-166°C (decomp.) Crystalline form: Pale brown powder Solvent for recrystaUization: Ethanol-water-diethyl ether Form: 3HCl*3H ₂ O NMR (2)

Example 387

R ^4: H M.p. 252-253.5°C Crystalline form: White powder

Solvent for recrystallization: Ethanol-water-diethyl ether Form: Free

Table 164

Example 388

R ^4: H M.p. 244-246°C (decomp.) Crystalline form: Pale brown powder Solvent for recrystaUization: Ethanol-chloroform Form: Free

Example 390

R ^4: H M.p. 161.2-163.0°C Crystalline form: Pale yellow powder

Solvent for recrystaUization: Ethanol-water-diethyl ether Form: 2HC1

Table 165

Example 392

R ^4: H M.p. 234.5-236.5°C CrystaUine form: Yellow powder

Solvent for recrystaUization: Ethanol-water Form: Methanesulfonate

Example 393

R ^4: H M.p. 114-117°C Crystalline form: Pale yellow powder

Solvent for recrystaUization: Ethanol-diethyl ether Form: Dimethanesulfonate

Table 166

Example 394

R ^: H M.p. 167.0-168.5°C Crystalline form: Pale yellow powder

Solvent for recrystaUization: Ethanol-water Form: 2HC1

Example 395

R ^4: H M.p. 183-183.5'C Crystalline form: Pale brown powder

Solvent for recrystaUization: Ethanol Form: Free

Example 396

R ^: H M.p. 237.5-238.5 ^β C Crystalline form: Yellow powder

Solvent for recrystaUization: Ethanol-water Form: 2HC1

Table 167

Example 397

R ^: H M.p. 158.0-161.0 ^β C CrystaUine form: Yellow powder

Solvent for recrystaUization: Ethanol-water Form: 2HC1

Example 398

R ^: H M.p. 162.0-164.3°C CrystaUine form: Pale yellow powder

Solvent for recrystaUization: Ethanol-water Form: 2HC1

Example 399

R ^4: H M.p. 133- 136°C Crystalline form: Yellow powder

Solvent for recrystaUization: Ethanol-water Form: Methanesulfonate

Table 168

Example 401

R ^4: H M.p. 220-240°C (decomp.) Crystalline form: Pale yellow powder Solvent for recrystaUization: Ethanol-diethyl ether Form: 2HC1

NMR (3)

Table 169

Example 403

R ^4: H M.p. 190-220°C (decomp.) Crystalline form: Pale orange powder Solvent for recrystaUization: Ethanol-diethyl ether Form: 2HC1

NMR (5)

Example 405

R ^4: H M.p. 217.4-219.0°C Crystalline form: Yellow powder

Solvent for recrystallization: Ethanol-diethyl ether-dichloromethane Form: Methanesulfonate

Table 170

Example 406

R ^4: H M.p. 138.2-139.5°C Crystalline form: Pale yellow powder

Solvent for recrystallization: Ethanol-water-diethyl ether Form: Methanesulfonate

Example 407

R ^4: H M.p. 168.5-171.0°C Crystalline form: YeUow powder

Solvent for recrystaUization: Ethanol-water-diethyl ether Form: 2HCI

Example 408

R ^: H M.p. 132- 134°C Crystalline form: White powder

Solvent for recrystaUization: Ethanol-diethyl ether Form: Methanesulfonate

Table 171

Example 409

R ^4: H M.p. 190-193°C Crystalline form: Yellow powder

Solvent for recrystaUization: Ethanol-acetone-diethyl ether Form: 2HC1

Example 410

R ^4: H M.p. 110-150°C (decomp.) CrystaUine form: Pale yellow powder Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether Form: Dimethanesulfonate NMR (6)

Example 411

R ^: H M.p. 190-240°C (decomp.) Crystalline form: Pale yellow powder Solvent for recrystaUization: Ethanol-diethyl ether Form: 2HC1 NMR (7)

Table 172

Example 412

R ^4: H M.p. 190-210°C (decomp.) Crystalline form: Pale yellow powder Solvent for recrystaUization: Ethanol-diethyl ether Form: 2HC1 NMR (8)

Example 413

R ^4: H M.p. 167.0-169.0°C Crystalline form: Yellow powder

Solvent for recrystalUzation: Ethanol Form: 2HCI

Example 414

R ^4: H M.p. 200-220°C (decomp.) Crystalline form: Pale yellow powder Solvent for recrystallization: Ethanol-water-diethyl ether Form: 2HC1 NMR (9)

Table 173

Example 415

R ^4: H M.p. 177-180 ^β C Crystalline form: Yellow powder Solvent for recrystaUization: Dichloromethane-dusopropyl ether Form: 2HC1

Example 416

R ^: H M.p. 179-182°C Crystalline form: Yellow powder

Solvent for recrystaUization: Dichloromethane-diisopropyl ether Form: 2HC1

Example 417

R ^4: H M.p. 158-159°C Crystalline form: Yellow powder

Solvent for recrystaUization: Dichloromethane-diisopropyl ether Form: 2HC1

Table 174

Example 418

R ^4: H M.p. 230-232°C CrystalUne form: Yellow powder Solvent for recrystaUization: Methanol-diethyl ether Form: 2HC1

Example 419

R ^4: H M.p. 221-224°C Crystalline form: Yellow powder

Solvent for recrystaUization: Methanol-diethyl ether Form: 2HC1

Example 420

R ^4: H M.p. 179-182°C Crystalline form: Yellow powder

Solvent for recrystallization: Methanol-diethyl ether Form: 2HC1

Table 175

Example 421

R ^: H M.p. 146.2- 148.5°C Crystalline form: Gray powder Solvent for recrystalUzation: Ethanol Form: HCl

R ^4: H M.p. 153-155°C Crystalline form: Yellow powder

Solvent for recrystalUzation: Dichloromethane Form: 2HC1

Example 423

R ^4: H M.p. 225-228°C Crystalline form: Pale yellow powder

Solvent for recrystallization: Ethanol Form: Methanesulfonate

R ^4: H NMR (10) Crystalline form:Pale yeUow amorphous

Form: Methanesulfonate

Example 425

R ^4: H M.p. 140- 143 °C CrystalUne form: Pale yellow powder

Solvent for recrystalUzation: Ethanol Form: Methanesulfonate

Example 426

R ^: H M.p. 152.4-154.8°C Crystalline form: Pale yellow powder

Solvent for recrystalUzation: Acetone-dichloromethane-water Form: 2HC1

Table 177

Example 427

R ^4: H M.p. 154-155°C Crystalline form: Yellow powder

Solvent for recrystaUization: Ethanol-diethyl ether Form: Methanesulfonate

Example 428

R ^4: H M.p. lόS-lόδ'C Crystalline form: Yellow powder

Solvent for recrystalUzation: Dichloromethane-diethyl ether Form: Methanesulfonate

Example 429

R ^4: H M.p. 234-235°C CrystaUine form: Yellow powder Solvent for recrystalUzation: Dichloromethane-diethyl ether Form: Methanesulfonate

Table 178

Example 430

R ^4: H M.p. 195-200°C (decomp.) Crystalline form: Pale yellow powder Solvent for recrystalUzation: Acetone- water-diethyl ether NMR (11) Form: Methanesulfonate

Example 431

R ^4: H M.p. 183-220°C (decomp.) Crystalline form: White powder

Solvent for recrystalUzation: Acetone-ethanol-diethyl ether NMR (12) Form: 2HC1

Example 432

R ^4: H M.p. 159-161°C Crystalline form: YeUow powder

Solvent for recrystaUization: Ethanol-acetone-diethyl ether

Form: 2HC1

Table 179

Example 433

R ^4: H M.p. 177-180°C Crystalline form: Yellow amorphous

Solvent for recrystallization: Ethanol-water-diethyl ether Form: 2HC1

Example 434

R ^4: H M.p. 178- 18 rC Crystalline form: YeUow powder

Solvent for recrystaUization: Ethanol-water Form: 2HC1

Example 435

R ^: H M.p. 199-202°C Crystalline form: Pale orange powder Solvent for recrystaUization: Ethanol-water Form: Methanesulfonate

Table 180

Example 436

R ⁴ = H NMR (13) Crystalline form: Yellow amorphous Form: 2HC1

Example 437

R ^4: H M.p. 151-154°C Crystalline form: Yellow powder

Solvent for recrystaUization: Ethanol-d ^■ liipetthhvyll e etthheerr F Fnormmv: M Mpe.tthhaannpe.ssπullffonate

Example 438

R ⁴ H M.p. 114-116°C Crystalline form: Yellow powder Solvent for recrystalUzation: Acetone-water Form: Methanesulfonate

Table 181

Example 439

R ^4: H M.p. 205-208°C Crystalline form: Yellow powder

Solvent for recrystallization: Acetone- water Form: 2HC1

Example 440

R ^4: H M.p. 185-190°C (decomp.) CrystalUne form: Pale yellow powder Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether NMR (14) Form: Methanesulfonate

Example 441

CHs

R ^: H M.p. 160-180°C (decomp.) Crystalline form: Pale yellow powder Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether NMR (15) Form: 2HC1

Table 182

Example 442

R ^4: H M.p. 170-190°C CrystaUine form: Pale yellow powder

Solvent for recrystaUization: Ethanol-dichloromethane-diethyl ether NMR (16) Form: 2HC1

Example 443

R ^4: H M.p. 178-183°C (decomp.) Crystalline form: Pale yellow powder Solvent for recrystaUization: Ethanol-dichloromethane-diethyl ether NMR (17) Form: 2HC1

Example 445

R ^4: H M.p. 138-150°C (decomp.) CrystalUne form: Pale brown powder Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether NMR ( 18) Form: Methanesulfonate

Table 183

Example 446

R ^4: H M.p. 120-160°C (decomp.) Crystalline form: Pale brown powder Solvent for recrystaUization: Ethanol-dichloromethane-diethyl ether-acetone NMR (19) Form: Methanesulfonate

Example 447

R ^4: H M.p. 169-17TC Crystalline form: Pale yellow powder

Solvent for recrystaUization: Ethanol-water Form: 2HC1

R ^4: H M.p. 178-180°C Crystalline form: Pale yellow powder

Solvent for recrystallization: Ethanol-water-diethyl ether Form: 2HC1

Table 184

Example 449

R ^4: H M .p. 162- 164°C Crystalline form: Pale yellow powder Solvent for recrystallization: Ethanol-water-diethyl ether Form: 2HC1

Example 450

R ^: H M.p. 172-175°C Crystalline form: Pale yellow powder

Solvent for recrystaUization: Ethanol-water Form: 2HC1

Example 451

R ^4: H M.p. 167-170 ^β C Crystalline form: Pale yellow powder

Solvent for recrystaUization: Ethanol-water Form: 2HC1

Table 185

Example 452

R ^4: H M.p. 208-209°C Crystalline form: Pale yeUow powder Solvent for recrystaUization: Ethanol-water Form: Methanesulfonate

Example 453

R ^4: H M.p. 246-249°C CrystalUne form: Yellow powder

Solvent for recrystaUization: Ethanol-water Form: 2HC1

Example 454

R ^4: H M.p. 188- 190°C Crystalline form: Pale yellow powder

Solvent for recrystaUization: Ethanol-water Form: 2HC1

Table 186

Example 455

R ^4: H M.p. 167-169°C Crystalline form: Pale yellow powder

Solvent for recrystaUization: Ethanol-water Form: 2HC1

Example 456

R ^4: H M.p. 170-173°C Crystalline form: Pale yeUow powder

Solvent for recrystaUization: Ethanol-water Form: 2HCI

Example 457

R ⁴ H M.p. 225-228 °C CrystalUne form: Pale yellow powder

Solvent for recrystaUization: Ethanol-dichloromethane Form: 2HC1

Table 187

Example 458

H M.p. 1 .0-163.5°C Crystalline form: Yellow powder

Solvent for recrystaUization: Ethanol-water Form: Methanesulfonate

Example 459

R ^4: H M.p. 209.5-212.5°C Crystalline form: White powder

Solvent for recrystaUization: Ethanol-water Form: 3HC1

Example 460

R ^4: H M.p. 155-185°C (decomp.) Crystalline form: Pale yellow powder Solvent for recrystalUzation: Ethanol-dichloromethane-diethyl ether NMR (20) Form: Methanesulfonate

Table 188

Example 461

R ^4: H M.p. 180-215°C (decomp.) Crystalline form: Pale yellow powder Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether NMR (21) Form: 2HC1

Example 462

R ^4: H M.p. 220-225°C (decomp.) Crystalline form: Pale yellow powder Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether NMR (22) Form: 2HC1

Example 463

R ^4: H M.p. 180-215°C (decomp.) CrystaUine form: Pale yellow powder Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether NMR (23) Form: 2HC1

Table 189

Example 465

R ^4: H M.p. 159.5-161.2°C Crystalline form: Pale yeUow powder

Solvent for recrystallization: Ethanol-dietiryl ether-water Form: 2HC1

Example 466

R ^4: H M.p. 150-158°C (decomp.) Crystalline form: Pale yellow powder Solvent for recrystaUization: Ethanol-dichloromethane-diethyl ether NMR (25) Form: Methanesulfonate

Table 190

Example 467

R ^4: H M.p. 193-204°C (decomp.)

Crystalline form: Pale yellow powder

Solvent for recrystallization: Ethanol-dichloromethane-dietiiyl ether

NMR (26) Form: 2HC1

Example 468

R ⁴ = H M.p. 205-213 ^β C (decomp.)

CrystaUine form: Pale yellow powder

Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether

NMR (27) Form: 2HC1

Example 469

R ^4: H M.p. 205-213°C (decomp.) Crystalline form: Pale yeUow powder Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether NMR (28) Form: 2HC1

Table 191

Example 470

R ^4: H M.p. 131 -160°C (decomp.) CrystalUne form: Pale yellow powder

Solvent for recrystalUzation: Dichloromethane-ethanol-diethyl ether NMR (29) Form: Methanesulfonate

Example 471

R ^4: H M.p. 180-210''C (decomp.) Crystalline form: Pale brown powder Solvent for recrystaUization: Dichloromethane-ethanol-diethyl ether NMR (30) Form: 2HC1

Example 472

R ^4: H M.p. 231-235°C (decomp.) Crystalline form: Pale yellow powder Solvent for recrystalUzation: Dichloromethane-ethanol-diethyl ether Form: 2HC1

Table 192

Example 473

R ^: H M.p. 216-221 °C (decomp.) Crystalline form: Pale yellow powder

Solvent for recrystalUzation: Dichloromethane-ethanol-diethyl ether NMR (31) Form: 2HCl

Example 474

R ^4: H M.p. 175-205 ^β C (decomp.) Crystalline form: Pale yellow powder Solvent for recrystalUzation: Dichloromethane-ethanol-dieuiyl ether NMR (32) Form: Methanesulfonate

Example 475

R ^4: H M.p. 185-230°C (decomp.) Crystalline form: Pale yellow powder Solvent for recrystalUzation: Dichloromethane-ethanol-diethyl ether NMR (33) Form: 2HC1

Table 193

Example 476

R ^: H M.p. 160-170°C Crystalline form: Pale yellow powder Solvent for recrystaUization: Ethanol-water NMR (34) Form: Dimethanesulfonate

Example 477

R ^4: H M.p. 172-178°C Crystalline form: Pale yellow powder

Solvent for recrystaUization: Ethanol-water NMR (35) Form: 3HC1

Example 478

R ^: H M.p. 185.2-186.0°C Crystalline form: White powder

Solvent for recrystalUzation: Ethanol Form: Free

Using the suitable starting compounds, the compounds as listed in Table 194 are obtained in the same manner as in Example 8.

Table 194

Example 479

R ^4: H M.p. 171.5-173.0°C

CrystalUne form: Pale yellow powder

Solvent for recrystallization: Ethanol-diethyl ether-dichloromethane

Form: 2HC1

Example 480

R ^4: H M.p. 111.5-114.5'C Crystalline form: Pale yellow powder

Solvent for recrystallization: Ethanol-water-isopropyl alcohol Form: 2HC1

Using the suitable starting compounds, the compound as listed in Table 195 are obtained in the same manner as in Example 3 or 4.

Table 195

Example 481

R ^4: H T: -CH ₂ - u: 1

M.p. 147-150°C CrystaUine form: Pale yellow powder

Solvent for recrystaUization: Ethanol-water-diethyl ether-isopropyl alcohol

Form: 2HC1

*H-NMR spectrum (NMR (1) to NMR (49)) as described in Tables 150- 195 are as follows:

NMR (1) (DMSO-dg) 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 (IH, dd, J=2Hz, J=8.5Hz), 6.81 (IH, d, J=2Hz), 7.29 (IH, d, J=15Hz), 7.48 (IH, br), 7.62 (IH, d, J=15Hz), 7.65 (IH, d, J=8.5Hz), 7.77 (IH, d, J=9Hz), 7.93 (IH, br), 11.0 (IH, br ), 12.7 (lH,br)

NMR (2) (DMSO-d ₆ ) 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 (IH, dd, J=2Hz, J=9Hz),

6.81 (IH, d, J=2Hz), 7.26 (IH, d, J=15Hz), 7.55 (IH, d, J=15Hz), 7.64 (IH, d, J=8.5Hz), 7.7-7.8 (IH, m), 7.88 (IH, d, J=9Hz), 8.31 (IH, br), 11.2-12.2 (2H, m) NMR (3) (DMSO-dg) 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 (IH, m), 4.4-4.7 (IH, m), 5.35 (IH, q, J=6.5Hz), 6.63 (IH, dd, J=2Hz, 9Hz), 6.77 (IH, d, J=2Hz), 7.15-7.7 (4H, m), 7.69 (IH, d, J=9Hz), 7.76 (IH, d, J=7.5Hz), 7.98 (IH, d, J=7.5Hz), 11.1-13.1 (3H, m)

NMR (4) (DMSO-dg) 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 (IH, m), 4.35-4.6 (IH, m), 5.38 (IH, q, J=6.5Hz), 6.63 (IH, dd, J=2Hz, 9Hz), 6.78 (IH, d, J=2Hz), 7.26 (IH, d, J=15Hz), 7.25-7.5 (2H, m), 7.59 (IH, d, J=15Hz), 7.63(1H, d, J=9Hz), 7.76 (IH, d, J=7.5Hz), 7.97 (IH, d, J=7Hz), 11.40 (IH, br), 12.9 (IH, br)

NMR (5) (DMSO-dg) δppm: 1.61 (3H, d, J=6.5Hz), 2.35-4.4 (23H, m), 5.37

(IH, q, J=6.5Hz), 6.63 (IH, dd, J=2Hz, J=8.5Hz), 6.78 (IH, d, J=2Hz), 7.1-7.7 (5H, m), 7.76 (IH, d, J=7.5Hz), 7.98 (IH, d, J=7Hz), 11.85 (2H, br) 12.90 (IH, br)

NMR (6) (DMSO-d ₆ ) 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 (IH, d, J=9Hz), 7.23 (IH, d, J=9Hz), 7.31 (IH, d, J=15Hz), 7.15-7.5 (2H, m), 7.61 (IH, d, J=15Hz), 7.76 (IH, d, J=7.5Hz), 7.98 (IH, d, J=7Hz), 9.85 (IH, br) NMR (7) (DMSO-d ₆ ) 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 (IH, d, J=9Hz), 7.22 (IH, d, J=9Hz), 7.25-7.6 (4H, m), 7.76 (IH, d, J=7.5Hz), 7.98 (IH, d, J=7.5Hz), 11.1-12.2 (2H, m), 12.65 (IH, br)

NMR (8) (DMSO-dg) δppm: 2.55-2.7 (IH, m), 2.79 (3H, s), 2.85-4.5 (20H,

m), 5.04 (2H, s), 6.68 (IH, d, J=8.5Hz), 7.15-7.7 (5H, m), 7.76 (IH, d, J=7.5Hz), 7.98 (IH, d, J=7Hz), 11.4 -13.1 (2H, m)

NMR (9) (DMSO-d ₆ ) 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 (IH, d, J=9Hz), 7.22 (IH, d, J=9Hz), 7.29 (IH, d, J=15.5Hz), 4.05-4.7 (6H, m), 5.03 (2H, s), 7.4-7.5 (IH, m), 7.53 (IH, d, J=15.5Hz), 7.76 (IH, d, J=7.5Hz), 7.98 (IH, d, J=7Hz), 11.5-13.0 (2H, m) NMR (10) (DMSO-dg) 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 (IH, d, J=8.8Hz), 7.19-7.37 (2H, m), 7.37-7.50 (IH, m), 7.50- 7.66 (2H, m), 7.75 (IH, d, J=7.9Hz), 7.99 (IH, d, J=7.9Hz), 9.82 (IH, brs), 11.95- 12.71 (lH, m)

NMR (11) (DMSO-dg) 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 (IH, br), 5.05 (2H, s), 6.83 (IH, d, J=9Hz), 7.28 (IH, d, J=15Hz), 7.29 (IH, d, J=9Hz), 7.25-7.35 (IH, m), 7.35-7.5 (IH, m), 7.52 (IH, d, J=15Hz), 7.76 (IH, d, J=7.5Hz), 7.98 (IH, d, J=7Hz), 9.81 (lH, br), 12.6 (lH. br)

NMR (12) (DMSO-c^) 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 (IH, m), 5.09 (2H, s), 7.12 (IH, dd, J=2.5Hz, J=8.5Hz), 7.25-7.41 (4H, m), 7.4-7.5 (IH, m), 7.69 (IH, d, J=8.5Hz), 7.77 (IH, d, J=7.5Hz), 7.99 (IH, d, J=7Hz), 11.0-12.2 (2H, m)

NMR (13) (DMSO-d ₆ ) 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 (IH, m), 4.41-4.69 (IH, m), 5.09 (2H, s), 6.83 (IH, d, J=8.9Hz), 7.20- 7.64 (5H, m), 7.76 (IH, d, J=7.9Hz), 7.97 (IH, d, J=7.9Hz), 11.11-12.29 (2H, m),

12.72 (IH, brs)

NMR (14) (DMSO-dg) 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 (IH, m), 4.4-4.6 (IH, m), 6.55-6.7 (2H, m), 7.2-7.35 (IH, m), 7.27 (IH, d, J=15Hz), 7.35-7.5 (IH, m), 7.63 (IH, d, J=9.5Hz), 7.63 (IH, d, J=15Hz), 7.72 (IH, d, J=7.5Hz), 7.9-8.0 (IH, m), 9.79 (IH, br), 12.38 (IH, br) NMR (15) (DMSO-dg) 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 (IH, m), 6.55-6.75 (2H, m), 7.0 (IH, br), 7.2-7.35 (2H, m), 7.35-7.45 (IH, m), 7.5-7.65 (2H, m), 7.65-7.75 (IH, m), 7.9-8.0 (IH, m), 11.2-12.6 (2H, m)

NMR (16) (DMSO-d ₆ ) 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 (IH, d, J=7Hz), 11.95 (IH, br), 12.41 (IH, br)

NMR (17) (DMSO-d ₆ ) δppm; 1.45-1.9 (2H, m), 2.0-2.35 (4H, m), 2.55-2.95

(6H, m), 2.95-3.25 (IH, m), 3.3-3.95 (12H, m), 4.0-4.35 (3H, m), 4.4-4.65 (IH, m), 6.4-6.75 (2H, m), 7.25 (IH, d, J=15Hz), 7.2-7.5 (2H, m), 7.55 (IH, d, J=15Hz), 7.61 (IH, d, J=9.5Hz), 7.71 (IH, d, J=7.5Hz), 7.96 (IH, d, J=7Hz), 11.9-12.8 (2H,m) NMR (18) (DMSO-d ₆ ) 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 (IH, s), 7.22 (IH, d, J=15Hz), 7.25-7.35 (IH, m), 7.4-7.5 (IH, m), 7.51 (IH, s), 7.66 (IH, dd, J=5.5Hz, J=15Hz), 7.77 (IH, d, J=7.5Hz), 7.98 (IH, d, J=7Hz), 9.55 (IH, br), 11.7 (lH,br)

NMR (19) (DMSO-dβ) 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 (IH, m), 3.3-3.55 (IH, m), 3.84 (3H, s), 4.05-4.25 (IH, m), 4.45-4.65 (IH, m), 5.16 (2H, s), 6.71 (IH, s), 7.26 (IH, d, J=15Hz), 7.25-7.35 (IH, m), 7.4-7.5 (IH, m), 7.50 (IH, s), 7.58 (IH, d, J=15Hz), 7.77 (IH, d, J=7.5Hz), 7.98 (IH, d, J=7Hz), 9.58 (IH, br) NMR (20) (DMSO-d ₆ ) 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 (IH, m), 4.4-4.65 (IH, m), 5.16 (2H, s), 6.70 (IH, s), 7.28 (IH, d, J=15Hz), 7.25-7.4 (IH, m), 7.4-7.5 (IH, m), 7.49 (IH, s), 7.66 (IH, d, J=15Hz), 7.77 (IH, d, J=8Hz), 7.98 (IH, d, J=7.5Hz), 9.85 (IH, br), 12.6 (lH, br)

NMR (21) (DMSO-de) 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 (IH, m), 4.45- 4.7 (IH, m), 5.17 (2H, s), 6.71 (IH, s), 7.15-7.35 (2H, m), 7.35-7.5 (IH, m), 7.48 (IH, s), 7.58 (IH, d, J=15Hz), 7.77 (IH, d, J=7.5Hz), 7.98 (IH, d, J=7Hz), 11.1-13.2 (2H, m)

NMR (22) (DMSO-dβ) 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 (IH, m), 2.81 (3H, s), 2.95-4.0 (10H, m), 3.84 (3H, s), 4.05-4.3 (IH, m), 4.4-4.65 (IH, m), 5.16 (2H, s), 6.70 (IH, s), 7.26 (IH, d, J=15Hz), 7.25-7.35 (IH, m), 7.35-7.5 (IH, m), 7.48 (IH, s), 7.58 (IH, d, J=15Hz), 7.77 (IH, d, J=7.5Hz), 7.98 (IH, d, J=7Hz), 11.4-13.0 (3H, m)

NMR (23) (DMSO-d ₆ ) 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 (IH, s), 7.15-7.5 (3H, m), 7.48 (IH, s), 7.5-7.8 (2H, m), 7.98 (IH, d,

J=7Hz), 11.0-13.0 (3H, m)

NMR (24) (DMSO-dg) 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 (IH, m), 5.20 (2H, s), 6.73 (IH, s), 7.18-7.38 (2H, m), 7.38-7.54 (2H, m), 7.54-7.74 (IH, m), 7.74-7.81 (lH, m), 7.92-8.05 (lH, m), 11.32-13.11 (3H, m)

NMR (25) (DMSO-d ₆ ) 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 (IH, m), 6.74 (IH, s), 7.28 (IH, d, J=15Hz), 7.25-7.55 (2H, m), 7.48(1H, s), 7.65 (IH, d, J=15Hz), 7.77 (IH, d, J=7.5Hz), 7.98 (IH, d, J=7Hz), 9.99 (IH, br), 12.6 (IH, br) NMR (26) (DMSO-d ₆ ) δppm; 1.65 (2H, br), 2.0-2.4 (4H, m), 2.55-2.95

(4H, m), 3.0-3.25 (IH, m), 3.25-4.05 (14H, m), 4.05-4.3 (IH, m), 4.45-4.7 (IH, m), 4.95-5.3 (4H, m), 5.85-6.1 (IH, m), 6.75 (IH, s), 7.15-7.7 (5H, m), 7.77 (IH, d, J=8Hz), 7.98 (IH, d, J=7.5Hz), 11.1-13.0 (3H, m)

NMR (27) (DMSO-de) δppm; 1.4-1.85 (2H, m), 1.95-2.3 (2H, m), 2.55-2.95

(4H, m), 2.95-3.2 (IH, m), 3.2-3.95 (11H, m), 5.86 (3H, s), 4.1-4.3 (IH, m), 4.45-4.7 (IH, m), 4.95-5.25 (4H, m), 5.86-6.1 (IH, m), 6.74 (IH, s), 7.26 (IH, d, J=15Hz), 7.25-7.55 (3H, m), 7.56 (IH, d, J=15Hz), 7.77 (IH, d, J=7.5Hz), 7.98 (IH, d, J=7Hz), 11.3-13.2 (3H, m)

NMR (28) (DMSO-d ₆ ) δppm; 2.55-4.45 (25H, m), 4.9-5.3 (4H, m), 5.85-

6.1 (IH, m), 6.75 (IH, s), 7.15-7.85 (6H, m), 7.98 (IH, d, J=7Hz), 11.0-13.3 (3H, m) NMR (29) (DMSO-dg) 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 (IH, s), 7.2-7.4 (3H, m), 7.44 (IH, t, J=8Hz), 7.69 (IH, d, J=15Hz), 7.77 (IH, d, J=8Hz), 7.98 (IH, d, J=8Hz), 9.83 (IH, br), 12.60 (IH, br)

NMR (30) (DMSO-d ₆ ) 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 (IH, m), 4.5-4.7 (IH, m), 5.17 (2H, s), 6.83 (IH, s), 7.2-7.4 (3H, m), 7.44 (IH, t, J=8Hz), 7.60 (IH, d, J=15.5Hz), 7.76 (IH, d, J=8Hz), 7.98 (IH, d, J=8Hz), 11.25-12.2 (2H, m)

NMR (31) (DMSO-d ₆ ) 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 (IH, s), 7.2-7.4 (3H, m), 7.44 (IH, t, J=8Hz), 7.64 (IH, d, J=15.5Hz), 7.76 (IH, d, J=8Hz), 7.98 (IH, d, J=8Hz), 11.5-12.5 (2H, m) NMR (32) (DMSO-dg) 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 (IH, s), 7.32 (IH, d, J=15Hz), 7.32 (IH, t, J=7.5Hz), 7.45 (IH, t, J=8Hz), 7.61 (IH, d, J=15Hz), 7.77 (IH, d, J=8Hz), 7.83 (lH,s), 7.98 (IH, d, J=7.5Hz), 9.78 (IH, br), 12.65 (IH, br) NMR (33) (DMSO-dg) 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 (IH, m), 5.27 (2H, s), 6.89 (IH, s), 7.2-7.4 (2H, m), 7.4-7.6 (2H, m), 7.77 (IH, d, J=8Hz), 7.81 (IH, s), 7.98 (IH, d, J=8Hz), 11.1- 12.1 (2H, m)

NMR (34) (DMSO-dg) δppm; 2.35(s, 6H), 2.82 (s, 3H), 2.92-3.27 (m, 9H),

3.30-3.59 (m, 3H), 4.18 (br, IH), 4.19-4.34 (m, IH), 4.47-4.65 (m, IH), 5.24 (s, 2H), 7.33 (t, J=7.6Hz, 2H), 7.44 (d, J=7.3Hz, IH), 7.46 (d, J=15.1Hz, IH), 7.78 (d, J=8.0Hz, IH), 7.84 (d, J=15.1Hz, IH), 7.96-8.15 (m, 3H), 9.82 (br, IH), 12.66 (br, IH)

NMR (35) (DMSO-dg) 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, IH), 4.51-4.68 (m, IH), 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, IH), 11.35-12.13 (m, 2H)

NMR (36) (DMSO-d ₆ ) δppm; 4.61-4.78 (2H, m), 5.05 (2H, s), 5.18-5.50

(2H, m), 5.91-6.17 (IH, m), 6.46 (IH, d, J=15.5Hz), 6.62-6.78 (IH, m), 6.78-6.88 (IH, m), 7.28-7.39 (IH, m), 7.39-7.52 (IH, m), 7.54-7.81 (2H, m), 7.71 (IH, d, J=15.5Hz), 7.92-8.05 (IH, m), 12.72 (2H, brs)

NMR (37) (DMSO-de) δppm; 4.97 (2H, s), 6.40-6.58 (2H, m), 6.91 (IH, 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 (IH, m), 12.75 (2H, brs)

NMR (38) (DMSO-d ₆ ) 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 (IH, d, J=15.5Hz), 6.71 (IH, s), 7.26-7.39 (IH, m), 7.39-7.50 (IH, m), 7.51 (IH, s), 7.68 (IH, d, J=15.5Hz), 7.72-7.81 (IH, m), 7.91- 8.03 (lH, m), 12.75 (2H, brs) NMR (39) (DMSO-dg) δppm; 2.19 (3H, s), 3.64 (3H, s), 5.07 (2H, s), 6.54

(IH, d, J=15.6Hz), 6.85 (IH, d, J=8.7Hz), 7.25-7.40 (IH, m), 7.40-7.51 (IH, m), 7.54 (IH, d, J=8.8Hz), 7.68 (IH, d, J=15.6Hz), 7.76 (IH, d, J=7.5Hz), 7.98 (IH, d, J=7.5Hz), 12.41-13.16 (2H, m)

NMR (40) (DMSO- tø δppm; 2.16 (3H, s), 3.88 (3H, s), 4.64 (2H, s), 6.52

(IH, d, J=15.6Hz), 6.95 (IH, d, J=8.8Hz), 7.21-7.38 (IH, m), 7.38-7.51 (IH, m), 7.55-7.80 (3H, m), 7.98 (IH, d, J=7.1Hz)

NMR (41) (DMSO-de) 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 (IH, d, J=15.6Hz), 6.84 (IH, d, J=8.7Hz), 7.21-7.39 (IH, m), 7.39-7.51 (IH, m), 7.55 (IH, d, J=8.7Hz), 7.67 (IH, d,

J=15.6Hz), 7.76 (IH, d, J=7.8Hz), 7.97 (IH, d, J=7.8Hz), 12.05-13.51 (2H, m) NMR (42) (DMSO-d ₆ ) δppm; 2.41 (3H, s), 5.10 (2H, s), 6.56 (IH, d,

J=15.5Hz), 6.90 (IH, dd, J=8.8Hz, J=2.2Hz), 6.98 (IH, d, J=2.2Hz), 7.32 (IH, t, J=7.2Hz), 7.45 (IH, t, J=7.2Hz), 7.65-7.85 (2H, m), 7.99 (IH, d, J=7.7Hz), 8.05 (IH, d, J=8.8Hz), 12.06-13.45 (2H, m)

NMR (43) (DMSO-d ₆ ) 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 (IH, d, J=15.6Hz), 6.85 (IH, d, J=8.9Hz), 7.30 (IH, dt, J=1.2Hz, J=7.1Hz), 7.43 (IH, dt, J=1.2Hz, J=7.1Hz), 7.56 (IH, d, J=8.9Hz),

7.67 (IH, d, J=15.6Hz), 7.76 (IH, d, J=7.1Hz), 7.97 (IH, d, J=7.1Hz), 12.51-13.12 (2H, m)

NMR (44) (DMSO-de) δppm; 3.79 (3H, s), 3.83 (3H, s), 5.12 (2H, s), 6.51

(IH, d, J=15.5Hz), 6.84 (IH, s), 7.15-7.54 (3H, m with IH s at 7.26), 7.61-7.86 (2H, m with IH, d at 7.76 J=15.5Hz), 7.99 (IH, d, J=7.1Hz), 12.20-13.25 (2H, m) NMR (45) (DMSO-d ₆ ) δppm; 2.19 (3H, s), 3.85 (3H, s), 5.14 (2H, s), 6.49

(IH, d, J=15.5Hz), 6.70 (IH, s), 7.20-7.56 (3H, m, with IH s at 7.52), 7.60-7.82 (2H, m, with IH d at 7.71 J=15.5Hz), 7.98 (IH, d, J=7.0Hz), 12.41-13.17(2H, m) NMR (46) (DMSO-dg) δppm; 1.19 (6H, d, J=6.9Hz), 3.10-3.42 (IH, m),

3.86 (3H, s), 5.16 (2H, s), 6.50 (IH, d, J=15.5Hz), 6.70 (IH, s), 7.21-7.60 (3H, m with IH s at 7.55), 7.65-7.82 (2H, m with IH d at 7.73 J=15.5Hz), 7.89-8.08 (IH, m), 12.42-13.12 (2H, m)

NMR (47) (DMSO-d ₆ ) 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 (IH, d, J=15.5Hz), 6.71 (IH, s), 7.20- 7.57 (3H, m), 7.62-7.85 (2H, m with IH d at 7.72 J=15.5Hz), 7.88-8.05 (IH, m), 12.45-13.12 (2H, m)

NMR (48) (DMSO- δppm; 3.17 (s, 6H), 5.28 (s, 2H), 6.71 (d, J=15.5Hz,

IH), 7.29-7.49 (m, 3H), 7.78 (d, J=8.0Hz, IH), 7.91-8.06 (m, 2H), 8.09 (d, J=8.4Hz, IH), 8.25 (s, IH)

NMR (49) (DMSO-dg) δppm; 3.87 (s, 3H), 4.75 (d, J=5Hz, 2H), 4.77 (s,

2H), 6.50 (d, J=15.5Hz, IH), 6.72 (dd, J=2.2Hz J=8.6Hz, IH), 6.78 (d, J=2.2Hz, IH), 7.33-7.57 (m, 2H), 7.66 (d, J=8.6Hz, IH), 7.69 (d, J=15.5Hz, IH), 7.94 (d, J=7.4Hz, IH), 8.05 (d, J=6.9Hz, IH), 9.18 (t, J=5.1Hz, IH), 12.99 (br, IH) PHARMACOLOGICAL EXPERIMENTS (1) Protein kinase C (PKC) inhibitory activity Method for determining PKC activity:

The purification of PKC using rat's brain soluble fractions was carried out by a method of Kikkawa et al. (cf. Ushio Kikkawa, Yoshimi Takai, Ryoji Minakuchi, Sinichi Inohara and Yasutomi Nishizuka: The Journal of Biological Chemistry, vol. 257, No. 22, pp. 13341-13348 (1982)). PKC activity was determined by the transfer of radio activity from the [γ- ³² P] adenosine

triphosphate (ATP) to HI histone derived from calf thymus in die presence of 20 mM Tris-HCl buffer (pH 7.5), HI histone derived from calf thymus (200 μg/ml), 10 μM [γ- ³² P]ATP, 5 mM magnesium acetate, 8 μg/ml phosphatidyl serine, 2

μg/ml diacylglycerol and 0.3 mM Ca ²⁺ . The test compound was dissolved in dimethylformamide, and the test compound solution was added to the assay system so that the final concentration thereof was adjusted to 0.8 %. The reaction mixture was incubated at 30°C for 30 minutes, and the reaction was quenched with 25 % trichloroacetic acid. The acid-insoluble protein was collected on a nitrocellulose membrane by suction filtration. The radio activity

of ³² P was determined by scintillation counter. The PKC inhibitory activity of the test compounds was expressed by IC5 ₀ , which is a concentration of the test

compound to be required to reduce the PKC activity by 50 %. The results are shown in Table 196. Results:

Table 196

(2) Mouse collagen arthritis

Bovine II -type collagen (provided by Collagen Gijyutsu Kensyukai) (0.1 %) was emulsified with Complete Fleund's adjuvant (CFA) (50 %)

(manufactured by DIFCO, Ltd.), and the emulsion thus obtained was injected intracutaneously to mice at the tail (primary sensitization). Three weeks later, bovine Il-type collagen (0.1 %) was injected intraperitoneally again to the mice

(secondary sensitization). Three weeks later, the swelling of limbs of the mice was observed, and evaluated by four-degree as 0 to 3 each limb. The degree (0 to 3) each limb was added, and the results were used a score of the arthritis.

That is, the maximum degree is 12 (degree 3 X 4 limb). The test compound was administered orally to the mice once a day, which started after two weeks from the primary sensitization.

In the mice treated with the compound of Example 182 at a dose of 30 to

50 mg/kg, the score of arthritis was significantly reduced in comparison with the control mice. In the mice treated with the compounds of Example 160, 192 or 197 at a dose of 50 mg/kg, the score of arthritis was significantly reduced in comparison with the control mice.

(3) Mouse cGVHD (chromic Graft-versus-host disease model)

Female mice (DB A/2NCrj) were subjected to an operation of cervical vertebra dislocation, and the spleen was taken out to give the spleen cells preparation. The preparation were adjusted to 37.5 x 10 ⁷ cells/ml, and administered to the BDF1 female mice on the tail vein at a dose of 200 μl per a mouse. Two weeks later, the blood was collected in the absence of heparin, and anti-DNA antibody therein was determined by ELISA. The compound of Example 182 was administered orally to the mice at a dose of 30 to 50 mg/kg once a day for two weeks, and the effect of the test compound on cGVHD was determined.

The amount of anti-DNA antibody in the blood was determined with

OD ₄₀₅ . The amounts of anti-DNA antibody were 0.348±0.111 (mean±s.e.) in

the control group, 0.255±0.062 (mean±s.e.) in the group treated with the compound of Example 182 at a dose of 30 mg/kg, and 0.094±0.026 (mean±s.e.) in the group treated with the compound of Example 182 at a dose of 50 mg/kg. From the results, it was proved that the compound of Example 182 reduced the anti-DNA antibody in the blood dose-dependently, compared with the control group.

Further, the compound of Example 100 was also administered orally to the mice at 30 mg/kg once a day for two weeks, and the effect of the compound on cGVHD was also determined. The amount of anti-DNA antibody in the blood was determined with

OD ₄₀₅ . The amounts of anti-DNA antibody were 0.258±0.084 (mean±s.e.) in

the control group, and 0.177±0.061 (mean±s.e.) in the group treated with the compound of Example 100 at a dose of 30 mg/kg. From the results, it was proved that the compound of Example 100 reduced the anti-DNA antibody in the blood, compared with the control group. (4) Rat kidney ischemic re-perfusion model

The right kidney of a SD male rat was taken out, and the left kidney artery was clumped, and then, re-perfused to give a kidney ischemic re-perfusion model. The effect of the compounds of Examples 71, 89 and 100 on the kidney ischemic re-perfusion model was estimated.

The compound of Example 71 was administered intravenously to the rat at a dose of 3 mg/kg 5 minutes before the ischemic. Twenty-four hours later, the blood was collected from the tail vein, and the amounts of creatine and urea nitrogen were determined. The amount of creatine in the blood was 2.19±0.21 (mean±s.e.) in the control group; 1.4±0.11 (mean±s.e.) in the group treated with

the compound of Example 71, and the amount of urea nitrogen in the blood was 78.8±5.6 (mean±s.e.) in the control group, and 54.1±5.0 (mean±s.e.) in the group treated with the compound of Example 71. That is, the compound of Example 71 significantly reduced the amounts of both of creatine and urea nitrogen, compared with the control group.

The compound of Example 89 was administered intravenously to the rat at a dose of 3 mg/kg 5 minutes before the ischemic and die re-perfusion. Forty- eight hours later, the blood was collected from the tail vein, and the amounts of creatine and urea nitrogen were determined. The amount of creatine in the blood was 4.31±0.53 (mean±s.e.) in the control group; 2.34±0.46 (mean±s.e.) in the group treated with the compound of Example 89, and the amount of urea nitrogen in the blood was 155.1+15.4 (mean±s.e.) in the control group, and 99.1±16.0 (mean±s.e.) in the group treated wit the compound of Example 89. That is, the compound of Example 89 significantly reduced the amounts of both of creatine and urea nitrogen, compared with the control group.

The compound of Example 100 was administered orally to the rat at a dose of 30 mg/kg one hour before the ischemic. Forty-eight hours later, the blood was collected from the tail vein, and the amounts of creatine and urea nitrogen were determined. The amount of creatine in the blood was 2.48±0.59 (mean±s.e.) in the control group; 1.53±0.20 (mean±s.e.) in the group treated with the compound of Example 100, and the amount of urea nitrogen in the blood was 91.3±20.1 (mean±s.e.) in the control group, and 63.1±10.3 (mean±s.e.) in the group treated with the compound of Example 100. Thus, it is proved that the compound of Example 100 reduced the amounts of both of creatine and urea nitrogen, compared with the control group.

(5) Phorbol ester (TPAVinduced mouse auricle edema, acanthosis model

A 200 μg/ml phorbol ester (TPA) (10 μl) was applied to the one side to the ear of a female mouse (ICR). Twenty-four hours later, the thickness of the auricle of the mouse was determined with using a dialthickness gage, and the increase in the thickness of auricle was calculated. A test compound was dissolved in acetone, and the solution of a test compound was applied to the both sides of the ear 30 minutes before the application of TPA.

The compound of Example 88 was applied to the ear at a dose of 20 μl of 0.3 % or 1 % solution. The increase in the thickness of auricle in the control group is 215±40 μm (mean±s.e.) after 24 hours, while 87±53 μm (mean±s.e.) in the group treated with the compound of Example 88 in 0.3 %, and 67±23 μm (mean±s.e.) in the group treated with the compound of Example 88 in 1 %. Thus, the compound of Example 88 significantly reduced the increase in auricle thickness, compared with the control group. (6) Mouse atopic dermatitis model:

1 % Trinitrobenzene (TNCB), (10 μl) was applied to each side of the ear of female mice (Balb/c), once every two days for 24 days. Twenty-four days later, the mice were grouped, and the auricle thickness of the mouse was determined by using a dial thickness gage, and the increase in the thickness of auricle was calculated. The compounds of Examples 88 and 89 were dissolved in acetone in a concentration of 1 %. The compound of Example 182 was dissolved in a mixture of acetone: methanol in a concentration of 0.75 %. Twenty-four days after the beginning of the experiment, the solution of a test compound was applied to each side of the ear 30 minutes before and after the application of TNCB, once a day for two weeks. The compound of Example 88

inhibited the increase in the auricle thickness by 25 to 30 %, and the compounds of Examples 89 and 182 inhibited the increase in the auricle thickness by about 25 %. Thus, it is proved that the compounds of die present invention is useful in the treatment of acanthosis induced by the application of TNCB.