# Patent

## Title
Aminodihydrothiazine derivatives substituted with a cyclic group

## Abstract

This invention provides a compound of the formula (I):




    
    
        wherein the ring A is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group; R1 is optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl; R2a and R2b are each independently hydrogen, optionally substituted lower alkyl or optionally substituted acyl; R3a, R3b, R3c and R3d are each independently hydrogen, halogen, hydroxy or optionally substituted lower alkyl etc.;
        a pharmaceutically acceptable salt or solvate thereof,
        which is useful for treating diseases induced by production, secretion and/or deposition of amyloid β protein.

## Background
This application is a Divisional of application Ser. No. 12/596,796, filed Dec. 3, 2009, which is a National Stage Application of PCT/JP2008/057847, filed Apr. 23, 2008, which applications are incorporated herein by reference.


TECHNICAL FIELD
This invention relates to a compound having an inhibitory activity against production of amyloid β protein and useful for treating diseases induced by production, secretion and/or deposition of amyloid β protein.
BACKGROUND ART
In the brain of Alzheimer's patient many insoluble spots (senile plaque) are found, which is formed by extraneuronal accumulation of a peptide called amyloid β protein comprised of about 40 amino acids. Neuronal death caused by the senile plaque is considered to develop Alzheimer's Disease and an enhancer of amyloid β protein decomposition or vaccine of amyloid β protein etc. are extensively studied as a remedy for Alzheimer's Disease.
Secretase is an enzyme producing amyloid β protein by intracellular cleavage of a protein called amyloid β protein precursor (APP). An enzyme playing a role for producing an N-terminal of the amyloid β protein is called BACE1 (beta-site APP-cleaving enzyme) and an inhibitor of the BACE1, which will reduce production of amyloid β protein, could be a remedy for treating Alzheimer's disease.
Patent literature 1 discloses a compound with a chemical structure similar to that of the compound of the present invention, having an inhibitory activity of NO synthetase and effective for treating dementia.
Patent literature 2-5 and non-patent literature 1-2 disclose compounds with a chemical structure similar to those of the compound of the present invention, and describe that each compound is useful as an anti-hypotensive agent, morphine-like analgesic or tranquilizer, intermediate of a therapeutic agent, NPYY5 antagonist, analgesic and the like.
Patent literatures 6-14 disclose BACE-1 inhibitors having a chemical structure different from that of the compound of the present invention. Also, patent literature 15 discloses a BACE-1 inhibitor.

    Patent literature 1: WO 96/014842 Pamphlet
    Patent literature 2: U.S. Pat. No. 3,235,551
    Patent literature 3: U.S. Pat. No. 3,227,713
    Patent literature 4: JP H09-067355
    Patent literature 5: WO 2005/111031 Pamphlet
    Patent literature 6: WO 02/96897 Pamphlet
    Patent literature 7: WO 04/043916 Pamphlet
    Patent literature 8: WO 2005/058311 Pamphlet
    Patent literature 9: WO 2005/097767 Pamphlet
    Patent literature 10: WO 2006/041404 Pamphlet
    Patent literature 11: WO 2006/041405 Pamphlet
    Patent literature 12: US 2007/0004786A
    Patent literature 13: US 2007/0004730A
    Patent literature 14: US 2007/27199A
    Patent literature 15: WO 2007/049532 Pamphlet
    Non-patent literature 1: Journal of Heterocyclic Chemistry, 14, 717-723 (1977)
    Non-patent literature 2: Journal of Organic Chemistry, 33 (8), 3126-3132 (1968).


DISCLOSURE OF INVENTION
Problem to be Solved
This invention provides with a compound having an inhibitory activity against BACE-1 and useful for treating diseases induced by production, secretion and/or deposition of amyloid β protein.
Means to Solve the Problem
The present invention provides with
1) a compound of the formula (I):




wherein the ring A is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group.

R1 is optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group,
R2a and R2b are each independently hydrogen, optionally substituted lower alkyl or optionally substituted acyl,
R3a, R3b, R3c and R3d are each independently hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted acyl, optionally substituted lower alkoxy, optionally substituted carbocyclyl lower alkyl, optionally substituted heterocyclyl lower alkyl, optionally substituted carbocyclyl lower alkoxy, optionally substituted heterocyclyl lower alkoxy, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted aralkyloxy, optionally substituted heteroaralkyloxy, optionally substituted lower alkylthio, carboxy, optionally substituted lower alkoxycarbonyl, optionally substituted amino, optionally substituted carbamoyl, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group, or R3a and R3b or R3c and R3d may form a carbocyclic ring together with a linked carbon atom or may form oxo,
provided the following compounds i) and ii) are excluded;
i) a compound in which R2a is hydrogen, R2b is hydrogen, acetyl or phenyl, R1 is methyl, and the ring A is phenyl or 4-methoxyphenyl;
ii) a compound in which R2a is hydrogen, R2b is hydrogen, acetyl or phenyl, R1 is ethyl and the ring A is 3,4-dimethoxyphenyl,
a pharmaceutically acceptable salt or solvate thereof;
1′) a compound of the formula (I):




wherein the ring A is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group,

R1 is optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group,
R2a and R2b are each independently hydrogen, optionally substituted lower alkyl or optionally substituted acyl,
R3a, R3b, R3c and R3d are each independently hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted acyl, optionally substituted lower alkoxy, optionally substituted lower alkylthio, carboxy, optionally substituted lower alkoxycarbonyl, optionally substituted amino, optionally substituted carbamoyl, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group, or
R3a and R3b or R3c and R3d may form a carbocyclic ring together with a linked carbon atom, provided the following compounds i) and ii) are excluded:
i) a compound in which R2a is hydrogen, R2b is hydrogen, acetyl or phenyl, R1 is methyl, and the ring A is phenyl or 4-methoxyphenyl;
ii) a compound in which R2a is hydrogen, R2b is hydrogen, acetyl or phenyl, R1 is ethyl and the ring A is 3,4-dimethoxyphenyl,
a pharmaceutically acceptable salt or solvate thereof;
2) the compound of 1) or 1′) described above,
wherein the ring A is




wherein the ring A′ is a carbocyclic group or a heterocyclic group,

G is





wherein R5 is hydrogen, lower alkyl or acyl,

R6 is optionally substituted lower alkyl, optionally substituted lower alkenyl or optionally substituted lower alkynyl,

W1 is O or S,

W2 is O, S or NR5,

Ak is optionally substituted lower alkylene, optionally substituted lower alkenylene or optionally substituted lower alkynylene,

the ring B is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group and each R5 may be independent:

R4 is halogen, hydroxyl, mercapto, halogeno lower alkyl, lower alkoxy, amino, lower alkylamino, acylamino or lower alkylthio and each R4 may be independent;

A pharmaceutically acceptable salt or solvate thereof;

2′) the compound of 1) or 1′) described above

wherein the ring A is





wherein the ring A′ is a carbocyclic group or a heterocyclic group,

G is





wherein R5 is hydrogen, lower alkyl or acyl,

R6 is optionally substituted lower alkyl, optionally substituted lower alkenyl or optionally substituted lower alkynyl,

W1 is O or S,

W2 is O, S or NR5,

Ak is optionally substituted lower alkylene, optionally substituted lower alkenylene or optionally substituted lower alkynylene,

the ring B is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group and each R5 may be independent:

R4 is halogen, hydroxyl, mercapto, halogeno lower alkyl, lower alkyl, lower alkoxy, amino, lower alkylamino, acylamino or lower alkylthio and each R4 may be independent;

A pharmaceutically acceptable salt or solvate thereof;

3) the compound of 2) or 2′) described above wherein the ring A′ is phenyl or a nitrogen-containing aromatic heterocyclic group, a pharmaceutically acceptable salt or solvate thereof;

3′) the compound of 2) or 2′) described above wherein the ring A′ is phenyl, a pharmaceutically acceptable salt or solvate thereof;

3′′) the compound of 2) or 2′) described above wherein the ring A′ is a nitrogen-containing aromatic monocyclic heterocyclic group, a pharmaceutically acceptable salt or solvate thereof;

3′′′) the compound of 2) or 2′) described above wherein the ring A′ is pyridyl, a pharmaceutically acceptable salt or solvate thereof;

4) the compound of 1)-3), 1′), 2′), 3′), 3′′) or 3′′′) described above wherein R1 is C1-C3 alkyl, a pharmaceutically acceptable salt or solvate thereof;

4′) the compound of 1)-3), 1′), 2′), 3′), 3′′) or 3′′′) described above wherein R1 is optionally substituted lower alkynyl, a pharmaceutically acceptable salt or solvate thereof;

5) the compound of 1)-4), 1′), 2′), 3′), 3′′), 3′′′) or 4′) described above wherein R2a and R2b are both hydrogen, a pharmaceutically acceptable salt or solvate thereof;

6) the compound of 1)-5), 1′), 2′), 3′), 3′′), 3′′′) or 4′) described above wherein all of R3a, R3b, R3c and R3d are hydrogen, a pharmaceutically acceptable salt or solvate thereof;

6′) the compound of 1) 5), 1′), 2′), 3′), 3′′), 3′′′) or 4′) described above wherein R3a and R3b are the same substituent selected from halogen and optionally substituted lower alkyl, a pharmaceutically acceptable salt or solvate thereof;

6′′) the compound of 1)-5), 1′), 2′), 3′), 3′′), 3′′′) or 4′) described above wherein R3c and R3d are the same substituent selected from halogen and optionally substituted lower alkyl, a pharmaceutically acceptable salt or solvate thereof;

6′′′) the compound of 1)-5), 1′), 2′), 3′), 3′′), 3′′′) or 4′) described above wherein R3a and R3b or R3c and R3d form a carbocyclic ring together with a linked carbon atom a pharmaceutically acceptable salt or solvate thereof;

7) the compound of 1)-5), 1′), 2′), 3′), 3′′), 3′′′) 4′) described above wherein R3c or R3d is optionally substituted carbocyclic ring lower alkoxy or optionally substituted heterocyclyl lower alkoxy, a pharmaceutically acceptable salt or solvate thereof;

7′) the compound of 1)-5), 1′), 2′), 3′), 3′′), 3′′′) or 4′) described above wherein R3c and R3d form oxo together with a linked carbon atom, a pharmaceutically acceptable salt or solvate thereof;

8) a pharmaceutical composition comprising a compound of 1)-7), 1′), 3′), 3′′), 3′′′), 4′) 6′), 6′′), 6′′′) or 7′) described above, a pharmaceutically acceptable salt or solvate thereof as an active ingredient; and

9) a pharmaceutical composition having a BACE 1 inhibitory activity comprising a compound of 1)-7), 1′), 2′), 3′), 3′′), 3′′′), 4′) 6′), 6′′), 6′′′) or 7′) described above, a pharmaceutically acceptable salt or solvate thereof as an active ingredient;

The present invention also provides with
10) the pharmaceutical composition having a BACE 1 inhibitory activity of 9) described above, which is a composition having inhibitory activity of amyloid β protein production;
11) the pharmaceutical composition having a BACE 1 inhibitory activity of 9) described above, which is a medicine for treating diseases induced by production, secretion and/or deposition of amyloid β protein;
12) the pharmaceutical composition having a BACE 1 inhibitory activity of 9) described above, which is a medicine for treating Alzheimer's disease;
13) a method for treating diseases induced by production, secretion and/or deposition of amyloid β protein, characterized in administering a compound of the formula (I) described in 1) above, a pharmaceutically acceptable salt or solvate thereof;
14) use of a compound of the formula (I) described in 1) above, a pharmaceutically acceptable salt or solvate thereof described in 1) above, in manufacturing a medicine for treating diseases induced by production, secretion and/or deposition of amyloid β protein;

15) a method for treating diseases induced by BACE 1 characterized in administering a compound of the formula (I) described in 1) above, a pharmaceutically acceptable salt or solvate thereof;

16) use of a compound of the formula (I) described in 1) above, a pharmaceutically acceptable salt or solvate thereof, in manufacturing a medicine for treating diseases induced by BACE 1;

17) a method for treating Alzheimer's disease characterized in administering a compound of the formula (I) described in 1) above, a pharmaceutically acceptable salt or solvate thereof; and

18) use of a compound of the formula (I) described in 1) above, a pharmaceutically acceptable salt or solvate thereof in manufacturing a medicine for treating Alzheimer's disease.

Effect of Invention
A compound of the present invention is useful for treating diseases induced by production, secretion and/or deposition of amyloid β protein (Alzheimer's disease etc.).


BEST MODE FOR CARRYING OUT THE INVENTION
In this description, “halogen” includes fluorine, chlorine, bromine and iodine.
A moiety of halogen in “halogen lower alkyl” and “halogeno lower alkoxycarbonyl” is the same as “halogen” above.
“Lower alkyl” includes C1-C15, preferably C1-C10, more preferably C1-C6 and further more preferably C1-C3 straight or branched alkyl, and for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl and n-decyl are exemplified.
A moiety of alkyl in “lower alkoxy”, “halogeno lower alkyl”, “hydroxyl lower alkyl”, “hydroxyl lower alkoxy”, “lower alkoxycarbonyl”, “halogeno lower alkoxycarbonyl”, “lower alkoxycarbonyl lower alkyl”, “lower alkylamino”, “lower alkoxy lower alkyl”, “hydroxyimino lower alkyl”, “lower alkoxyimino lower alkyl”, “amino lower alkyl” “lower alkoxy lower alkoxy”, “lower alkoxy lower alkenyl”, “lower alkoxycarbonyl lower alkenyl”, “lower alkoxy lower alkynyl”, “lower alkoxycarbonyl lower alkynyl”, “lower alkyl carbamoyl”, “hydroxyl lower alkyl carbamoyl”, “lower alkoxyimino”, “lower alkylthio”, “lower alkylsulfonyl”, “lower alkylsulfonyloxy”, “lower alkyl sulfamoyl”, “lower alkyl sulfinyl”, “carbocyclyl lower alkyl”, “carbocyclyl lower alkyl”, “carbocyclyl lower alkoxy”, “carbocyclyl lower alkoxycarbonyl”, “carbocyclyl lower alkylamino”, “carbocyclyl lower alkyl carbamoyl”, “cycloalkyl lower alkyl”, “cycloalkyl lower alkoxy”, “cycloalkyl lower alkylamino”, “cycloalkyl lower alkoxycarbonyl”, “cycloalkyl lower alkylcarbamoyl”, “aryl lower alkyl”, “aryl lower alkoxy”, “aryl lower alkylamino”, “aryl lower alkoxycarbonyl.”, “aryl lower alkoxycarbamoyl”, “heterocyclyl lower alkyl”, “heterocyclyl lower alkoxy”, “heterocyclyl lower alkylamino”, “heterocyclyl lower alkoxycarbonyl” and “heterocyclyl lower alkylcarbamoyl” is the same as “alkyl” above.
“Optionally substituted lower alkyl” may be substituted with one or more of substituent(s) selected from a substituent group α.
Group α is a group consisting of halogen, hydroxy, lower alkoxy, hydroxy lower alkoxy, lower alkoxy lower alkoxy, acyl, acyloxy, carboxy, lower alkoxycarbonyl, amino, acylamino, lower alkylamino, imino, hydroxyimino, lower alkoxyimino, lower alkylthio, carbamoyl, lower alkylcarbamoyl, hydroxy lower alkylcarbamoyl, sulfamoyl, lower alkylsulfamoyl, lower alkylsulfonyl, cyano, nitro, a carbocyclic group and a heterocyclic group.
One or more of substituent(s) selected from the substituent group α is exemplified as a substituent of “optionally substituted lower alkoxy”, “optionally substituted lower alkoxycarbonyl” and “optionally substituted lower alkylthio”
“Lower alkylidene” includes a divalent group derived from the “lower alkyl” above, and methylidene, ethylidene, propylidene, isopropylidene, butylidene, pentylidene and hexylidene etc. are exemplified.
“Lower alkenyl” includes C2-C15, preferably C2-C10, more preferably C2-C6 and further more preferably C2-C4 straight or branched alkenyl having one or more double bond(s) at any position thereof. Examples of lower alkenyl include vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl and the like.
“Lower alkynyl” includes C2-C10, preferably C2-C8, more preferably C3-C6 straight or branched alkynyl having one or more triple bond(s) at any position thereof. Examples of lower alkynyl include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like. Lower alkynyl may additionally have a double bond at any position thereof.
One or more of substituent(s) selected from the substituent group α is exemplified as a substituent of “optionally substituted lower alkenyl” and “optionally substituted lower alkynyl”.
A moiety of lower alkenyl in “hydroxyl lower alkenyl”, “lower alkoxy lower alkenyl”, “lower alkoxycarbonyl lower alkenyl”, “carbocyclyl lower alkenyl”, “lower alkenyloxy”, “lower alkenylthio” and “lower alkenylamino” is the same as that of “lower alkenyl”.
A moiety of lower alkynyl in “hydroxyl lower alkynyl”, “lower alkoxy lower alkynyl”, “lower alkoxycarbonyl lower alkynyl”, “carbocyclyl lower alkynyl”, “lower alkynyloxy”, “lower alkenylamino” and “lower alkynylamino” is the same as that of “lower alkynyl” above.
One or more substituents selected from lower alkyl, acyl, hydroxyl, lower alkoxy, lower alkoxycarbonyl, a carbocyclic group and a heterocyclic group etc. is exemplified as a substituent of “optionally substituted amino” and “optionally substituted carbamoyl”.
“Acyl” includes C1-C10 aliphatic acyl, carbocyclyl carbonyl and heterocyclic carbonyl, and examples of acyl include formyl, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, hexanoyl, acryloyl, propioloyl, methacryloyl, crotonoyl, benzoyl, cyclohexanecarbonyl, pyridinecarbonyl, furancarbonyl, thiophenecarbonyl, benzothiazolecarbonyl, pyrazinecarbonyl, piperidinecarbonyl, thiomorpholino and the like.
A moiety of acyl in “acylamino” and “acyloxy” is the same as described above.
One or more substituents selected from the substituent group α is exemplified as a substituent in “optionally substituted acyl” and a moiety of the ring in carbocyclyl carbonyl and heterocyclylcarbonyl is optionally substituted with one or more substituent(s) selected from lower alkyl, the substituent group α and lower alkyl substituted with one or more substituent(s) selected from the substituent group α.
“A carbocyclic group” includes cycloalkyl, cycloalkenyl, aryl, and non-aromatic fused carbocyclic group etc.
“Cycloalkyl” includes C3-C10, preferably C3-C8 and more preferably C4-C8 carbocyclic group and examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like.
A moiety of cycloalkyl in “cycloalkyl lower alkyl”, “cycloalkyloxy”, “cycloalkyl lower alkoxy”, “cycloalkylthio”, “cycloalkylamino”, “cycloalkyl lower alkylamino”, “cycloalkylsulfamoyl”, “cycloalkylsulfonyl”, “cycloalkylcarbamoyl”, “cycloalkyl lower alkylcarbamoyl”, “cycloalkyl lower alkoxycarbonyl” and “cycloalkylcarbonyl” is the same as “cycloalkyl” described above
“Cycloalkenyl” includes the above cycloalkyl having one or more double bond(s) at any position on the ring, and examples of the cycloalkenyl include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptynyl, cyclooctynyl, and cyclohexadienyl etc.
Examples of “aryl” include phenyl, naphthyl, anthryl and phenanthryl etc. and especially phenyl is preferable.
“Non-aromatic fused carbocyclic group” includes a group in which two or more cyclic groups selected front “cycloalkyl”, “cycloalkenyl” and “aryl” described above fused, and examples of “Non-aromatic fused carbocyclic group” include indanyl, indenyl, tetrahydronaphthyl and fluorenyl etc.
“Forming a carbocyclic ring together with a linked carbon atom” means that two substituents jointly form “cycloalkyl” above.
A moiety of the carbocyclic ring in “carbocyclyloxy”, “carbocyclyl lower alkyl”, “carbocyclyl lower alkenyl”, “carbocyclyl lower alkynyl”, “carbocyclyl lower alkoxy”, “carbocyclyl lower alkoxycarbonyl”, “carbocyclylthio”, “carbocyclyl amino”, “carbocyclyl lower alkylamino”, “carbocyclylcarbonyl”, “carbocyclylsulfamoyl”, “carbocyclylsulfonyl”, “carbocyclylcarbamoyl”, “carbocyclyl lower alkyl carbamoyl”, “carbocyclyloxycarbonyl” is the same as the “carbocyclic group”.
A moiety of aryl in “aryl lower alkyl”, “aryloxy”, “aryloxycarbonyl”, “aryloxylcarbonyloxy”, “aryl lower alkoxycarbonyl”, “arylthio”, “arylamino”, “aryl lower alkoxy”, “aryl lower alkylamino”, “arylsulfonyl”, “arylsulfonyloxy”, “arylsulfinyl”, “arylsulfamoyl”, “arylcarbamoyl” and “aryl lower alkylcarbamoyl” is the same as the “aryl” above.
“Heterocyclic group” includes a heterocyclic group containing one or more heteroatom(s) each independently selected from O, S and N, and examples of “heterocyclic group” include 5- or 6-membered heteroaryl such as pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl and thiadiazolyl etc.; a non-aromatic heterocyclic group such as dioxanyl, thin-amyl, oxiranyl, oxetanyl, oxathiolanyl, azetidinyl, thianyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pirazolinyl, piperidyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, dihydropyridyl, tetrahydropyridyl, tetrahydrofuryl, tetrahydropyranyl, dihydrothiazolyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, dihydrooxazinyl, hexahydroazepinyl, tetrahydrodiazepinyl and tetrahydropyridazinyl etc.;
a fused bicyclic heterocyclic group such as indolyl, isoindolyl, indazolyl, indolidinyl, indolinyl, isoindolinyl, quinolyl, isoquinolyl, cinnolinyl, phthaladinyl quinazolinyl, naphthilidinyl, quinoxalinyl, purinyl, pteridinyl, benzopyranyl, benzimidazolyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzoisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, thienopyridyl, thienopyrrolyl, thienopyrazolyl, thienopyrazinyl, furopyrrolyl, thienothienyl, imidazopyridyl, pyrazolopyridyl, thiazolopyridyl, pyrazolopyrimidinyl, pyrazolotriazinyl, pyridazolopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, quinazolinyl, quinolyl, isoquinolyl, naphthilidinyl, dihydrothiazolopyrimidinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, dihydrobenzofuryl, dihydrobenzoxazinyl, dihydrobenzimidazolyl, tetrahydrobenzothienyl, tetrahydrobenzofuryl, benzodioxolyl, benzodioxonyl, chromanyl, chromenyl, octahydrochromenyl, dihydrobenzodioxinyl, dihydrobenzooxedinyl, dihydrobenzooxepinyl and dihydrothienodioxinyl etc.; and a fused tricyclic heterocyclic group such as carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathiinyl, phenoxadinyl, dibenzofuryl, imidazoquinolyl and tetrahydrocarbazolyl etc.; and preferably includes 5- or 6-membered heteroaryl and a non-aromatic heterocyclic group.
A moiety of the heterocyclic group in “heterocyclyl lower alkyl”, “heterocyclyloxy”, “heterocyclylthio”, “heterocyclylcarbonyl”, “heterocyclyl lower alkoxy”, “heterocyclyl amino”, “heterocyclyl carbonylamino”, “heterocyclyl sulfamoyl”, “heterocyclylsulfonyl”, “heterocyclylcarbamoyl”, “heterocyclyloxylcarbonyl”, “heterocyclyl lower alkylamino”, “heterocyclyl lower alkoxycarbonyl” and “heterocyclyl lower alkylcarbamoyl” is the same as the “heterocyclic group” above.
“A nitrogen-containing aromatic heterocyclic group” means a group of the “heterocyclic group” above containing at least one nitrogen atom, and examples of the “nitrogen-containing aromatic heterocyclic group” include 5- or 6-membered heteroaryl such as pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl and thiadiazolyl etc.;
a fused bicyclic heterocyclo group such as indolyl, isoindolyl, indazolyl, indolidinyl, indolinyl, isoindolinyl, quinolyl, isoquinolyl, cinnolinyl, phthaladinyl, quinazolinyl, naphthilidinyl, quinoxalinyl, purinyl, pteridinyl, benzopyranyl, benzimidazolyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzoisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, imidazopyridyl, pyrazolopyridine, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, quinazolinyl, quinolyl, isoquinolyl, naphthylidinyl, dihydrobenzofuryl, tetrahydroquinolyl, tetrahydroisoquinolyl, dihydobenzoxazine etc.; and

a fused tricyclic heterocyclo group such as carbazolyl, acridinyl, xanthenyl and imidazoquinolyl etc.; and pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, dihydropiridyl, dihydrobenzimidazolyl, tetrahydropyridyl, tetrahydrothiazolyl and tetrahydroisothiazolyl etc.

“The heterocyclic group” or “nitrogen-containing aromatic heterocyclic group” above may be linked to other group at any position on the ring.
“Nitrogen-containing aromatic monocyclic heterocyclic group” means a monocyclic group in the “nitrogen-containing aromatic heterocyclic group” and examples of the “Nitrogen-containing aromatic monocyclic heterocyclic group” include 5- or 6-membered heteroaryl such as pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl and thiadiazolyl etc.
“The nitrogen-containing aromatic monocyclic heterocyclic group” above may be linked to other group at any carbon atom on the ring.
Examples of a substituent in the “optionally substituted carbocyclic group” and “optionally substituted heterocyclic group” of the ring A and B include
the substituent group α (preferably halogen, hydroxyl, acyl, acyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, amino, cyano, lower alkylamino, lower alkylthio etc);
lower alkyl optionally substituted with one or more substituent(s) selected from the substituent group α, hydroxyimino and lower alkoxyimino, wherein examples of preferable substituents include halogen, hydroxyl, lower alkoxy, lower alkoxycarbonyl etc.;
amino lower alkyl substituted with one or more substituent(s) selected from the substituent group α, wherein examples of preferable substituents include acyl, lower alkyl and/or lower alkoxy etc.;
hydroxyimino lower alkyl, lower alkoxyimino lower alkyl;
lower alkenyl optionally substituted with one or more substituent(s) selected from the substituent group α, wherein examples of preferable substituents include lower alkoxycarbonyl, halogen and/or halogen lower alkoxycarbonyl;
lower alkynyl optionally substituted with one or more substituent(s) selected from the substituent group α, wherein examples of preferable substituents include lower alkoxycarbonyl etc;
lower alkoxy optionally substituted with one or more substituent(s) selected from the substituent group α, wherein examples of preferable substituents include halogenocarbamoyl, oxetane, lower alkylcarbamoyl, hydroxyl lower alkylcarbamoyl;
lower alkoxy lower alkoxy optionally substituted with one or more substituent(s) selected from the substituent group α;
lower alkenyloxy optionally substituted with one or more substituent(s) selected from the substituent group α wherein examples of preferable substituents include halogen, hydroxyl, amino, lower alkyl etc.;
lower alkoxy lower alkenyloxy optionally substituted with one or more substituent(s) selected from the substituent group α;
lower alkynyloxy optionally substituted with one or more substituent(s) selected from the substituent group α, wherein examples of preferable substituents include halogen, hydroxyl etc.;
lower alkoxy lower alkynyloxy optionally substituted with one or more substituent(s) selected from the substituent group α;
lower alkylthio optionally substituted with one or more substituent(s) selected from the substituent group α;
lower alkenylthio optionally substituted with one or more substituent(s) selected from the substituent group α;
lower alkynylthio optionally substituted with one or more substituent(s) selected from the substituent group α;
lower alkylamino substituted with one or more substituent(s) selected from the substituent group α;
lower alkenylamino substituted with one or more substituent(s) selected from the substituent group α;
lower alkynylamino substituted with one or more substituent(s) selected from the substituent group α;
aminooxy optionally substituted with one or more substituent(s) selected from lower alkylidene and the substituent group α;
acyl substituted with one or more substituent(s) selected from the substituent group α;
lower alkylsulfonyl optionally substituted with one or more substituent(s) selected from the substituent group α;
lower alkylsulfinyl optionally substituted with one or more substituent(s) selected from the substituent group α;
sulfamoyl;
lower alkylsulfamoyl optionally substituted with one or more substituent(s) selected from the substituent group α;
a carbocyclic group (preferably cycloalkyl, aryl etc.) optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
a heterocyclic group optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
carbocyclyl lower alkyl (preferably cycloalkyl lower alkyl, aryl lower alkyl etc.) optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
heterocyclyl lower alkyl optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
carbocyclyloxy (preferably cycloalkyloxy, aryloxy etc.) optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
heterocyclyloxy optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
carbocyclyl lower alkoxy (preferably cycloalkyl lower alkoxy, aryl lower alkoxy, etc.) optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
heterocyclyl lower alkoxy (preferably cycloalkyl lower alkoxycarbonyl, aryl lower alkoxycarbonyl etc.) optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl,
carbocyclyl lower alkoxycarbonyl optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogen° lower alkyl;
heterocyclyl lower alkoxycarbonyl optionally substituted with one or more substituent(s) selected from the substituent group α, wide, lower alkyl and halogeno lower alkyl;
carbocyclylthio (preferably cycloalkylthio, arylthio etc.) optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogen lower alkyl;
heterocyclylthio optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
carbocyclyl amino(preferably cycloalkylamino, arylamino etc.) optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
heterocyclyl amino optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
carbocyclyl lower alkylamino (preferably cycloalkyl lower alkylamino, aryl lower alkylamino etc.) optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
heterocyclyl lower allylamino optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
lower alkylsulfamoyl optionally substituted with one or more substituent(s) selected from the substituent group α;
carbocyclylsulfamoyl (preferably cycloalkyl sulfamoyl, arylsulfamoyl etc.) optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
heterocyclylsulfamoyl optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
carbocyclylsulfonyl (preferably cycloalkyl sulfonyl, arylsulfonyl etc.) optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
heterocyclylsulfonyl optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
carbocyclylcarbamoyl (preferably cycloalkyl carbamoyl, aryl carbamoyl etc.) optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
heterocyclyl carbamoyl optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
carbocyclyl lower alkylcarbamoyl (preferably cycloalkyl lower alkylcarbamoyl, aryl lower alkylcarbamoyl etc.) optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
heterocyclyl lower alkylcarbamoyl optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogen lower alkyl,
carbocyclyloxycarbonyl (preferably cycloalkyloxycarbonyl, aryloxycarbonyl etc.) optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogen lower alkyl;
heterocyclyloxycarbonyl optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogen lower alkyl;
lower alkylenedioxy optionally substituted with halogen;
oxo, azide and the like.
These may be substituted with one or more substituents selected from these groups.
Also the ring A may be substituted with one or more group(s) selected from







wherein Ak1, Ak2 and Ak3 are each independently a single bond, optionally substituted lower alkylene, optionally substituted lower alkenylene or optionally substituted lower alkynylene;

Ak4 is optionally substituted lower alkylene, optionally substituted lower alkenylene or optionally substituted lower alkynylene;

W1 and W3 are each independently O or S,

W2 is O, S or NR5,

R5 and R6 are each independently hydrogen, lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl, lower alkoxycarbonyl lower alkyl, carbocyclyl lower alkyl, lower alkenyl, hydroxyl lower alkenyl, lower alkoxy lower alkenyl, lower alkoxycarbonyl lower alkenyl, carbocyclyl lower alkenyl, lower alkynyl, hydroxyl lower alkynyl, lower alkoxy lower alkynyl, lower alkoxycarbonyl lower alkynyl, carbocyclyl lower alkynyl or acyl;

R7 is hydrogen or lower alkyl;

the ring B is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group; and

p is 1 or 2; W1, W3 or W5 may be independent when it is pluralized. Additionally the oxygen atom of (xii) may be cis or trans to the substituent R7.

Preferable examples of (i) to (xixi) above include




wherein Ak is optionally substituted lower alkylene, optionally substituted lower alkenylene or optionally substituted lower alkynylene, and the other symbols are the same as described above.

In other cases of “an optionally substituted carbocyclic group” and “an optionally substituted heterocyclic group”, one or more substituent(s) selected from a group of lower alkyl and the substituent group a may be exemplified as a substituent of “an optionally substituted carbocyclic group” and “an optionally substituted heterocyclic group”
“Heteroaryl” includes an aromatic cyclic group among the “heterocyclic group” above.
“Lower alkylene” includes C1-C10, preferably C1-C6; more preferably C1-C3 straight or branched divalent carbon chain, and for example, methylene, dimethylene, trimethylene, tetramethylene and methyl trimethylene are exemplified.
A moiety of lower alkylene in “lower alkylenedioxy” is the same as the “lower alkylene” described above.
“Lower alkenylene” includes C2-C10, preferably C2-C6, more preferably C2-C4 straight or branched divalent carbon chain having a double bond at any arbitrary position thereof, and vinylene, propenylene, butenylene, butadienylene, methyl propenylene, pentenylene and hexenylene are exemplified.
“Lower alkynylene” includes C2-C10, preferably C2-C6, more preferably C2-C4 straight or branched divalent carbon chain having a triple bond and also a double bond at any arbitrary position thereof, and for example, ethynylene, propynylene, butynylene, pentynylene and hexynylene are exemplified.
Examples of a substituent in “optionally substituted lower alkylene”, “optionally substituted lower alkenylene” and “optionally substituted lower alkynylene” include the substituent group α, and preferably halogen and hydroxyl etc. are exemplified.
Examples of a substituent in “optionally substituted carbocyclyl lower alkyl”, “optionally substituted heterocyclyl lower alkyl”, “optionally substituted carbocyclyl lower alkoxy”, and “optionally substituted heterocyclyl lower alkoxy” include one or more substituent(s) selected from lower alkyl and the substituent group α.
In this specification, “solvate” includes a solvate with an organic solvent and a hydrate etc. and hydrate may be coordinated with optional number of water molecule.
The compound (I) includes pharmaceutical acceptable salt thereof. Examples of the pharmaceutical acceptable salt include a salt with an alkali metal such as lithium, sodium and potassium etc., an alkali earth metal such as magnesium, calcium etc., ammonium, an organic base and an amino acid; a salt with an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid or hydroiodic acid etc., and an organic acid such as acetic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, benzensulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, etc. Especially hydrochloric acid, phosphoric acid, tartaric acid or methane sulfuric acid is preferable. These salts can be prepared by a method usually carried out.
The compound (I) is not construed to be limited to a specific isomer but to include all possible isomers such as a keto-enol isomer, an imine-enamine isomer, a diastereoisomer, an optical isomer and a rotational isomer etc. For example, a compound (I) in which R2a is hydrogen includes a tautomer as follows;




The compound (I) of the present invention can be prepared, for example, according to the non-patent literature 1 or a method described below;
Preparation of an Aminodihydrothiazine Ring (I-1) or (I-2):




(In the scheme above, at least one of R2b and R2c is hydrogen, R3b and R3d are each independently hydrogen, halogen, hydroxyl, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted acyl, optionally substituted lower alkoxy, optionally substituted lower alkylthio, carboxy, optionally substituted lower alkoxycarbonyl, optionally substituted amino, optionally substituted carbamoyl, an optionally substituted carbocyclic group, or an optionally substituted heterocyclic group, and the other symbols are the same as described above.)

The 1st step: A Grignard reagent having a corresponding substituent of the objective compound such as vinyl magnesium chloride, vinyl magnesium bromide and propenyl magnesium bromide etc. is added to a compound a, which is commercially available or can be prepared by a known method, in a solvent such as ether, tetrahydrofuran etc. or a mixed solvent of ether-tetrahydrofuran etc., at −100° C. to 50° C., preferably −80° C. to 0° C. and the mixture is stirred for 0.2 to 24 hours, preferably 0.2 to 5 hours to give a compound b.

The 2nd step: To a compound b in an acid such as acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid etc. or a mixture thereof under the presence of a solvent such as toluene etc. or without a solvent, is added a substituted thiourea having a corresponding substituent of the objective compound such as thiourea, N-methylthiourea, N,N′-dimethylthiourea etc., and the mixture is stirred at −20° C. to 100° C., preferably 0° C. to 80° C. for 0.5 hours to 120 hours, preferably 1 hour to 72 hours to give a compound c.

The 3rd step: To a compound c in a solvent such as toluene etc. or without a solvent, is added an acid such as trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, sulfuric acid etc. or a mixture thereof and reacted at −20° C. to 100° C., preferably 0° C. to 50° C. for 0.5 hours to 120 hours, preferably 1 hour to 72 hours to give a compound (I-2) when R2b is hydrogen or a compound (I-1) when R2c is hydrogen.

Preparation of an Aminodihydrothiazine Ring (I-3):





(In the scheme above, L is a leaving group such as halogen or lower alkylsulfonyl etc. and the other symbols are the same as described above.)

The 1st step: Thiocyanate such as sodium thiocyanate or ammonium thiocyanate etc. is reacted with a compound d, which is commercially available or can be prepared by a known method, in a solvent such as toluene, chloroform, tetrahydrofuran etc. under the presence of water and an acid such as hydrochloric acid or sulfuric acid etc. at 0° C. to 150° C., preferably at 20° C. to 100° C. for 0.5 to 24 hours, preferably 1 to 12 hours to give a compound e.

The 2nd step: A reducing agent such as sodium borohydride etc. is added to and reacted with a compound e in a solvent such as tetrahydrofuran, methanol, ethanol, water etc. or a mixture of ethanol-water etc. under the presence of buffering agent such as sodium dihydrogen phosphate at −80° C. to 50° C., preferably at −20° C. to 20° C. for 0.1 to 24 hours, preferably 0.5 to 12 hours to give a compound f.

The 3rd step: A compound f is reacted with a halogenating agent such as thionyl chloride, phosphoryl chloride, carbon tetrachloride-triphenylphosphine etc. in a solvent such as toluene, dichloromethane etc. or without a solvent at −80° C. to 50° C., preferably at −20° C. to 20° C. for 0.1 to 24 hours, preferably 0.5 to 12 hours; or it is reacted with a sulfonating agent such as methanesulfonyl chloride, p-toluenesulfonyl chloride etc. in a solvent such as toluene, dichloromethane etc. under the presence of a base such as triethylamine etc. at −80° C. to 50° C., preferably at −20° C. to 20° C. for 0.1 to 24 hours, preferably 0.5 to 12 hours to give a compound g.

The 4th step: A compound g is reacted with ammonia or a primary amine such as methylamine etc. in a solvent such as methanol, ethanol, water etc. or a mixture of methanol-water etc. at −20° C. to 80° C., preferably at 0° C. to −40° C. for 0.5 to 48 hours, preferably 1 to 24 hours to give the compound (I-3).

Preparation of an Aminodihydrothiazine Ring (I-6) or an Aminotetrahydrothiazine Ring (I-7)





(In the scheme above, at least one of R2b and R2c is hydrogen and the other symbols are the same as described above.)

The 1st step: Thiourea or a substituted thiourea corresponding to the objective compound such as N-methyl thiourea, N,N-dimethylthiouers, N,N′-dimethylthiouera etc. is reacted with a compound o, which is commercially available or can be prepared by a known method, in a solvent such as ethanol, methanol, tetrahydrofuran, toluene etc. at −20° C. to 200° C., preferably at 0° C. to 150° C. for 0.5 to 200 hours, preferably 1 to 120 hours to give a compound p.

The 2nd step: A Grignard reagent corresponding to the objective compound such as methyl magnesium chloride, ethyl magnesium bromide and benzyl magnesium bromide etc. is added to a compound p in a solvent such as ether, tetrahydrofuran etc. or a mixed solvent thereof at −100° C. to 50° C., preferably −80° C. to 30° C. and the mixture is stirred for 0.2 to 24 hours, preferably 0.5 to 5 hours to give a compound q.

The 3rd step: To a compound q in a solvent such as toluene etc. or without a solvent, is added an acid such as trifluoroacetic methanesulfonic acid, trifluoromethanesulfonic acid, sulfuric acid etc. or a mixture thereof and reacted at −20° C. to 100° C., preferably 0° C. to 50° C. for 0.5 hours to 200 hours, preferably 1 hour to 150 hours to give a compound (I-6) (R2c═H) or a compound (I-7) (R2b═H).

Preparation of an Aminodihydrothiazine Ring (I-8)





(In the scheme, each symbol is the same as described above)

The 1st step: Ammonium chloride is added to a compound r which be prepared by a known method in a solvent such as acetic acid etc. at 0° C. to 200° C., preferably 10° C. to 100° C. for 0.1 hours 100 hours, preferably 0.5 hour to 24 hours to give a compound.

The 2nd step: A reducing agent such as lithium aluminium hydride, diisobutyl aluminum hydride etc. is reacted with a compounds in a solvent such as tetrahydrofuran, diethyl ether etc. at −80° C. to 150° C., preferably 0° C. to 100° C. for 0.1 hours to 24 hours, preferably 0.5 hour to 12 hours to give a compound t.

The 3rd step: Isothiocyanate corresponding to the objective compound such as 4-methoxybenzyl isothiocyanate, t-butyl isothiocyanate etc. or carbamoyl halide corresponding to the objective compound such as N,N-dimethyl thiocarbamoyl chloride, N,N-diethyl thiocarbamoyl chloride etc. is reacted with a compound t in a solvent such as toluene, chloroform, tetrahydrofuran etc. under the presence of a base such as diisopropylethylamine, triethylamine, pyridine, sodium hydroxide etc. or without a base at 0° C. to 150° C., preferably 20° C. to 100° C. for 0.5 hours to 120 hours, preferably 1 hour to 72 hours to give a compound u.

The 4th step: A halogenating agent such as thionyl chloride, phosphoryl oxychloride, carbon tetrachloride-triphenyl phosphine etc. is reacted with a compound u in a solvent such as acetonitrile, toluene, dichloromethane etc. at −80° C. to 50° C., preferably −20° C. to 20° C. for 0.1 hours to 24 hours, preferably 0.5 hour to 12 hours, or a sulfonylating agent such as methanesulfonyl chloride, p-toluenesulfonyl chloride is reacted with a compound u in a solvent such as toluene, dichloromethane etc. under the presence of a base such as triethylamine at −80° C. to 50° C., preferably −20° C. to 20° C. for 0.1 hours to 24 hours, preferably 0.5 hour to 12 hours. The resulting halogenated compound or sulfonate ester derivative is reacted with a base such as diisopropylethylamine, potassium carbonate, sodium bicarbonate, sodium hydride, sodium hydroxide etc. at 0° C. to 150° C. preferably 20° C. to 100° C. for 0.5 hours to 120 hours, preferably 1 hour to 72 hours to give a compound (I-8).

Preparation of an Acylamino Derivative (I-13) and/or (I-14)





(In the scheme, R17 is optionally substituted lower alkyl, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group and other symbols are the same as described above)

An acylating agent corresponding to the objective compound such as benzoyl chloride, 2-furoyl chloride, acetic anhydride etc. is reacted with a compound (I-12) in which R2b is hydrogen under the presence of a solvent such as tetrahydrofuran, dichloromethane etc. or without a solvent and under the presence of a base such as pyridine or triethylamine etc. or without a solvent at −80° C. to 100° C., preferably −20° C. to 40° C. for 0.1 hours to 24 hours, preferably 1 hour to 12 hours, or a compound (I-12) is reacted with a carboxylic acid having a substituent corresponding to the objective compound such as amino acid or glycolic acid etc. in a solvent such as dimethylformamide, tetrahydrofuran, dichloromethane etc. under the presence of a condensation agent such as dicyclohexylcarbodiimide, carbonyldiimidazole etc. at −80° C. to 100° C., preferably −20° C. to 40° C. for 0.1 hours to 24 hours, preferably 1 hour to 12 hours to give a compound (I-13) and/or (I-14) (when R2a is hydrogen).
Preparation of a Carbamoyl Derivative (I-17)




(In the scheme above. CONR18R19 is optionally substituted carbamoyl and the other symbols are the same as described above)

A compound (I-16) having a carboxyl group as a substituent on the ring A is reacted with a primary or secondary amine having a substituent corresponding to the objective compound (e.g., aniline, 2-aminopyridine, dimethylamine etc.) in a solvent such as dimethylformamide, tetrahydrofuran, dichloromethane etc. under the presence of a condensation agent such as dicyclohexylcarbodiimide, carbonyldiimidazole, dicyclohexylcarbodiimide-N-hydroxybenzotriazole etc. at −80° C. to 100° C., preferably −20° C. to 40° C. for 0.1 hours to 24 hours, preferably 1 hour to 12 hours to give a compound (I-17).
Preparation of an Acylamino Derivative (I-19)




(In the scheme, NHR20 is optionally substituted amino, NR20COR21 is optionally substituted acylamino, optionally substituted ureido or carboxyamino having a substituent on the oxygen atom and the other symbols are the same as described above.)

A compound (I-18) having an optionally substituted amino group on the ring A is reacted with a reagent having a substituent corresponding to the objective compound such as acid chlorides, acid anhydrides, chlorocarbonate esters, isocyanates etc. under the presence of a solvent such as tetrahydrofuran, dichloromethane etc. or without a solvent under the presence of a base such as pyridine, triethylamine etc. or without a base at −80° C. to 100° C., preferably −20° C. to 40° C. for 0.1 hours to 24 hours, preferably 1 hour to 12 hours, or a compound (I-18) is reacted with a carboxylic acid having a substituent corresponding to the objective compound such as benzoic acid, 2-pyridinecarboxylic acid etc. in a solvent such as dimethylformamide, tetrahydrofuran, dichloromethane etc. under the presence of a condensation agent such as dicyclohexylcarbodiimide, carbonyldiimidazole, dicyclohexylcarbodiimide-N-hydroxybenzothiazole etc. at −80° C. to 100° C., preferably −20° C. to 40° C. for 0.1 hours to 24 hours, preferably 1 hour to 12 hours to give a compound (I-19).
Preparation of an Alkylamino Derivative (I-20)




(In the scheme, NHR20 is optionally substituted amino and R22 is lower alkyl.)

A compound (I-18) having an amino group on the ring A is reacted with an aldehyde having a substituent corresponding to the objective compound such as benzaldehyde, pyridin-2-carboaldehyde etc. and a reducing agent such as sodium cyanoborohydride, sodium triacetoxyborohydride etc. in a solvent such as dichloromethane, tetrahydrofuran etc. under the presence of an acid such as acetic acid etc. or without an acid at −80° C. to 100° C., preferably 0° C. to 40° C. for 0.5 hours to 1.50 hours, preferably 1 hour to 24 hours to give a compound (I-20).
Preparation of a Substituted Alkoxy Derivative (I-22),




(In the scheme above, R23 is optionally substituted lower alkyl, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group and the other symbols are the same as described above.)

A compound (I-21) having a hydroxy group on the ring A is reacted with an alkylating agent having a substituent corresponding to the objective compound such as benzyl chloride, methyl iodide etc. in a solvent such as dimethylformamide, tetrahydrofuran etc. under the presence of a base such as potassium carbonate, sodium hydroxide, sodium hydride etc. at −80° C. to 100° C., preferably 0° C. to 40° C. for 0.5 hours to 150 hours, preferably 1 hour to 24 hours, or a compound (I-18) is reacted with an alcohol such as 2-aminoethanol etc. in a solvent such as dimethylformamide, tetrahydrofuran etc. under the presence of a Mitsunobu reagent such as triphenylphosphine-azodicarboxylic acid diethyl ester etc. at −80° C. to 100° C., preferably 0° C. to 40° C. for 0.5 hours to 72 hours, preferably 1 hour to 24 hours to give a compound (I-22).
Introduction of a Substituent by Palladium Coupling




(In the scheme above, Hal is halogen, G is optionally substituted lower alkenyl, optionally substituted alkynyl, optionally substituted alkoxycarbonyl, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group etc. and the other symbols are the same as described above.)

A compound (I-23) having halogen as a substituent on the ring A is reacted with a compound having a substituent corresponding to the objective compound (e.g., styrene, propargyl alcohol, aryl boronic acid, carbon monoxide etc.) in a solvent such as tetrahydrofuran, dimethylformamide, 1,2-dimethoxyethane, methanol etc. under the presence of a base such as triethylamine, sodium carbonate etc., a palladium catalyst such as palladium acetate, palladium chloride etc. and a ligand such as triphenylphosphine etc. and under irradiation of microwave or without the irradiation, at −80° C. to 150° C., preferably 0° C. to 100′C for 0.5 hours to 72 hours, preferably 1 hour to 24 hours to give a compound (I-24).
Preparation of an Oxime Derivative (I-26)




(In the scheme above, R24 is hydrogen, optionally substituted lower alkyl etc., R25 is hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group etc., and the other symbols are the same as described above.)

A compound (I-25) having an acyl group as a substituent of the ring A is reacted with a hydroxylamine having a substituent corresponding to the objective compound such as hydroxylamine, methoxylamine, O-benzylhydroxylamine etc. or a salt thereof in a solvent such as methanol, ethanol etc. under the presence of an additive such as potassium acetate etc. or without an additive at −80° C. to 100′C, preferably 0° C. to 40° C. for 0.5 hours to 150 hours, preferably 1 hour to 72 hours to give a compound (I-26).
Coupling Reaction




(In the scheme above, R26 is a substituent corresponding to each objective compound)

The 1st Step:

A compound v is reacted with a reagent having substituent corresponding to the objective compound such as acyl halide, acid anhydride, chlorocarbonate ester, isocyanate etc. (e.g., benzoyl chloride, 2-furoyl chloride, acetic anhydride, benzyl chloroformate, di-tert-butyl dicarbonate, phenyl isocyanate etc.) in a solvent such as tetrahydrofuran, dichloromethane, dimethylformamide etc. or without a solvent under the presence of a base such as pyridine, triethylamine etc. or without a base at −80° C. to 100° C., preferably −20° C. to 40° C. for 0.1 hours to 24 hours, preferably 1 hour to 12 hours, or a compound A is reacted with a carboxylic acid having a substituent corresponding to the objective compound such as benzoic acid, 2-pyridinecarboxylic acid etc. in a solvent such as dimethylformamide, tetrahydrofuran, dichloromethane, methanol etc. under the presence of a condensation agent such as dicyclohexylcarbodiimide, carbonyl diimidazole, dicyclohexylcarbodiimide-N-hydroxybenzotriazole, 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride, 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate etc. at −80° C. to 100° C., preferably −20° C. to 40° C. for 0.1 hours to 24 hours, preferably 1 hour to 12 hours to give a compound w.
When the substituent R has a functional group which disturb the said reaction, it can be carried out by protecting the functional group with a suitable protecting group and then deprotecting it at a subsequent appropriate step.
The 2nd Step:
A compound w is reacted in a solvent such as methanol, ethanol, ether, tetrahydrofuran, 1,4-dioxane, dichloromethane, ethyl acetate etc. containing trifluoroacetic acid etc. or in neat, or in neat trifluoroacetic acid at −30° C. to 100° C., preferably 0° C. to 90° C. for 0.5 to 12 hours to give a compound (I-27). Alternatively, the objective compound can be synthesized according to the method described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons) etc.
Preparation of an Optically Active Isomer
1) Preparation of an Optically Active Isomer ae
For example, an optically active isomer ae, one embodiment of the compounds of the present invention, can be prepared according to the following scheme:




(In the scheme above, R1 is optionally substituted lower alkyl, optionally substituted lower alkenyl or optionally substituted lower alkynyl, R27 is a chiral sulfoxide having optionally substituted lower alkyl, optionally substituted lower alkenyl, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group, or a chiral auxiliary group such as α-methyl benzyl etc.; R3a, R3b, R3c and R3d are each independently hydrogen, halogen, hydroxyl, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted acyl, carboxy, optionally substituted lower alkoxycarbonyl, optionally substituted amino, optionally substituted carbamoyl, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group; R28 is optionally substituted lower alkyl or optionally substituted lower alkenyl; R2a and R2b are each independently hydrogen, optionally substituted lower alkyl or optionally substituted acyl; and the other symbols are the same as described above.)

The compounds y and z above can be prepared by a method described in

    (1) T. Fujisawa et al., Tetrahedron Lett., 37, 3881-3884 (1996),
    (2) D. Hua et al, Sulfur Reports, vol. 21, pp. 211-239 (1999)
    (3) Y. Koriyama et al., Tetrahedron, 58, 9621-9628 (2002), or
    (4) T. Vilavan et al, Current Organic Chemistry, 9, 1315-1392 (2005).


Alternatively, these compounds can be prepared by optical resolution of each intermediate or the final product, or according to methods described below. Examples of the optical resolution method include a separation of optical isomers using an optically active column, kinetic resolution by an enzyme reaction etc., crystallization of diastereomers by salt formulation using a chiral acid or chiral base, and a preferential crystallization etc.
The 1st step: Compound y can be obtained by reacting Compound x, which is commercially available or can be prepared by a known method, with a chiral reagent having a substituent corresponding to the objective compound such as α-methylbenzylamine, para-toluene, tert-butylsulfine amide etc. at 60° C. to 120° C., preferably 80° C. to 100° C. in a solvent such as ether, tetrahydrofuran, toluene, benzene etc. or a mixed solvent such as ether-tetrahydrofuran etc. for 0.5 to 24 hours, preferably 0.5 to 5 hours, in the presence of molecular sieves or magnesium sulfate etc., under continuous evaporation by Dean-Stark apparatus, or according to the method described in the above literatures.

The 2nd step: A compound z can be diastereo-selectively obtained by reacting an enolate of lithium, aluminium, zinc, titan etc. prepared form a reagent having a substituent corresponding to the objective compound such as acetate ester etc., which is commercially available or can be prepared by a known method, or ketenesilyl acetate prepared from a reagent having a substituent corresponding to the objective compound such as ethyl acetate etc. with a compound a in a solvent such as ether, tetrahydrofuran, toluene, dichloromethane etc. or a mixed solvent such as ether-tetrahydrofuran etc. under the presence of a Lewis acid such as titanium tetrachloride, ether-trifluoroborane complex etc. or without a Lewis acid at −100° C. to 50° C., preferably −80° C. to −30° C. for 0.5 to 24 hours, preferably 0.5 to 5 hours. Alternatively, the compound z can be diastereo-selectively prepared by the method described in the literature (1) or (3).

The 3rd step: A compound z is reacted with a compound c in a solvent such as methanol, ethanol, ether, tetrahydrofuran, 1,4-dioxane, dichloromethane, ethyl acetate etc. containing hydrogen chloride, trifluoroacetic acid etc. or in neat trifluoroacetic acid at −30° C. to 100° C., preferably −10° C. to 90° C. for 0.5 to 12 hours, preferably 0.5 to 5 hours to give a compound aa.

The 4th step: A reducing agent such as borane-tetrahydrofuran complex, borane-dimethyl sulfoxide complex, borane-triethylamine complex, borane-pyridine complex etc. or ether- or tetrahydrofuran-solution thereof is reacted with a compound aa in a solvent such as ether, tetrahydrofuran, toluene etc. or a mixed solvent such as ether-tetrahydrofuran etc. at −30° C. to 30° C., preferably −10° C. to 20° C. for 0.5 to 12 hours, preferably 0.5 to 5 hours to give a compound ab.

The 5th step: Calcium carbonate or potassium carbonate etc. is added to a compound ab in a solvent such as dichloromethane, toluene etc. or a mixed solvent such as dichloromethane-water etc. and thiophosgene is added at −30° C. to 50° C., preferably −10° C. to 25° C. and the mixture is reacted for 0.5 to 12 hours, preferably 0.5 to 5 hours to give a compound ac.

The 6th step: Oxalyl chloride or thionyl chloride etc. and a catalytic amount of N,N-dimethylformamide are added to a compound ac in a solvent such as dichloromethane, tetrahydrofuran, toluene etc. at −30° C. to 50° C., preferably −10° C. to 20° C. and the mixture is reacted at 0° C. to 100° C., preferably 20° C. to 90° C. for 0.5 to 12 hours, preferably 0.5 to 5 hours to give a compound ad. Alternatively, it is obtained by a method described in Comprehensive Organic Transformations, Richard C Larock (Megaw-Hill).

The 7th step: 15% to 30% Ammonia water or a reagent having a substituent corresponding to the objective compound such as tert-butylamine etc. is added to a compound ad in a solvent such as ethyl acetate, dichloromethane, tetrahydrofuran, toluene etc. at −30° C. to 50° C., preferably −10° C. to 30° C. and the mixture is reacted at −10° C. to 30° C., preferably 0° C. to 30° C. for 0.5 to 72 hours to give a compound ae-i or a compound ae-ii.

When R2a and/or R2b is hydrogen in the resulting compound ae-i or ae-ii, a substituent of the objective compound, R2a and/or R2b, may be further introduced by a conventional method if it is necessary,
1′) Method for Preparing an Optically Active Isomer Method B
An optically active compound ah of the present invention can be also prepared by a method below:




(In the scheme the symbols are the same as described above.)

The 1st step to the 4th step: the same as described in 1) above.

The 5th step: isothiocyanate having a protecting group which is commercially available or can be prepared by a known method is added to a compound ab in a solvent such as dichloromethane, toluene, acetone etc. or a mixed solvent at −30° C. to 50° C., preferably −10° C. to 25° C. and the mixture is reacted for 0.5 to 12 hours, preferably 0.5 to 5 hours to give a compound ag.

The 6th step: Oxalyl chloride or thionyl chloride etc. and a catalytic amount of N,N-dimethylformamide are added to a compound ag in a solvent such as dichloromethane, tetrahydrofuran, toluene etc. at −30° C. to 50° C., preferably −10° C. to 25° C., or 1-chloro-N,N-2-trimethyl-1-propenenylamine is added to a compound ag, and reacted at 0° C. to 100° C., preferably 20° C. to 90′C for 0.5 to lot to give a compound ah-i ah-ii,

2) Introduction of R3a and R3b 

An optically active compound ae-iii or ae-iv of the present invention can be also prepared by introducing R3a and R3b as shown below:




(In the scheme above, each symbol is the same as described above)

When preparing a compound ae-iii or ae-iv in which R3a and R3b are substituted on the carbon atom next to S atom, a compound z is processed through the 3rd and 4th steps in place of the 3rd and 4th steps of 1) described above, and R3a and R3b are introduced in advance.
The 3rd step: A Grignard reagent having a substituent corresponding to the objective compound such as methyl magnesium chloride, ethyl magnesium bromide etc: is added to a compound z in a solvent such as ether, tetrahydrofuran etc. or a mixed solvent such as ether-tetrahydrofuran etc. at −100° C. to 50° C., preferably −80° C. to 30° C., or a compound z is converted to Weinreb Amide and reacted with a Grignard reagent having a substituent corresponding to the objective compound such as R3aMgBr, R3bMgBr. The reaction mixture is reacted for 0.2 to 24 hours, preferably 0.2 to 5 hours to give a compound aa′.

The 4th step: A compound aa′ is reacted in a solvent such as methanol, ethanol, ether, tetrahydrofuran, 1,4-dioxane, dichloromethane, ethyl acetate etc. containing hydrogen chloride, trifluoroacetic acid etc. or in neat, trifluoroacetic acid at −30° C. to 100° C., preferably −10° C. to 90° C. for 0.5 to 12 hours, preferably 0.5 to 5 hours to give a compound ab′.

The compound ab′ is processed in the same reactions as the 5th to 7th steps of 1) above to give the objective compound ae-iii or ae-iv.
When the substituent L of a compound ad′ is eliminated to give a compound ad′′ shown below, the objective compound ae′-iii or ae′-iv is obtained by processing the compound ad′′ it through the 7th step in place of the 7th step described in 1) above.




The 7th step: A compound ad′′ is dissolved in cone, sulfuric acid, trifluoroacetic acid, trifluoromethanesulfonic acid etc. and reacted at −30° C. to 100° C., preferably −10° C. to 40° C. for 0.1 to 12 hours, preferably 0.5 to 5 hours to give a compound ae′.

3) Conversion of a Substituent (1)

A preparation of a compound af-1 by conversion of the substituent is illustrated below:




(In the scheme, R8a and R8b are an amino-protecting up, and the other symbols are the same as described above.)

Trisdibenzylideneacetonedipalladium, palladium acetate, palladium(0) prepared situ etc. and a phosphine ligand such as tri-tert-butylphosphine, dicyclohexylbiphenylphosphine etc. are added to a compound ae-1 in a solvent such as tetrahydrofuran, toluene, xylene etc. and further a reagent having a substituent corresponding to the objective compound such as lithium hexamethylenedisilazide, benzophenonimine etc. is added thereto at −10° C. to 30° C., then the reaction mixture is reacted at 30° C. to 120° C., preferably 50° C. to 100° C. for 0.5 to 48 hours, preferably 3 to 20 hours to give a compound af-1.
Any amino-protecting group which is deprotected by a method described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons) etc. can be used and examples of the protecting group include lower alkoxycarbonyl, lower alkenyloxycarbonyl, trialkylsilyl, acyl, methanesulfonyl, trifluoromethanesulfonyl and toluenesulfonyl etc.
4) Conversion of a Substituent (2)
A preparation of a compound af-2 by conversion of the substituent is illustrated below:




(In the scheme, each symbol is the same as described above.)

A catalyst of catalytic reduction such as 10% palladium-carbon etc. is added to a compound ae-2 in a solvent such as tetrahydrofuran, ethyl acetate, methanol etc. and it is reacted under the pressure of normal to 5 atom, preferably normal to 2 atom of hydrogen atmosphere at 30° C. to 120° C., preferably 50′C to 80° C. for 0.5 to 48 hours, preferably 6 to 20 hours to give a compound af-2. Alternatively, the compound af-2 is Obtained by a method described in Comprehensive Organic Transformations, Richard C Larock (Mcgraw-Hill).
5) Conversion of a Substituent (3)
A preparation of a compound af-3 by conversion of the substituent is illustrated below:




(In the scheme, R9 is hydroxyl, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkylthio, optionally substituted lower alkyl amino, optionally substituted aromatic carbocyclyloxy, optionally substituted heterocyclyloxy, optionally substituted aromatic carbocyclylthio, optionally substituted heterocyclylthio, optionally substituted carbocyclylamino, optionally substituted heterocyclylamino, cyano, azide, an optionally substituted carbocyclic group, an optionally substituted heterocyclic group, optionally substituted carbamoyl etc. and the other symbols are the same as described above.)

A reagent having a substituent corresponding to the objective compound such as ethanol, methanthiol, dimethylamine etc. is added to a compound ae-3 in a solvent such as tetrahydrofuran, ethanol etc. under the presence of a base such as sodium methoxide, potassium tert-butoxide, sodium hydroxide, sodium hydride etc. or without a base at −10° C. to 50° C. and it is reacted for 0.5 to 12 hours, preferably 1 to 8 hours to give a compound af-3. If necessary, a coupling reaction may be carried out in the same manner as the method for preparing a compound (I-19) described above.
In every step described above, if a starting compound has a functional group which disturb the reaction (e.g., hydroxyl, mercapto, amino, formyl, carbonyl, carboxyl etc.), it is recommended to protect the functional group and deprotect it at a subsequent appropriate step with a method described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons) etc.
Further the order of steps may be changed and each reaction intermediate may be isolated and used in the subsequent step.
Examples of a preferable compound in the present invention include the followings:
In a formula (I′)




1) a compound in which the ring A′ is phenyl or a nitrogen-containing aromatic heterocyclic getup (hereinafter called a compound in which the ring A′ is A′1),

a compound in which the ring A′ is benzene, pyridine, indole, benzisoxazole, benzopyrazole, benzofuran, benzothiophene, benzodioxole, or dihydrobenzodioxolane (hereinafter called a compound in which the ring A′ is A′2),
a compound in which the ring A′ is benzene (hereinafter called a compound in which the ring A′ is A′3),
a compound in which the ring A′ is pyridine (hereinafter called a compound in which the ring A′ is A′4)
2) a compound in which R1 is optionally substituted lower alkyl (hereinafter called a compound in which R1 is R1-1),
a compound in which R1 is methyl (hereinafter called a compound in which R1 is R1-2),
3) a compound in which R2a and R2b are each independently hydrogen, lower alkyl or acyl (hereinafter called a compound in which R2a and R2b are R2-1),
a compound in which both of R2a and R2b are hydrogens (hereinafter called a compound in which R2a and R2b are R2-2),
4) a compound in which R3a, R3b, R3c and R3d are each independently hydrogen, halogen, hydroxyl, lower alkyl or amino (hereinafter called a compound in which R3a, R3b, R3c and R3d are R3-1),
a compound in which R3a and R3b, or R3c and R3d taken together form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl together (hereinafter called a compound in which R3a, R3b, R3c and R3d are R3-2),
a compound in which R3a and R3b, or R3c and R3d are the same substituent selected from halogen and lower alkyl (hereinafter called a compound in which R3a, R3b, R3c and R3d are R3-3),
a compound in which all of R3a, R3b, R3c and R3d are hydrogens (hereinafter called a compound in which R3a, R3b, R3c, and R3d are R3-4),
5) a compound in which n is 0 to 2, R4 is each independently halogen, lower alkoxy, lower alkylamino, lower alkylthio, oxo or lower alkylenedioxy (hereinafter called a compound in which R4 is R4-1),
a compound in which n is 0 to 2, R4 is each independently halogen (hereinafter called a compound in which R4 is R4-2),
6) a compound in which G is (ii), (iv), (v), (x), (xiii) or (xiv) above (hereinafter called a compound in which G is G1),
a compound in which G is (ii′), (ii′′), (iv′), (v′), (x′), (xiii′) or (xiv′) above (hereinafter called a compound in which G is G2),
a compound in which G is (ii′), (ii′′), (iv′), (v′), (x′), (xiii′) or (xiv′) above, and the ring B is optionally substituted pyridyl, optionally substituted pyrazinyl, optionally substituted thiazolyl, optionally substituted isoxazolyl, optionally substituted benzothiazolyl, optionally substituted thiazolopyridyl, optionally substituted quinolyl, optionally substituted isoquinolyl or optionally substituted naphthylidinyl, optionally substituted quinazolinyl, or optionally substituted pyridopyrimidinyl (hereinafter called a compound in which G is G3),
a compound in which G is (ii′) above (hereinafter called a compound in which G is G4),
a compound in which a combination of the ring A′, R1, R2a and R2b, R3a, R3b, R3c and R3d, n and R4, and G is as follows;
(A′1,R1-1,R2-1,R3-1,R4-1,G1), (A′1,R1-1,R2-1,R3-1,R4-1,G2), (A′1,R1-1,R2-1,R3-1,R4-1, G3), (A′1,R1-1,R2-1,R3-1,R4-1,G4), (A′1,R1-1,R2-1,R3-1,R4-2,G1), (A′1,R1-1,R2-1,R3-1,R4-2,G2), (A′1,R1-1,R2-1,R3-1,R4-2,G3), (A′1,R1-1,R2-1,R3-1,R4-2,G4), (A′1,R1-1,R2-1,R3-2,R4-1,G1), (A′1,R1-1,R2-1,R3-2,R4-1,G2), (A′1,R1-1,R2-1,R3-2,R4-1,G3), (A′1,R1-1,R2-1, R3-2,R4-1,G4), (A′1,R1-1,R2-1,R3-2,R4-2,G1), (A′1,R1-1,R2-1,R3-2,R4-2,G2), (A′1,R1-1,R2-1,R3-2,R4-2,G3), (A′1,R1-1,R2-1,R3-2,R4-2,G4), (A′1,R1-1,R2-1,R3-3,R4-1,G1), (A′1,R1-1,R2-1,R3-3,R4-1,G2), (A′1,R1-1,R2-1,R3-3,R4-1,G3), (A′1,R1-1,R2-1,R3-3,R4-1,G4), (A′1,R1-1,R2-1,R3-3,R4-2,G1), (A′1,R1-1,R2-1,R3-3,R4-2,G2), (A′1,R1-1,R2-1,R3-3,R4-2,G3), (A′1,R1-1,R2-1,R3-3,R4-2,G4), (A′1,R1-1,R2-1,R3-4,R4-1,G1), (A′1,R1-1,R2-1,R3-4,R4-1,G2), (A′1,R1-1,R2-1,R3-4,R4-1,G3), (A′1,R1-1,R2-1,R3-4,R4-1,G4), (A′1,R1-1,R2-1,R3-4,R4-2,G1), (A′1,R1-1,R2-1,R3-4,R4-2,G2), (A′1,R1-1,R2-1,R3-4,R4-2,G3), (A′1,R1-1,R2-1,R3-4,R4-2,G4), (A′1,R1-1,R2-2,R3-1,R4-1,G1), (A′1,R1-1,R2-2,R3-1,R4-1,G2), (A′1,R1-1,R2-2,R3-1,R4-1,G3), (A′1,R1-1,R2-2,R3-1,R4-1,G4), (A′1,R1-1,R2-2,R3-1,R4-2,G1), (A′1,R1-1,R2-2,R3-1,R4-2,G2), (A′1,R1-1,R2-2,R3-1,R4-2,G3), (A′1,R1-1,R2-2,R3-1,R4-2,G4), (A′1,R1-1,R2-2,R3-2,R4-1,G1), (A′1,R1-1,R2-2,R3-2,R4-1,G2), (A′1,R1-1,R2-2,R3-2,R4-1,G3), (A′1,R1-1,R2-2,R3-2,R4-1,G4), (A′1,R1-1,R2-2,R3-2,R4-2,G1), (A′1,R1-1,R2-2,R3-2,R4-2,G2), (A′1,R1-1,R2-2,R3-2,R4-2,G3), (A′1,R1-1,R2-2,R3-2,R4-2,G4), (A′1,R1-1,R2-2,R3-3,R4-1,G1), (A′1,R1-1,R2-2,R3-3,R4-1,G2), (A′1,R1-1,R2-2,R3-3,R4-1,G3), (A′1,R1-1,R2-2,R3-3,R4-1, G4), (A′1,R1-1,R2-2,R3-3,R4-2,G1), (A′1,R1-1,R2-2,R3-3,R4-2,G2), (A′1,R1-1,R2-2,R3-3,R4-2,G3), (A′1,R1-1,R2-2,R3-3,R4-2,G4), (A′1,R1-1,R2-2,R3-4,R4-1,G1), (A′1,R1-1,R2-2,R3-4,R4-1,G2), (A′1,R1-1,R2-2,R3-4,R4-1,G3), (A′1,R1-1,R2-2,R3-4,R4-1,G4), (A′1,R1-1,R2-2,R3-4,R4-2,G1), (A′1,R1-1,R2-2,R3-4,R4-2,G2), (A′1,R1-1,R2-2,R3-4,R4-2,G3), (A′1,R1-1,R2-2,R3-4,R4-2,G4), (A′1,R1-2,R2-1,R3-1,R4-1,G1), (A′1,R1-2,R2-1,R3-1,R4-1,G2), (A′1,R1-2,R2-1,R3-1,R4-1,G3), (A′1,R1-2,R2-1,R3-1,R4-1,G4), (A′1,R1-2,R2-1,R3-1,R4-2,G1), (A′1,R1-2,R2-1,R3-1,R4-2,G2), (A′1,R1-2,R2-1,R3-1,R4-2,G3), (A′1,R1-2,R2-1,R3-1,R4-2,G4), (A′1,R1-2,R2-1,R3-2,R4-1,G1), (A′1,R1-2,R2-1,R3-2,R4-1,G2), (A′1,R1-2,R2-1,R3-2,R4-1,G3), (A′1,R1-2,R2-1,R3-2,R4-1,G4), (A′1,R1-2,R2-1,R3-2,R4-2,G1), (A′1,R1-2,R2-1,R3-2,R4-2,G2), (A′1,R1-2,R2-1,R3-2,R4-2,G3), (A′1,R1-2,R2-1,R3-2,R4-2,G4), (A′1,R1-2,R2-1,R3-3, R4-1,G1), (A′1,R1-2,R2-1,R3-3,R4-1,G2), (A′1,R1-2,R2-1,R3-3,R4-1,G3), (A′1,R1-2,R2-1,R3-3,R4-1,G4), (A′1,R1-2,R2-1,R3-3,R4-2,G1), (A′1,R1-2,R2-1,R3-3,R4-2,G2), (A′1,R1-2,R2-1,R3-3,R4-2,G3), (A′1,R1-2,R2-1,R3-3,R4-2,G4), (A′1,R1-2,R2-1,R3-4,R4-1,G1), (A′1,R1-2,R2-1,R3-4,R4-1,G2), (A′1,R1-2,R2-1,R3-4,R4-1,G3), (A′1,R1-2,R2-1,R3-4,R4-1,G4), (A′1,R1-2,R2-1,R3-4,R4-2,G1), (A′1,R1-2,R2-1,R3-4,R4-2,G2), (A′1,R1-2,R2-1,R3-4,R4-2,G3), (A′1,R1-2,R2-1,R3-4,R4-2,G4), (A′1,R1-2,R2-2,R3-1,R4-1,G1), (A′1,R1-2,R2-2,R3-1,R4-1,G2), (A′1,R1-2,R2-2,R3-1,R4-1,G3), (A′1,R1-2,R2-2,R3-1,R4-1,G4), (A′1,R1-2,R2-2,R3-1,R4-2,G1), (A′1,R1-2,R2-2,R3-1,R4-2,G2), (A′1,R1-2,R2-2,R3-1,R4-2,G3), (A′1,R1-2,R2-2,R3-1,R4-2,G4), (A′1,R1-2,R2-2,R3-2,R4-1,G1), (A′1,R1-2,R2-2,R3-2,R4-1,G2), (A′1,R1-2,R2-2,R3-2,R4-1,G3), (A′1,R1-2,R2-2,R3-2,R4-1,G4), (A′1,R1-2,R2-2,R3-2,R4-2,G1), (A′1,R1-2,R2-2,R3-2,R4-2,G2), (A′1,R1-2,R2-2,R3-2,R4-2,G3), (A′1,R1-2,R2-2,R3-2,R4-2,G4), (A′1,R1-2,R2-2,R3-3,R4-1,G1), (A′1,R1-2,R2-2,R3-3,R4-1,G2), (A′1,R1-2,R2-2,R3-3,R4-1,G3), (A′1,R1-2,R2-2,R3-3,R4-1,G4), (A′1,R1-2,R2-2,R3-3,R4-2,G1), (A′1,R1-2,R2-2,R3-3,R4-2,G2), (A′1,R1-2,R2-2,R3-3,R4-2,G3), (A′1,R1-2,R2-2,R3-3,R4-2,G4), (A′1,R1-2,R2-2,R3-4,R4-1,G1), (A′1,R1-2,R2-2,R3-4,R4-1,G2), (A′1,R1-2,R2-2,R3-4,R4-1,G3), (A′1,R1-2,R2-2,R3-4,R4-1,G4), (A′1,R1-2,R2-2,R3-4,R4-2,G1), (A′1,R1-2,R2-2,R3-4,R4-2,G2), (A′1,R1-2,R2-2,R3-4,R4-2,G3), (A′1,R1-2,R2-2,R3-4,R4-2,G4),

(A′2,R1-1,R2-1,R3-1,R4-1,G1), (A′2,R1-1,R2-1,R3-1,R4-1,G2), (A′2,R1-1,R2-1,R3-1,R4-1,G3), (A′2,R1-1,R2-1,R3-1,R4-1,G4), (A′2,R1-1,R2-1,R3-1,R4-2,G1), (A′2,R1-1,R2-1,R3-1,R4-2,G2), (A′2,R1-1,R2-1,R3-1,R4-2,G3), (A′2,R1-1,R2-1,R3-1,R4-2,G4), (A′2,R1-1,R2-1,R3-2,R4-1,G1), (A′2,R1-1,R2-1,R3-2,R4-1,G2), (A′2,R1-1,R2-1,R3-2,R4-1,G3), (A′2,R1-1,R2-1,R3-2,R4-1,G4), (A′2,R1-1,R2-1,R3-2,R4-2,G1), (A′2,R1-1,R2-1,R3-2,R4-2,G2), (A′2,R1-1,R2-1,R3-2,R4-2,G3), (A′2,R1-1,R2-1,R3-2,R4-2,G4), (A′2,R1-1,R2-1,R3-3,R4-1,G1), (A′2,R1-1,R2-1,R3-3,R4-1,G2), (A′2,R1-1,R2-1,R3-3,R4-1,G3), (A′2,R1-1,R2-1,R3-3,R4-1,G4), (A′2,R1-1,R2-1,R3-3,R4-2,G1), (A′2,R1-1,R2-1,R3-3,R4-2,G2), (A′2,R1-1,R2-1,R3-3,R4-2,G3), (A′2,R1-1,R2-1,R3-3,R4-2,G4), (A′2,R1-1,R2-1,R3-4,R4-1,G1), (A′2,R1-1,R2-1,R3-4,R4-1,G2), (A′2,R1-1,R2-1,R3-4,R4-1,G3), (A′2,R1-1,R2-1,R3-4,R4-1,G4), (A′2,R1-1,R2-1,R3-4,R4-2,G1), (A′2,R1-1,R2-1,R3-4,R4-2,G2), (A′2,R1-1,R2-1,R3-4,R4-2,G3), (A′2,R1-1,R2-1,R3-4,R4-2,G4), (A′2,R1-1,R2-2,R3-1,R4-1,G1), (A′2,R1-1,R2-2,R3-1,R4-1,G2), (A′2,R1-1,R2-2,R3-1,R4-1,G3), (A′2,R1-1,R2-2,R3-1,R4-1,G4), (A′2,R1-1,R2-2,R3-1,R4-2,G1), (A′2,R1-1,R2-2,R3-1,R4-2,G2), (N′2,R1-1,R2-2,R3-1,R4-2,G3), (A′2,R1-1,R2-2,R3-1,R4-2,G4), (A′2,R1-1,R2-2,R3-2,R4-1,G1), (A′2,R1-1,R2-2,R3-2,R4-1,G2), (A′2,R1-1,R2-2,R3-2,R4-2,G3), (A′2,R1-1,R2-2,R3-2,R4-1,G4), (A′2,R1-1,R2-2,R3-2,R4-2,G1), (A′2,R1-1,R2-2,R3-2,R4-2,G2), (A′2,R1-1,R2-2,R3-2,R4-2,G3), (A′2,R1-1,R2-2,R3-2,R4-2,G4), (A′2,R1-1,R2-2,R3-3,R4-1,G1), (A′2,R1-1,R2-2,R3-3,R4-1,G2), (A′2,R1-1,R2-2,R3-3,R4-1,G3), (A′2,R1-1,R2-2,R3-3,R4-1, G4), (A′2,R1-1,R2-2,R3-3,R4-2,G1), (A′2,R1-1,R2-2,R3-3,R4-2,G2), (A′2,R1-1,R2-2,R3-3,R4-2,G3), (A′2,R1-1,R2-2,R3-3,R4-2,G4), (A′2,R1-1,R2-2,R3-4,R4-1,G1), (A′2,R1-1,R2-2,R3-4,R4-1,G2), (A′2,R1-1,R2-2,R3-4,R4-1,G3), (A′2,R1-1,R2-2,R3-4,R4-1,G4), (A′2,R1-1,R2-2,R3-4,R4-2,G1), (A′2,R1-1,R2-2,R3-4,R4-2,G2), (A′2,R1-1,R2-2,R3-4,R4-2,G3), (A′2,R1-1,R2-2,R3-4,R4-2,G4), (A′2,R1-2,R2-1,R3-1,R4-1,G1), (A′2, R1-2,R2-1,R3-1,R4-1,G2), (A′2, R1-2,R2-1,R3-1,R4-1,G3), (A′2,R1-2,R2-1,R3-1,R4-1,G4), (A′2,R1-2,R2-1,R3-1,R4-2,G1), (A′2, R1-2,R2-1,R3-1,R4-2,G2), (A′2,R1-2,R2-1,R3-1,R4-2,G3), (A′2,R1-2,R2-1,R3-1,R4-2,G4), (A′2,R1-2,R2-1,R3-2,R4-1,G1), (A′2,R1-2,R2-1,R3-2,R4-1,G2), (A′2,R1-2,R2-1,R3-2,R4-1,G3), (A′2,R1-2,R2-1,R3-2,R4-1,G4), (A′2,R1-2,R2-1,R3-2,R4-2,G1), (A′2,R1-2,R2-1,R3-2,R4-2,G2), (A′2,R1-2,R2-1,R3-2,R4-2,G3), (A′2,R1-2,R2-1,R3-2,R4-2,G4), (A′2,R1-2,R2-1,R3-3,R4-1,G1), (A′2,R1-2,R2-1,R3-3,R4-1,G2), (A′2,R1-2,R2-1,R3-3,R4-1,G3), (A′2,R1-2,R2-1,R3-3,R4-1,G4), (A′2,R1-2,R2-1,R3-3,R4-2,G1), (A′2,R1-2,R2-1,R3-3,R4-2,G2), (A′2,R1-2,R2-1,R3-3,R4-2,G3), (A′2,R1-2,R2-1,R3-3,R4-2,G4), (A′2,R1-2,R2-1,R3-4,R4-1,G1), (A′2,R1-2,R2-1,R3-4,R4-1,G2), (A′2,R1-2,R2-1,R3-4,R4-1,G3), (A′2,R1-2,R2-1,R3-4,R4-1,G4), (A′2,R1-2,R2-1,R3-4,R4-2,G1), (A′2,R1-2,R2-1,R3-4,R4-2,G2), (A′2,R1-2,R2-1,R3-4,R4-2,G3), (A′2,R1-2,R2-1,R3-4,R4-2,G4), (A′2,R1-2,R2-2,R3-1,R4-1,G1), (A′2,R1-2,R2-2,R3-1,R4-1,G2), (A′2,R1-2,R2-2,R3-1,R4-1,G3), (A′2,R1-2,R2-2,R3-1,R4-1,G4), (A′2,R1-2,R2-2,R3-1,R4-2,G1), (A′2,R1-2,R2-2,R3-1,R4-2,G2), (A′2,R1-2,R2-2,R3-1,R4-2,G3), (A′2,R1-2,R2-2,R3-1,R4-2,G4), (A′2,R1-2,R2-2,R3-2,R4-1,G1), (A′2,R1-2,R2-2,R3-2,R4-1,G2), (A′2,R1-2,R2-2,R3-2,R4-1,G3), (A′2,R1-2,R2-2,R3-2,R4-1,G4), (A′2,R1-2,R2-2,R3-2,R4-2,G1), (A′2,R1-2,R2-2,R3-2,R4-2,G2), (A′2,R1-2,R2-2,R3-2,R4-2,G3), (A′2,R1-2,R2-2,R3-2,R4-2,G4), (A′2,R1-2,R2-2,R3-3,R4-1,G1), (A′2,R1-2,R2-2,R3-3,R4-1,G2), (A′2,R1-2,R2-2,R3-3,R4-1,G3), (A′2,R1-2,R2-2,R3-3,R4-1,G4), (A′2,R1-2,R2-2,R3-3,R4-2,G1), (A′2,R1-2,R2-2,R3-3,R4-2,G2), (A°2,R1-2,R2-2,R3-3,R4-2,G3), (A′2,R1-2,R2-2,R3-3,R4-2,G4), (A′2,R1-2,R2-2,R3-4,R4-1,G1), (A′2,R1-2,R2-2,R3-4,R4-1,G2), (A′2,R1-2,R2-2,R3-4,R4-1,G3), (A′2,R1-2,R2-2,R3-4,R4-1,G4), (A′2,R1-2,R2-2,R3-4,R4-2,G1), (A′2,R1-2,R2-2,R3-4,R4-2,G2), (A′2,R1-2,R2-2,R3-4,R4-2,G3), (A′2,R1-2,R2-2,R3-4,R4-2,G4),

(A′3,R1-1,R2-1,R3-1,R4-1,G1), (A′3,R1-1,R2-1,R3-1,R4-1,G2), (A′3,R1-1,R2-1,R3-1,R4-1,G3), (A′3,R1-1,R2-1,R3-1,R4-1,G4), (A′3,R1-1,R2-1,R3-1,R4-2,G1), (A′3,R1-1,R2-1,R3-1,R4-2,G2), (A′3,R1-1,R2-1,R3-1,R4-2,G3), (A′3,R1-1,R2-1,R3-1,R4-2,G4), (A′3,R1-1,R2-1,R3-2,R4-1,G1), (A′3,R1-1,R2-1,R3-2,R4-1,G2), (A′3,R1-1,R2-1,R3-2,R4-1,G3), (A′3,R1-1,R2-1,R3-2,R4-1,G4), (A′3,R1-1,R2-1,R3-2,R4-2,G1), (A′3,R1-1,R2-1,R3-2,R4-2,G2), (A′3,R1-1,R2-1,R3-2,R4-2,G3), (A′3,R1-1,R2-1,R3-2,R4-2,G4), (A′3,R1-1,R2-1,R3-3,R4-1,G1), (A′3,R1-1,R2-1,R3-3,R4-1,G2), (A′3,R1-1,R2-1,R3-3,R4-1,G3), (A′3,R1-1,R2-1,R3-3,R4-1,G4), (A′3,R1-1,R2-1,R3-3,R4-2,G1), (A′3,R1-1,R2-1,R3-3,R4-2,G2), (A′3,R1-1,R2-1,R3-3,R4-2,G3), (A′3,R1-1,R2-1,R3-3,R4-2,G4), (A′3,R1-1,R2-1,R3-4,R4-1,G1), (A′3,R1-1,R2-1,R3-4,R4-1,G2), (A′3,R1-1,R2-1,R3-4,R4-1,G3), (A′3,R1-1,R2-1,R3-4,R4-1,G4), (A′3,R1-1,R2-1,R3-4,R4-2,G1), (A′3,R1-1,R2-1,R3-4,R4-2,G2), (A′3,R1-1,R2-1,R3-4,R4-2,G3), (A′3,R1-1,R2-1,R3-4,R4-2,G4), (A′3,R1-1,R2-2,R3-1,R4-1,G1), (A′3,R1-1,R2-2,R3-1,R4-1,G2), (A′3,R1-1,R2-2,R3-1,R4-1,G3), (A′3,R1-1,R2-2,R3-1,R4-1,G4), (A′3,R1-1,R2-2-1,R4-2,G1), (A′3,R1-1,R2-2,R3-1,R4-2,G2), (A′3,R1-1,R2-2,R3-1,R4-2,G3), (A′3,R1-1,R2-2,R3-1,R4-2,G4), (A′3,R1-1,R2-2,R3-2,R4-1,G1), (A′3,R1-1,R2-2,R3-2,R4-1,G2), (A′3,R1-1,R2-2,R3-2,R4-1,G3), (A′3,R1-1,R2-2,R3-2,R4-1,G4), (A′3,R1-1,R2-2,R3-2,R4-2,G1), (A′3,R1-1,R2-2,R3-2,R4-2,G2), (A′3,R1-1,R2-2,R3-2,R4-2,G3), (A′3,R1-1,R2-2,R3-2,R4-2,G4), (A′3,R1-1,R2-2,R3-3,R4-1,G1), (A′3,R1-1,R2-2,R3-3,R4-1,G2), (A′3,R1-1,R2-2,R3-3,R4-1,G3), (A′3,R1-1,R2-2,R3-3,R4-1,G4), (A′3,R1-1,R2-2,R3-3,R4-2,G1), (A′3,R1-1,R2-2,R3-3,R4-2,G2), (A′3,R1-1,R2-2,R3-3,R4-2,G3), (A′3,R1-1,R2-2,R3-3,R4-2,G4), (A′3,R1-1,R2-2,R3-4,R4-1,G1), (A′3,R1-1,R2-2,R3-4,R4-1,G2), (A′3,R1-1,R2-2,R3-4,R4-1,G3), (A′3,R1-1,R2-2,R3-4,R4-1,G4), (A′3,R1-1,R2-2,R3-4,R4-2,G1), (A′3,R1-1,R2-2,R3-4,R4-2,G2), (A′3,R1-1,R2-2,R3-4,R4-2,G3), (A′3,R1-1,R2-2,R3-4,R4-2,G4), (A′3,R1-2,R2-1,R3-1,R4-1,G1), (A′3,R1-2,R2-1,R3-1,R4-1,G2), (A′3,R1-2,R2-1,R3-1,R4-1,G3), (A′3,R1-2,R2-1,R3-1,R4-1,G4), (A′3,R1-2,R2-1,R3-1,R4-2,G1), (A′3,R1-2,R2-1,R3-1,R4-2,G2), (A′3,R1-2,R2-1,R3-1,R4-2,G3), (A′3,R1-2,R2-1,R3-1,R4-2,G4), (A′3,R1-2,R2-1,R3-2,R4-1,G1), (A′3,R1-2,R2-1,R3-2,R4-1,G2), (A′3,R1-2,R2-1,R3-2,R4-1,G3), (A′3,R1-2,R2-1,R3-2,R4-1,G4), (A′3,R1-2,R2-1,R3-2,R4-2,G1), (A′3,R1-2,R2-1,R3-2,R4-2,G2), (A′3,R1-2,R2-1,R3-2,R4-2,G3), (A′3,R1-2,R2-1,R3-2,R4-2,G4), (A′3,R1-2,R2-1,R3-3,R4-1,G1), (A′3,R1-2,R2-1,R3-3,R4-1,G2), (A′3,R1-2,R2-1,R3-3,R4-1,G3), (A′3,R1-2,R2-1,R3-3,R4-1,G4), (A′3,R1-2,R2-1,R3-3,R4-2,G1), (A′3,R1-2,R2-1,R3-3,R4-2,G2), (A′3,R1-2,R2-1,R3-3,R4-2,G3), (A′3,R1-2,R2-1,R3-3,R4-2,G4), (A′3,R1-2,R2-1,R3-4,R4-1,G1), (A′3,R1-2,R2-1,R3-4,R4-1,G2), (A′3,R1-2,R2-1,R3-4,R4-1,G3), (A′3,R1-2,R2-1,R3-4,R4-1,G4), (A′3,R1-2,R2-1,R3-4,R4-2,G1), (A′3,R1-2,R2-1,R3-4,R4-2,G2), (A′3,R1-2,R2-1,R3-4,R4-2,G3), (A′3,R1-2,R2-1,R3-4,R4-2,G4), (A′3,R1-2,R2-2,R3-1,R4-1,G1), (A′3,R1-2,R2-2,R3-1,R4-1,G2), (A′3,R1-2,R2-2,R3-1,R4-1,G3), (A′3,R1-2,R2-2,R3-1,R4-1,G4), (A′3,R1-2,R2-2,R3-1,R4-2,G1), (A′3,R1-2,R2-2,R3-1,R4-2,G2), (A′3,R1-2,R2-2,R3-1,R4-2,G3), (A′3,R1-2,R2-2,R3-4-2,G4), (A′3,R1-2,R2-2,R3-2,R4-1,G1), (A′3,R1-2,R2-2,R3-2,R4-1,G2), (A′3,R1-2,R2-2-2,R4-1,G3), (A′3,R1-2,R1-2,R3-2,R4-1,G4), (A′3,R1-2,R2-2,R3-2,R4-2,G1), (A′3,R1-2,R2-2,R3-2,R4-2,G2), (A′3,R1-2,R2-2,R3-2,R4-2,G3), (A′3,R1-2,R2-2,R3-2,R4-2,G4), (A′3,R1-2,R2-2,R3-3,R4-1,G1), (A′3,R1-2,R2-2,R3-3,R4-1,G2), (A′3,R1-2,R2-2,R3-3,R4-1,G3), (A′3,R2,R2-2,R3-3,R4-1,G4), (A′3,R1-2,R2-2,R3-3,R4-2,G1), (A′3,R1-2,R2-2,R3-3,R4-2,G2), (A′3,R1-2,R2-2,R3-3,R4-2,G3), (A′3,R1-2,R2-2,R3-3,R4-2,G4), (A′3,R1-2,R2-2,R3-4,R4-1,G1), (A′3,R1-2,R2-2,R3-4,R4-1,G2), (A′3,R1-2,R2-2,R3-4,R4-1,G3), (A′3,R1-2,R2-2,R3-4,R4-1,G4), (A′3,R1-2,R2-2,R3-4,R4-2,G1), (A′3,R1-2,R2-2,R3-4,R4-2,G2), (A′3,R1-2,R2-2,R3-4,R4-2,G3), (A′3,R1-2,R2-2,R3-4,R4-2,G4),

(A′4,R1-1,R2-1,R3-1,R4-1,G1), (A′4,R1-1,R2-1,R3-1,R4-1,G2), (A′4,R1-1,R2-1,R3-1,R4-1,G3), (A′4,R1-1,R2-1,R3-1,R4-1,G4), (A′4,R1-1,R2-1,R3-1,R4-2,G1), (A′4,R1-1,R2-1,R3-1,R4-2,G2), (A′4,R1-1,R2-1,R3-1,R4-2,G3), (A′4,R1-1,R2-1,R3-1,R4-2,G4), (A′4,R1-1,R2-1,R3-2,R4-1,G1), (A′4,R1-1,R2-1,R3-2,R4-1,G2), (A′4,R1-1,R2-1,R3-2,R4-1,G3), (A′4,R1-1,R2-1,R3-2,R4-1,G4), (A′4,R1-1,R2-1,R3-2,R4-2,G1), (A′4,R1-1,R2-1,R3-2,R4-2,G2), (A′4,R1-1,R2-1,R3-2,R4-2,G3), (A′4,R1-1,R2-1,R3-2,R4-2,G4), (A′4,R1-1,R2-1,R3-3,R4-1,G1), (A′4,R1-1,R2-1,R3-3,R4-1,G2), (A′4,R1-1,R2-1,R3-3,R4-1,G3), (A′4,R1-1,R2-1,R3-3,R4-1,G4), (A′4,R1-1,R2-1,R3-3,R4-2,G1), (A′4,R1-1,R2-1,R3-3,R4-2,G2), (A′4,R1-1,R2-1,R3-3,R4-2,G3), (A′4,R1-1,R2-1,R3-3,R4-2,G4), (A′4,R1-1,R2-1,R3-4,R4-1,G1), (A′4,R1-1,R2-1,R3-4,R4-1,G2), (A′4,R1-1,R2-1,R3-4,R4-1,G3), (A′4,R1-1,R2-1,R3-4,R4-1,G4), (A′4,R1-1,R2-1,R3-4,R4-2,G1), (A′4,R1-1,R2-1,R3-4,R4-2,G2), (A′4,R1-1,R2-1,R3-4,R4-2,G3), (A′4,R1-1,R2-1,R3-4,R4-2,G4), (A′4,R1-1,R2-2,R3-1,R4-1,G1), (A′4,R1-1,R2-2,R3-1,R4-1,G2), (A′4,R1-1,R2-2,R3-1,R4-1,G3), (A′4,R1-1,R2-2,R3-1,R4-1,G4), (A′4,R1-1,R2-2,R3-1,R4-2,G1), (A′4,R1-1,R2-2,R3-1,R4-2,G2), (A′4,R1-1,R2-2,R3-1,R4-2,G3), (A′4,R1-1,R2-2,R3-1,R4-2,G4), (A′4,R1-1,R2-2,R3-2,R4-1,G1), (A′4,R1-1,R2-2,R3-2,R4-1,G2), (A′4,R1-1,R2-2,R3-2,R4-1,G3), (A′4,R1-1,R2-2,R3-2,R4-1,G4), (A′4,R1-1,R2-2,R3-2,R4-2,G1), (A′4,R1-1,R2-2,R3-2,R4-2,G2), (A′4,R1-1,R2-2,R3-2,R4-2,G3), (A′4,R1-1,R2-2,R3-2,R4-2,G4), (A′4,R1-1,R2-2,R3-3,R4-1,G1), (A′4,R1-1,R2-2,R3-3,R4-1,G2), (A′4,R1-1,R2-2,R3-3,R4-1,G3), (A′4,R1-1,R2-2,R3-3,R4-1,G4), (A′4,R1-1,R2-2,R3-3,R4-2,G1), (A′4,R1-1,R2-2,R3-3,R4-2,G2), (A′4,R1-2,R2-2,R3-3,R4-2,G3), (A′4,R1-1,R2-2,R3-3,R4-2,G4), (A′4,R1-1,R2-2,R3-4,R4-1,G1), (A′4,R1-1,R2-2,R3-4,R4-1,G2) (A′4,R1-1,R2-2,R3-4,R4-1,G3), (A′4,R1-1,R2-2,R3-4,R4-1,G4), (A′4,R1-1,R2-2,R3-4,R4-2,G1), (A′4,R1-1,R2-2,R3-4,R4-2,G2), (A′4,R1-1,R2-2,R3-4,R4-2,G3), (A′4,R1-1,R2-2,R3-4,R4-2,G4), (A′4,R1-2,R2-1,R3-1,R4-1,G1), (A′4,R1-2,R2-1,R3-1,R4-1,G2), (A′4,R1-2,R2-1,R3-1,R4-1,G3), (A′4,R1-2,R2-1,R3-1,R4-1,G4), (A′4,R1-2,R2-1,R3-1,R4-2,G1), (A′4,R1-2,R2-1,R3-1,R4-2,G2), (A′4,R1-2,R2-1,R3-1,R4-2,G3), (A′4,R1-2,R2-1,R3-1,R4-2,G4), (A′4,R1-2,R2-1,R3-2,R4-1,G1), (A′4,R1-2,R2-1,R3-2,R4-1,G2), (A′4,R1-2,R2-1,R3-2,R4-1,G3), (A′4,R1-2,R2-1,R3-2,R4-1,G4), (A′4,R1-2,R2-1,R3-2,R4-2,G1), (A′4,R1-2,R2-1,R3-2,R4-2,G2), (A′4,R1-2,R2-1,R3-2,R4-2,G3), (A′4,R1-2,R2-1,R3-2,R4-2,G4), (A′4,R1-2,R2-1,R3-3,R4-1,G1), (A′4,R1-2,R2-1,R3-3,R4-1,G2), (A′4,R1-2,R2-1,R3-3,R4-1,G3), (A′4,R1-2,R2-1,R3-3,R4-1,G4), (A′4,R1-2,R2-1,R3-3,R4-2,G1), (A′4,R1-2,R2-1,R3-3,R4-2,G2), (A′4,R1-2,R2-1,R3-3,R4-2,G3), (A′4,R1-2,R2-1,R3-3,R4-2,G4), (A′4,R1-2,R2-1,R3-4,R4-1,G1), (A′4,R1-2,R2-1,R3-4,R4-1,G2), (A′4,R1-2,R2-1,R3-4,R4-1,G3), (A′4,R1-2,R2-1,R3-4,R4-1,G4), (A′4,R1-2,R2-1,R3-4,R4-2,G1), (A′4,R1-2,R2-1,R3-4,R4-2,G2), (A′4,R1-2,R2-1,R3-4,R4-2,G3), (A′4,R1-2,R2-1,R3-4,R4-2,G4), (A′4,R1-2,R2-2,R3-1,R4-1,G1), (A′4,R1-2,R2-2,R3-1,R4-1,G2), (A′4,R1-2,R2-2,R3-1,R4-1,G3), (A′4,R1-2,R2-2,R3-1,R4-1,G4), (A′4,R1-2,R2-2,R3-1,R4-2,G 1), (A′4,R1-2,R2-2,R3-1,R4-2,G2), (A′4,R1-2,R2-2,R3-1,R4-2,G3), (A′4,R1-2,R2-2,R3-1,R4-2,G4), (A′4,R1-2,R2-2,R3-2,R4-1,G1), (A′4,R1-2,R2-2,R3-2,R4-1,G2), (A′4,R1-2,R2-2,R3-2,R4-1, G3), (A′4,R1-2,R2-2,R3-2,R4-1,G4), (A′4,R1-2,R2-2,R3-2,R4-2,G1), (A′4,R1-2,R2-2,R3-2,R4-2,G2), (A′4,R1-2,R2-2,R3-2,R4-2,G3), (A′4,R1-2,R2-2,R3-2,R4-2,G4), (A′4,R1-2,R2-2,R3-3,R4-1,G1), (A′4,R1-2,R2-2,R3-3,R4-1,G2), (A′4,R1-2,R2-2,R3-3,R4-1,G3), (A′4,R1-2,R2-2,R3-3,R4-1,G4), (A′4,R1-2,R2-2,R3-3,R4-2, G1), (A′4,R1-2,R2-2,R3-3,R4-2,G2), (A′4,R1-2,R2-2,R3-3,R4-2,G3), (A′4,R1-2,R2-2,R3-3,R4-2, G4), (A′4,R1-2,R2-2,R3-4,R4-1,G1), (A′4,R1-2,R2-2,R3-4,R4-1,G2), (A′4,R1-2,R2-2,R3-4,R4-1,G3), (A′4,R1-2,R2-2,R3-4,R4-1,G4), (A′4,R1-2,R2-2,R3-4,R4-2,G1), (A′4,R1-2,R2-2,R3-4,R4-2,G2), (A′4,R1-2,R2-2,R3-4,R4-2,G3) or (A′4,R1-2,R2-2,R3-4,R4-2,G4).

Compounds of the present invention are useful for treating diseases induced by production, secretion or deposition of amyloid β protein, and effective for the treatment and/or prophylaxis, or improvement of conditions for Alzheimer's dementia (Alzheimer's disease, senile dementia of Alzheimer type etc.), Down's disease, disturbance of memory, prion disease (Creutzfeldt-Jakob disease etc.), mild cognitive impairment (MCI), Dutch-type hereditary cerebral hemorrhage with amyloidosis, cerebral amyloid angiopathy, other degenerated dementia, vascular degenerated mixed dementia, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear paralysis, dementia associated with corticobasal degeneration, diffuse Lewy Bodies Alzheimer's disease, age-related macular degeneration, Parkinson's disease, or amyloid angiopathy etc.
Since compounds of the present invention have several efficacies such as having a potent inhibitory activity against BACE-1 having a high selectivity against other enzymes etc., they can be a drug with less side effects. Moreover they can be a drug having a wide margin of safety by choosing an optically active isomer of appropriate stereochemistry. Further they have a lot of merits such as good metabolic stability, high solubility, high absorbability of oral administration, high bioavailability, good clearance and high transitivity to brain, long half-life, high ratio of non protein binding, lower inhibition of hERG channel and CYP, and/or negative result of Ames Test, and, therefore, they can be superior drugs.
A compound of the present invention may be administrated together with other agent (e.g., other agent for treating Alzheimer's disease such as acetylcholine esterase etc.). The compound can be given in combination with an antidementia drug such as donepezil hydrochloride, tacrine, galantamine, rivastigmine, zanapezil, memantine or vinpocetine, for example.
A compound of the present invention may be orally administrated as powder, granule, tablet, capsule, pill or liquid formulation, or parentally administrated as injection, suppository, formulation of transdermal absorption or inhalation. Also, an effective amount of the compound may be formulated together with medicinal additives suitable for the formulation such as an excipient, binder, moistening agent, disintegrant and/or lubricant etc.
Dose of a compounds of the present invention depends on condition of diseases, route of administration, age and body weight of a patient, but in the case of oral administration to an adult, the dose range is usually 0.1 μg to 1 g/day, preferably 0.01 to 200 mg/day and in the case of parenteral administration the dose range is usually 1 μg to 10 g/day, preferably 0.1 to 2 g/day.
EXAMPLES
The present invention is illustrated in details by examples and test examples but the present invention is not limited to these examples.
In EXAMPLES, each abbreviation has the following meaning:

    Me: methyl
    Et: ethyl
    iPr, Pri isopropyl
    tBu: t-butyl
    Ph: phenyl
    Bn: benzyl
    Boc: tert-butoxycarbonyl
    TFA: trifluroacetic acid
    THF: tetrahydrofuran
    DMT-MM: 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n-hydrate
    DMF: N,N-dimethylformamide


Reference Example 1




The 1st step: Compound (1) (101.5 g) was cooled to −18° C. and conc. sulfuric acid (400 ml) was added dropwise in 65 minutes while the inner temperature was kept at −15° C. or below. Separately fuming nitric acid (60 ml) was added to conc. sulfuric acid (180 ml) chilled to 4° C. in 45 minutes while the temperature was kept at 10° C. or below and the resulted mixed acid was added dropwise to the solution of (1) prepared before in an hour while the temperature was kept at −30° C. or below. The mixture was stirred at −20° C. or below for 1.5 hours, poured into 2.5 kg of ice-water and stirred for an hour. The precipitated crystals were filtered to give compound (2) (121.5 g).

1H-NMR (CDCl3): 2.71 (3H, d, J=5.1 Hz), 7.35 (1H, dd, J=9.3, 9.0 HZ), 8.41 (1H, ddd, J=9.0, 3.9, 3.0 Hz), 8.78 (1H, dd, J=6.3, 3.0 Hz).
The 2nd step: Compound (2) (20 g) was dissolved in ethanol (400 ml), Pd—C (10% dry) (2.0 g) was added thereto and the mixture was stirred in a hydrogen atmosphere at room temperature for 2 hours. Then Pd—C (10% dry) (1.0 g) was added and the mixture was stirred in a hydrogen atmosphere at room temperature for 1.5 hours, and further Pd—C (10% dry) (1.0 g) was added and the mixture was stirred in a hydrogen atmosphere at room temperature for 15 minutes. Pd—C was filtered off, the solvent was evaporated under reduced pressure and the residue of compound (3) (15.9 g) was obtained.
1H-NMR (DMSO-d6): 2.50 (3H, d, J=4.8 Hz), 5.21 (2H, brs, 1H), 6.78 (1H, ddd, J=8.7, 4.2, 3.0 Hz), 6.94 (1H, dd, J=6.3, 3.0 Hz), 6.99 (1H, dd, J=11.4, 8.7 Hz).
The 3rd step: Compound (3) (15.8 g) was dissolved in THF (79 ml), anhydrous trifluoroacetic acid (16.1 ml) and triethylamine (20.2 ml) were added under ice cooling and the mixture was stirred for 20 minutes. After the addition of water (30 ml), it was stirred under ice cooling for 20 minutes and the precipitated crystals were filtered. The filtrate was extracted with ethyl acetate (80 ml) and 50 ml, the organic layer was washed with water (60 ml), saturated brine. The crystals filtered previously were dissolved in the organic layer and dried over sodium sulfate. Sodium sulfate was filtered, the filtrate was concentrated under reduced pressure and the residue was dissolved in ethyl acetate under warming. After the addition of hexane (50 ml) and stirring under ice cooling for 20 minutes, the precipitated crystals were filtered. The mother liquid was concentrated again under reduced pressure, crystallized by the addition of ethyl acetate (8 ml) and hexane (2 ml) and compound (4) (totally 20.4 g) was obtained.
1H-NMR (CDCl3): 2.70 (3H, d, J=5.1 Hz), 7.24 (1H, dd, J=10.5, 9.3 Hz), 8.00 (1H, dd, J=6.2, 2.9 Hz), 8.21 (1H, m), 8.78 (1H, brs).
The 4th step: 1.6 M Vinyl magnesium chloride-THF solution (122 ml) was dissolved in THF (161 ml), cooled to −40° C. in a nitrogen atmosphere and a THF (81 ml) solution of compound (4) (16.1 g) was added dropwise thereto. The reaction solution was stirred at −40° C. for 20 minutes, 1.6 M vinyl magnesium chloride-THF solution (20 ml) was further added and the mixture was stirred at −40° C. for 15 minutes. The reaction solution was poured into a mixture of chilled ethyl acetate (480 ml), a saturated aqueous solution of ammonium chloride (80 and water (80 ml) with stirring, and the organic layer was separated. The aqueous layer was further extracted with ethyl acetate (200 ml), the organic layers were combined, washed with water (80 ml), and saturated brine successively, and dried over sodium sulfate. Sodium sulfate was filtered, the filtrate was concentrated under reduced pressure and the residue of compound (5) (22.4 g) was obtained.
1H-NMR (CDCl3): 1.74 (3H, d, J=1.2 Hz), 5.16 (1H, dd, J=10.5, 0.9 Hz), 5.27 (1H, d, J=17.3 Hz), 6.26 (1H, ddd, J=17.3, 10.5, 1.7 Hz), 7.07 (1H, dd, J=11.1, 9.6 Hz), 7.64-7.69 (2H, m), 7.94 (1H, brs).
The 5th step: The residue of compound (5) (22.3 g) and thiourea (5.17 g) were dissolved in acetic acid (112 ml), 1 M HCl-ethyl acetate (97 ml) was added thereto and the mixture was stirred at 40° C. for 18 hours. The solvent was evaporated under reduced pressure, toluene (150 ml) was added and again concentrated under reduced pressure. After repeating the same procedure, crystals were precipitated. Ethyl acetate (100 ml) was added to the crystalline residue, the mixture was stirred under ice cooling for an hour and the crystals were filtered to give compound (6) (15.1 g).
1H-NMR (DMSO-d6): 2.08 (3H, s), 4.10 (2H, d, J=7.8 Hz), 5.72 (1H, t, J=7.8 Hz), 7.23-7.32 (1H, m), 7.60-7.69 (2H, m), 9.25 (3H, brs), 11.39 (1H, brs),
The 6th step: Compound (6) (10.0 g) was dissolved in THF (50 ml), conc. sulfuric acid (5.74 ml) was added thereto and stared at 60° C. for 2 hours. After evaporation of TFA under reduced pressure, ice-water (100 ml) was added. The mixture was stirred under ice-cooling for an hour, and the precipitated crystals were filtered to give compound (7) (11.2 g).
1H-NMR (CDCl3): 1.72 (3H, s), 2.02-2.18 (1H, m), 2.54-2.76 (2H, m), 3.14-3.28 (1H, m), 7.37 (1H, dd, J=11.9, 8.8 Hz), 7.62 (1H, dd, J=7.5, 3.0 Hz), 7.80 (1H, ddd, J=8.8, 3.9, 3.0 Hz), 8.77 (1H, brs), 9.38 (1H, hrs), 10.66 (1H, brs), 11.50 (1H, brs).
The 7th step: MeOH (28 ml), THE (35 ml) and 5 hr NaOH (10.9 ml) were added to compound (7) (7.00 g) and stirred at 50° C. for 4 hours. Toluene (50 ml) was added and extracted, and the aqueous layer was further extracted with toluene (50 ml) and ethyl acetate (60 ml). All the organic layers were combined, washed with water and saturated brine, and dried over sodium sulfate. The solvent was concentrated under reduced pressure, the resulted crystalline residue was washed with hexane (20 ml) to give compound (8) (3.45 g).
1H-NMR (CDCl3): 1.60 (3H, d, J=1.5 Hz), 1.76-1.87 (1H, m), 2.11-2.54 (1H, m), 2.66-2.76 (1H, m), 2.86-2.94 (1H, m), 6.50 (1H, ddd, J=8.7, 3.6, 3.0 Hz), 6.66 (1H, dd, J=7.1, 3.0 Hz), 6.81 (1H, dd, J=12.0, 8.7 Hz).
Reference Example 2




The 1st step: Compound (3) (15.6 g) was dissolved in ethyl acetate (78 ml), acetic anhydride (10.6 ml) and pyridine (9.07 ml) were added under ice cooling, and the mixture was stirred for 15 minutes. Ethyl acetate (100 ml) and water (50 ml) were added, extracted, and the aqueous layer was extracted with ethyl acetate (50 ml). The organic layers were combined, washed with 2 M HCl (50 ml), a saturated solution of sodium bicarbonate (50 ml) and saturated brine, dried over sodium sulfate. Sodium sulfate was filtered, the filtrate was concentrated under reduced pressure, and ethyl acetate (50 ml) and hexane (50 ml) were added to the residue. The mixture was stirred under ice cooling for 30 minutes and the precipitated crystals were filtered to give compound (9) (total 14.9 g).

1H-NMR (CDCl3) 2.20 (3H, s), 2.66 (3H, d, J=5.1 Hz), 7.13 (1H, dd, J=10.5, 9.0 Hz), 7.70 (1H, dd, J=6.3, 3.0 Hz), 7.79 (1H, brs), 8.11 (1H, ddd, J=9.0, 4.1, 3.0 Hz).
The 2nd step: Compound (9) (10.0 g) was dissolved in THF (50 ml), cooled in ice and sodium hydride (2.25 g) was added in a nitrogen atmosphere. After stirring for 15 minutes, the resulted mixture was added dropwise to a solution of 1.6 M vinyl magnesium chloride (86 ml)/THF (70 ml) cooled to −40° C. After stirring at −40° C. for 15 minutes and then 0° C. for 20 minutes, a saturated aqueous solution of ammonium chloride (50 ml)/water (50 ml) was chilled and added. The layers were separated and the aqueous layer was extracted with ethyl acetate (100 ml). Organic layers were combined, washed with water and saturated brine, dried over sodium sulfate. Sodium sulfate was filtered, the filtrate was concentrated under reduced pressure to give a residue of compound (10) (13.7 g).
1H-NMR (CDCl3): 1.69 (3H, s), 2.16 (3H, s), 5.12 (1H, d, J=10.5 Hz), 5.24 (1H, d, J=17.4 Hz), 6.26 (1H, ddd, J=1.7.4, 10.5, 1.5 Hz), 6.98 (1H, dd, J=11.1, 8.7 Hz), 7.33 (1H, brs), 7.50-7.59 (2H, m).
The 3rd step: The residue of compound (10) (6.56 g) and thiourea (1.88 g) were dissolved in acetic acid (33 ml), 1 M HO-acetic acid (37 ml) was added and stirred at 40° C. for 7 hours. The solvent was evaporated under reduced pressure, toluene (50 ml) was added and concentrated again under reduced pressure. The same procedure was repeated again, ethyl acetate (30 ml) was added to the residue and stirred at room temperature overnight. The precipitate was filtered to give compound (11) (5.77 g).
1H-NMR (DMSO-d6): 2.03 (3H, s), 2.06 (3H, s), 4.09 (2H, d, J=7.5 Hz), 5.67 (1H, t, J=7.5 Hz), 7.12 (1H, dd, J=10.7, 8.9 Hz), 7.46-7.59 (2H, m), 9.24 (4H, brs), 10.11 (1H, s).
The 4th step: compound (11) (5.16 g) was dissolved in cone, sulfuric acid (15.5 ml) and stirred at room temperature for an hour. It was poured into ice-water (100 ml), adjusted to pH 10 by the addition of an aqueous solution of potassium hydroxide and extracted with ethyl acetate (200 ml) and a little amount of MeOH. The organic layer was washed with water and saturated brine, dried over sodium sulfate. Sodium sulfate was filtered, the filtrate was concentrated under reduced pressure, ethyl acetate (20 ml) and hexane (15 ml) were added to the residue and the precipitate was filtered. The filtrate was concentrated, ethyl acetate (5 ml) and hexane (5 ml) were added and the precipitate was filtered to give compound (12) (total 3.16 g).
1H-NMR (CDCl3): 1.62 (3H, d, J=0.9 Hz), 1.80-1.91 (1H, m), 2.16 (3H, s), 2.47-2.58 (1H, m), 2.62-2.73 (1H, m), 2.87-2.98 (1H, m), 4.36 (2H, brs), 6.99 (1H, dd, J=11.7, 8.7 Hz), 7.14 (1H, dd, J=7.1, 3.0 Hz), 7.80 (1H, ddd, J=8.7, 4.2, 3.0 Hz), 7.97 (1H, brs),
The 5th step: Compound (12) (2.50 g) was suspended in ethanol (25 ml), 6 M HCl (10.2 ml) was added and the mixture was stirred at 90° C. for 3 hours. 2 M NaOH (35 ml) was added, the organic solvent was evaporated and the residue was extracted with ethyl acetate (70 ml). The aqueous layer was further extracted with ethyl acetate (30 ml), organic layers were combined, washed with water and saturated brine, and dried over sodium sulfate.
Sodium sulfate was filtered, the filtrate was concentrated under reduced pressure, and the crystalline residue was washed with ethyl acetate (3 ml) and hexane (10 ml). The crystals were filtered to give compound (8) (total 1.22 g).
Reference Example 3




The 1st step: A ethanol solution of 20% sodium ethoxide (5.12 ml, 16.2 mmol, 40 eq.) was added to compound (13) (150 mg, 406 μmol) and stirred at room temperature for 6 hours. The reaction solvent was evaporated under reduced pressure, 2 M hydrochloric acid (8.12 ml, 16.2 mmol, 40 eq.) was added to the resulted residue and extracted with chloroform. The extracting solution was washed with water and dried over anhydrous sodium sulfate. The chide product (189 mg) was obtained by evaporation of the solvent under reduced pressure, to which 4 M HCl-ethyl acetate solution (1.89 ml) was added and the mixture was stirred at room temperature for 14 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution, extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give compound (14) (90.8 mg, 76% yield) as a yellow powder.

1H NMR (CDCl3) δ1.52 (3H, t, 6.8 Hz), 1.67 (3H, s), 1.93-2.00 (1H, m), 2.60-2.67 (2H, m), 2.94-3.00 (1H, m), 4.19 (2H, q, J=6.8 Hz), 6.93 (1H, d, J=9.3 Hz), 8.14 (1H, dd, J=8.7, 2.4 Hz), 8.31 (1H, d, 2.5 Hz).
The 2nd step: A powder of 10% palladium-carbon (45.4 mg) was added to a methanol (908 μl) solution of compound (14) (90.8 mg, 307 μmol) and the mixture was stirred in a hydrogen atmosphere for 22 hours. The reaction mixture was filtered through a Celite pad and the filtrate was evaporated under reduced pressure. The residue was washed with ethyl acetate to give compound (15) (65.8 mg, 81% yield) as an yellow powder.
1H NMR (DMSO-d6) δ 1.29 (3H, t, J=6.9 Hz), 1.45 (3H, s), 1.51-1.58 (1H, m), 2.46-2.48 (1H, m), 2.61-2.64 (1H, m), 2.80-2.83 (1H, m), 3.85-3.91 (2H, m), 6.38 (1H, dd, J=8.3, 2.5 Hz), 6.52 (1H, d, J=2.4 Hz), 6.67 (1H, d, J=8.6 Hz)
Reference Example 4







The 1st step: 3′-Bromoacetophenone (15.0 g) and compound (16) (9.13 g) were dissolved in tetrahydrofuran (250 ml), and tetraethoxy, titanium (39.5 ml) was added thereto at room temperature with stirring. Then the reaction mixture was stirred at 75° C. for 5 hours, and saturated brine was added after disappearance of compound (1) was confirmed. Titanium oxide formed in the reaction was filtered off, the filtrate was extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified with a column chromatography to give compound (17) (20.1 g).

1H-NMR (CDCl3): 1.33 (9H, s), 2.75 (3H, s), 7.30 (1H, t, J=7.8) 7.59-7.63 (1H, m), 7.79 (1H, d, J=7.8) 8.0 (1H, s)
The 2nd step: A 2.64 M hexane solution of n-butyllithium (79.5 ml) is added dropwise to a tetrahydrofuran (100 ml) solution of diisopropylamine (42.1 ml) in a nitrogen atmosphere at −78° C. After stiffing at 0° C. for 30 minutes, the reaction solution was again cooled to −78° C. and tert-butyl acetate (26.9 ml) dissolved in tetrahydrofuran (100 ml) is added dropwise. After stirring at −78° C. for 30 minutes, chlorotriisopropoxytitanium dissolved in tetrahydrofuran (150 ml) is added dropwise. After stirring at the same temperature for 70 minutes, compound (2) (20.1 g) dissolved in tetrahydrofuran (100 ml) was added dropwise. After then, the reaction solution was stirred at −78° C. for 3 hours, and an aqueous solution of ammonium chloride was added after disappearance of compound (2) was confirmed. Titanium oxide formed in the reaction was filtered off, the filtrate was extracted with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a crude product of compound (18) (26.4 g).

The 3rd step: The crude product of compound (18) (26.4 g) was dissolved in toluene (80 ml), the solution was added dropwise to a 1 M solution of aluminium diisobutyl hydride in toluene (253 ml) with stirring at 0° C. The reaction solution was stirred at room temperature for 1.5 hours and 1 N hydrochloric acid solution was added after disappearance of compound (3) was confirmed. The mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by crystallization to give compound (19) (18.1 g).

1H-NMR (CDCl3): 1.28 (9H, s), 1.71 (3H, s), 2.19-2.24 (2H, m), 3.27-3.32 (1H, m), 3.54-3.66 (1H, m), 3.87-3.97 (1H, m), 5.10-5.11 (1H, m), 7.22 (1H, t, J=8.1) 7.32-7.41 (2H, m), 7.56-7.58 (1H, m)
The 4th step: Compound (19) (18 g) was dissolved in methanol (30 ml), and 10% hydrochloric acid in methanol (130 ml) was added dropwise therein at room temperature. The reaction solution was stirred at room temperature for 4 hours and 1 N hydrochloric acid was added after disappearance of compound (4) was confirmed. The mixture was extracted with ethyl acetate, the aqueous layer was neutralized with a 2 N aqueous solution of sodium hydroxide and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to give a crude product of compound (20) (14.1 g).

The 5th step: The crude product of compound (20) (32.8 g) and potassium carbonate (37.1 g) were dissolved in a mixed solvent of toluene (450 ml) and water (225 ml) and thiophosgene (15.3 ml) was added dropwise cooled at 0° C. with stirring. After then, the reaction solution was stirred at 0° C. for an hour and water was added when disappearance of compound (5) was confirmed. The mixture was extracted with ethyl acetate and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a crude product of compound (21) (38.4 g).

The 6th step: The crude product of (21) (38.4 g) was dissolved in toluene (384 ml), and thionyl chloride (29.4 ml) and N,N-dimethylformamide (1.04 ml) were added dropwise at 0° C. with stirring. After then, the reaction solution was stirred at 80° C. for 5 hours, and after disappearance of compound (6) was confirmed, the reaction solution was evaporated under reduced pressure to give a crude product of compound (22) (40.9 g).

The 7th step: The crude product of compound (22) (40.9 g) was dissolved in tetrahydrofuran (250 ml) and 25% ammonia-water (250 ml) was added with stirring at 0° C. After then the reaction solution was stirred at room temperature for 16 hours, and a saturated aqueous solution of sodium bicarbonate was added after disappearance of compound (21) was confirmed. The organic layer was separated and the aqueous solution was extracted with dichloromethane. The organic layers were combined, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give a crude product of compound (23) (38.3 g).

The 8th step: The crude product of compound (23) (38.3 g) is dissolved in tetrahydrofuran (383 ml), di-tert-butyl dicarbonate (61.5 g) and N,N-dimethylaminopyridine (1.64 g) are added and the mixture was stirred at room temperature for 72 hours. After disappearance of compound (23) was confirmed, the solvent was evaporated under reduced pressure. The residue was purified with a silicagel column chromatography to give compound (24) (45.3 g)

1H-NMR (CDCl3): 1.54 (9H, s), 1.57 (3H, s), 1.96 (2H, t, J=6.0), 2.80-2.92 (1H, 3.00-3.13 (1H, m), 7.21 (1H, t, J=8.1) 7.28-7.41 (2H, m), 7.52-7.55 (1H, m)
The 9th step: In a nitrogen atmosphere, compound (24) (12.1 g), trisdibenzylideneacetonedipalladium (1.14 g) and dicyclohexylbiphenylphosphine (0.88 g) were dissolved in toluene (125 ml), and a 1.6 M solution of lithium hexamethyldisilazide in tetrahydrofuran (46.9 ml) was added with stirring at room temperature. The reaction solution was warmed up to 80° C. and stirred for 16 hours. After disappearance of compound (21) was confirmed, the reaction solution was cooled at 0° C. and diethyl ether and 1 N hydrochloric acid were added. After stirring at 0° C. for 10 minutes, the solution was neutralized with a saturated aqueous solution of sodium carbonate. It was extracted with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (25) (6.84 g).
1H-NMR (CDCl3) 1.51 (9H, s), 1.69 (3H, s), 2.01-2.12 (1H, m), 140-2.51 (1H, m), 2.67-2.76 (2H, m), 6.55-6.67 (3H, m), 7.15 (1H, t, J=8.1).
Reference Example 5







The 1st step: After the addition of compound (1) (70.00 g) to conc. sulfuric acid (279 ml) cooled in an acetonitrile/dry ice bath with stirring, a mixture of fuming nitric acid (42 ml) and conc. sulfuric acid (98 ml) were added dropwise. After stiffing for 16 minutes, the mixture was gradually poured into ice, the precipitated crystals were filtered and dried to give compound (2) (77.79 g).

1H-NMR (CDCl3) δ: 2.71 (3H, d, J=4.9 Hz), 7.34 (1H, t, J=9.3 Hz), 8.40 (1H, ddd, J=9.3, 6.2, 3.0 Hz), 8.78 (1H, dd, J=6.2, 3.0 Hz).
The 2nd step: A solution of compound (2) (73.94 g), (R)-(+)-2-methyl-2-propanesulfinamide (53.82 g) and tetraethyl orthotitanate (230.20 g) in tetrahydrofuran (500 ml) were reacted for 2.5 hours under heating to reflux, and then the reaction mixture was gradually poured into ice and the resulted insoluble materials were filtered. It was extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was crystallized from ethyl acetate/n-hexane to give compound (26) (85.44 g).
1H-NMR (CDCl3) δ: 1.34 (9H, s), 2.81 (3H, d, J=3.5 Hz), 7.29 (1H, t, J=8.9 Hz), 8.31 (1H, dt, J=8.9, 2.9 Hz), 8.55 (1H, dd, J=6.3, 2.9 Hz).
The 3rd step: A solution of tert-butyl acetate (6.08 g) in tetrahydrofuran (10 ml) was added dropwise to a 2 M solution of lithium diisopropylamide/tetrahydrofuran/n-heptane/ethylbenzene (27.9 ml) cooled in an acetone/day ice bath with stirring. After stirring for 20 minutes, a solution of chlorotitanium isopropoxide (17.5 ml) in tetrahydrofuran (30 ml) was added dropwise, the mixture was stirred for an hour and a solution of compound (26) (5.00 g) in tetrahydrofuran (10 ml) was added dropwise. After reacting for an hour, the reaction solution was gradually poured into an aqueous solution of ammonium chloride cooled in ice with stiffing, and the resulted insoluble materials were filtered. It was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (27) (5.49 g).
1H-NMR (CDCl3) δ: 1.30 (9H, s), 1.35 (9H, s), 1.86 (3H, s), 3.11 (1H, dd, J=16.2, 2.1 Hz), 3.26 (1H, dd, J=16.2, 2.1 Hz), 5.55 (1H, s), 7.18 (1H, dd, J=11.1, 8.9 Hz), 8.18 (1H, ddd, J=8.9, 4.0, 2.9 Hz), 8.53 (1H, dd, J=7.0, 2.9 Hz).
Ratio of diastereomers (3S:3R=97:3) HPLC Column: CHIRALPAK AS-RH, Detection: 254 nm: Column temp.: 25° C., Mobile phase: 40% MeCNaq., Flow rate: 0.5 ml/min.
Note: As to the stereochemistry of compound (27) obtained above, it is known that 3S-isomer is preferentially prepared as written in the literature A etc. and it is also possible to prepare each diastereomer selectively by choosing appropriate metal species and/or a reaction condition.

    Literature A: (1) T. Fujisawa et al., Tetrahedron Lett., 37, 3881-3884 (1996), (2) D. H. Hua et al, Sulfur Reports, vol. 21, pp. 211-239 (1999), (3) Y. Koriyama et al., Tetrahedron, 58, 9621-9628 (2002), (4) Yong Qin et al., J. Org. Chem., 71, 1588-1591 (2006).

The 4th step: A solution of 4 M HCl/1,4-dioxane (50 ml) was added to compound (27) (12.74 g) and the mixture was stirred at 80° C. for an hour, diethyl ether (50 ml) was added, the precipitated crystals were filtered and dried to give compound (28) (7.67 g).



1H-NMR (DMSO-d6) δ: 1.76 (3H, s), 3.25 (2H, s), 7.62 (1H, dd, J=11.4, 9.4 Hz), 8.33-8.48 (2H, m).
The 5th step: A solution of 1 M tetrahydrofuran-borane in tetrahydrofuran (2029 ml) was added dropwise to a solution of compound (28) (141.32 g) in tetrahydrofuran (707 ml) cooled in ice with stirring and it was reacted for 3 hours and 6 minutes. The reaction mixture was poured into a mixture of sodium bicarbonate (511 g), ice (1500 g) and ethyl acetate (3000 ml) stirred at room temperature, extracted with ethyl acetate and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give compound (29) (115.46 g) as a crude product.

The 6th step: Toluene (25 ml) and water (12.5 ml) were added to the compound (29) (3.76 g) obtained in the 5th step and stilled under ice cooling. After the addition of potassium carbonate (7.97 g), thiophosgene (2.85 g) was added dropwise. After reacting for 3 hours, water was added, extracted with toluene and the organic layer was dried over anhydrous magnesium sulfate. A part of the solvent was evaporated under reduced pressure to give compound (30) as a crude product.

The 7th step: Compound (30) obtained in the 6th step was dissolved in toluene (17.4 ml) and thionyl chloride (6.67 g) and N,N-dimethylformamide (0.128 ml) were added with stirring at mom temperature. The mixture was stirred at 80° C. for 2 hours, water was added, extracted with toluene and concentrated under reduced pressure to give compound (31) (4.03 g) as a crude product.

The 8th step: Compound (31) (4.03 g) obtained in the 7th step was dissolved in tetrahydrofuran (23.8 ml) and 28% ammonia-water (23.8 ml) was added under ice cooling with stirring. The mixture was trued at room temperature for 3 days, the reaction solution was concentrated under reduced pressure and ethyl acetate was added therein. Conc. hydrochloric acid (6 ml) was added under ice cooling with stirring, the precipitated crystals were washed with ethyl acetate and water and dried to give compound (32) (2.14 g).

1H-NMR (DMSO-d6) δ: 1.76 (3H, s), 2.13-2.24 (1H, m), 2.68-2.74 (2H, m), 3.19-3.25 (1H, m), 7.63 (1H, dd, J=11.4, 8.9 Hz), 8.07 (1H, dd, J=7.0, 3.5 Hz), 8.36 (1H, dt, J=8.9, 3.5 Hz), 11.22 (1H, s).
The 9th step: Compound (32) (100 mg) was dissolved in methanol (2 ml), 10% palladium-carbon powder (50 mg) was added, and the mixture was stirred in a hydrogen atmosphere at room temperature for 18 hours. Insoluble materials were filtered off, the filtrate was evaporated under reduced pressure, sodium carbonate and water were added therein and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give compound (33) (68 mg).
1H-NMR (CDCl3) δ: 1.59 (3H, s), 1.81 (1H, ddd, J=14.1, 10.9, 3.5 Hz), 2.47 (1H, ddd, J=14.1, 5.9, 3.5 Hz), 2.71 (1H, td, J=10.9, 3.5 Hz), 2.89 (1H, ddd, J=10.9, 5.9, 3.5 Hz), 3.57 (2H, br s), 6.49 (1H, dt, J=8.5, 3.3 Hz), 6.67 (1H, dd, J=6.9, 3.3 Hz), 6.80 (1H, dd, J=11.8, 8.5 Hz).
Reference Example 6







The 1st step: A solution of compound (38) (5.00 g), (R)-(+)-2-methyl-2-propanesulfinamide (3.33 g) and tetraethyl orthotitanate (17.11 g) in tetrahydrofuran (50 ml) was reacted under heating to reflux for 7 hours, and then, it was poured portionwise into saturated brine and the resulted insoluble materials were filtered off.

It was extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified with a silicagel column chromatography to give compound (39) (6.37 g).
1H-NMR (CDCl3) δ: 1.34 (9H, s), 2.79 (3H, s), 8.26 (1H, t, J=2.3 Hz), 8.76 (1H, d, J=2.3 Hz), 8.96 (1H, d, J=2.3 Hz).
The 2nd Step: A solution of 2.66 M n-butyllithium/n-hexane (32.4 ml) was added dropwise to a solution of diisopropylamine (9.36 g) in tetrahydrofuran (39 ml) cooled in an acetone/dry ice bath with stirring and the mixture was stirred under ice cooling for 30 minutes. The reaction solution was stirred again in an acetone/dry ice bath and a solution of tert-butyl acetate (4.88 g) in tetrahydrofuran (8 ml) was added dropwise. After stirring for 40 minutes, a solution of chlorotitanium triisopropoxide (23.00 g) in tetrahydrofuran (88 ml) was added dropwise. After stirring for 10 minutes, a solution of compound (39) (637 g) in tetrahydrofuran (65 ml) was added dropwise. After reacting for 30 minutes, the reaction solution was poured portionwise into an aqueous solution of ammonium chloride and the resulted insoluble materials were filtered off. It was extracted with ethyl acetate and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give compound (40) (8.03 g) as a crude product.

The 3rd step: Lithium aluminium hydride (2.85 g) was added portionwise to a solution of the compound (40) (8.03 g) obtained in the 2nd step in tetrahydrofuran (100 ml) cooled in ice with stirring and the mixture was stirred for 2 hours. Acetone, water, and a 1N aqueous solution of sodium hydroxide were added portionwise and the mixture was stirred at room temperature for 30 minutes. The insoluble materials were filtered off and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give compound (41) (5.83 g) as a crude product.

The 4th step: A solution of 10% HCl/methanol (60 ml) was added to a solution of the compound (41) (5.83 g) obtained in the 3rd step in methanol (60 ml) cooled in ice with stirring and stirred at room temperature for 16 hours. The reaction solution was made alkaline by the addition of water and potassium carbonate, extracted with chloroform, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound (42) (5.07 g) as a elude product.

The 5th step: Imidazole (2.24 g) and t-butyldimethylsilyl chloride (3.77 g) were added to a solution of the compound (42) (5.07 g) obtained in the 4th step in N,N-dimethylformamide (26 ml) with stirring at room temperature and the mixture was stirred for 1 hour and 40 minutes. After extraction with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (43) (3.82 g).

1H-NMR (CDCl3) δ: −0.04 (3H, s), −0.01 (3H, s), 0.85 (9H, s), 1.51 (3H, s), 1.98 (2H, t, J=6.0 Hz), 3.49-3.54 (1H, m), 3.65 (1H, dt, J=6.0 Hz), 8.02 (1H, t, J=2.2 Hz), 8.53 (1H, d, J=2.2 Hz), 8.63 (1H, d, J=2.2 Hz).
The 6th step: Toluene (25 ml) and water (13 ml) were added to compound (43) (3.82 g) and stirred under ice cooling. After the addition of potassium carbonate (5.14 g), thiophosgene (1.83 g) was added dropwise. After reacting for 2 hours, water was added, extracted with chloroform and the organic layer was dried over anhydrous magnesium sulfate. A part of the solvent was evaporated under reduced pressure to give compound (44) as a crude product.

The 7th step: Thionyl chloride (4.43 g) and N,N-dimethylformamide (0.08 ml) were added to a solution of the compound (7) obtained in the 6th step in toluene (25 ml) with stirring at room temperature. The mixture was stirred at 80° C. for 5 hours, concentrated under reduced pressure to give compound (45) (5.03 g) as a crude product.

The 8th step: 28% Ammonia water (60 ml) was added to a solution of the compound (45) (5.03 g) obtained in the 7th step in tetrahydrofuran (60 ml) stirred under ice cooling and the mixture was stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure to give compound (46) (4.92 g) as a crude product.

The 9th step: A mixture of the compound (46) (4.92 g) obtained in the 8th step, di-t-butyl dicarbonate (9.28 g), triethylamine (3.23 g), 4-dimethylaminopyridine (0.13 g) and tetrahydrofuran (106 ml) was stirred at room temperature for 3 days. The insoluble materials were filtered off, water was added to the filtrate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound (47) (8.31 g) as a crude product.

The 10th step: A mixture of the compound (47) (8.31 g) obtained in the 9th step, di-t-butyl dicarbonate (6.96 g), triethylamine (3.23 g), 4-dimethylaminopyridine (0.13 g) and tetrahydrofuran (50 ml) was stirred at room temperature for an hour. After the addition of water, it was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (48) (1.23 g).

1H-NMR (CDCl3) δ: 1.53 (18H, s), 1.60 (3H, s), 1.93 (1H, ddd, J=13.8, 9.4, 3.9 Hz), 2.06 (1H, ddd, J=13.8, 3.9, 1.9 Hz), 2.91 (1H, ddd, J=12.9, 3.9, 1.9 Hz), 3.15 (1H, ddd, J=12.9, 9.4, 3.9 Hz), 7.89 (1H, t, J=2.1 Hz), 8.55-8.57 (2H, m).
The 11th step: Compound (48) (190 mg), trisdibenzylideneacetonedipalladium (54 mg), dicyclohexylbiphenylphosphine (41 mg) were dissolved in toluene (5 ml), stirred at room temperature, and 1.6 M solution of lithium hexamethyldisilazide in tetrahydrofuran (0.73 ml) was added therein. The reaction solution was warmed up to 85° C. and stirred for 9 hours, then, it was cooled in ice and diethyl ether and a 1 N solution of hydrochloric acid were added. After stirring for 10 minutes, it was neutralized by the addition of a saturated aqueous solution of sodium carbonate and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (49) (27 mg).
1H-NMR (CDCl3) δ: 1.51 (9H, s), 1.68 (3H, s), 2.12 (1H, ddd, J=14.8, 11.0, 3.0 Hz), 2.38-2.47 (1H, m), 2.64-2.70 (1H, m), 2.78-2.82 (1H, m), 3.80 (2H, br s), 6.90 (1H, t, J=2.4 Hz), 7.98 (1H, dd, J=10.4, 2.4 Hz).
Reference Example 7







The 1st step: A solution of compound (50) (38.93 g), (R)-(+)-2-methyl-2-propanesulfinamide (13.20 g) and tetraethyl orthotitanate (67.76 g) in tetrahydrofuran (389 ml) was reacted under heating to reflux for 4 hours. A saturated aqueous solution of ammonium chloride was added portionwise therein and the resulted insoluble materials were filtered off. The filtrate was concentrated and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give compound (51) (30.52 g) as a crude product.

1H-NMR (CDCl3) δ: 1.32 (9H, s), 2.83 (3H, s), 7.55-7.65 (2H, m), 8.06 (1H, d, J=8.5 Hz).
The 2nd step: A solution of tert-butyl acetate (22.99 g) in tetrahydrofuran (148 ml) was added dropwise to a 2.0 M solution of lithium diisopropylamide/n-heptane/ethylbenzene/tetrahydrofuran (202.5 ml) cooled in an acetone/dry ice bath with stirring. After stirring for 45 minutes, a solution of chlorotitanium triisopropoxide (108.36 g) in tetrahydrofuran (342 ml) was added dropwise and stirred for 40 minutes. A solution of the compound (51) (30.52 g) in tetrahydrofuran (342 ml) was added dropwise and reacted for an hour. The reaction solution was poured portionwise into an aqueous solution of ammonium chloride with stirring under ice cooling and the resulted insoluble materials were filtered off. It was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (52) (27.40 g).
1H-NMR (CDCl3) δ: 1.30 (9H, s), 1.35 (9H, s), 1.65 (3H, s), 3.01 (1H, d, J=16.5 Hz), 3.38 (1H, d, J=16.5 Hz), 5.60 (1H, s), 7.31 (1H, dd, J=5.9, 2.7 Hz), 7.48-7.50 (2H, m).
The 3rd step: Lithium aluminum hydride (5.67 g) was added portionwise to a solution of the compound (52) (22.40 g) in tetrahydrofuran (336 ml) stirred in an ice salt bath and stirred for 7 hours. After the addition of acetone, water and a 1 N aqueous solution of sodium hydroxide, the insoluble materials were filtered off and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound (53) (18.75 g) as a crude product.

The 4th step: A solution of 10% HCl/methanol (94 ml) was added to a solution of the compound (53) (18.75 g) obtained in the 3rd step in methanol (94 ml) stirred under ice cooling and stirred at room temperature for 1.5 hours. The reaction solution was made alkaline by the addition of water and potassium carbonate and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound (54)(21.03 g) as a mute product.

The 5th step: Imidazole (5.49 g) and tert-butyldimethylsilyl chloride (10.53 g) were added to a solution of the compound (54) (21.03 g) in N,N-dimethylformamide (210 ml) stirred at room temperature and the mixture was stirred for an hour. After extraction with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (55) (20.12 g).

1H-NMR (CDCl3) δ: −0.04 (3H, s), −0.02 (3H, s), 0.84 (9H, s), 1.47 (3H, s), 1.95-2.15 (2H, m), 3.54-3.63 (2H, m), 7.29 (1H, dd, J=6.1, 2.6 Hz), 7.45-7.48 (2H, m).
The 6th step: Toluene (66 ml) and water (33 ml) were added to compound (55) (10.06 g) and stirred under ice cooling. After the addition of potassium carbonate (11.13 g), thiophosgene (2.86 ml) was added dropwise. After reacting for an hours, water was added, extracted with chloroform and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (56) (9.43 g).
1H-NMR (CDCl3) δ: −0.03 (6H, s), 0.82 (9H, s), 1.80 (3H, s), 2.21-2.24 (1H, m), 2.44-2.48 (1H, m), 3.57 (1H, ddd, J=12.0, 5.8, 4.8 Hz), 3.71 (1H, ddd, J=12.0, 5.8, 4.8 Hz), 7.37 (1H, dd, J=7.5, 1.2 Hz), 7.48-7.58 (2H, m).
The 7th step: 28% Ammonia water (47 ml) was added to compound (56) (9.43 g) dissolved in tetrahydrofuran (94 ml) stirred at room temperature. After stilling for 16 hours, water was added, extracted with ethyl acetate and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give compound (57) (6.35 g) as a crude product.

The 8th step: Acetic acid (1.09 g) and a 1.0 M solution of tetrabutylammonium fluoride/tetrahydrofuran (18.20 ml) were added to a solution of the compound (57) (6.35 g) obtained in the 7th step in tetrahydrofuran (127 ml) stirred under ice cooling. After stirring at room temperature for 3 hours, water and potassium carbonate were added and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (58) (4.47 g).

1H-NMR (CDCl3) δ: 1.85 (3H, s), 2.27-2.31 (2H, br m), 3.73-3.83 (2H, m), 5.86 (2H, br s), 7.43 (1H, d, J=7.8 Hz), 7.52 (1H, d, J=7.8 Hz), 7.61 (1H, t, J=7.8 Hz), 7.81 (1H, br s).
The 9th step: 1-Chloro-N,N,2-trimethyl-1-propenylamine (2.16 g) was added to compound (58) (4.47 g) dissolved in dichloromethane (89 ml) stirred under ice cooling. After stirring at room temperature for 1.5 hours, water was added and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (59) (2.91 g).
1H-NMR (CDCl3) δ: 1.53 (3H, s), 1.88 (1H, ddd, J=13.9, 10.1, 3.8 Hz), 2.40 (1H, ddd, J=13.9, 6.6, 3.8 Hz), 2.71 (1H, ddd, J=13.9, 10.1, 3.8 Hz), 2.95 (1H, tt, J=6.6, 3.8 Hz), 4.33 (2H, br s), 7.29 (1H, dd, J=7.5, 1.2 Hz), 7.41-7.50 (1H, m).
The 10th step: A mixture of compound (59) (2.91 g), di-tert-butyl dicarbonate (5.52 g), 4-dimethylaminopyridine (0.12 g) and tetrahydrofuran (29 ml) was stirred at room temperature for 2.5 hours. The reaction solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (60) (1.23 g).
1H-NMR (CDCl3) δ: 1.53 (23H, s), 1.60 (3H, s), 1.93 (1H, ddd, J=13.8, 9.4, 3.9 Hz), 2.06 (1H, ddd, J=13.8, 3.7, 1.8 Hz), 2.91 (1H, ddd, J=12.7, 3.7, 1.9 Hz), 3.15 (1H, ddd, J=12.9, 9.2, 3.7 Hz), 7.89 (1H, t, J=2.1 Hz), 8.55-8.57 (2H, m).
The 11th step: Compound (60) (3.30 g), trisdibenzylideneacetonedipalladium (0.93 g), dicyclohexylbiphenylphosphine (0.73 g) were dissolved in toluene (66 ml), stirred at room temperature, and a 1.6 M solution of lithium hexamethyldisilazide in tetrahydrofuran (12.7 ml) was added therein. The reaction solution was warmed up to 80° C. and stirred for 8 hours, than, it was cooled in ice and diethyl ether and a 1 N solution of hydrochloric acid were added. After stirring for 5 minutes, it was neutralized by the addition of a saturated aqueous solution of sodium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (61) (1.55 g).
1H-NMR (CDCl3) δ: 1.61 (3H, s), 1.74-1.80 (1H, n), 1.96-2.11 (1H, m), 2.64-2.82 (2H, m), 4.41 (2H, br s), 6.39 (1H, dd, J=8.1, 0.6 Hz), 6.71 (1H, dd, J=8.1, 0.6 Hz), 7.42 (1H, t, J=8.1 Hz).
Reference Example 8




The 1st step: Compound (63) (3.31 g) prepared in the same manner as Reference Example 6 and 7 described above was dissolved in dichloromethane (16.5 nit), bis(2,4-dimethoxybenzyl)amine (4.45 g) was added and the solvent was evaporated under reduced pressure after stirring at room temperature for an hour and standing for 15 hours. The residue was purified with silicagel chromatography to give compound (63) (5.7 g).

1H-NMR (CDCl3): −0.10 (3H, s), −0.07 (3H, s), 0.77 (9H, s), 1.93 (3H, s), 2.08-2.27 (1H, m), 3.06-3.28 (1H, m), 3.38 (1H, ddd, J=10.8, 6.8, 6.8 Hz), 3.55 (1H, ddd, J=10.8, 6.8, 6.8 Hz), 3.78 (6H, s), 3.79 (6H, s), 4.81-5.05 (1H, br), 6.43-6.50 (4H, m), 7.07 (1H, d, J=1.9 Hz), 7.17 (2H, d, J=7.3 Hz), 8.05-8.16 (2H, m).
The 2nd step: Compound (63) (5.77 g) was dissolved in tetrahydrofuran (60 ml) and acetic acid (1.01 g) and 1M tetrabutylammonium fluoride/tetrahydrofuran-solution (15 ml) were added and the mixture was stirred at room temperature for 150 minutes. Water was added, extracted with ethyl acetate and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel chromatography to give compound (64) (3.94 g).
1H-NMR (CDCl3): 1.99 (3H, s), 1.91-2.02 (1H, m), 3.10 (1H, ddd, J=14.6, 6.6, 5.2), 3.36-3.51 (2H, m), 3.78 (6H, s), 3.80 (6H, s), 4.58 (2H, d, J=15.8 Hz), 4.72 (2H, d, J=15.8 Hz), 6.43-6.51 (4H, m), 7.12 (1H, dd, J=5.3, 2.0 Hz), 7.18-7.29 (3H, m), 8.20 (1H, dd, J=5.3, 0.6 Hz), 8.28-8.34 (1H, br).
The 3rd step: Compound (64) (3.94 g) was dissolved in dichloromethane (20 ml) and 1-chloro-N,N′,2-trimethyl-1-propenylamine (1.86 ml) was added under ice cooling with stirring. After stirring at room temperature for 2 hours, water was added, extracted with chloroform and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give a compound (65) (3.41 g).
1H-NMR (CDCl3): 1.49 (3H, s), 1.99 (1H, ddd, J=13.3, 7.6, 3.2 Hz), 2.31 (1H, ddd, J=13.3, 8.6, 3.7), 2.78 (1H, ddd, J=12.2, 8.6, 3.2 Hz), 3.04 (1H, ddd, J=12.2, 7.6, 3.7 Hz), 3.77 (6H, s), 3.79 (6H, s), 4.60 (2H, d, J=15.8 Hz), 4.76 (2H, d, J=15.8 Hz), 6.45-6.52 (4H, m), 7.08 (1H, dd, J=5.3, 2.1 Hz), 7.17-7.27 (3H, m), 8.40 (1H, dd, J=5.3, 0.5 Hz).
Reference Example 9




The 1st step: Compound (66) (4.72 g) derived by a conventional method from an intermediate prepared in the same manner as the compound (27) described above was dissolved in tetrahydrofuran (150 ml) and a diethylether solution of methyl magnesium bromide (3M, 37 ml) was added dropwise with stirring under ice cooling in a nitrogen stream for 12 minutes. After stirring 3 hours, a saturated aqueous solution of ammonium chloride (190 ml) was added dropwise, extracted with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give a compound (67) (2.11 g).

1H-NMR (DMSO-d6) 0.75 (3H, s), 1.09 (3H, s), 1.21 (9H, s), 1.79 (3H, s), 2.06 (1H, m), 2.29 (1H, m), 4.97 (1H, s), 6.57 (1H, s), 7.17 (1H, dd, J=8.7, 12.0 Hz), 7.48-7.53 (1H, m), 7.99-8.03 (1H, m), 11.26 (1H, bs).
The 2nd step: Compound (67) (2.11 g) was dissolved in methanol (7.8 ml) and hydrochloric acid-methanol solution (5-10%) (15:6 ml) was added with stirring at room temperature, and the mixture was stirred for 1.5 hams. Then the reaction solution was poured into ice water and ethyl acetate (100 ml), a saturated aqueous solution of sodium bicarbonate (50 ml) was added and extracted with ethyl acetate. The aqueous layer was further extracted with ethyl acetate (50 ml), organic layers were combined, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was crystallized from n-hexane to give compound (68) (1.42 g).
1H-NMR (DMSO-d6): 0.65 (3H, s), 1.10 (3H, s), 1.43 (3H, s), 1.85 (1H, d, J=14.4 Hz), 2.17 (1H, dd, J=1.5, 14.4 Hz), 7.12 (1H, dd, J=2.7, 12.0 Hz), 7.60-7.64 (1H, m), 7.90 (1H, dd, 7.5 Hz), 11.35 (1H, bs).
The 3rd step: Toluene (9.6 ml) and water (4.8 ml) were added to compound (68) (1.42 g) and suspended, potassium carbonate (2.13 g) was added with stirring under ice cooling and 2 minutes later thiophosgene (0.51 ml) was added at once and the stirring was continued.
The temperature was back to room temperature 40 minutes later, toluene (40 ml) and water were added and extracted an hour later. The aqueous layer was further extracted with toluene, organic layers were combined, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give a crude product (69) (2.02 g).
The 4th step: Tetrahydrofuran (17 ml) was added to triphenylphosphine (1.735 g) and N-chlorosuccinimide (833 mg), suspended in a nitrogen stream and stirred at room temperature for 10 minutes. A tetrahydrofuran (21 ml) solution of the crude product (69) (2.02 g) was added dropwise using a dropping funnel for 2 minutes. After stirring for 6 hours, the mixture was left stand at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give a compound (70) (828 mg).
1H-NMR (DMSO-d6): 1.54 (3H, s), 1.86 (3H, s), 2.81 (1H, d, J=13.8 Hz), 2.92 (1H, d, J=13.8 Hz), 4.73 (1H, s), 4.85 (1H, m), 7.28-7.35 (1H, m), 7.77-7.82 (2H, m), 11.39 (1H, bs).
The 5th step: Compound (70) (828 mg) was dissolved in tetrahydrofuran (4 ml), conc. ammonia water (28%) (4 ml) was added with stirring under ice cooling and the temperature was back to room temperature after stirring for 5 minutes. After 25 hours, the reaction mixture was poured into ice water and extracted with ethyl acetate (50 ml). The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel chromatography to give a compound (71) (260 mg).
1H-NMR (DMSO-d6): 1.47 (3H, bs), 1.66 (3H, bs), 2.58 (1H, d, J=12.3 Hz), 4.71 (1H, s), 4.87 (3H, bs), 6.42 (1H, bs), 6.51 (1H, dd, 7.2 Hz), 6.75 (2H, bs), 7.54 (1H, bs).
The 6th step: Compound (71) (245 mg) was dissolved in chilled conc. sulfuric acid (4.9 ml) and stirred under ice cooling for 2 hours. The reaction solution was poured into ice water with stilling and pH was adjusted to 2-3 by the addition of a 5N aqueous solution of sodium hydroxide. Ethyl acetate (100 ml) and an aqueous solution of potassium carbonate were added and extracted under alkaline condition. The alkaline layer was further extracted with ethyl acetate (50 ml). Organic layers were combined, washed with saturated brine (50 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give a compound (72) (101 mg) as a crystal.
1H-NMR (DMSO-d6): 0.83 (3H, s), 1.27 (3H, s), 1.44 (3H, s), 1.54 (1H, d, J=14.1 Hz), 2.45 (1H, d, J=14.1 Hz), 4.79 (2H, s), 5.89 (2H, bs), 6.32-6.37 (1H, m), 6.58 (1H, dd, J=2.7, 7.2 Hz), 6.72 (1H, dd, J=8.7, 12.3 Hz).
Reference Example 10







The 1st step: Ethyl bromodifluoroacetate (0.77 ml) was added to a suspension of zinc dust (392 mg) in tetrahydrofuran (4 ml) with stirring in a nitrogen stream at room temperature, stirred for 15 minutes, ethyl bromodifluoroacetate (0.29 ml) was added, stirred for 30 minutes to prepare a solution of ethyl bromozincdifluoroacetate. This solution was added to a solution of compound (73) in tetrahydrofuran (3 ml) in a nitrogen stream and stirred for 8 hours. 3% Ammonia water was added to the reaction mixture with stirring under ice cooling, extracted with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give a compound (74) (696 mg).

1H-NMR (DMSO-d6) δ: 1.17 (3H, t, J=7.2 Hz), 1.18 (9H, s), 2.00 (3H, brs), 4.24 (2H, q, J=7.2 Hz), 5.56 (1H, brs), 7.56 (dd, J=9.0, 11.7 Hz), 8.36 (1H, m), 8.49 (1H, dd, J=3.0, 6.6 Hz).
The 2nd step: Compound (74) (670 mg) was dissolved in tetrahydrofuran (6.7 ml) and lithium borohydride (71 mg) was added in a nitrogen stream with stirring under ice cooling. After stirring for 30 minutes, acetic acid (198 mg) and ice water were added to the reaction mixture, extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give a compound (75) (401 mg).
1H-NMR (DMSO-d6) δ: 1.20 (9H, s), 2.00 OH, d, J=3.6 Hz), 3.80 (1H, m), 4.00 (1H, m), 5.99 (1H, s), 6.34 (1H, t, J=5.7 Hz), 7.53 (1H, dd, J=9.0, 12.0 Hz), 8.31 (1H, m), 8.50 (1H, dd, J=2.7, 6.6 Hz).
The 3rd step: Compound (75) (394 mg) was dissolved in methanol (3 ml), and 4N—HCl/1,4-dioxane (1.35 ml) was added with stirring under ice cooling. After stirring for 30 minutes, the mixture was stirred at room temperature for 1.5 hours. Ice water was added to the reaction solution and washed with ethyl acetate. The aqueous layer was made alkaline by the addition of a 2M aqueous solution of potassium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure to give compound (76) (293 mg).
1H-NMR (DMSO-d6) δ: 1.62 (3H, d, J=2.7 Hz), 2.62 (2H, brs), 3.65-3.83 (2H, m), 5.31 (1H, brt), 7.41 (1H, dd, J=9.0, 11.4 Hz), 8.23 (1H, m), 8.59 (1H, dd, J=3.0, 6.9 Hz).
The 4th step: Compound (76) (266 mg) was dissolved in acetone (3 ml) and benzoyl isothiocyanate (164 mg) was added in a nitrogen stream with stirring under ice cooling. After stirring for an hour, the mixture was stirred at room temperature for an hour. The reaction solution was concentrated under reduced pressure and the residue was purified with a silicagel column chromatography to give a compound (77) (353 mg).
1H-NMR (DMSO-d6) δ: 2.30 (3H, brs), 3.65-3.96 (2H, m), 5.90 (1H, brt), 7.42-7.68 (4H, m), 7.93-7.96 (2H, m), 8.17-8.33 (2H, m), 11.42 (1H, brs), 12.31 (1H, brs).
The 5th step: Compound (77) (348 mg) was dissolved in dichloromethane (4 ml) and 1-chloro-N,N-2-trimethyl-1-propenylamine (131 mg) was added in a nitrogen stream with stirring under ice cooling. After stirring for 15 hours at room temperature, ice water was added and neutralized by the addition of potassium carbonate. It was extracted with ethyl acetate, washed with brine and dried over anhydrous magnesium sulfite. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give a compound (78) (308 mg).
1H-NMR (CDCl3) δ: 1.89 (3H, d, J=3.0 Hz), 3.17 (1H, ddd, J=8.4, 10.2, 13.2 Hz), 3.51 (1H, ddd, J=6.0, 13.2, 19.2 Hz), 7.23 (1H, dd, J=9.0, 10.8 Hz), 7.49-7.64 (3H, m), 7.91 (2H, d, J=7.2 Hz), 8.24 (1H, m), 8.43 (1H, dd, J=3.0, 6.6 Hz), 8.57 (1H, br).
The 6th step: Compound (78) (297 mg) was dissolved in ethanol (4 ml), water (1.5 ml) and cone, hydrochloric acid (1.5 ml) were added and the mixture was stirred at 90° C. for 2.5 hours. Water was added to the reaction solution, washed with ethyl acetate and the aqueous layer was made alkaline by the addition of a 2M aqueous solution of potassium carbonate. It was extracted with ethyl acetate, washed with brine and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give a compound (79) (89 mg).
1H-NMR (CDCl3) δ: 1.85 (3H, d, J=3.6 Hz), 3.15 (1H, ddd, J=8.7, 10.5, 12.9 Hz), 3.50 (1H, ddd, J=5.4, 12.9, 18.3 Hz), 4.51 (2H, brs), 7.19 (1H, dd, J=9.0, 11.1 Hz), 8.20 (1H, ddd, J=3.0, 6.9, 9.0 Hz), 8.54 (1H, dd, J=3.0, 6.9 Hz).
The 7th step: Compound (79) (82 mg) was dissolved in dichloromethane (1 ml), di-tert-butyldicarbonate (176 mg) and 4-dimethylaminopyridine (4 mg) were added and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure and the residue was purified with a silicagel column chromatography to give a compound (80) (101 mg).
1H-NMR (CDCl3) δ: 1.56 (18H, s), 1.90 (3H, d, J=3.6 Hz), 3.27 (1H, ddd, J=6.6, 9.3, 12.9 Hz), 3.69 (1H, ddd, J=4.2, 12.9, 17.4 Hz), 7.23 (1H, dd, J=9.0, 12.0 Hz), 8.24 (1H, ddd, J=3.0, 9.0, 12.0 Hz), 8.41 (1H, ddd, J=2.4, 3.0, 6.0 Hz).
The 8th step: Compound (80) (4.76 g) was dissolved in methanol (70 ml), 10% Pd—C (containing 50% water) (2.38 g) was added and the mixture was stirred in a hydrogen atmosphere for 20 hours. The catalyst was filtered off the solvent was evaporated under reduced pressure to give compound (81) (4.43 g)
1H-NMR (CDCl3) δ: 1.54 (18H, s), 1.85 (3H, d, J=2.4 Hz), 3.24 (1H, m), 3.41 (1H, m), 3.53 (2H, brs), 6.61 (1H, m), 6.82-6.89 (2H, m).
Reference Example 11







The 1st step: A solution of 2.0M lithium diisopropylamide/n-heptane/ethyl benzene (182 ml) in tetrahydrofuran (150 ml) was cooled in a dry ice-acetone bath, and a solution of methyl isobutyrate (27.17 g) iii tetrahydrofuran (90 ml) was added dropwise with stirring. After stirring for 40 minutes, a solution of chlorotitanium triisopropoxide (97.07 g) in tetrahydrofuran (300 ml) was added dropwise. After stirring for 15 minutes, a solution of compound (86) (25.39 g) in tetrahydrofuran (150 ml) was added dropwise. After the reaction for 2.5 hours, the reaction mixture was poured portionwise into an aqueous solution of ammonium chloride stirred under ice cooling and the formed insoluble materials were filtered. It was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give a compound (87) (23.98 g).

1H-NMR (CDCl3) δ: 1.12 (3H, s), 1.22 (3H, s), 1.35 (9H, s), 1.99 (3H, d, J=5.8 Hz), 3.75 (3H, s), 5.65 (1H, s), 7.20 (OH, dd, J=11.5, 8.9 Hz), 8.18-8.21 (1H, m), 8.45 (1H, dd, J=6.9, 2.9 Hz).
The 2nd step: Compound (87) (391 mg) was dissolved in tetrahydrofuran (4 ml) and lithium borohydride (44 mg) was added in 3 minutes in a nitrogen stream with stirring at room temperature. After stirring for 2 hours, lithium borohydride (22 mg) was further added and the stirring was continued. After stirring for 2 hours, a saturated aqueous solution of ammonium chloride was slowly added to the reaction solution with stirring under ice cooling, extracted with ethyl acetate 5 minutes later, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give a compound (88) (175 mg).
1H-NMR (DMSO-d6) δ: 0.65 (3H, d, J=1.8 Hz), 0.93 (3H, s), 1.22 (9H, s), 1.93 (3H, d, J=6.6 Hz), 3.24 (1H, d, J=8.4 Hz), 3.74 (1H, d, J=8.4 Hz), 5.96 (1H, bs), 6.75 (1H, s), 7.47 (1H, dd, J=9.0, 12.0 Hz), 8.23 (1H, ddd, J=3.0, 3.0, 9.0 Hz), 8.39 (1H, dd, J=3.0, 6.9 Hz).
The 3rd step: Compound (88) (331 mg) was dissolved in methanol (1.5 ml), and a hydrogen chloride-methanol solution (5-10%) (3 ml) was added with stirring at room temperature. After stirring for 1.5 hours, the reaction solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate-methanol (9:1), poured into ice water, and a saturated aqueous solution of sodium bicarbonate (4 ml) was added, extracted, washed with saturated brine and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the powder obtained by the addition of n-hexane to the solid was filtered to give a compound (89) (207 mg).
1H-NMR (DMSO-d6) δ: 0.80 (6H, s), 1.59 (3H, d, J=4.5 Hz), 3.16 (1H, d, J=10.8 Hz), 7.38 (1H, dd, J=9.0, 12.0 Hz), 8.17 (1H, ddd, J=3.0, 3.0, 9.0 Hz), 8.64 (1H, dd, J=3.0, 6.9 Hz).
The 4th step: Compound (89) (150 mg) was dissolved in acetone (3 ml) and benzoyl isothiocyanate (0.079 ml) was added in a nitrogen stream with stirring under ice cooling. After stirring for 2 hours, the reaction solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give a compound (90) (236 mg).
LCMS: 420 m/z[M+H]+
The 5th step: Compound (90) (233 mg) was dissolved in dichloromethane (4 ml) and chloropropenylamine (0.081 ml) was added at once in a nitrogen stream with stiffing at room temperature. After stirring for 23 hours, the reaction solution was poured into ice water, extracted with ethyl acetate, washed with saturated brine and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give a compound (91) (128 mg).
1H-NMR (DMSO-d6) δ: 0.83 (3H, s), 1.12 (3H, s), 1.72 (3H, s), 2.69 (1H, d, J=13.2 Hz), 2.90-3.10 (1H, m), 7.44-7.58 (4H, m), 8.00 (2H, d, J=7.5 Hz), 8.23-8.35 (2H, m), 10.75 (1H, bs).
The 6th step: Compound (91) (20 mg) was suspended in 99.5% ethanol (0.4 ml), 6N hydrochloric acid (0.2 ad) was added and the mixture was stirred in a oil bath heated to 90° C. After stifling for 17 hours, the reaction solution was poured into water, and extracted with ethyl acetate. The aqueous layer was made alkaline by the addition of a saturated aqueous solution of potassium carbonate (pH=11), extracted with ethyl acetate, washed with saturated brine and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give compound (92) (14 mg).
1H-NMR (DMSO-d6) δ: 0.72 (3H, s), 1.00 (3H, d, J=3.6 Hz), 1.54 (3H, d, J=4.8 Hz), 2.61 (1H, d, J=12.3 Hz), 3.09 (1H, d, J=12.3 Hz), 5.98 (2H, s), 7.41 (1H, dd, J=9.0, 11.7 Hz), 8.16-8.21 (1H, m), 8.42 (1H, dd, J=3.0, 6.9 Hz).
The 7th step: Compound (92) (12 mg) was dissolved in dichloromethane (0.1 ml) and a di-tert-butyldicarbonate-dichloromethane solution (0.0966M, 1.2 ml) was added with stirring at room temperature. After stifling for 2 hours, the reaction solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give a compound (93) (15 mg).
1H-NMR (DMSO-d6) δ: 0.70 (3H, s), 1.02 (3H, s), 1.43 (9H, s), 1.56 (3H, bs), 2.61 (1H, d, J=12.9 Hz), 3.16 (1H, m), 7.45 (1H, dd, J=9.0, 11.4 Hz), 8.20-8.24 (1H, m), 8.35 (1H, m), 9.87 (1H, bs).
The 8th step: Methanol (4.1 ml) was added to compound (93) (823 mg), suspended, and 10% Pd—C (50% wet) (412 mg) was added. A catalytic reduction was carried out at normal pressure, and methanol (8.2 ml) was added when a solid was precipitated and the reduction was further continued. After 23 hours, the catalyst was filtered through a Celite pad, washed with warm methanol, and the washings were combined. The solvent was evaporated under reduced pressure and the powder precipitated by the addition of diisopropylether to the residue was filtered to give compound (94) (638 mg).
1H-NMR (DMSO-d6) δ: 0.87 (3H, bs), 1.06 (3H, bs), 1.39 (9H, s), 1.57 (3H, bs), 2.66-2.72 (2H, m), 4.97 (2H, bs), 6.45-6.47 (2H, m), 6.78 in), 9.65 (1H, bs).
Reference Example 12




The 1st step: 3-(Trifluoromethyl)-1H-pyrazole (591 mg) was dissolved in dimethylformamide (7 ml), potassium carbonate (601 mg) and compound (104) (500 mg) were added thereto and stirred at room temperature overnight. The reaction was quenched by an addition of water. The insoluble materials were filtered and washed with diisopropylether. The resulted solid was dried under reduced pressure to give compound (105) (644 mg).

1H-NMR (CDCl3) δ: 4.08 (3H, s), 6.81 (1H, d, J=2.5 Hz), 8.65 (1H, s), 9.14 (1H, s), 9.45 (1H, s).
The 2nd step: Compound (105) (640 mg) was added to a mixed solvent of water-methanol (6 ml, 1:1), lithium hydroxide (84 mg) was added and the mixture was stirred at room temperature for 4 hours. The reaction solution was acidified by the addition of 2N hydrochloric acid, the insoluble materials were filtered off and washed with diisopropylether.
The resulted solid was dried under reduced pressure to give compound (106) (343 mg).
1H-NMR (DMSO-d6) δ: 7.20 (1H, d, 2.5 Hz), 8.93 (1H, s), 9.12 (1H, s), 9.33 (1H, s).
Reference Example 13




The 1st step: A mixture of compound (107) (1000 mg), dioxane (2 ml), and 28% ammonia water (2 ml) was stirred at 50° C. for 19 hours. The reaction solution was concentrated under reduced pressure. Water was added to the residue, extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give a compound (108) (476 mg).

1H-NMR (CDCl3) δ: 1.63 (9H, s), 5.04 (2H, br s), 8.03 (1H, s), 8.69 (1H, s).
The 2nd step: 3-Bromo-2-oxopropanoic acid ethyl ester (1582 mg) was added to compound (108) (475 mg) in dimethoxyethane (4 ml) and the mixture was stirred at 75° C. for 2.5 hours. The reaction solution was diluted with diisopropylether, the insoluble materials were filtered, washed with diisopropylether and hexane, and dried under reduced pressure. The residue was stirred in tert-butyl alcohol (7.5 ml) at 95° C. for 2 hours. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (109) (709 mg).
1H-NMR (CDCl3) δ: 1.46 (3H, t, J=7.1 Hz), 1.66 (9H, s), 4.50 (2H, q, J=7.1 Hz), 8.35 (1H, s), 8.89 (1H, s), 9.24 (1H, s).
The 3rd step: A mixture of compound (09) (270 mg), dioxane (3 ml) and 28% ammonia water (2.5 ml) was stirred in a pressure bottle at 50° C. for 6 hours. The reaction solution was concentrated under reduced pressure to give a crude product of compound (110) (249 mg).
1H-NMR of the crude product (CDCl3) δ: 1.67 (9H, s), 5.79 (1H, br s), 8.35 (1H, s), 8.90 (1H, s), 9.15 (1H, s).
The 4th step: 2,2,2-Trichloroacetyl chloride (253 mg) was added at 0° C. to a mixture of compound (10) (146 mg), triethylamine (282 mg) and dimethylaminopyridine (6.8 mg) in tetrahydrofuran (9 ml), and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate and the reaction was quenched by the addition of a saturated aqueous solution of sodium bicarbonate. It was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to give compound (111) (99 mg) as a crude product.

The 5th step: Compound (111) (95 mg) was dissolved in chloroform (3 ml), trifluoroacetic acid (1330 mg) was added and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure to give a crude product. The residue was suspended with ethyl acetate and diisopropylether and the insoluble materials were filtered and washed with diisopropylether. The residue was dried under reduced pressure to give a composition including compound (112).

Reference Example 14







The 1 step: A 2.6M n-butyl lithium/hexane solution (9.38 ml) was added dropwise for 10 minutes to diisopropylamine (2.75 g) dissolved in tetrahydrofuran (25 ml) under stirring in a dry ice/acetone bath. After stirring in a ice bath for 10 minutes and in a dry ice/acetone bath for 10 minutes, tert-butyl α-benzyloxyacetate (5.21 g) dissolved in tetrahydrofuran (25 ml) was added dropwise for 30 minutes. After stirring for 40 minutes, chlorotitaniumtriisopropoxide (6.60 g) dissolved in tetrahydrofuran (50 ml) was added dropwise. After stirring for 30 minutes, compound (73) (2.68 g) dissolved in tetrahydrofuran (50 ml) was added dropwise for 10 minutes and stirred for 90 minutes. A suspension of ammonium chloride (7.52 g) in tetrahydrofuran-water (1:1, 40 ml) was stirred at room temperature, and the reaction mixture was added thereto at once and the precipitated insoluble materials were filtered. The filtrate was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (4.49 g).

1H-NMR (CDCl3) δ: 1.14 (3.6H, s), 1.22 (3.6H, s), 1.27 (5.4H, s), 1.39 (5.4H, s), 1.96 (1.2H, s), 1.99 (1.8H, s), 4.31 (0.4H, s), 4.34 (0.6H, d, J=11.6 Hz), 4.41 (0.4H, d, J=11.6 Hz), 4.45 (0.6H, s), 4.56 (0.4H, s), 4.68 (0.6H, d, J=11.6 Hz), 4.81 (0.41H, d, J=11.6 Hz), 5.01 (0.6H, s), 7.06-7.38 (6H, m), 8.18 (0.61H, d, J=8.8 Hz), 8.24 (0.4H, d, J=9.1 Hz), 8.42-8.47 (1H, m).
The 2nd step: Compound (113) (4.49 g) was dissolved in trifluoroacetic acid (44 ml), stirred at room temperature for an hour and the solvent was evaporated under reduced pressure. The resulted residue was dissolved in 10% hydrochloric acid-methanol (44 ml), stirred at room temperature overnight and the reaction solution was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (22 ml) and a solution of 1M-borane-tetrahydrofuran complex in tetrahydrofuran (44.1 ml) was added dropwise for 15 minutes under ice cooling, and the mixture was stirred at room temperature for 2.5 hours. Water (50 ml) was added therein with stirring under ice cooling, stirred for 15 minutes and ethyl acetate (50 ml) and potassium carbonate (16 g) were added. It was extracted with ethyl acetate and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained compound (114) (3.27 g) was used in the next step without purification.

The 3rd step: Benzoyl isothiocyanate (1.41 ml) was added to compound (114) (3.27 g) in methylenechloride (16.5 ml), stirred at room temperature for an hour and the solvent was evaporated under reduced pressure. The residue was purified with a silicagel column chromatography to give compound (115) (3.14 g).

1H-NMR (CDCl3) δ: 2.14 (1.35H, s), 2.21 (1.65H, s), 3.73-4.07 (3H, m), 4.43 (0.55H, d, J=11.5 Hz), 4.63 (0.55H, d, J=11.5 Hz), 4.74 (0.45H, d, J=11.5 Hz), 4.78 (0.45H, d, J=11.5 Hz), 7.20-7.38 (4H, 7.43-7.51 (2H, m), 7.56-7.63 (1H, m), 7.75-7.86 (2H, m), 8.08-8.17 (1H, m), 8.24-8.34 (1H, m), 8.91-9.01 (1H, m), 11.81 (0.55H, s), 11.90 (0.45H, s).
The 4th step: α-Chlorotetramethylenamine (1.67 ml) was added to compound (115) (3.14 g) methylenechloride (15.5 ml), stirred at room temperature for 30 minutes and pH was adjusted to over 11 by the addition of water (15 ml) and potassium carbonate. It was extracted with chloroform and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (116) (2.66 g).
1H-NMR (CDCl3) δ: 1.58 (3bH, s), 1.81 (3aH, s), 2.76 (bH, dd, J=13.4, 1.8 Hz), 3.09 (bH, dd, J=13.4, 6.1 Hz), 3.16 (aH, dd, J=13.8, 3.9 Hz), 3.35 (aH, dd, J=13.8, 1.8 Hz), 4.21-4.25 (aH, m), 4.28 (aH, d, J=12.4 Hz), 4.33-4.38 (bH, m), 4.49-4.56 (a+bH, m), 4.73 (bH, d, J=11.9 Hz), 6.83-7.60 (10H, m), 7.91-8.23 (3H, m), 8.25-8.30 m), 8.74 (aH, m).
The 5th step: Hydrazine monohydrate (0.73 ml) was added to compound (116) (1.44 g) in ethanol (7.2 ml) and stirred at room temperature for 2 hours. Water was added, extracted with ethyl acetate and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained compound (117) (1.14 g) was used in the next step without purification.

The 6th step: A solution of di-tert-butyl dicarbonate (1.65 g) in methylenechloride (5.5 ml) and 4-dimethylaminopyridine (37 mg) were added to compound (117) (1.14 g) in methylenechloride (5.5 ml) and stirred at room temperature for an hour. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (118) (1.52 g).

1H-NMR (CDCl3) δ: 1.47 (8.1H, s), 1.51 (9.9H, s), 1.53 (1.35H, s), 1.75 (1.65H, s), 3.01-3.49 (2H, m), 3.81-3.86 (0.55H, m), 4.07-4.09 (0.45H, m), 4.17 (0.45H, d, J=12.1 Hz), 4.25 (0.55H, d, J=11.6 Hz), 4.41 (0.45H, d, J=12.1 Hz), 4.49 (0.55H, d, J=11.6 Hz), 6.73-6.78 (1H, m), 6.94-7.23 (5H, m), 8.11-8.18 (1H, m), 8.22-8.27 (0.55H, m), 8.51-8.55 (0.45H, m).
The 7th step: 20 w/w % Palladium hydroxide supported by carbon (40 mg) was added to a solution of compound (118) (211.3 mg) in ethanol (2 ml), stirred in a hydrogen atmosphere of 1 atom at room temperature for 22 hours and filtered through a Celite pad. The filtrate was concentrated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (119) (149.1 mg).
1H-NMR (CDCl3) δ: 1.46 (8.1H, s), 1.51 (9.9H, s), 1.54 (1.35H, s), 1.74 (1.65H, s), 2.91 (0.55H, d, J=12.9 Hz), 3.02 (0.55H, dd, J=12.9, 6.3 Hz), 3.15 (0.45H, dd, J=13.3, 3.0 Hz), 3.37-3.73 (2H, hr), 3.43 (0.45H, d, J=13.3 Hz), 4.13-4.18 (1H, m), 4.22 (0.45H, d, J=11.9 Hz), 4.34 (0.45H, d, J=11.9 Hz), 4.49 (0.55H, d, J=11.6 Hz), 4.59 (0.55H, d, J=11.6 Hz), 6.45-6.61 (1H, m), 6.71-7.39 (7H, m).
Example 1
Preparation of Compound 46




Compound (34) (125 mg) and DMT-MM (162 mg) were suspended in methanol (1.2 ml), stiffed at room temperature for 30 minutes and compound (33) (117 mg) was added therein. After stiffing for 5 hours, the product was isolated by a silicagel thin-layer chromatography to give the objective compound (46) (13.5 mg).
1H-NMR (DMSO-d6) δ: 1.47 (3H, s), 1.81 (1H, 11.6 Hz), 2.12 (1H, bs), 2.54-2.59 (1H, m), 2.97 (1H, bs), 3.28 (2H, d, 6.4 Hz), 3.52 (2H, d, 6.5 Hz), 3.88 (3H, s), 5.69 (2H, s), 7.09 (1H, dd, J=11.8, 6.8 Hz), 7.50 (1H, s), 7.60 (1H, d, 7.8 Hz), 7.67 (1H, s), 10.06 (1H, s).
Example 2
Preparation of Compound 86




The 1st step: Sodium hydride (302 mg) is added to DMF (3.0 ml) and 3-butene alcohol (3.0 ml) under ice cooling in a nitrogen atmosphere. After stirring at room temperature for 1.0 hour, compound (35) (300 mg) was added and stirred under heating at 65° C. After 7 hours, the reaction solution was neutralized by the addition of 2M hydrochloric acid and concentrated under reduced pressure. Water was added to the resulted residue and filtered to give compound (36) (87 mg, 23.7%).

The 2nd step: Compound (36) (65.8 mg) and compound (37) (50 mg) were dissolved in methanol (2.0 ml), DMT-MM (93.7 mg) was added and the mixture was stirred at room temperature. After 6 hours, the solvent was evaporated under reduced pressure and the residue was purified with a column chromatography using chloroform/methanol to give compound (86) (40 mg, 44.5%).

1H-NMR (DMSO-d6) δ: 1.65 (3H, s), 2.03-2.09 (1H, m), 2.34-2.38 (1H, m), 2.51-2.61 (2H, m), 3.10-3.13 (1H, m), 3.57 (2H, t, J=4.4 Hz), 4.45 (2H, t, J=6.4 Hz), 5.13 (2H, dd, J=29.1, 13.9 Hz), 5.83-5.92 (1H, m), 7.08 (1H, d, J=7.8 Hz), 7.40 (1H, t, J=8.0 Hz), 7.84 (1H, s), 7.91 (1H, d, J=8.1 Hz), 8.36 (1H, s), 8.87 (1H, s), 10.56 (1H, s).
Example 3




A carboxylic acid, R—COOH corresponding to the objective compound (0.115 mmol) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (0.106 mmol) were dissolved in methanol (0.4 ml) and stirred by shaking at room temperature for 1.5 hours. A solution of compound A (0.0884 mmol) in methanol (0.4 ml) was added and the mixture was stirred for 8 hours. The reaction solvent was concentrated, dissolved in ethyl acetate (1 ml) and dimethylsulfoxide (0.5 ml), a 2N aqueous solution of sodium hydroxide (1 ml) was added and stirred by shaking for 2 hours. The organic layer was separated and concentrated to give a crude product of compound B. Trifluoroacetic acid (0.3 ml) was added and stirred by shaking at room temperature for 14 hours, dimethylsulfoxide (0.4 ml) was added and the product was purified with preparative LC/MS to give the objective compound C.
Example 4
Preparation of Compound 668




The 1st step: Compound (82) (506 mg) was dissolved in chloroform (30.0 ml), an aqueous solution (10.0 ml) of sodium bicarbonate (851 mg) and thiophosgene (0.111 ml) were added and stirred under ice cooling for 40 minutes. The organic layer was separated from the reaction solution and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give compound (83) (457 mg).

1H-NMR (DMSO-d6) δ: 1.44 (9H, s), 1.51 (3H, s), 1.60 (1H, s), 2.17 (1H, 2.68 (1H, s), 3.05 (1H, s), 7.30 (1H, t, J=10.1 Hz), 7.42 (1H, s), 7.58 (1H, s).
The 2nd step: Compound (83) (240 mg) was dissolved in methylenechloride (3.60 pyridine-2-ylmethanamine (74.8 mg) and triethylamine (0.192 ml) were added and the mixture was stirred at room temperature for 40 minutes. The reaction solution was washed with distilled water, the separated organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give compound (84) (210 mg).
1H-NMR (DMSO-d6) δ: 1.46 (9H, s), 1.65 (3H, s), 2.05 (2H, s), 2.57 (1H, s), 2.97 (1H, s), 4.86 (2H, s), 7.29 (3H, m), 7.40 (1H, d, J=7.3 Hz), 7.66 (1H, s), 7.84 (1H, s), 8.27 (1H, s), 8.58 (1H, s), 9.96 (1H, s).
The 3rd step: Compound (84) (95.1 ml) was dissolved in toluene (1.50 ml), dicyclohexylcarbodiimide (40.1 mg) was added and the mixture was stirred under irradiation of microwave at 100° C. for 20 minutes. The reaction solution was concentrated under reduced pressure and the residue was purified with a chromatography to give compound (85) (38.0 mg).
1H-NMR (DMSO-d6) δ: 1.40 (9H, s), 1.61 (3H, s), 1.94 (2H, s), 2.57 (1H, s), 2.88 (1H, s), 6.55 (1H, d, J=6.3 Hz), 6.59 (1H, d, J=8.6 Hz), 7.07 (1H, d, 8.6 Hz), 7.13 (2H, s), 7.29 (1H, s), 7.41 (1H, s, J=9.3 Hz), 7.96 (1H, d, J=6.8 Hz), 8.85 (1H, s).
The 4th step: Compound (85) (38.0 mg) was dissolved in chloroform (0.50 ml), trifluoroacetic acid (1.00 ml) was added and stirred at room temperature for 2 hours. The reaction solution was extracted with a mixture of chloroform/methanol and washed with an aqueous solution of potassium carbonate and distilled water. The separated organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. Diisopropylether was added to the residue and the precipitated powder was filtered to give compound (668) (9.39 mg).
1H-NMR (DMSO-d6) δ: 1.58 (3H, s), 1.90 (1H, s), 2.44 (1H, s), 2.62 (1H, t, J=9.7 Hz), 3.06 (1H, s), 6.57 (2H, td, J-15.0, 6.3 Hz), 7.05 (1H, dd, J=12.1, 10.6 Hz), 7.15 (1H, s), 7.24 (1H, d, J=5.3 Hz), 7.31 (1H, dd, J=7.7, 3.7 Hz), 7.42 (1H, d, J-8.8 Hz), 7.99 (1H, d, J=6.8 Hz), 8.85 (1H, s).
Example 5
Preparation of Compound 674







The 1st step: A solution of 2.0M lithium diisopropylamide/n-heptane/ethylbenzene (172 ml) in tetrahydrofuran (280 ml) was cooled in a dry ice/acetone bath and a solution of tert-butyl cyclopropancarboxylate (36.6 g) in tetrahydrofuran (60 ml) was added dropwise with stirring. After stirring for an hour, a solution of chlorotitanium tirisopropoxide (92 g) in tetrahydrofuran (190 ml) was added dropwise, stirred for 10 minutes and a solution of compound (73) (24.56 g) in tetrahydrofuran (120 ml) was added dropwise. After reaction for 2 hours, the reaction solution was added portionwise to an aqueous solution of ammonium chloride with stirring under ice cooling and the precipitated insoluble materials were filtered. It was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate.

The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (95) (15.49 g).

1H-NMR (CDCl3) δ: 1.16-1.19 (2H, m), 1.24 (9H, s), 1.28-1.32 (2H, m), 1.36 (9H, s), 1.46 (3H, s), 1.50-1.55 (2H, m), 1.64-1.72 (2H, m), 5.45 (1H, s), 7.11-7.16 (1H, m), 8.11-8.16 (1H, m), 8.67 (1H, dd, J=6.9, 2.9 Hz).
The 2nd step: 2.0 M Hydrochloric acid/ethyl acetate (30 ml) was added to compound (95) (2.48 g) and stirred at 65° C. for 5.5 hours. Diisopropylether was added and the precipitated solid was filtered to give a crude product of compound (96) (1.66 g).
The 3rd step: A solution of compound (96) (1.66 g) in tetrahydrofuran (8.3 ml) was stirred under ice cooling and a solution of 1M borane/tetrahydrofuran (21.8 ml) was added and the mixture was stirred at room temperature for 2 hours and 45 minutes. Ice and sodium bicarbonate were added, extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a crude product of compound (97) (1.36 g).

The 4th step: A solution of compound (97) (1.36 g) in acetone (20 ml) was stirred under ice cooling, a solution of benzoyl isothiocyanate (0.92 g) in acetone (6 ml) was added and the mixture was stirred for 40 minutes. After the addition of water, the reaction solution was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (98) (1.68 g).

1H-NMR (CDCl3) δ: 0.67-0.73 (3H, m), 0.84-0.88 (1H, m), 1.73 (1H, t, J=5.6 Hz), 2.29 (3H, d, J=2.0 Hz), 3.11 (1H, dd, J=12.2, 5.1 Hz), 3.82 (1H, J=12.2, 5.1 Hz), 7.14 (1H, dd, J=11.0, 9.0 Hz), 7.52 (2H, t, 7.6 Hz), 7.63 (1H, t, J=7.6 Hz), 7.87 (2H, d, J=7.6 Hz), 8.17 (1H, ddd, J=9.0, 3.9, 2.9 Hz), 8.27 (1H, dd, J=6.8, 2.9 Hz), 8.82 (1H, s), 11.75 (1H, s).
The 5th step: Compound (98) (1.68 g) was dissolved in dichloromethane (17 ml), stirred under ice cooling and 1-chloro-N,N,2-trimethyl-1-propenylamine (0.60 g) was added.
After stirring at room temperature for an hour, water was added, the reaction solution was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (99) (1.34 g).
1H-NMR (CDCl3) δ: 0.77-0.82 (1H, m), 0.95-1.07 (2H, m), 1.38-1.40 (1H, m), 1.52 (3H, d, J=1.1 Hz), 2.25 (1H, d, J=13.0 Hz), 3.05 (1H, d, J=13.0 Hz), 7.27 (1H, dd, J=10.8, 8.9 Hz), 7.40-7.54 (3H, m), 8.18-8.27 (3H, m), 8.36 (H, dd, J=6.7, 2.7 Hz).
The 6th step: Hydrazine monohydrate (038 g) was added to a solution of compound (99) (1.00 g) in ethanol (10 ml) under stifling at room temperature. After stirring for 4 hours, it was stirred under heating at 50° C. for 2 hours. The reaction solution was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give compound (100) (0.69 g) as a crude product.

The 7th step: A mixture of compound (100) (0.91 g), di-tert-butyldicarbonate (1.55 g), 4-dimethylaminopyridine (0.04 g) and tetrahydrofuran (9.1 ml) was stirred at room temperature for 1 hour and 15 minutes. Water was added, the reaction solution was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (101) (1.28 g).

1H-NMR (CDCl3) δ: 0.37-0.41 (1H, m), 0.50-0.54 (1H, m), 0.68 (2H, t, J=7.7 Hz), 1.56 (18H, s), 1.78 (3H, d, J=4.0 Hz), 2.35 (1H, d, J=12.7 Hz), 3.57 (1H, dd, J=12.7, 1.8 Hz), 7.12-7.21 (1H, m), 8.15 (1H, ddd, J=8.9, 3.9, 3.0 Hz), 8.39 (1H, dd, J=6.7, 3.0 Hz).
The 8th step: Compound (101) (1.28 g) was dissolved in ethyl acetate (13 ml), 10% Pd—C (0.64 g) was added and the mixture was stirred at room temperature for 13 hours and 30 minutes. The insoluble materials were filtered the filtrate was concentrated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (102) (1.07 g).
1H-NMR (CDCl3) δ: 0.51-0.58 (2H, m), 0.81-0.86 (2H, m), 1.54 (18H, s), 1.64 (3H, d, J=3.0 Hz), 2.60 (1H, d, J=12.4 Hz), 3.08 (1H, d, J=12.4 Hz), 3.50 (2H, s), 6.51 (1H, ddd, J=8.6, 3.7, 3.0 Hz), 6.78-6.84 (2H, m), 7.18-7.21 (1H, m).
The 9th step: A solution of 5-ethylpyrazine-2-carboxylic acid (59 mg) in N,N-dimethylformamide (1.5 ml) was stirred under ice cooling, and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo(4,5-b)pyridinium-3-oxide hexafluorophosphate (196 mg) and triethylamine (61 mg) were added and the mixture vas stirred for 10 minutes. A solution of compound (102) (200 mg) in N,N-dimethylformamide (3 ml) was added and the mixture was stirred at room temperature for 4 hours. Water was added, extracted with ethyl acetate and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (103) (170 mg).

The 10th step: Compound (103) (170 mg) was dissolved in dichloromethane (0.75 ml), stirred under ice cooling, trifluoroacetic acid (0.75 ml) was added and the mixture was stirred at room temperature for 3 hours. After concentration of the reaction solution under reduced pressure, ice water was added, potassium carbonate was added with stirring under ice cooling and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure and ether/hexane was added to the residue. The precipitated solid was filtered to give compound (674) (104 mg)

1H-NMR (CDCl3) δ: 0.53-0.59 (1H, m), 0.65-0.72 (1H, m), 0.85-0.91 (1H, m), 1.14-1.17 (1H, m), 1.47 (3H, d, J=2.0 Hz), 2.46 (1H, d, J=12.1 Hz), 2.69 (3H, s), 2.89 (1H, dd, J=12.1, 1.3 Hz), 7.06 (1H, dd, J=11.5, 8.8 Hz), 7.45 (1H, dd, J=6.8, 2.8 Hz), 7.94 (1H, ddd, J=8.8, 4.0, 2.8 Hz), 8.44 (1H, d, J=1.3 Hz), 9.36 (1H, d, J=1.3 Hz), 9.60 (1H, s).
Example 6
Reparation of Compound 687




The 1st step: Dichloromethane-trifluoroacetic acid (1:1, 1 ml) was added to compound (120) (49 mg) and stirred at room temperature for an hour. The reaction solution was concentrated under reduced pressure, dimethyl sulfoxide-acetic anhydride (1:1, 1 ml) was added to the residue, stirred at 50° C. for 1.5 hours and the solvent was evaporated under reduced pressure. Hydrochloric acid (1M, 0.5 ml) was added to the residue and stirred at 50° C. for 1 hours. A saturated aqueous solution of sodium bicarbonate was added, extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography. A mixture of chloroform-diethyl ether/ethyl acetate was added and the precipitated slid was filtered to give compound 687 (17 mg).

1H-NMR (CDCl3) δ: 1.78 (3H, s), 3.52 (1H, d, J=15.1 Hz), 3.73 (1H, d, 15.1 Hz), 7.06 (1H, dd, J=10.4, 8.6 Hz), 7.73 (1H, dd, J=6.6, 1.3 Hz), 7.82-7.86 (1H, m), 7.90 (1H, d, J=1.3 Hz), 8.48 (1H, d, J=1.3 Hz), 9.79 (1H, s).
Example 7
Preparation of Compound 680, 681 and 682







The 1st step: In a nitrogen atmosphere, diisopropylamine (20.3 ml) and tetrahydrofuran (83.5 ml) were added and cooled to −60° C. in an acetone/dry ice bath and a solution of 1.63M n-butyl lithium/n-hexane was added dropwise while stirring was continued until the temperature rose to 0° C. After stirring for 30 minutes, the reaction solution was cooled to −60° C. in an acetone/dry ice bath and a solution of tert-butyl acetate (16.8 ml) in tetrahydrofuran (22.2 ml) was added dropwise with stirring. After stirring for 45 minutes, a solution of compound (121) (11.1 g) in tetrahydrofuran (22.2 ml) was added dropwise. After 2.5 hours, a saturated aqueous solution of ammonium chloride (100 ml) was stirred under ice cooling and the reaction solution was poured portionwise therein, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (122) (8.83 g).

1H-NMR (CDCl3) δ: 1.32 (17H, s), 1.93 (3H, s), 3.15 (1H, d, J=16.4 Hz), 3.66 (1H, d, 16.2 Hz), 5.50 (1H, s), 8.12 (1H, s), 8.36 (1H, s).
The 2nd step: Lithium aluminium hydride (0.76 g) and tetrahydrofuran (15 ml) were cooled in an ice-salt bath in a nitrogen atmosphere and a solution of compound (122) (3.03 g) in tetrahydrofuran (10 ml) was added dropwise with stirring. After stirring for 15 minutes, acetone (4 ml) was added, insoluble materials were filtered, extracted with ethyl acetate, and the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give compound (123) (2.30 g) as a crude product.
MS: 385 m/z [M+H]+
The 3rd step: 10% Hydrochloric acid/methanol solution (30 ml) was added to compound (123) (2.2 g) and stirred at room temperature for 1.5 hours. The solvent was evaporated under reduced pressure, the residue was basified with a 2.0M aqueous solution of potassium carbonate and extracted with ethyl acetate (100 ml). The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. Toluene (30 ml) and water (15 ml) were added to the resulted crude product (2.25 g), cooled in a ice bath and potassium carbonate (1.58 g) and thiophosgene (0.656 ml) were added with stirring. After stirring at room temperature for 30 minutes, the reaction solution was extracted with toluene, the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, toluene (30 ml), thionyl chloride (1.25 ml) and N,N-dimethylformamide (0.044 ml) were added to the resulted residue and the mixture was stirred under heating at 80° C. for 1.5 hours. The solvent was evaporated under reduced pressure, ice water was added, extracted with ethyl acetate, and the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (124) (1.26 g).
1H-NMR (CDCl3) δ: 1.56 (3H, s), 2.54-2.64 (1H, m), 3.07-3.17 (1H, m), 3.29-3.38 (1H, m), 3.50-3.57 (1H, m), 8.13 (1H, d, J=2.4 Hz), 8.44 (1H, d, J=2.4 Hz).
The 4th step: Tetrahydrofuran (12.6 ml) and 28% ammonia water (6.3 ml) were added to compound (124) (1.26 g) and stirred at room temperature for 1.5 hours. The reaction solution was extracted with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give compound (125) (1.13 g) as a crude product.
1H-NMR (CDCl3) δ: 1.70 (3H, s), 2.15-2.21 (1H, m), 2.52-2.58 (1H, m), 2.70-2.77 (1H, m), 3.05-3.11 (1H, m), 4.44 (2H, br a), 8.12 (1H, a), 8.34 (1H, s).
The 5th step: Tetrahydrofuran (11.3 ml) and di-tert-butyldicarbonate (0.89 ml) were added to compound (125) (1.13 g) and stirred at room temperature for an hour. Di-tert-butyldicarbonate (1.13 ml) and 4-dimethylaminopyridine (0.086 g) were added and further stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (126) (1.59 g).
1H-NMR (CDCl3) δ: 1.53 (18H, s), 1.73 (3H, s), 1.90-1.97 (1H, m), 2.63-2.69 (1H, m), 293-2.99 (1H, m), 3.21-3.28 (1H, m), 8.24 (1H, d, J=2.3 Hz), 8.36 (1H, d, J=2.3 Hz).
The 6th step: N,N-Dimethylformamide (40 ml) was added to compound (126) (2.00 g) in a nitrogen stream, cooled in an ice bath with stiffing and sodium methoxide (2.074 g) was added therein. After stifling at room temperature for 1.5 hours, the reaction solution was warmed up to 60° C. and stirred for 2 hours. It was cooled in a ice bath, neutralized by the addition of 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with 2M aqueous solution of potassium carbonate and brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (127) (1.69 g).
1H-NMR (CDCl3) δ: 1.52 (9H, s), 1.70 (3H, s), 1.96-2.03 (1H, m), 2.54-2.61 (1H, m), 2.80-2.85 (1H, m), 2.97-3.00 (1H, m), 3.97 (3H, s), 7.62 (1H, 1.5 Hz), 8.15 (1H, d, J=1.5 Hz).
The 7th step: Compound (127) (1.571 g), trisdibenzylideneacetonedipalladium (0, 4-14 g) and butynyl-1-adamantylphosphine (0.324 g) were dissolved in toluene under a nitrogen stream, and a solution of 1.6M lithium hexamethyldisilazide/tetrahydrofuran (5.66 ml) was added at room temperature with stirring. The reaction solution was warmed up to 80° C. and stirred for 3 hours. Then diethyl ether and 1N hydrochloric acid were added with stirring under ice cooling. After stirring for 5 minutes, it was neutralized by the addition of a saturated aqueous solution of sodium carbonate, extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (128) (1.55 g).
1H-NMR (CDCl3) δ: 1.52 (9H, s), 1.72 (3H, s), 1.86-1.93 (1H, m), 2.02 (2H, s), 2.52-2.59 (1H, m), 2.74-2.79 (1H, m), 3.13-3.18 (1H, m), 3.90 (3H, s), 6.96 (1H, d, J=2.3 Hz), 7.59 (1H, J=1.8 Hz).
The 8th step: Compound (128) (0.20 g), 5-methylpyridine-2-carboxylic acid (0.10 g) and O-(7-azabenzotriazole-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (0.28 g) were dissolved in N,N-dimethylformamide (2 ml), triethylamine (0.119 ml) was added and the mixture was stirred at room temperature for 1.0 hours. A 2M aqueous solution of potassium carbonate was added, extracted with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the resulted residue was dissolved in chloroform (4.0 ml), trifluoroacetic acid (1.0 ml) was added and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, the residue was made basic by the addition of a 2.0M aqueous solution of potassium carbonate, extracted with ethyl acetate and the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (680) (0.096 g).
1H-NMR (DMSO-d6) δ: 1.47 (3H, s), 1.77-1.83 (1H, m), 2.34-2.39 (1H, m), 2.48-2.53 (1H, m), 2.63 (3H, s), 2.89-2.96 (1H, m), 3.90 (3H, s), 5.86 (2H, br s), 8.10 (1H, d, J=2.3 Hz), 8.47 (1H, d, J=2.5 Hz), 8.69 (1H, s), 9.14 (1H, s), 10.69 (1H, s).
The 9th step: Compound (680) (0.096 g) and sodium iodide (0.193 g) were dissolved in acetonitrile (5.0 ml), trimethylsilylchloride (0.164 ml) was added and the mixture was stirred at room temperature for 2.5 hours. Sodium iodide (0.193 g) and trimethyl silylchloride (0.164 ml) were added and stirring was continued at room temperature for 12 hours. A 2.0M aqueous solution of potassium carbonate, extracted with ethyl acetate and the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give compound (681) (0.073 g) as a crude product.
1H-NMR (DMSO-d6) δ: 1.52 (3H, s), 1.80-1.85 (1H, m), 2.62 (3H, s), 2.64-2.69 (2H, m), 2.96-3.01 (1H, m), 7.77 (1H, d, J=2.5 Hz), 7.96 (1H, d, J=2.3 Hz), 8.67 (1H, s), 9.10 (1H, s), 10.58 (1H, s).
The 10th step: Compound (681) (0.031 g) was dissolved in tetrahydrofuran (2.0 ml), di-tert-butyldicarbonate (0.030 ml) was added and the mixture was stirred at room temperature for 1.5 hours. Di-tert-butyldicarbonate (0.030 ml) was further added and the stirring was continued at room temperature for 2.0 hours. The reaction solution was concentrated under reduced pressure, the resulted residue was dissolved in N, N-dimethylformamide (0.5 ml) and potassium carbonate (23.9 mg) was added. A solution of methyl iodide (12.2 mg) in N,N-dimethylformamide (0.5 ml) was added with stirring at room temperature. After stirring at room temperature for 3 hours, methyl iodide (11.05 mg) was added and the mixture was stirred at room temperature for 2 hours. Brine was added, extracted with ethyl acetate and the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the resulted residue was dissolved in chloroform (2.0 ml), trifluoroacetic acid (0.5 ml) was added and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, the resulted residue was made alkaline by the addition of a 2.0M aqueous solution of potassium carbonate, extracted with ethyl acetate and the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (682) (4.2 mg).
1H-NMR (DMSO-d6) δ: 1.46 (3H, s), 1.95-2.01 (1H, m), 2.33-2.39 (1H, m), 2.62 (3H, s), 0.64-2.69 (1H, m), 2.74 (3H, s), 2.92-2.98 (1H, m), 7.90 (1H, d, J=2.5 Hz), 7.94-7.95 (1H, m), 8.67 (1H, s), 9.09 (1H, s), 10.57 (1H, s).
The other compounds are prepared in the same manner Chemical structures and physical constants are shown below.








TABLE 1





Compound



No.
Structure







1






 


2






 


3






 


4






 


5





















TABLE 2





Compound



No.
Structure







 6






 


 7






 


 8






 


 9






 


10





















TABLE 3





Compound



No.
Structure







11






 


12






 


13






 


14






 


15





















TABLE 4





Compound



No.
Structure







16






 


17






 


18






 


19






 


20





















TABLE 5





Compound



No.
Structure







21






 


22






 


23






 


24






 


26





















TABLE 6





Compound



No.
Structure







27






 


28






 


29






 


30






 


31





















TABLE 7





Compound



No.
Structure







32






 


33






 


34






 


35






 


36





















TABLE 8





Compound



No.
Structure







37






 


38






 


39






 


40






 


41





















TABLE 9





Compound



No.
Structure







42






 


43






 


44






 


45






 


46





















TABLE 10





Compound



No.
Structure







47






 


48






 


49






 


50






 


51





















TABLE 11





Compound



No.
Structure







52






 


53






 


54






 


55






 


56





















TABLE 12





Compound



No.
Structure







57






 


58






 


59






 


60






 


61





















TABLE 13





Compound



No.
Structure







62






 


63






 


64






 


65






 


66





















TABLE 14





Compound



No.
Structure







67






 


68






 


69






 


70






 


71





















TABLE 15





Compound



No.
Structure







72






 


73






 


74






 


75






 


76





















TABLE 16





Compound



No.
Structure







77






 


78






 


79






 


80






 


81





















TABLE 17





Compound



No.
Structure







82






 


83






 


84






 


85






 


86





















TABLE 18





Compound



No.
Structure







87






 


88






 


89






 


90






 


91





















TABLE 19





Compound



No.
Structure







92






 


93






 


94






 


95






 


96





















TABLE 20





Compound



No.
Structure







 97






 


 98






 


 99






 


100






 


101





















TABLE 21





Compound



No.
Structure







102






 


103






 


104






 


105






 


106





















TABLE 22





Compound



No.
Structure







107






 


108






 


109






 


110






 


111





















TABLE 23





Compound



No.
Structure







112






 


113






 


114






 


115






 


116





















TABLE 24





Compound



No.
Structure







117






 


118






 


119






 


120






 


121





















TABLE 25





Compound



No.
Structure







122






 


123






 


124






 


125






 


126





















TABLE 26





Compound



No.
Structure







127






 


128






 


129






 


130






 


131





















TABLE 27





Compound



No.
Structure







132






 


133






 


134






 


135






 


136





















TABLE 28





Compound



No.
Structure







137






 


138






 


139






 


140





















TABLE 29





Compound



No.
Structure







141






 


142






 


143






 


144






 


145





















TABLE 30





Compound 



No.
Structure







146






 


147






 


148






 


149






 


150





















TABLE 31





Compound



No.
Structure







151






 


152






 


153






 


154






 


155





















TABLE 32





Compound 



No.
Structure







156






 


157






 


158






 


159






 


160





















TABLE 33





Compound 



No.
Structure







161






 


162






 


163






 


164






 


165





















TABLE 34





Compound 



No.
Structure







166






 


167






 


168






 


169






 


170






 


171
























TABLE 35





Compound
MS





No.
(M + 1)
MP
NMR (solvent, shift value ascending order)
uv



















1


1H-NMR (CDCl3) δ: 8.69 (1.0H, br s), 8.57 (1.0H, s),






8.53-8.41 (1.0H, m), 8.36-8.33 (1.0H, m), 7.90-7.81 (1.0H, m),






7.56 (1.0H, br s), 7.41-7.29 (2.0H, m), 7.00-6.88 (2.0H, m),






2.88-2.63 (2.0H, m), 2.50-2.38 (1.0H, m), 2.06-2.00 (1.0H, m), 1.66 (3.0H,



2
344





3


1H-NMR (CDCl3) δ: 7.79 (1.0H, br s), 7.65-7.64 (1.0H, m),






7.48-7.41 (1.0H, m), 7.31 (1.0H, t, J = 8.01 Hz),






7.04-7.01 (1.0H, m), 6.23 (1.0H, br s), 2.93-2.65 (2.0H, m), 2.57 (3.0H, br






s), 2.40 (1.0H, ddd, J = 14.11, 5.34, 3.43 Hz), 2.27 (3.0H, br s),






2.09-1.92 (1.0H, m), 1.67 (3.0H, s).



4


1H-NMR (CDCl3) δ: 7.86-7.83 (1.0H, m), 7.45-7.42 (1.0H, m),






7.35 (1.0H, t, J = 12.96 Hz), 7.21 (1.0H, br s), 7.04-7.01 (1.0H,






m), 4.23 (3.0H, s), 2.90-2.86 (1.0H, m), 2.77-2.61 (1.0H, m),






2.38-2.30 (1.0H, m), 1.99-1.89 (1.0H, m), 1.60 (3.0H, s).



5


1H-NMR (DMSO-d6) δ: 9.81 (1.0H, br s), 7.70-7.65 (2.0H, m),






7.22 (1.0H, t, J = 7.85 Hz), 7.06-7.03 (1.0H, m), 6.53 (1.0H, s),






2.92-2.85 (1.0H, m), 2.61-2.52 (1.0H, m), 2.28 (3.0H, s),






2.02-1.97 (1.0H, m), 1.73-1.67 (1.0H, m), 1.39 (3.0H, s).



6
425





7
415





8
361





9
331





10
347





11
360





12
379





13
367





14
331





15


1H-NMR (DMSO-d6) δ: 10.02 (1.0H, s), 7.61-7.55 (2.0H, m),






7.25 (1.0H, t, J = 7.93 Hz), 7.09 (1.0H, d, J = 7.78 Hz),






6.26 (1.0H, s), 3.86 (3.0H, s), 2.91-2.87 (1.0H, m), 2.59-2.54 (1.0H,






m), 2.00-1.96 (1.0H, m), 1.75-1.62 (1.0H, m), 1.39 (3.0H, s).



16
404





17
422





18
360





19
349





20
349





21
388





22
365





23
392





24
385





26


1H-NMR (MeOD) δ: 1.73 (1H, s), 1.98 (1H, s), 2.29 (1H, s),






2.76 (1H, s), 6.58 (1H, s), 6.79 (1H, s), 6.92 (1H, s), 7.13 (1H, s),






8.01 (1H, s), 8.55 (1H, s)



27


1H-NMR (DMSO-d6) δ: 1.65 (1H, s), 2.07 (1H, t, J = 13.1 Hz),






2.57 (1H, d, J = 11.6 Hz), 3.10 (1H, s), 7.10 (1H, d, J = 7.1 Hz),






7.42 (1H, t, J = 7.5 Hz), 7.72 (2H, s), 7.84 (1H, d, J = 8.3 Hz),






7.92 (1H, t, J = 9.5 Hz), 8.55 (1H, s), 10.74 (1H, s)



28
358





29


1H-NMR (CDCl3) δ: 1.71 (s3H, s), 2.00 (1H, d, J = 8.8 Hz),






2.45 (1H, d, J = 12.4 Hz), 2.78 (1H, t, J = 12.5 Hz), 2.88 (aH, s, J = 13.6 Hz),






3.94 (3H, s), 5.30 (1H, s) 7.05 (1H, d, J = 7.8 Hz),






7.35 (1H, t, J = 8.2 Hz), 7.48 (1H, s), 7.56 (1H, s), 7.65 (1H, d, J = 7.8 Hz),






9.58 (1H, s)




















TABLE 36





Compound
MS





No
(M + 1)
MP
NMR (solvent, shift value: ascending order)
uv







30
376





31


1H-NMR (MeOD) δ: 1.75 (3H, s), 2.10-2.13 (1H, m),






2.49-2.62 (1H, m), 2.65-2.71 (2H, m), 2.80 (3H, s), 7.02 (1H, d, J = 8.6 Hz),






7.41 (1H, t, J = 7.8 Hz), 7.53 (1H, s), 8.12 (1H, d, J = 8.1 Hz),






9.34 (2H, s), 9.79 (1H, s)



32
372





33
373





34


1H-NMR (DMSO-d6) δ: 1.63 (3H, s), 1.70 (3H, s, J = 5.3 Hz),






1.99-2.02 (1H, br m), 2.28 (1H, s), 2.57-2.60 (1H, dr m), 3.07 (1H,






d, J = 10.1 Hz), 4.65 (2H, s), 5.70 (1H, d, 14.1 Hz), 5.91 (1H, d,






7.3 Hz), 7.06 (1H, s), 7.36 (1H, s), 7.59 (1H, d, J = 5.1 Hz),






7.82 (1H, s), 7.89 (1H, s, J 5.1 Hz), 8.36 (1H, s), 10.48 (1H, s)



35
395





36
428





37
412





38
396





39
238





40
408





41
428





42
379





43
390





44
386





45
420





46
435





47


1H-NMR (DMSO-d6) δ: 1.41 (3H, s), 1.69-1.75 (1H, m),






2.01-2.05 (1H, m), 2.55-2.58 (1H, m), 2.74-2.76 (2H, m),






2.88-2.91 (1H, m), 7.06 (1H, d, J = 7.8 Hz), 7.26 (1H, t, J = 7.8 Hz),






7.70-7.73 (2H, m), 7.91 (1H, br s), 7.99 (1H, s), 8.63 (1H, s),






9.97 (1H, s).



48


1H-NMR (DMSO-d6) δ: 1.42 (3H, s), 1.71-1.85 (3H, m),






2.04-2.08 (1H, m), 2.56-2.58 (1H, m), 2.82 (2H, t, J = 7.2 Hz),






2.88-2.93 (1H, m), 3.41-3.43 (2H, m), 7.06 (1H, d, J = 7.8 Hz),






7.26 (1H, t, J = 7.6 Hz), 7.70-7.73 (2H, m), 7.99 (2H, s), 8.65 (1H, s),






10.00 (1H, s).



49


1H-NMR (DMSO-d6) δ: 1.57 (3H, s), 1.62 (3H, s),






1.94-1.97 (1H, m), 2.37-2.40 (1H, m), 2.56-2.60 (1H, m), 2.80-2.82 (2H,






m), 3.03-3.06 (1H, m), 7.04 (1H, d, J = 7.6 Hz), 7.34 (1H, t, J = 7.6 Hz),






7.78-7.82 (2H, m), 8.01 (1H, s), 8.06 (1H, br s),






8.64 (1H, s), 10.13 (1H, s).



50


1H-NMR (DMSO-d6) δ: 1.45 (3H, s), 1.76-1.79 (1H, m),






2.09-2.13 (1H, m), 2.40 (3H, br s), 2.57-2.60 (1H, m), 2.83 (2H, t, J = 5.9 Hz),






2.93-2.94 (1H, m), 3.49-3.51 (2H, m), 5.74 (1H, s),






7.06 (1H, d, J = 7.6 Hz), 7.27 (1H, t, J = 7.8 Hz), 7.74 (1H, br s),






7.77 (1H, s), 7.95 (2H, br s), 8.02 (1H, s), 8.66 (1H, s), 10.02 (1H, s).



51


1H-NMR (DMSO-d6) δ: 1.40 (3H, s), 1.70-1.75 (1H, m),






1.85-1.90 (2H, m), 1.93-2.02 (2H, m), 2.14-2.21 (1H, m),






2.53-2.60 (1H, m), 2.86-2.94 (1H, m), 3.82 (1H, q, J = 7.1 Hz), 3.98 (1H, q,






J = 7.2 Hz), 4.35-4.39 (1H, m), 7.06 (1H, d, J = 7.6 Hz),






7.23 (1H, t, J = 7.8 Hz), 7.56-7.60 (2H, m), 9.57 (1H, s).




















TABLE 37





Compound
MS





No
(M + 1)
MP
NMR (solvent, shift value: ascending order)
uv







52


1H-NMR (DMSO-d6) δ: 1.38 (3H, s), 1.61-1.81 (5H, m),






1.95-2.08 (2H, m), 2.53-2.58 (1H, m), 2.88 (4H, t, J = 6.6 Hz),






3.65-3.68 (1H, m), 5.67-5.85 (2H, m), 7.04 (1H, d, J = 7.8 Hz),






7.22 (1H, t, J = 7.8 Hz), 7.48 (1H, s), 7.59 (1H, d, J = 7.8 Hz),






9.87 (1H, s).



53


1H-NMR (DMSO-d6) δ: 1.39 (3H, s), 1.62-1.80 (5H, m),






1.99-2.07 (2H, m), 2.52-2.58 (1H, m), 2.87-2.91 (3H, m), 3.68 (2H,






dd, J = 8.7, 5.9 Hz), 7.04 (1H, d, J = 7.6 Hz), 7.23 (1H, t, J = 8.0 Hz),






7.47 (1H, s), 7.61 (1H, d, J = 7.8 Hz), 9.90 (1H, s).



54


1H-NMR (DMSO-d6) δ: 1.40 (3H, s), 1.70-1.75 (1H, m),






1.95-2.05 (2H, m), 2.09-2.37 (2H, m), 2.52-2.57 (1H, m),






2.87-2.94 (1H, m), 4.03 (1H, q, J = 7.1 Hz), 4.19 (1H, dd, J = 8.6, 4.3 Hz),






7.06 (1H, d, J = 7.3 Hz), 7.25 (1H, t, J = 8.0 Hz), 7.49 (1H, s),






7.56 (1H, d, J = 7.8 Hz), 7.86 (1H, s), 10.01 (1H, s).



55


1H-NMR (DMSO-d6) δ: 1.40 (3H, s), 1.69-1.75 (1H, m),






1.97-2.03 (2H, m), 2.09-2.36 (4H, m), 2.52-2.57 (1H, m),






2.87-2.93 (1H, m), 4.17-4.20 (1H, m), 7.06 (1H, d, J = 7.8 Hz), 7.25 (1H, t,






J = 8.0 Hz), 7.54 (2H, t, J = 8.0 Hz), 7.87 (1H, s), 10.00 (1H, s).



56


1H-NMR (DMSO-d6) δ: 1.40 (3H, s), 1.71-1.76 (1H, m),






2.00-2.03 (1H, m), 2.19-2.26 (1H, m), 2.46-2.58 (5H, m),






2.88-2.94 (1H, m), 5.03-5.06 (1H, m), 7.09 (1H, d, J = 7.1 Hz), 7.27 (1H, t,






J = 8.1 Hz), 7.50 (1H, s), 7.56 (1H, d, J = 8.1 Hz), 10.22 (1H, s).



57


1H-NMR (DMSO-d6) δ: 1.40 (3H, s), 1.69-1.75 (1H, m),






2.00-2.04 (1H, m), 2.19-2.27 (1H, m), 2.46-2.57 (6H, m),






2.87-2.94 (1H, m), 5.03-5.06 (1H, m), 7.09 (1H, d, J = 8.3 Hz), 7.26 (1H, t,






J = 8.0 Hz), 7.51 (1H, s), 7.56 (1H, d, J = 8.3 Hz), 10.22 (1H, s).



58


1H-NMR (DMSO-d6) δ: 1.48 (3H, s), 1.78-1.84 (1H, m),






2.11-2.18 (1H, m), 2.55-2.61 (1H, m), 2.93-2.99 (1H, m), 7.14 (1H, d,






J = 7.8 Hz), 7.34 (1H, t, J = 8.0 Hz), 7.77-7.82 (2H, m),






8.93 (1H, s), 9.11 (1H, s).



59


1H-NMR (DMSO-d6) δ: 1.43 (3H, s), 1.73-1.78 (1H, m),






2.01-2.08 (1H, m), 2.54-2.59 (1H, m), 2.89-2.96 (1H, m), 7.16 (1H, d,






J = 8.1 Hz), 7.34 (1H, t, J = 8.0 Hz), 7.57 (1H, s), 7.68 (1H, d, J = 7.1 Hz),






8.70 (1H, d, J = 2.5 Hz), 8.77 (1H, d, J = 2.3 Hz),






10.80 (1H, s).



50


1H-NMR (DMSO-d6) δ: 1.42 (3H, s), 1.70-1.76 (1H, m)






2.01-2.06 (1H, m), 2.54-2.60 (1H, m), 2.88-2.95 (1H, m), 3.97 (3H, s),






7.12 (1H, d, J = 7.8 Hz), 7.30 (1H, t, J = 7.8 Hz), 7.62-7.68 (2H,






m), 8.29 (1H, d, J = 2.3 Hz), 8.40 (1H, d, J = 2.5 Hz), 10.53 (1H,






s).



61


1H-NMR (DMSO-d6) δ: 0.91 (3H, t, J = 7.2 Hz), 1.32-1.40 (5H,






m), 1.51-1.58 (2H, m), 1.68-1.73 (1H, m), 1.97-2.05 (0H, m),






2.55-2.60 (1H, m), 2.85-2.92 (1H, m), 5.77 (2H, br s), 7.07 (1H,






d, J = 7.6 Hz), 7.25 (1H, t, J = 8.0 Hz), 7.73 (2H, t, J = 6.7 Hz),






7.83-7.87 (1H, m), 7.96 (1H, s), 8.64 (1H, s), 9.95 (1H, s).



62


1H-NMR (DMSO-d6) δ: 1.43 (3H, s), 1.71-1.77 (1H, m),






2.02-2.09 (1H, m), 2.55-2.61 (1H, m), 2.87-2.95 (1H, m), 3.31 (3H, s),






3.70-3.74 (2H, m), 4.51-4.54 (2H, m), 7.11 (1H, d, J = 7.1 Hz),






7.29 (1H, t, J = 7.7 Hz), 7.75 (1H, d, J = 8.3 Hz), 7.80 (1H, s),






8.43 (1H, s), 8.87 (1H, s), 10.35 (1H, s).




















TABLE 38





Compound
MS





No.
(M + 1)
MP
NMR (solvent, shift value: ascending order)
uv







63


1H-NMR (DMSO-d6) δ: 1.29 (3H, t, J = 7.5 Hz), 1.43 (3H, s),






1.71-1.77 (1H, m), 2.01-2.09 (1H, m), 2.55-2.61 (1H, m),






2.90-2.96 (3H, m), 7.12 (1H, d, J = 7.8 Hz), 7.30 (1H, t, J = 7.8 Hz),






7.76 (1H, d, J = 8.1 Hz), 7.82 (1H, s), 8.70 (1H, s), 9.18 (1H, s),






10.53 (1H, s).



64


1H-NMR (DMSO-d6) δ: 1.41 (3H, s), 1.70-1.75 (1H, m),






1.99-2.06 (1H, m), 2.52-2.57 (1H, m), 2.87-2.94 (1H, m), 7.11 (1H, d,






J = 7.6 Hz), 7.28 (1H, t, J = 7.8 Hz), 7.47-7.59 (5H, m),






7.65 (2H, d, J = 7.6 Hz), 8.30 (0H, s).



65


1H-NMR (DMSO-d6) δ: 1.38 (3H, s), 1.67-1.72 (1H, m),






1.94-2.00 (1H, m), 2.03 (3H, s), 2.50-2.55 (1H, m), 2.85-2.92 (1H, m),






7.06 (1H, d, J = 7.1 Hz), 7.23 (1H, t, J = 7.7 Hz), 7.48 (2H, t, J = 8.3 Hz),






10.55 (1H, s).



66
707.0 (2M + 1)





67
743.1 (2M + 1)





68


1H-NMR (DMSO-d6) δ: 1.45 (3H, s), 1.74-1.80 (1H, m),






2.06-2.13 (1H, m), 2.56-2.61 (1H, m), 2.90-2.97 (1H, m), 7.15 (1H, d,






J = 7.6 Hz), 7.33 (1H, t, J = 7.7 Hz), 7.79 (1H, d, J = 7.8 Hz),






7.87 (1H, s), 8.04 (1H, s), 8.45 (1H, s), 9.29 (2H, d, J = 8.3 Hz),






10.79 (1H, s).



69


1H-NMR (DMSO-d6) δ: 1.43 (3H, s), 1.71-1.76 (1H, m),






2.02-2.09 (1H, m), 2.55-2.63 (4H, m), 2.88-2.94 (1H, m), 7.12 (1H, d,






J = 8.1 Hz), 7.29 (1H, t, J = 7.8 Hz), 7.74 (1H, d, J = 8.1 Hz),






7.81 (1H, s), 8.70 (1H, s), 9.08 (1H, s), 10.45 (1H, s).



70


1H-NMR (DMSO-d6) δ: 1.43 (3H, s), 1.71-1.77 (1H, m),






2.02-2.09 (1H, m), 2.55-2.61 (1H, m), 2.87-2.95 (1H, m), 3.31 (3H, s),






3.70-3.74 (2H, m), 4.51-4.54 (2H, m), 7.11 (1H, d, J = 7.1 Hz),






7.29 (1H, t, J = 7.7 Hz), 7.75 (1H, d, J = 8.3 Hz), 7.80 (1H, s),






8.43 (1H, s), 8.87 (1H, s), 10.35 (1H, s).



71


1H-NMR (DMSO-d6) δ: 0.94 (3H, t, J = 7.3 Hz), 1.43-1.47 (4H,






m), 1.72-1.79 (3H, m), 2.02-2.09 (1H, m), 2.58 (1H, t, J = 9.7 Hz),






2.91 (1H, s), 4.40 (2H, t, J = 6.6 Hz), 7.11 (1H, d, J = 7.8 Hz),






7.29 (1H, t, J = 8.1 Hz), 7.75 (1H, d, J = 7.3 Hz), 7.80 (1H,






s), 8.37 (1H, s), 8.86 (1H, s), 10.34 (1H, s).



72
771.1 (2M + 1)





73


1H-NMR (DMSO-d6) δ: 1.40 (3H, s) 1.68-1.73 (1H, m),






1.98-2.05 (1H, m), 2.11 (3H, s), 2.55-2.60 (1H, m), 2.69 (2H, t, J = 6.8 Hz),






2.86-2.92 (1H, m), 3.55-3.59 (2H, m), 5.77 (2H, br s),






7.07 (1H, d, J = 8.1 Hz), 7.25 (1H, t, J = 8.0 Hz), 7.71-7.75 (2H,






m), 8.00 (2H, s), 8.65 (1H, s), 9.98 (1H, s).



74


1H-NMR (DMSO-d6) δ: 0.99 (3H, t, J = 7.5 Hz), 1.39 (3H, s),






1.56 (2H, td, J = 14.3, 7.2 Hz), 1.67-1.73 (1H, m),






1.95-2.02 (1H, m), 2.38 (2H, t, J = 6.8 Hz), 2.50-2.55 (1H, m),






2.86-2.93 (1H, m), 7.06 (1H, d J = 7.8 Hz), 7.23 (1H, t, J = 8.3 Hz),






7.47-7.51 (2H, m).



75
839.1 (2M + 1)





76
835.1 (2M + 1)





77
782.9 (2M + 1)





78


1H-NMR (DMSO-d6) δ: 1.50 (3H, s), 1.79-1.84 (1H, m),






2.23-2.30 (1H, m), 2.55-2.60 (1H, m), 2.96-3.02 (1H, m), 7.16 (1H,






dd, J = 11.6, 8.8 Hz), 7.75-7.78 (2H, m), 8.89 (1H, s), 9.07 (1H,






s), 10.74 (1H, br s).




















TABLE 39





Compound
MS





No
(M + 1)
MP
NMR (solvent, shift value: ascending order)
uv







79


1H-NMR (DMSO-d6) δ: 1.49 (4H, s), 1.77-1.83 (1H, m),






2.16-2.23 (1H, m), 2.56-2.62 (1H, m), 2.95-3.01 (1H, m), 5.87 (2H, br






s), 7.17 (1H, dd, J = 11.7, 8.5 Hz), 7.76-7.82 (2H, m), 9.96 (2H,






d, J = 3.8 Hz), 10.82 (1H, s).



80


1H-NMR (DMSO-d6) δ: 1.33 (3H, t, J = 7.2 Hz), 1.42 (3H, s),






1.71-1.76 (1H, m), 2.03-2.07 (1H, m), 2.55-2.59 (1H, m),






2.89-2.92 (1H, m), 3.25 (2H, q, J = 7.3 Hz), 7.11 (1H, d, J = 7.8 Hz),






7.29 (1H, t, J = 7.8 Hz), 7.74 (1H, d, J = 8.1 Hz), 7.79 (1H, s),






8.66 (1H, s), 9.07 (1H, s), 10.45 (1H, s).



81
831.1 (2M + 1)





82
850.9 (2M + 1)





83
795.0 (2M + 1)





84
758.8 (2M + 1)





85
750.9 (2M + 1)





86
795.1 (2M + 1)





87


1H-NMR (DMSO-d6) δ: 1.01 (6H, d, J = 6.8 Hz), 1.44 (3H, s),






1.73-1.78 (1H, m), 2.05-2.13 (2H, m), 2.56-2.61 (1H, m),






2.89-2.95 (1H, m), 4.19 (2H, d, J = 6.6 Hz), 7.12 (1H, d, J = 8.1 Hz),






7.29 (1H, t, J = 7.8 Hz), 7.76 (1H, d, J = 7.8 Hz), 7.82 (1H, s),






8.41 (1H, d, J = 1.3 Hz), 8.87 (1H, s), 10.36 (1H, s).



88


1H-NMR (DMSO-d6) δ: 1.70 (3H, s), 2.02-2.08 (1H, m),






2.58-2.64 (2H, m), 3.15-3.19 (1H, m), 5.16 (2H, q, J = 8.8 Hz),






7.27 (1H, dd, J = 11.9, 8.8 Hz), 7.85-7.98 (2H, m), 8.62 (1H, s),






8.92 (1H, s), 10.83 (1H, s).



89


1H-NMR (DMSO-d6) δ: 1.65 (3H, s), 2.04-2.11 (1H, m),






2.54-2.62 (3H, m), 2.83-2.95 (2H, m), 3.11-3.14 (1H, m), 4.65 (2H, t,






J = 5.8 Hz), 7.09 (1H, d, J = 7.6 Hz), 7.42 (1H, t, J = 8.0 Hz),






7.87-7.92 (2H, m), 8.48 (1H, s), 8.91 (1H, s), 10.62 (1H, s).



90


1H-NMR (DMSO-d6) d: 1.41 (3H, s), 1.69-1.74 (1H, m),






2.00-2.04 (1H, m), 2.56-2.61 (1H, m), 2.87-2.92 (1H, m), 3.24 (6H, s),






3.37-3.52 (12H, m), 3.59 (2H, t, J = 4.5 Hz), 3.80 (2H, t, J = 4.3 Hz),






4.52 (2H, t, J = 4.4 Hz), 5.81 (2H, br s), 7.12 (1H, d, J = 7.6 Hz),






7.28 (1H, t, J = 8.0 Hz), 7.75 (1H, d, J = 8.3 Hz), 7.81 (1H,






s), 8.42 (1H, s), 8.87 (1H, s), 10.33 (1H, s).



91


1H-NMR (DMSO-d6) δ: 1.41 (3H, s), 1.69-1.75 (1H, m),






1.85 (3H, s), 1.98-2.05 (1H, m), 2.55-2.61 (1H, m), 2.86-2.93 (1H,






m), 5.09 (2H, d, J = 2.0 Hz), 5.79 (2H, br s), 7.12 (1H, d, J = 7.8 Hz),






7.28 (1H, t, J = 7.8 Hz), 7.74 (1H, d, J = 8.3 Hz), 7.80 (1H,






s), 8.45 (1H, s), 8.90 (1H, s), 10.36 (1H, s).



92


1H-NMR (DMSO-d6) δ: 1.41 (4H, s), 1.69-1.74 (1H, m),






1.98-2.05 (1H, m), 2.56-2.61 (1H, m), 2.87-2.93 (1H, m), 4.74 (2H, td,






J = 15.0, 3.1 Hz), 5.79 (2H, br s), 6.34-6.61 (1H, m), 7.12 (1H,






d, J = 7.8 Hz), 7.29 (1H, t, J = 8.0 Hz), 7.74 (1H, d, J = 8.1 Hz),






7.81 (1H, s), 8.54 (1H, s), 8.90 (1H, s), 10.40 (1H, s).



93
837.0 (2M + 1)





94


1H-NMR (DMSO-d6) δ: 1.41 (4H, s), 1.69-1.74 (1H, m),






1.98-2.05 (1H, m), 2.55-2.61 (2H, m), 2.71-2.75 (1H, m),






2.87-2.93 (1H, m), 4.49-4.61 (4H, m), 5.05-5.11 (1H, m), 5.79 (2H, br s),






7.12 (1H, d, J = 7.3 Hz), 7.26 (1H, t, J = 8.0 Hz), 7.74 (1H, d, J = 8.6 Hz),






7.81 (1H, s), 8.47 (1H, s), 8.88 (1H, s), 10.36 (1H, s).



95
801.0 (2M + 1)




















TABLE 40





Compound
MS





No.
(M + 1)
MP
NMR (solvent, shift value: ascending order)
uv



















96


1H-NMR (DMSO-d6) δ: 1.42 (3H, s), 1.70-1.78 (1H, m),






1.97-2.04 (3H, m), 2.55-2.60 (1H, m), 2.87-2.93 (1H, m), 3.26 (3H, s),






3.49 (2H, t, J = 6.2 Hz), 4.20 (2H, t, J = 6.4 Hz), 5.86 (2H, br s),






7.10 (1H, d, J = 7.8 Hz), 7.28 (1H, t, J = 8.1 Hz), 7.61 (1H, dd, J = 8.8,






2.8 Hz), 7.77-7.78 (2H, m), 8.11 (1H, d, J = 8.6 Hz),






8.38 (1H, d, J = 2.8 Hz), 10.32 (1H, s).



97


1H-NMR (DMSO-d6) δ: 1.41 (3H, s), 1.70-1.75 (1H, m),






1.99-2.06 (1H, m), 2.56-2.61 (1H, m), 2.87-2.93 (1H, m),






4.40-4.50 (2H, m), 4.74-4.88 (2H, m), 5.81 (2H, br s), 7.10 (1H, d, J = 7.6 Hz),






7.28 (1H, t, J = 8.2 Hz), 7.66 (1H, dd, J = 8.8, 2.8 Hz),






7.77-7.78 (2H, m), 8.13 (1H, d, J = 8.8 Hz), 8.43 (1H, d, J = 2.5 Hz),






10.33 (1H, s).



98


1H-NMR (DMSO-d6) δ: 1.41 (3H, s), 1.74-1.76 (7H, m),






1.99-2.06 (1H, m), 2.56-2.61 (1H, m), 2.86-2.93 (1H, m), 4.71 (2H, d,






J = 6.3 Hz), 5.44-5.49 (1H, m), 5.81 (2H, br s), 7.10 (1H, d, J = 7.3 Hz),






7.28 (1H, t, J = 8.1 Hz), 7.60 (1H, d, J = 8.8 Hz),






7.77 (2H, s), 8.11 (1H, d, J = 8.6 Hz), 8.36 (1H, s), 10.30 (1H, s).



99
799.0 (2M + 1)





100
827.0 (2M + 1)





101
867.1 (2M + 1)





102
885.1 (2M + 1)





103
382





104
412





105


1H-NMR (DMSO-d6) δ: 1.41 (4H, s), 1.69-1.74 (1H, m),






1.98-2.05 (1H, m), 2.55-2.60 (1H, m), 2.69-2.75 (2H, m),






2.86-2.93 (2H, m), 4.49 (2H, t, J = 6.4 Hz), 5.82 (2H, br s), 7.12 (1H, d, J = 7.3 Hz),






7.28 (1H, t, J = 7.7 Hz), 7.74 (1H, d, J = 7.8 Hz),






7.80 (1H, s), 8.42 (1H, s), 8.88 (1H, s), 10.34 (1H, s).



106


1H-NMR (DMSO-d6) δ: 1.41 (3H, s), 1.69-1.76 (3H, m),






1.98-2.05 (1H, m), 2.56-2.61 (1H, m), 2.64-2.69 (2H, m),






2.87-2.93 (1H, m), 4.45 (2H, t, J = 6.4 Hz), 5.80 (2H, br s), 7.12 (1H, d, J = 7.8 Hz),






7.28 (1H, t, J = 7.8 Hz), 7.74 (1H, d, J = 8.3 Hz),






7.80 (1H, s), 8.42 (1H, s), 8.88 (1H, s), 10.34 (1H, s).



107


1H-NMR (DMSO-d6) δ: 1.47-1.54 (1H, m), 1.86 (3H, s),






2.03-2.09 (1H, m), 2.88-2.94 (1H, m), 3.09-3.15 (1H, m),






4.43-4.47 (1H, m), 5.08-5.11 (2H, m), 5.76 (2H, br s), 7.04-7.06 (1H, m),






7.27-7.31 (1H, m), 7.68-7.70 (1H, m), 7.79 (1H, s), 8.45 (1H, s),






8.89 (1H, s), 10.39 (1H, s).



108
412





109
398





110


1H-NMR (DMSO-d6) δ: 1.45 (3H, s), 1.75-1.81 (1H, m),






2.08-2.14 (1H, m), 2.56-2.61 (1H, m), 2.90-2.97 (1H, m), 7.08 (1H, d,






J = 6.8 Hz), 7.27-7.36 (2H, m), 7.77-7.79 (2H, m), 8.01 (1H, d, J = 8.6 Hz),






8.22 (1H, d, J = 2.8 Hz), 10.27 (1H, s).



111


1H-NMR (DMSO-d6) δ: 1.45 (3H, s), 1.75-1.80 (1H, m),






2.07-2.14 (1H, m), 2.56-2.61 (1H, m), 2.90-2.97 (1H, m), 5.28 (2H, s),






7.09 (1H, d, J = 7.8 Hz), 7.23-7.32 (3H, m), 7.57 (2H, dd, J = 8.3,






5.6 Hz), 7.70 (1H, dd, J = 8.7, 2.7 Hz), 7.78-7.81 (2H, m),






8.13 (1H, d, J = 8.6 Hz), 8.45 (1H, d, J = 2.8 Hz), 10.36 (1H, s).



112
441




















TABLE 41





Compound
MS





No.
(M + 1)
MP
NMR (solvent, shift value: ascending order)
uv







113


1H-NMR (DMSO-d6) δ: 1.43 (3H, s), 1.71-1.77 (1H, m),






2.05-2.13 (7H, m), 2.56-2.61 (1H, m), 2.88-2.94 (1H, m), 5.75 (2H, s),






7.12 (1H, d, J = 8.1 Hz), 7.30 (1H, t, J = 7.8 Hz), 7.74-7.80 (2H,






m), 8.66 (1H, s), 8.93 (1H, s), 10.44 (1H, s).



114


1H-NMR (DMSO-d6) δ: 1.47 (3H, s), 1.77-1.82 (1H, m),






2.13-2.20 (1H, m), 2.57-2.62 (1H, m), 2.93-3.00 (1H, m),






3.75-3.79 (2H, m), 4.18 (2H, t, J = 4.4 Hz), 5.00 (1H, br s), 5.89 (2H, br s),






7.12 (1H, dd, J = 11.4, 8.8 Hz), 7.58-7.63 (1H, m),






7.72-7.82 (2H, m), 8.09 (1H, d, J = 8.6 Hz), 8.39 (1H, s), 10.34 (1H, s).



115
416





116


1H-NMR (DMSO-d6) δ: 1.47 (4H, s), 1.76-1.81 (1H, m),






2.15-2.22 (1H, m), 2.55-2.60 (1H, m), 2.93-2.99 (1H, m), 4.47 (3H, s),






5.87 (2H, br s), 7.13 (1H, dd, J = 12.0, 8.7 Hz), 7.79 (2H, ddd, J = 18.3,






8.0, 3.1 Hz), 8.89 (1H, s), 9.23 (1H, s), 10.72 (1H, s).



117


1H-NMR (DMSO-d6) δ: 1.48 (3H, s), 1.77-1.82 (1H, m),






2.14-2.21 (1H, m), 2.57-2.62 (1H, m), 2.93-3.00 (1H, m), 3.32 (3H, s),






4.56-4.59 (2H, m), 5.87 (2H, br s), 6.27-6.33 (1H, m), 6.75 (1H,






d, J = 12.4 Hz), 7.13 (1H, dd, J = 11.9, 8.8 Hz), 7.77-7.83 (2H,






m), 8.77 (1H, s), 9.25 (1H, s), 10.64 (1H, s).



118
418





119
361





120
825.1 (2M + 1)





121
416





122


1H-NMR (DMSO-d6) δ: 1.41 (3H, s), 1.68-1.74 (1H, m),






1.98-2.05 (1H, m), 2.21 (6H, s), 2.55-2.60 (1H, m), 2.67 (2H, t, J = 5.6 Hz),






2.86-2.93 (1H, m), 4.48 (2H, t, J = 5.4 Hz), 5.79 (2H, br






s), 7.11 (1H, d, J = 7.8 Hz), 7.28 (1H, t, J = 7.8 Hz), 7.73 (1H, d,






J = 7.6 Hz), 7.79 (1H, s), 8.39 (1H, s), 8.86 (1H, s), 10.33 (1H,






s).



123
395





124
414





125
417





126


1H-NMR (DMSO-d6) δ: 1.45 (3H, s), 1.75-1.81 (1H, m),






2.13-2.20 (1H, m), 2.55-2.60 (1H, m), 2.92-2.99 (1H, m), 3.88 (6H, s),






5.81 (2H, br s), 7.08 (1H, dd, J = 11.6, 8.8 Hz), 7.50-7.55 (1H,






m), 7.66-7.69 (1H, m), 10.07 (1H, s).



127
380





128
372





129
418





130
412





131


1H-NMR (DMSO-d6) δ: 1.48 (3H, s), 1.77-1.82 (1H, m),






2.18-2.25 (1H, m), 2.55-2.60 (1H, m), 2.94-3.01 (1H, m), 4.72 (2H, t,






J = 13.8 Hz), 6.45 (1H, t, J = 53.9 Hz), 7.10-7.15 (1H, m),






7.74-7.79 (2H, m), 8.50 (1H, s), 8.87 (1H, s), 10.47 (1H, s).



132


1H-NMR (DMSO-d6) δ: 1.49 (3H, s), 1.78-1.83 (1H, m),






2.19-2.26 (1H, m), 2.56-2.60 (1H, m), 2.94-3.01 (1H, m),






4.61-4.86 (4H, m), 7.09-7.14 (1H, m), 7.75-7.79 (2H, m), 8.43 (1H, s),






8.84 (1H, s), 10.43 (1H, s).



133
400




















TABLE 42





Compound
MS





No.
(M + 1)
MP
NMR (solvent, shift value: ascending order)
uv







134


1H-NMR (DMSO-d6) δ: 1.37 (3H, t, J = 7.1 Hz), 1.49 (3H, s),






1.78-1.83 (1H, m), 2.19-2.26 (1H, m), 2.56-2.61 (1H, m),






2.95-3.01 (1H, m), 4.44 (2H, q, J = 7.0 Hz), 7.13 (1H, dd, J = 11.6,






9.1 Hz), 7.73-7.78 (2H, m), 8.35 (1H, s), 8.83 (1H, s), 10.41 (1H,






s)



135
411





136
412





137


1H-NMR (CDCl3) δ: 1.63 (3H, s), 1.81-1.91 (1H, m),






2.21-2.32 (1H, m), 2.56-2.67 (1H, m), 2.75-2.83 (1H, m), 3.77 (3H, s),






5.24 (2H, s), 6.47 (1H, dd, J = 3.2, 0.6 Hz), 6.83 (2H, d, J = 8.9 Hz),






7.02 (1H, dd, 8.0, 1.8 Hz), 7.07 (1H, d, 3.2 Hz), 7.12 (2H, d, J = 8.9 Hz),






7.26 (1H, dd, 1.8, 0.6 Hz), 7.57 (1H, d, J = 8.0 Hz).



138
400





139
246





140
356





141
376





142
410





143
378





144
398





145
432





146
529





147
377





148
438





149
390





150



212.2


151



211.0, 266.3,






301.8


152



285.2


153
403





154
403





155
404





156
388





157
389





158
412





159
380





160
381





161


1H-NMR (DMSO-d6) δ: 1.47 (3H, s), 1.77-1.82 (1H, m),






2.15-2.21 (8H, m), 2.56-2.67 (3H, m), 2.93-3.00 (1H, m), 4.21 (2H, t,






J = 5.4 Hz), 5.88 (2H, br s), 7.11 (1H, dd, J = 11.6, 9.3 Hz),






7.59-7.61 (1H, m), 7.73-7.80 (2H, m), 8.09 (1H, d, J = 8.6 Hz),






8.37 (1H, s), 10.33 (1H, s).



162
402





163
408





164
464





165
459





166
404





167
420





168
375





169
432





170
380





171
376


















TABLE 43





Compound 

MS 


No.
Structure
(M + 1)







172







 


173




459


 


174




403


 


175




426


 


176




393


















TABLE 44





Compound 

MS 


No.
Structure
(M + 1)







177




359


 


178




402


 


179




447


 


180




435


 


181




396


















TABLE 45





Compound 

MS


No.
Structure
(M + 1)







182




376


 


183




385


 


184




375


 


185




378


 


186




412


















TABLE 46





Compound 

MS 


No.
Structure
(M + 1)







187




366


 


188




429


 


189




364


 


190




404


 


191




439


















TABLE 47





Compound 

MS 


No.
Structure
(M + 1)







192




412


 


193




426


 


194




393


 


195




352


 


196




414


















TABLE 48





Compound 

MS 


No.
Structure
(M + 1)







197







 


198




414


 


199




364


 


200




397


 


201




428


















TABLE 49





Compound 

MS 


No.
Structure
(M + 1)







202







 


203




398


 


204




410


 


205




422


 


206




395


















TABLE 50





Compound




No.
Structure
MS(M + 1)







207




414


 


208




410


 


209




402


 


210







 


211






















TABLE 51





Compound




No.
Structure
MS(M + 1)







212




433


 


213




466


 


214




464


 


215




427


 


216




400


















TABLE 52





Compound




No.
Structure
MS(M + 1)







217




442


 


218




386


 


219




402


 


220




362


 


221






















TABLE 53





Compound




No.
Structure
MS(M + 1)







222




399


 


223







 


224




352


 


225




402


 


226




395


















TABLE 54





Compound




No.
Structure
MS(M + 1)







227




362


 


228




375


 


229




380


 


230







 


231




400


















TABLE 55





Compound




No.
Structure
MS(M + 1)







232







 


233







 


234




422


 


235




395


 


236




364


















TABLE 56





Compound




No.
Structure
MS(M + 1)







237




362


 


238




427


 


239




455


 


240




420


 


241




406


















TABLE 57





Compound




No.
Structure
MS(M + 1)







242




471


 


243




406


 


244




420


 


245




383


 


246






















TABLE 58





Compound




No.
Structure
MS(M + 1)







247




455


 


248




435


 


249




416


 


250




416


















TABLE 59





Compound




No.
Structure
MS(M + 1)







251




402


 


252




388


 


253




420


 


254







 


255




524


















TABLE 60





Compound




No.
Structure
MS(M + 1)







256




348


 


257







 


258




395


 


259




395


 


260




402


















TABLE 61





Compound




No.
Structure
MS(M + 1)







261




336


 


262







 


263







 


264




334


 


265




384


















TABLE 62





Compound




No.
Structure
MS(M + 1)







266




402


 


267




402


 


268







 


269




396


 


270




427


















TABLE 63





Compound




No.
Structure
MS(M + 1)







271




444


 


272




416


 


273




429


 


274







 


275




376


















TABLE 64





Compound




No
Structure
MS(M + 1)







276




425


 


277




425


 


278




429


 


279




430


 


280






















TABLE 65





Compound




No
Structure
MS (M + 1)







281




448


 


282




411


 


283







 


284




438


 


285






















TABLE 66





Compound




No.
Structure
MS (M + 1)







286




437


 


287




437


 


288




348


 


289




429


 


290




448


















TABLE 67





Compound




No.
Structure
MS (M + 1)







291




398


 


292







 


293




419


 


294







 


295




422


















TABLE 68





Compound




No.
Structure
MS (M + 1)







296




430


 


297




410


 


298




410


 


299







 


300




401


















TABLE 69





Compound




No.
Structure
MS (M + 1)







301







 


302




400


 


303




349


 


304




426


 


305




363


















TABLE 70





Compound




No.
Structure
MS (M + 1)







306




415


 


307







 


308




424


 


309




406


 


310




383


















TABLE 71





Compound




No.
Structure
MS (M + 1)







311




470


 


312




422


 


313




476


 


314




401


 


315




428


















TABLE 72





Compound




No.
Structure
MS (M + 1)







316




413


 


317




442


 


318




442


 


319




411


 


320




434


















TABLE 73





Compound




No.
Structure
MS (M + 1)







321







 


322




463


 


323







 


324







 


325




410


















TABLE 74





Compound




No.
Structure
MS (M + 1)







326




390


 


327




410


 


328




410


 


329




410


 


330




384


















TABLE 75





Compound




No.
Structure
MS (M + 1)







331




479


 


332




429


 


333




427


 


334




427


 


335




410


















TABLE 76





Compound




No.
Structure
MS (M + 1)







336




428


 


337




426


 


338




401


 


339




400


 


340






















TABLE 77





Compound




No.
Structure
MS (M + 1)







341




441


 


342




442


 


343




442


 


344




430


 


345




428


















TABLE 78





Compound




No.
Structure
MS (M + 1)







346




430


 


347




411


 


348




413


 


349




478


 


350






















TABLE 79





Compound




No.
Structure
MS (M + 1)







351




384


 


352




443


 


353




403


 


354







 


355




421


















TABLE 8





Compound




No.
Structure
MS (M + 1)







356




422


 


357




421


 


358




369


 


359




430


 


360




424


















TABLE 81





Compound




No.
Structure
MS (M + 1)







361




416


 


362




429


 


363







 


364







 


365




398


















TABLE 82





Compound




No.
Structure
MS (M + 1)







366




425


 


367




425


 


368







 


369




424


















TABLE 83





Compound




No.
Structure
MS (M + 1)







370




413


 


371




430


 


372




408


 


373




426


 


374




437


















TABLE 84





Compound




No.
Structure
MS (M + 1)







375




424


 


376







 


377




427


 


378




424


















TABLE 85





Compound




No.
Structure
MS (M + 1)







379




424


 


380




493


 


381




458


 


382




395


 


383




407


















TABLE 86





Compound




No.
Structure
MS (M + 1)







384




416


 


385




364


 


386







 


387







 


388






















TABLE 87





Compound




No.
Structure
MS (M + 1)







389







 


390







 


391







 


392




413


 


393




446


















TABLE 88





Compound




No.
Structure
MS (M + 1)







394




445


 


395




428


 


396




413


 


397




494


 


398




428


















TABLE 89





Compound




No.
Structure
MS (M + 1)







399




404


 


400




375


 


401




444


 


402




444


 


403




448


















TABLE 90





Compound




No.
Structure
MS (M + 1)







404




440


 


405




365


 


406




414


 


407




443


 


408




385


















TABLE 91





Compound




No.
Structure
MS (M + 1)







409




423


 


410




410


 


411







 


412




393


 


413




348


















TABLE 92





Compound




No.
Structure
MS (M + 1)







414




414


 


415




438


 


416




410


 


417







 


418




464


















TABLE 93





Compound




No.
Structure
MS (M + 1)







419




461


 


420




462


 


421




412


 


422




466


 


423




437


















TABLE 94





Compound




No.
Structure
MS (M + 1)







424




411


 


425




411


 


426




351


 


427




478


 


428




462


















TABLE 95





Com-




pound

MS


No.
Structure
(M + 1)







429







 


430




443


 


431




470


 


432







 


433




378


















TABLE 96





Compound

MS


No.
Structure
(M + 1)







434




451


 


435




355


 


436




351


 


437




509


 


438




420


















TABLE 97





Com-




pound

MS


No.
Structure
(M + 1)







439




429


 


440




406


 


441




494


 


442




458


 


443




483


















TABLE 98





Compound

MS


No
Structure
(M + 1)







444




457


 


445




452


 


446




550


 


447




437


















TABLE 99





Compound

MS


No.
Structure
(M + 1)







448




495


 


449




455


 


450




481


 


451




426


















TABLE 100





Compound

MS


No.
Structure
(M + 1)







452




454


 


453




480


 


454




404


 


455




441


















TABLE 101





Com-




pound

MS


No.
Structure
(M + 1)







456




417


 


457




395


 


458




362


 


459




393


 


460

























TABLE 102





Compound

MS

NMR (solvent,) shift



No.
Structure
(M + 1)
MP
value: ascending order)
uv







461




346





 


462




349

1H-NMR (DMSO-d6) d: 10.02 (1.0H, s), 8.59 (1.0H, s), 7.73-7.66 (2.0H, m), 7.09 (1.0H, dd, J = 12.00, 8.97 Hz), 5.83 (2.0H, br s), 2.97-2.95 (1.0H, m), 2.59-2.56 (1.0H, m), 2.17-2.16 (1.0H, m), 1.79-1.76 (1.0H, m), 1.47 (3.0H, s).



 


463




362





 


464




441





 


465




456





 


466






1H-NMR (DMSO-d6) d: 10.70 (1.0H, s), 8.76 (1.0H, s), 8.36 (1.0H, s), 8.03 (1.0H, s), 6.44 (1.0H, s), 5.93 (2.0H, br s), 3.00- 2.97 (1.0H, m), 2.63-2.61 (1.0H, m), 2.19 (3.0H, s), 2.00-1.98 (1.0H, m), 1.82-1.80 (1.0H, m), 1.60 (9.0H, s), 1.43 (3.0H, s).





















TABLE 103





Compound

MS

NMR (solvent, shift



No
Structure
(M + 1)
MP
value: ascending order)
uv







467




369





 


468




396





 


469




450





 


470




383





 


471




417





 


472




364





















TABLE 104





Compound

MS

NMR (solvent, shift 



No.
Structure
(M + 1)
MP
value ascending order)
uv







473




361





 


474




332





 


475




378





 


476




345





 


477




392





 


478




365





 


479




359





















TABLE 105





Compound

MS

NMR (solvent, shift



No
Structure
(M + 1)
MP
value: ascending order)
uv







480




360





 


481




366





 


482




345





 


483




394





 


484




385





 


485




347





 


486




347





















TABLE 106





Compound

MS

NMR (solvent, shift



No
Structure
(M + 1)
MP
value: ascending order)
uv







487




347





 


488




362





 


489




405





 


490




381





 


491




379





 


492




421





 


493




379





















TABLE 107





Compound

MS

NMR (solvent, shift



No
Structure
(M + 1)
MP
value: ascending order)
uv







494




426





 


495




363





 


496




378





 


497




426





 


498




374





 


499




374





 


500




363





















TABLE 108





Compound

MS

NMR (solvent, shift 



No
Structure
(M + 1)
MP
value: ascending order)
uv







501




400





 


502




384





 


503




359





 


504




367





 


505




365





 


506




365





 


507




365





















TABLE 109





Compound

MS

NMR (solvent, shift 



No
Structure
(M + 1)
MP
value: ascending order)
uv







508




365





 


509




411





 


510




363





 


511




363





 


512




393





 


513




408





 


514




413





















TABLE 110





Compound

MS

NMR (solvent,



No
Structure
(M + 1)
MP
shift value: ascending order)
uv







515




411





 


516




413





 


517




441





 


518




348





 


519




429





 


520




394





 


521




402





















TABLE 111





Compound

MS

NMR (solvent,



No
Structure
(M + 1)
MP
shift value: ascending order)
uv







522




378





 


523




441





 


524




380





 


525




379





 


526




414





 


527




428





















TABLE 112





Compound

MS

NMR (solvent,



No
Structure
(M + 1)
MP
shift value: ascending order)
uv







528




433





 


529




362





 


530




392





 


531




426





 


532




364





 


533




364





















TABLE 113





Compound

MS

NMR (solvent,



No
Structure
(M + 1)
MP
shift value: ascending order)
uv







534




404





 


535




394





 


536




383





 


537




428





 


538




404





 


539




401





















TABLE 114





Compound

MS

NMR (solvent,



No.
Structure
(M + 1)
MP
shift value: ascending order)
uv







540




384





 


541




442





 


542




401





 


543




404





 


544




511





 


545




400





















TABLE 115





Compound

MS

NMR (solvent,



No
Structure
(M + 1)
MP
shift value: ascending order)
uv







546






1H-NMR (DMSO-d6) d: 10.92 (1H,  s), 10.45 (1H, s), 8.45 (1H, s), 8.42  (1H, s), 8.30 (1H, d, J = 8.8 Hz),  7.79-7.78 (3H, m), 7.31 (1H, dd, J =  12.3, 9.2 Hz), 3.22 (1H, d, J =  13.4 Hz), 2.72-2.65 (2H, m), 2.11  (1H, t, J = 11.5 Hz), 1.73 (3H, s).



 


547




359





 


548




359





 


549




403





 


550




343





 


551




343





















TABLE 116





Compound

MS

NMR (solvent,



No.
Structure
(M + 1)
MP
shift value: ascending order)
uv







552




363





 


553




348





 


554




363





 


555




374





 


556




383





 


557






1H-NMR (DMSO-d6) δ: 10.72 (1H,  s), 8.93 (1H, s), 8.90 (1H, s), 8.49 (1H,  s), 8.36 (1H, s), 8.24 (1H, s), 4.88-4.64  (4H, m), 3.03-2.97 (1H, m), 2.65-2.58  (1H, m), 2.13-2 07 (1H, m), 1.89-1.81  (1H, m), 1.48 (3H, s). 



 


558




402





















TABLE 117





Compound

MS

NMR (solvent,



No.
Structure
(M + 1)
MP
shift value: ascending order)
uv







559




418





 


560




387





 


561




411





 


562




431





 


563




342





 


564




372





 


565




390





















TABLE 118





Compound

MS

NMR (solvent,



No
Structure
(M + 1)
MP
shift value: ascending order)
uv







566




428





 


567




429





 


568




419





 


569




442





 


570




456





 


571




443





 


572




396





















TABLE 119





Compound

MS

NMR (solvent,



No.
Structure
(M + 1)
MP
shift value: ascending order)
uv







573




447





 


574




430





 


575




458





 


576




412





 


577




426





 


578




426





 


579




440





















TABLE 120





Compound

MS

NMR (solvent,



No
Structure
(M + 1)
MP
shift value: ascending order)
uv







580




480





 


581




363





 


582




393





 


583




437





 


584




366





 


585




360





 


586




380





















TABLE 121





Compound

MS

NMR (solvent,



No
Structure
(M + 1)
MP
shift value: ascending order)
uv







587




363





 


588




323





 


589







250.9, 288.7


 


590







298.2


 


591







252.1, 305.3


 


592







250.9, 288.7


 


593







216.9, 292.3





















TABLE 122





Compound

MS

NMR (solvent,



No
Structure
(M + 1)
MP
shift value: ascending order)
uv







594







214.5, 289.9


 


595







297


 


596







250.9, 302.9


 


597







289.9


 


598







297


 


599







214.5, 289.9


 


600




404, 807  (2M + 1)





















TABLE 123





Compound

MS

NMR (solvent,



No.
Structure
(M + 1)
MP
shift value: ascending order)
uv







601




448, 895  (2M + 1)





 


602




389





 


603




391





 


604




391





 


605




436





 


606




388





















TABLE 124





Compound

MS

NMR (solvent,



No
Structure
(M + 1)
MP
shift value: ascending order)
uv







607










 


608










 


609




377





 


610










 


611










 


612




332





















TABLE 125





Compound

MS

NMR (solvent,



No
Structure
(M + 1)
MP
shift value: ascending order)
uv




















613




346





 


614










 


615










 


616










 


617










 


618

























TABLE 126





Compound

MS

NMR (solvent,



No.
Structure
(M + 1)
MP
shift value: ascending order)
uv




















619










 


620










 


621










 


622










 


623










 


624

























TABLE 127





Compound

MS

NMR (solvent,



No
Structure
(M + 1)
MP
shift value: ascending order)
uv




















625










 


626










 


627










 


628










 


629










 


630

























TABLE 128





Compound

MS

NMR (solvent,



No.
Structure
(M + 1)
MP
shift value: ascending order)
uv




















631










 


632










 


633










 


634










 


635










 


636

























TABLE 129





Compound

MS

NMR (solvent,



No
Structure
(M + 1)
MP
shift value: ascending order)
uv




















637




387





 


638










 


639










 


640










 


641










 


642

























TABLE 130





Compound

MS

NMR (solvent,



No
Structure
(M + 1)
MP
shift value: ascending order)
uv




















643










 


644




475





 


645




397





 


646




414



















TABLE 131





Compound

MS



No
Structure
[M + 1]
NMR (solvent, shift value)







647




404



 


648




377



 


649




388



 


650




389



 


651




453



 


652




399



 


653




371



















TABLE 132





Compound

MS



No
Structure
[M + 1]
NMR (solvent, shift value)







654




360



 


655




374



 


656




456



 


657




411



 


658




419



 


659




383



 


660





1H-NMR (CDCl3) δ: 1.84 (3H, d-like), 3.16 (1H, ddd, J = 6 9, 12.6, 14.4 Hz), 3.36 (1H, ddd, J = 6.0, 12.6, 18.9 Hz), 4.61 (2H, br), 7.07 (1H, dd, J = 8.7, 11.7 Hz), 7.49-7.63 (2H, m), 7.67 (1H, dd, J = 3.0, 6.9 Hz), 7.95 (1H, ddd, J = 3.0, 6.9, 8.7 Hz), 8.41 (1H, m), 9.85 (1H, brs).



















TABLE 133





Compound

MS



No
Structure
[M + 1]
NMR (solvent, shift value)







661





1H-NMR (CDCl3) δ: 0.89 (3H, s), 1.11 (3H, d, J = 3.0 Hz), 1.67 (3H, d, J = 4.2 Hz), 2.63 (1H, d, J = 12.0 Hz), 3.12 (1H, d, J = 12 0 Hz), 4.29 (2H, br), 7.02 (1H, dd, J = 8.7, 12.3 Hz), 7.49-7.64 (3H, m), 7.96 (1H, ddd, J = 3.0, 6.6, 8.7 Hz), 8.45 (1H, m), 9.81 (1H, brs).


 


662





1H-NMR (CDCl3) δ: 1.85 (3H, d-like), 2.69 (3H, s), 3.17 (1H, ddd, J = 6.9, 12.6, 14.4 Hz), 3.37 (1H, ddd, J = 6.3, 12.9, 18 9 Hz), 4.54 (2H, brs), 7.08 (1H, dd, J = 8.7, 11.7 Hz), 7.69 (1H, dd, J = 2 7, 6.9 Hz), 7 87 (1H, dd, J = 2.4, 8 4 Hz), 7 93 (1H, ddd, J = 2.7, 6.6, 8 7 Hz), 8.24 (1H, dd, J = 0.6, 8.4 Hz), 8.55 (1H, dd, J = 0.6, 2.4 Hz), 9.82 (1H, brs).


 


663





1H-NMR (CDCl3) δ: 1.85 (3H, d-like), 3.18 (1H, ddd, J = 7 2, 12.9, 15.0 Hz), 3.37 (1H, ddd, J = 6.0, 12.6, 18.9 Hz), 4.60 (2H, br), 7.08 (1H, dd, J = 8.7, 11.7 Hz), 7.71 (1H, dd, J = 3.0, 6.6 Hz), 7.90 (1H, ddd, J = 3.0, 6.6, 8.7 Hz), 8.41 (1H, d, J = 0.9 Hz), 9.35 (1H, d, J = 0.9 Hz), 9.63 (1H, brs).


 


664





1H-NMR (CDCl3) δ: 1.83 (3H, d-like), 2 51 (3H, s), 3.16 (1H, ddd, J = 6.9, 12.9, 15.3 Hz), 3.34 (1H, ddd, J = 6.3, 12.9, 19.2 Hz), 4.53 (2H, brs), 7.05 (1H, dd, J = 8.7, 11.4 Hz), 7.62 (1H, dd, J = 2.7, 6.9 Hz), 7.82 (1H, ddd, J = 2.7, 6.9, 8.7 Hz), 8.16 (1H, s), 8.70 (1H, brs).


 


665





1H-NMR (CDCl3) δ: 0.95 (3H, t, J = 7.5 Hz), 1.32- 1.44 (2H, m), 1.59-1.69 (2H, m), 1.85 (3H, d-like), 2.70 (2H, t, J = 7.5 Hz), 3.17 (1H, ddd, J = 6.9, 12.9, 15.3 Hz), 3.34 (1H, ddd, J = 6.3, 12.9, 19.2 Hz), 4.53 (2H, brs), 7.07 (1H, dd, J = 8.7, 11.7 Hz), 7.67- 7.70 (2H, m), 7.94 (1H, ddd, J = 2.7, 6.6, 8.7 Hz), 8.18 (1H, dd, J = 0.6, 7.8 Hz), 8.40 (1H, dd, J = 0.6, 1.8 Hz), 9.97 (1H, brs).


 


666




396



 


667




365



















TABLE 134





Compound

MS



No.
Structure
[M + 1]
NMR (solvent, shift value)







668




356



 


669




403



 


670





1H-NMR (CDCl3) δ: 1.38 (3H, t, J = 7.6 Hz), 1.63 (3H, s), 1.88-1.97 (1H, m), 2.41-2.50 (1H, m), 2.69- 2.78 (1H, m), 2.84 (2H, q, J = 7.6 Hz), 2.93-3.01 (1H, m), 7.02 (1H, dd, J = 11.8, 8 8 Hz), 7.34 (1H, dd, J = 7.1, 2.8 Hz), 7.89 (1H, ddd, J = 8.8, 4.3, 2.8 Hz), 8.16 (1H, s), 8.69 (1H, s)


 


671




370



 


672




432



 


673




412



 


674





1H-NMR (CDCl3) δ: 0.53-0.59 (1H, m), 0.65-0.72 (1H, m), 0.85-0.91 (1H, m), 1.14-1.17 (1H, m), 1.47 (3H, d, J = 2.0 Hz), 2.46 (1H, d, J = 12.1 Hz), 2.69 (3H, s), 2.89 (1H, dd, J = 12.1, 1.3 Hz), 7.06 (1H, dd, J = 11.5, 8.8 Hz), 7.45 (1H, dd, J = 6.8, 2.6 Hz), 7.94 (1H, ddd, J = 8.8, 4 0, 2.8 Hz), 8.44 (1H, d, J = 1.3 Hz), 9.36 (1H, d, J = 1.3 Hz), 9.60 (1H, s).



















TABLE 135





Compound

MS



No.
Structure
[M + 1]
NMR (solvent, shift value)







675




402



 


676




426



 


677




396



 


678




430



 


679




372



 


680





1H-NMR (DMSO-d6) δ: 1.47 (3H, s), 1.77-1.83  (1H, m), 2.34-2.39 (1H, m), 2.48-2.53 (1H, m), 2.63  (3H, s), 2.89-2.96 (1H, m), 3.90 (3H, s), 5.86 (2H,  br s), 8.10 (1H, d, J = 2.3 Hz), 8.47 (1H, d, J = 2.5  Hz), 8.69 (1H, s), 9.14 (1H, s), 10.59 (1H, s).


 


681





1H-NMR (DMSO-d6) δ: 1 52 (3H, s), 1.80-1.85  (1H, m), 2.62 (3H, s), 2.64-2.69 (2H, m), 2.96-3 01  (1H, m), 7.77 (1H, d, J = 2.5 Hz), 7.96 (1H, d, J =  2.3 Hz), 8.67 (1H, s), 9.10 (1H, s), 10.58 (1H, s).



















TABLE 136





Compound

MS



No
Structure
[M + 1]
NMR (solvent, shift value)







682





1H-NMR (DMSO-d6) δ: 1.46 (3H, s), 1.95-2.01 (1H, m), 2.33-2.39 (1H, m), 2.62 (3H, s), 2.64-2.69 (1H, m), 2.74 (2H, s), 2.92-2.98 (1H, m), 7.90 (1H, d, J = 2.5 Hz), 7.94-7.95 (1H, m), 8.67 (1H, s), 9.09 (1H, s), 10.57 (1H, s).


 


683




482



 


684




482



 


685




400



 


686




424



 


687




427



 


688




402



















TABLE 137





Compound

MS



No
Structure
[M + 1]
NMR (solvent, shift value)







689




390



 


690




413



 


691




374



 


692




428



 


693





1H-NMR (DMSO-d6) δ: 0.77 (3H, s), 1.30 (3H, s), 1.43 (3H, s), 1.71 (1H, d, J = 13.8 Hz), 2.33 (1H, d,  J = 13.8 Hz), 3.65 (1H, t, J = 2.4 Hz), 5.13 (2H, d, J = 2.4 Hz), 6.05 (2H, br), 7.19 (1H, d-like), 7 25 (1H, t, J = 7 8 Hz), 7.71 (1H, d-like), 7.87 (1H, s-like), 8.47 (1H, d, J = 1.2 Hz), 8.90 (1H, d, J = 1.2 Hz), 10.37 (1H, brs).


 


694





1H-NMR (DMSO-d6) δ: 0.77 (3H, s), 1.28 (3H, s), 1.42 (3H, s), 1.67 (1H, d, J = 14.1 Hz), 2.23 (1H, d,  J = 14.1 Hz), 4.02 (3H, s), 5.82 (2H, brs), 7.19 (1H, d- like), 7.24 (1H, t, J = 7.8 Hz), 7.70 (1H, d-like), 7.86 (1H, s-like), 8.40 (1H, d, J = 1.2 Hz), 8.89 (1H, d, J = 1.2 Hz), 10.31 (1H, brs).


 


695





1H-NMR (DMSO-d6) δ: 0.79 (3H, s), 1.32 (3H, s), 1.46 (3H, s), 1.78 (1H, d, J = 14.1 Hz), 1.86 (3H, t, J = 2.4 Hz), 2.39 (1H, d, J = 14.1 Hz), 5.90 (1H, q, J = 2.4 Hz), 6.49 (2H, br), 7.16 (1H, (d-like), 7 27 (1H, t,  J = 7.8 Hz), 7.73 (1H, d-like), 7.87 (1H, s-like), 8.44 (1H, d, J = 1.2 Hz), 8.89 (1H, d, J = 1.2 Hz), 10.38 (1H, brs).



















TABLE 138





Compound

MS



No
Structure
[M + 1]
NMR (solvent, shift value)







696





1H-NMR (DMSO-d6) δ: 0.77 (3H, s), 1.30 (3H, s), 1.43 (3H, s), 1.71 (1H, d, J = 14.1 Hz), 2.32 (1H, d,  J = 14.1 Hz), 5.95 (2H, br), 7.22 (1H, d-like), 7.27 (1H, t, J = 7.8 Hz), 7.75 (1H, d-like), 7.88 (1H, s-like), 8.29 (1H, dd, J = 0.6, 8.1 Hz), 8.58 (1H, dd, J = 2.1, 8.1 Hz), 8.19 (1H, dd, J = 0.6, 2.1 Hz), 10.65 (1H, brs).


 


697




410



 


698








 


699








 


700








 


701




400



 


702




443









Test Example Assay of β-Secretase-Inhibiting Activity

Forty eight point five μL of substrate peptide solution (Biotin-XSEVNLDAEFRHDSGC-Eu: X=ε-amino-n-capronic acid, Eu=Europium cryptate) was added to each well of 96-hole half-area plate (a black plate: Corning Incorporated), and after addition of 0.5 μl of the test sample (dissolved in N,N′-dimethylformaldehyde) and 1 μl of Recombinant human BACE-1 (R&D Systems), the reaction mixture was incubated at 30° C. for 3 hours. The substrate peptide was synthesized by reacting Cryptate TBPCOOH mono SMP (CIS bio international) with Biotin-XSEVNLDAEFRHDSGC (Peptide Institute, Inc.). The final concentrations of the substrate peptide and Recombinant human BACE-1 were adjusted to 18 nM and 7.4 nM respectively, and the reaction was performed in sodium acetate buffer (50 mM sodium acetate, pH 5.0, 0.008% Triton X-10).
After the incubation for reaction, 50 μl of 8.0 μg/ml Streptavidin-XL665 (CIS bio international) dissolved in phosphate buffer (150 mM K2 HPO4—KH2 PO4, pH 7.0, 0.008% Triton X-100, 0.8 M KF) was added to each well and left stand at 30° C. for an hour. After then, fluorescence intensity was measured (excitation wavelength: 320 nm, measuring wavelength: 620 nm and 665 nm) using Wallac 1420 multilabel counter (Perkin Elmer life sciences). Enzymatic activity was determined from counting ratio of each wavelength (10,000×Count 665/Count 620) and 50% inhibitory concentration against the enzymatic activity was calculated. IC50 values of the test compounds are indicated in Table 139.







TABLE 139







P










Compound No.
IC50 (uM)













3
0.08



11
0.17



12
0.16



26
4.85



34
0.10



38
0.14



41
0.15



62
0.17



65
0.72



66
0.15



70
0.09



71
0.16



72
0.11



76
0.18



80
0.07



86
0.19



87
0.09



92
0.08



93
0.08



94
0.17



101
0.08



105
0.13



106
0.12



109
0.10



111
0.18



114
0.16



126
2.14



136
0.11



141
0.12



149
9.25



150
2.48



151
6.77



155
5.96



163
6.79



164
0.08









The following compounds have shown IC50 values equal to or under 1 μM in the same assay;
compounds 4, 5, 6, 8, 10, 18, 19, 20, 21, 22, 29, 32, 33, 35, 43, 45, 46, 58, 59, 63, 64, 68, 69, 75, 77, 78, 79, 81, 82, 83, 84, 85, 88, 89, 90, 91, 95, 96, 97, 98, 100, 102, 103, 104, 107, 108, 110, 112, 113, 115, 116, 117, 118, 119, 120, 121, 123, 124, 125, 127, 131, 132, 133, 134, 135, 142, 143, 144, 145, 148, 152, 157, 158, 162 and 165.
Also, compounds 462, 463, 465, 467, 469, 470, 471, 472, 479, 482, 483, 486, 489, 490, 492, 501, 503, 507, 508, 509, 510, 511, 512, 516, 518, 519, 523, 527, 528, 531, 532, 533, 536, 538, 539, 540, 542, 545, 546, 547, 548, 549, 552, 553, 554, 555, 556, 557, 558, 560, 561, 562, 564, 565, 567, 568, 569, 570, 571, 572, 573, 574, 575, 578, 581, 582, 583, 584, 586, 587, 590, 595, 596, 600, 601, 602, 603, 604, 605, 606, 609, 612, 613, 637, 644, 646, 461, 468, 478, 491, 502, 505, 508, 517, 530, 537, 542, 544, 559, 563, 566, 576, 577, 597, 598, 599 and 645 showed IC50 values equal to or under 1 μM in the same assay.













Compound No.
IC50 (μM)








652
0.06



655
0.01



660
0.11



662
0.17



664
0.02



665
0.87



668
0.51



669
0.01



674
0.01



680
0.05



689
0.04



701
0.20



702
0.16









The following compounds also showed IC50 values equal to or under 1 μM in the same assay;
compounds 647, 648, 649, 650, 651, 654, 656, 657, 658, 659, 661, 666, 670, 671, 672, 673, 675, 676, 677, 678, 679, 683, 684, 685, 686, 687, 688, 690, 691, 692, 693, 694, 695, 696 and 697, 652, 655, 660, 662, 664, 665, 667, 669, 674 and 689.
Formulation Example 1
Granular formulation is prepared with the following ingredients;
















Ingredient
compound of the formula (I)
 10 mg




lactose
700 mg




corn starch
274 mg




HPC-L
 16 mg





1000 mg 









Compound of the formula (I) and lactose are put through a sieve of No. 60 mesh. Corn starch is put through a sieve of No. 120 mesh and these are mixed with V-shaped mixer.
An aqueous solution of HPC-L (Hydroxypropyl cellulose of Low viscosity) is added to the mixed powder, kneaded, granulated (extrusion granulation; pore diameter 0.5-1 mm) and put into a drying process. The resulted dried granule is sieved with vibrating screen (12/60 mesh) to give a granular formulation.
Formulation Example 2
Granular formulation for capsule filling is prepared with the following ingredients;
















Ingredient
compound of the formula (I)
15 mg




lactose
90 mg




corn starch
42 mg




HPC-L
 3 mg





150 mg 









Compound of the formula (I) and lactose are put through a sieve of No. 60 mesh. Corn starch is put through a sieve of No. 120 mesh and these are mixed. An aqueous solution of HPC-L is added to the mixed powder, kneaded, granulated and dried. Particle size of the resulted dried granule is regulated and each of 150 mg is filled in No. 5 hard-gelatin capsule.
Formulation Example 3
Tablet is prepared with the following ingredients;
















Ingredient
compound of the formula (I)
10 mg




lactose
90 mg




microcrystalline cellulose
30 mg




CMC-Na
15 mg




magnesium stearate
 5 mg





150 mg 









Compound of the formula (I), lactose, microcrystalline cellulose and CMC-Na (sodium salt of carboxymethylcellulose) are put through sieve of No. 60 mesh and mixed. Magnesium stearate is mixed with the mixed granule above to give a mixed powder for tablet, which is compressed by a tabletting machine to give a tablet of 150 mg.
Formulation Example 4
The following ingredients were warmed, mixed and sterilized to give an injection.
















Ingredient
compound of the formula (I)
 3 mg




non-ionic surfactant
15 mg




purified water for injection
 1 ml









INDUSTRIAL APPLICABILITY
A compound of the present invention can be a useful drug for treating diseases induced by production, secretion and/or deposition of amyloid β protein.

## Claims

1. A compound of the formula (I):



wherein the ring A is an optionally substituted benzofuran, wherein a substituent of the optionally substituted benzofuran is at least one selected from the group consisting of
(A) the substituent group α, the substituent group α being at least one selected from the group consisting of halogen, hydroxy, lower alkoxy, hydroxy lower alkoxy, lower alkoxy lower alkoxy, acyl, acyloxy, carboxy, lower alkoxycarbonyl, amino, acylamino, lower alkylamino, imino, hydroxyimino, lower alkoxyimino, lower alkylthio, carbamoyl, lower alkylcarbamoyl, hydroxy lower alkylcarbamoyl, sulfamoyl, lower alkylsulfamoyl, lower alkylsulfonyl, cyano, nitro, a carbocyclic group and a heterocyclic group;
(B) lower alkyl optionally substituted with one or more substituent(s) selected from the substituent group α, hydroxyimino and lower alkoxyimino;
(C) amino lower alkyl substituted with one or more substituent(s) selected from the substituent group α;
(D) hydroxyimino lower alkyl;
(E) lower alkoxyimino lower alkyl;
(F) lower alkenyl optionally substituted with one or more substituent(s) selected from the substituent group α;
(G) lower alkynyl optionally substituted with one or more substituent(s) selected from the substituent group α;
(H) lower alkoxy optionally substituted with one or more substituent(s) selected from the substituent group α;
(I) lower alkoxy lower alkoxy optionally substituted with one or more substituent(s) selected from the substituent group α;
(J) lower alkenyloxy optionally substituted with one or more substituent(s) selected from the substituent group α;
(K) lower alkoxy lower alkenyloxy optionally substituted with one or more substituent(s) selected from the substituent group α;
(L) lower alkynyloxy optionally substituted with one or more substituent(s) selected from the substituent group α;
(M) lower alkoxy lower alkynyloxy optionally substituted with one or more substituent(s) selected from the substituent group α;
(N) lower alkylthio optionally substituted with one or more substituent(s) selected from the substituent group α;
(O) lower alkenylthio optionally substituted with one or more substituent(s) selected from the substituent group α;
(P) lower alkynylthio optionally substituted with one or more substituent(s) selected from the substituent group α;
(Q) lower alkylamino substituted with one or more substituent(s) selected from the substituent group α;
(R) lower alkenylamino substituted with one or more substituent(s) selected from the substituent group α;
(S) lower alkynylamino substituted with one or more substituent(s) selected from the substituent group α;
(T) aminooxy optionally substituted with one or more substituent(s) selected from lower alkylidene and the substituent group α;
(U) acyl substituted with one or more substituent(s) selected from the substituent group α;
(V) lower alkylsulfonyl optionally substituted with one or more substituent(s) selected from the substituent group α;
(W) lower alkylsulfinyl optionally substituted with one or more substituent(s) selected from the substituent group α;
(X) sulfamoyl;
(Y) lower alkylsulfamoyl optionally substituted with one or more substituent(s) selected from the substituent group α;
(Z) a carbocyclic group optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
(AA) a heterocyclic group optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
(AB) carbocyclyl lower alkyl optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
(AC) heterocyclyl lower alkyl optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
(AD) carbocyclyloxy optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
(AE) heterocyclyloxy optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
(AF) carbocyclyl lower alkoxy optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
(AG) heterocyclyl lower alkoxy optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
(AH) carbocyclyl lower alkoxycarbonyl optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
(AI) heterocyclyl lower alkoxycarbonyl optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
(AJ) carbocyclylthio optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
(AK) heterocyclylthio optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
(AL) carbocyclyl amino optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
(AM) heterocyclyl amino optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
(AN) carbocyclyl lower alkylamino optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
(AO) heterocyclyl lower alkylamino optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
(AP) lower alkylsulfamoyl optionally substituted with one or more substituent(s) selected from the substituent group α;
(AQ) carbocyclylsulfamoyl optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
(AR) heterocyclylsulfamoyl optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
(AS) carbocyclylsulfonyl optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
(AT) heterocyclylsulfonyl optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
(AU) carbocyclylcarbamoyl optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
(AV) heterocyclyl carbamoyl optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
(AW) carbocyclyl lower alkylcarbamoyl optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
(AX) heterocyclyl lower alkylcarbamoyl optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
(AY) carbocyclyloxycarbonyl optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
(AZ) heterocyclyloxycarbonyl optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
(BA) lower alkylenedioxy optionally substituted with halogen;
(BB) oxo;
(BC) azide; and
(BD) one of the following formulae:







wherein Ak1, Ak2 and Ak3 are each independently a single bond, optionally substituted lower alkylene wherein the substituent(s) is selected from the substituent group α, optionally substituted lower alkenylene wherein the substituent(s) is selected from the substituent group α, or optionally substituted lower alkynylenewherein the substituent(s) is selected from the substituent group α;
Ak4 is optionally substituted lower alkylene wherein the substituent(s) is selected from the substituent group α, optionally substituted lower alkenylene wherein the substituent(s) is selected from the substituent group α, or optionally substituted lower alkynylene wherein the substituent(s) is selected from the substituent group α;
W1 and W3 are each independently O or S,
W2 is O, S or NR5,
R5 and R6 are each independently hydrogen, lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl, lower alkoxycarbonyl lower alkyl, carbocyclyl lower alkyl, lower alkenyl, hydroxyl lower alkenyl, lower alkoxy lower alkenyl, lower alkoxycarbonyl lower alkenyl, carbocyclyl lower alkenyl, lower alkynyl, hydroxyl lower alkynyl, lower alkoxy lower alkynyl, lower alkoxycarbonyl lower alkynyl, carbocyclyl lower alkynyl or acyl;
R7 is hydrogen or lower alkyl;
the ring B is a carbocyclic group or a heterocyclic group, the carbocyclic group and the heterocyclic group being substituted optionally with at least one selected from the above (A) to (BC) and
p is 1 or 2; W1, W3 or W5 may be independent when it is pluralized,
R1 is optionally substituted lower alkyl wherein the substituent(s) is selected from the substituent group α, optionally substituted lower alkenyl wherein the substituent(s) is selected from the substituent group α, optionally substituted lower alkynyl wherein the substituent is selected from the substituent group α, an optionally substituted carbocyclic group wherein the substituent(s) is selected from a group of lower alkyl and the substituent group α, or an optionally substituted heterocyclic group wherein the substituent(s) is selected from a group of lower alkyl and the substituent group α,
R2a and R2b are each independently hydrogen, optionally substituted lower alkyl wherein the substituent(s) is selected from the substituent group a or optionally substituted acyl wherein acyl includes aliphatic acyl, carbocyclyl carbonyl and heterocyclyl carbonyl, and the substituent(s) is selected from the substituent group α, and the substituent(s) for a moiety of the ring in carbocyclyl carbonyl and heterocyclylcarbonyl is selected from a group of lower alkyl, the substituent group α and lower alkyl substituted with one or more substituent(s) selected from the substituent group α, and
R3a, R3b, R3c and R3d are each independently hydrogen, halogen, hydroxy, optionally substituted lower alkyl wherein the substituent(s) is selected from the substituent group α, optionally substituted lower alkenyl wherein the substituent(s) is selected from the substituent group α, optionally substituted acyl wherein acyl includes aliphatic acyl, carbocyclyl carbonyl and heterocyclic carbonyl, and the substituent(s) is selected from the substituent group α, and the substituent(s) for a moiety of the ring in carbocyclyl carbonyl and heterocyclylcarbonyl is selected from a group of lower alkyl, the substituent group α and lower alkyl substituted with one or more substituent(s) selected from the substituent group α, optionally substituted lower alkoxy wherein the substituent(s) is selected from the substituent group α, optionally substituted carbocyclyl lower alkyl wherein the substituent(s) is selected from the substituent group α, optionally substituted heterocyclyl lower alkyl wherein the substituent(s) is selected from a group of lower alkyl and the substituent group α, optionally substituted carbocyclyl lower alkoxy wherein the substituent(s) is selected from a group of lower alkyl and the substituent group α, optionally substituted heterocyclyl lower alkoxy wherein the substituent(s) is selected from a group of lower alkyl and the substituent group α, optionally substituted aralkyl wherein the substituent(s) is selected from a group of lower alkyl and the substituent group α, optionally substituted heteroaralkyl wherein the substituent(s) is selected from a group of lower alkyl and the substituent group α, optionally substituted aralkyloxy wherein the substituent(s) is selected from a group of lower alkyl and the substituent group α, optionally substituted heteroaralkyloxy wherein the substituent(s) is selected from a group of lower alkyl and the substituent group α, optionally substituted lower alkylthio wherein the substituent(s) is selected from the substituent group α, carboxy, optionally substituted lower alkoxycarbonyl wherein the substituent(s) is selected from the substituent group α, optionally substituted amino wherein the substituent(s) is selected from a group of lower alkyl, acyl, hydroxyl, lower alkoxy, lower alkoxycarbonyl, a carbocyclic group and a heterocyclic group, optionally substituted carbamoyl wherein the substituent(s) is selected from a group of lower alkyl, acyl, hydroxyl, lower alkoxy, lower alkoxycarbonyl, a carbocyclic group and a heterocyclic group, an optionally substituted carbocyclic group wherein the substituent(s) is selected from a group of lower alkyl and the substituent group a or an optionally substituted heterocyclic group wherein the substituent(s) is selected from a group of lower alkyl and the substituent group α, or

R3a and R3b or R3c and R3d may form a carbocyclic ring together with a linked carbon atom or may form oxo,
or a pharmaceutically acceptable salt.

2. The compound of claim 1,
wherein the ring A is




wherein the ring A′ is benzofuran and,
G is




wherein R5 is hydrogen, lower alkyl or acyl,
R6 is optionally substituted lower alkyl which is substituted with one of more of substituent(s) selected from the substituent group α, optionally substituted lower alkenyl which is substituted with one of more of substituent(s) selected from the substituent group α or optionally substituted lower alkynyl which is substituted with one of more of substituent(s) selected from the substituent group α,
W1 is O or S,
W2 is O, S or NR5,
Ak is optionally substituted lower alkylene wherein the substituent(s) is selected from the substituent group α, optionally substituted lower alkenylene wherein the substituent(s) is selected from the substituent group α or optionally substituted lower alkynylene wherein the substituent(s) is selected from the substituent group α,
the ring B is a carbocyclic group or a heterocyclic group, the carbocyclic group and the heterocyclic group being substituted optionally with at least one selected from the above (A) to (BC) and each R5 may be independent:
R4 is halogen, hydroxyl, mercapto, halogeno lower alkyl, lower alkoxy, amino, lower alkylamino, acylamino or lower alkylthio, n is an integer of 0 to 2, and each R4 may be independent;
or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1, wherein R1 is C1-C3 alkyl; or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1, wherein both of R2a and R2b are hydrogen; or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1, wherein all of R3a, R3b, R3c and R3d are hydrogen; or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1, wherein R3a and R3b are the same substituent selected from halogen and optionally substituted lower alkyl wherein the substituent(s) is selected from the substituent group a; or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1, wherein R3c and R3d are the same substituent selected from halogen and optionally substituted lower alkyl wherein the substituent(s) is selected from the substituent group α; or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1, wherein R3a and R3b, or R3c and R3d form a carbocyclic ring together with a linked carbon atom; or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier.

10. A method for treating a condition selected from the group consisting of Alzheimer's dementia, Down's disease, prion disease, mild cognitive impairment (MCI), Dutch-type hereditary cerebral hemorrhage with amyloidosis, cerebral amyloid angiopathy, vascular degenerated mixed dementia, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear paralysis, dementia associated with corticobasal degeneration, diffuse Lewy Bodies Alzheimer's disease, age-related macular degeneration, Parkinson's disease, or amyloid angiopathy in a subject in need thereof, comprising administering to the subject an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.