WO1999036408A1 - Novel pyrimidine derivatives - Google Patents

Abstract

Compounds represented by general formula (I), pharmaceutically acceptable salts thereof, or hydrates of both; and endothelin B receptor selective antagonists containing the same. In said formula4R?1 and R2¿ are each independently optionally substituted aryl; R3 is hydrogen or the like; X is O, S or the like; Y is lower alkylene or the like; Z is CONR?4R5, CH=CR6R7¿ or CH=NNR?8R9; R4 and R5¿ are each independently hydrogen, lower alkyl or the like; R?6 and R7¿ are each independently acyl, lower alkoxycarbonyl or the like; and R?8 and R9¿ are each hydrogen, acyl or the like.

Description

 Description New pyrimidine derivative Technical field

 The present invention relates to compounds useful as medicaments and uses thereof. More specifically, it contains a novel pyrimidine derivative having a selective antagonistic activity of endoselin B receptor, and useful for the prevention and / or treatment of diseases involving endoselin receptor or endoselin B receptor, and the novel pyrimidine derivative. Pharmaceutical compositions or endoselin B receptor selective antagonists. Background art

 Endothelin is a vasoactive peptide derived from endothelial cells consisting of 21 amino acids and is involved in vasculature homeostasis. Endothelin is also involved in some cardiovascular diseases, such as exacerbation of cardiovascular diseases such as hypertension, cerebral vasoconstriction, acute renal failure, acute proliferative nephropathy, acute myocardial infarction, and intimal hyperplasia. It exerts its action via end serine receptor as a factor.

Endothelin receptors have two types of sub-ends, endothelin A and endothelin B, and three types of receptor antagonists are known: A-selective, B-selective, and AB-nonselective. It is gradually becoming clear what kind of disease each type of receptor antagonist is involved in, and selective endothelin A receptor antagonists are effective in the acute phase of cardiovascular disease It is expected that the results may not be satisfactory, but no satisfactory results have been obtained. This suggests that not only endothelin A receptor, but also endothelin B receptor may be involved in the development and progression of cardiovascular lesions. It is thought to be involved in the metabolism of intestine, intimal thickening of blood vessels, and development and differentiation of certain cells. Compounds having an endoselin receptor antagonistic action and having a pyrimidine structure are disclosed in JP-A-5-155864, JP-A-5-222003, JP-A-6-21810, and Kaihei 7—1 7 9 7 2, JP 8-99961, JP 8-311 104, JP 959 1960, JP 9-59 261, W 09 5 2 6 9 5 7, W 9 6 1 9 4 5 9, WO 9 7 2 5 9 5, USP 5 5 4 1 1 8 6 and GB 2 2 9 5 6 16 However, there is no mention of endothelin B selectivity here. In addition, as a non-peptide endothelin B receptor selective antagonist, a compound having a pyrimidine skeletal structure is available from FBS Letters, 383, pp. 37-41. Page, WO97 / 09318, WO96 / 207177, but none of the compounds of the present invention are described.

 While many endocrine receptor antagonists are being developed, there are relatively few endocrine B receptor selective antagonists, and most of them are non-peptide and have high selectivity. Not. As the function of endothelin B receptor is still being elucidated, it has high activity and selectivity as a prophylactic and therapeutic agent for diseases involving endothelin B and a useful reagent for elucidating the function of receptor. There has been a need for the development of a selective serine antagonist of noserine B receptor.

Disclosure of the invention

 The present inventors have found that a compound represented by the following formula (I) has high activity and selectivity as an antagonist. That is, the present invention provides a compound represented by the formula (I):

(Ri

(Wherein R 1 and R ² are each independently

Aryl which may have a substituent (where the substituent is a lower alkyl, a lower alkenyl, a lower alkoxy, a lower alkenyloxy, a halogen, a hydroxy, an R ³ is hydrogen, hydrogen, carboxy or lower alkoxycarbonyl)

Lower alkyl optionally having substituent (s) (wherein the substituent is lower alkoxy, lower alkenyloxy, halogen, hydroxy, amino, acyl, carboxy or lower alkoxycarbonyl)

Or an aryl which may have a substituent (where the substituent is a lower alkyl, a lower alkenyl, a lower alkoxy, a lower alkenyloxy, a halogen, a hydroxy, an amino, an acyl, a carboxy or a lower alkoxycarbonyl) X is o, S or a single bond;

Y is lower alkylene or lower alkenylene,

Z is

a) C 0 NR ⁴ R ⁵

R ⁴ and R 5 are each independently hydrogen, hydroxy,

A lower alkyl which may have a substituent (where the substituent means a lower alkoxy, lower alkenyloxy, halogen, hydroxy, amino, acyl, carboxy, lower alkoxycarbonyl, cycloalkyl, aryl or hetero ring); ), A lower alkenyl which may have a substituent (where the substituent is a lower alkoxy, a lower alkenyloxy, a halogen, a hydroxy, an amino, an acyl, a carboxy or a lower alkoxycarbonyl),

Aryl lower alkyl which may have a substituent (here, the substituent means lower alkyl which may be substituted with halogen or hydroxy, lower alkenyl, lower alkoxy, lower alkenyloxy, halogen, hydroxy, Lower alkylene dioxy, amino optionally substituted with lower alkyl, asyl, nitro, cyano, carboxy, lower alkoxycarbonyl, aryl, aryl lower alkyl or rubamoyl),

Aryl lower alkenyl which may have a substituent (where the substituent means lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, halogen, hydride Oxy, amino, alkyl, carboxy or lower alkoxycarbonyl), lower alkoxy which may have a substituent (substituent means lower alkoxy, lower alkenyloxy, halogen, hydroxy, amino, acryl, Carboxy, lower alkoxycarbonyl or aryl)),

A lower alkenyloxy which may have a substituent (where the substituent is a lower alkoxy, a lower alkenyloxy, a halogen, a hydroxy, an amino, an acyl, a carboxy or a lower alkoxycarbonyl),

A heterocyclic ring which may have a substituent (where the substituent is a lower alkyl, a lower alkenyl, a lower alkoxy, a lower alkenyloxy, a halogen, a hydroxy, an amino, an acyl, a carboxy or a lower alkoxycarbonyl ),

A carbocyclic ring which may have a substituent (where the substituent means a lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, halogen, hydroxy, amino, acyl, carboxy, lower alkoxycarbonyl or aryl) Or an optionally substituted amino (where the substituent means a lower alkyl, a lower alkenyl, a lower alkoxy, a lower alkenyloxy, a halogen, a hydroxy, an amino or a heterocyclic ring) Is also a carboxy or lower alkoxycarbonyl) or

Or a lower alkylene which may have a substituent together (where the substituent is a lower alkyl, a lower alkenyl, a lower alkoxy, a lower alkenyloxy, a halogen, a hydroxy, an amino, an acyl, a carboxy, a lower Which is an alkoxycarbonyl or aryl)

b) CH = CR ⁶ R ⁷

R ⁶ and R ⁷ are each independently hydrogen,

An optionally substituted acyl group (where the substituent means lower alkyl, lower alkenyl, lower alkenylene, lower alkoxy, lower alkenyloxy, halogen, hydroxy, amino, acyl, carboxy, lower alkoxycarbonyl or Kiso), Force ropoxy,

A lower alkoxycarbonyl optionally having a substituent (where the substituent is a lower alkoxy, a lower alkenyloxy, a halogen, a hydroxy, an amino, an acyl, a sulfoxy, a lower alkoxycarbonyl or an aryl);

Optionally substituted substituents (where the substituent is lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, halogen, hydroxy, amino, acyl, carboxy, lower alkoxycarbonyl or aryl) Siano,

Cyanocarbonyl,

Or nitro,

Or together, one CO— U— CO—, — CO— V— CS— W— or one CO— V— CO— W—,-(CH 2) mN RSO 2-(where U is lower alkyl, C2-C3 alkylene optionally substituted by phenyl, heterocycle or oxo; C2-C3 alkylene optionally substituted by phenyl or hydroxy; Cycloalkylene; one CH2— T— (where T is cycloalkylene optionally substituted with lower alkyl, cycloalkenylene optionally substituted with lower alkyl, phenylene optionally substituted with lower alkyl); phenylene; Naphthylene; alkylenedioxy having 2 to 3 carbon atoms which may be substituted by lower alkyl; one SCH ₂ — or —〇 CH 2, V and W are each independently NR, S or O; Is 2 or 3 and R Forming a hydrogen, methyl or E chill)

Is or

c) CH = NN R ⁸ R ⁹

R ⁸ and R ⁹ are each independently hydrogen,

An optionally substituted acyl group (where the substituent means a lower alkyl, a lower alkenyl, a lower alkoxy, a lower alkenyloxy, a halogen, a hydroxy, an amino, an acyl, a carboxy, a cyano, a lower alkoxycarbonyl, Substitute with lower alkyl Optionally substituted aryl, aryloxy, arylthio, lower alkylsulfonyl, arylsulfonyl optionally substituted with lower alkyl), and optionally substituted rubamoyl (here And the substituent is a lower alkyl, a lower alkenyl, a lower alkoxy, a lower alkenyloxy, a halogen, a hydroxy, an amino, an acyl, a carboxy, a lower alkoxycarbonyl or an aryl)), a thiocarbamoyl which may have a substituent (Where the substituent is a lower alkyl, a lower alkenyl, a lower alkoxy, a lower alkenyloxy, a halogen, a hydroxy, an amino, an acyl, a carboxy, a lower alkoxycarbonyl or an aryl)

Carboxy,

A lower alkoxycarbonyl optionally having a substituent (where the substituent is a lower alkoxy, a lower alkenyloxy, a halogen, a hydroxy, an amino, an acyl, a sulfoxy or a lower alkoxycarbonyl),

Aryloxycarbonyl optionally having substituent (s) (wherein the substituent is lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, halogen, hydroxy, amino, acyl, carboxy or lower alkoxycarbonyl); is there) ,

Lower alkoxy optionally having substituent (s) (wherein substituent is lower alkoxy, lower alkenyloxy, halogen, hydroxy, amino, acyl, carboxy or lower alkoxycarbonyl)

Aryloxy (thiol propyl) which may have a substituent (wherein the substituent means lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, halogen, hydroxy, amino, acyl, carboxy or lower alkoxy carboxy) Nil),

Cycloalkyloxy (thiocarbonyl) optionally having substituent (s) (where the substituent is lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, halogen, hydroxy, amino, acyl, carboxy or lower) Alkoxy Carbonyl),

Optionally substituted rubamoylcarbonyl (where the substituent is a lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, halogen, hydroxy, amino, acyl, carboxy or lower alkoxycarbonyl Or an arylsulfonyl which may have a substituent (here, the substituent means a lower alkyl, a lower alkenyl, a lower alkoxy, a lower alkenyloxy, a halogen, a hydroxy or an alkyl. Is a good amino, acyl, carboxy or lower alkoxycarbonyl)

Or a pharmaceutically acceptable salt thereof or a hydrate thereof. Further, a pharmaceutical composition containing a compound represented by the above formula (I) (hereinafter, referred to as compound (I)) or a pharmaceutically acceptable salt thereof or a hydrate thereof, and selective antagonist of endoselin B receptor The agent is provided. Furthermore, the present invention relates to a method for treating and / or preventing a disease caused by endothelin B, which comprises administering compound (I), a pharmaceutically acceptable salt thereof, or a hydrate thereof. Furthermore, the present invention relates to the use of compound (I), a pharmaceutically acceptable salt thereof, or a hydrate thereof for producing an endothelin B receptor selective antagonist. In the present specification, “aryl” specifically includes phenyl, naphthyl, anthracenyl and the like, and is preferably phenyl. The same applies to the aryl portion of "aryl sulfonyl".

"Lower alkyl" means a straight or branched alkyl having 1 to 6 carbon atoms, and specifically, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, pentyl and It includes hexyl and the like, and is preferably alkyl having 1 to 4 carbon atoms. Lower alkyl as a substituent on aryl of R ¹ is most preferably tert-butyl.

 "Lower alkenyl" means two or more carbon atoms having one or more double bonds at any position.

6 means a linear or branched alkenyl, specifically, vinyl, aryl, n-propenyl, isopropyl, n-butenyl, isobutenyl, sec-butenyl, tert-butenyl, butenylenyl, n-pentenyl, isopentenyl, neopentenyl, tert-pentenyl, pentenylenyl, n_hexenyl, isohexenyl, hexenyl and the like. The lower alkenyl moiety of "lower alkenyloxy" is the same as described above.

 “Lower alkoxy” means a straight or branched alkoxy having 1 to 6 carbon atoms, specifically, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, Includes pentyloxy and hexyloxy. Preferably, it is an alkoxy having 1 to 3 carbon atoms, and more preferably, methoxy. The same applies to the lower alkoxy moiety of “lower alkoxycarbonyl”.

 “Halogen” refers to fluorine, chlorine, bromine or iodine.

 The term "acyl" means a chain or branched isyl having 1 to 8 carbon atoms, an alicyclic isyl having 4 to 9 carbon atoms, aroyl and heterocyclic carbonyl. Specifically, formyl, acetyl, propionyl, butyryl, isoptyryl, norrelyl, pivaloyl, hexanoyl, acryloyl, propioloyl, methacryloyl, crotonyl, cyclopropylcarbonyl, cyclohexanecarbonyl, benzoyl, pyridine propylonyl, Chenylcarponyl and furylcarponyl and the like.

“Lower alkylene” refers to a group represented by — (CH ₂ ) n-(n = 1 to 6), and specifically includes methylene, ethylene, trimethylene, tetramethylene, pentamethylene and hexamethylene. And preferably ethylene or trimethylene. The same applies to the alkylene moiety of “lower alkylenedioxy”.

 “Lower alkenylene” refers to a group having 2 to 7 carbon atoms having at least one double bond, and specifically, vinylene, probenylene, butenylene, butenegenylene, pentenylene, pentagenylene. , Hexenylene, hexenenylene, hexatorienylene, heptenylene, heptagenenylene, heptatrienylene and the like. The positions of these double bonds may be arbitrary.

“Cycloalkyl” is cyclic alkyl having 3 to 6 carbon atoms, and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. “Heterocycle” means a heterocycle having at least one heteroatom in the ring arbitrarily selected from 0, S and N, and specifically, pyrrolyl, imidazolyl, virazolyl, pyridyl, pyridazinyl, pyrimidinyl , Pyrazinyl, triazolyl, triazinyl, isoxazolyl, oxazolyl, oxaziazolyl, isothiazolyl, thiazolyl, thiadiazolyl, furyl and chenyl, etc. Indolidinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzoisoxazolyl, benzoxazolyl, benzodioxolyl, Condensed aromatic heterocycles such as benzoxaziazolyl, benzoisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, benzochenyl, benzotriazolyl, etc. , Imidazolinyl, birazolidinyl, pyrazolinyl, piperidyl, piperazinyl, morpholinyl and the like. The same applies to the heterocyclic moiety of “heterocyclic carbonyl”.

 The aryl and lower alkyl portions of "aryl lower alkyl" are the same as the above "aryl" and "lower alkyl", and are preferably benzyl. The substituent of “aryl lower alkyl optionally having substituent (s)” may be substituted on the aryl moiety or the lower alkyl moiety.

 The aryl portion and the lower alkenyl portion of "aryl lower alkenyl"

Same as "aryl" and "lower alkenyl". The substituent of “aryl lower alkenyl optionally having substituent (s)” may be substituted on either the aryl part or the lower alkenyl part.

 “Carbocycle” includes the above “aryl” and non-aromatic carbocycle. Specifically, in addition to those exemplified in the above “aryl” and “cycloalkyl”,

3 to 6 cycloalkenyl (for example, cyclohexenyl) and 4 to 8 carbon atoms Bicycloalkyl (eg, bicyclopentane, bicyclooctane, etc.), tricycloalkyl having 4 to 10 carbon atoms (eg, tricycloheptane, tricyclodecane, etc.) and condensed polycyclic hydrocarbon (eg, indanyl, indenyl, fluorenyl, dihydronaphthalenyl) Is included.

"Once together, one CO—U—C〇 one, one CO—V—CS—W—or—CO one V—CO—W—,-(CH 2) mN RSO ₂ ~ ((where U is lower Alkylene having 2 to 3 carbon atoms which may be substituted by alkyl, phenyl, heterocycle or oxo; alkenylene having 2 to 3 carbon atoms which may be substituted by phenyl or hydroxy; cycloalkylene; —CH 2—T— (where T is cycloalkylene optionally substituted with lower alkyl, cycloalkenylene optionally substituted with lower alkyl, phenylene optionally substituted with lower alkyl); Phenylene; naphthylene; alkylenedioxy having 2 to 3 carbon atoms which may be substituted by lower alkyl; one S CH ₂ — or one OCH 2 —, and V and W are each independently NR, S or O Where m is 2 or 3 and R is hydrogen The form of methyl or E is a chill) ", in particular = CR 6 R 7 is

(Where R is hydrogen, methyl or ethyl). Preferably

It is.

 The "compound of the present invention" also includes a pharmaceutically acceptable salt of compound (I). For example, salts of mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, and hydrobromic acid; formic acid, acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, and methanesulfonic acid Salts of organic acids such as ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, camphorsulfonic acid; salts of organic bases such as ammonium, trimethylammonium, and triethylammonium; Examples thereof include salts of alkali metals such as sodium and potassium, and salts of alkaline earth metals such as calcium and magnesium. These salts can be formed by a commonly used method.

 The compound according to the present invention also includes a hydrate thereof, and one molecule of the compound (I) may be coordinated with an arbitrary number of water molecules. BEST MODE FOR CARRYING OUT THE INVENTION

 The compound represented by the general formula (I) has a selective endothelin B receptor antagonistic activity. Among them,

[1] R ¹ is phenyl substituted with lower alkyl (hereinafter, R ¹ - and is 1) compounds, Ru preferably phenyl der substituted with alkyl of 3-6 carbon atoms (hereinafter, R ^A compound, more preferably a phenyl substituted with tert-butyl (hereinafter, referred to as R ^1-3 ),

[2] a compound in which R 2 is phenyl substituted with lower alkyloxy (hereinafter referred to as R 21), preferably substituted with alkyloxy having 1 to 3 carbon atoms A compound that is a phenyl (hereinafter, referred to as R ² —2), more preferably a compound that is a phenyl substituted with methoxy (hereinafter, referred to as R ² —3),

[3] a compound in which R ³ is hydrogen or lower alkyl (hereinafter, referred to as R ³ -1), more preferably a compound which is hydrogen (hereinafter, referred to as R ³ —2), [4 A compound wherein X is O,

 [5] A compound in which Y is alkylene having 1 to 6 carbon atoms (hereinafter, referred to as Y-1), preferably an alkylene having 1 to 4 carbon atoms (hereinafter, referred to as Y-2) A compound, more preferably a compound having 2 to 3 carbon atoms (hereinafter referred to as Y-3),

 [6] Z is

a) CONR ⁴ R ⁵ , wherein one of R ⁴ and R ⁵ is hydrogen and the other is hydroxy, or lower alkyl which may have a substituent (where the substituent means lower alkoxy, lower alkenyl Oxy, halogen, hydroxy, amino, acyl, carboxyl, lower alkoxycarbonyl, cycloalkyl, aryl or heterocycle), aryl lower alkyl which may have a substituent (wherein Is lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, halogen, hydroxy, lower alkylenedioxy, lower amino optionally substituted by halogen or hydroxy, amino, acyl, nitro, Ano, alkoxy, lower alkoxycarbonyl, aryl, aryl lower alkyl Is Taha force Rubamoiru),

Lower alkoxy which may have a substituent (here, the substituent is lower alkoxy, lower alkenyloxy, halogen, hydroxy, amino, acyl, carboxy, lower alkoxycarbonyl or aryl),

A heterocyclic ring which may have a substituent (here, the substituent means lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, halogen, hydroxy, amino, acyl, carboxy or lower alkoxycarbonyl; is there) ,

A carbocyclic ring which may have a substituent (where the substituent means a lower alkyl, Alkenyl, lower alkoxy, lower alkenyloxy, halogen, hydroxy, amino, acyl, carboxy, lower alkoxycarbonyl or aryl, or an optionally substituted amino (where the substituent is lower) Alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, halogen, hydroxy, amino, heterocyclic-substituted acyl, carboxy or lower alkoxycarbonyl), or

Or a lower alkylene which may have a substituent together (where the substituent is a lower alkyl, a lower alkenyl, a lower alkoxy, a lower alkenyloxy, a halogen, a hydroxy, an amino, an acyl, a carboxy, a lower alkoxy, Carbonyl or aryl)

b) CH = CR ⁶ R ⁷ , wherein R ⁶ and R ⁷ are each independently hydrogen or an optionally substituted acyl (where the substituent is lower alkyl, lower alkenyl, lower alkenylene, lower Alkoxy, lower alkenyloxy, halogen, hydroxy, amino, acyl, carboxy, lower alkoxycarbonyl or oxo), carboxy, lower alkoxycarbonyl which may have a substituent (where the substituent is lower alkoxy) Lower alkenyloxy, halogen, hydroxy, amino, acyl, carboxy, lower alkoxycarbonyl or aryl), optionally substituted rubamoyl (where the substituent means lower alkyl, lower alkenyl, Lower alkoxy, lower alkenyloxy, halogen, hydroxy, a Bruno, Ashiru, carboxy, lower alkoxycarbonyl or Ariru), or a Shiano or two Bok port,

Or together with one CO—U—CO—, one CO—V—CS—W—, one CO—V—CO—W—or— (CH ₂ ) m NRSO 2-(where U is lower alkyl, C 2-3 alkylene optionally substituted by phenyl, heterocycle or oxo; C 2-3 alkylene optionally substituted by phenyl or hydroxy; cycloalkylene; one CH 2— T— (where T is cycloalkylene optionally substituted by lower alkyl, cycloalkyl optionally substituted by lower alkyl) Chloroalkenylene, phenylene which may be substituted with lower alkyl); phenylene; naphthylene; alkylene dioxy having 2 to 3 carbon atoms which may be substituted with lower alkyl; one SCH ₂ — or —OCH ₂ — V and W are each independently NR, S or O, m is 2 or 3, and R is hydrogen, methyl or ethyl) to form

Is or

c) CH = NNR ⁸ R 9, one of R ⁸ and R ⁹ is hydrogen, and the other is optionally substituted with a substituent (where the substituent means lower alkyl, lower alkenyl, lower Alkoxy, lower alkenyloxy, halogen, hydroxy, amino, acyl, carboxy, cyano, lower alkoxycarbonyl, aryl which may be substituted with lower alkyl, aryloxy, arylthio, lower alkylsulfonyl, lower Arylsulfonyl which may be substituted with alkyl), and rubamoyl which may have a substituent (where the substituent means lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, Halogen, hydroxy, amino, acyl, carboxy, lower alkoxycarbonyl or aryl)), Thiocarbamoyl which may have a substituent (wherein the substituent is lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, halogen, hydroxy, amino, acyl, carboxy, lower alkoxycarbonyl or aryl) ), Lower alkoxycarbonyl which may have a substituent (where the substituent is lower alkoxy, lower alkenyloxy, halogen, hydroxy, amino, acryl, acyloxy, or lower alkoxycarbonyl) ), An optionally substituted carbamoylcarbonyl (where the substituent is a lower alkyl, a lower alkenyl, a lower alkoxy, a lower alkenyloxy, a halogen, a hydroxy, an amino, an acyl, a carboxy or a lower alkoxy) Carbonyl) Arylsulfonyl which may have a substituent (where the substituent is a lower alkyl, a lower alkenyl, a lower alkoxy, a lower alkenyloxy, a halogen optionally substituted by a hydroxy, an alkyl, or an acyl , Force ropoxy or lower alkoxy carb Nil),

(Hereinafter referred to as Z—1) a compound,

Preferably

a) R ³ is hydrogen, Z is CONR ⁴ R ⁵ , one of R ⁴ and R ⁵ is hydrogen, and the other is an alkyl which may have a substituent (wherein Is a lower alkoxy, a lower alkenyloxy, a halogen, a hydroxy, an amino, an acyl, a carboxy, a lower alkoxycarbonyl, a cycloalkyl, an aryl or a heterocyclic ring) or an aryl lower alkyl which may have a substituent ( Here, the substituent means a lower alkyl which may be substituted with halogen or hydroxy, lower alkenyl, lower alkoxy, lower alkenyloxy, halogen, hydroxy, lower alkylenedioxy or lower alkyl. Good amino, acyl, nitro, cyano, alkoxy, lower alkoxycarbonyl, aryl, aryl lower Alkyl or halbamoyl).

b) Z is CH = CR ⁶ R ⁷ , and R ⁶ and R ⁷ may each independently have an optionally substituted substituent (here, the substituent means lower alkyl, lower alkenyl, lower alkyl Len, lower alkoxy, lower alkenyloxy, halogen, hydroxy, amino, acyl, carboxy, lower alkoxycarbonyl or oxo), carboxy, lower alkoxycarbonyl optionally having substituent (s) Is a lower alkoxy, a lower alkenyloxy, a halogen, a hydroxy, an amino, an acyl, a carboxy, a lower alkoxycarbonyl or an aryl), an optionally substituted rubamoyl (where the substituent is a lower alkyl, Lower alkenyl, lower alkoxy, lower alkenyloxy, halogen, hydroxy, amine , Acyl, carboxy, lower alkoxycarbonyl or aryl) or a cyano force,

Or together C 0— U— C〇—, — C O— V— C S— W—,-C O-V

— CO— W—or — (CH ₂ ) m NRSO 2-(where U is alkylene having 2 to 3 carbon atoms which may be substituted with lower alkyl; alkene having 2 to 3 carbon atoms) Len; phenylene; alkylene dioxy having 2 to 3 carbon atoms which may be substituted by lower alkyl; one S CH 2— or —〇CH ₂ —, and V and W are each independently NR, S or M, m is 2 or 3, and R is hydrogen, methyl or ethyl) or

c) Z is CH = NNR ⁸ R ⁹ , one of R ⁸ and R ⁹ is hydrogen and the other is an aliphatic acyl having 1 to 3 carbon atoms, and an optionally substituted aryloyl (wherein The substituent is amino, hydroxy or alkoxy), a heterocyclic carbonyl, an optionally substituted rubamoyl (where the substituent is an alkyl or aryl), and a substituent. Thiocarbamoyl (where the substituent is alkyl or aryl), alkoxycarbonyl or carbamoylcarbonyl having 1 to 3 carbon atoms or arylsulfonyl which may have a substituent (wherein Substituent is alkyl or aryl.)

(Hereinafter referred to as Z—2),

More preferably

a) R ³ is hydrogen, Z is C 0 NR ⁴ R ⁵ , one of R ⁴ and R ⁵ is hydrogen, and the other is an aryl lower alkyl which may have a substituent (where The substituent is halogen, alkyl, aryl or carboxy) b) Z is CH = CR ⁶ R ⁷ , and R ⁶ and R ⁷ are each independently substituted with acyl or aryl. Optionally substituted lower alkoxycarbonyl, optionally substituted rubamoyl (where the substituent is lower alkyl or aryl) or cyano, or

c) Z is CH = NN R ⁸ R 9, one of R ⁸ and R ⁹ is hydrogen, and the other is an aliphatic acyl having 1 to 3 carbon atoms, an optionally substituted aryloyl (here And the substituent is amino, hydroxy or alkoxy), a heterocyclic carbonyl, a carbamoyl optionally substituted with an aryl, a thiocarbamoyl optionally substituted with an aryl, an alkoxyl propylon having 1 to 3 carbon atoms, Carbamoylcarbonyl or arylsulfonyl optionally having substituent (s) (wherein the substituent is alkyl or aryl) Is)

(Hereinafter referred to as Z—3),

Most preferably

b) Z is CH = CR ⁶ R ⁷ , one of R ⁶ and R ⁷ is acyl or lower alkoxycarbonyl, and the other is acyl, lower alkoxycarbonyl, optionally substituted rubamoyl (Where the substituent is lower alkyl or aryl) or cyano, or

c) Z is CH = NNR ⁸ R ⁹ , one of R ⁸ and R ⁹ is hydrogen and the other is an aliphatic acyl having 1 to 3 carbon atoms, an optionally substituted aryloyl (where The substituent is amino, hydroxy or lower alkoxy), heterocyclic carbonyl, rubamoyl optionally substituted with aryl, thiocarbamoyl optionally substituted with aryl, alkoxycarbonyl having 1 to 3 carbon atoms, Rubamoylcarbonyl or arylsulfonyl optionally having substituents (where the substituents are lower alkyl or aryl)

(Hereinafter referred to as Z—4) a compound,

[7] R ¹ is R ¹ — 1, R ² is R ² — 1, R ³ is R ³ — 1,

A compound wherein Y is Y—1 and Z is Z — 1;

[8] R ¹ is R ¹ — 2, R ² is R ² _2, R ³ is R ³ — 1,

A compound wherein Y is Y—1 and Z is Z—1, preferably R ¹ is R ¹ —2, R ² is R ² —3, R ³ is R ³ —1, Y Is Y _ 1, Z is Z— 1, R ¹ is R i — S, R ² is R ² — 2, R ³ is R 3-1, and Y is Y— A compound wherein Z is Z—1, more preferably R ¹ is

A compound wherein R ¹ — 3, R ² is R ² — 3, R 3 is R 3 — 1, γ is γ-i, and Z is Z— 1,

[9] R ¹ is R 1-2, R ² is R ² _ 1, R ³ is R ³ - 2,

A compound wherein Y is Y—1 and Z is Z—1, preferably R ¹ is R ¹ —3;

R ² is R ² - is 1, R 3 is R 3- 2, Y is Y- 1, Z is Z- A compound that is 1,

[1 0] R ¹ is R ¹ — 2, R ² is R ² — 1, R ³ is R 3 — 1, X is 、, Y is Y—1, and Z is A compound that is Z — ¹ , preferably R ¹ is R ¹ —3, R ² is R ² —1, R ³ is R ³ —1, X is 〇, and Y is Y—1 Wherein Z is Z—1,

[1 1] Compounds in which R ¹ is R ¹ — 2, R ² is R ² — 1, R ³ is R 3 — 1, Y is Y— 2 and Z is Z— 1 A compound wherein R ¹ is R ¹ —3, R ² is R ² —1, R 3 is R 3 _1, γ is γ—2, and Z is Z—1, A compound wherein R ¹ is R ¹ — 2, R ² is R ² — 1, R ³ is R 3 _ 1, Y is Y—3 and Z is Z—1, most preferably A compound wherein R ¹ is R ¹ — 3, R ² is R ² −1, R ³ is R ³ — 1, Y is Y _ 3, and Z is Z _ 1,

[1 2] Compounds where R ¹ is R ¹ — 2, R ² is R ² — 1, R ³ is R 3 — i, Y is Y— 1, and Z is Z— 2 , preferably R ¹ is R 1 - is 3, R ² is R ² - is 1, R ³ is R ³ - is 1, Y is Y- 1, compound Z is Z- 2, A compound wherein R ¹ is R ^1-2 , R ² is R 2-1, R 3 is _R 3-11, Y is Y-1 and Z is Z-3, most preferably A compound wherein R ¹ is R 丄 — 3, R ² is R ² — 1, R ³ is R ³ — 1, Y is Y— 1, and Z is Z _ 3,

[1 3] Compounds in which R ¹ is R ¹ — 1, R ² is R ² — 2, R ³ is R 3 — 2, Y is Y — 1, and Z is Z — 1. A compound wherein R ¹ is R ¹ —1, R ² is R ² _3, R ³ is R ³ —2, Y is Y—1 and Z is Z—1,

[1 4] R ¹ is R ¹ — 1, R ² is R ² — 2, R ³ is R 3 — i, X is 〇, Y is Y—1, and Z is A compound that is Z—1, preferably R ¹ is R ¹ —1, R ² is R ² —3, R ³ is R ³ —1, X is 、,

A compound wherein Y is Y—1 and Z is Z—1; [1 5] Compounds in which R ¹ is R l — 1, R ² is R ² — 2, R ³ is R 3 — l, Y is Y — 2, and Z is Z — 1. A compound wherein R ¹ is R ¹ —1, R ² is R ² —3, R ³ is R ³ —1, Y is Y—2, and Z is Z—1, A compound wherein R ¹ is R ¹ —1, R ² is R ² —2, R ³ is R 3 — 1, Y is Y—3, and Z is Z—1, most preferably A compound wherein R ¹ is R 丄 —1, R ² is R ² — 3, R ³ is R ³ — 1, Y is Y—3 and Z is Z— 1,

[16] A compound in which R ¹ is R ¹ — 1, R ² is R ² — 2, R ³ is R ³ — 1, Y is Y — 1, and Z is Z—2 A compound wherein R ¹ is R ¹ —1, R ² is R ² —3, R ³ is R ³ —1, Y is Y—1 and Z is Z—2; A compound wherein R ¹ is R ¹ —1, R ² is R ² —2, R ³ is R 3-1, Y is Y—1 and Z is Z—3, more preferably A compound wherein R ¹ is R ¹ —1, R ² is R ² —3, R ³ is R ³ —1, Y is Y-1 and Z is Z—3, most preferably A compound wherein R 1 is R ¹ — 1, R 2 is R ² — 3, R ³ is R ³ — 1, Y is Y—1, and Z is Z—4;

[1 7] R ¹ is R ¹ — 1, R ² is R ² -1, R ³ is R ³ — 2, X is 〇, Y is Y—1, and Z is A compound that is Z—1,

[18] A compound in which R ¹ is R ¹ — 1, R ² is R ² — 1, R ³ is R ³ — 2, Y is Y—2, and Z is Z—1 A compound wherein R ¹ is R ¹ —1, R ² is R ² —1, R 3 is R 3-12, Y is Y—3, and Z is Z— 1, A compound wherein R ¹ is R ¹ -1, R ² is R ² — 1, R ³ is R ³ — 2, Y is Y—3, and Z is Z—1;

[1 9] Compounds in which R ¹ is R l — 1, R ² is R ² — 1, R ³ is R ³ — 2, Y is Y—1, and Z is Z—2 Preferably R ¹ is R ¹ —1,

A compound wherein R ² is R ² — 1, R ³ is R ³ -2, Y is Y—1 and Z is Z _ 2, R ¹ is R ¹ — 1 and R ² is R ² _ 1 and R ³ is R 3 — 2, a compound wherein Y is Y—1 and Ζ is Ζ—3, most preferably R ¹ is a shaku 、 -1, R ² is R ^{2 —} l, and R ³ is R ³ — 2, a compound wherein Y is Y—1 and Z is Z—4;

[2 0] R ¹ is R ¹ — 1, R ² is R ² — 1, R ³ is R 3 — 1, X is O, Y is Y—2, and Z is A compound that is Z—1, preferably R ¹ is R ¹ —1, R ² is R ² —1, R ³ is R ³ —1, X is O, and Y is Y—3 Wherein Z is Z—1, R ¹ is R 1 — 1, R 2 is R ² — 1, R ³ is R ³ — 1, X is 〇, and Y is A compound wherein Y is 3 and Z is Z-1 1;

[2 1] R l is R ¹ — 1, R ² is R ² — 1, R ³ is R 3 — 1, X is 、, Y is Y—1, and Z is A compound that is Z—2, preferably R ¹ is R ¹ —1, R ² is R ² —1, R ³ is R ³ —1, X is 、, and Y is Y—1 A compound wherein Z is Z—3, most preferably R 1 is R ¹ —1, R ² is R ² —1, R ³ is R ³ —1, and X is 〇 Wherein Y is Y—1 and Z is Z—4,

[2 2] Compounds in which R ¹ is R 1 — 1, R ² is R ² — 1, R ³ is R 3 — 1, Y is Y—2, and Z is Z—2 A compound wherein preferably R ¹ is R ¹ —1, R ² is R ² —1, R ³ is R 3 —1, Y is Y—3, and Z is Z — 2. R ¹ is R ¹ — 1, R ² is R ² — 1, R 3 is R 3 — 1, Y is Y—2, and Z is Z—3. 1 -1 Deari, R ² is R ² - is 1, R ³ is R 3 - is 1, Y is the Y- 3, compound Z is Z- 3, most preferably R ¹ A compound wherein R ¹ — 1, R 2 is R 2-1, R ³ is R ³ — 1, Y is Y — 3 and Z is Z — 4;

[2 3] Compounds in which R ¹ is R ¹ — 2, R ² is R ² — 2, R ³ is R 3 — 2, Y is Y—1, and Z is Z—1 A compound wherein R ¹ is R ¹ —3, R ² is R ² —3, R ³ is R ³ —2, Y is Y — 1 and Z is Z—1, [24] R ¹ is R ¹ — 2, R ² is R ² _2, R ³ is R 3 _i, X is O, Y is Y—1, and Ζ is Ζ A compound that is —1, preferably R 1 is R ¹ —3, R ² is R ² —3, R ³ is R ^{3 —} l, X is O, Y is Y—1 There is a compound wherein Z is Z—1,

[2 5] Compounds in which R ¹ is R ¹ — 2, R ² is R ² — 2, R ³ is R ³ — 1, Y is Y—2, and Z is Z-1 A compound wherein R 1 is R 1-3, R ² is R ² —3, R ³ is R ³ —1, Y is Y—3, and Z is Z—1,

[2 6] Compounds in which R ¹ is R ¹ — 2, R ² is R ² — 2, R ³ is R ³ — 1, Y is Y—1, and Z is Z—2 A compound wherein R 1 is R 1-3, R ² is R ² — 3, R ³ is R ³ — 1, Y is Y — 1, and Z is Z—3; Most preferably, compounds wherein R ¹ is R ¹ —3, R ² is R ² —3, R ³ is R ³ —1, Y is Y—1, and Z is Z—4;

[2 7] R l is R l—2, R ² is R 2—1, R 3 is _R 3-2, X is O, Y is Y—1, and Z is A compound that is Z—1, preferably R 1 is R ¹ — 3, R 2 is R 2 — I, R 3 is _R 3 — 2, X is 、, and Y is Y—1 Wherein Z is Z—1,

[2 8] Compounds in which R ¹ is R ¹ — 2, R ² is R ² — 1, R ³ is R 3—2, Y is Y—2, and Z is Z—1 A compound wherein R ¹ is R ¹ —3, R ² is R ² —1, R ³ is R ³ —2, Y is Y _3, and Z is Z— 1,

[2 9] R ¹ is 1? 丄 _2, R ² is R ² — 1, R ³ is R ³ — 2,

A compound wherein Y is Y—1 and Z is Z—2, preferably R ¹ is R ¹ _3;

A compound wherein R ² is R ² —1, R ³ is R ³ —2, Y is Y—1 and Z is Z—3, most preferably R 1 is R 1—3; R 2 is R 2 1 1;

A compound wherein R ³ is R ³ — 2, Y is Y—1, and Z is Z—4;

[3 0] R i is R l—2, R ² force R ² — 1, and R ³ is R 3— i Wherein X is 〇, Y is Y—2, and Z is Z—1, preferably R

¹ is R ¹ — 3, R ² is R ² — 1, R ³ is R ³ — 1, X is O, Y is Y — 3, and Z is Z — 1. Compound,

[3 1] R ¹ is R ¹ — 2, R ² is R ^{2 —} l, R ³ is R ³ — 1, X is O, Y is Y—1, and Z is A compound that is Z—2, preferably R ¹ is R ¹ —3, R ² is R ² —1, R ³ is R ³ —1, X is O, and Y is Y—1 And Z is Z—3, most preferably R ¹ is R ¹ —3, R ² is R ² —1, R ³ is R ³ — 1, X is O A compound wherein Y is Y—1 and Z is Z—4;

[3 2] Compounds in which R ¹ is R ¹ — 2, R ² is R ² — 1, R ³ is R ³ — 1, Y is Y—2, and Z is Z—2 A compound wherein R ¹ is R ¹ —3, R ² is R ² —1, R 3 is R 3-1 and γ is Y—3, and Z is Z—3; Most preferably, a compound wherein R ¹ is R ¹ —3, 1 ² is 112—1, R 3 is R 3 _1, γ is γ—3, and Z is Z—4;

[3 3] R ¹ is R ¹ — 1, R ² is R ² — 2, R ³ is R 3 — 2, X is ◦, Y is Y—1, and Z is compound is a Z _ 1, preferably R ¹ is R ¹ - is 1, R 2 is R 2 one _3, R 3 is _R 3 - is _3, a χ is o, Y is Y- 1 Wherein Z is Z—1,

[34] a compound wherein R ¹ is R ¹ — 1, R ² is R ² — 2, R ³ is R ³ — 2, Y is Y—2, and Z is Z—1, Preferably, compounds wherein R ¹ is R ¹ —1, R ² is R ² —3, R ³ is R ³ —3, Y is Y—3, and Z is Z— 1,

[3 5] R ¹ is R ¹ — 1, R ² is R ² — 2, R ³ is R ³ — 2,

A compound wherein Y is Y—1 and Z is Z — 2, preferably R ¹ is R ¹ —1, R ² is R ² -3, R ³ is R ³ -3, Y Is Y—1 and Z is Z—3, most preferably R ¹ is R ¹ —1, R ² is R ² —3,

A compound wherein R ³ is R ³ — 3, Y is Y—1 and Z is Z—4; [3 6] R ¹ is R ¹ — 1, R ² is R ² — 2, R ³ is R ³ — 1, X is 〇, Y is Y — 2, and Ζ is A compound that is Ζ—1, preferably R 1 is R i — l, R ² is R ² — ³ , R ³ is R ³ — 1, X is 、, and Y is Y— 3 Wherein Z is Z—1,

[3 7] R ¹ is R ¹ — 1, R ² is R ² — 2, R ³ is R 3 — i, X is 、, Y is Y—1, and Z is A compound that is Z—2, preferably R 1 is R ¹ —1, R ² is R ² —3, R ³ is R ^{3 —} l, X is 〇, and Y is Y— 1 And Z is Z—3,

[38] A compound in which R ¹ is R ¹ — 1, R ² is R ² — 2, R 3 is R 3 i, Y is Y—2, and Z is Z — 2. A compound wherein preferably R ¹ is R ¹ -1, R ² is R ² _ 3, R ³ is R ³ — 1, Y is Y—3 and Z is Z— 3, Most preferably, compounds wherein R ¹ is R ¹ —1, R ² is R ² —3, R ³ is R ³ —1, Y is Y—3 and Z is Z _4,

[3 9] R ¹ is R ¹ — 1, R ² is R 2 — 1, R 3 is R 3 _2, X is 2, Y is Y—2, and Z is A compound that is Z—1, preferably R 1 is R ¹ —, R ² is R ² — 1, R ³ is R ³ — 3, X is O, Y is Y—3 There is a compound wherein Z is Z—1,

[4 0] R ¹ is R ¹ — 1, R ² is R ² — 1, R ³ is R ³ — 2, X is O, is Y—1, and Z is Z — A compound that is —2, preferably R ¹ is R ¹ — 1, R ² is R ² — 1, R ³ is R ³ — 3, X is —, Y is Y— 1 A compound wherein Z is Z—3, most preferably R 1 is R 1 —1, R ² is R ² —1, R ³ is R ³ —3, X is 、, A compound wherein Y is Y—1 and Z is Z—4,

[4 1] compounds wherein R ¹ is R ¹ — 1, R ² is R ² — 1, R 3 is R 3-1, Y is Y—2, and Z is Z—2 Preferably R ¹ is R ¹ —1,

R ² is R 2-1, R 3 is R 3 _ ₃ , γ is γ _ 3, Z is Z— 3, most preferably R ¹ is R ¹ — 1, R ² is R ² — 1; A compound wherein R ³ is R ³ — 3, Y is Y—3, and Ζ is Ζ— 4,

[42] R ¹ is R 1- 1, R ² is R ² - is 1, R ³ is R 3- iota, X is O, Y is Y- 2, Z is Z _2, preferably R ¹ is R ¹ — 1, R ² is R ² — 1, R ³ is R ³ _l, X is O, Y is Y—3 A compound wherein Z is Z—3, most preferably R ¹ is R ¹ —1, R ² is R ² —1, R ³ is R ³ —1, X is 〇, A compound wherein Y is Y—3 and Z is Z—4,

[43] R ¹ is R ¹ — 2, R ² is R ² _2, R ³ is R 3 — 2, X is O, Y is Y—2, and Z is Z A compound that is ^—1 , preferably R ¹ is R ¹ —3, R ² is R ² —3, R ³ is R ³ —2, X is O, Y is Y—3 There is a compound wherein Z is Z—1,

[44] R ¹ is R ¹ — 2, R ² is R ² — 2, R ³ is R 3 — 2, X is 〇, Y is Y—2, and Z is Z — A compound that is 2,

Preferably, R ¹ is R i _3, R ² is R ² —3, R ³ is R ³ —2, X is O, Y is Y—3, and Z is Z — A compound that is 2,

Preferably, R ¹ is R ¹ — 3, R ² is R ² — 3, R ³ is R ³ — 2, X is O, Y is Y—3, and Z is Z — A compound that is 3,

Most preferably, R ¹ is R ¹ — 3, R ² is R ² _ 3, R 3 is R 3-1, X is 〇, Y is Y—3, and Z is Z — A compound that is 4,

Is preferred. The compound of the present invention can be synthesized, for example, according to the following reaction scheme.

[If X = 〇 or S]

H ₂ OH d ^β f

 First, in the presence of a base such as an alkali metal alcoholate, a compound a and a phenol compound such as guaiacol, m-methoxyphenol, or o-methoxybenzenethiol represented by the general formula R 2 -XH in a solvent such as alcohol, —Reaction of a thiol compound such as methoxybenzenthiol to give compound b.

 Next, compound b and amidine or a salt thereof (for example, formamidine acetate, pyrimidine-12-carboxamidine benzenesulfonate, etc.) are added to a suitable solvent in the presence of a base such as alkali metal alcoholate. Condensation gives compound c. Next, compound c is reacted with a halogenating agent or the like in the presence or absence of an organic base to obtain compound d. The solvent in this case may be any organic solvent that does not react with the halogenating agent, but when the organic base or the haptic agent is in a liquid state, it can be used as a solvent.

Compound e is obtained by reacting compound d with compound g (R ¹ S〇2 NHM; M is a metal salt). Compound g is preferably 1.5 to 2 mol with respect to compound d, and may be reacted in a solution such as dimethylsulfoxide or dimethylformamide.

Next, compound e and a diol such as ethylene glycol, propylene glycol, 1,4-butanediol, 1,5-pentanediol, and 1,6-hexanediol in the presence of a base such as sodium hydride and butyllithium. (HO—Y—CH 2 OH) to give compound f. In the reaction between the compound e and the diol, it is preferable to use the diol in excess, and the diol may be used as the solvent. W

[x = single bond]

 f

 (X = Single

 For example, after substituting the 4- and 6-positions of 4,6-dihalogenopyrimidine by the same method as above, halogenating the 5-position with N-prosuccinimide, etc., and catalyzing the palladium catalyst with the aryltin compound Introduced aryl groups in the cross-coupling reaction used (Journal of Organic Chemistry, Vol. 58, 1963-1966, 1999). This gives the desired compound.

 As the compound g, a known compound may be used. For example, it can be synthesized from a known compound by the following method.

MOH

R -S0 ₂ CI ~~ ^NH 3, R ¹ -S0 ₂ NH ₂ -R ¹ -S0 ₂ NHM h 9

 First, a known compound h is reacted with aqueous ammonia in an appropriate solvent such as toluene to obtain a compound i, and then the compound i is dissolved in a solvent such as methanol or ethanol in an alkali such as potassium hydroxide or sodium hydroxide. (M〇H; M is a metal atom, such as potassium and sodium) to give compound g.

 Using the compound f thus obtained as an intermediate, the following compound (I) is obtained by the following reaction.

a) When Z is CONR 4 R 5 [Compound (I _a )] W

 Compound f is oxidized by a conventional method to obtain compound k. As the oxidizing agent, those usually used for an oxidation reaction from alcohol to carboxylic acid may be used. For example, pyridinium dichromate, Collins reagent, Johns reagent, manganese dioxide, potassium permanganate, ruthenium tetroxide and the like can be mentioned. As the solvent, for example, dimethylformamide, tetrahydrofuran, methylene chloride, benzene, acetate, etc. can be used, and the reaction may be performed at 0 ° C. to under heating, preferably around room temperature for several hours to several tens hours. .

 The obtained compound k is amidated to obtain compound (la). For example, using methylene chloride, tetrahydrofuran, dimethylformamide, getyl ether, or the like as a solvent, under nitrogen atmosphere, at 0 ° C. to under heating, preferably at around room temperature, the number of amine compounds corresponding to the number of amine compounds is reduced. The reaction may be performed for a period of time to several tens of hours. If necessary, the reaction can be suitably promoted by activating with a suitable activator (eg, thionyl chloride, acid halide, acid anhydride, activated ester, etc.).

b) When Z is CH = C R 6 R 7 [Compound (lb)]

 Compound f is oxidized by a conventional method. The oxidizing agent used in the oxidation reaction of alcohols to aldehydes may be a commonly used one (eg, pyridinium dichromate, chromic anhydride, sodium chlorite, dimethyl sulfoxide oxalyl chloride, etc.). The reaction may be carried out in an active solvent (methylene chloride, dimethylformamide, tetrahydrofuran, etc.) at 0 ° C to heating under heating for several ten minutes to several hours.

The obtained compound 1 is reacted with a malonic ester derivative or an active methylene compound corresponding to the target compound. The reaction is ethanol, methanol, methylene chloride, The reaction may be carried out in a solvent such as ethylene glycol dimethyl ether or tetrahydrofuran in the presence of a base such as piperidine, pyridine or pyrrolidine at 0 ° C. to under heating, preferably at room temperature to under heating for several tens to ten hours.

A compound in which one of R ⁶ and R ⁷ is hydrogen can be obtained by first obtaining a compound in which both R ⁶ and R ⁷ are carboxy and decarboxylating it by a conventional method. c) When Z is CH = NNR ⁸ R ⁹ [Compound (I c)]

R ¹ SO NH R ¹ SOoNH

RS ^ N ΟΎ-CHO R ^{3 / U} NOY CH = NNR ⁸ R ⁹

 I (lc)

 The compound 1 obtained above is reacted with a hydrazine derivative corresponding to the target compound to obtain a compound (Ic). This reaction may be carried out in a solvent such as ethanol, methanol, methylene chloride or tetrahydrofuran at 0 ° C. to under heating, preferably at about room temperature for several tens minutes to several hours.

 In the above process, each substituent of the compound can be converted to another substituent by an ordinary method at an appropriate stage.

 For example, when the substituent of any of the obtained compounds is nitro, a lower alcohol such as methanol is used as a solvent, and catalytic reduction using PdZC is performed to obtain a compound in which the substitution group is amino. Can be

 A compound in which the substituent of any of the obtained compounds is alkoxycarbonyl is reacted with an amine compound such as ammonia or dimethylamine using a lower alcohol such as methanol or an appropriate solvent such as tetrahydrofuran to obtain a substituent. Compounds that are carbamoyl can be obtained.

 In addition, when the substituent of the obtained compound is carboxy, a compound having a substituent of hydroxyalkyl can be obtained by using a reducing agent such as lithium aluminum hydride or sodium borohydride, or by performing catalytic reduction. Can be

In the case of a compound having a substituent which hinders the reaction in each step, the compound may be protected in advance and eliminated at an appropriate stage. The compound (I) of the present invention has high activity and selectivity as an endothelin B receptor selective antagonist, and can be used as a medicament. Endothelin B receptor, together with endothelin A receptor, is involved in the development of cardiovascular diseases such as hypertension, acute renal failure, heart failure, renal ischemia, cerebral ischemia, cerebral infarction, cerebral edema, migraine, etc. It is considered. Furthermore, endothelin B receptor is considered to be involved in the metabolism of blood endothelin and intimal hyperplasia of blood vessels, and is therefore very useful as an agent for treating and preventing these diseases. It is also useful as a reagent for elucidating the function of endothelin B receptor.

 When the compound of the present invention is administered as a medicament, it can be administered safely orally or parenterally. Oral administration may be carried out in a usual dosage form such as tablets, granules, powders, capsules, pills, liquids, suspensions, syrups, buccals or sublinguals according to a conventional method. For parenteral administration, any commonly used dosage form, such as injections such as intramuscular administration, suppositories, transdermal absorbents, and inhalants, can be suitably administered, but oral administration is particularly preferred.

 The pharmaceutical composition of the present invention requires various pharmaceutical additives such as a pill, a binder, a wetting agent, a disintegrant, a lubricant and a diluent suitable for the final dosage form in an effective amount of the active ingredient. Can be prepared by mixing. In the case of injections, the preparation may be prepared by sterilizing with an appropriate carrier.

Specifically, excipients such as lactose, sucrose, glucose, starch, calcium carbonate or crystalline cellulose, binders such as methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, gelatin or polyvinylpyrrolidone, etc. Examples of the agent include carboxymethylcellulose, sodium carboxymethylcellulose, starch, sodium alginate, powdered agar or sodium lauryl sulfate, and examples of the lubricant include talc, magnesium stearate, and macrogol. As a suppository base, cocoa butter, macrogol, methylcellulose, or the like can be used. In addition, when it is prepared as a liquid or emulsion or suspension injection, it is usually used as a solubilizing agent or suspension. Additives, emulsifiers, stabilizers, preservatives, isotonic agents, and the like may be added as appropriate. In the case of oral administration, a flavoring agent, a fragrance, and the like may be added.

 The dose of the endothelin B receptor selective antagonist should be set in consideration of the patient's age, weight, administration route, type and degree of disease, etc., but was orally administered to humans. In this case, the dose may be administered to an adult in a daily dose of 1 g to 20 Omg / kgZ once to several times. In the case of parenteral administration, it varies depending on the administration route, but it is usually sufficient to administer 0.1 g to 2 OmgZkg gZ once or several times a day.

 Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.

Example

 The structural formulas of the compounds of the present invention are summarized in Tables 1 to 13.

Reference example 1

/} ~ 28% NH ₃ /} ~ KOH // ~

t-Bu— V-S0 ₂ CI —; t-Bu-Hf 'V-S0 ₂ NH ₂ t-Bu— V-S0 ₂ NHK

\ = / Torueno \ = / eOH \ = /

 1 2 3 (First step)

 Compound 1 (4-tert-butylbenzenesulfonyl chloride, 9.9 g, 42.5 mm o 1, Aldrich 'Chemical Company 21) in toluene (100 ml) solution of 28% Aqueous ammonia (100 ml) was added with stirring, and the mixture was reacted at room temperature for 4 hours. The reaction solution was concentrated, adjusted to pH = 13 with concentrated hydrochloric acid under ice cooling, and separated. The aqueous layer was further adjusted to pH = 7 with concentrated hydrochloric acid, and extracted with ethyl acetate. On the other hand, the organic layer was concentrated, combined with ethyl acetate from the aqueous layer, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain 8.888 g of compound 2 (4-tert-butylbenzenesulfonamide). Was.

Yield 98%

! H-NMRCDMSO-de) (5 ppm: 1.30 (s, 9H), 7.26 (s, 2H), 7.56-7.77 (m, 4H). (2nd step)

 To a solution of compound 2 (3.0 g, 14.0 mmo 1) in methanol (20 ml) was added, at room temperature, potassium hydroxide (922 mg) and water (4 ml). Stirred for hours. The reaction solution was concentrated, methanol was added thereto, and the operation of reconcentration was repeated three times to obtain 3.18 g of compound 3 (4-tert-butylbenzenesulfonamide).

90% yield

 ! H-NMRCDMSO-de) δ ppm: 1.27 (s, 9H), 7.29, 7.57 (ABq, 4H, J = 8.4Hz, Δv = 85.4 Hz).

 8

 (3rd step)

 1.35 mo 1/1 sodium methylate methanol solution 150.Oml was added dropwise with guaiacol 25.0 g (0.2m01) over 10 minutes under ice-cooling, and at the same temperature. Stirred for 10 minutes. Compound 4 (dimethylchloromalonone, 37.0 g, 0.2 m 01, manufactured by Aldrich 'Chemical Company) was added dropwise over 20 minutes under ice-cooling, and the mixture was reacted at room temperature for 2.5 hours. I let it. The reaction solution was concentrated, water was added, and extracted with toluene. The organic layer was sequentially washed with a 1% aqueous sodium hydroxide solution and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by distillation under reduced pressure (3 mmHg, 142-145 ° C) to obtain compound 5 (dimethyl-2-methoxyphenoxymalonate, 29.3 g).

Yield 58% iH-NMR (CDCh) (5 ppm: 3.85 (s, 6H), 3.86 (s, 3H), 5.27 (s, 1H), 6.82-7.10 (m, 4H)

 (4th step)

 1 mo 1 ノ 1 of sodium methyl methanol solution 30.4 ml was added with 1.lg of formamidine acetate and compound 5 (1.4 g, 5.5 mm o 1) under ice cooling. At the same temperature for 1 hour. The reaction solution was concentrated, water was added, and extracted with toluene. The aqueous layer was adjusted to pH = 4 using 1N hydrochloric acid under ice-cooling, and the precipitated crystals were collected by filtration and washed repeatedly with water to give compound 6 (5- (2-methoxyphenoxy) -1H-pyrimidine-4 , 6-dione, 1.12 g).

Yield 8 7%

 ! H-NMR (CD3OD) (5 ppm: 3.87 (s, 3H), 6.68-7.04 (m, 4H), 7.97 (s, 1H).

Anal.Calcd for C11H10N2O40.37H ₂ O

 C, 54.85; H, 4.49; N, 11.63;

Found C, 54.82; H, 4.53; N, 11.78.

 (Fifth step)

 Add collidine (1.41 ml) to compound 6 (1.0 g, 4.27 mmo 1), add phosphorus oxychloride (5.8 ml) in portions under ice-cooling, and add an oil bath. The reaction was carried out at a temperature of 135 ° C for 4 hours. After cooling, the mixture was concentrated, the residue was poured on ice, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium bicarbonate and brine in that order, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography to obtain compound 7 (4,6-dichloro-1-5- (2-methoxyphenoxy) -pyrimidine, 1.0 g).

Yield 86%

^{! H-NMR (CDCls) (} 5 ppm: 3.88 (s, 3H), 6.64-6.68 (m, 1H), 6.84-7.17 (m, 3H), 8.63 (s, 1H).

 (Step 6)

Compound 7 (2.0 g, 5.97 mm o 1) and Compound 3 (3.43 g, 13. A solution of 6 mm 0 1) in dimethyl sulfoxide (10 ml) was reacted at 120 ° C for 2 hours. After cooling, 1N aqueous hydrochloric acid (10 ml) was added, and the mixture was extracted with ethyl acetate. After washing with water three times and drying over anhydrous magnesium sulfate, the solvent was distilled off. The residue was purified by silica gel column chromatography to give compound 8 (4-tert-butyl-N- [6-chloro-5- (2-methoxyphenoxy) -pyrimidine-14-yl] benzenesulfonamide, 2.78 g ).

Yield 84%

 O-NMR (CDCls) δ ppm: 1.33 (s, 9H), 3.97 (s, 3H), 6.88-7.20 (m, 4H), 7.49, 7.97 (ABq, 4H, J = 8.6Hz, Δ = 95.6Hz ), 8.41 (s, IH).

Example 1 Synthesis of Compound (Ia-1)

 (First step)

 Sodium hydride (7.20 g, 180 mm01) was added to 1,3-propanediol (200 mL) at room temperature under a nitrogen atmosphere over 13 minutes, and the mixture was stirred at room temperature for 1 hour. Compound 8 ′ (20.16 g, 45 mmo 1) obtained in the same manner as in Reference Example 1 was added over 5 minutes, and the mixture was stirred at 94 ° C. for 5 hours. After cooling, the reaction solution was poured into 4N hydrochloric acid, adjusted to pH 2 and extracted twice with ethyl acetate. The organic layer was washed with brine three times and concentrated. The obtained crude crystals were recrystallized from ethyl acetate-hexane to give Compound 9. 2 1.0 2 g (96%).

 ! H-NMR (CDCI3) δ ppm: 1.34 (s, 9H), 1.79 (quintet, 2H, J = 6.0 Hz), 3.43 (t, 2H, J = 6.0 Hz), 3.78 (s, 3H), 4.43 ( t, 2H, J = 6.0 Hz), 6.34 (ddd, 1H, J = 0.6, 2.4, 8.1 Hz), 6.40 (t, IH, J = 2.4 Hz), 6.65 (ddd, IH, J = 0.6, 2.4, 8.1 Hz), 7.17 (t, IH, J = 8.1 Hz), 7.52, 8.04 (A2B2, 4H, J = 8.7 Hz), 7.68 (br s, IH), 8.30 (s, IH).

(2nd step)

Compound 9 (9.75 g, 20 mmo 1) was dissolved in DMF (200 mL) at room temperature under a nitrogen atmosphere, and PDC (154 g, 400 mmo 1) was charged. The mixture was stirred at room temperature for 15 hours, poured into 4N hydrochloric acid, and extracted twice with ethyl acetate. The organic layer was washed twice with a saline solution and extracted with a 0.5 M aqueous sodium hydrogen carbonate solution. After extraction with saline, the aqueous layers were combined and poured into a mixture of 4 N ethyl acetate monohydrochloride. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. Each organic layer was washed with brine, dried over MgSO ₄ and concentrated. Crystals precipitated during the concentration were collected by filtration. After concentration of the filtrate, the residue was recrystallized from ethyl acetate-hexane. 6.82 g (68%).

! H-NMR (CDC) δ ppm: 1.34 (s, 9H), 2.61 (t, 2H, J = 6.3 Hz), 3.75 (s, 3H), 4.53 (t, 2H, J = 6.2 Hz), 6.32 ( ddd, 1H, J = 0.6, 2.4, 8.1 Hz), 6.37 (t, 1H, J = 2.4 Hz), 6.61 (ddd, 1H, J = 0.6, 2.4, 8.1 Hz), 7.13 (t, 1H, J = 8.1 Hz), 7.51, 8.03 (A2B2, 4H, J = 8.7 Hz), 8.30 (s, 1H).

 (3rd step)

t-Bu- <Q-

Compound 10 (200 mg, 0.40 mmo 1) was suspended in methylene chloride (2 mL) at room temperature under a nitrogen atmosphere, and benzylamine (0.52 mm 01), PyBOP (250 mg, 0 . 48 mm o 1), HOBT -H 2 O (74 mg, 0. 48 mm o 1), N- methylmorpholine (5 3 L, 0. 4 8 mm o 1) were sequentially introduced. After stirring at room temperature for 18 hours, the reaction solution was directly purified by silica gel chromatography to obtain the compound (Ia-1). ! H-NMR (CDCla) δ ppm: 1.34 (s, 9H), 2.44 (t, 2H, J = 6.0 Hz), 3.69 (s, 3H), 4.23 (d, 2H, J = 6.0 Hz), 4.58 ( t, 2H, J = 6.0 Hz), 5.68 (br s, 2H), 6.22-6.23 (m, IH), 6.33 (t, 2H, J = 2.4 Hz), 6.56-6.60 (m, 1H), 7.08 ( t, IH, J = 8.1 Hz), 7.12- 7.17 (m, 2H), 7.23-7.34 (m, 3H), 7.51, 8.02 (A2B2, 4H, J = 8.4 Hz), 7.76 (brs, 1H), 8.29 (s, IH). Example 2 Synthesis of Compound (Ia—31)

 Compound (la-29) (300 mg, 0.462 mmo 1) obtained in the same manner as in Example 1 was dissolved in methanol (3 mL), 10% PdZC was added, and hydrogen was added. The mixture was stirred at room temperature for 3 hours in an atmosphere. After removing insolubles, the filtrate was concentrated and purified by silica gel chromatography to obtain a compound (Ia_31). 24.4 mg (85%). Example 3 Synthesis of Compound (Ia-24)

 The compound (Ia—22) (33 mg, 0.05 mmo 1) obtained in the same manner as in Example 1 was placed in a Teflon container for ultrahigh pressure reaction, and Me CN (3.5 m L), N-methylmorpholine (6.5 L, 0.06 mm 01) and water (60 L) were added. The vessel was set in an ultrahigh pressure reactor and allowed to stand at 50 ° C. at llkbar for 4 days. The pressure was returned to normal pressure, and the reaction solution was concentrated and fractionated by silica gel chromatography to obtain a compound (Ia_24). 20 mg (63%). Example 4 Synthesis of Compound (Ia-26)

Compound (Ia-23) (33 mg, 0.05 mmo1) obtained in the same manner as in Example 1 was dissolved in methanol (0.5 mL), and 28% aqueous ammonia (0%) was added at room temperature. .5 mL) was added. The mixture was stirred at room temperature for 2 hours, heated for 1.5 hours under reflux, and allowed to cool. Compound (Ia-26) was obtained by fractionation by silica gel chromatography. 15.4 mg (49%). Example 5 Synthesis of Compound (Ia-27)

Compound (Ia-23) (36 mg, 0.055 mmo 1) obtained in the same manner as in Example 1 was dissolved in THF (1 mL), and Li _{a l H 4 (1 1 mg} , 0. 2 7 7 mm o 1) was added. After stirring at 0 ° C for 30 minutes, the mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and brine, dried and concentrated. Purification by silica gel chromatography gave the desired product. 1 8.9 mg (55%). Example 6 Synthesis of Compound (I b-1)

 (First step)

 To a methylene chloride (5 ml) solution of compound 11 (500 mg, 1.0 mmol) obtained in the same manner as in Example 1 was added pyridinium chromate chromate (430 mg, 2.0 mmol) at room temperature. The reaction was performed for 2 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography to obtain compound 12 (378 mg).

 (2nd step)

 Compound 12 (499.58 mg,] Ommol) was suspended in 5 ml of ethanol at room temperature, and getyl malonate (1.2 mmol) and piperidine (0.2 mmol) were suspended.

1) was added. The reaction solution is reacted for 1 hour under heating and reflux.After cooling, the reaction solution is poured into water. 66dr / l:> d,

 0ε / 66 OAV

ON

 -i

Z gz u 1 and benzoithydrazide (1.2 mm o 1) was added. The reaction liquid gradually became homogeneous within several minutes. The reaction was allowed to proceed at room temperature for 1 hour, and the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain a compound (Ic-11).

_{Ή-NMR (CDC1 3) δ} ppm: 1.33 (s, 9H), 1.74-1.88 (m, 2H), 2.10-2.24 (m, 2H), 3.72 (s, 3H), 4.32 (t, 2H, J = (6.3 Hz), 6.30-6.39 (m, 2H), 6.57-6.62 (m, 1H), 7.12 (t, 1H, J = 8.1 Hz), 7.41 (t, 2H, J = 6.9 Hz), 6.45-6.55 ( m, 1H), 7.50, 8.01 (A2B2, 4H, J = 8.4 Hz), 7.77 (d, 2H, J = 7.2 Hz), 8.26 (s, 1H), 9.12 (s, 1H). Synthesis of compound (I)

Other compounds (I) were synthesized in the same manner. The structural formula and physical properties are shown below.

 Two

la-67 m-OMe H

la-68 m-OMe H (CH ₂ ) ₂

C0 ₂ H la-79 m-OMe H (CH ₂ ) ₃

 Me Me

R ² 'R ⁶ R ⁷ YR ² ' R ⁶ R ⁷ Y lb-1 m-OMe C0 ₂ Et C0 ₂ Et (CH2) ₃ lb-1 'o-OMe C0 ₂ Et C0 ₂ Et (CH ₂ ) ₃ lb -2 m-OMe C0 ₂ Me C0 ₂ Me (CHs) 3 lb-2 'o-OMe C (¾Me C0 ₂ Me (CH ₂ ) ₃ lb-3 m-OMe C0 ₂ t-Bu C0 ₂ f-Bu ( CHs) 3 lb-3 'o-OMe C0 ₂ f-Bu C0 ₂ i-Bu (CH ₂ ) ₃ lb-4 m-OMe C0 ₂ Bn C0 ₂ Bn (CH ₂ ) 3 lb-4' o-OMe C0 ₂ Bn C0 ₂ Bn (CH ₂ ) ₃ lb-5 m-OMe CN C0 ₂ Et (CHs) ₃ lb-5 'o-OMe CN C0 ₂ Et (CH ₂ ) ₃

Ib-6 m-OMe CN C0 ₂ e (CH ₂ ) 3 lb-6 ¹ o-OMe CN C0 ₂ Me (CH ₂ ) ₃ lb-7 m-OMe CN CN (CH ₂ ) _£ lb-7 ¹ o- OMe CN CN (CH ₂ ) ₃

1b-8 m-OMe COMe COMe ( ^CH 2) 3 lb-8 'o-OMe COMe COMe (CH ₂ ) ₃ lb-9 m-OMe N0 ₂ C0 ₂ Et (CH2) 3 lb-9' o-OMe N0 ₂ C0 ₂ Et (CH ₂ ) ₃ lb-10 m-OMe C0 ₂ H C0 ₂ H (CH2) 3 lb-10 ¹ o-OMe C0 ₂ H C0 ₂ H (CH ₂ ) ₃ lb-11 m-OMe H C0 ₂ i-Bu (CH2) 3 o-OMe H C0 ₂ i-Bu l ⁿ 2 lb-12 m-OMe H C0 ₂ H (CH2) ₃ lb-12 'o-OMe H C0 ₂ H (CH ₂ ) ₃ lb-13 m-OMe CN C0 ₂ H (CHs) 3 ib-13 ¹ o-OMe CN C0 ₂ H (CH ₂ ) ₃ lb-17 m-OMe COMe COEt (CH2) 3 lb-17 'o-OMe COMe COEt (CH ₂ ) ₃ lb-18 m-OMe COMe CO-/-Bu (CHs) 3 lb-18 'o-OMe COMe CO-ABu (CH ₂ ) ₃ lb-18 "o-OMe CO-i- Bu COMe (CH ₂ ) ₃ lb-19 m-OMe COMe CO-n-Bu (Ch½) ₃ lb-19 'o-OMe COMe CO-n-Bu (CH ₂ ) ₃ lb-20 m-OMe COMe CO- n-Pen (CH ₂ ) 3 lb-20 ¹ o-OMe COMe CO-n-Pen (CH ₂ ) ₃ lb-21 m-OMe COMe (CHs) 3

lb-21 ¹ o-OMe COMe (CH ₂ ) ₃

Ib-22 m-OMe COE1 COEt (CH2) 3 Ib-22 ¹ o-OMe COEt COEt (CH ₂ ) ₃ lb-23 m-OMe CO Small Pr CO- Pr (CH2) 3 lb-23 ¹ o-OMe CO --Pr CO- Pr (CH ₂ ) ₃ lb-24 m-OMe COMeCONH (CH2) 3 lb-24 'o-OMe COMe CONH ^ j> (CH ₂ ) ₃

Five

6

7

(lb)

oo

— = CR ⁶ R ⁷ YR = CR ⁶ R ⁷ Y lb-56 m-OMe (CH ₂ ) ₃ lb-56 ¹ o-OMe (CH ₂ ) ₃ lb-57 m- -OMe (CH ₂ ) ₃ lb- 57 'o-OMe (CH ₂ ) ₃

(CH ₂ ) ₃ lb-58 'o-OMe (CH _{2) 3}

lb-59 m -OMe ° rV ° (CH ₂ ) ₃ lb-59 'o-OMe ° Ύ ⁽

O Me O Me lb-60 m-OMe (CH ₂ ) ₃ lb-60 'o-OMe (CH ₂ ) ₃

lb-61 m-OMe (CH ₂ ) ₃

 o ^ JLo

lb-62 m-OMe (CH ₂ ) ₃ lb-62 'o-OMe

Me V (CH ₂ ) ₃

 Me

 o ^ JLo

lb-63 m-OMe (CH ₂ ) ₃ lb-63 'o-OMe ^e (CH ₂ ) ₃ o ^ JLo

lb-64 m-OMe (CH ₂ ) ₃ lb-64 'o-OMe T (CH ₂ ) ₃

Ph Ph (lb)

 2,

R = CR ⁶ R ⁷ Y = CR ⁶ R ⁷ Y lb-65 m-OMe oJLo (CH ₂ ) ₃ lb-65 'o-OMe (CH ₂ ) ₃

 Ph lb-66 m-OMe. oJLo

MMe (CH ₂ ) ₃ lb-66 'o-OMe -Me ( ^CH 2) 3 Me Me

^{0 0} oJLo lb-67 m-OMe l ^ J (CH ₂ ) ₃ lb-67 'o-OMe T (CH ₂ ) ₃ i-Pr i-Pr lb-68 m-OMe (CH ₂ ) ₃

lb-69 m-OMe (CH ₂ ) ₃

lb-70 m-OMe (CH ₂ ) ₃

lb-71 m-OMe (CH ₂ ) ₃

 〇j

 oJLo

lb-72 m-OMe Ί T (CH ₂ ) ₃ lb-72 'o-OMe (CH ₂ ) ₃

Me ^^ Me

9

R ² 'R ⁶ R ⁷ R ² ' R ⁶ R ⁷ lb-73 m-OMe C0 ₂ Et C0 ₂ Et (CH ₂ ) ₂ lb-73 'O-OMe C0 ₂ Et C0 ₂ Et (CH ₂ ) ₂ lb -74 m-OMe C0 ₂ Me C0 ₂ e (CH ₂ ) ₂ lb-74 'o-OMe C0 ₂ Me C0 ₂ Me (CH ₂ ) ₂ lb-75 m-OMe C0 ₂ i-Bu C0 ₂ t-Bu (CH ₂ ) ₂ lb-75 'o-OMe C0 ₂ t-Bu C0 ₂ f-Bu (CH ₂ ) ₂ lb-76 m-OMe C0 ₂ Bn C0 ₂ Bn (CH ₂ ) ₂ lb-76' o- OMe C0 ₂ Bn C0 ₂ Bn (CH ₂ ) ₂ lb-77 m-OMe CN C0 ₂ Et (CH ₂ ) ₂ lb-77 'o-OMe CN C0 ₂ Et (CH ₂ ) ₂ lb-78 m-OMe CN C0 ₂ Me (CH ₂ ) ₂ lb-78 'o-OMe C C0 ₂ Me (CH ₂ ) ₂ lb-79 m-OMe CN CN (CH ₂ ) ₂ lb-79' o-OMe C CN (CH ₂ ) ₂ lb-80 m-OMe COMe COMe (CH ₂ ) ₂ lb-80 'o-OMe COMe COMe (CH ₂ ) ₂ lb-81 m-OMe COMe COEt CH ₂ lb-81' o-OMe COMe COEt CH ₂ lb -82 m-OMe COMe CO- Bu CH ₂ lb-82 ¹ o-OMe COMe CO- Bu CH ₂ lb-83 m-OMe COMe CO- ^ Bu CH ₂ lb-83 ¹ o-OMe COMe CO-n-Bu CH ₂ lb-84 m-OMe COMe CO-n-Pen CH ₂ lb-84 'o-OMe COMe CO-n-Pen CH ₂ lb-85 m-OMe COMe ° -Q ^CH 2 lb-85' o-OMe COMe ^CH 2

lb-86 m-OMe COEt COEt CH ₂ lb-86 'o-OMe COEt COEt CH ₂ lb-87 m-OMe CO-APr CO- -Pr CH ₂ lb-87' o-OMe CO- Pr CO-APr CH ₂ lb "88 m-OMe COMe CONH- ^ CH ₂ " b " ⁸⁸ 'o-OMe COMe CO H" ^^ ^CH 2

Ten

R ² '/ R ² ' 8 R ⁹ lc-1 m-OMe ^H (CH ₂ ) ₃ lc-ro-OMe H JO (CH ₂ > ₃ lc-2 m-OMe H ( ^ch 2) 3 lc-2 'o-OMe H ( ^CH 2) 3 lc-3 m-OMe H (CH ₂ ) ₃ lc-3' o-OMe H

lc-4 m-OMe lc-4 ¹ o-OMe H

H ^{(CH2) 3 (CH2) 3} lc-5 m-OMe H (CH ₂ ) ₃ lc-6 m-OMe H (CH ₂ ) ₃

lc-7 m-OMe ^{0Me (CH2) 3} lc-7 ¹ o-OMe H

H " ^{0Me (CH2> 3} lc-8 m-OMe H (CH ₂ ) ₃ lc-8 'o-OMe HJ] (CH ₂ ) ₃

 o 0,

lc-9 m-OMe H (CH ₂ ) ₃ lc-9 ¹ o-OMe H (CH ₂ ) ₃ C-10 0 0

m-OMe H, (CH ₂ ) ₃ lc-10 ¹ o-OMe H, pottery ₃

 O p 0 0

tc-11 m-OMe H (CH ₂ ) ₃ lc-11 'o-OMe H (CH ₂ ) ₃

'H ₂ ' NH ₂

 0,

 tc-12 m-OMe 0

 H,

ΝΗ ₂ (CH ₂ ) ₃ lc-12 ¹ o-OMe HH ₂ (CH ₂ ) ₃

Q IC-13 m-OMe HN (Ph) ₂ (CH ₂ ) ₃ lc-13 'o-OMe HN (Ph> ₂ < ^CH 2> 3

 0

 IC-14 m-OMe H,

^ • OMe (CH ₂ ) ₃ lc-14 'o-OMe H OMe ( ^CH 2> 3 C-15 m-OMe H (CH ₂ ) ₃ lc-15 ¹ o-OMe H NH ₂ ( ^CH 2) 3 g

IC-16 m-OMe H (CH ₂ ) ₃ lc-16 'o-OMe H -NHPh ( ^CH 2) 3

R ² 'R ⁸ R ⁹ R ^2, R ⁸

IC-20 m-OMe H ⁰ , i-Bu (CH ₂ ) ₃ lc-20 'o-OMe H ^ ° "f-Bu (CH ₂ ) ₃ r 0, lc-21" o-OMe H * " ^ ⁰ 'Et (CH ₂ ) ₃ IC-21 m-OMe H r>

O oo Et (CH ₂ ) ₃

(CH ₂ ) ₃ lc-22 'o-OMe H

IC-22 m-OMe H ^ ° "Q (CH ₂ ) ₃

(CH ₂ ) ₃ lc-23 'o-OMe H (CH ₂ ) ₃ IC-23 m-OMe H

 Me Me

(CH ₂ ) ₃ lc-24 'o-OMe H (CH ₂ ) ₃ IC-24 m-OMe H

 O O

 Et Et

lc-25 'o-OMe H (CH ₂ ) ₃ lc-25 m-OMe H (CH ₂ ) ₃

 O 0

 Me Me

lc-26 'o-OMe H (CH ₂ ) ₃ lc-26 m-OMe H (CH ₂ ) ₃

_R 2, _R 8 _R 9

 9 lc-38 m-OMe H (CH lc-38 'm-OMe H

O Me ₂ ) ₃

o Me (CH ₂ ) ₃ lc-39 m-OMe H lc-40 m-OMe H lc-41 m-OMe H

 lc-42 m-OMe H lc-43 m-OMe H lc- 4 m-OMe H lc- 5 m-OMe H

 Me

lc-46 m-OMe H ^ N ^-Me (CH ₂ ) ₃ lc-46 'm-OMe H ヽ N no Me (CH ₂ ) ₃

 O O

 Me

IC "47 -O e H r (CH ₂ ) ₃ lc-47 'm-OMe H (CH 2) ₃ e

O O

 Me Me

lc-48 m-OMe HN, (CH ₂ ) ₃ lc-48 'm-OMe H (CH ₂ ) ₃

S ^M e S ^Me

13

lc-62 m-OMe H. j ~, N CH ₂

lc-62 'm-OMe CH ₂ lc-63 m-OMe O e (CH ₂ ) ₂

lc-63 'm-OMe H -OMe (CH ₂ ) ₂ lc-64 m-OMe H 0 ..

^ -OMe (CH ₂ ) ₂

lc-64 'm-OMe H OMe (CH ₂ ) ₂

 O

lc-65 m-OMe H (CH ₂ ) ₂

lc-65 'm-OMe H ( ^CH 2) 2

O (I a-2)

 O-NMR (CDCla) δ ppm: 1.34 (s, 9H), 2.45 (t, 2H, J = 5.7 Hz), 3.71 (s, 3H), 4.19 (d, 2H, J = 5.7), 4.58 (t, 2H, J = 5.7 Hz), 5.66 (br s, IH), 6.26 (ddd, 1H, J = 0.6, 2.4, 8.4 Hz), 6.34 (t, IH, J = 2.4 Hz), 6.60 (ddd, 1H, J = 0.6, 2.4, 8.4 Hz), 6.97 (t, 2H, J = 8.7 Hz), 7.07-7.15 (m, 3H), 7.52, 8.02 (A2B2, 4H, J = 8.4 Hz), 7.71 (br s, IH), 8.29 (s, IH).

 (I a-3)

 ! H-NMR (CDCI3) δ ppm: 1.29 (s, 9H), 3.72 (s, 3H), 4.18 (d, 2H, J = 5.6 Hz), 4.49 (t, 2H, J = 6.2 Hz), 6.30 ( dd, 1H, J = 2.2, 8.0 Hz), 6.40 (t, IH, J = 2.3 Hz), 6.64 (dd, IH, J = 2.1, 8.2 Hz), 7.08-7.33 (m, 5H), 7.59, 7.88 (A2B2, 4H, J = 8.2 Hz), 8.29 (s, 2H)

 (I a-4)

iH-NMR (CDCls) δ ppm: 1.34 (s, 9H), 2.47 (t, 2H, J = 6.0 Hz), 3.71 (s, 3H), 4.29 (d, 2H, J = 6.0 Hz), 4.58 (t , 2H, J = 6.0 Hz), 5.79 (br s, IH), 6.26 (ddd, IH, J = 0.6, 2.4, 8.1 Hz), 6.32 (t, IH, J = 2.4 Hz), 6.59 (ddd, IH , J = 0.6, 2.4, 8.1 Hz), 7.10 (t, IH, J = 8.1 Hz), 7.10-7.27 (m, 4H), 7.52, 8.02 (A2B2, 4H, J = 8.4 Hz), 7.64 (br s , IH), 8.29 (s, IH).

 (I a-5)

 ! H-NMR (CDCls) δ ppm: 1.34 (s, 9H), 2.46 (t, 2H, J = 6.0 Hz), 3.74 (s, 3H), 4.19 (d, 2H, J = 5.7 Hz), 4.58 ( t, 2H, J = 6.0 Hz), 5.60 (br s, IH), 6.24-6.34 (m, 2H), 6.57-6.62 (m, 1H), 7.05-7.18 (m, 3H), 7.24-7.40 (m , 2H), 7.52, 8.03 (A2B2, 4H, J = 8.7 Hz), 7.63 (br s, IH), 8.31 (s, IH).

 (I a-6)

 ! H-NMR (CDCls) δ ppm: 1.34 (s, 9H), 2.46 (t, 2H, J = 6.0 Hz), 3.71 (s, 3H), 4.17 (d, 2H, J = 6.0 Hz), 4.58 ( t, 2H, J = 6.0 Hz), 5.62 (br s, IH), 6.27 (ddd, IH,

J = 0.6, 2.4, 8.4 Hz), 6.34 (t, IH, J = 2.4 Hz), 6.59 (ddd, 1H, J = 0.6, 2.4, 8.4 Hz),

7.02, 7.41 (A2B2, 4H, J = 8.4 Hz) 7.11 (t, IH, J = 8.1 Hz), 7.52, 8.02 (A2B2, 4H, J = 8.7 Hz), 8.30 (s, IH).

 (I a-7)

! H-NMR (CDCh) δ ppm: 1.32 (s, 9H), 2.37 (t, 2H, J = 6.0 Hz), 2.91 (s, 6H), 3.67 (s, 3H), 4.11 (d, 2H, J = 5.7 Hz), 4.53 (t, 2H, J = 6.0 Hz), 5.71 (t, IH, J = 5.7 Hz), 6.23 (ddd, 1H, J = 0.6, 2.4, 8.1 Hz), 6.34 (t, IH , J = 2.4 Hz), 6.56 (ddd, IH, J = 0.6, 2.4, 8.1 Hz), 6.64, 7.02 (A ₂ B ₂₎ 4H, J = 8.7 Hz), 7.05 (t, 1H, J = 8.1 Hz) ), 7.48, 7.98 (A2B2, 4H, J = 8.4 Hz), 8.26 (s, IH).

 (I a-8)

 ! H-NMR (CDCI3) δ ppm: 1.34 (s, 9H), 2.52 (t, 2H, J = 6.0 Hz), 3.71 (s, 3H), 4.29 (d, 2H, J = 6.0 Hz), 4.60 ( t, 2H, J = 6.0 Hz), 5.77 (t, IH, J = 6.0 Hz), 6.30 (dd, IH, J = 2.4, 8.4 Hz), 6.35 (t, IH, J = 2.4 Hz), 6.59 ( dd, IH, J = 2.4, 8.4 Hz), 7.12 (t, IH, J = 8.1 Hz), 7.29, 8.14 (A2B2, 4H, J = 8.4 Hz), 7.52, 8.03 (A2B2, 4H, J = 8.4 Hz ), 7.63 (br s, IH), 8.32 (s, IH).

 (I a-9)

! H-NMR (CDCI3) δ ppm: 1.34 (s, 9H), 2.39 (t, 2H, J = 6.0 Hz), 3.72 (s, 3H), 4.12 (d, 2H, J = 5.7 Hz), 4.56 ( t, 2H, J = 6.0 Hz), 5.57 (br s, IH), 6.23 (dd, IH, J = 2.4, 8.1 Hz), 6.33 (t, IH, J = 2.4 Hz), 6.59 (dd, IH, J = 2.4, 8.1 Hz), 6.60, 6.94 (A ₂ B ₂₎ 4H, J = 8.4 Hz), 7.09 (t, IH, J = 8.4 Hz), 7.50, 8.01 (A2B2, 4H, J = 8.4 Hz) , 8.27 (s, IH).

 (I a-10)

 ! H-NMR (CDCh) δ ppm: 1.33 (s, 9H), 2.48 (t, 2H, J = 5.4 Hz), 3.69 (s, 3H), 4.12 (d, 2H, J = 6.0 Hz), 4.56 ( t, 2H, J = 5.4 Hz), 5.98 (br s, IH), 6.28 (ddd, IH, J = 0.6, 2.4, 8.4 Hz), 6.34 (t, IH, J = 2.4 Hz), 6.62 (ddd, IH, J = 0.6, 2.4, 8.4 Hz), 6.96 (t, 2H, J = 8.7 Hz), 7.12 (t, IH, J = 8.1 Hz), 7.16 (dd, 2H, J = 5.4, 8.7 Hz), 7.51, 8.01 (A2B2, 4H, J = 8.4 Hz), 7.69 (br s, IH), 8.29 (s, IH).

 (I a-1 1)

! H-NMR (CDCI3) δ ppm: 1.29 (s, 9H), 3.72 (s, 3H), 4.17 (d, 2H, J = 5.5 Hz), 4.51 (t, 2H, J = 5.7 Hz), 6.30 (dd, IH, J = 2.2, 8.1 Hz), 6.39 (t, IH, J = 2.2 Hz), 6.64 (dd, 1H, J = 2.2, 8.2 Hz) ), 7.14-7.26 (m, 3H), 7.41 (dd, 1H, J = 2.3, 8.9 Hz), 7.59, 7.90 (A2B2, 4H, J = 8.4 Hz), 8.30 (s, IH), 8.34 (t, (IH, J = 6.0 Hz)

 (I a-1 2)

! H-NMR (CDCls) (5 ppm: 1.29 (s, 9H), 3.72 (s, 3H), 4.15 (d, 2H, J = 5.3 Hz),

4.49 (t, 2H, J = 6.0 Hz), 6.29 (dd, 1H, J = 2.1, 8.2 Hz), 6.39 (t, IH, J = 2.3 Hz),

6.63 (dd, 1H, J = 2.3, 8.6 Hz), 7.17 (t, IH, J = 8.0 Hz), 7.24 (s, 2H), 7.37 (d, 1H, J = 10.8 Hz), 7.59, 7.89 (A2B2 , 4H, J = 8.5 Hz), 8.29 (s, IH), 8.32 (t, 1H, J = 6.0 Hz)

 (I a-13)

 ! H-NMR (CDCls) δ ppm: 1.34 (s, 9H), 2.39 (t, 2H, J = 6.0 Hz), 3.74 (s, 3H), 3.76 (s, 3H), 3.80 (s, 3H), 4.21 (d, 2H, J = 5.7 Hz), 4.55 (t, 2H, J = 6.0 Hz), 5.78 (br s, 1H), 6.27 (ddd, IH, J = 0.6, 2.4, 8.4 Hz), 6.34 ( t, 1H, J = 2.4 Hz), 6.39-6.43 (m, 2H), 6.60 (ddd, 1H, J = 0.6, 2.4, 8.4 Hz), 7.06-7.10 (m, IH), 7.10 (t, IH, J = 8.1 Hz), 7.52, 8.02 (A2B2, 4H, J = 8.7 Hz), 8.28 (s, IH).

 (I a-14)

 O-NMR (CDCls) δ ppm: 1.29 (s, 9H), 3.72 (s, 3H), 4.13 (d, 2H, J = 6.2 Hz),

4.50 (t, 2H, J = 5.8 Hz), 6.29 (dd, 1H, J = 2.1, 7.7 Hz), 6.39 (t, IH, J = 2.3 Hz),

6.64 (dd, IH, J = 2.3, 8.3 Hz), 7.13-7.21 (m, 2H), 7.31-7.40 (m, 2H), 7.59, 7.89 (A2B2, 4H, J = 8.4 Hz), 8.29 (s, IH), 8.32 (t, IH, J = 6.0 Hz)

 (I a-15)

 ! H-NMR (CDCls) δ ppm: 1.34 (s, 9H), 2.43 (t, 2H, J = 6.0 Hz), 3.72 (s, 3H), 4.13 (d, 2H, J = 5.78 Hz), 4.56 ( t, 2H, J = 6.0 Hz), 5.66 (t, IH, J = 5.7 Hz), 5.93 (s, 2H), 6.27 (ddd, 1H, J = 0.6, 2.4, 8.4 Hz), 6.34 (t, IH , J = 2.4 Hz), 6.58-6.65 (m, 3H), 6.71 (d, IH, J = 7.5 Hz), 7.11 (t, 1H, J = 8.4 Hz), 7.51, 8.01 (A2B2, 4H, J = 8.7 Hz), 7.79 (br s, IH), 8.28 (s, IH).

(I a-16) Ή-NMR (CDCla) 6 ppm: 1.35 (d, 3H, J = 6.9 Hz), 1.34 (s, 9H), 2.41 (t, 2H, J = 6.0 Hz), 3.72 (s, 3H), 4.50-4.63 (m, 2H), 5.00 (quintet, 1H, J = 7.2 Hz), 5.92 (br d, IH, J = 7.8 Hz), 6.26 (ddd, 1H, J = 0.6, 2.4, 8.1 Hz), 6.34 (t , 1H, J = 2.4 Hz), 6.62 (ddd, 1H, J = 0.6, 2.4, 8.1 Hz), 7.10 (t, IH, J = 8.1 Hz), 7.18-7.32 (m, 5H), 7.51, 8.01 ( A2B2, 4H, J = 8.4 Hz), 7.72 (br s, IH), 8.28 (s, IH).

 (I a-1 7)

 ! H-NMR (CDCla) δ ppm: 1.35 (d, 3H, J = 6.9 Hz), 1.34 (s, 9H), 2.41 (t, 2H, J = 6.0 Hz), 3.72 (s, 3H), 4.50- 4.63 (m, 2H), 5.00 (quintet, 1H, J = 7.2 Hz), 5.92 (br d, IH, J = 7.8 Hz), 6.26 (ddd, 1H, J = 0.6, 2.4, 8.1 Hz), 6.34 ( t, IH, J = 2.4 Hz), 6.62 (ddd, 1H, J = 0.6, 2.4, 8.1 Hz), 7.10 (t, IH, J = 8.1 Hz), 7.18-7.32 (m, 5H), 7.51, 8.01 (A2B2, 4H, J = 8.4 Hz), 7.72 (br s, 1H), 8.28 (s, IH).

 (I a-18)

 ! H-NMR (CDCI3) δ ppm: 1.35 (d, 3H, J = 6.9 Hz), 1.34 (s, 9H), 2.41 (t, 2H, J = 6.0 Hz), 3.72 (s, 3H), 4.50- 4.63 (m, 2H), 5.00 (quintet, IH, J = 7.2 Hz), 5.92 (br d, IH, J = 7.8 Hz), 6.26 (ddd, IH, J = 0.6, 2.4, 8.1 Hz), 6.34 ( t, IH, J = 2.4 Hz), 6.62 (ddd, 1H, J = 0.6, 2.4, 8.1 Hz), 7.10 (t, IH, J = 8.1 Hz), 7.18-7.32 (m, 5H), 7.51, 8.01 (A2B2, 4H, J = 8.4 Hz), 7.72 (br s, 1H), 8.28 (s, IH).

 (I a-19)

^J H-NMR (CDC) δ ppm: 1.34 (s, 9H), 2.50 (t, 2H, J = 6.0 Hz), 3.70 (s, 3H), 4.60 (t, 2H, J = 6.0 Hz), 6.08 ( d, IH, J = 8.1 Hz), 6.16 (d, IH, J = 8.1 Hz), 6.21 (dd, IH, J = 2.1, 8.1 Hz), 6.30 (t, IH, J = 2.4 Hz), 6.59 ( dd, 1H, J = 2.1, 8.1 Hz), 7.06 (t, 1H, J = 8.1 Hz), 7.09-7.14 (m, 4H), 7.20-7.32 (m, 8H), 7.52, 8.03 (A2B2, 4H, J = 8.7 Hz), 8.27 (s, IH).

 (I a-20)

Ή-NMR (CDCh) δ ppm: 1.33 (s, 9H), 2.47 (t, 2H, J = 5.7 Hz), 3.54 (s, 3H), 4.61 (t, 2H, J = 5.7 Hz), 5.72 (br d, IH, J = 6.0 Hz), 6.00 (ddd, IH, J = 0.9, 1.5,

8.1 Hz), 6.09 (d, IH, J = 6.0 Hz), 6.11 (t, IH, J = 2.4 Hz), 6.41 (ddd, IH, J = 0.9, 1.5, 8.1 Hz), 6.85 (t, 2H, J = 8.1 Hz), 7.16-7.23 (m, 2H), 7.32-7.38 (m, 4H), 7.51, 8.01 (A2B2, 4H, J = 8.4 Hz), 7.64-7.68 (m, 2H), 8.26 (s, IH).

 (I a-2 1)

 ! H-NMR (CDC) δ ppm: 1.33 (s, 9H), 2.36 (t, 2H, J = 6.0 Hz), 2.87-3.01 (m, 2H), 3.67 (s, 3H), 4.35-4.51 (m , 2H), 5.16 (dt, IH, J = 7.5, 7.5 Hz), 5.93 (br d, 1H, J = 7.5 Hz), 6.26 (dd, IH, J = 2.1, 8.1 Hz), 6.35 (t, 2H , J = 2.7 Hz), 6.57 (dd, IH, J = 2.1, 8.1 Hz), 6.91-6.96 (m, 2H), 7.05-7.14 (m, 6H), 7.18-7.27 (m, 4H), 7.50, 8.01 (A2B2, 4H, J = 8.7 Hz), 8.26 (s, IH).

 (I a-2 2)

! H-NMR (CDCI3) δ ppm: 1.34 (s, 9H), 2.45-2.52 (m, 2H), 3.71 (s, 3H), 3.75 (s, 3H), 4.50-4.60 (m, 2H), 5.44 (d, IH, J = 6.9 Hz), 6.26 (dd, IH, J = 2.4, 8.1 Hz), 6.36 (t, IH, J = 2.4 Hz), 6.53 (br d, IH, J = 6.6 Hz), 6.62 (dd, IH, J = 2.4, 8.14 Hz), 7.10 (t, IH, J = 8.1 Hz), 7.24-7.33 (m, 5H), 7.51, 8.02 (A2B2, 4H, J = 8.4 Hz), 7.58 (br s, IH), 8.27 (s, IH).

 (I a-2 3)

 ! H-NMR (CDCh) δ ppm: 1.34 (s, 9H), 2.45-2.52 (m, 2H), 3.71 (s, 3H), 3.75 (s, 3H), 4.50-4.60 (m, 2H), 5.44 (d, IH, J = 6.9 Hz), 6.26 (dd, IH, J = 2.4, 8.1 Hz), 6.36 (t, IH, J = 2.4 Hz), 6.53 (br d, IH, J = 6.6 Hz), 6.62 (dd, IH, J = 2.4, 8.1 Hz), 7.10 (t, 1H, J = 8.1 Hz), 7.24-7.33 (m, 5H), 7.51, 8.02 (A2B2, 4H, J = 8.4 Hz), 7.58 (br s, IH), 8.27 (s, IH).

 (I a— 2 4)

 ! H-NMR (CD3OD) δ ppm: 1.33 (s, 9H), 2.54 (t, 2H, J = 6.0 Hz), 3.71 (s, 3H), 4.46-4.58 (m, 2H), 5.26 (s, 1H ), 6.25 (dd, IH, J = 2.4, 8.1 Hz), 6.38 (t, IH, J = 2.4 Hz), 6.60 (dd, IH, J = 2.4, 8.1 Hz), 7.08 (t, IH, J = 8.1 Hz), 7.21-7.36 (m, 5H), 7.56, 7.95 (A2B2, 4H, J = 8.4 Hz), 8.17 (s, IH).

 (I a-25)

! H-NMR (CD3OD) δ ppm: 1.33 (s, 9H), 2.54 (t, 2H, J = 6.0 Hz), 3.71 (s, 3H), 4.46-4.58 (m, 2H), 5.26 (s, IH), 6.25 (dd, IH, J = 2.4, 8.1 Hz), 6.38 (t, IH, J = 2.4 Hz), 6.60 (dd, IH , J = 2.4, 8.1 Hz), 7.08 (t, IH, J = 8.1 Hz), 7.21-7.36 (m, 5H), 7.56, 7.95 (A2B2, 4H, J = 8.4 Hz), 8.17 (s, IH) .

 (I a-2 6)

Ή-NMR (CDCI3) (5 ppm: 1.33 (s, 9H), 2.44-2.48 (m, 2H), 3.73 (s, 3H), 4.45- 4.60 (m, 2H), 5.37 (d, 1H, J = 6.6 Hz), 5.71 (br s, IH), 5.90 (br s, IH), 6.26 (dd, IH, J = 2.1, 8.1 Hz), 6.35 (t, 1H, J = 2.1 Hz), 6.59 (dd, IH, J = 2.1, 8.1 Hz), 6.94 (d, 1H, J = 6.3 Hz), 7.08 (t, IH, J = 8.1 Hz), 7.28 (s, 5H), 7.50, 8.00 (A2B2, 4H, J = 8.4 Hz), 8.25 (s, IH).

 (I a-2 7)

 O-NMR (CDCI3) δ ppm: 1.34 (s, 9H), 2.49 (t, 2H, J = 6.0 Hz), 3.74 (s, 3H), 4.52-4.62 (m, 2H), 4.93 (dt, IH, J = 4.8, 6.9 Hz), 6.24 (br d, IH, J = 6.9 Hz), 6.29 (dd, IH, J = 2.4, 8.4 Hz), 6.37 (t, IH, J = 2.4 Hz), 6.62 (dd , 1H, J = 2.4, 8.4 Hz), 7.12 (t, IH, J = 8.1 Hz), 7.17-7.21 (m, 2H), 7.27-7.34 (m, 3H), 7.51, 8.01 (A2B2, 4H, J = 8.4 Hz), 8.28 (s, IH).

 (I a-2 8)

 ! H-NMR (CDCb) δ ppm: 1.33 (d, 3H, J = 6.0 Hz), 1.34 (s, 9H), 2.42 (t, 2H, J = 6.0 Hz), 3.74 (s, 3H), 4.50- 4.63 (m, 2H), 4.97 (quintet, IH, J = 7.2 Hz), 5.69 (br d, 1H, J = 7.2 Hz), 6.28 (ddd, IH, J = 0.6, 2.4, 8.4 Hz), 6.34 ( t, IH, J = 2.4 Hz), 6.62 (ddd, IH, J = 0.6, 2.4, 8.4 Hz), 6.96 (t, 2H, J = 8.7 Hz), 7.12 (t, IH, J = 8.1 Hz), 7.16 (dd, 2H, J = 5.4, 8.7 Hz), 7.51, 8.01 (A2B2, 4H, J = 8.4 Hz), 7.69 (br s, IH), 8.29 (s, IH).

 (I a-2 9)

 Ή-NMR (CDCb) δ ppm: 1.34 (s, 9H), 1.36 (d, 3H, J = 7.2 Hz), 2.47 (t, 2H, J = 6.0 Hz), 3.75 (s, 3H), 4.49-4.66 (m, 2H), 5.01 (quintet, IH, J = 7.2 Hz), 5.77 (br d, 1H, J = 5.4 Hz), 6.32 (dd, IH, J = 2.4, 8.4 Hz), 6.36 (t, IH , J = 2.4 Hz), 6.64 (dd,

IH, J = 2.4, 8.4 Hz), 7.16 (t, IH, J = 8.4 Hz), 7.34, 8.14 (A2B2, 4H, J = 8.4 Hz), 7.52, 8.03 (A2B2, 4H, J = 8.4 Hz), 8.31 (s, IH).

 (I a-30)

 ! H-NMR (CDCls) δ ppm: 1.34 (s, 9H), 1.36 (d, 3H, J = 7.2 Hz), 2.47 (t, 2H, J = 6.0 Hz), 3.75 (s, 3H), 4.49- 4.66 (m, 2H), 5.01 (quintet, IH, J = 7.2 Hz), 5.77 (br d, IH, J = 5.4 Hz), 6.32 (dd, IH, J = 2.4, 8.4 Hz), 6.36 (t, IH, J = 2.4 Hz), 6.64 (dd, IH, J = 2.4, 8.4 Hz), 7.16 (t, 1H, J = 8.4 Hz), 7.34, 8.14 (A2B2, 4H, J = 8.4 Hz), 7.52, 8.03 (A2B2, 4H, J = 8.4 Hz), 8.31 (s, IH).

 (I a-3 1)

! H-NMR (CDCls) δ ppm: 1.29 (d, 3H, J = 6.9 Hz), 1.32 (s, 9H), 2.35 (t, 2H, J = 6.0 Hz), 3.68 (s, 3H), 4.52 ( t, 2H, J = 6.0 Hz), 4.88 (quintet, IH, J = 6.9 Hz), 5.23 (br s, 2H), 5.79 (br d, IH, J = 8.1 Hz), 6.21 (dd, 1H, J = 1.8, 8.1 Hz), 6.32 (t, IH, J = 1.8 Hz), 6.54-6.61 (m, 1H), 6.58, 6.97 (A 2 B 2) 4H, J = 8.4 Hz), 7.05 (t, 1H , J = 8.1 Hz), 7.48, 7.98 (A2B2, 4H, J = 8.4 Hz), 8.24 (s, IH).

 (I a-3 2)

_{! H-NMR (CDC1 3)} δ ppm: 1.29 (d, 3H, J = 6.9 Hz), 1.32 (s, 9H), 2.35 (t, 2H, J = 6.0 Hz), 3.68 (s, 3H), 4.52 (t, 2H, J = 6.0 Hz), 4.88 (quintet, IH, J = 6.9 Hz), 5.23 (br s, 2H), 5.79 (br d, IH, J = 8.1 Hz), 6.21 (dd, 1H, J = 1.8, 8.1 Hz), 6.32 (t, IH, J = 1.8 Hz), 6.54-6.61 (m, IH), 6.58, 6.97 (A2B2, 4H, J = 8.4 Hz), 7.05 (t, 1H, J = 8.1 Hz), 7.48, 7.98 (A2B2, 4H, J = 8.4 Hz), 8.24 (s, IH).

 (I a-3 3)

 ! H-NMR (CDCls) δ ppm: 1.34 (s, 9H), 1.53 (d, 3H, J = 6.3 Hz), 2.27-2.43 (m, 2H), 3.66 (s, 3H), 4.49 (t, 2H , J = 5.7 Hz), 5.76-5.83 (m, 2H), 6.06 (dd, IH, J = 1.8, 8.1 Hz), 6.15 (t, 1H, J = 2.4 Hz), 6.53 (dd, IH, J = 1.8, 8.1 Hz), 6.99 (t, IH, J = 8.1 Hz), 7.27-7.40 (m, 2H), 7.43 (d, 2H, J = 8.1 Hz), 7.52, 8.03 (A2B2, 4H, J = 8.7 Hz), 7.70-7.78 (m, 2H), 7.92 (d, 1H, J = 8.4 Hz), 8.22 (s, IH).

 (I a-3 4)

! H-NMR (CDCI3) δ ppm: 1.34 (s, 9H), 1.53 (d, 3H, J = 6.3 Hz), 2.27-2.43 (m, 2H), 3.66 (s, 3H), 4.49 (t, 2H, J = 5.7 Hz), 5.76-5.83 (m, 2H), 6.06 (dd, IH, J = 1.8, 8.1 Hz), 6.15 (t, IH , J = 2.4 Hz), 6.53 (dd, IH, J = 1.8, 8.1 Hz), 6.99 (t, IH, J = 8.1 Hz), 7.27-7.40 (m, 2H), 7.43 (d, 2H, J = 8.1 Hz), 7.52, 8.03 (A ₂ B ₂₎ 4H, J = 8.7 Hz), 7.70-7.78 (m, 2H), 7.92 (d, IH, J = 8.4 Hz), 8.22 (s, IH).

 (I a-3 5)

 Ή-NMR (CDCb) δ ppm: 1.34 (s, 9H), 1.55 (s, 3H), 1.58 (s, 3H), 2.40 (t, 2H, J = 6.0 Hz), 3.74 (s, 3H), 4.55 (t, 1H, J = 6.6 Hz), 5.70 (br s, IH), 6.32 (dd, IH, J = 2.4, 8.4 Hz), 6.37 (t, IH, J = 2.4 Hz), 6.63 (dd, IH , J = 2.4, 8.4 Hz), 7.14 (t, 1H, J = 8.4 Hz), 7.27-7.29 (m, 5H), 7.52, 8.03 (A2B2, 4H, J = 8.4 Hz), 8.30 (s, IH) (I a-3 6)

 ! H-NMR (CDCla) δ ppm: 1.22 (s, 6H), 1.34 (s, 9H), 2.34 (t, 2H, J = 6.0 Hz), 2.93 (s, 2H), 3.73 (s, 3H), 4.52 (t, 2H, J = 6.0 Hz), 5.08 (br s, IH), 6.26 (ddd, 1H, J = 0.9, 2.4, 8.4 Hz), 6.33 (t, IH, J = 2.4 Hz), 6.59 ( ddd, 1H, J = 0.9, 2.4, 8.4 Hz), 7.01-7.19 (m, 6H), 7.51, 8.02 (A2B2, 4H, J = 8.7 Hz), 7.63 (br s, IH), 8.30 (s, IH ). (I a-3 7)

 ! H-NMR (CDCI3) δ ppm: 1.22 (s, 9H), 1.34 (s, 9H), 2.33 (t, 2H, J = 6.0 Hz), 3.76 (s, 3H), 4.54 (t, 2H, J = 6.0 Hz), 5.27 (br s, IH), 6.31 (ddd, IH, J = 0.6, 2.4, 8.4 Hz), 6.37 (t, IH, J = 2.4 Hz), 6.62 (ddd, IH, J = 0.6 , 2.4, 8.4 Hz), 7.15 (t, 1H, J = 8.1 Hz), 7.51, 8.01 (A2B2, 4H, J = 8.7 Hz), 8.30 (s, IH).

 (I a-3 8)

^J H-NMR (CDCb) (5 ppm: 1.34 (s, 9H), 1.60-1.70 (m, 6H), 1.82 (d, 6H, J = 2.7 Hz), 2.01 (br s, 3H), 2.33 (t , 2H, J = 6.0 Hz), 3.77 (s, 3H), 4.53 (t, 2H, J = 6.0 Hz), 5.10 (br s, IH), 6.32 (ddd, IH, J = 0.6, 2.4, 8.1 Hz ), 6.39 (t, IH, J = 2.4 Hz), 6.63 (ddd, IH, J2 0.6, 2.4, 8.1 Hz), 7.16 (t, IH, J = 8.1 Hz), 7.51, 8.01 (A2B2, 4H, J = 8.4 Hz), 7.61 (br s, 1H), 8.30 (s, IH).

 (I a-3 9)

! H-NMR (CDCI3) δ ppm: 1.34 (s, 9H), 1.39 (s, 6H), 2.41 (t, 2H, J = 6.0 Hz), 3.67 (s, 3H), 3.74 (s, 3H), 4.53 (t, 2H, J = 6.0 Hz), 6.16 (br s, IH), 6.29 (dd, IH, J = 2.4, 8.4 Hz), 6.37 ( t, IH, J = 2.4 Hz), 6.59 (dd, 1H, J = 2.4, 8.4 Hz), 7.1 1 (t, 1H, J = 8.1 Hz), 7.49, 7.99 (A ₂ B _2> 4H, J = 8.4 Hz), 8.29 (s, IH).

 (I a-4 2)

! H-NMR (CDCls) δ ppm: 0.73- 1.80 (m, 11H), 1.34 (s, 9H), 2.41 (t, 2H, J = 6.0 Hz), 2.89 (t, 2H, J = 6.3 Hz) , 3.78 (s, 3H), 4.55 (m, 2H), 5.38 (br s, 1H), 6.32 (dd, 1H, J = 2.4, 8.1 Hz), 6.38 (t, 1H, J = 2.4 Hz), 6.34 (dd, IH, J = 2.4, 8.1 Hz), 7.17 (t, IH, J = 8.1 Hz), 7.51, 8.02 (A2B2, 4H, J = 8.4 Hz), 7.66 (br s, IH), 8.30 (s, IH). (I a-4 3)

iH-NMR (CDCls) δ ppm: 0.91 -0.98 (m, IH), 1.08-1.16 (m, 1H), 1.33 (s, 9H), 1.81-1.88 (m, 1H), 2.37 (t, 2H, J = 6.0 Hz), 2.63-2.69 (m, IH), 3.68 (s, 3H), 4.54 (t, 1H, J = 6.0 Hz), 5.75 (br s, IH), 6.30 (dd, IH, J = 2.4 , 8.1 Hz), 6.37 (t, 1H, J = 2.4 Hz), 6.55 (dd, IH, J = 2.4, 8.1 Hz), 7.06-7.27 (m, 6H), 7.49, 8.00 (A2B2, 4H, J = 8.4 Hz), 7.91 (br s, IH), 8.28 (s, IH).

 (I a-4 4)

 ! H-NMR (CDCls) δ ppm: 1.32 (s, 9H), 2.53 (t, 2H, J = 6.0 Hz), 3.66 (s, 3H), 3.61 -3.92 (m, 2H), 4.56 (t, 2H , J = 6.0 Hz), 5.62 (dd, IH, J = 3.6, 9.6 Hz), 6.28 (dd, 1H, J = 2.4, 8.4 Hz), 6.38 (t, IH, J = 2.4 Hz), 6.57 (dd , 1H, J = 2.4, 8.4 Hz), 6.95-7.00 (m, IH), 7.09 (t, IH, J = 8.4 Hz), 7.13- 7.21 (m, IH), 7.40- 7.52 (m, 3H), 7.49, 8.01 (A2B2, 4H, J = 8.4 Hz), 7.65 (br s, 1H), 7.66-7.87 (m, 2H), 8.28 (s, IH). (Ia-46)

 ! H-NMR (CDCls) <3 ppm: 1.34 (s, 9H), 1.97 (s, 3H), 1.98 (s, 6H), 2.57 (t, 2H, J = 6.0 Hz), 3.64 (s, 3H) , 3.67 (s, 3H), 4.64 (t, 2H, J = 6.0 Hz), 6.22 -6.34 (m, 2H), 6.52 (dd, IH, J = 1.8, 8.4 Hz), 7.07 (t, IH, J = 8.1 Hz), 7.52, 8.03 (A2B2, 4H, J = 8.7 Hz), 7.75 (br s, IH), 8.33 (s, IH).

 (I a-4 8)

! H-NMR (CDCI3) δ ppm: 1.16 (d, 6H, J = 6.9 Hz), 1.34 (s, 9H), 2.64 (t, 2H, J = 6.0 Hz), 2.82-2.91 (m, IH), 3.62 (s, 3H), 4.67 (t, 2H, J = 6.0), 6.27-6.34 (m, 2H), 6.49-6.52 (m, IH), 6.87 (br s, IH), 7.05 (t, IH, J = 8.4 Hz), 7.13-7.22 (m, 2H), 7.36-7.40 (m, IH), 7.52, 8.02 (A2B2, 4H, J = 8.4 Hz ), 8.33 (s, IH).

 (I a-4 9)

 ! H-NMR (CDCla) (5 ppm: 1.34 (s, 9H), 2.55 (t, 2H, J = 5.7 Hz), 3.67 (s, 3H), 4.58 (t, 2H, J = 5.7 Hz), 6.32 -6.38 (m, 2H), 6.50-6.54 (m, IH), 7.10 (t, IH, J = 8.1 Hz), 7.51, 8.03 (A2B2, 4H, J = 8.4 Hz), 7.61 (d, 2H, J = 5.7 Hz), 8.29 (s, IH), 8.34 (brs, IH), 8.76 (brs, IH), 9.03 (brs, IH).

 (I a-5 0)

 ! H-NMR (CDCI3) (5 ppm: 1.33 (s, 9H), 2.50 (t, 2H, J = 6.0 Hz), 3.69 (s, 3H), 4.55 (t, 2H, J = 6.0 Hz), 6.32 -6.39 (m, 2H), 6.55 (dd, IH, J = 2.1, 8.1 Hz), 7.07 (dd, 1H, J = 3.6, 4.8 Hz), 7.12 (t, IH, J = 8.1 Hz), 7.48- 7.54 (m, IH), 7.51, 8.03 (A2B2, 4H, J = 8.4 Hz), 7.83 (br s, IH), 8.27 (s, IH), 8.37 (br s, IH), 8.74 (br s, IH ).

(I a-5 1)

 ! H-NMR (CDCb) δ ppm: 1.34 (s, 9H), 2.46 (t, 2H, J = 5.7 Hz), 3.71 (s, 3H), 3.78 (s, 3H), 4.55 (t, 2H, J = 5.7 Hz), 6.35-6.46 (m, 3H), 6.63-6.68 (m, IH), 6.99 (br s, IH), 7.18 (t, IH, J = 8.4 Hz), 7.52, 8.03 (A2B2, 4H , J = 8.7 Hz), 7.77 (br s, 1H), 8.30 (s, IH).

 (I a-54)

¹ H-NMR (CDCI3) δ ppm: 1.34 (s, 9H), 2.50 (t, 2H, J = 5.7 Hz), 3.67 (s, 3H), 4.25 (d, 2H, J = 6.0 Hz), 4.58 ( t, 2H, J = 5.7 Hz), 5.79 (t, IH, J = 6.0 Hz), 6.24-6.33 (m, 2H), 6.54-6.59 (m, 1H), 7.10 (t, 2H, J = 8.1 Hz) ), 7.51, 8.02 (A2B2, 4H, J = 9.0 Hz), 7.76 (br s, IH), 8.31 (s, IH).

 (I a-55)

 O-NMR (CDCls) δ ppm: 1.34 (s, 9H), 2.49 (t, 2H, J = 5.7 Hz), 3.69 (s, 3H),

4.21 (d, 2H, J = 6.3 Hz), 4.57 (t, 2H, J = 5.7 Hz), 5.78 (t, 1H, J = 6.0 Hz), 6.27 (dd,

IH, J = 2.4, 8.1 Hz), 6.32 (t, IH, J = 2.4 Hz), 6.57 (dd, IH, J = 2.4, 8.1 Hz), 7.04 (br d, IH, J = 9.3 Hz), 7.10 (t, IH, J = 8.1 Hz), 7.17-7.22 (m, 2H), 7.51, 8.01 (A2B2, 4H, J = 8.4 Hz), 8.30 (s, IH).

 (I a-5 6)

 ! H-NMR (CDCh) (5 ppm: 1.33 (s, 9H), 2.45-2.50 (m, 2H), 3.70 (s, 3H), 4.49- 4.63 (m, 2H), 5.97 (d, IH, J = 8.1 Hz), 6.20 (dd, IH, J = 2.4, 8.4 Hz), 6.28 (t, 1H, J = 2.4 Hz), 6.29 (d, 1H, J = 8.1 Hz), 6.57 (dd, IH, J = 2.4, 8.4 Hz), 7.50, 8.00 (A2B2, 4H, J = 8.4 Hz), 7.60-7.90 (br s, IH), 8.24 (s, IH).

 (I a-5 7)

 ! H-NMR (CDCls) δ ppm: 1.34 (s, 9H), 2.46 (t, 2H, J = 6.0 Hz), 3.69 (s, 3H), 4.20 (d, 2H, J = 6.0 Hz), 4.57 ( t, IH, J = 6.0 Hz), 5.74 (br s, 1H), 6.25 (dd, IH, J = 2.4, 8.1 Hz), 6.33 (t, 1H, J = 2.4 Hz), 6.57 (dd, 1H, J = 2.4, 8.1 Hz), 6.84 (br d, IH, J = 9.6 Hz), 6.90-6.96 (m, 2H), 7.09 (t, 1H, J = 8.4 Hz), 7.20-7.28 (m, IH), 7.50, 8.01 (A2B2, 4H, J = 8.4 Hz), 7.60-7.90 (br s, IH), 8.29 (s, IH).

 (I a-65)

O-NMR (CDCh) δ ppm: 1.34 (s, 9H), 2.48 (t, 2H, J = 5.7 Hz), 3.68 (s, 3H), 4.22 (d, 2H, J = 6.3 Hz), 4.57 (t , IH, J = 5.7 Hz), 5.81 (t, IH, J = 6.0 Hz), 6.27 (ddd, 1H, J = 0.6, 2.4, 8.4 Hz), 6.31 (t, 1H, J = 2.4 Hz), 6.55 (ddd, IH, J = 0.6, 2.4, 8.4 Hz), 7.08 (t, 1H, J = 8.4 Hz), 7.10- 7.17 (m, 2H), 7.24 (d, IH, J = 8.4 Hz), 7.51, 8.01 (A2B2, 4H, J = 8.7 Hz), 8.29 (s, IH).

 (I a-6 6)

 O-NMR (CDCls) (5 ppm: 1.34 (s, 9H), 2.48 (t, 2H, J = 6.0 Hz), 3.71 (s, 3H), 4.16 (d, 2H, J = 6.0 Hz), 4.58 ( t, IH, J = 6.0 Hz), 5.73 (br s, 1H), 6.28 (ddd, IH, J = 0.6, 2.4, 8.4 Hz), 6.34 (t, IH, J = 2.4 Hz), 6.58 (ddd, IH, J = 0.6, 2.4, 8.4 Hz), 6.63-6.71 (m, 3H), 7.11 (t, 1H, J = 8.4 Hz), 7.51, 8.02 (A2B2, 4H, J = 8.7 Hz), 8.30 (s , IH).

 (I a-6 7)

Ή-NMR (CDCI3) δ pp m: 0.79 (t, 3H, J = 7.5 Hz), 1.34 (s, 9H), 1.67 (quintet, 2H, J = 7.5 Hz), 2.42 (t, 2H, J = 6.0 Hz), 3.73 (s, 3H), 4.48-4.62 (m, 2H), 4.76 (q, IH, J = 7.5 Hz), 5.76 ( d, IH, J = 8.4 Hz), 6.27 (dd, 1H, J = 2.4, 8.4 Hz), 6.35 (t, 1H, J = 2.4 Hz), 6.61 (dd, 1H, J = 2.4, 8.4 Hz), 7.11 (t, IH, J = 8.4 Hz), 7.14-7.31 (m, 5H), 7.51, 8.01 (A2B2, 4H, J = 8.4 Hz), 7.74 (br s, 1H), 8.28 (s, IH).

 (I a-7 2)

 Ή-NMR (CDCls) δ ppm: 1.32 (s, 9H), 2.66 (t, 2H, J = 6.1 Hz), 3.96 (s, 3H), 4.70 (t, 2H, J = 6.0 Hz), 6.22-6.25 (m, 2H), 6.70-6.79 (m, 1H), 6.94-7.28 (m, 13H), 7.48, 7.97 (A2B2, 4H, J = 8.8 Hz), 8.19 (s, IH), 8.97 (br s, IH)

 (I a-7 3)

 Ή-NMR (CDCI3) <5 ppm: 1.32 (s, 9H), 1.63 (s, 6H), 2.55 (t, 2H, J = 5.9 Hz), 3.99 (s, 3H), 4.65 (t, IH, J = 5.9 Hz), 5.85 (br s, 1H), 6.78-6.87 (m, 1H), 6.96-7.34 (m, 8H), 7.47, 7.96 (A2B2, 4H, J = 8.7 Hz), 8.22 (s, 1H ), 8.95 (br s, IH)

 (I a-7 4)

 O-NMR (CDCI3) (5 ppm: 1.32 (s, 9H), 1.58 (d, 3H, J = 6.4 Hz), 2.54 (t, 2H, J = 6.0 Hz), 3.94 (s, 3H), 4.63 ( t, 2H, J = 6.0 Hz), 5.82-5.94 (m, 2H), 6.69-6.77 (m, IH), 6.91-7.11 (m, 3H), 7.36-7.50 (m, 4H), 7.71-7.80 ( m, 2H), 7.97-8.03 (m, 1H), 7.48, 7.98 (A2B2, 4H, J = 8.8 Hz), 8.16 (s, IH).

 (I b-2)

 O-NMR (CDCI3) δ ppm: 1.34 (s, 9H), 1.65- 1.79 (m, 2H), 2.05-2.18 (m, 2H), 3.75-3.78 (m, 9H), 4.27 (t, 2H, J = 6.4 Hz), 6.31-6.41 (m, 2H), 6.59-6.65 (m, 1H), 6.86 (t, 1H, J = 7.8 Hz), 7.15 (t, IH, J = 8.2 Hz), 7.51, 8.03 (A2B2, 4H, J = 8.6 Hz), 7.72 (brs, IH), 8.29 (s, 2H).

 (I b-3)

Ή-NMR (CDCI3) δ ppm: 1.34 (s, 9H), 1.44 (s, 9H), 1.46 (s, 9H), 1.58- 1.87 (m, 2H), 3.05-3.07 (m, 1H), 3.29- 3.31 (m, IH), 3.78 (s, 3H), 4.25-4.33 (m, 2H), 6.32-6.41 (m, 2H), 6.62-6.66 (m, IH), 7.16 (t, IH, J = 8.1 Hz), 7.51, 8.03 (A2B2, 4H, J = 8.4 Hz), 8.29 (s, IH). (I b— 4)

 ! H-NMR (CDCh) (5 ppm: 1.33 (s, 9H), 1.60-1.75 (m, 2H), 1.85- 1.99 (m, 2H), 3.71 (s, 3H), 4.20-4.31 (m, 2H ), 5.14-5.18 (m, 4H), 6.31-6.42 (m, 2H), 6.58-6.65 (m, IH), 6.74-6.89 (m, IH), 7.13 (t, IH, J = 7.8 Hz), 7.21-7.35 (m, 10H), 7.50, 8.03 (A2B2, 4H, J = 8.6 Hz), 7.90 (brs, IH), 8.28 (s, 2H).

 (I b-5)

 ! H-NMR (CDCI3) δ ppm: 1.30-1.39 (m, 3H), 1.35 (s, 9H), 1.75- 1.85 (m, 2H), 2.29-2.37 (m, 2H), 3.79 (s, 3H) , 4.27-4.34 (m, 4H), 6.35-6.43 (m, 2H), 6.62-6.67 (m, 1H), 7.18 (t, 1H, J = 8.1 Hz), 7.46 (t, IH, J = 9.0 Hz ), 7.66 (s, IH), 7.53, 8.05 (A2B2, 4H, J = 9.0 Hz), 8.30 (s, IH).

 (I b— 6)

 ! H-NMR (CDCh) (5 ppm: 1.34 (s, 9H), 1.75-1.84 (m, 2H), 2.29-2.36 (m, 2H), 3.77 (s, 3H), 3.85 (s, 3H), 4.31 (t, 2H, J = 6.0 Hz), 6.34-6.42 (m, 2H), 6.61-6.65 (m, IH), 7.17 (t, IH, J = 8.4 Hz), 7.47 (t, IH, J = (7.8 Hz), 7.70 (brs, IH), 7.52, 8.04 (A2B2, 4H, J = 8.4 Hz), 8.29 (s, IH).

 (I b-7)

 O-NMR (CDCh) 6 ppm: 1.34 (s, 9H), 1.76- 1.88 (m, 2H), 2.32-2.43 (m, 2H), 3.79 (s, 3H), 4.32 (t, 2H, J = 6.0 Hz), 6.35-6.43 (m, 2H), 6.63-6.68 (m, IH), 7.08 (t, IH, J = 7.06 Hz), 7.19 (t, 1H, J = 8.2 Hz), 7.71 (brs, 1H ), 7.53, 8.05 (A2B2, 4H, J = 8.4 Hz), 8.31 (s, IH).

 (I b-9)

 O-NMR (CDCls) δ ppm: 1.30 (t, 3H, J = 7.2 Hz), 1.34 (s, 9H), 1.63- 1.68 (m, 2H), 3.50-3.58 (m, 1H), 3.76 (s, 3H), 4.18-4.35 (m, 5H), 6.34-6.38 (m, 2H), 6.61-6.65 (m, IH), 7.17 (t, IH, J = 8.7 Hz), 7.52, 8.04 (A2B2, 4H, J = 8.4 Hz), 7.71 (s, IH), 8.29 (s, IH).

 (I b-10)

! H-NMR (CD3OD) δ ppm: 1.33 (s, 9H), 1.60-1.80 (m, 2H), 2.48-2.68 (m, W

2H), 3.72 (s, 3H), 4.21-4.34 (m, 2H), 6.28-6.45 (m, 2H), 6.52-6.64 (m, IH), 7.12 (t, IH, J = 7.8 Hz), 7.25 (brs, IH), 7.52, 7.90 (A2B2, 4H, J = 8.6 Hz), 8.11 (s, IH). (I b-13)

 ! H-NMR (CDCls) (5 ppm: 1.29 (s, 9H), 1.46-1.72 (m, 2H), 2.02-2.26 (m, 2H), 3.61 (s, 3H), 4.04-4.26 (m, 2H ), 6.14-6.38 (m, 2H), 6.42-6.54 (m, IH), 7.00 (t, 1H, J = 7.8 Hz), 7.28-7.50 (m, IH), 7.46, 7.98 (A2B2, 4H, J = 8.6 Hz), 8.17 (s, IH). (I b-14)

 Ή-NMR (CDCls) δ ppm: 1.34 (s, 9H), 1.70 (s, 3H), 1.78 (s, 3H), 1.72- 1.90 (m, 2H), 2.73 (q, 2H, J = 7.6 Hz) , 3.77 (s, 3H), 4.33 (t, 2H, J = 6.1 Hz), 6.33-6.44 (m, 2H), 6.58-6.63 (m, IH), 7.14 (t, IH, J = 8.3 Hz), 7.52, 8.03 (A2B2, 4H, J = 8.5 Hz), 7.73 (t, IH, J = 7.6 Hz), 8.29 (s, IH).

 (I b-15)

 ! H-NMR (CDCh) <5 ppm: 1.33 (s, 9H), 1.65-1.90 (m, 2H), 2.76-2.95 (m, 2H), 3.71 (s, 3H), 4.26 (t, 2H, J = 5.5 Hz), 6.23-6.37 (m, 2H), 6.47-6.52 (m, IH), 7.04 (t, IH, J = 8.2 Hz), 7.54-7.64 (m, IH), 7.51, 8.23 (A2B2, 4H, J = 8.7 Hz), 7.78-8.01 (m, IH), 8.21 (s, IH).

 (I b-17)

_{O-NMR (CDC1 3) δ} ppm: 1.03 (t, 3H, J = 6.9 Hz), 1.34 (s, 9H), 1.69- 1.78 (m, 2H), 1.96-2.05 (m, 2H), 2.25 (s , 3H), 2.47 (q, 2H, J = 7.5 Hz), 3.77 (s, 3H), 4.29 (t, 2H, J = 6.0 Hz), 6.31-6.40 (m, 2H), 6.49 (t, IH, J = 7.8 Hz), 6.61-6.64 (m, IH),

7.16 (t, IH, J = 8.1 Hz), 7.71 (brs, IH), 7.51, 8.03 (A ₂ B ₂₎ 4H, J = 8.4 Hz), 8.29 (s, IH).

 (I b-18)

 O-NMR (CDCI3) δ ppm: 0.92 (s, 3H), 0.94 (s, 3H), 1.34 (s, 9H), 1.69-1.78 (m, 2H), 2.00-2.16 (m, 3H), 2.21 ( s, 3H), 2.43 (d, 2H, J = 6.9 Hz), 3.78 (s, 3H), 4.29 (t, 2H, J = 6.0 Hz), 6.33-6.41 (m, 2H), 6.46 (t, 1H , J = 7.8 Hz), 6.62-6.65 (m, IH),

7.17 (t, IH, J = 7.8 Hz), 7.62 (brs, IH), 7.51, 8.04 (A2B2, 4H, J = 8.7 Hz), 8.29 (s, IH).

 (I b-1 9)

 ! H-NMR (CDCls) (5 ppm: 0.91 (t, 3H, J = 7.2 Hz), 1.25-1.36 (m, 2H), 1.34 (s, 9H), 1.52-1.62 (m, 2H), 1.71- 1.78 (m, 2H), 2.00-2.08 (m, 2H), 2.20 (s, 3H), 2.56 (t, 2H, J two 7.5 Hz), 3.76 (s, 3H), 4.28 (t, 2H, J = 6.0 Hz), 6.31-6.40 (m, 2H), 6.48 (t, IH, J = 7.8 Hz), 6.60-6.64 (m, IH), 7.14 (t, IH, J = 8.1 Hz), 7.81 (brs, IH), 7.51, 8.03 (A2B2, 4H, J = 8.7 Hz), 8.29 (s, IH).

 (I b-20)

 ! H-NMR (CDC) (5 ppm: 0.89 (t, 3H, J = 6.7 Hz), 1.20-1.34 (m, 4H), 1.34 (s, 9H), 1.50-1.63 (m, 2H), 1.62- 1.77 (m, 2H), 1.98-2.07 (m, 2H), 2.21 (s, 3H), 2.56 (t, 2H, J = 7.6 Hz), 3.78 (s, 3H), 4.29 (t, 2H, J = (6.3 Hz), 6.31-6.41 (m, 2H), 6.47 (t, IH, J = 7.8 Hz), 6.61-6.66 (m, 1H), 7.16 (t, IH, J = 8.2 Hz), 7.52, 8.02 ( A2B2, 4H, J = 8.8 Hz), 8.29 (s, IH).

 (I b— 2 1)

O-NMR (CDCh) δ ppm: 1.34 (s, 9H), 1.60-1.74 (m, 2H), 1.87-1.97 (m, 2H), 2.26 (s, 3H), 3.76 (s, 3H), 4.18 ( t, 2H, J = 6.0 Hz), 6.20-6.25 (m, IH), 6.34 (t, IH, J = 2.3 Hz), 6.57-6.62 (m, 1H), 6.79 (t, IH, J = 7.8 Hz) ), 7.09 (t, 1H, J = 8.2 Hz), 7.33-7.54 (m, 3H), 7.74-7.79 (m, 2H), 7.52, 8.04 (A2B2, 4H, J = 8.6 Hz), 8.24 (s, IH).

 (I b-2 2)

 Ή-NMR (CDCh) δ ppm: 1.03 (t, 3H, J = 7.2 Hz), 1.08 (t, 3H, J = 7.2 Hz), 1.34 (s, 9H), 1.68-1.77 (m, 2H), 1.95 -2.02 (m, 2H), 2.48 (q, 2H, J = 7.2 Hz), 2.59 (q, 2H, J = 7.2 Hz), 3.78 (s, 3H), 4.28 (t, 2H, J = 6.0 Hz) , 6.31-6.36 (m, 1H), 6.39 (t, IH, J = 2.4 Hz), 6.48 (t, IH, J = 7.8 Hz), 6.62-6.65 (m, IH), 7.16 (t, IH, J = 8.4 Hz), 7.63 (brs, 1H), 7.52, 8.03 (A2B2, 4H, J = 9.0 Hz), 8.29 (s, IH).

 (I b-2 3)

Ή-NMR (CDCls) δ ppm: 1.02 (d, 6H, J = 6.9 Hz), 1.10 (t, 6H, J = 6.9 Hz), 1.34 (s, 9H), 1.71- 1.78 (m, 2H), 1.95-2.03 (m, 2H), 2.70 (quint, 2H, J = 6.9 Hz), 3.08 (quint, 2H, J = 6.9 Hz), 3.78 (s, 3H), 4.29 (t, 2H, J = 6.3 Hz), 6.32-6.36 (m, 1H), 6.39 (t, IH, J = 2.1 Hz), 6.50 (t, IH, J = 7.5 Hz) , 6.61-6.65 (m, IH), 7.16 (t, IH, J = 8.1 Hz), 7.63 (brs, IH), 7.52, 8.03 (A2B2, 4H, J = 8.7 Hz), 8.29 (s, IH ). (I b-2 4)

 O-NMR (CDCls) (5 ppm: 1.34 (s, 9H), 1.83 (quint, 2H, J = 6.6 Hz), 2.37 (s, 3H), 2.58 (q, 2H, J = 7.2 Hz), 3.72 ( s, 3H), 4.34 (t, 2H, J = 6.6 Hz), 6.30-6.39 (m, 2H), 6.56-6.60 (m, IH), 6.93 (t, IH, J = 7.5 Hz), 7.07-7 .14 (m, 2H), 7.26- 7.32 (m, 2H), 7.49-7.54 (m, 2H), 7.78 (brs, IH), 7.52, 8.02 (A2B2, 4H, J = 8.4 Hz), 8.28 (s , IH), 9.32 (s, IH).

 (I b-2 ')

 ! H-NMR (CDCls) δ ppm: 1.30 (s, 9H), 1.78-1.88 (m, 2H), 2.21-2.29 (m, 2H), 3.72 (s, 3H), 3.73 (s, 3H), 3.93 (s, 3H), 4.32 (t, 2H, J = 6.0 Hz), 6.81-7.12 (m, 5H), 7.46, 7.99 (A2B2, 4H, J = 8.4 Hz), 8.21 (s, IH), 8.80 (s, IH).

 (I b-8 ')

 ! H-NMR (CDCls) δ ppm: 1.33 (s, 9H), 1.87 (quint, 2H, J = 6.6 Hz), 2.17-2.23 (m, 2H), 2.24 (s, 3H), 2.27 (s, 3H ), 3.97 (s, 3H), 4.37 (t, 2H, J = 6.3 Hz), 6.60 (t, IH, J = 7.5 Hz), 6.84-6.90 (m, IH), 7.00 (d, 2H, J = 8.1 Hz), 7.09-7.15 (m, 1H), 7.48, 8.00 (A2B2, 4H, J = 8.7 Hz), 8.23 (s, IH), 8.78 (s, IH).

 (I b-1 7 ')

 ! H-NMR (CDCI3) δ ppm: 1.02 (t, 3H, J = 7.2 Hz), 1.34 (s, 9H), 1.81-1.92 (m, 2H), 2.14-2.21 (m, 2H), 2.26 (s , 3H), 2.50 (q, 2H, J = 7.2 Hz), 3.97 (s, 3H), 4.37 (t, 2H, J = 6.3 Hz), 6.59 (t, IH, J = 7.8 Hz), 6.85-6.90 (m, IH), 6.99- 7.03 (m, 2H), 7.09-7.15 (m, 1H), 7.48, 8.00 (A2B2, 4H, J = 8.7 Hz), 8.23 (s, IH), 8.78 (s, IH ). (I b— 1 8 ')

 ! H-NMR (CDCh) (5 ppm: 0.86 (s, 3H), 0.90 (s, 3H), 1.32 (s, 9H), 1.80-1.94 (m,

2H), 2.04-2.20 (m, 3H), 2.26 (s, 3H), 2.40 (d, 2H, J = 6.6 Hz), 3.98 (s, 3H), 4.36 (t, 2H, J = 6.2 Hz), 6.58 (t, IH, J = 7.6 Hz), 6.82-7.22 (m, 4H), 7.48, 7.99 (A2B2, 4H, J = 8.7 Hz), 8.23 (s , IH), 8.80 (brs, IH).

 (I b-18 ")

 JH-NMR (CDCI3) 6 ppm: 0.90 (s, 3H), 0.93 (s, 3H), 1.32 (s, 9H), 1.80-1.94 (m, 2H), 2.04-2.27 (m, 3H), 2.24 ( s, 3H), 2.44 (d, 2H, J = 6.8 Hz), 3.98 (s, 3H), 4.37 (t, 2H, J = 6.3 Hz), 6.56 (t, IH, J = 7.7 Hz), 6.82- 7.17 (m, 4H), 7.48, 7.99 (A2B2, 4H, J = 8.8 Hz), 8.23 (s, IH), 8.79 (brs, IH).

 (I b-1 9 ')

 ! H-NMR (CDCI3) δ ppm: 0.90 (t, 3H, J = 7.2 Hz), 1.24- 1.35 (m, 2H), 1.34 (s, 9H), 1.51- 1.61 (m, 2H), 1.86 (quint , 2H, J = 6.3 Hz), 2.18-2.26 (m, 2H), 2.23 (s, 3H), 2.57 (t, 2H, J = 7.5 Hz), 3.98 (s, 3H), 4.37 (t, 2H, J = 6.0 Hz), 6.59 (t, IH, J = 7.8 Hz), 6.84-6.90 (m, 1H), 6.98-7.03 (m, 2H), 7.09-7.15 (m, IH), 7.48, 8.00 (A2B2 , 4H, J = 8.7 Hz), 8.23 (s, IH), 8.79 (s, IH).

 (I b-2 0 ')

JH-NMR (CDCh) δ ppm: 0.89 (t, 3H, J = 7.2 Hz), 1.23- 1.34 (m, 2H), 1.34 (s, 9H), 1.53- 1.63 (m, 4H), 1.86 (quint, 2H, J = 6.6 Hz), 2.18-2.26 (m, 2H), 2.23 (s, 3H), 2.57 (t, 2H, J = 7.5 Hz), 3.98 (s, 3H), 4.37 (t, 2H, J = 6.3 Hz), 6.58 (t, IH, J = 7.8 Hz), 6.84-6.90 (m, 1H), 6.98-7.03 (m, 2H), 7.09-7.15 (m, 1H), 7.48, 8.00 (A2B2, 4H, J = 8.4 Hz), 8.23 (s, IH), 8.79 (s, IH).

 (I b-2 1 ')

 ! H-NMR (CDCI3) (5 ppm: 1.31 (s, 9H), 1.73-1.87 (m, 2H), 2.02-2.10 (m, 2H), 2.27 (s, 3H), 3.94 (s, 3H), 4.25 (t, 2H, J = 6.0 Hz), 6.75-7.12 (m, 5H), 7.32-7.44 (m, 3H), 7.76-7.79 (m, 2H), 7.48, 8.00 (A2B2, 4H, J = 8.9 Hz), 8.18 (s, IH), 8.72 (brs, IH).

 (I b-2 2 ')

 ! H-NMR (CDCh) δ ppm: 1.03 (t, 3H, J = 7.4 Hz), 1.06 (t, 3H, J = 7.4 Hz), 1.32

(s, 9H), 1.78-1.92 (m, 2H), 2.11-2.22 (m, 2H), 2.50 (q, 2H, J = 7.4 Hz), 2.60 (q, 2H, J = 7.4 Hz), 3.98 (s, 3H), 4.36 (t, 2H, J = 6.3 Hz), 6.59 (t, IH, J = 7.6 Hz), 6.83-7.23 (m, 4H), 7.48, 7.99 (A2B2, 4H, J = 8.8 Hz), 8.22 (s, IH).

 (I b-2 4 ')

 ! H-NMR (CDCI3) δ ppm: 1.32 (s, 9H), 1.90-2.04 (m, 2H), 2.38 (s, 3H), 2.77 (q, 2H, J = 7.0 Hz), 3.96 (s, 3H ), 4.43 (t, 2H, J = 6.2 Hz), 6.80-7.14 (m, 6H), 7.30-7.34 (m, 2H), 7.46-7.56 (m, 2H), 7.99 (d, 1H, J = 8.6 Hz), 8.22 (s, IH), 8.80 (br s, IH), 9.42 (br s, IH).

 (Ic-1 2)

 ! H-NMR (CDCls) δ ppm: 1.33 (s, 9H), 1.70-1.90 (m, 2H), 2.02-2.24 (m, 2H), 3.72 (s, 3H), 4.30 (t, 2fl, J = 5.6 Hz), 6.26-6.38 (m, 2H), 6.54-6.63 (m, IH), 7.12 (t, IH, J = 8.2 Hz), 7.51-7.72 (m, 3H), 7.50, 8.00 (A2B2, 4H , J = 8.6 Hz), 8.25 (s, IH), 8.67 (s, 2H).

 (I c-3)

 ! H-NMR (CDCI3) δ ppm: 1.33 (s, 9H), 1.70-1.90 (m, 2H), 1.96-2.26 (m, 2H), 3.71 (s, 3H), 4.29 (t, 2H, J = (5.8 Hz), 6.28-6.37 (m, 2H), 6.56-6.60 (m, IH), 7.11 (t, 1H, J = 7.8 Hz), 7.26-7.50 (m, 2H), 7.50, 8.01 (A2B2, 4H , J = 8.6 Hz), 8.12 (s, IH), 8.25 (s, 1H), 8.66 (s, 1H), 8.99 (s, IH).

 (I c— 4)

 ! H-NMR (CDCI3) δ ppm: 1.34 (s, 9H), 1.82- 1.91 (m, 2H), 2.21-2.27 (m, 2H), 3.76 (s, 3H), 4.34 (t, 2H, J = (6.3 Hz), 6.37-6.42 (m, 2H), 6.62-6.64 (m, 1H), 7.12 (t, IH, J = 8.1 Hz), 7.42 (t, 1H, J = 5.4 Hz), 7.50, 8.01 ( A2B2, 4H, J = 8.7 Hz), 7.88 (t, 1H, J = 8.1 Hz), 8.26-8.29 (m, IH), 8.29 (s, IH), 8.56-8.58 (m, IH), 10.64 (s , IH).

 (Ic-1 5)

! H-NMR (CDCls) δ ppm: 1.58 (s, 9H), 1.79-1.88 (m, 2H), 2.12-2.24 (m, 2H),

3.75 (s, 3H), 4.33 (t, 2H, J = 6.0 Hz), 6.34-6.41 (m, 2H), 6.61-6.70 (m, 3H), 7.15

(t, IH, J = 8.1 Hz), 7.51, 8.03 (A2B2, 4H, J = 8.4 Hz), 7.63-7.66 (m, 2H), 8.29 (s, IH), 8.63 (s, IH).

 (I c-6)

Ή-NMR (CD ₃ OD) δ ppm: 1.34 (s, 9H), 1.75-1.87 (m, 2H), 2.05-2.15 (m, 2H),

3.72 (s, 3H), 4.33 (t, 2H, J = 6.3 Hz), 6.32-6.36 (m, IH), 6.41-6.43 (m, IH), 6.84 (d, 2H, J = 8.7 Hz), 7.15 (t, IH, J = 8.1 Hz), 7.47-7.53 (m, IH), 7.56, 7.95 (A2B2,

4H, J = 8.7 Hz), 7.73 (d, 2H, J = 8.7 Hz), 8.18 (s, IH).

 (I c-7)

 ! H-NMR (CDC) δ ppm: 1.33 (s, 9H), 1.74-1.88 (m, 2H), 2.10-2.22 (m, 2H),

3.73 (s, 3H), 3.84 (s, 3H), 4.31 (t, 2H, J = 6.0 Hz), 6.32-6.35 (m, 1H), 6.38-6.39 (m, IH), 6.90 (d, 2H, J = 9.0 Hz), 7.13 (t, IH, J = 8.4 Hz), 7.50, 8.02 (A2B2, 4H,

J = 8.7 Hz), 7.77 (d, 2H, J = 8.1 Hz), 8.27 (s, IH), 8.98 (s, IH).

 (I c-8)

 ! H-NMR (CDCh) δ ppm: 1.34 (s, 9H), 1.82- 1.98 (m, 2H), 2.10-2.22 (m, 2H), 3.75 (s, 3H), 4.37 (t, 2H, J = 6.0 Hz), 6.35-6.42 (m, 2H), 6.62-6.66 (m, IH), 7.10 (t, IH, J = 4.8 Hz), 7.18 (t, 1H, J = 8.4 Hz), 7.51, 8.04 ( A2B2, 4H, J = 8.7 Hz), 8.29 (s, IH), 8.91 (s, IH).

 (I c-9)

 ! H-NMR (CDCls) (5 ppm: 1.34 (s, 9H), 1.80-1.88 (m, 2H), 2.12-2.25 (m, 2H), 3.75 (s, 3H), 4.33 (t, 2H, J = 5.7 Hz), 6.34-6.41 (m, 2H), 6.50-6.56 (m, IH), 6.61-6.64 (m, IH), 7.16 (t, IH, J = 8.1 Hz), 7.28-7.36 (m, 1H), 7.44-7.52 (m, IH), 7.51, 8.02 (A2B2, 4H, J = 8.7 Hz), 8.28 (s, IH), 9.11 (s, IH).

 (I c one 10)

 ! H-NMR (CDCls) 6 ppm: 1.34 (s, 9H), 1.78-1.86 (m, 2H), 2.00-2.10 (m, 2H), 2.17 (s, 3H), 3.78 (s, 3H), 4.33 (t, 2H, J = 6.3 Hz), 6.34-6.41 (m, 2H), 6.62-6.66 (m, IH), 6.83 (t, IH, J = 5.4 Hz), 7.18 (t, IH, J = 8.1 Hz), 7.52, 8.04 (A2B2, 4H, J = 8.7 Hz), 8.17 (s, IH), 8.29 (s, IH).

(I c-1 1) 'H-NMR (CDCI3) δ ppm: 1.33 (s, 9H), 1.76-1.88 (m, 2H), 2.12-2.24 (m, 2H),

3.75 (s, 3H), 4.31 (t, 2H, J = 6.3 Hz), 6.00-6.08 (m, 1H), 6.32-6.42 (m, 2H),

6.60- 6.63 (m, 1H), 7.16 (t, 1H, J = 8.1 Hz), 7.38 (t, IH, J = 5.4 Hz), 7.42-7.48 (m, 1H), 7.51, 8.02 (A2B2, 4H, J = 8.4 Hz), 8.27 (s, IH), 10.14 (s, IH).

 (I c-1 2)

^! H-NMR (CDCh) δ ppm: 1.33 (s, 9H), 1.70-1.79 (m, 2H), 1.95-2.04 (m, 2H), 3.74 (s, 3H), 4.29 (t, 2H, J = 6.0 Hz), 6.33-6.36 (m, IH), 6.40-6.42 (m, IH), 6.59-6.62 (m, 1H), 6.90 (t, IH, J = 4.8 Hz), 7.13 (t, 1H, J = 8.4 Hz), 7.50, 8.02 (A2B2, 4H, J = 9.0 Hz), 8.26 (s, IH), 9.16 (s, IH).

 (I c one 13)

 ! H-NMR (CDCh) (5 ppm: 1.34 (s, 9H), 1.68-1.80 (m, 2H), 2.02-2.14 (m, 2H),

3.74 (s, 3H), 4.26 (t, 2H, J = 6.0 Hz), 6.27-6.31 (m, IH), 6.34-6.35 (m, IH), 6.57-6.61 (m, IH), 6.92 (t, IH, J = 5.4 Hz), 7.11 (t, IH, J = 8.1 Hz), 7.51, 8.02 (A2B2, 4H, J = 9.0 Hz), 8.27 (s, IH).

 (I c-14)

 ! H-NMR (CDCh) (5 ppm: 1.34 (s, 9H), 1.74-1.83 (m, 2H), 2.09-2, 16 (m, 2H),

3.76 (s, 6H), 4.30 (t, 2H, J = 6.0 Hz), 6.33-6.37 (m, 1H), 6.39-6.40 (m, IH),

6.61- 6.65 (m, IH), 6.86-6.94 (m, 1H), 7.16 (t, IH, J = 8.1 Hz), 7.51, 8.02 (A2B2, 4H, J = 8.7 Hz), 8.28 (s, IH) .

 (I c— 15)

 ! H-NMR (CDCh) δ ppm: 1.33 (s, 9H), 1.73-1.81 (m, 2H), 1.97-2.04 (m, 2H),

3.75 (s, 3H), 4.29 (t, 2H, J = 6.3 Hz), 6.34-6.48 (m, 3H), 6.61-6.66 (m, IH), 7.00-7.16 (m, 2H), 7.15 (t, IH, J = 8.1 Hz), 7.51, 8.02 (A2B2, 4H, J = 8.4 Hz), 8.28 (s, IH), 9.84 (s, IH).

 (I c-16)

 ! H-NMR (CDCh) <5 ppm: 1.33 (s, 9H), 1.73-1.90 (m, 2H), 2.00-2.14 (m, 2H),

3.74 (s, 3H), 4.33 (t, 2H, J = 5.8 Hz), 6.34-6.45 (m, 2H), 6.60-6.68 (m, 1H), 7.02 (t, IH, J = 4.6 Hz), 7.18 (t, IH, J = 8.2 Hz), 7.30-7.82 (m, 6H), 7.51, 8.04 (A2B2, 4H, J = 8.6 Hz), 8.27 (s , IH), 8.99 (s, IH), 9.23 (s, IH).

 (I c-1 7)

O-NMR (CDCI3) δ ppm: 1.33 (s, 9H), 1.65-1.76 (m, 2H), 1.93-2.04 (m, 2H), 3.74 (s, 3H), 4.16 (t, 2H, J = 5.7 Hz), 6.27-6.35 (m, 2H), 6.58-6.62 (m, 1H), 6.87 (t, IH, J = 5.1 Hz), 7.12 (t, IH, J = 8.1 Hz), 7.36-7.90 (m , 6H), 7.52, 8.04 ( A 2 B 2, 4H, J = 8.7 Hz), 8.25 (s, IH).

 (I c-18)

 ! H-NMR (CDCI3) δ ppm: 1.33 (s, 9H), 1.62-1.78 (m, 2H), 1.92-2.03 (m, 2H), 2.34 (s, 3H), 3.73 (s, 3H), 4.17 (t, 1H, J = 5.0 Hz), 6.26-6.37 (m, 2H), 6.56-6.62 (m, 1H), 6.86 (t, IH, J = 5.0 Hz), 7.07-7.23 (m, 3H), 7.52, 8.04 (A2B2, 4H, J = 8.6 Hz), 7.70-7.79 (m, 3H), 8.25 (s, IH).

 (I c one 19)

 ! H-NMR (CDCls) <5 ppm: 1.34 (s, 9H), 1.56-1.64 (m, 2H), 1.82-1.90 (m, 2H), 2.86 (s, 6H), 3.73 (s, 3H), 4.06 (t, 2H, J = 6.3 Hz), 6.23-6.34 (m, 2H), 6.53-6.58 (m, IH), 6.78 (t, 1H, J = 4.8 Hz), 7.06 (t, IH, J = 8.4 Hz), 7.13-7.15 (m, IH), 7.42-7.66 (m, 6H), 8.02-8.09 (m, 2H), 8.23-8.33 (m, 3H), 8.50-8.53 (m, IH).

(I c one 1 ')

 ! H-NMR (CDCh) δ ppm: 1.40 (s, 9H), 1.84-2.02 (m, 2H), 2.34-2.50 (m, 2H), 3.93 (s, 3H), 4.40 (t, 2H, J = 5.6 Hz), 6.86-7.16 (m, 4H), 7.38-7.58 (m, 6H), 7.73-8.00 (m, 5H), 8.24 (s, IH), 9.24 (s, IH).

 (I c-2 ')

 ! H-NMR (CDCls) <5 ppm: 1.32 (s, 9H), 1.76-1.98 (m, 2H), 2.24-2.40 (m, 2H), 3.84 (s, 3H), 4.27-4.40 (m, 2H ), 6.76-7.10 (m, 4H), 7.42-7.67 (m, 3H), 7.44, 7.92 (A2B2, 4H, J = 8.6 Hz), 8.20 (s, IH), 8.63-8.66 (m, 3H).

 (I c-14 ')

! H-NMR (CDCh) δ ppm: 1.32 (s, 9H), 1.83-1.91 (m, 2H), 2.24-2.31 (m, 2H), 3.76 (s, 3H), 3.97 (s, 3H), 4.35 (t, 2H, J = 5.7 Hz), 6.82-7.13 (m, 5H), 7.49, 8.00 (A 2 B 2, 4H, J = 8.7 Hz ), 8.13 (brs, 1H), 8.23 (s, 1H), 8.65 (s, 1H). Test Example 1 Measurement of (ETA-R) affinity for endothelin A receptor

Rat aortic smooth muscle A 7 r ^{5 1 2} 5 I-labeled endothelin to the cell - 1 was determined from the intensity of inhibiting binding. Specifically, 48 after washing the cells with buffer cultured in well plates, ¹²⁵ I-labeled endothelin ^{8. 3 X 1 0- 12 M -} HE PES buffer containing 1 and various proteolytic enzyme inhibitors Hanks' solution (0.3 ml) was added, and the mixture was incubated at 37 ° C for 1 hour in the presence or absence of the compound of the present invention. After completion of the reaction, the reaction solution was removed by suction, and the cells were washed with a Hank's solution buffered with HE PES. Then, the radioactivity bound to the cells was measured with a gamma counter. Specific binding is 1 0 - was obtained by ⁷ M subtracting nonspecific binding determined under conditions comprising non-radioactive endothelin-one 1. ^{1 25} I-labeled Endoserin - 1 of the specific binding to a concentration of the present compound prejudice 50% inhibitory (IC _50). Table 14 shows the results. Test Example 2 Measurement of affinity for endothelin B receptor (ETB-R)

It was determined from the potency of inhibiting the binding of ¹²⁵ I-labeled endoselin-3 to COS-7 cells expressing the putaendothelin B receptor. Specifically, a plasmid vector incorporating the endothelin ETB receptor yuichi gene was introduced into COS-7 cells by the lipofectin method. After washing the cultured cells with buffer, 2 5 X 1 0 one ¹ of ² M ^{1 2 5} I-labeled Endoseri emissions - HE PES buffered Hank's solution containing 3 and various protease inhibitors (0. 1 ml) 1 0 ³ suspended to 1 0 ⁴ cells, the present invention compounds presence, or absence, and incubated for 1 hour at 3 7 ° C in. After the completion of the reaction, the radioactivity bound to the cells was separated by glass fiber filter paper and measured with a gamma counter. Specific binding was obtained by subtracting nonspecific binding determined under conditions comprising 1 0- ⁷ M non-radioactive endothelin-_ 1. ^{1 25} I-labeled Endoserin - to a concentration of 3 of JP specific binding of 50% inhibition for the compound of the present invention (IC _{S 0).} Table of results

Four Table 14 shows that the compound of the present invention has a strong endendothelin B receptor selective antagonism. Formulation example

 Compound of the present invention (Ia-1) 5Omg

 Lactose 46mg

 Corn starch 20mg

 Low substituted hydroxypropylcellulose 8mg

 Hydroxypropyl methylcellulose 5mg

 Magnesium stearate l mg

 Total 1 30 mg

 After uniformly mixing the above ingredients except hydroxypropylmethylcellulose and magnesium stearate, granules for tableting were prepared by wet granulation using an aqueous solution of 8% (w / w) hydroxypropylmethylcellulose as a binder. After mixing with magnesium stearate, it was formed into a tablet with a diameter of 7 mm and a tablet weight of 13 Omg using a tableting machine. Industrial applicability

 INDUSTRIAL APPLICABILITY The compound of the present invention has a strong endothelin B receptor antagonistic action and its selectivity is very high, and thus is useful as an endothelin B receptor selective antagonist.

Claims

The scope of the claims

 1. Formula (I)

(Wherein R ¹ and R ² are each independently

Aryl which may have a substituent (where the substituent is a lower alkyl, a lower alkenyl, a lower alkoxy, a lower alkenyloxy, a halogen, a hydroxy, an amino, an acyl, a carboxy or a lower alkoxycarbonyl) R ³ is hydrogen,

Lower alkyl optionally having substituent (s) (wherein the substituent is lower alkoxy, lower alkenyloxy, halogen, hydroxy, amino, acyl, carboxy or lower alkoxycarbonyl)

Or optionally substituted aryl (where the substituent is a lower alkyl, a lower alkenyl, a lower alkoxy, a lower alkenyloxy, a halogen, a hydroxy, an amino, an acyl, a carboxy or a lower alkoxycarbonyl) X is 〇, S or a single bond;

 Y is lower alkylene or lower alkenylene,

Z is

a) CONR ⁴ R ⁵

R ⁴ and R ⁵ are each independently hydrogen, hydroxy,

A lower alkyl which may have a substituent (where the substituent is a lower alkoxy, a lower alkenyloxy, a halogen, a hydroxy, an amino, an acryl, a carboxy, a lower alkoxycarbonyl, a cycloalkyl, an aryl or a heterocycle) ), An optionally substituted lower alkenyl (where the substituent is a lower alkoxy, a lower alkenyloxy, a halogen, a hydroxy, an amino, an acyl, a carbonyloxy or a lower alkoxycarbonyl), Aryl lower alkyl which may have a substituent (here, the substituent means lower alkyl which may be substituted with halogen or hydroxy, lower alkenyl, lower alkoxy, lower alkenyloxy, halogen, hydroxy, lower Alkylene dioxy, amino optionally substituted with lower alkyl, acyl, nitro, cyano, carboxy, lower alkoxycarbonyl, aryl, aryl lower alkyl or carbamoyl),

Aryl lower alkenyl optionally having substituent (s) (where the substituent is lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, halogen, hydroxy, amino, acyl, carboxy or lower alkoxy); Carboxy), a lower alkoxy optionally having a substituent (where the substituent is a lower alkoxy, a lower alkenyloxy, a halogen, a hydroxy, an amino, an acyl, a carboxy, a lower alkoxycarbonyl or an aryl)

A lower alkenyloxy which may have a substituent (where the substituent is a lower alkoxy, a lower alkenyloxy, a halogen, a hydroxy, an amino, an acyl, a carbonyl or a lower alkoxycarbonyl),

A heterocyclic ring which may have a substituent (where the substituent is a lower alkyl, a lower alkenyl, a lower alkoxy, a lower alkenyloxy, a halogen, a hydroxy, an amino, an acyl, a carboxy or a lower alkoxycarbonyl) ),

A carbocyclic ring which may have a substituent (where the substituent means a lower alkyl, a lower alkenyl, a lower alkoxy, a lower alkenyloxy, a halogen, a hydroxy, an amino, an acyl, a propyloxy, a lower alkoxycarbonyl) Or an aryl which may have a substituent (wherein the substituent is a lower alkyl, a lower alkenyl, a lower alkoxy, a lower alkenyloxy, a halogen, a hydroxy, an amino, or a heterocyclic ring) Optionally, carboxy or lower alkoxycarbonyl) or

Or a lower alkylene optionally having a substituent (s) wherein the substituent is a lower alkyl, a lower alkenyl, a lower alkoxy, a lower alkenyloxy, A halogen, hydroxy, amino, acyl, carboxy, lower alkoxycarbonyl or aryl).

b) CH = CR ⁶ R ⁷

R ⁶ and R ⁷ are each independently hydrogen,

An optionally substituted acyl group (where the substituent means lower alkyl, lower alkenyl, lower alkenylene, lower alkoxy, lower alkenyloxy, halogen, hydroxy, amino, acyl, carboxy, lower alkoxycarbonyl or Kiso),

Carboxy,

A lower alkoxycarbonyl optionally having a substituent (where the substituent is a lower alkoxy, a lower alkenyloxy, a halogen, a hydroxy, an amino, an acyl, a sulfoxy, a lower alkoxycarbonyl or an aryl),

Optionally substituted rubamoyl (where the substituent is lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, halogen, hydroxy, amino, acyl, carbonyl, lower alkoxycarbonyl or aryl) ) Siano,

Cyanocarbonyl

Or two toro

Or together with one CO— U— CO—, — CO— V— CS— W— or one CO— V— CO—W—, one (CH _2- ) m NRSO ₂ ~ (where U is lower alkyl Alkylene having 2 to 3 carbon atoms which may be substituted by phenyl, heterocycle or oxo; alkenylene having 2 to 3 carbon atoms which may be substituted by phenyl or hydroxy; cycloalkylene; — CH 2 — T— (where T is cycloalkylene optionally substituted with lower alkyl, cycloalkenylene optionally substituted with lower alkyl, phenylene optionally substituted with lower alkyl); phenylene Naphthylene; alkylenedioxy having 2 to 3 carbon atoms which may be substituted with lower alkyl; — SCH 2— or —〇 CH 2—, and V and W are each independently NR, S or O, m is 2 or 3, and R is hydrogen, methyl or ethyl)

Is or

c) CH = NNR ⁸ R ⁹

R ⁸ and R ⁹ are each independently hydrogen,

Optionally substituted acyl (where the substituent means lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, halogen, hydroxy, amino, acyl, carboxy, cyano, lower alkoxycarbonyl, lower alkyl Optionally substituted with aryl, aryloxy, arylthio, lower alkylsulfonyl, arylsulfonyl optionally substituted with lower alkyl), and optionally substituted rubamoyl (here And the substituent is a lower alkyl, a lower alkenyl, a lower alkoxy, a lower alkenyloxy, a halogen, a hydroxy, an amino, an acyl, a carboxy, a lower alkoxycarbonyl or an aryl), or a thiocarbamoyl which may have a substituent ( Here, the substituent means lower Alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, halogen, hydroxy, amino, acyl, carboxy, lower alkoxycarbonyl or aryl)),

Carboxy,

A lower alkoxycarbonyl optionally having a substituent (where the substituent is a lower alkoxy, a lower alkenyloxy, a halogen, a hydroxy, an amino, an acyl, a propyloxy or a lower alkoxycarbonyl),

Aryloxycarbonyl optionally having substituent (s) (where the substituent is lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, halogen, hydroxy, amino, acryl, carboxy or lower alkoxy); Carbonyl),

Lower alkoxy (thiocarbonyl) optionally having substituent (s) (where the substituent is lower alkoxy, lower alkenyloxy, halogen, hydroxy, amino, a Sil, carboxy or lower alkoxycarbonyl)

Aryloxy (thiol propyl) which may have a substituent (wherein the substituent is lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, halogen, hydroxy, amino, acyl, carboxy or lower alkoxy) Ruponil),

Cycloalkyloxy (thiocarbonyl) which may have a substituent (where the substituent is a lower alkyl, a lower alkenyl, a lower alkoxy, a lower alkenyloxy, a halogen, a hydroxy, an amino, an acyl, a carboxy or a lower alkoxy) Carbonyl),

Optionally substituted rubamoylcarbonyl (where the substituent is a lower alkyl, a lower alkenyl, a lower alkoxy, a lower alkenyloxy, a halogen, a hydroxy, an amino, an acyl, a carboxy or a lower alkoxycarbonyl) Or an arylsulfonyl which may have a substituent (where the substituent means a lower alkyl, a lower alkenyl, a lower alkoxy, a lower alkenyloxy, a halogen, a hydroxy, an alkyl, Good amino, acyl, carboxy or lower alkoxycarbonyl)

Or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

2. The compound according to claim ^{1, wherein} R ¹ is phenyl substituted with lower alkyl, a pharmaceutically acceptable salt thereof, or a hydrate thereof.

3. The compound according to claim 1, wherein R ² is phenyl substituted with lower alkyloxy, a pharmaceutically acceptable salt thereof, or a hydrate thereof.

 4. The compound according to claim 1, wherein R 3 is hydrogen, a pharmaceutically acceptable salt thereof, or a hydrate thereof.

 5. The compound according to claim 1, wherein Y is alkylene having 2 to 3 carbon atoms, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

6. R ³ is hydrogen, Z is CONR ⁴ R ⁵ , one of R ⁴ and R 5 is hydrogen, and the other has an alkyl or a substituent which may have a substituent. hand 2. The compound according to claim 1, which is optionally lower alkyl, a pharmaceutically acceptable salt thereof, or a hydrate thereof.

7. Z is CH = CR ⁶ R ⁷ , R ⁶ and R ⁷ are each independently an optionally substituted acyl, carboxy, optionally substituted lower alkoxy group, luponyl, An optionally substituted moiety such as luvamoyl or cyano, or together with one CO—U—CO—, one CO—V—CS—W—or—CO-V-CO-W -, One (CH 2) mN RSO _2- (where U is optionally substituted with lower alkyl, alkylene having 2 to 3 carbon atoms; alkenylene having 2 to 3 carbon atoms; phenylene; lower alkyl And SCH ₂ — or 1 CH ₂ —, and V and W are each independently N

R, S or O, m is 2 or 3, and R is hydrogen, methyl or ethyl)) or a pharmaceutically acceptable salt thereof or a water thereof. Japanese food.

8. Z is CH = NNR ⁸ R ⁹ , one of R ⁸ and R ⁹ is hydrogen, and the other is an optionally substituted acyl group, an optionally substituted amino group. Thiocarbamoyl optionally having substituent (s), lower alkoxycarbonyl optionally having substituent (s), carbamoylcarbonyl optionally having substituent (s) or having substituent (s) 2. The compound according to claim 1, which is arylsulfonyl, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8.

 10. A selective endothelin B receptor antagonist comprising the compound according to any one of claims 1 to 8.