# Patent

## Title
Aminodihydrothiazine derivatives

## Abstract

A composition having BACE 1 inhibitory activity containing a compound represented by the formula (I):




    
    
        wherein ring A is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group;
        E is lower alkylene;
        X is S, O, or NR1;
        R1 is a hydrogen atom or lower alkyl;
        R2a, R2b, R3a, R3b, R4a, and R4b, is each independently a hydrogen atom, halogen, or hydroxyl etc.;
        n and m are each independently an integer of 0 to 3;
        n+m is an integer of 0 to 3;
        R5 is a hydrogen atom or substituted lower alkyl;
        its pharmaceutically acceptable salt or a solvate thereof.

## Background
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a Division of application Ser. No. 13/768,557 filed Feb. 15, 2013, which is a Division of application Ser. No. 13/243,971, filed Sep. 23, 2011, which is a Division of application Ser. No. 12/089,409, filed Apr. 7, 2008, which is a U.S. National Stage of PCT/JP2006/321015, filed Oct. 23, 2006, which applications are incorporated herein by reference.


TECHNICAL FIELD
The present invention relates to a compound which has reducing effect to produce amyloid β protein and is useful as an agent for treating disease induced by production, secretion and/or deposition of amyloid β protein.
BACKGROUND ART
In the brain of Alzheimer's patient, the peptide composed of about 40 amino acids residue as is called amyloid β protein, that accumulates to form insoluble specks (senile specks) outside nerve cells is widely observed. It is concerned that this senile specks kill nerve cells to cause Alzheimer's disease. The therapeutic agents for Alzheimer's disease, such as decomposition agents of amyloid β protein and amyloid β vaccine, are under investigation.
Secretase is an enzyme which cleaves amyloid β precursor protein (APP) in cell and produce amyloid β protein. The enzyme which controls the production of N terminus of amyloid β protein is called as BACE 1 (beta-site APP-cleaving enzyme 1, β-secretase). It is thought that inhibition of this enzyme leads to reduction of producing amyloid β protein and that the therapeutic agent for Alzheimer's disease will be created by the inhibition.
Patent Literature 1 describes the compounds which are similar to those of the present invention, and the compounds have NO synthase enzyme inhibitory activity and are useful for dementia.
Patent Literatures 2 to 4 and Non-patent Literatures 1 and 2 describe the compounds which are similar to those of the present invention, and are useful for hypertensive agent, analgesic like morphine, or tranquilizers, intermediate for medicine, analgesic respectively.
Patent Literature 5 to 13 are known as BACE 1 inhibitor, however, all compounds in these literatures have different structures from the present invention.

    [Patent Literature 1] International Patent Application Publication WO96/014842
    [Patent Literature 2] U.S. Pat. No. 3,235,551
    [Patent Literature 3] U.S. Pat. No. 3,227,713
    [Patent Literature 4] JP Application Publication H09.067355
    [Patent Literature 5] International Patent Application Publication WO01/187293
    [Patent Literature 6] International Patent Application Publication WO04/014843
    [Patent Literature 7] JP Application Publication 2004-149429
    [Patent Literature 8] International Patent Application Publication WO02/96897
    [Patent Literature 9] International Patent Application Publication WO04/043916
    [Patent Literature 10] International Patent Application Publication WO2005/058311
    [Patent Literature 11] International Patent Application Publication WO2005/097767
    [Patent Literature 12] International Patent Application Publication WO2006/041404
    [Patent Literature 13] International Patent Application Publication WO2006/041405
    [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
Problems to be Solved by the Invention
The present invention provides compounds which have reducing effects to produce amyloid β protein, especially BACE 1 inhibitory activity, and are useful as an agent for treating disease induced by production, secretion and/or deposition of amyloid β protein.
Means to Solve the Problems
The present invention provides:
(a) a composition having BACE 1 inhibitory activity containing a compound represented by the general formula (I):




wherein ring A is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group;





Alk1 is lower alkylene or lower alkenylene;

R0 is a hydrogen atom, lower alkyl or acyl;

X is S, O, or NR1;

R1 is a hydrogen atom or lower alkyl;

R2a and R2b are each independently a hydrogen atom, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted amino, optionally substituted amidino, optionally substituted acyl, optionally substituted carbamoyl, optionally substituted carbamoylcarbonyl, optionally substituted lower alkylsulfonyl, optionally substituted arylsulfonyl, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group;

R3a, R3b, R4a and R4b are each independently a hydrogen atom, halogen, hydroxy, 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;

n and m are each independently an integer of 0 to 3;

n+m is an integer of 1 to 3;

each R3a, each R3b, each R4a, and each R4b may be independently different;

R5 is a hydrogen atom, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkenyl, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group;





R5 and ring A can be taken together to form





wherein R5a and R5b are each independently a hydrogen atom or lower alkyl;

s is an integer of 1 to 4;

each R5a and each R5b may be different;

with the proviso that the compound wherein n+m is 2; R5 is a hydrogen atom; and

ring A is non-substituted phenyl is excluded,

its pharmaceutically acceptable salt, or a solvate thereof,

(a1) a composition having BACE 1 inhibitory activity containing a compound represented by the general formula (I):





wherein ring A is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group;





Alk1 is lower alkylene;

R0 is a hydrogen atom, lower alkyl or acyl;

X is S, O, or NR1;

R1 is a hydrogen atom or lower alkyl;

R2a and R2b are each independently a hydrogen atom, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted amino, optionally substituted amidino, optionally substituted acyl, optionally substituted carbamoyl, optionally substituted lower alkylsulfonyl, optionally substituted arylsulfonyl, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group;

R3a, R3b, R4a, and R4b are each independently a hydrogen atom, halogen, hydroxy, 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;

n and m are each independently an integer of 0 to 3;

n+m is an integer of 1 to 3;

each R3a, each R3b, each R4a, and each R4b may be independently different;

R5 is a hydrogen atom, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group;





R5 and ring A can be taken together to form





wherein R5a and R5b are each independently a hydrogen atom or lower alkyl;

s is an integer of 1 to 4;

each R5a and each R5b may be different;

with the proviso that the compound wherein n+m is 2; R5 is a hydrogen atom; and

ring A is non-substituted phenyl is excluded,

its pharmaceutically acceptable salt, or a solvate thereof,

(b) a composition having BACE 1 inhibitory activity according to (a), wherein X is S,

(c) a composition having BACE 1 inhibitory activity according to (a), wherein n is 2, and m is 0,

(d) a composition having BACE 1 inhibitory activity according to (a), wherein E is a bond,

(e) a compound represented by the general formula (I):





wherein each symbols are the same as described in (a), with the proviso that the compounds as shown below;

i) wherein n+m is 2, R5 is a hydrogen atom, and ring A is non-substituted phenyl;

ii) wherein n is 2, m is 0, R2a is a hydrogen atom, R2b is a hydrogen atom or acetyl, R5 is methyl, and ring A is phenyl or 4-methoxyphenyl;

iii) wherein n is 2, m is 0, R2a is a hydrogen atom, R2b is a hydrogen atom or acetyl, R5 is ethyl, and ring A is 3,4-dimethoxyphenyl;

iv) wherein n is 2, m is 0, R2a is a hydrogen atom, R2b is a hydrogen atom or acetyl, and R5 and ring A is phenyl;

v) wherein n is 2, m is 0, R2a and R2b is a hydrogen atom, R5 and ring A are taken together to form





wherein Me is methyl, and each symbols are the same as described above; and

vi) wherein n+m is 2,

R5 is a hydrogen atom,

ring A is phenyl substituted with one or two substituent(s) selected from the group of hydroxy, halogen, lower alkyl, lower alkoxy, nitro, amino, lower alkylcarbonylamino, mercapto, lower alkylthio, and carbamoyl,

non-substituted phenyl,

or non-substituted naphthyl; are excluded,

its pharmaceutically acceptable salt, or a solvate thereof,

j) the compound according to (e), wherein X is S,

its pharmaceutically acceptable salt, or a solvate thereof,

(g) the compound according to (e) or (i), wherein n is 2, and m is 0,

its pharmaceutically acceptable salt, or a solvate thereof,

(h) the compound according to any one of (e) to (g), wherein R5 is optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group,

its pharmaceutically acceptable salt, or a solvate thereof,

(i) the compound according to any one of (e) to (h), wherein R2a is a hydrogen atom;

R2b is a hydrogen atom, optionally substituted lower alkyl, optionally substituted acyl, optionally substituted lower alkylsulfonyl, or optionally substituted amidino, its pharmaceutically acceptable salt, or a solvate thereof,

(j) the compound according to any one of (e) to (h), wherein NR2aR2b is represented by the formula:





R6, R7, and R8 are each independently a hydrogen atom, lower alkyl or acyl,

Y is optionally substituted lower alkylene, optionally substituted lower alkenylene or optionally substituted lower alkenylene;

Z is O or S;

its pharmaceutically acceptable salt, or a solvate thereof,

(k) the compound according to any one of (e) to (j), wherein ring A is substituted phenyl,

its pharmaceutically acceptable salt, or a solvate thereof,

(l) the compound according to any one of (e) to (j), wherein ring A is represented by the formula:





wherein R9, R10 and R11 are hydrogen atom or G;

G is halogen, hydroxy, cyano, nitro, mercapto, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted acyl, optionally substituted acyloxy, carboxy, optionally substituted lower alkoxycarbonyl, optionally substituted lower alkoxycarbonyloxy, optionally substituted aryloxycarbonyloxy, optionally substituted amino, optionally substituted carbamoyl, optionally substituted carbamoyloxy, optionally substituted lower alkylthio, optionally substituted arylthio, optionally substituted lower alkylsulfonyl, optionally substituted arylsulfonyl, optionally substituted lower alkylsulfinyl, optionally substituted arylsulfinyl, optionally substituted lower alkylsulfonyloxy, optionally substituted arylsulfonyloxy, an optionally substituted carbocyclic group, optionally substituted carbocyclicoxy, an optionally substituted heterocyclic group or optionally substituted heterocyclicoxy;

each G may be independently different;

its pharmaceutically acceptable salt, or a solvate thereof,

(m) the compound according to (l), wherein G is represented by the formula:











Q1, Q2, and Q3 are each independently a bond, optionally substituted lower alkylene, or optionally substituted lower alkenylene;

Q4 is optionally substituted lower alkylene or optionally substituted lower alkenylene;

W1 and W2 are each independently O or S;

W3 is O, S or NR12;

R12 is a hydrogen atom, lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl, lower alkoxycarbonyl lower alkyl, carbocyclic lower alkyl or acyl;

R14 is a hydrogen atom or lower alkyl;

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

Alk2 is optionally substituted lower alkyl;

p is 1 or 2;

if there are multiple W1, multiple W3, and multiple R12, each may be independently different;

in (xii), the position of an oxygen atom may be cis or trans to a substituent R14,

its pharmaceutically acceptable salt, or a solvate thereof,

(n) the compound according to (m), wherein ring B is aryl optionally substituted with one or more substituents selected from the group of halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted acyl, optionally substituted amino, cyano, optionally substituted carbamoyl, an optionally substituted carbocyclic group, optionally substituted carbocyclicoxy or an optionally substituted heterocyclic group, or

heteroaryl optionally substituted with one or more substituents selected from the group of halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted acyl, optionally substituted amino, cyano, optionally substituted carbamoyl, an optionally substituted carbocyclic group, optionally substituted carbocyclicoxy or an optionally substituted heterocyclic group,

its pharmaceutically acceptable salt, or a solvate thereof,

(o) the compound according to (m), wherein G is represented by the formula:





wherein, each symbols are the same as described above,

its pharmaceutically acceptable salt, or a solvate thereof,

(p) the compound according to any one of (e) to (o), wherein R5 is C1 to C3 alkyl,

its pharmaceutically acceptable salt, or a solvate thereof,

(q) the compound according to any one of (e) to (o), wherein R5 is methyl,

its pharmaceutically acceptable salt, or a solvate thereof,

(r) the compound according to any one of (e) to (q), wherein

R3a and R3b are each independently a hydrogen atom, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkoxy or optionally substituted aryl,

its pharmaceutically acceptable salt, or a solvate thereof,

(s) the compound according to any one of (e) to (q), wherein

R3a and R3b are both hydrogen atoms,

its pharmaceutically acceptable salt, or a solvate thereof,

(t) a pharmaceutical composition containing the compound according to any one of (e) to (s),

its pharmaceutically acceptable salt, or a solvate thereof as an active ingredient,

(u) a composition having BACE 1 inhibitory activity containing the compound according to any one of (e) to (s),

its pharmaceutically acceptable salt, or a solvate thereof,

(v) a composition having BACE 1 inhibitory activity containing the compound according to any one of (a) to (d) or (u) as amyloid β reducing agent,

(w) a composition having BACE 1 inhibitory activity according to any one of (a) to (d), (u) or (v) as therapeutic agent for disease induced by production, secretion and/or deposition of amyloid β protein,

(x) a composition having BACE 1 inhibitory activity according to any one of (a) to (d), (u) or (v) as therapeutic agent for Alzheimer's disease.

in addition, the present invention provides:

(y) a method for treating disease induced by production, secretion and/or deposition of amyloid β protein comprising administering the compound as defined in any one of formula (I) in above (a),

its pharmaceutically acceptable salt, or a solvate thereof,

(z) use of compound as defined in any one of formula (I) in above (a),

its pharmaceutically acceptable salt, or a solvate thereof, in the manufacture of a medicament for the treatment of disease induced by production, secretion and/or deposition of amyloid β protein,

(aa) a method for treating Alzheimer's disease characterizing in administering the compound as defined in any one of formula (I) in above (a),

its pharmaceutically acceptable salt, or a solvate thereof,

(ab) use of compound as defined in any one of formula (I) in above (a),

its pharmaceutically acceptable salt, or a solvate thereof, in the manufacture of a medicament for the treatment of Alzheimer's disease.

Effect of the Invention
The compounds in this invention are useful as an agent for treating disease such as Alzheimer's disease induced by production, secretion and/or deposition of amyloid β protein.


BEST MODE FOR CARRYING OUT THE INVENTION
As used herein, the “halogen” includes fluorine, chlorine, bromine, and iodine. A halogen part of the “halogeno lower alkyl”, the “halogeno lower alkoxy”, the “halogeno acyl”, the “halogeno lower alkylthio” and the “halogeno lower alkoxycarbonyl” is the same.
The “lower alkyl” includes a straight or branched alkyl of a carbon number of 1 to 15, preferably a carbon number of 1 to 10, further preferably a carbon number of 1 to 6, and more further preferably a carbon number of 1 to 3, and examples include 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.
A lower alkyl part of the “carbocyclic lower alkyl”, the “lower alkoxy”, the “halogeno lower alkyl”, the “halogen lower alkoxy”, the “halogeno lower alkylthio”, the “hydroxy lower alkyl”, the “lower alkoxycarbonyl”, the “halogen lower alkoxycarbonyl”, the “lower alkoxycarbonyl lower alkyl”, the “lower alkoxycarbonyloxy”, the “lower alkylamino”, the “lower alkylcarbonylamino”, the “lower alkoxycarbonylamino”, the “lower alkoxy lower alkyl”, the “lower alkylcarbamoyl”, the “hydroxy lower alkylcarbamoyl”, the “amino lower alkyl”, the “hydroxy imino lower alkyl”, the “lower alkoxy imino lower alkyl”, the “lower alkylthio”, the “lower alkylsulfonyl”, the “lower alkyl sulfamoyl”, the “lower alkylsulfinyl”, the “lower alkylsulfonyloxy”, the “lower alkoxycarbonyl lower alkynyl”, the “lower alkylthio lower alkyl”, the “aryl lower alkyl”, the “aryl lower alkylamino”, the “aryl lower alkoxycarbonyl”, the “aryl lower alkylcarbamoyl”, the “heterocyclic group lower alkylamino” and the “heterocyclic group lower alkylcarbamoyl” is the same as that of the aforementioned “lower alkyl”.
The example of the “optionally substituted lower alkyl” as a substituent of ring A is lower alkyl optionally substituted with one or more substituents selected from the “substituent group α”, “hydroxyimino” and “lower alkoxyimino”; the group defined as above (i), (ii), (iv), (vi), (viii), (x) (wherein each Q1 is optionally substituted lower alkylene); the group defined as (iii), (v), (vii), (ix) (wherein Q2 is optionally substituted lower alkylene); and the group (xii).
In other “optionally substituted lower alkyl” is optionally substituted with one or more substituents selected from the “substituent group α”.
The “substituent group α” is selected from the group of halogen, hydroxy, lower alkoxy, hydroxy lower alkoxy, lower alkoxy lower alkoxy, acyl, acyloxy, carboxy, lower alkoxycarbonyl, amino, acylamino, lower alkylamino, lower alkylthio, carbamoyl, lower alkylcarbamoyl, hydroxy lower alkylcarbamoyl, sulfamoyl, lower alkylsulfamoyl, lower alkylsulfinyl, cyano, nitro, aryl, and heterocyclic group.
Especially as a substituent of the “optionally substituted lower alkyl” in Alk2, halogen, hydroxy, lower alkoxy, lower alkoxy lower alkoxy, lower alkoxycarbonyl, amino, acylamino, lower alkylamino and/or lower alkylthio are preferable.
The example of the “optionally substituted lower alkoxy” as a substituent of ring A is lower alkoxy optionally substituted with one or more substituents selected from the above “substituent group α”; above (iii) wherein Q1 is optionally substituted lower alkylene, Q2 is a bond, W2 is O; above (v) wherein Q1 is optionally substituted lower alkylene, Q2 is a bond, W3 is O; above (vi) wherein Q1 is a bond, Q2 is optionally substituted lower alkylene, W2 is O; or above (xi) wherein Q4 is optionally substituted lower alkylene, W2 is O.
In other case, the substituents of the “optionally substituted lower alkoxy”, the “optionally substituted lower alkoxycarbonyl”, the “optionally substituted lower alkoxycarbonyloxy”, the “optionally substituted lower alkylsulfonyl”, the “optionally substituted lower alkylsulfinyl”, the “optionally substituted lower alkylsulfonyloxy” and the “optionally substituted lower alkylthio” are one or more substituents selected from the “substituent group α”.
The “lower alkenyl” includes a straight or branched alkenyl of a carbon number of 2 to 15, preferably a carbon number of 2 to 10, further preferably a carbon number of 2 to 6 and more further preferably a carbon number of 2 to 4 having one or more double bonds at an arbitrary position. Specifically examples include vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodenyl, tridecenyl, tetradecenyl, and pentadecenyl.
The “lower alkynyl” includes a straight or branched alkynyl of a carbon number of 2 to 10, preferably a carbon number of 2 to 8, further preferably a carbon number of 3 to 6, having one or more triple bonds at an arbitrary position. Specifically, examples include ethynyl, propenyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, and decynyl. These may further have a double bond at an arbitrary position.
A lower alkynyl part of the “lower alkoxycarbonyl lower alkynyl” is the same as that of above “lower alkynyl”.
The example of the “optionally substituted lower alkenyl” as a substituent of ring A is lower alkenyl optionally substituted with one or more substituents selected from the above “substituent group α”; above (i), (ii), (iv), (vi), (viii) or (x), wherein Q1 is optionally substituted lower alkenylene; (iii), (v), (vii) or (ix), wherein Q2 is optionally substituted lower alkenylene.
In other case, the substituents of the “optionally substituted lower alkenyl” and the “optionally substituted lower alkynyl” are one or more substituents selected from the “substituent group α”.
The example of the “optionally substituted lower amino” as a substituent of ring A is amino optionally substituted with one or more substituents selected from the group of lower alkyl, acyl, hydroxy, lower alkoxy, lower alkoxycarbonyl, a carbocyclic group and a heterocyclic group; (ii), wherein Q1 is a bond; (iv), wherein Q1 is a bond; (v), wherein Q2 is a bond, W3 is NR12; (ix), wherein Q2 is a bond; (xiii); or (xiv).
The example of the “optionally substituted carbamoyl” as a substituent of ring A is carbamoyl optionally substituted with one or more substituents selected from the group of lower alkyl, acyl, hydroxy, lower alkoxy, lower alkoxycarbonyl, a carbocyclic group and a heterocyclic group; (i), (viii), wherein each Q1 is bond; or (xv).
In other case, the substituents of the “optionally substituted amino”, the “optionally substituted amidino”, the “optionally substituted carbamoyl”, the “optionally substituted carbamoylcarbonyl”, and the “optionally substituted carbamoyloxy” are one or two substituents selected from the group of lower alkyl, acyl, hydroxy, lower alkoxy, lower alkoxycarbonyl, a carbocyclic group and a heterocyclic group, and the like.
The “acyl” includes aliphatic acyl of a carbon number of 1 to 10, carbocyclic carbonyl and heterocyclic carbonyl. Specifically, formyl, acetyl, propyonyl, butylyl, isobutylyl, valeryl, pivaloyl, hexanoyl, acryloyl, propioloyl, methacryloyl, crotonoyl, benzoyl, cyclohexanecarbonyl, pyridinecarbonyl, furancarbonyl, thiophenecarbonyl, benzothiazolcarbonyl, pyradinecarbonyl, piperidinecarbonyl, thiomorpholinocarbonyl, and the like.
The part of the acyl of the “halogenoacyl”, the “acylamino” and the “acyloxy” is the same as the aforementioned “acyl”.
The substituent of the “optionally substituted acyl” and “optionally substituted acyloxy” is one or more substituents selected from the group of the “substituent group α”. The ring part of the “carbocyclic carbonyl” and the “heterocyclic carbonyl” is optionally substituted with one or more substituents selected from the group of “lower alkyl”; the “substituent group α”; and “lower alkyl substituted with one or more substituents selected from the group of the substituent α”.
The “carbocyclic group” includes cycloalkyl, cycloalkenyl, aryl and non-aromatic fused carbocyclic group.
The “cycloalkyl” includes a carbocyclic group of a carbon number of 3 to 10, preferably a carbon number of 3 to 8, further preferably a carbon number of 4 to 8, and examples include, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl, and the like.
The “cycloalkenyl” includes cycloalkenyl having one or more double bonds at an arbitrary position in a ring of the aforementioned cycloalkyl, and examples include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptynyl, cyclooctynyl, and cyclohexadienyl, and the like.
The “aryl” includes phenyl, naphthyl, anthryl, and phenanthryl, and the like, and phenyl is particularly preferable.
The “non-aromatic fused a carbocyclic group” includes group fused with two or more ring groups selected from the group of the above “cycloalkyl”, the “cycloalkenyl” and the “aryl”. Specifically, examples include indanyl, indenyl, tetrahydronaphthyl, and fluorenyl, and the like.
The carbocyclic part of the “carbocyclicoxy”, and the “carbocyclic lower alkyl” is the same as the aforementioned “carbocyclic group”.
The aryl part of the “aryl lower alkyl”, the “aryloxy”, the “aryloxycarbonyl”, the “aryloxycarbonyloxy”, the “aryl lower alkoxycarbonyl”, the “arylthio”, the “arylamino”, the “aryl lower alkylamino”, the “arylsulfonyl”, the “arylsulfonyloxy”, the “arylsulfinyl”, the “arylsulfamoyl”, the “arylcarbamoyl” and the “aryl lower alkylcarbamoyl” is the same as the aforementioned “aryl”.
The “heterocyclic group” includes a heterocyclic group having one or more heteroatoms arbitrary selected from O, S, and N in a ring, specifically includes a 5- to 6-membered heteroaryl such as pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furyl and thienyl; a bicyclic fused heterocyclic group such as indolyl, isoindolyl, indazolyl, indolidinyl, indolinyl, isoindolinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthridinyl, quinoxalinyl, purinyl, pteridinyl, benzopyranyl, benzimidazolyl, benzioxazolyl, benzoxazolyl, benzoxadiazolyl, benzoisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, pyrazolopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, quinazolinyl, quinolyl, isoquinolyl, naphthyridinyl, dihydrobenzofuryl, tetrahydroquinolyl, tetrahydroisoquinolyl, dihydrobenzoxazine, tetrahydrobenzothienyl; a tricyclic fused heterocyclic group such as carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, dibenzofuryl, and imidazoquinolyl; a non-aromatic heterocyclic group such as dioxanyl, thiiranyl, oxyranyl, oxathioranyl, azethidinyl, thianyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, dihydropyridyl, dihydrobenzoimidazolyl, tetrahydropyridyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, dihydroxadinyl, hexahydroazepinyl, tetrahydroazepyinyl. Preferable is a 5- to 6-membered heteroaryl, or a non-aromatic heterocyclic group.
The heterocyclic part of the “heterocyclicoxy”, the “heterocyclic thio”, the “heterocyclic carbonyl”, the “heterocyclic amino”, the “heterocyclic carbonylamino”, the “heterocyclic sulfamoyl”, the “heterocyclic sulfonyl”, the “heterocyclic carbamoyl”, the “heterocyclicoxycarbonyl”, the “heterocyclic lower alkylamino” and the “heterocyclic lower alkyl carbamoyl” is the same as the aforementioned “heterocyclic group”.
The example of the substituent of the “optionally substituted carbocyclic group” and the “optionally substituted heterocyclic group” in ring A is; the substituent α, wherein preferable is for example, halogen, hydroxy, acyl, acyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, amino, lower alkylamino, lower alkylthio;
lower alkyl substituted with one or more substituents selected from the group of substituent α, wherein preferable is halogen, hydroxy, lower alkoxy, lower alkoxycarbonyl, and the like;
amino lower alkyl substituted with one or more substituents selected from the group of substituent α, wherein preferable is acyl, lower alkyl and for lower alkoxy, and the like;
hydroxyimino lower alkyl; lower alkoxyimino lower alkyl;
lower alkenyl substituted with one or more substituents selected from the group of substituent α, wherein preferable is lower alkoxycarbonyl, halogen and for halogeno lower alkoxycarbonyl, and the like;
lower alkynyl substituted with one or more substituents selected from the group of substituent α, wherein preferable is for example, lower alkoxycarbonyl,
lower alkoxy substituted with one or more substituents selected from the group of substituent α, wherein preferable is for example, lower alkyl carbamoyl and for hydroxy lower alkyl carbamoyl,
lower alkylthio substituted with one or more substituents selected from the group of substituent α,
lower alkylamino substituted with one or more substituents selected from the group of substituent α,
lower alkylsulfonyl substituted with one or more substituents selected from the group of substituent α,
aryl lower alkoxycarbonyl substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl,
acyl substituted with one or more substituents selected from the group of substituent α,
cycloalkyl substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl,
lower alkylsulfinyl substituted with one or more substituents selected from the group of substituent α,
sulfamoyl,
aryl substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl,
heterocyclic group substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl,
aryloxy substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl,
heterocyclicoxy substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl,
arylthio substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl,
heteroarylthio substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl,
arylamino substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl,
heterocyclicamino substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl,
aryl lower alkylamino substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl,
heterocyclic lower alkylamino substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl,
lower alkyl sulfamoyl substituted with one or more substituents selected from the group of substituent α,
aryl sulfamoyl substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl,
heterocyclic sulfamoyl substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl,
arylsulfonyl substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl,
heterocyclic sulfonyl substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl,
aryl carbamoyl substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl,
heterocyclic carbamoyl substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl,
aryl lower alkylcarbamoyl substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl,
heterocyclic lower alkylcarbamoyl substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl,
aryloxycarbonyl substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl,
heterocyclicoxycarbonyl substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl,
lower alkylenedioxy optionally substituted with halogen; oxo; azido;










wherein Q1, Q2 and Q3 are each independently a bond, optionally substituted lower alkylene or optionally substituted lower alkenylene;

Q4 is optionally substituted lower alkylene or optionally substituted lower alkenylene;

W1 and W2 are each independently O or S;

W3 is O, S or NR12;

R12 is a hydrogen atom, lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl, lower alkoxycarbonyl lower alkyl, carbocyclic group lower alkyl or acyl;

R14 is a hydrogen atom or lower alkyl;

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

Alk2 is optionally substituted lower alkyl;

and the ring A is optionally substituted with one or more substituents selected from these groups.

If there are multiple W1, multiple W3, and multiple R12, each may be independently different.
In addition, an oxygen atom in (xii) may be cis or trans position to the substituent R14.
The substituent of the “substituted phenyl” is, in the same way, phenyl substituted with one or two substituents selected preferably from the group of the substituent α or (i) to (xv).
The substituent of the “optionally substituted carbocyclic group” or the “optionally substituted heterocyclic group” in ring B is optionally substituted with one or more substituents selected from the following group of, for example;
the substituent α, wherein preferable is halogen, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, acyl, amino, lower alkylamino, acylamino, carbamoyl, lower alkylcarbamoyl, cyano, and nitro, and the like;
lower alkyl substituted with one or more substituents selected from the group of the substituent α, wherein preferable is halogen, hydroxy, and lower alkoxy, and the like;
amino lower alkyl, hydroxyimino lower alkyl, or lower alkoxyimino lower alkyl, substituted with one or more substituents selected from the group of substituent α;
lower alkenyl substituted with one or more substituents selected from the group of substituent α;
lower alkynyl substituted with one or more substituents selected from the group of substituent α;
lower alkoxy substituted with one or more substituents selected from the group of substituent α, wherein preferable is halogen, hydroxy, and the like;
lower alkylthio substituted with one or more substituents selected from the group of substituent α, wherein preferable is halogen;
lower alkylamino substituted with one or more substituents selected from the group of substituent α, wherein preferable is amino;
lower alkylsulfonyl substituted with one or more substituents selected from the group of substituent α;
aryl lower alkoxycarbonyl substituted with one or more substituents selected from the group of substituent α and lower alkyl;
acyl substituted with one or more substituents selected from the group of substituent α, wherein preferable is halogen;
lower alkylsulfonyl substituted with one or more substituents selected from the group of substituent α;
sulfamoyl;
lower alkyl sulfamoyl substituted with one or more substituents selected from the group of substituent α;
cycloalkyl substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
aryl substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
heterocyclic group substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl, wherein preferable is halogen, lower alkyl, and the like;
aryloxy substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
heterocyclicoxy substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
arylthio substituted with one pr more substituents selected from the group of substituent α, azido and lower alkyl, wherein preferable is halogen, hydroxy, lower alkoxy, acyl, and the like;
heterocyclic thio substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
arylamino substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl, wherein preferable is halogen, hydroxy, lower alkoxy, acyl;
heterocyclic amino substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
aryl lower alkylamino substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl, wherein preferable is halogen, hydroxy, lower alkoxy, acyl;
heterocyclic lower alkylamino substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
arylsulfamoyl substituted with one or more substituents selected from the group of substituent α azido and lower alkyl;
heterocyclic sulfamoyl substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
arylsulfonyl substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
heterocyclic sulfonyl substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
arylcarbamoyl substituted with one or more substituents selected from the group of substituent α, ado and lower alkyl;
heterocyclic carbamoyl substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
aryl lower alkylcarbamoyl substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
heterocyclic lower alkylcarbamoyl substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
aryloxy carbonyl substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
heterocyclicoxycarbonyl substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
lower alkylenedioxy optionally substituted with halogen; oxo; and the like.
In other case, the substituent of the “optionally substituted carbocyclic group”, the “optionally substituted heterocyclic group”, the “optionally substituted carbocyclicoxy”, the “optionally substituted arylsulfonyl”, the “optionally substituted aryloxycarbonyloxy”, the “optionally substituted heterocyclicoxy”, the “optionally substituted arylsulfinyl”, the “optionally substituted arylsulfonyloxy”, the “optionally substituted arylthio” is one or more substituents selected from the group of “lower alkyl” and the “substituent α”.
“heteroaryl” include aromatic ring group in the aforementioned “heterocyclic group”.
The substituent of the “optionally substituted 5- to 6-membered heteroaryl” is the same as the substituent of the “optionally substituted heterocyclic group” in the aforementioned “ring B”. Preferable is one or more substituent selected from lower alkyl and a substituent α.
The “lower alkylene” includes a straight or branched bivalent carbon chain of a carbon number of 1 to 10, preferably a carbon number of 1 to 6, further preferably a carbon number of 1 to 3. Specifically, examples include methylene, dimethylene, trimethylene, teteramethylene, and methyltrimethylene, and the like.
The part of lower alkylene of the “lower alkylenedioxy” is the same as the aforementioned “lower alkylene”.
The “lower alkenylene” includes a straight or branched bivalent carbon chain of a carbon number of 2 to 10, preferably a carbon number of 2 to 6, further preferably a carbon number of 2 to 4 having double bond at an arbitrary position. Specifically, examples include vinylene, propenylene, butenylene, butadienylene, methylpropenylene, pentenylene, and hexenylene, and the like.
The “lower alkynylene” includes a straight or branched bivalent carbon chain of a carbon number of 2 to 10, preferably a carbon number of 2 to 6, further preferably a carbon number of 2 to 4 having triple bond at an arbitrary position. Specifically, examples include ethynylene, propynylene, butynylene, pentynylene, and hexynylene, and the like.
The substituent of the “optionally substituted lower alkylene”, the “optionally substituted lower alkenylene”, the “optionally substituted lower alkynylene” is the substituent α, preferable is halogen, hydroxy and the like.
The “each R3a, each R3b, each R4a, and each R4b may be independently different” means when n is 2 or 3, two or three R3a may be independently different, and two or three R3b may be independently different. In the same way, when m is 2 or 3, two or three R4a may be independently different, and two or three R4b may be independently different.




R5 and ring A can be taken together to form





means for example, include the following structures.





wherein each symbols are the same as described above;

preferably, R5a and R5b are all hydrogen atoms.

In this description, “solvate” includes, for example, a solvate with an organic solvent and a hydrate, and the like. When hydrate is formed, arbitrary number of water molecules may be coordinated.
The compound (I) includes a pharmaceutically acceptable salt. Examples include salts with alkali metals (lithium, sodium or potassium, and the like), alkaline earth metals (magnesium or calcium, and the like), ammonium, organic bases or amino acids, and salts with inorganic acids (hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid or hydroiodic acid, and the like), and organic acid (acetic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, manderic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, or ethanesulfonic acid, and the like). Particularly, hydrochloric acid, phosphoric acid, tartaric acid, or methanesulfonic acid is preferable. These salts can be formed by a conventional method.
In addition, the compound (I) is not limited to a specific isomer, but includes all possible isomers (keto-enol isomer, imine-enamine isomer, diastereo isomer, optical isomer, and rotational isomer, and the like) and racemates. For example, the compound (I), wherein R2a is a hydrogen atom, includes following tautomer.




The compound (I) in this invention can be prepared by the process described in, for example Non-patent Document 1 or following process.
The synthesis of aminodihydrothiazine ring; Method A




In formula, at least either R2b or R2c is a hydrogen atom, either R8c or R3d is each independently a hydrogen atom, halogen, hydroxy, 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. Other symbols are the same as described above.
(Step 1)
To a solution of compound (a), which is commercially available or prepared by known method, in appropriate solvent or mixture of solvents, such as ether, tetrahydrofuran, and the like is added the Grignard reagent having substituent corresponds to the target compound; for example vinylmagnesium chloride, vinylmagnesium bromide, or propenylmagnesium bromide, and the like; at −100° C. to 50° C., preferably −80° C. to 0° C. The mixture is reacted for 0.2 to 24 hours, preferably 0.5 to 5 hours, to obtain compound (b).
(Step 2)
The compound (b) in solvent, such as toluene or absence of solvent is treated with thiourea derivatives having substituent corresponds to the target compound, such as thiourea, N-methylthiourea, N,N′-dimethylthiourea, and the like in the presence of an acid or mixture of acids, such as acetic acid, trifluoroacetic acid, hydrochloric acid, or sulfuric acid, and the like. The mixture is reacted at −20° C. to 100° C., preferably 0° C. to 50° C. for 0.5 to 120 hours, preferably 1 to 72 hours, to obtain the compound (c).
(Step 3)
The compound (c) in solvent, such as toluene or absence of solvent is treated with an acid or mixture of acids, such as trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, and the like. The mixture is reacted at −20° C. to 100° C., preferably 0° C. to 60° C. for 0.6 to 120 hours, preferably 1 to 72 hours, to obtain the compound (I-2), wherein R2b is a hydrogen atom, or the compound (I-1), wherein R2c is a hydrogen atom.
The synthesis of aminodihydrothiazine ring; Method B




In formula, L is leaving group such as halogen or sulfonyloxy, and the like. Other symbols are the same as described above.
(Step 1)
The compound (d) which is commercially available or prepared by known method is reacted with thiocyanic acid; for example, sodium thiocyanic acid, ammonium thiocyanic acid, and the like; in solvent; for example, toluene, chloroform, tetrahydrofuran, and the like; in the presence of acid; for example, water, hydrochloric acid, sulfuric acid, and the like; at 0° C. to 150° C., preferably 20° C. to 100° C. for 0.5 to 24 hours, preferably 1 to 12 hours, to obtain the compound (e).
(Step 2)
To the compound (e) in solvent or mixture of solvents; for example, tetrahydrofuran, methanol, ethanol, water, and the like; in the presence or the absence of buffer like sodium dihydrorgen phosphate, and the like; reducing agent; for example sodium borohydride, and the like; is added and the mixture is reacted at −80° C. to 50° C., preferably −20° C. to 20° C. for 0.1 to 24 hours, preferably 0.5 to 12 hours, to obtain the compound (f).
(Step 3)
The compound (f) in the presence or the absence of solvent; for example, toluene, dichloromethane, and the like; is reacted with halogenating agent; for example thionyl chloride, phosphorus oxychloride, carbon tetrabromide-triphenylphosphine, and the like; at −80° C. to 50° C., preferably −20° C. to 20° C. for 0.1 to 24 hours, preferably 0.5 to 12 hours, to obtain the compound (g). Alternatively, the compound (f) in the presence or the absence of solvent; for example, toluene, dichloromethane, and the like; under base; for example triethylamine, and the like; is reacted with sulfonating agent; for example, methanesulfonyl chloride, p-toluenesulfonylchloride, and the like; at −80° C. to 50° C., preferably −20° C. to 20° C. for 0.1 to 24 hours, preferably 0.5 to 12 hours, to obtain the compound (g).
(Step 4)
To the compound (g) in solvent or mixture of solvents, for example methanol, ethanol, water, and the like; is reacted with primary amine; for example, ammonia or methylamine, and the like; at −20° C. to 80° C., preferably 0° C. to 40° C. for 0.5 to 48 hours, preferably 1 to 24 hours, to obtain the compound (I-3).
The synthesis of aminodihydrothiazine ring; Method C




In formula, R is a hydrogen atom or protective groups of carboxyl group. Other symbols are the same as described above.
(Step 1)
The compound (h) which is commercially available or prepared by known method is reacted with reducing agent; for example, lithium aluminium hydride, diisobutyl aluminium hydride, and the like; in solvent; for example tetrahydrofuran, ether, and the like; at −80° C. to 150° C., preferably 25° C. to 100° C. for 0.1 to 24 hours, preferably 0.5 to 12 hours, to obtain the compound (i).
(Step 2)
The compound (i) in solvent; for example, toluene, chloroform, tetrahydrofuran, and the like; in the presence or the absence of base; for example, diisopropylethylamine, triethylamine, pyridine, sodium hydroxide, and the like; is reacted with corresponding isothiocyanate; for example, 4-methoxybenzylisothiocyanate, t-butylisothiocyanate, and the like; or corresponding thiocarbamoylhalide; for example, N,N-dimethylthiocarbamoylchloride, N,N-diethylthiocarbamoylchloride, and the like; at 0° C. to 150° C., preferably 20° C. to 100° C. for 0.5 to 120 hours, preferably 1 to 72 hours, to obtain the compound (j).
(Step 3)
The compound (j) in solvent; for example, acetonitrile, toluene, dichloromethane, and the like; is reacted with halogenating agent; for example thionyl chloride, phosphorus oxychloride, carbon tetrabromide-triphenylphosphine, and the like; at −80° C. to 50° C., preferably −20° C. to 20° C. for 0.1 to 24 hours, preferably 0.5 to 12 hours, or alternatively, the compound (j) in solvent; for example, toluene, dichloromethane, and the like; in the presence of base; for example triethylamine, and the like; is reacted with sulfonating agent; for example, methanesulfonyl chloride, p-toluenesulfonylchloride, and the like; at −80° C. to 50° C., preferably −20° C. to 20° C. for 0.1 to 24 hours, preferably 0.5 to 12 hours. The obtained halogenated compound or sulfonylated compound is reacted with base; for example, diisopropylamine, potassium carbonate, sodium hydrogencarbonate, sodium hydride, sodium hydroxide, and the like; at 0° C. to 150° C., preferably 20° C. to 100° C. for 0.5 to 120 hours, preferably 1 to 72 hours, to obtain the compound (I-4).
The synthesis of aminodihydrothiazine ring; Method D
The synthesis of aminothiazoline ring; Method A
The synthesis of tetrahydrothiazepine ring; Method A




In formula, L is leaving group such as halogen or sulfonyloxy, and the like; m is an integer of 1 to 3; and the other symbols are the same as described above.
(Step 1)
The compound (k) which is commercially available or prepared by known method is reacted with azide reagent; for example, sodium azide, and the like; in solvent; for example N,N-dimethylformamide, tetrahydrofuran, and the like; at 0° C. to 200° C., preferably 40° C. to 150° C. for 0.5 to 24 hours, preferably 1 to 12 hours, to obtain the compound (l).
(Step 2)
The compound (l) is reacted with reducing agent; for example, lithium aluminium hydride, diisobutyl aluminium hydride, and the like; in solvent; for example tetrahydrofuran, ether, and the like; at −80° C. to 150° C., preferably 25° C. to 100° C. for 0.1 to 24 hours, preferably 0.5 to 12 hours, to obtain the compound (m).
(Step 3)
The compound (m) in solvent; for example, toluene, chloroform, tetrahydrofuran, and the like; is reacted with corresponding isothiocyanate; for example, methylisothiocyanate, ethylisothiocyanate, and the like; or corresponding thiocarbamoylhalide; for example, N,N-dimethylthiocarbamoylchloride, N,N-diethylthiocarbamoylchloride, and the like; at 0° C. to 150° C., preferably 20° C. to 100° C. for 0.5 to 120 hours, preferably 1 to 72 hours, to obtain the compound (n).
(Step 4)
The compound (n) in solvent; for example, acetonitrile, toluene, dichloromethane and the like; is reacted with halogenating agent; for example thionyl chloride, phosphorus oxychloride, carbon tetrabromide-triphenylphosphine, and the like; at −80° C. to 50° C., preferably −20° C. to 20° C. for 0.1 to 24 hours, preferably 0.5 to 12 hours, or alternatively, the compound (n) in solvent; for example, toluene, dichloromethane, and the like; in the presence of base; for example diisopropylethylamine, triethylamine, and the like; is reacted with sulfonating agent; for example, methanesulfonyl chloride, p-toluenesulfonylchloride, and the like; at −80° C. to 50° C., preferably −20° C. to 20° C. for 0.1 to 24 hours, preferably 0.5 to 12 hours. The obtained halogenated compound or sulfonylated compound is reacted with base; for example, diisopropylamine, potassium carbonate, sodium hydrogencarbonate, sodium hydride, sodium hydroxide, and the like; at 0° C. to 150° C., preferably 20° C. to 100° C. for 0.5 to 120 hours, preferably 1 to 72 hours, to obtain the compound (I-5).
The synthesis of aminodihydrothiazine ring; Method E
The synthesis of aminothiazoline ring; Method B
The synthesis of tetrahydrothiazepine ring; Method B




In formula, at least one of R2b and R2c is a hydrogen atom, n is an integer of 1 to 3, and the other symbols are the same as described above.
(Step 1)
The compound (o) which is commercially available or prepared by known method is reacted with substituted thiourea; for example, thiourea, N-methylthiourea, N,N,-dimethylthiourea, N,N′-dimethylthiourea, and the like; in solvent; for example, ethanol, methanol, tetrahydrofuran, toluene, and the like; at 20° C. to 200° C., preferably 0° C. to 150° C. for 0.5 to 200 hours, preferably 1 to 120 hours, to obtain the compound (p).
(Step 2)
To the compound (p) in solvent or mixture of solvents; for example, ether, tetrahydrofuran, and the like; the Grignard reagent having substituent corresponding to target compound; for example methylmagnesium chloride, ethylmagnesium bromide, or benzylmagnesium bromide, and the like; is added at −100° C. to 50° C., preferably −80° C. to 30° C., and the mixture is reacted for 0.2 to 24 hours, preferably 0.5 to 5 hours, to obtain the compound (q).
(Step 3)
To the compound (q) in the presence or the absence of solvent; for example, toluene, and the like; acid or mixture of acids, such as trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, and the like; is added and the mixture is reacted at −20° C. to 100° C., preferably 0° C. to 50° C. for 0.5 to 200 hours, preferably 1 to 150 hours, to obtain the compound (I-6) (wherein R2c is H), or the compound (I-7) (wherein R2b is H).
The synthesis of aminodihydrothiazine ring; Method F




In formula, each symbols are the same as described above.
(Step 1)
The compound (r) which is commercially available or prepared by known method is reacted with ammonium chloride in solvent; for example, acetic acid, and the like; at 0° C. to 200° C., preferably 10° C. to 100° C. for 0.1 to 100 hours, preferably 0.5 to 24 hours, to obtain the compound (s).
(Step 2)
The compound (s) is reacted with reducing agent; for example, lithium aluminium hydride, diisobutyl aluminium hydride, and the like; in solvent; for example tetrahydrofuran, ether, and the like; at −80° C. to 150° C., preferably 0° C. to 100° C. for 0.1 to 24 hours, preferably 0.5 to 12 hours, to obtain the compound (t).
(Step 3)
The compound (t) in solvent; for example, toluene, chloroform, tetrahydrofuran, and the like; in the presence or the absence of base; for example, diisopropylethylamine; triethylamine, pyridine, sodium hydroxide, and the like; is reacted with corresponding isothiocyanate; for example, 4-methoxybenzylisothiocyanate, t-butylisothiocyanate, and the like; or corresponding carbamoylhalide; for example, N,N-dimethylthiocarbamoylchloride, N,N-diethylthiocarbamoylchloride, and the like; at 0° C. to 150° C., preferably 20° C. to 100° C. for 0.5 to 120 hours, preferably 1 to 72 hours, to obtain the compound (u).
(Step 4)
The compound (u) in solvent; for example, acetonitrile, toluene, dichloromethane, and the like; is reacted with halogenating agent; for example thionyl chloride, phosphorus oxychloride, carbon tetrabromide-triphenylphosphine, and the like; at −80° C. to 50° C., preferably −20° C. to 20° C. for 0.1 to 24 hours, preferably 0.5 to 12 hours, or alternatively, the compound (u) in solvent; for example, toluene, dichloromethane, and the like; in the presence of base; for example triethylamine, and the like; is reacted with sulfonating agent; for example, methanesulfonyl chloride, p-toluenesulfonylchloride, and the like; at −80° C. to 50° C., preferably −20° C. to 20° C. for 0.1 to 24 hours, preferably 0.5 to 12 hours. The obtained halogenated compound or sulfonylated compound is reacted with base; for example, diisopropylamine, potassium carbonate, sodium hydrogencarbonate, sodium hydride, sodium hydroxide, and the like; at 0° C. to 150° C., preferably 20° C. to 100° C. for 0.5 to 120 hours, preferably 1 to 72 hours, to obtain the compound (I-8).
The synthesis of aminodihydrooxazine ring; Method A
The synthesis of aminotetrahydrooxazepine ring; Method A




In formula, each symbols are the same as described above.
(Step 1)
The compound (n) which is obtained by Step 3 (the compound (m) to the compound (n)) of “The synthesis of aminodihydrothiazine ring; Method D”, in solvent; for example, methanol, ethanol, N,N-dimethylformamide, tetrahydrofuran, and the like; in the presence or the absence of base; for example, diisopropylethylamine, triethylamine, pyridine, sodium hydroxide, and the like; is reacted with alkylating agent; for example, methyl iodide, dimethyl sulfate, benzyl bromide, and the like; at 0° C. to 200° C., preferably 40° C. to 150° C. for 0.1 to 48 hours, preferably 0.5 to 24 hours, to obtain the compound (v).
(Step 2)
The compound (v) in solvent; for example, N,N-dimethylformamide, tetrahydrofuran, dichloromethane, and the like; in the presence or the absence of base; for example, diisopropylethylamine, triethylamine, pyridine, sodium hydroxide, and the like; is reacted with metallic oxide; for example, silver oxide, mercury oxide, manganese dioxide, and the like; at 0° C. to 200° C., preferably 10° C. to 160° C. for 1 to 120 hours, preferably 0.5 to 100 hours, to obtain the compound (I-9).
The synthesis of aminodihydrooxazine ring; Method B
The synthesis of aminoxazoline ring
The synthesis of aminotetrahydrooxazepine ring; Method B




In formula, R15 is optionally substituted lower alkyl; for example, t-butyl, benzyl, and the like; R16 is hydrogen atom or lower alkyl; n is an integer of 1 to 3, and the other symbols are the same as described above.
(Step 1)
The compound (w) which is commercially available or prepared by known method in solvent; for example, toluene, t-butylalcohol, tetrahydrofuran, and the like; in the presence of base; for example, diisopropylethylamine, triethylamine, pyridine, and the like; is reacted with azide reagent; for example, diphenyl phosphoryl azide, and the like; at 0° C. to 200° C., preferably 40° C. to 150° C. for 1 to 48 hours, preferably 0.5 to 24 hours, to obtain the compound (x).
(Step 2)
The compound (x) in solvent; for example, toluene, xylene, N,N-dimethylformamide, tetrahydrofuran, and the like; is reacted with alcohol; for example, t-butylalcohol, 3,4-dimethoxybenzylalcohol, 4-methoxybenzylalcohol, and the like; at 0° C. to 300° C., preferably 50° C. to 200° C. for 1 to 800 hours, preferably 5 to 500 hours, to obtain the compound (y).
(Step 3)
The compound (y) in the presence or the absence of solvent; for example, water, toluene, dichloromethane, methanol, 1,4-dioxane, acetic acid, ethyl acetate, and the like; in the presence of acid; for example, hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid, and the like; at 0° C. to 200° C., preferably 25° C. to 150° C. for 0.1 to 48 hours, preferably 0.5 to 24 hours, to obtain the compound (z).
(Step 4)
The compound (z) in solvent; for example, toluene, chloroform, tetrahydrofuran, and the like; in the presence of base; for example, diisopropylethylamine, triethylamine, pyridine, and the like; is reacted with corresponding isothiocyanate, or thiocarbamoylhalide corresponding to target compound; for example, N,N-dimethylthiocarbamoylchloride, N,N-diethylthiocarbamoylchloride, and the like; at 0° C. to 150° C., preferably 20° C. to 100° C. for 0.5 to 120 hours, preferably 1 to 72 hours, to obtain the compound (aa).
(Step 5)
The compound (aa) in solvent; for example, methanol, ethanol, N,N-dimethylformamide, tetrahydrofuran, and the like; in the presence or the absence of base; for example, diisopropylethylamine, triethylamine, pyridine, sodium hydroxide, and the like; is reacted with alkylating agent; for example, methyl iodide, dimethyl sulfate, benzyl bromide, and the like; at 0° C. to 200° C., preferably 40° C. to 150° C. for 1 to 48 hours, preferably 0.5 to 24 hours, to obtain the compound (ab).
(Step 6)
The compound (ab) in solvent; for example, N,N-dimethylformamide, tetrahydrofuran, dichloromethane, and the like; in the presence of base; for example, diisopropylethylamine, triethylamine, pyridine, sodium hydroxide, and the like; is reacted with metallic oxide; for example, silver oxide, mercury oxide, manganese dioxide, and the like; at 0° C. to 200° C., preferably 10° C. to 150° C. for 1 to 120 hours, preferably 0.5 to 100 hours, to obtain the compound (I-10).
The synthesis of aminotetrahydropyrimidine ring




In formula, each symbols are the same as described above.
(Step 1)
To the compound (ac) prepared by known method in solvent; for example, N,N-dimethylformamide, methanol, and the like; is reacted with azide reagent; for example, sodium azide, lithium azide, and the like; at 20° C. to 150° C., preferably 50° C. to 100° C. for 0.5 to 120 hours, preferably 1 to 72 hours, to obtain the compound (ad).
(Step 2)
To the suspension of lithium aluminium hydride in solvent; for example, tetrahydrofuran, or ether, and the like; the compound (ad) dissolved in solvent; for example, tetrahydrofuran, or diethyl ether, and the like; is added under nitrogen atmosphere, at −80° C. to 20° C., preferably −30° C. to 0° C., and the mixture is reacted for 1 minute to 10 hours, preferably 10 minutes to 1 hour, or alternatively to the compound (ad) in solvent; for example, ethanol, isopropanol, or n-butanol, and the like; Raney-Nickel is added at 10° C. to 110° C., preferably 50° C. to 80° C., and reacted for 1 minute to 10 hours, preferably 10 minutes to 1 hour, to obtain the compound (ae).
(Step 3)
The compound (ae) in solvent; for example, tetrahydrofuran, dichloromethane, and the like; in the presence of acid; for example, acetic acid, or propionic acid, and the like; is reacted with reducing agent; for example, sodium cyanoborohydride, sodium triacetoxyborohydride, and the like; at −50° C. to 100° C., preferably 0° C. to 50° C., for 0.1 to 48 hours, preferably 0.5 to 24 hours, or the compound (ae) in solvent; for example, tetrahydrofuran, N,N-dimethylformamide, and the like; in the presence of dehydrating agent; for example, 1-ehthyl-3-(3-dimethylaminopropyl)carbodiimide-N-hydroxybenzotriazole, carbonyldiimidazole, and the like; or in the presence of base; for example, triethylamine, potassium carbonate, and the like; is reacted with carboxylic acid; for example, formic acid, acetic acid, and the like; at −50° C. to 100° C., preferably 0° C. to 50° C. for 0.1 to 48 hours, preferably 0.5 to 16 hours, to obtain the compound (af). And next, to the suspension of lithium aluminium hydride in solvent; for example, tetrahydrofuran, or diethyl ether, and the like; the aforementioned amide compound dissolved in solvent; for example, tetrahydrofuran, or ether, and the like; is added at −50° C. to 60° C., preferably 0° C. to 50° C., and the mixture is reacted for 1 minute to 48 hours, preferably 10 minutes to 10 hours, to obtain the compound (af).
(Step 4)
The compound (ae) or the compound (af) in solvent; for example, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, and the like; is reacted with 3,5-dimethylpyrazole-1-carboxyamidine or S-methylthiourea at 0° C. to 150° C., preferably 20° C. to 100° C., and the mixture is reacted for 0.5 to 120 hours, preferably 1 to 24 hours, to obtain the compound (ag).
(Step 5)
To the compound (ag) (wherein at least either R2b or R2c is a hydrogen atom) in the presence or the absence of solvent; for example, toluene, and the like; acid; for example, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, and the like, or the mixture thereof; is added and the mixture is reacted at −20° C. to 100° C., preferably 0° C. to 50° C., and the mixture is reacted for 0.5 to 120 hours, preferably 1 to 72 hours, to obtain the compound (I-2) (wherein R2b is a hydrogen atom) or the compound (I-1) (wherein R2c is a hydrogen atom) respectively. Proviso, if R2a, R2b, and R2c have fragile structure under acidic condition; for example, t-butyloxycarbonyl, and the like; R2a, R2b, and R2c in the compound (I-1) or the compound (I-2) may be transformed into a hydrogen atom.
The synthesis of aminothiazoline ring; Method C




In formula, Hal is halogen, and other symbols are the same as described above.
(Step 1)
The compound (ah) which is commercially available or prepared by known method in solvent; for example, toluene, chloroform, tetrahydrofuran, and the like; or in mixed-solvent; for example, chloroform-water, and the like; is reacted with halogen; for example, including iodine, bromine, chorine; phase transfer catalyst; for example, sodium thiocyanic acid, ammonium thiocyanic acid, and the like; at 0° C. to 150° C., preferably 20° C. to 100° C., for 0.5 to 48 hours, preferably 1 to 24 hours, to obtain the compound (ai).
(Step 2)
The compound (ai) in solvent; for example, toluene, chloroform, tetrahydrofuran, and the like; is reacted with amine having substituent corresponding to target compound; for example ammonia, methylamine, diethylamine, and the like; at 0° C. to 150° C., preferably 20° C. to 100° C., for 0.5 to 48 hours, preferably 1 to 24 hours, to obtain the compound (I-11).
The aminoacyl derivative-1




In formula, R17 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.
The compound (I-12) wherein R2b is a hydrogen atom in the presence or the absence of solvent; for example, tetrahydrofuran, dichloromethane, and the like; in the presence of base; for example, pyridine, triethylamine, and the like; is reacted with acylating agent having substituent corresponding to target compound; for example, benzoyl chloride, 2-furoyl chloride, acetic anhydride, and the like; at −80° C. to 100° C., preferably −20° C. to 40° C., for 0.1 to 24 hours, preferably 1 to 12 hours, or alternatively, the compound (I-12) in solvent; for example, N,N-dimethylformamide, tetrahydrofuran, dichloromethane, and the like; in the presence of dehydrating agent; for example, dicyclohexylcarbodiimide, carbonyldiimidazole, and the like; is reacted with carboxylic acid having substituent corresponding to target compound; for example, amino acid, glycolic acid, and the like; at −80° C. to 100° C., preferably −20° C. to 40° C., for 0.1 to 24 hours, preferably 1 to 12 hours, to obtain the compound (I-13) and/or the compound (I-14) (wherein R2a is a hydrogen atom).
The guanidino derivatives




In formula, each symbols are the same as described above.
The compound (I-12) wherein R2b is a hydrogen atom in solvent; for example, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, and the like; in the presence or the absence of base; for example, triethylamine, sodium hydrogencarbonate, and the like; is reacted with 3,5-dimethylpyrazole-1-carboxyamidine, or S-methylisothiourea etc. at 0° C. to 150° C., preferably 20° C. to 100° C., for 0.5 to 120 hours, preferably 1 to 24 hours, to obtain the compound (I-15).
The carbamoyl derivatives




In formula, CONR18R19 is optionally substituted carbamoyl, and the other symbols axe the same as described above.
The compound (I-16) having a carboxyl group as substituent of ring A in solvent; for example, N,N-dimethylformamide, tetrahydrofuran, dichloromethane, and the like; in the presence of dehydrating agent; for example, dicyclohexylcarbodiimide, carbonyldiimidazole, dicyclohexylcarbodiimide-N-hydroxybenzotriazole, and the like; is reacted with primary amine or secondary amine (aniline, 2-aminopyridine, dimethylamine etc.) at −80° C. to 100° C., preferably −20° C. to 40° C., for 0.1 to 24 hours, preferably 1 to 12 hours, to obtain the compound (I-17).
The acylamino derivative-2




In formula, NHR20 is optionally substituted amino; NR20COR21 is optionally substituted acyl amino, optionally substituted ureido, carboxy amino having substituent on oxygen atom, and the other symbols are the same as described above.
The compound (I-18) having an optionally substituted amino group on ring A in the presence or the absence of solvent; for example, tetrahydrofuran, dichloromethane, and the like; in the presence or the absence of base; for example, pyridine, triethylamine, and the like; is reacted with reagent including acid chloride, acid anhydride, chloroformate ester derivatives, isocyanate derivatives (benzoyl chloride, 2-furoyl chloride, acetic anhydride, benzyl chloroformate, di-t-butyl dicarbonate, phenyl isocyanate etc.), at −80° C. to 100° C., preferably −20° C. to 40° C., for 0.1 to 24 hours, preferably 1 to 12 hours. Or alternatively, the compound (I-18) having an optionally substituted amino group on ring A in solvent; for example, N,N-dimethylformamide, tetrahydrofuran, dichloromethane, and the like; in the presence of dehydrating agent; for example, dicyclohexylcarbodiimide, carbonyldiimidazole, dicyclohexylcarbodiimide-N-hydroxybenzotriazole, and the like; is reacted with carboxylic acid having substituent corresponding to target compound; for example, benzoic acid, 2-pyridinecarboxylic acid, and the like; at −80° C. to 100° C., preferably −20° C. to 40° C., for 0.1 to 24 hours, preferably 1 to 12 hours, to obtain the compound (I-19).
The alkylamino derivatives




In formula, NHR20 is optionally substituted amino, R22 is lower alkyl.
The compound (I-18) having an amino group on ring A in solvent; for example, dichloromethane, tetrahydrofuran, and the like; in the presence or the absence of acid; for example, acetic acid, and the like; is reacted with aldehyde having substituent corresponding to target compound; for example, benzaldehyde, pyridine-2-carboaldehyde, and the like; and reducing agent; for example, sodium borohydride, sodium triacetoxyborohydride, and the like; at −80° C. to 100° C., preferably 0° C. to 40° C., for 0.5 to 150 hours, preferably 1 to 24 hours, to obtain the compound (I-20).
The substituted alkoxy derivatives




In formula, R23 is optionally substituted lower alkyl, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group, etc., and the other symbols are the same as described above.
The compound (I-21) having a hydroxy group as substituent of A ring in solvent; for example, N,N-dimethylformamide, tetrahydrofuran, and the like; in the presence of base; for example potassium carbonate, sodium hydroxide, sodium hydride, and the like; is reacted with alkylating agent having substituent corresponding to target compound; for example, benzylchloride, methyl iodide, and the like; at −80° C. to 100° C., preferably 0° C. to 40° C., for 0.5 to 150 hours, preferably 1 to 24 hours, or alternatively, the compound (I-18) in solvent; for example, N,N-dimethylformamide, tetrahydrofuran, and the like; under Mitsunobu reagent; for example triphenylphosphine-azodicarboxylic acid ethyl ester, and the like; is reacted with alcohol; for example, 2-aminoethanol, and the like; at −80° C. to 100° C., preferably 0° C. to 40° C., for 0.5 to 72 hours, preferably 1 to 24 hours, to obtain the compound (I-22).
The introduction of substituent with palladium coupling reaction




In formula, Hal is halogen, G is optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkoxycarbonyl, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group etc., and the other symbols are the same as described above.
The compound (I-23) having halogen as substituent of A ring in solvent; for example, tetrahydrofuran, N,N-dimethylformamide, 1,2-dimethoxyethane, methanol, and the like; in the presence of base; for example, triethylamine, sodium carbonate, and the like; palladium catalyst; for example, palladium acetate, palladium chloride, and the like; and ligand; for example triphenylphosphine, and the like; is reacted with compound having substituent corresponding to target compound (styrene, propargyl alcohol, aryl boronic acid, carbon monoxide), with or without microwave irradiation, at −80° C. to 150° C., preferably 0° C. to 100° C., for 0.5 to 72 hours, preferably 1 to 24 hours, to obtain the compound (I-24).
The oxime derivatives




In formula, in R24 is a hydrogen atom or optionally substituted lower alkyl etc., R25 is a hydrogen atom, optionally substituted lower alkyl, optionally substituted lower alkenyl or an optionally substituted carbocyclic group or an optionally substituted heterocyclic group etc., and the other symbols are the same as described above.
The compound (I-25) having an acyl group as substituent of A ring in solvent; for example, methanol, ethanol, and the like; in the presence or the absence of additives; for example, potassium acetate, and the like; is reacted with hydroxylamine having substituent corresponding to target compound (hydroxylamine, methoxylamine, O-benzylhydroxylamine, etc.) or the salt thereof at 0° C. to 100° C., preferably 0° C. to 40° C., for 0.5 to 150 hours, preferably 1 to 72 hours, to obtain the compound (I-26).
In all of above mentioned steps, if a compound having substituent which interrupts the reaction; (for example, hydroxy, mercapto, amino, formyl, carbonyl, carboxyl, etc.), the substituent of the compound is protected by methods described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons) beforehand, and is deprotected at preferable step.
The compound (I) in this invention presented below; in particular, X is S, and E is a bond or methylene; is preferable.
1) A compound represented by the general formula (I′),




in formula, t is 0 or 1, the other symbols are the same as above (a), with the proviso that the compounds represented below;

i) wherein n+m is 2, R5 is a hydrogen atom, and ring A is unsubstituted phenyl;

ii) wherein n is 2, m is 0, R2a is a hydrogen atom, R2b is a hydrogen atom or acetyl, R5 is methyl, and ring A is phenyl or 4-methoxyphenyl;

iii) Wherein n is 2, m is 0, R2a is a hydrogen atom, R2b is a hydrogen atom or acetyl, R5 is ethyl, and ring A is 3,4-dimethoxyphenyl;

iv) wherein n is 2, m is 0, R2a is a hydrogen atom, R2b is a hydrogen atom or acetyl, R5 and ring A are phenyl;

v) wherein n is 2, m is 0, R2a and R2b is a hydrogen atom, R5 and ring A are taken together to form





and

vi) the compound, wherein n+m is 1 or 2; R5 is a hydrogen atom; ring A is phenyl substituted by one or two substituent selected from hydroxy, halogen, lower alkyl, lower alkoxy, nitro, amino, lower alkyl carbonylamino, mercapto, lower alkylthio, carbamoyl, lower alkylamino, lower alkyl carbamoyl and lower alkoxycarbonyl; non-substituted phenyl, or non-substituted naphthyl; are excluded.

In addition, in formula (I′), preferable is the compound represented below.
2) The compound, wherein n is 1 and m is 0 (this compound is represented by nm-1),
3) the compound, wherein n is 2 and m is 0 (this compound is represented by nm-2),
4) the compound, wherein n is 3 and m is 0 (this compound is represented by nm-3),
5) the compound, wherein R2a is a hydrogen atom; R2b is a hydrogen atom, optionally substituted lower alkyl, optionally substituted acyl, optionally substituted lower alkylsulfonyl, or optionally substituted amidino (this compound is represented by R2-1),
6) the compound, wherein R2a is a hydrogen atom; R2b is a hydrogen atom, optionally substituted lower alkyl or optionally substituted acyl (this compound is represented by R2-2),
7) the compound, wherein NR2aR2b is represented by the following formula:




wherein each symbols are the same as described above.

R6, R7 and R8 are each independently a hydrogen atom, lower alkyl or acyl,

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

Z is O or S (this compound is represented by R2-3),

8) the compound, wherein NR2aR2b is NH2 (this compound is represented by R2-4),

9) the compound, wherein ring A is substituted phenyl or substituted pyridyl (this compound is represented by A-1),

10) the compound, wherein ring A is represented by the following formula:





wherein R9, R10 and R11 is a hydrogen atom or G,

G is halogen, hydroxy, cyano, nitro, mercapto, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted acyl, optionally substituted acyloxy, carboxy, optionally substituted lower alkoxycarbonyl, optionally substituted lower alkoxycarbonyloxy, optionally substituted aryloxycarbonyloxy, optionally substituted amino, optionally substituted carbamoyl, optionally substituted carbamoyloxy, optionally substituted lower alkylthio, optionally substituted arylthio, optionally substituted lower alkylsulfonyl, optionally substituted arylsulfonyl, optionally substituted lower alkylsulfinyl, optionally substituted arylsulfinyl, optionally substituted lower alkylsulfonyloxy, optionally substituted arylsulfonyloxy, optionally substituted sulfamoyl, an optionally substituted carbocyclic group, optionally substituted carbocyclicoxy, an optionally substituted heterocyclic group or optionally substituted heterocyclicoxy, each G may be different (this compound is represented by A-2),

11) the compound, wherein ring A is represented by the following formula:





wherein R9 and R10 are each independently a hydrogen atom, halogen, hydroxy, optionally substituted lower alkyl, cyano, nitro, optionally substituted lower alkoxy, optionally substituted acyl, optionally substituted amino, optionally substituted carbamoyl, optionally substituted carbamoyloxy, optionally substituted lower alkylsulfonyl, optionally substituted arylsulfonyl, optionally substituted lower alkylsulfonyloxy, optionally substituted arylsulfonyloxy, an optionally substituted carboncyclic group, optionally substituted carbocyclicoxy, an optionally substituted heterocyclic group or optionally substituted heterocyclicoxy, G is the same as described above 10) (this compound is represented by A-3),

12) the compound, wherein ring A is represented by the following formula:





wherein R9 and R10 is the same as described in 11), G is the same as described in 10) (this compound is represented by A-4),

13) the compound, wherein ring A, R9, and R10 are defined in 11), G is optionally substituted amino (this compound is represented by A-5),

14) the compound, wherein ring A, R9 and R10 are defined in 11), G is optionally substituted arylcarbonylamino or optionally substituted heterocyclic carbonylamino,

15) the compound, wherein ring A, R9 and R10 are defined in 11), G is optionally substituted heterocyclic carbonylamino (this compound is represented by A-6),

16) the compound, wherein ring A is defined in 11), G is represented by the following formula:











wherein Q1, Q2 and Q3 are each independently a bond, optionally substituted lower alkylene or optionally substituted lower alkenylene;

Q4 is optionally substituted lower alkylene or optionally substituted lower alkenylene;

W1 and W2 are each independently O or S;

W3 is O, S or NR12;

R12 is a hydrogen atom, lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl, lower alkoxycarbonyl lower alkyl, carbocyclic lower alkyl or acyl;

R14 is hydrogen atom or lower alkyl;

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

Alk2 is optionally substituted lower alkyl;

R9 and R10 are the same as described in 11) (this compound is represented by A-7),

17) the compound, wherein ring A, R9 and R10 are the group defined in 11); G is the group defined in 16); ring B is aryl optionally substituted with one or more substituents selected from halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted acyl, optionally substituted amino, cyano, optionally substituted carbamoyl, an optionally substituted carbocyclic group, optionally substituted carbocyclicoxy or an optionally substituted heterocyclic group or

heteroaryl optionally substituted with one or more substituents selected from halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted acyl, optionally substituted amino, cyano, optionally substituted carbamoyl, an optionally substituted carbocyclic group, optionally substituted carbocyclicoxy or an optionally substituted heterocyclic group; and the other symbols are the same as described in 16) (this compound is represented by A-8),

18) the compound, wherein ring A, R9 and R10 are defined in 11), G is represented by the following formula:





in formula, wherein each symbols are the same as described in 16)

(this compound is represented by A-9),

19) the compound, wherein ring A is represented by the following formula:





G is defined in 16), ring B is optionally substituted aryl or optionally substituted heteroaryl, either R9 or R10 is a hydrogen atom; and the other is a hydrogen atom, halogen, optionally substituted lower alkyl, cyano, nitro, optionally substituted lower alkoxy, optionally substituted amino, optionally substituted carbamoyl, optionally substituted lower alkylsulfonyl, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group (this compound is represented by A-10),

20) the compound, wherein ring A is represented by the following formula:





G is defined in 18), the other symbols are the same as described in 19) (this compound is represented by A-11),

21) the compound, wherein ring A is represented by the following formula:





G is defined in 16), ring B is optionally substituted phenyl, 6- to 6-membered heteroaryl, benzothiazolyl or benzothienyl, R9 and R10 are the same as described in 19) (this compound is represented by A-12),

22) the compound, wherein ring A is represented by the following formula:





G is defined in 18), ring B is defined in 21), R9 and R10 are the same as described in 19) (this compound is represented by A-13),

23) the compound, wherein ring A is represented by the following formula:





wherein R9 is a hydrogen atom, halogen, optionally substituted lower alkyl, cyano, nitro, optionally substituted lower alkoxy, optionally substituted amino, optionally substituted carbamoyl, optionally substituted lower alkylsulfonyl, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group, ring B is the same as described in 21); R12 is a hydrogen atom or lower alkyl (this compound is represented by A-14),

24) the compound, wherein R5 is a hydrogen atom or C1 to C3 alkyl (this compound is represented by R5-1),

25) the compound, wherein R5 is C1 to C3 alkyl (this compound is represented by R5-2),

26) the compound, wherein R5 is methyl (this compound is represented by R5-3),

27) the compound, wherein R3a and R3b are each independently a hydrogen atom, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkoxy or optionally substituted aryl (this compound is represented by R3-1),

28) the compound wherein, Ran is a hydrogen atom, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkoxy or optionally substituted aryl, R3b is a hydrogen atom, one R3 is a hydrogen atom when n is 2, one or two R2a is(are) a hydrogen atom when n is 3 (this compound is represented by R3-2),

29) the compound, wherein R3a and R3b are all hydrogen atoms (this compound is represented by R3-3), and

in a compound represented by the general formula (I′), a compound, wherein the combination of n, m, R2a, R2b, ring A, R5, R3a, and R3b(nm, R2, A, R5, R3) is the following compound.

(nm, R2, A, R5, R3)=(nm-1,R2-1,A-1,R5-1,R3-1),(nm-1,R2-1,A-1,R5-1,R3-2),(nm-1,R2-1,A-1,R5-2,R3-1),(nm-1,R2-1,A-1,R5-2,R3-2),(nm-1,R2-1,A-1,R5-3,R3-1),(nm-1,R2-1,A-1,R5-3,R3-2),(nm-1,R2-1,A-2,R5-1,R3-1),(nm-1,R2-1,A-2,R5-1,R3-2),(nm-1,R2-1,A-2,R5-2,R3-1),(nm-1, R2-1,A-2,R5-2,R3-2),(nm-1,R2-1,A-2,R5-3,R3-1),(nm-1,R2-1,A-2,R5-3,R3-2),(nm-1, R2-1,A-3,R5-1,R3-1),(nm-1,R2-1,A-3,R5-1,R3-2),(nm-1,R2-1,A-3,R5-2,R3-1),(nm-1,R 2-1,A-3,R5-2,R3-2),(nm-1,R2-1,A-3,R5-3,R3-1),(nm-1,R2-1,A-3,R5-3,R3-2),(nm-1,R2-1,A-4,R5-1,R3-1),(nm-1,R2-1,A-4,R5-1,R3-2),(nm-1,R2-1,A-4,R5-2,R3-1),(nm-1,R2-1, A-4,R5-2,R3-2),(nm-1,R2-1,A-4,R5-3,R3-1),(nm-1,R2-1,A-4,R5-3,R3-2),(nm-1,R2-1,A-5,R5-1,R3-1),(nm-1,R2-1,A-5,R5-1,R3-2),(nm-1,R2-1,A-5,R5-2,R3-1),(nm-1,R2-1,A-5, R5-2,R3-2),(nm-1,R2-1,A-5,R5-3,R3-1),(nm-1,R2-1,A-5,R5-3,R3-2),(nm-1,R2-1,A-6, R5-1,R3-1),(nm-1,R2-1,A-6,R5-1,R3-2),(nm-1,R2-1,A-6,R5-2,R3-1),(nm-1,R2-1,A-6,R 5-2,R3-2),(nm-1,R2-1,A-6,R5-3,R3-1),(nm-1,R2-1,A-6,R5-3,R3-2),(nm-1,R2-1,A-7,R5-1,R3-1),(nm-1,R2-1,A-7,R5-1,R3-2),(nm-1,R2-1,A-7,R5-2,R3-1),(nm-1,R2-1,A-7,R5-2, R3-2),(nm-1,R2-1,A-7,R5-3,R3-1),(nm-1,R2-1,A-7,R5-3,R3-2),(nm-1,R2-1,A-8,R5-1,R 3-1),(nm-1,R2-1,A-8,R5-1,R3-2),(nm-1,R2-1,A-8,R5-2,R3-1),(nm-1,R2-1,A-8,R5-2,R3-2),(nm-1,R2-1,A-8,R5-3,R3-1),(nm-1,R2-1,A-8,R5-3,R3-2),(nm-1,R2-1,A-9,R5-1,R3-1), (nm-1,R2-1,A-9,R5-1,R3-2),(nm-1,R2-1,A-9,R5-2,R3-1),(nm-1,R2-1,A-9,R5-2,R3-2),(nm-1,R2-1,A-9,R5-3,R3-1),(nm-1,R2-1,A-9,R5-3,R3-2),(nm-1,R2-1,A-10,R5-1,R3-1),(nm-1,R2-1,A-10,R5-1,R3-2),(nm-1,R2-1,A-10,R5-2,R3-1),(nm-1,R2-1,A-10,R5-2,R3-2), (nm-1,R2-1,A-10,R5-3,R3-1),(nm-1,R2-1,A-10,R5-3,R3-2),(nm-1,R2-1,A-11,R5-1,R3-1),(nm-1,R2-1,A-11,R5-1,R3-2),(nm-1,R2-1,A-11,R5-2,R3-1),(nm-1,R2-1,A-11,R5-2, R3-2),(nm-1,R2-1,A-11,R5-3,R3-1),(nm-1,R2-1,A-11,R5-3,R3-2),(nm-1,R2-1,A-12,R5-1,R3-1),(nm-1,R2-1,A-12,R5-1,R3-2),(nm-1,R2-1,A-12,R5-2,R3-1),(nm-1,R2-1,A-12,R 5-2,R3-2),(nm-1,R2-1,A-12,R5-3,R3-1),(nm-1,R2-1,A-12,R5-3,R3-2),(nm-1,R2-1,A-13, R5-1,R3-1),(nm-1,R2-1,A-13,R5-1,R3-2),(nm-1,R2-1,A-13,R5-2,R3-1),(nm-1,R2-1,A-13,R5-2,R3-2),(nm-1,R2-1,A-13,R5-3,R3-1),(nm-1,R2-1,A-13,R5-3,R3-2),(nm-1,R2-1,A-14,R5-1,R3-1),(nm-1,R2-1,A-14,R5-1,R3-2),(nm-1,R2-1,A-14,R5-2,R3-1),(nm-1,R2-1, A-14,R5-2,R3-2),(nm-1,R2-1,A-14,R5-3,R3-1),(nm-1,R2-1,A-14,R5-3,R3-2),(nm-1,R2-2,A-1,R5-1,R3-1),(nm-1,R2-2,A-1,R5-1,R3-2),(nm-1,R2-2,A-1,R5-2,R3-1),(nm-1,R2-2, A-1,R5-2,R3-2),(nm-1,R2-2,A-1,R5-3,R3-1),(nm-1,R2-2,A-1,R5-3,R3-2),(nm-1,R2-2,A-2,R5-1,R3-1),(nm-1,R2-2,A-2,R5-1,R3-2),(nm-1,R2-2,A-2,R5-2,R3-1),(nm-1,R2-2,A-2, R5-2,R3-2),(nm-1,R2-2,A-2,R5-3,R3-1),(nm-1,R2-2,A-2,R5-3,R3-2),(nm-1,R2-2,A-3, R5-1,R3-1),(nm-1,R2-2,A-3,R5-1,R3-2),(nm-1,R2-2,A-3,R5-2,R3-1),(nm-1,R2-2,A-3,R 5-2,R3-2),(nm-1,R2-2,A-3,R5-3,R3-1),(nm-1,R2-2,A-3,R5-3,R3-2),(nm-1,R2-2,A-4,R5-1,R3-1),(nm-1,R2-2,A-4,R5-1,R3-2),(nm-1,R2-2,A-4,R5-2,R3-1),(nm-1,R2-2,A-4,R5-2, R3-2),(nm-1,R2-2,A-4,R5-3,R3-1),(nm-1,R2-2,A-4,R5-3,R3-2),(nm-1,R2-2,A-5,R5-1,R 3-1),(nm-1,R2-2,A-5,R5-1,R3-2),(nm-1,R2-2,A-5,R5-2,R3-1),(nm-1,R2-2,A-5,R5-2,R3-2),(nm-1,R2-2,A-5,R5-3,R3-1),(nm-1,R2-2,A-5,R5-3,R3-2),(nm-1,R2-2,A-6,R5-1,R3-1), (nm-1,R2-2,A-6,R5-1,R3-2),(nm-1,R2-2,A-6,R5-2,R3-1),(nm-1,R2-2,A-6,R5-2,R3-2),(nm-1,R2-2,A-6,R5-3,R3-1),(nm-1,R2-2,A-6,R5-3,R3-2),(nm-1,R2-2,A-7,R5-1,R3-1),(nm-1,R2-2,A-7,R5-1,R3-2),(nm-1,R2-2,A-7,R5-2,R3-1),(nm-1,R2-2,A-7,R5-2,R3-2),(nm-1,R2-2,A-7,R5-3,R3-1),(nm-1,R2-2,A-7,R5-3,R3-2),(nm-1,R2-2,A-8,R5-1,R3-1),(nm-1, R2-2,A-8,R5-1,R3-2),(nm-1,R2-2,A-8,R5-2,R3-1),(nm-1,R2-2,A-8,R5-2,R3-2),(nm-1, R2-2,A-8,R5-3,R3-1),(nm-1,R2-2,A-8,R5-3,R3-2),(nm-1,R2-2,A-9,R5-1,R3-1),(nm-1,R 2-2,A-9,R5-1,R3-2),(nm-1,R2-2,A-9,R5-2,R3-1),(nm-1,R2-2,A-9,R5-2,R3-2),(nm-1,R2-2,A-9,R5-3,R3-1),(nm-1,R2-2,A-9,R5-3,R3-2),(nm-1,R2-2,A-10,R5-1,R3-1),(nm-1,R2-2,A-10,R5-1,R3-2),(nm-1,R2-2,A-10,R5-2,R3-1),(nm-1,R2-2,A-10,R5-2,R3-2),(nm-1,R 2-2,A-10,R5-3,R3-1),(nm-1,R2-2,A-10,R5-3,R3-2),(nm-1,R2-2,A-11,R5-1,R3-1),(nm-1, R2-2,A-11,R5-1,R3-2),(nm-1,R2-2,A-11,R5-2,R3-1),(nm-1,R2-2,A-11,R5-2,R3-2),(nm-1,R2-2,A-11,R5-3,R3-1),(nm-1,R2-2,A-11,R5-3,R3-2),(nm-1,R2-2,A-12,R5-1,R3-1),(nm-1,R2-2,A-12,R5-1,R3-2),(nm-1,R2-2,A-12,R5-2,R3-1),(nm-1,R2-2,A-12,R5-2,R3-2), (nm-1,R2-2,A-12,R5-3,R3-1),(nm-1,R2-2,A-12,R5-3,R3-2),(nm-1,R2-2,A-13,R5-1,R3-1),(nm-1,R2-2,A-13,R5-1,R3-2),(nm-1,R2-2,A-13,R5-2,R3-1),(nm-1,R2-2,A-13,R5.2,R 3-2),(nm-1,R2-2,A-13,R5-3,R3-1),(nm-1,R2-2,A-13,R5-3,R3-2),(nm-1,R2-2,A-14,R5-1, R3-1),(nm-1,R2-2,A-14,R5-1,R3-2),(nm-1,R2-2,A-14,R5-2,R3-1),(nm-1,R2-2,A-14,R5-2,R3-2),(nm-1,R2-2,A-14,R5-3,R3-1),(nm-1,R2-2,A-14,R5-3,R3-2),(nm-1,R2-3,A-1,R5-1,R3-1),(nm-1,R2-3,A-1,R5-1,R3-2),(nm-1,R2-3,A-1,R5-2,R3-1),(nm-1,R2-3,A-1,R5-2, R3-2),(nm-1,R2-3,A-1,R5-3,R3-1),(nm-1,R2-3,A-1,R5-3,R3-2),(nm-1,R2-3,A-2,R5-1, R3-1),(nm-1,R2-3,A-2,R5-1,R3-2),(nm-1,R2-3,A-2,R5-2,R3-1),(nm-1,R2-3,A-2,R5-2,R 3-2),(nm-1,R2-3,A-2,R5-3,R3-1),(nm-1,R2-3,A-2,R5-3,R3-2),(nm-1,R2-3,A-3,R5-1,R3-1),(nm-1,R2-3,A-3,R5-1,R3-2),(nm-1,R2-3,A-3,R5-2,R3-1),(nm-1,R2-3,A-3,R5-2,R3-2), (nm-1,R2-3,A-3,R5-3,R3-1),(nm-1,R2-3,A-3,R5-3,R3-2),(nm-1,R2-3,A-4,R5-1,R3-1),(nm-1,R2-3,A-4,R5-1,R3-2),(nm-1,R2-3,A-4,R5-2,R3-1),(nm-1,R2-3,A-4,R5-2,R3-2),(nm-1,R2-3,A-4,R5-3,R3-1),(nm-1,R2-3,A-4,R5-3,R3-2),(nm-1,R2-3,A-5,R5-1,R3-1),(nm-1,R2-3,A-5,R5-1,R3-2),(nm-1,R2-3,A-5,R5-2,R3-1),(nm-1,R2-3,A-5,R5-2,R3-2),(nm-1, R2-3,A-5,R5-3,R3-2),(nm-1,R2-3,A-5,R5-2,R3-2),(nm-1,R2-3,A-6,R5-1,R3-1),(nm-1, R2-3,A-6,R5-1,R3-2),(nm-1,R2-3,A-6,R5-2,R3-1),(nm-1,R2-3,A-6,R5.2,R3-2),(nm-1,R 2-3,A-6,R5-3,R3-1),(nm-1,R2-3,A-6,R5-3,R3-2),(nm-1,R2-3,A-7,R5-1,R3-1),(nm-1,R2-3,A-7,R5-1,R3-2),(nm-1,R2-3,A-7,R5-2,R3-1),(nm-1,R2-3,A-7,R5-2,R3-2),(nm-1,R2-3, A-7,R5-3,R3-1),(nm-1,R2-3,A-7,R5-3,R3-2),(nm-1,R2-3,A-8,R5-1,R3-1),(nm-1,R2-3,A-8,R5-1,R3-2),(nm-1,R2-3,A-8,R5-2,R3-1),(nm-1,R2-3,A-8,R5-2,R3-2),(nm-1,R2-3,A-8, R5-3,R3-1),(nm-1,R2-3,A-8,R5-3,R3-2),(nm-1,R2-3,A-9,R5-1,R3-1),(nm-1,R2-3,A-9, R5-1,R3-2),(nm-1,R2-3,A-9,R5-2,R3-1),(nm-1,R2-3,A-9,R5-2,R3-2),(nm-1,R2-3,A-9,R 5-3,R3-1),(nm-1,R2-3,A-9,R5-3,R3-2),(nm-1,R2-3,A-10,R5-1,R3-1),(nm-1,R2-3,A-10, R5-1,R3-2),(mar 1,R2-3,A-10,R5-2,R3-1),(nm-1,R2-3,A-10,R5-2,R3-2),(nm-1,R2-3,A-10,R5-3,R3-1),(nm-1,R2-3,A-10,R5-3,R3-2),(nm-1,R2-3,A-11,R5-1,R3-1),(nm-1,R2-3,A-11,R5-1,R3-2),(nm-1,R2-3,A-11,R5-2,R3-1),(nm-1,R2-3,A-11,R5-2,R3-2),(nm-1,R2-3, A-11,R5-3,R3-1),(nm-1,R2-3,A-11,R5-3,R3-2),(nm-1,R2-3,A-12,R5-1,R3-1),(nm-1,R2-3,A-12,R5-1,R3-2),(nm-1,R2-3,A-12,R5-2,R3-1),(nm-1,R2-3,A-12,R5-2,R3-2),(nm-1,R 2-3,A-12,R5-3,R3-1),(nm-1,R2-3,A-12,R5-3,R3-2),(nm-1,R2-3,A-13,R5-1,R3-1),(nm-1, R2-3,A-13,R5-1,R3-2),(nm-1,R2-3,A-13,R5-2,R3-1),(nm-1,R2-3,A-13,R5-2,R3-2),(nm-1,R2-3,A-13,R5-3,R3-1),(nm-1,R2-3,A-13,R5-3,R3-2),(nm-1,R2-3,A-14,R5-1,R3-1),(nm-1,R2-3,A-14,R5-1,R3-2),(nm-1,R2-3,A-14,R5-2,R3-1),(nm-1,R2-3,A-14,R5-2,R3-2), (nm-1,R2-3,A-14,R5-3,R3-1),(nm-1,R2-3,A-14,R5-3,R3-2),(nm-1,R2-4,A-1,R5-1,R3-1), (nm-1,R2-4,A-1,R5-1,R3-2),(nm-1,R2-4,A-1,R5-2,R3-1),(nm-1,R2-4,A-1,R5-2,R3-2),(nm-1,R2-4,A-1,R5-3,R3-1),(nm-1,R2-4,A-1,R5-3,R3-2),(nm-1,R2-4,A-2,R5-1,R3-1),(nm-1,R2-4,A-2,R5-1,R3-2),(nm-1,R2-4,A-2,R5-2,R3-1),(nm-1,R2-4,A-2,R5-2,R3-2),(nm 1,R2-4,A-2,R5-3,R3-1),(nm-1,R2-4,A-2,R5-3,R3-2),(nm-1,R2-4,A-3,R5-1,R3-1),(nm-1, R2-4,A-3,R5-1,R3-2),(nm-1,R2-4,A-3,R5-2,R3-1),(nm-1,R2-4,A-3,R5-2,R3-2),(nm-1, R2-4,A-3,R5-3,R3-1),(nm-1,R2-4,A-3,R5-3,R3-2),(nm-1,R2-4,A-4,R5-1,R3-1),(nm-1,R 2-4,A-4,R5-1,R3-2),(nm-1,R2-4,A-4,R5-2,R3-1),(nm-1,R2-4,A-4,R5-2,R3-2),(nm-1,R2-4,A-4,R5-3,R3-1),(nm-1,R2-4,A-4,R5-3,R3-2),(nm-1,R2-4,A-5,R5-1,R3-1),(nm-1,R2-4, A-5,R5-1,R3-2),(nm-1,R2-4,A-5,R5-2,R3-1),(nm-1,R2-4,A-5,R5-2,R3-2),(nm-1,R2-4,A-5,R5-3,R3-1),(nm-1,R2-4,A-5,R5-3,R3-2),(nm-1,R2-4,A-6,R5-1,R3-1),(nm-1,R2-4,A-6, R5-1,R3-2),(nm-1,R2-4,A-6,R5-2,R3-1),(nm-1,R2-4,A-6,R5-2,R3-2),(nm-1,R2-4,A-6, R5-3,R3-1),(nm-1,R2-4,A-6,R5-3,R3-2),(nm-1,R2-4,A-7,R5-1,R3-1),(nm-1,R2-4,A-7,R 5-1,R3-2),(nm-1,R2-4,A-7,R5-2,R3-1),(nm-1,R2-4,A-7,R5-2,R3-2),(nm-1,R2-4,A-7,R5-3,R3-1),(nm-1,R2-4,A-7,R5-3,R3-2),(nm-1,R2-4,A-8,R5-1,R3-1),(nm-1,R2-4,A-8,R5-1, R3-2),(nm-1,R2-4,A-8,R5-2,R3-1),(nm-1,R2-4,A-8,R5-2,R3-2),(nm-1,R2-4,A-8,R5-3,R 3-1),(nm-1,R2-4,A-8,R5-3,R3-2),(nm-1,R2-4,A-9,R5-1,R3-1),(nm-1,R2-4,A-9,R5-1,R3-2),(nm-1,R2-4,A-9,R5-2,R3-1),(nm-1,R2-4,A-9,R5-2,R3-2),(nm-1,R2-4,A-9,R5-3,R3-1), (nm-1,R2-4,A-9,R5-3,R3-2),(nm-1,R2-4,A-10,R5-1,R3-1),(nm-1,R2-4,A-10,R5-1,R3-2), (nm-1,R2-4,A-10,R5-2,R3-1),(nm-1,R2-4,A-10,R5-2,R3-2),(nm-1,R2-4,A-10,R5-3,R3-1),(nm-1,R2-4,A-10,R5-3,R3-2),(nm-1,R2-4,A-11,R5-1,R3-1),(nm-1,R2-4,A-11,R5-1, R3-2),(nm-1,R2-4,A-11,R5-2,R3-1),(nm-1,R2-4,A-11,R5-2,R3-2),(nm-1,R2-4,A-11,R5-3,R3-1),(nm-1,R2-4,A-11,R5-3,R3-2),(nm-1,R2-4,A-12,R5-1,R3-1),(nm-1,R2-4,A-12,R 5-1,R3-2),(nm-1,R2-4,A-12,R5-2,R3-1),(nm-1,R2-4,A-12,R5-2,R3-2),(nm-1,R2-4,A-12, R5-3,R3-1),(nm-1,R2-4,A-12,R5-3,R3-2),(nm-1,R2-4,A-13,R5-1,R3-1),(nm-1,R2-4,A-13,R5-1,R3-2),(nm-1,R2-4,A-13,R5-2,R3-1),(nm-1,R2-4,A-13,R5-2,R3-2),(nm-1,R2-4,A-13,R5-3,R3-1),(nm-1,R2-4,A-13,R5-3,R3-2),(nm-1,R2-4,A-14,R5-1,R3-1),(nm-1,R2-4, A-14,R5-1,R3-2),(nm-1,R2-4,A-14,R5-2,R3-1),(nm-1,R2-4,A-14,R5-2,R3-2),(nm-1,R2-4,A-14,R5-3,R3-1),(nm-1,R2-4,A-14,R5-3,R3-2),

(nm-2,R2-1,A-1,R5-1,R3-1),(nm-2,R2-1,A-1,R5-1,R3-2),(nm-2,R2-1,A-1,R5-2,R3-1),(nm-2,R2-1,A-1,R5-2,R3-2),(nm-2,R2-1,A-1,R5-3,R3-1),(nm-2,R2-1,A-1,R5-3,R3-2),(nm-2,R2-1,A-2,R5-1,R3-1),(nm-2,R2-1,A-2,R5-1,R3-2),(nm-2,R2-1,A-2,R5-2,R3-1),(nm-2, R2-1,A-2,R5-2,R3-2),(nm-2,R2-1,A-2,R5-3,R3-1),(nm-2,R2-1,A-2,R5-3,R3-2),(nm-2, R2-1,A-3,R5-1,R3-1),(nm-2,R2-1,A-3,R5-1,R3-2),(nm-2,R2-1,A-3,R5-2,R3-1),(nm-2,R 2-1,A-3,R5-2,R3-2),(nm-2,R2-1,A-3,R5-3,R3-1),(nm-2,R2-1,A-3,R5-3,R3-2),(nm-2,R2-1,A-4,R5-1,R3-1),(nm-2,R2-1,A-4,R5-1,R3-2),(nm-2,R2-1,A-4,R5-2,R3-1),(nm-2,R2-1, A-4,R5-2,R3-2),(nm-2,R2-1,A-4,R5-3,R3-1),(nm-2,R2-1,A-4,R5-3,R3-2),(nm-2,R2-1,A-5,R5-1,R3-1),(nm-2,R2-1,A-5,R5-1,R3-2),(nm-2,R2-1,A-5,R5-2,R3-1),(nm-2,R2-1,A-5, R5-2,R3-2),(nm-2,R2-1,A-5,R5-3,R3-1),(nm-2,R2-1,A-5,R5-3,R3-2),(nm-2,R2-1,A-6, R5-1,R3-1),(nm-2,R2-1,A-6,R5-1,R3-2),(nm-2,R2-1,A-6,R5-2,R3-1),(nm-2,R2-1,A-6,R 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R3-2),(nm-2,R2-2,A-4,R5-3,R3-1),(nm-2,R2-2,A-4,R5-3,R3-2),(nm-2,R2-2,A-5,R5-1,R 3-1),(nm-2,R2-2,A-5,R5-1,R3.2),(nm-2,R2-2,A-5,R5-2,R3-1),(nm-2,R2-2,A-5,R5-2,R3-2),(nm-2,R2-2,A-5,R5-3,R3-1),(nm-2,R2-2,A-5,R5-3,R3-2),(nm-2,R2-2,A-6,R5-1,R3-1), (nm-2,R2-2,A-6,R5-1,R3-2),(nm-2,R2-2,A-6,R5-2,R3-1),(nm-2,R2-2,A-6,R5-2,R3-2),(nm-2,R2-2,A-6,R5-3,R3-1),(nm-2,R2-2,A-6,R5-3,R3-2),(nm-2,R2-2,A-7,R5-1,R3-1),(nm-2,R2-2,A-7,R5-1,R3-2),(nm-2,R2-2,A-7,R5-2,R3-1),(nm-2,R2-2,A-7,R5-2,R3-2),(nm-2,R2-2,A-7,R5-3,R3-1),(nm-2,R2-2,A-7,R5-3,R3-2),(nm-2,R2-2,A-8,R5-1,R3-1),(nm-2, R2-2,A-8,R5-1,R3-2),(nm-2,R2-2,A-8,R5-2,R3-1),(nm-2,R2-2,A-8,R5-2,R3-2),(nm-2, R2-2,A-8,R5-3,R3-1),(nm-2,R2-2,A-8,R5-3,R3-2),(nm-2,R2-2,A-9,R5-1,R3-1),(nm-2,R 2-2,A-9,R5-1,R3-2),(nm-2,R2-2,A-9,R5-2,R3-1),(nm-2,R2-2,A-9,R5-2,R3-2),(nm-2,R2-2,A-9,R5-3,R3-1),(nm-2,R2-2,A-9,R5-3,R3-2),(nm-2,R2-2,A-10,R5-1,R3-1),(nm-2,R2-2,A-10,R5-1,R3-2),(nm-2,R2-2,A-10,R5-2,R3-1),(nm-2,R2-2,A-10,R5-2,R3-2),(nm-2,R 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R5-3,R3-1),(nm-2,R2-3,A-8,R5-3,R3-2),(nm-2,R2-3,A-9,R5-1,R3-1),(nm-2,R2-3,A-9, R5-1,R3-2),(nm-2,R2-3,A-9,R5-2,R3-1),(nm-2,R2-3,A-9,R5-2,R3-2),(nm-2,R2-3,A-9,R 5-3,R3-1),(nm-2,R2-3,A-9,R5-3,R3-2),(nm-2,R2-3,A-10,R5-1,R3-1),(nm-2,R2-3,A-10, R5-1,R3-2),(nm-2,R2-3,A-10,R5-2,R3-1),(nm-2,R2-3,A-10,R5-2,R3-2),(nm-2,R2-3,A-10,R5-3,R3.1),(nm-2,R2-3,A-10,R5-3,R3-2),(nm-2,R2-3,A-11,R5-1,R3-1),(nm-2,R2-3,A-11,R5-1,R3-2),(nm-2,R2-3,A-11,R5-2,R3-1),(nm-2,R2-3,A-11,R5-2,R3-2),(nm-2,R2-3, A-11,R5-3,R3-1),(nm-2,R2-3,A-11,R5-3,R3-2),(nm-2,R2-3,A-12,R5-1,R3-1),(nm-2,R2-3,A-12,R5-1,R3-2),(nm-2,R2-3,A-12,R5-2,R3-1),(nm-2,R2-3,A-12,R5-2,R3-2),(nm-2,R 2-3,A-12,R5-3,R3-1),(nm-2,R2-3,A-12,R5-3,R3-2),(nm-2,R2-3,A-13,R5-1,R3-1),(nm-2, R2-3,A-13,R5-1,R3-2),(nm-2,R2-3,A-13,R5-2,R3-1),(nm-2,R2-3,A-13,R5-2,R3-2),(nm-2,R2-3,A-13,R5-3,R3-1),(nm-2,R2-3,A-13,R5-3,R3-2),(nm-2,R2-3,A-14,R5-1,R3-1),(nm-2,R2-3,A-14,R5-1,R3-2),(nm-2,R2-3,A-14,R5-2,R3-1),(nm-2,R2-3,A-14,R5-2,R3-2), (nm-2,R2-3,A-14,R5-3,R3-1),(nm-2,R2-3,A-14,R5-3,R3-2),(nm-2,R2-4,A-1,R5-1,R3-1), (nm-2,R2-4,A-1,R5-1,R3-2),(nm-2,R2-4,A-1,R5-2,R3-1),(nm-2,R2-4,A-1,R5-2,R3-2),(nm-2,R2-4,A-1,R5-3,R3-1),(nm-2,R2-4,A-1,R5-3,R3-2),(nm-2,R2-4,A-2,R5-1,R3-1),(nm-2,R2-4,A-2,R5-1,R3-2),(nm-2,R2-4,A-2,R5-2,R3-1),(nm-2,R2-4,A-2,R5-2,R3-2),(nm-2,R2-4,A-2,R5-3,R3-1),(nm-2,R2-4,A-2,R5-3,R3-2),(nm-2,R2-4,A-3,R5-1,R3-1),(nm-2, R2-4,A-3,R5-1,R3-2),(nm-2,R2-4,A-3,R5-2,R3-1),(nm-2,R2-4,A-3,R5-2,R3-2),(nm-2, R2-4,A-3,R5-3,R3-1),(nm-2,R2-4,A-3,R5-3,R3-2),(nm-2,R2-4,A-4,R5-1,R3-1),(nm-2,R 2-4,A-4,R5-1,R3-2),(nm-2,R2-4,A-4,R5-2,R3-1),(nm-2,R2-4,A-4,R5-2,R3-2),(nm-2,R2-4,A-4,R5-3,R3-1),(nm-2,R2-4,A-4,R5-3,R3-2),(nm-2,R2-4,A-5,R5-1,R3-1),(nm-2,R2-4, A-5,R5-1,R3-2),(nm-2,R2-4,A-5,R5-2,R3-1),(nm-2,R2-4,A-5,R5-2,R3-2),(nm-2,R2-4,A-5,R5-3,R3-1),(nm-2,R2-4,A-5,R5-3,R3-2),(nm-2,R2-4,A-6,R5-1,R3-1),(nm-2,R2-4,A-6, R5-1,R3-2),(nm-2,R2-4,A-6,R5-2,R3-1),(nm-2,R2-4,A-6,R5-2,R3-2),(nm-2,R2-4,A-6, R5-3,R3-1),(nm-2,R2-4,A-6,R5-3,R3-2),(nm-2,R2-4,A-7,R5-1,R3-1),(nm-2,R2-4,A-7,R 5-1,R3-2),(nm-2,R2-4,A-7,R5-2,R3-1),(nm-2,R2-4,A-7,R5-2,R3-2),(nm-2,R2-4,A-7,R5-3,R3-1),(nm-2,R2-4,A-7,R5-3,R3-2),(nm-2,R2-4,A-8,R5-1,R3-1),(nm-2,R2-4,A-8,R5-1, R3-2),(nm-2,R2-4,A-8,R5-2,R3-1),(nm-2,R2-4,A-8,R5-2,R3-2),(nm-2,R2-4,A-8,R5-3,R 3-1),(nm-2,R2-4,A-8,R5-3,R3-2),(nm-2,R2-4,A-9,R5-1,R3-1),(nm-2,R2-4,A-9,R5-1,R3-2),(nm-2,R2-4,A-9,R5-2,R3-1),(nm-2,R2.4,A-9,R5-2,R3-2),(nm-2,R2-4,A-9,R5-3,R3-1), (nm-2,R2-4,A-9,R5-3,R3-2),(nm-2,R2-4,A-10,R5-1,R3-1),(nm-2,R2-4,A-10,R5-1,R3-2), (nm-2,R2-4,A-10,R5-2,R3.1),(nm-2,R2-4,A-10,R5-2,R3-2),(nm-2,R2-4,A-10,R5-3,R3-1),(nm-2,R2-4,A-10,R5-3,R3-2),(nm-2,R2-4,A-11,R5.1,R3-1),(nm-2,R2-4,A-11,R5-1, R3-2),(nm-2,R2-4,A-11,R5-2,R3-1),(nm-2,R2-4,A-11,R5-2,R3-2),(nm-2,R2-4,A-11,R5-3,R3-1),(nm-2,R2-4,A-11,R5-3,R3-2),(nm-2,R2-4,A-12,R5-1,R3-1),(nm-2,R2-4,A-12,R 5-1,R3-2),(nm-2,R2-4,A-12,R5-2,R3-1),(nm-2,R2-4,A-12,R5-2,R3-2),(nm-2,R2-4,A-12, R5-3,R3-1),(nm-2,R2-4,A-12,R5-3,R3-2),(nm-2,R2-4,A-13,R5-1,R3-1),(nm-2,R2-4,A-13,R5-1,R3-2),(nm-2,R2-4,A-13,R5-2,R3-1),(nm-2,R2-4,A-13,R5-2,R3-2),(nm-2,R2-4,A-13,R5-3,R3-1),(nm-2,R2-4,A-13,R5-3,R3-2),(nm-2,R2-4,A-14,R5-1,R3-1),(nm-2,R2-4, A-14,R5-1,R3-2),(nm-2,R2-4,A-14,R5-2,R3-1),(nm-2,R2-4,A-14,R5-2,R3-2),(nm-2,R2-4,A-14,R5-3,R3-1),(nm-2,R2-4,A-14,R5-3,R3-2),

(nm-3,R2-1,A-1,R5-1,R3-1),(nm-3,R2-1,A-1,R5-1,R3-2),(nm-3,R2-1,A-1,R5-2,R3-1),(nm-3,R2-1,A-1,R5-2,R3-2),(nm-3,R2-1,A-1,R5-3,R3-1),(nm-3,R2-1,A-1,R5-3,R3-2),(nm-3,R2-1,A-2,R5-1,R3-1),(nm-3,R2-1,A-2,R5-1,R3-2),(nm-3,R2-1,A-2,R5-2,R3-1),(nm-3, R2-1,A-2,R5-2,R3-2),(nm-3,R2-1,A-2,R5-3,R3.1),(nm-3,R2-1,A-2,R5-3,R3-2),(nm-3, R2-1,A-3,R5-1,R3-1),(nm-3,R2-1,A-3,R5-1,R3-2),(nm-3,R2-1,A-3,R5-2,R3-1),(nm-3,R 2-1,A-3,R5-2,R3-2),(nm-3,R2-1,A-3,R5-3,R3-1),(nm-3,R2-1,A-3,R5-3,R3-2),(nm-3,R2-1,A-4,R5-1,R3-1),(nm-3,R2-1,A-4,R5-1,R3-2),(nm-3,R2-1,A-4,R5-2,R3-1),(nm-3,R2-1, A-4,R5-2,R3-2),(nm-3,R2-1,A-4,R5-3,R3-1),(nm-3,R2-1,A-4,R5-3,R3-2),(nm-3,R2-1,A-5,R5-1,R3-1),(nm-3,R2-1,A-5,R5-1,R3-2),(nm-3,R2-1,A-5,R5-2,R3-1),(nm-3,R2-1,A-5, R5-2,R3-2),(nm-3,R2-1,A-5,R5-3,R3-1),(nm-3,R2-1,A-5,R5-3,R3-2),(nm-3,R2-1,A-6, R5-1,R3-1),(nm-3,R2-1,A-6,R5-1,R3-2),(nm-3,R2-1,A-6,R5-2,R3-1),(nm-3,R2-1,A-6,R 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R3-2),(nm-3,R2-2,A-4,R5-3,R3-1),(nm-3,R2-2,A-4,R5-3,R3-2),(nm-3,R2-2,A-5,R5-1,R 3-1),(nm-3,R2-2,A-5,R5-1,R3-2),(nm-3,R2-2,A-5,R5-2,R3-1),(nm-3,R2-2,A-5,R5-2,R3-2),(nm-3,R2-2,A-5,R5-3,R3-1),(nm-3,R2-2,A-5,R5-3,R3-2),(nm-3,R2-2,A-6,R5-1,R3-1), (nm-3,R2-2,A-6,R5-1,R3-2),(nm-3,R2-2,A-6,R5-2,R3-1),(nm-3,R2-2,A-6,R5-2,R3-2),(nm-3,R2-2,A-6,R5-3,R3-1),(nm-3,R2-2,A-6,R5-3,R3-2),(nm-3,R2-2,A-7,R5-1,R3-1),(nm-3,R2-2,A-7,R5-1,R3-2),(nm-3,R2-2,A-7,R5-2,R3-1),(nm-3,R2-2,A-7,R5-2,R3-2),(nm-3,R2-2,A-7,R5-3,R3-1),(nm-3,R2-2,A-7,R5-3,R3-2),(nm-3,R2-2,A-8,R5-1,R3-1),(nm-3, R2-2,A-8,R5-1,R3-2),(nm-3,R2-2,A-8,R5-2,R3-1),(nm-3,R2-2,A-8,R5-2,R3-2),(nm-3, R2-2,A-8,R5-3,R3-1),(nm-3,R2-2,A-8,R5-3,R3-2),(nm-3,R2-2,A-9,R5.1,R3-1),(nm-3,R 2-2,A-9,R5-1,R3-2),(nm-3,R2-2,A-9,R5-2,R3-1),(nm-3,R2-2,A-9,R5-2,R3-2),(nm-3,R2-2,A-9,R5-3,R3-1),(nm-3,R2-2,A-9,R5.3,R3-2),(nm-3,R2-2,A-10,R5-1,R3-1),(nm-3,R2-2,A-10,R5-1,R3-2),(nm-3,R2-2,A-10,R5-2,R3-1),(nm-3,R2-2,A-10,R5-2,R3-2),(nm-3,R 2-2,A-10,R5-3,R3-1),(nm-3,R2-2,A-10,R5-3,R3-2),(nm-3,R2-2,A-11,R5-1,R3-1),(nm-3, R2-2,A-11,R5-1,R3-2),(nm-3,R2-2,A-11,R5-2,R3-1),(nm-3,R2-2,A-11,R5-2,R3-2),(nm-3,R2-2,A-11,R5-3,R3-1),(nm-3,R2-2,A-11,R5-3,R3-2),(nm-3,R2-2,A-12,R5-1,R3-1),(nm-3,R2-2,A-12,R5-1,R3-2),(nm-3,R2-2,A-12,R5-2,R3-1),(nm-3,R2-2,A-12,R5-2,R3-2), (nm-3,R2-2,A-12,R5-3,R3-1),(nm-3,R2-2,A-12,R5-3,R3-2),(nm-3,R2-2,A-13,R5-1,R3-1),(nm-3,R2-2,A-13,R5-1,R3-2),(nm-3,R2-2,A-13,R5-2,R3-1),(nm-3,R2-2,A-13,R5-2,R 3-2),(nm-3,R2-2,A-13,R5-3,R3-1),(nm-3,R2-2,A-13,R5-3,R3-2),(nm-3,R2-2,A-14,R5-1, R3-1),(nm-3,R2-2,A-14,R5-1,R3-2),(nm-3,R2-2,A-14,R5-2,R3-1),(nm-3,R2-2,A-14,R5-2,R3-2),(nm-3,R2-2,A-14,R5-3,R3-1),(nm-3,R2-2,A-14,R5-3,R3-2),(nm-3,R2-3,A-1,R5-1,R3-1),(nm-3,R2-3,A-1,R5-1,R3-2),(nm-3,R2-3,A-1,R5-2,R3-1),(nm-3,R2-3,A-1,R5-2, R3-2),(nm-3,R2-3,A-1,R5-3,R3-1),(nm-3,R2-3,A-1,R5-3,R3-2),(nm-3,R2-3,A-2,R5-1, R3-1),(nm-3,R2-3,A-2,R5-1,R3-2),(nm-3,R2-3,A-2,R5-2,R3-1),(nm-3,R2-3,A-2,R5-2,R 3-2),(nm-3,R2-3,A-2,R5-3,R3-1),(nm-3,R2-3,A-2,R5-3,R3-2),(nm-3,R2-3,A-3,R5-1,R3-1),(nm-3,R2-3,A-3,R5-1,R3-2),(nm-3,R2-3,A-3,R5-2,R3-1),(nm-3,R2-3,A-3,R5-2,R3-2), (nm-3,R2-3,A-3,R5-3,R3-1),(nm-3,R2-3,A-3,R5-3,R3-2),(nm-3,R2-3,A-4,R5-1,R3-1),(nm-3,R2-3,A-4,R5-1,R3-2),(nm-3,R2-3,A-4,R5-2,R3-1),(nm-3,R2-3,A-4,R5-2,R3-2),(nm-3,R2-3,A-4,R5-3,R3-1),(nm-3,R2-3,A-4,R5-3,R3-2),(nm-3,R2-3,A-5,R5-1,R3-1),(nm-3,R2-3,A-5,R5-1,R3-2),(nm-3,R2-3,A-5,R5-2,R3-1),(nm-3,R2-3,A-5,R5-2,R3-2),(nm-3, R2-3,A-5,R5-3,R3-1),(nm-3,R2-3,A-5,R5-3,R3-2),(nm-3,R2-3,A-6,R5-1,R3-1),(nm-3, R2-3,A-6,R5-1,R3-2),(nm-3,R2-3,A-6,R5-2,R3-1),(nm-3,R2-3,A-6,R5-2,R3-2),(nm-3,R 2-1,A-6,R5-3,R3-1),(nm-3,R2-3,A-6,R5-3,R3-2),(nm-3,R2-3,A-7,R5-1,R3-1),(nm-3,R2-3,A-7,R5-1,R3-2),(nm-3,R2-3,A-7,R5-2,R3-1),(nm-3,R2-3,A-7,R5-2,R3-2),(nm-3,R2-3, A-7,R5-3,R3-1),(nm-3,R2-3,A-7,R5-3,R3-2),(nm-3,R2-3,A-8,R5-1,R3-1),(nm-3,R2-3,A-8,R5-1,R3-2),(nm-3,R2-3,A-8,R5-2,R3-1),(nm-3,R2-3,A-8,R5-2,R3-2),(nm-3,R2-3,A-8, R5-3,R3-1),(nm-3,R2-3,A-8,R5-3,R3-2),(nm-3,R2-3,A-9,R5-1,R3-1),(nm-3,R2.3,A-9, R5-1,R3-2),(nm-3,R2-3,A-9,R5-2,R3-1),(nm-3,R2-3,A-9,R5-2,R3-2),(nm-3,R2-3,A-9,R 5-3,R3-1),(nm-3,R2-3,A-9,R5-3,R3-2),(nm-3,R2-3,A-10,R5-1,R3-1),(nm-3,R2-3,A-10, R5-1,R3-2),(nm-3,R2-3,A-10,R5-2,R3-1),(nm-3,R2-3,A-10,R5-2,R3-2),(nm-3,R2-3,A-10,R5-3,R3-1),(nm-3,R2-3,A-10,R5-3,R3-2),(nm-3,R2-3,A-11,R5-1,R3.1),(nm-3,R2-3,A-11,R5-1,R3-2),(nm-3,R2-3,A-11,R5-2,R3-1),(nm-3,R2-3,A-11,R5-2,R3-2),(nm-3,R2-3, A-11,R5-3,R3-1),(nm-3,R2-3,A-11,R5-3,R3-2),(nm-3,R2-3,A-12,R5-1,R3-1),(nm-3,R2-3,A-12,R5-1,R3-2),(nm-3,R2-3,A-12,R5-2,R3-1),(nm-3,R2-3,A-12,R5-2,R3-2),(nm-3,R 2-3,A-12,R5-3,R3-1),(nm-3,R2-3,A-12,R5-3,R3-2),(nm-3,R2-3,A-13,R5-1,R3-1),(nm-3, R2-3,A-13,R5-1,R3-2),(nm-3,R2-3,A-13,R5-2,R3-1),(nm-3,R2-3,A-13,R5-2,R3-2),(nm-3,R2-3,A-13,R5-3,R3-1),(nm-3,R2-3,A-13,R5-3,R3-2),(nm-3,R2-3,A-14,R5-1,R3-1),(nm-3,R2-3,A-14,R5-1,R3-2),(nm-3,R2-3,A-14,R5-2,R3-1),(nm-3,R2-3,A-14,R5-2,R3-2), (nm-3,R2-3,A-14,R5-3,R3-1),(nm-3,R2-3,A-14,R5-3,R3-2),(nm-3,R2-4,A-1,R5-1,R3-1), (nm-3,R2-4,A-1,R5-1,R3-2),(nm-3,R2-4,A-1,R5-2,R3-1),(nm-3,R2-4,A-1,R5-2,R3-2),(nm-3,R2-4,A-1,R5-3,R3-1),(nm-3,R2-4,A-1,R5-3,R3-2),(nm-3,R2-4,A-2,R5-1,R3-1),(nm-3,R2-4,A-2,R5-1,R3-2),(nm-3,R2-4,A-2,R5-2,R3-1),(nm-3,R2-4,A-2,R5-2,R3-2),(nm-3,R2-4,A-2,R5-3,R3-1),(nm-3,R2-4,A-2,R5-3,R3-2),(nm-3,R2-4,A-3,R5-1,R3-1),(nm-3, R2-4,A-3,R5-1,R3-2),(nm-3,R2-4,A-3,R5-2,R3-1),(nm-3,R2-4,A-3,R5-2,R3-2),(nm-3, R2-4,A-3,R5-3,R3-1),(nm-3,R2-4,A-3,R5-3,R3-2),(nm-3,R2-4,A-4,R5-1,R3-1),(nm-3,R 2-4,A-4,R5-1,R3-2),(nm-3,R2-4,A-4,R5-2,R3-1),(nm-3,R2-4,A-4,R5-2,R3-2),(nm-3,R2-4,A-4,R5-3,R3-1),(nm-3,R2-4,A-4,R5-3,R3-2),(nm-3,R2-4,A-5,R5-1,R3-1),(nm-3,R2-4, A-5,R5-1,R3-2),(nm-3,R2-4,A-5,R5-2,R3-1),(nm-3,R2-4,A-5,R5-2,R3-2),(nm-3,R2-4,A-5,R5-3,R3-1),(nm-3,R2-4,A-5,R5-3,R3-2),(nm-3,R2-4,A-6,R5-1,R3-1),(nm-3,R2-4,A-6, R5-1,R3-2),(nm-3,R2-4,A-6,R5-2,R3-1),(nm-3,R2-4,A-6,R5-2,R3-2),(nm-3,R2-4,A-6, R5-3,R3-1),(nm-3,R2-4,A-6,R5-3,R3-2),(nm-3,R2-4,A-7,R5-1,R3-1),(nm-3,R2-4,A-7,R 5-1,R3-2),(nm-3,R2-4,A-7,R5-2,R3-1),(nm-3,R2-4,A-7,R5-2,R3-2),(nm-3,R2-4,A-7,R5-3,R3-1),(nm-3,R2-4,A-7,R5-3,R3-2),(nm-3,R2-4,A-8,R5-1,R3-1),(nm-3,R2-4,A-8,R5-1, R3-2),(nm-3,R2-4,A-8,R5-2,R3-1),(nm-3,R2-4,A-8,R5-2,R3-2),(nm-3,R2-4,A-8,R5-3,R 3-1),(nm-3,R2-4,A-8,R5-3,R3-2),(nm-3,R2-4,A-9,R5-1,R3-1),(nm-3,R2-4,A-9,R5-1,R3-2),(nm-3,R2-4,A-9,R5-2,R3-1),(nm-3,R2-4,A-9,R5-2,R3-2),(nm-3,R2-4,A-9,R5-3,R3-1), (nm-3,R2-4,A-9,R5-3,R3-2),(nm-3,R2-4,A-10,R5-1,R3-1),(nm-3,R2-4,A-10,R5-1,R3-2), (nm-3,R2-4,A-10,R5-2,R3-1),(nm-3,R2-4,A-10,R5-2,R3-2),(nm-3,R2-4,A-10,R5-3,R3-1),(nm-3,R2-4,A-10,R5-3,R3-2),(nm-3,R2-4,A-11,R5-1,R3-1),(nm-3,R2-4,A-11,R5-1, R3-2),(nm-3,R2-4,A-11,R5-2,R3-1),(nm-3,R2-4,A-11,R5-2,R3-2),(nm-3,R2-4,A-11,R5-3,R3-1),(nm-3,R2-4,A-11,R5-3,R3-2),(nm-3,R2-4,A-12,R5-1,R3-1),(nm-3,R2-4,A-12,R 5-1,R3-2),(nm-3,R2-4,A-12,R5-2,R3-1),(nm-3,R2-4,A-12,R5-2,R3-2),(nm-3,R2-4,A-12, R5-3,R3-1),(nm-3,R2-4,A-12,R5-3,R3-2),(nm-3,R2-4,A-13,R5-1,R3-1),(nm-3,R2-4,A-13,R5-1,R3-2),(nm-3,R2-4,A-13,R5-2,R3-1),(nm-3,R2-4,A-13,R5-2,R3-2),(nm-3,R2-4,A-13,R5-3,R3-1),(nm-3,R2-4,A-13,R5-3,R3-2),(nm-3,R2-4,A-14,R5-1,R3-1),(nm-3,R2-4, A-14,R5-1,R3-2),(nm-3,R2-4,A-14,R5-2,R3-1),(nm-3,R2-4,A-14,R5-2,R3-2),(nm-3,R2-4,A-14,R5-3,R3-1),(nm-3,R2-4,A-14,R5-3,R3-2),(nm-3,R2-4,A-14,R5-3,R3-3).

In a compound represented by the general formula (I′), a compound, wherein the combination of n, m, R2a, R2b, ring A, R5, R3a, and R3b (nm, R2, A, R5, R3) is one of the above compound, and E is a bond.
The compounds of the invention can be employed in the treatment and/or prevention of disease associated with the generation, secretion or deposition of β-amyloid protein, such as dementia of the Alzheimer's type (Alzheimer's disease, senile dementia of Alzheimer type), Down's syndrome, memory impairment, prion disease (Creutzfeldt-Jakob disease), mild cognitive impairment (MCI), Dutch type of hereditary cerebral hemorrhage with amyloidosis, cerebral amyloid angiopathy, other type of degenerative dementia, mixed dementia with Alzheimer's and vascular type, dementia with Parkinson's Disease, dementia with progressive supranuclear palsy, dementia with Cortico-basal degeneration, Alzheimer's disease with diffuse Lewy body disease, age-related macular degeneration, Parkinson's Disease, amyloid angiopathy and so on.
The compounds of the invention can be administrated in combination with other pharmaceutical agents such as other therapeutic drugs for Alzheimer's disease, acetylcholinesterase inhibitors and so on. The compounds of the invention can be treated with concomitantly with the anti-dementia agents such as Donepezil Hydrochloride, Tacrine, Galantamine, Rivastigmine, Zanapezil, Memantine, Vinpocetine.
When the present compound is administered to a human, it can be administered orally as powders, granules, tablets, capsules, pills, solutions, or the like, or parenterally as injectables, suppositories, transdermal absorbable agents, absorbable agents, or the like. In addition, the present compound can be formulated into pharmaceutical preparations by adding pharmaceutical additives such as excipients, binders, wetting agents, disintegrating agents, lubricants and the like, which are suitable for formulations and an effective amount of the present compound.
A dose is different depending on state of disease, an administration route, and an age and a weight of a patient, and is usually 0.1 μg to 1 g/day, preferably 0.01 to 200 mg/day when orally administered to an adult, and is usually 0.1 μg to 10 g/day, preferably 0.1 to 2 g/day when parenterally administered.
Following examples and test examples illustrate the present invention in more detail, but the present invention is not limited by these examples.
In example, the meaning of each abbreviation is following.
Me methyl
Et ethyl
iPr or Pri isopropyl
Ph phenyl
Bn benzyl
Boc t-butoxycarbonyl
TBDPS t-butyldiphenylsilyl
Example 1
The synthesis of compound 588







Step 1

Under nitrogen atmosphere, the compound (1-1)(7.98 g) was dissolved into diethyl ether (330 ml)-tetrahydrofuran (36 ml), vinylmagnesium chloride in tetrahydrofuran solution (1.32 mol/L, 44.8 ml) was added under cooling with dryice-acetone bath, and stirred for 20 min. Then, the reaction solution was stirred for 30 min under cooling with ice-water bath and stirred for 36 min at room temperature. And then, saturated ammonium chloride solution was added to the mixture, the mixture was extracted with ethyl acetate, and organic layer was washed with saturated ammonium chloride solution, saturated sodium hydrogencarbonate solution, and brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated. Then, the residue was purified by silica gel column chromatography to afford the compound (1-2)(6.00 g).
1H-NMR (CDCl3) 1.63 (3H, s), 2.08 (1H, br), 5.20 (1H, dd, J=10.6, 1.6 Hz), 5.31 (1H, dd, J=17.1, 1.6 Hz), 6.09 (1H, m), 7.46 (1H, m), 7.52 (1H, dd, J=3.4, 2.6 Hz), 7.80 (1H, dd, J=3.9, 2.6 Hz), 8.06 (1H, br)
Step 2
The compound (1-2)(6.36 g) was dissolved into acetic acid (30 ml), and added thiourea (1.50 g), 1 mol/L hydrochloride-acetic acid solution (20.7 ml). The reaction mixture was stirred at room temperature for 3 hours, then stirred at 40° C. for 3 hours, then stirred at room temperature for 66 hours, and at 40° C. for 19 hours. Thiourea (0.450 g), and 1 mol/L hydrochloric acid-acetic acid solution (7.53 ml) was added, and stirred at 40° C. for 23 hours. After the consumption of the compound (1-2), the solvent was evaporated under reduced pressure, then the obtained residue was crystallized from methanol-diethyl ether to afford the compound (1-3)(5.23 g) as crystal. On the other hand, mother liquid was evaporated under reduced pressure, and the compound (1-3)(3.00 g) was obtained as crude solid product.
1H-NMR (DMSO-d6) 2.09 (3H, s), 4.10 (2H, d, J=7.3 Hz), 5.94 (1H, t, J=7.7 Hz), 7.50 (1H, s), 7.75 (1H, s), 7.87 (1H, s), 9.17 (3H, br), 11.46 (1H, s)
Step 3
The compound (1-3)(5.23 g) dissolved in trifluoroacetic acid (25 ml) was added methanesulfonic acid (2.14 ml) dropwise under cooling with ice-water bath. After addition, the reaction mixture was stirred at room temperature for 3.5 hours. After the consumption of the compound (1-3), the solvent was evaporated under reduced pressure. To the residue obtained was added water and sodium carbonate, and then extracted with ethyl acetate. The organic layer was washed with saturated sodium hydrogencarbonate solution, and was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to afford the compound (1-4)(4.90 g) as crude product.
1H-NMR (CDCl3) 1.53 (3H, s), 1.90 (1H, m), 2.09 (1H, m), 2.74 (1H, m), 2.97 (1H, m), 4.32 (2H, br), 7.34 (1H, t, J=1.6 Hz), 7.37 (1H, t, J=1.8 Hz), 7.86 (1H, t, J=1.8 Hz)
Step 4
Under nitrogen atmosphere, the compound (I-4)(4.90 g) dissolved in tetrahydrofuran was added di-t-butyl-dicarbonate (2.97 g) and triethylamine (1.89 ml) under cooling with ice-water bath and then stirred for 2 hours. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was added water, and then extracted with ethyl acetate. The organic layer was washed with water, and dried over anhydrous magnesium sulfate, then the solvent was evaporated under reduced pressure. Then the obtained residue was crystallized from ethyl acetate-diethyl ether to afford the compound (1-5)(4.62 g) as crystal.
1H-NMR (CDCl3) 1.36 (9H, s), 1.72 (3H, s), 2.10 (1H, m), 2.41 (1H, m), 2.62 (1H, m), 2.75 (1H, m), 7.22 (1H, s), 7.48 (1H, s), 8.29 (1H, s)
Step 5
The compound (1-5)(1.00 g) was dissolved into tetrahydrofuran (8.7 ml), and 1 mol/L lithium hydroxide (4.43 ml) was added and stirred at 50° C. for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, and the organic layer was washed with water, brine successively, and dried over anhydrous magnesium sulfate, and the solution was evaporated under reduced pressure. The obtained residue was purified by medium-pressured silica gel column chromatography to afford the compound (1-6)(0.668 g).
1H-NMR (CDCl3) 1.51 (9H, s), 1.63 (3H, s), 2.06 (1H, m), 2.40 (1H, m), 2.68-2.74 (2H, m), 3.83 (2H, br), 6.51 (1H, t, J=1.8 Hz), 6.72-6.74 (2H, m)
Step 6
The compound (1-6)(20.0 mg) was dissolved into 4 mol/L hydrochloric acid in 1,4-dioxane, and the mixture was stirred for 16 hours. The reaction solvent was evaporated under reduced pressure and the obtained residue was crystallized from methanol-diethyl ether to afford the compound (588)(14.7 mg).
1H-NMR (DMSO-d6) 1.59 (3H, s), 2.09-2.76 (4H, m), 6.44 (1H, t, J=1.6 Hz), 6.60 (1H, t J=1.9 Hz), 6.71 (1H, t, J=2.0 Hz), 10.4 (1H, s)
Example 2
The synthesis of compound 835




Step 1

The compound (2-1)(2020 mg) was dissolved into chloroform (20 ml), then water (4 ml) and sodium thiocyanic acid (1470 mg) were added at room temperature with stirring, and then sulfuric acid (1.94 ml) was added dropwise under cooling with ice-water bath. After an addition was complete, the reaction mixture was warmed to room temperature and then stirred for 345 minutes, then stirred at 60° C. overnight. Because the compound (2-1) was remained (checked by TLC), the reaction mixture was cooled to room temperature, then sodium thiocyanic acid (1470 mg), water (5 ml) and sulfuric acid (1.94 ml) were added successively. After the reaction mixture was warmed to 60° C., the mixture was stirred for 1 day. Saturated sodium carbohydrate solution was added to the reaction mixture to be basic condition under cooling with ice-water bath, and then the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, then dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography to afford the compound (2-2)(968 mg).
1H-NMR (CDCl3, 270 MHz) 1.99 (3H, s), 3.55 (1H, d, J=16.1 Hz), 3.69 (1H, d, J=16.1 Hz), 7.12-7.64 (8H, m), 7.82-7.96 (2H, m)
Step 2
The compound (2-2)(842 mg) was dissolved into ethanol (8.4 ml), sodium dihydrorgen phosphate, sodium borohydride (113.2 mg), and water (2.8 ml), were added successively under cooling with ice-water bath with stirring, and the mixture was stirred for 30 minutes. After the consumption of the compound (2-2)(checked by TLC), ethyl acetate and water were added to the reaction mixture under cooling with ice-water bath, and then stirred for a few minutes. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, brine successively, and dried over anhydrous magnesium sulfate. The solvent was evaporated to afford the compound (2-3)(904.8 mg) as crude product.
Step 3
To a solution of compound (2-3)(900 mg) in toluene (10 ml) was added a solution of thionyl chloride (0.7 ml) in toluene (5 ml) under cooling with ice-water bath, and then stirred for 1 hour. After the consumption of the compound (2-3)(checked by TLC), the reaction solvent was evaporated under reduced pressure to afford the compound (2-4)(1076.8 mg) as crude product.
Step 4
The compound (2-4)(1070 mg) was dissolved into about 7 mol/L ammonia in methanol (20 ml) at room temperature, then the mixture was stirred for 1 day. After the consumption of the compound (2-4)(checked by TLC), the reaction solvent was evaporated under reduced pressure to afford the compound (835)(2633 mg) as crude product.
Example 3
The synthesis of compound 561




Step 1

To tetrahydrofuran (30 ml) under cooling with ice-water bath with stirring, lithium aluminium hydride (0.63 g) was added portionwise, then a solution of compound (3-1)(1.94 g) in tetrahydrofuran (40 ml) was added dropwise. The reaction mixture was reacted for 20 minutes at room temperature, then reacted for 3 hours under reflux. Then ice was added in small portions under cooling, and then stirred for 1 day at room temperature. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to afford the compound (3-2)(0.90 g).
1H-NMR (CDCl3) 1.22 (3H, s), 3.08 (1H, d, J=12.5 Hz), 3.34 (1H, d, J=12.5 Hz), 3.85 (1H, d, J=11.0 Hz), 4.11 (1H, d, J=11.0 Hz), 7.21-7.25 (1H, m), 7.34-7.40 (2H, m), 7.46-7.50 (2H, m).
Step 2
The compound (3-2)(0.90 g) was dissolved into tetrahydrofuran (15 ml), t-butylisothiocyanate (0.69 g) in tetrahydrofuran (5 ml) was added under cooling with ice-water bath with stirring. The reaction mixture was stirred for 3 days at room temperature, water was added and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to afford the compound (3-3)(1.33 g).
1H-NMR (CDCl3) 1.12 (9H, s), 1.34 (3H, s), 3.15 (1H, br), 3.76 (1H, d, J=11.2 Hz), 3.87 (1H, dd, J=14.2, 4.6 Hz), 4.13 (1H, d, J=11.2 Hz), 4.23 (1H, dd, J=14.2, 6.6 Hz), 5.18 (1H, br), 6.01 (1H, br), 7.23-7.28 (1H, m), 7.34-7.41 (4H, m).
Step 3
The compound (3-3)(315 mg) was dissolved into acetonitrile (3 ml), triphenylphosphine (440 mg), and carbon tetrachloride (520 mg) in acetonitrile (3 ml) were added under cooling with ice-water bath with stirring. The reaction mixture was stirred for 1 hour at room temperature, and then potassium carbonate (460 mg) was added and stirred for 2 days at room temperature. Then water was added to the reaction mixture and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to afford the compound (3-4)(0.23 g).
1H-NMR (CDCl3) 1.30 (9H, s), 1.36 (3H, s), 3.13 (1H, d, J=12.2 Hz), 3.24 (1H, dd, J=12.2, 2.3 Hz), 3.51 (1H, br), 3.53 (1H, d, J=15.2 Hz), 3.99 (1H, dd, J=15.2, 2.3 Hz), 7.20-7.25 (1H, m), 7.30-7.36 (2H, m), 7.39-7.43 (2H, m).
Step 4
To the compound (3-4)(0.22 g), conc. hydrochloric acid (4.5 ml) was added, then stirred for 2 hours under reflux, and then the reaction solvent was evaporated under reduced pressure. The obtained residue was crystallized from methanol-diethyl ether to afford the compound (561)(0.16 g).
1H-NMR (DMSO-d6) 1.33 (3H, s), 3.33-3.49 (2H, m), 3.65-3.96 (2H, m), 7.29 (111, t. J=7.6 Hz), 7.40 (211, t. J=7.6 Hz), 7.48 (2H, t. J=7.6 Hz).
Example 4
The synthesis of compound 534




Step 1

The compound (4-1)(0.72 g) was dissolved into N,N-dimethylformamide (15 ml), then sodium azide (0.31 g) was added. The reaction mixture was stirred at 100° C. for 13 hours, then water was added and the mixture was extracted with diethyl ether, the organic layer was dried over anhydrous magnesium sulfate to afford the compound (4-2)(0.71 g) as crude product.
Step 2
To a solution of the compound (4-2)(0.71 g) in tetrahydrofuran (10 ml), lithium aluminium hydride (0.14 g) was added portionwise under cooling with ice-water bath with stirring, then stirred for 2 hours at room temperature. After the consumption of the starting material, ice was added in small portions, then stirred for 18 hours at room temperature. The reaction mixture was filtered then filtrate was evaporated under reduced pressure to afford the compound (4-3)(0.89 g) as crude product.
Step 3
The compound (4-3)(0.89 g) was dissolved into tetrahydrofuran (10 ml), then t-butylisothiocyanate (0.56 g) in tetrahydrofuran (5 ml) was added under cooling with ice-water bath with stirring. The reaction mixture was stirred for 4 hours at room temperature, and water was added, and then extracted with dichloromethane, and the organic layer was dried over anhydrous magnesium sulfate. Then the residue was purified by silica gel column chromatography to afford the compound (4-4)(0.72 g).
1H-NMR (CDCl3) 1.39 (9H, s), 2.08 (3H, s), 2.09-2.15 (2H, m), 3.37-3.44 (1H, m), 3.80-3.87 (1H, m), 5.97 (1H, br.), 6.86 (1H, br.), 7.28-7.43 (5H, m).
Step 4
The compound (4-4)(120 mg) was dissolved into acetonitrile (2 ml), triphenylphosphine (170 mg), and carbon tetrachloride (200 mg) in acetonitrile (1 ml) were added under cooling with ice-water bath with stirring. The reaction mixture was stirred for 5 hours at room temperature, and then potassium carbonate (177 mg) was added and stirred for 6 days at room temperature. Then water was added to the reaction mixture and the mixture was extracted with dichloromethane, the organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to afford the compound (4-6)(0.06 g).
1H-NMR (CDCl3) 1.35 (9H, s), 1.59 (3H, s), 1.91 (1H, ddd, J=13.5, 8.8, 6.0 Hz), 2.06 (1H, dt, J=13.6, 6.0 Hz), 3.00 (1H, ddd, J=16.1, 8.8, 6.0 Hz), 3.30 (1H, dt, J=16.1, 6.0 Hz), 7.24-7.38 (6H, m).
Step 6
To the compound (4-5)(0.06 g), conc. hydrochloric acid (3 ml) was added, then the mixture was stirred for 1 hour under reflux, and the solvent was evaporated under reduced pressure. The obtained residue was crystallized from methanol-water to afford the compound (534)(0.02 g).
1H-NMR (DMSO-d6) 1.43 (3H, s), 1.77 (1H, dt. J=8.4, 3.4 Hz), 2.11 (1H, d. J=9.2 Hz), 2.48-2.50 (1H, m), 2.83-2.99 (1H, m), 6.12 (1H, br), 6.65 (1H, br), 7.21-7.24 (1H, m), 7.31-7.37 (4H, m).
Example 6
The synthesis of compound 1008




Step 1

The compound (5-1)(3.00 g) was dissolved into ethanol (30 ml), and thiourea (1.13 g) was added, and then the mixture was refluxed for 26 hours, and the solvent was evaporated under reduced pressure. The obtained residue was crystallized from ethyl acetate/hexane to afford the compound (5-2)(4.03 g).
1H-NMR (DMSO-d6) 1.95 (2H, quint, J=6.8 Hz), 3.13 (2H, t, J=6.8 Hz), 3.21 (2H, t, J=6.8 Hz), 3.85 (3H, s), 7.06 (2H, d, J=8.8 Hz), 7.95 (2H, d, J=8.8 Hz), 9.18 (4H, br).
Step 2
The compound (5-2)(1.00 g) was dissolved into tetrahydrofuran (25 ml), then di-t-butyl-dicarbonate (1.74 g), and triethylamine (0.88 g) were added, and then the mixture was stirred for 3 hours at room temperature. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to afford the compound (5-3)(1.24 g).
1H-NMR (CDCl3) 1.50 (9H, s), 2.07-2.17 (2H, m), 2.98 (2H, t, J=7.8 Hz), 3.09 (2H, t, J=6.3 Hz), 6.95 (2H, d, J=8.9 Hz), 7.95 (2H, d, J=8.9 Hz).
Step 3
The compound (5-3)(1.18 g) was dissolved into tetrahydrofuran (12 ml), then 0.9 mol/L methylmagnesium bromide in tetrahydrofuran solution (10.1 ml) was added under cooling with acetonitrile-dryice bath with stirring, and then reaction mixture was stirred for 1 hour, then stirred for 30 minutes at room temperature. After the reaction, saturated ammonium chloride solution was added under cooling with ice-water bath with stirring, then the mixture was extracted with diethyl ether, and the organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to afford the compound (5-4)(0.39 g).
1H-NMR (CDCl3) 1.51 (9H, a), 1.63 (3H, s), 1.55-1.65 (2H, m), 1.87-1.91 (2H, m), 2.96-3.12 (2H, m), 6.86 (2H, d, J=8.9 Hz), 7.36 (2H, d, J=8.9 Hz).
Step 4
The compound (5-4)(0.24 g) was dissolved into trifluoroacetic acid (6 ml), and stirred for 20 hours at room temperature, then the reaction solvent was evaporated under reduced pressure. To the residue, water and saturated sodium hydrogencarbonate was added, and then extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to afford the compound (1008)(0.06 g).
1H-NMR (CDCl3) 1.54 (3H, s), 1.77-1.87 (1H, m), 1.90-1.97 (1H, m), 2.20-2.36 (2H, m), 2.67-2.79 (2H, m), 3.81 (3H, s), 5.30 (2H, br), 6.87 (2H, d, J=9.0 Hz), 7.33 (2H, d, J=9.0 Hz).
Example 6
The synthesis of compound 783




Step 1

The compound (6-1)(0.55 g) was dissolved into methanol (7 ml), and methyl iodide (0.36 g) was added at room temperature with stirring. The mixture was stirred at room temperature for 18 hours, then the reaction solvent was evaporated under reduced pressure to afford the compound (6-2)(0.92 g) as crude product.
Step 2
The compound (6-2)(0.92 g) was dissolved into tetrahydrofuran (7 ml), then triethylamine (0.24 g) and silver oxide (1.1 g) was added. The mixture was stirred at room temperature for 3 days, then the insolubles was removed by filtration, then the filtrate was evaporated under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to afford the compound (6-3)(0.31 g).
1H-NMR (CDCl3) 1.35 (9H, s), 1.60 (3H, s), 1.92 (1H, ddd, J=9.2, 5.8, 3.4 Hz), 2.07 (1H, dt, J=9.2, 3.4 Hz), 3.00 (1H, ddd, J=9.2, 5.8, 3.4 Hz), 3.30 (1H, dt, J=9.2, 3.4 Hz), 7.24-7.38 (5H, m).
Step 3
To the compound (6-3)(0.22 g), conc. hydrochloric acid (3 ml) was added, then the mixture was stirred for 1 hour under reflux, and then the reaction solvent was evaporated under reduced pressure. The obtained residue was crystallized from water to afford the compound (783)(0.13 g).
1H-NMR (DMSO-d6) 1.44 (3H, s), 1.78 (1H, dt. J=12.4, 4.2 Hz), 2.12 (1H, d. J=8.9 Hz), 2.51-2.52 (1H, m), 2.96 (1H, d. J=4.2 Hz), 6.12 (1H, br), 6.66 (1H, br), 7.21-7.24 (1H, m), 7.32-7.37 (4H, m).
Example 7
The synthesis of compound 69




Step 1

A solution of the compound (7-1)(1.93 g), diphenylphosphoryl azide (1.60 g), and triethylamine (0.59 g) in toluene (20 ml) was stirred at 80° C. for 3 hours, and water was added, and then the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to afford the compound (7-2)(1.69 g).
1H-NMR (CDCl3) 1.00 (9H, s), 1.72 (3H, s), 2.17-2.22 (2H, m), 3.49-3.58 (1H, m), 3.70-3.80 (1H, m), 7.20-7.42 (10H, m), 7.58-7.63 (5H, m).
Step 2
The compound (7-2)(1.68 g) was dissolved into toluene (9 ml), and 3,4-dimethoxybenzylalcohol (0.79 g) was added, the mixture was refluxed for 8 hours. To the reaction mixture, water was added, then the mixture was extracted with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to afford the compound (7-3)(2.09 g).
1H-NMR (CDCl3) 1.03 (9H, s), 1.87 (3H, s), 2.04 (2H, m), 3.48 (1H, m), 3.51 (1H, m), 3.62 (3H, s), 3.65 (3H, s), 4.95 (1H, d, J=12.2 Hz), 5.03 (1H, d, J=12.2 Hz), 6.80-7.09 (3H, m), 7.22-7.42 (10H, m), 7.56-7.64 (5H, m).
Step 3
The compound (7-3)(2.09 g) was dissolved into 1,4-dioxane (15 ml), and 4 mol/L hydrochloric acid-1,4-dioxane (15 ml) solution was added, then stirred at room temperature for 24 hours. To the reaction mixture, water and 1 mol/L—sodium hydroxide solution were added and extracted with dichloromethane, then the organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to afford the compound (7-4)(0.45 g).
1H-NMR (CDCl3) 1.57 (3H, s), 1.07-1.98 (2H, m), 3.48-3.56 (1H, m), 3.72-3.86 (1H, m), 7.23-7.45 (15H, m).
Step 4
The compound (7-4)(0.44 g) was dissolved into tetrahydrofuran (15 ml), t-butylisothiocyanate (0.41 g) and diisopropylethylamine (0.46 g) were added. After the mixture was stirred at room temperature for 3 days, water was added, and extracted with dichloromethane, then the organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to afford the compound (7-5)(0.17 g).
1H-NMR (CDCl3) 1.79 (3H, s), 1.82-2.20 (2H, m), 3.71-3.81 (2H, m), 5.09 (1H, br), 7.30-7.52 (5H, m).
Step 5
The compound (7-5)(0.17 g) was dissolved into tetrahydrofuran (3.4 ml), then methyl iodide (0.11 g) was added at room temperature with stirring. The mixture was stirred for 23 hours, the reaction solvent was evaporated under reduced pressure to afford the compound (7-6)(0.28 g) as crude product.
Step 6
The compound (7-6)(0.28 g) was dissolved into tetrahydrofuran (5 ml), then triethylamine (74 mg) and silver oxide (0.34 g) were added. The mixture was stirred at room temperature for 20 hours, then insolubles were removed by filtration, and then the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to afford the compound (7-7)(0.14 g).
1H-NMR (CDCl3) 1.36 (9H, s), 1.49 (3H, s), 1.96-2.09 (2H, m), 2.77-3.83 (1H, m), 4.05-4.10 (1H, m), 7.19 (1H, t, J=7.3 Hz), 7.31 (2H, t, J=7.3 Hz), 7.44 (2H, d, J=7.3 Hz).
Step 7
To the compound (7-7)(0.12 g) conc. hydrochloric acid (9 ml) was added, then stirred for 1 hour under reflux, and then the reaction solvent was evaporated under reduced pressure. The obtained residue was crystallized from methanol-water to afford the compound (69)(0.10 g).
1H-NMR (DMSO-d6) 1.65 (3H, s), 2.28-2.35 (1H, m), 2.39-2.44 (1H, m), 3.97 (1H, dt, J=7.8, 3.0 Hz), 4.53 (1H, dt, J=7.8, 3.0 Hz), 7.32-7.44 (5H, m), 8.44 (2H, br), 10.33 (1H, s).
Example 8
The synthesis of compound 256




Step 1

The compound (8-1)(4890 mg) was dissolved into N,N-dimethylformamide (100 ml), then sodium azide (5720 mg) was added at room temperature with stirring, and the solution was warmed to 80° C., and stirred for 12 hours. After the consumption of the compound (8-1)(checked by TLC), the reaction mixture was cooled to room temperature, then diethyl ether and water were added, and then the mixture was extracted with diethyl ether. The organic layer was washed with brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to afford the compound (8-2)(4940 mg) as crude product.
Step 2
To the suspension of lithium aluminium hydride (1080 mg) in tetrahydrofuran (90 ml) under nitrogen atmosphere under cooling with ice-water bath, the compound (8-2)(4940 mg) in tetrahydrofuran (15 ml) solution was added, the reaction mixture was stirred for 30 minutes. After the consumption of the compound (8-2)(checked by TLC), 1 mol/L sodium hydroxide solution was added under cooling with ice-water bath, then stirred for a while. The generated gel was removed with filtration, and the mother liquid was extracted with diethyl ether. The organic layer was washed with brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to afford the compound (8-3)(4219.1 mg) as crude product.
Step 3
The compound (8-3)(800 mg) was dissolved into acetonitrile (16 ml), the compound (8-4)(1840 mg) was added with stirring at room temperature, and stirred for 13 hours. After the consumption of the compound (8-3)(checked by no, the reaction solvent was evaporated under reduced pressure, the obtained residue was purified by silica gel column chromatography to afford the compound (8-5)(1550.7 mg).
8-5-(Z) 1H-NMR (CDCl3, 270 MHz) 1.49 (18H, s), 2.06 (3H, d, J=1.4 Hz), 3.91-4.00 (2H, m), 5.54 (1H, td, J=7.1, 1.4 Hz), 7.12-7.41 (5H, m), 8.17-8.25 (1H, m), 11.47 (1H, s)
8-5-(E) 1H-NMR (CDCl3, 270 MHz) 1.49 (9H, s), 1.52 (9H, s), 2.09 (3H, d, J=1.5 Hz), 4.24 (2H, dd, J=6.6, 5.3 Hz), 5.80 (1H, td, J=6.6, 1.5 Hz), 7.21-7.48 (5H, m), 8.28-8.38 (1H, m), 11.51 (1H, s)
Step 4
The compound (8-5)(474.1 mg) was dissolved into trifluoroacetic acid (4.5 ml) under cooling with ice-water bath, then warmed to room temperature, and stirred for 4 hours. After the consumption of the compound (8-5)(checked by NMR), the reaction mixture was poured into floating ice −1 mol/L sodium hydroxide solution to be neutralized, then the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to afford the compound (8-6)(326.4 mg) as crude product.
Step 5
The compound (8-6)(326.4 mg) was dissolved into 1,4-dioxane (2.4 ml), sodium hydroxide (195 mg) and water (1.2 ml) were added successively, then di-t-butyl dicarbonate (0.84 ml) was added under cooling with ice-water bath. The reaction mixture was warmed to room temperature, and stirred for 15 hours, then the consumption of the compound (8-6) was checked by LC-MS. After added water to the reaction mixture, the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to afford the compound (8-7)(113.6 mg).
1H-NMR (CDCl3, 400 MHz) 1.46 (9H, s), 1.51 (9H, s), 1.64 (3H, s), 2.06 (1H, ddd, J=13.4, 11.4, 5.0 Hz), 2.27 (1H, dt, J=13.4, 4.6 Hz), 3.15 (1H, ddd, J=12.9, 11.3, 4.6 Hz), 3.70 (1H, dt, J=12.9, 4.7 Hz), 7.23-7.29 (1H, m), 7.33-7.38 (4H, m)
Step 6
The compound (8-7)(110 mg) was dissolved into 4 mol/L hydrochloric acid-1,4-dioxane solution (1 ml) under cooling ice-water bath, the mixture was warmed to room temperature, and stirred for 2 days, then the consumption of the compound (8-7) was checked by LC-MS, and diethyl ether and water were added at room temperature. After separation of diethyl ether layer, water layer was evaporated under reduced pressure. To the obtained residue, methanol was added, then the generated crystal was filtered. The methanol in mother liquid was evaporated under reduced pressure to afford the compound (256)(69 mg).
1H-NMR (DMSO-d6, 400 MHz) 1.57 (3H, s), 1.87-1.96 (1H, m), 2.30 (1H, dt, J=13.6, 3.8 Hz), 2.60 (1H, td, J=12.0, 3.7 Hz), 3.25 (1H, ddd, J=12.8, 8.2, 4.4 Hz), 6.93 (2H, s), 7.27-7.44 (5H, m), 7.94 (1H, s), 8.63 (1H, s)
Example 9
The synthesis of compound 24




Step 1

The compound (9-1)(0.39 g) was dissolved into chloroform (20 ml), iodine (1.53 g), potassium thiocyanate (1.25 g), catalytic amount of tetrabutylammonium chloride, and water (1 ml) were added at room temperature, then stirred for 15 hours. To the reaction mixture, 10% thiosodium sulfate solution and water were added, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to afford the compound (9-2)(0.56 g).
1H-NMR (CDCl3) 1.95 (3H, s), 3.62 (2H, s), 7.30-7.40 (4H, m).
Step 2
To a solution of the compound (9-2)(0.56 g) in tetrahydrofuran (10 ml), t-butylamine (0.24 g) was added and stirred at room temperature for 18 hours. The reaction solvent was evaporated under reduced pressure, then the obtained residue was purified by silica gel column chromatography to afford the compound (9-3)(190 mg).
1H-NMR (CDCl3) 1.43 (9H, s), 1.56 (3H, s), 3.27 (1H, d, J=10.6 Hz), 3.36 (1H, d, J=10.6 Hz), 7.28 (2H, d, J=8.2 Hz), 7.43 (2H, d, J=8.2 Hz).
Step 3
To the compound (9-3)(190 mg), conc. hydrochloric acid (3 ml) was added, then stirred at 100° C. for 3 hours. To the reaction mixture, 6 mol/L sodium hydroxide was added to neutralize, the mixture was extracted with dichloromethane. The organic layer was dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography, then crystallized from dichloromethane/n-hexane to afford the compound (24)(110 mg).
1H-NMR (CDCl3) 1.62 (3H, s), 3.47 (1H, d, J=10.6 Hz), 3.52 (1H, d, J=10.6 Hz), 4.59 (2H, br), 7.29 (2H, d, J=8.6 Hz), 7.39 (2H, d, J=8.6 Hz).
Example 10
The synthesis of compound 48




Step 1

The compound (10-1)(79.6 mg) and (10-2)(120 mg) were dissolved into N,N-dimethylformamide (3 ml), then 1-hydroxybenzotriazole (54.6 mg) and N,N′-diisopropylcarbodiimide (0.063 ml) were added, then the reaction mixture was stirred overnight at room temperature. Then after the consumption of the compound (10-1), water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to afford the compound (10-3)(110.2 mg) as crude product of diastereomer.
1H-NMR (CDCl3) 0.78-1.00 (6H, m), 1.14 (9/2H, s), 1.16 (9/2H, s) 1.52 (3/2H, s), 1.54 (3/2H, s) 1.86-2.28 (3H, m), 2.56-2.89 (2H, m), 3.80 (3/2H, s), 3.81 (3/2H, s) 4.04-4.14 (1H, m), 6.80-6.91 (2H, m), 7.08-7.22 (2H, m), 7.30-7.51 (6H, m), 7.61-7.76 (4H, m)
Step 2
The compound (10-3)(100 mg) was dissolved into tetrahydrofuran (3 ml) under nitrogen atmosphere, then 1 mol/L tetrabutylammonium fluoride in tetrahydrofuran (0.18 ml) was added at 0° C. with stirring, then the reaction mixture was stirred at 0° C. for 5 minutes. After the consumption of the compound (10-3), water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate, then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to afford the compound (48)(40.7 mg) as a mixture of diastereomers.
1H-NMR (CDCl3) 0.80-0.90 (3H, m) 1.01-1.12 (3H, m) 1.70 (3H, m), 2.02-2.31 (2H, m) 2.39-2.55 (1H, m), 2.61-2.90 (2H, m) 3.53-3.70 (1H, m) 3.81 (3H, m), 3.96-4.08 (1H, m) 6.87-6.96 (2H, m), 7.13-7.22 (2H, m)
Example 11
The synthesis of compound 707




Step 1

The compound (11-1)(150 mg) was dissolved into acetonitrile (5 ml), then the compound (11-2)(219.6 mg) was added at room temperature with stirring, and then the reaction mixture was warmed to 60° C., and stirred for 25 hours. The compound (11-1) was remained (checked by TLC). The reaction solvent was evaporated under reduced pressure, then the obtained residue was purified by silica gel column chromatography to afford the compound (11-1)(211.4 mg).
1H-NMR (CDCl3, 400 MHz) 1.46 (9H, s), 1.50 (9H, s), 1.57 (3H, s), 1.90 (1H, ddd, J=13.7, 10.0, 3.8 Hz) 2.11 (1H, ddd, J=13.7, 6.5, 3.7 Hz) 2.68-2.76 (1H, m), 2.86-2.93 (1H, m), 3.88 (3H, s), 6.91 (1H, t, J=8.6 Hz) 6.99-7.03 (1H, m), 7.06 (1H, dd, J=13.0, 2.2 Hz), 10.14 (1H, s), 13.93 (1H, s)
Step 2
The compound (11-3)(210 mg) was dissolved into 4 mol/L hydrochloric acid in 1,4-dioxane (4 ml) under cooling with ice-water bath, then the mixture was warmed to room temperature and stirred for 67 hours. After the consumption of the compound (11-3)(checked by LC/MS), the reaction solvent was evaporated under reduced pressure. The obtained residue was crystallized from methanol-diethyl ether, and crystal was collected by filtration and washed with diethyl ether to afford compound (707)(140.2 mg).
1H-NMR (DMSO-d6, 400 MHz) 1.56 (3H, s), 1.90-2.01 (1H, m), 2.43-2.62 (2H, m), 2.95-3.03 (1H, m), 3.84 (3H, s), 7.10-7.27 (3H, m), 7.76 (3H, br s), 8.26 (1H, br s), 9.42 (1H, s)
Example 12
The synthesis of compound 845




Step 1

The compound (12-1)(50 mg) and piperidine (17.9 mg) were dissolved into N,N-dimethylformamide (2 ml), then O-(7-azabenzotriazo-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (79.8 mg) was added, and then the mixture was stirred at room temperature for 40 hours. After the consumption of the compound (12-1), the solvent was evaporated under reduced pressure with heating. To the obtained residue, saturated sodium hydrogencarbonate solution was added, and extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate, then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to afford the compound (845)(30.7 mg).
1H-NMR (CDCl3) 1.60 (3H, s), 1.51-1.82 (61-1, m), 1.87-1.98 (1H, m), 2.09-2.19 (1H, m), 2.91-2.97 (2H, m), 3.64-3.68 (4H, m), 6.73 (1H, d, J=4.05 Hz), 7.14 (1H, d, J=4.05 Hz)
Example 13
The synthesis of compound 1262




Step 1

The compound (13-1)(50.0 mg) was dissolved into tetrahydrofuran (1 ml) under nitrogen atmosphere, then triethylamine (19 μl), and 4-bromobenzoyl chloride (30.1 mg) were added under cooling with ice-water bath, and stirred for 40 minutes. The reaction solvent was evaporated under reduced pressure, and then the obtained residue was dissolved into ethyl acetate. The solution was washed with saturated sodium hydrogencarbonate solution, and dried over magnesium sulfate, and then the solvent was evaporated under reduced pressure. The generated crystal was collected by filtration to afford the compound (13-2)(57.2 mg).
1H-NMR (CDCl3) 1.48 (9H, s), 1.68 (3H, s), 2.08 (1H, m), 2.44 (1H, m), 2.65 (1H, m), 2.78 (1H, m), 7.18 (1H, s), 7.32 (1H, s), 7.64 (2H, d, J=8.2 Hz), 7.78 (2H, d, J=8.2 Hz), 8.15 (1H, s), 8.25 (1H, br)
Step 2
The compound (13-2)(62.3 mg) was dissolved into 4 mol/L hydrochloric acid-1,4-dioxane and stirred for 24 hours. The reaction solvent was evaporated under reduced pressure. The obtained residue was crystallized from methanol/diethyl ether to afford the compound (1262)(44.7 mg).
1H-NMR (DMSO-ds) 1.67 (3H, s), 2.10 (1H, m), 2.50-2.61 (3H, m), 7.33 (1H, s), 7.74 (1H, s), 7.77 (2H, d, J=8.6 Hz), 7.91 (2H, d, J=8.6 Hz), 8.08 (1H, s), 10.6 (1H, s)
Example 14
The synthesis of compound 753




Step 1

The compound (14-1)(46 mg) was dissolved into dichloromethane (2 ml), then 4-chlorobenzaldehyde (20 mg) and acetic acid (17 mg) was added at room temperature, and then stirred for 20 minutes, and then sodium triacetoxyborohydride (45 mg) was added under cooling with ice-water bath. The mixture was stirred at room temperature for 14 hours, and then water was added and extracted with dichloromethane. The organic layer was dried over sodium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to afford the compound (14-2)(52 mg).
1H-NMR(CDCl3) 1.50 (9H, s), 1.64 (3H, s), 2.02-2.10 (1H, m), 2.40 (1H, dt, J=14.0, 4.1 Hz), 2.62-2.74 (2H, m), 4.30 (2H, s), 6.49 (1H, ddd, J=, 7.8, 2.0, 0.8 Hz), 6.52 (1H, t, J=2.0 Hz), 6.60 (1H, ddd, J=, 7.8, 2.0, 0.8 Hz), 7.16 (1H, t, J=7.8 Hz), 7.18-7.33 (4H, m).
Step 2
To the compound (14-2)(52 mg), 4 mol/L hydrochloric acid in 1,4-dioxane solution (4 ml) was added, then the mixture was stirred at room temperature for 4 days, and then the reaction solvent was evaporated under reduced pressure. The obtained residue was crystallized from methanol/diethyl ether to afford the compound (753)(42 mg).
1H-NMR (DMSO-d6) 1.58 (3H, s), 2.00 (1H, ddd, J=, 14.3, 11.3, 3.3 Hz), 2.49-2.57 (2H, m), 3.07 (1H, dt, J=12.7, 3.3 Hz), 4.27 (2H, s), 6.47 (1H, d, J=8.2 Hz), 6.51-6.53 (2H, m), 7.08 (1H, t, J=8.2 Hz), 7.37 (4H, s), 8.80 (2H, br).
Example 15
The synthesis of compound 1135




Step 1

To a solution of the compound (15-1)(101 mg), 2-propanol (56 μl), and triphenylphosphine (189 mg) in tetrahydrofuran (2 ml), diethyl azodicarboxylate (2.2 mol/L) in toluene (328 μl) was added dropwise, then stirred for 1 hour at room temperature. After the consumption of the compound (15-1), the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to afford the compound (15-2)(280 mg) as a mixture of triphenylphosphine oxide and diethyl hydrazodicarboxylate.
Step 2
To the suspension of 5-chloropyridine-2-carboxylic acid (47 mg) in toluene (1 ml), N,N-dimethylformamide (1 drop) and thionylchloride (91 μl) were added and stirred at 100° C. for 1 hour. The solvent was evaporated under reduced pressure, then the obtained residue was dissolved into tetrahydrofuran (1 ml), and then the mixture of the compound (15-2) (280 mg), and pyridine (194 μl) in tetrahydrofuran (0.5 ml) were added dropwise at 0° C. and stirred for 10 minutes. After the consumption of the compound (15-2), water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to afford the compound (15-3)(68 mg) as a mixture of diethyl hydrazodicarboxylate.
Step 3
To the compound (15-3)(68 mg) as a mixture of diethyl hydrazodicarboxylate, 4 mol/L in hydrochloric acid in 1,4-dioxane solution (1 ml) was added, then the mixture was stirred at room temperature for 16 hours. After the consumption of the compound (44), the reaction solvent was evaporated under reduced pressure. The obtained residue was crystallized from 2-propanol/diethyl ether to afford the compound (1135)(36 mg).
1H-NMR (DMSO-d6) 1.30 (3H, d, J=6.4 Hz), 1.31 (3H, d, J=6.4 Hz), 1.65 (3H, s), 2.04-2.11 (1H, m), 2.50-2.64 (2H, m), 3.12-3.16 (1H, m), 4.61 (1H, sep, J=6.4 Hz), 6.66 (1H, t, J=2.0 Hz), 7.48 (1H, t, J=2.0 Hz), 7.60 (1H, t, J=2.0 Hz), 8.16 (1H, dd, J=8.4, 0.8 Hz), 8.22 (1H, dd, J=8.4, 2.4 Hz), 8.79 (1H, dd, J=2.4, 0.8 Hz), 10.33 (1H, a), 10.72 (1H, s).
Example 16
The synthesis of compound 161




Step 1

The compound (16-1)(200 mg), palladium acetate (4.7 mg), and tri-(o-tolyl)phosphine (12.5 mg), were dissolved into N,N-dimethylformamide (2 ml) under nitrogen atmosphere, then n-butylamine (0.196 ml), and p-chlorostyrene (0.074 ml) were added at room temperature with stirring, then the solution was warmed to 80° C., and stirred for 3 hours. After the consumption of the compound (16-1)(checked by TLC), the reaction mixture was cooled to room temperature, and saturated ammonium chloride solution was added to the mixture. The mixture was extracted with ethyl acetate, the organic layer was washed with water and brine, and dried over magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to afford the compound (16-2)(213.1 mg).
1H-NMR (CDCl3, 400 MHz) 1.54 (18H, s), 1.64 (3H, s), 1.96 (1H, ddd, J=13.7, 9.1, 4.0 Hz) 2.10 (1H, ddd, J=13.7, 8.1, 3.4 Hz) 2.86 (1H, ddd, J=12.3, 9.1, 3.4 Hz), 3.03 (1H, ddd, J=12.3, 8.1, 4.0 Hz), 7.08 (1H, d, J=16.4 Hz) 7.15 (1H, d, J=16.4 Hz), 7.27-7.40 (5H, m) 7.44 (2H, d, J=8.8 Hz), 7.58 (1H, s)
Step 2
The compound (16-2)(213 mg) was dissolved into 4 mol/L hydrochloric acid in 1,4-dioxane (5 ml) under cooling with ice-water bath, then the mixture was warmed to room temperature and stirred for 63 hours. After the consumption of the compound (16-2)(checked by LC/MS), the reaction mixture was diluted with diethyl ether. The generated crystal was collected by filtration, and washed with diethyl ether to afford the compound (161)(108.6 mg).
1H-NMR (DMSO-d6, 400 MHz) 1.69 (3H, s), 2.08-2.18 (1H, m), 2.56-2.70 (2H, m), 3.13-3.20 (1H, m), 7.23 (1H, d, J=8.0 Hz), 7.31 (1H, d, J=17.0 Hz), 7.35 (1H, d, J=17.0 Hz), 7.45 (2H, d, J=8.6 Hz), 7.46 (1H, t, 7.6 Hz), 7.59 (1H, d, J=2.0 Hz), 7.61-7.64 (1H, m), 7.64 (2H, d, J=8.6 Hz), 8.53-9.50 (2H, br), 10.67 (1H, br)
Example 17
The synthesis of compound 597




Step 1

The solution of compound (17-1)(135 mg), O-methxylhydroxylamine hydrochloride (39 mg), and potassium acetate (27 mg) in methanol (3 ml) was stirred at room temperature for 16 hours, then water was added. The mixture was extracted with dichloromethane, the organic layer was dried over anhydrous sodium sulfate, then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to afford the compound (17-2)(110 mg).
1H-NMR (CDCl3) 1.51 (9H, s), 1.70 (3H, s), 2.14 (1H, ddd, J=14.4, 11.4, 3.4 Hz), 2.22 (3H, s), 2.48 (1H, m), 2.65 (1H, dt, J=12.6, 11.4 Hz), 2.78 (1H, ddd, J=12.6, 5.6, 3.4 Hz), 4.00 (3H, s), 7.30 (1H, d, J=7.8 Hz), 7.38 (1H, d, J=7.8 Hz), 7.54-7.57 (2H, m).
Step 2
To the compound (17-2)(110 mg), 4 mol/L hydrochloric acid in 1,4-dioxane (4.5 ml) solution was added and stirred for 4 days at room temperature, then the reaction solvent was evaporated under reduced pressure. The obtained residue was crystallized from methanol/diethyl ether to afford compound (597)(65 mg).
1H-NMR (DMSO-d6) 1.67 (3H, s), 2.08-2.15 (1H, m), 2.20 (3H, s), 2.56-2.64 (2H, m), 3.14-3.17 (1H, m), 3.92 (3H, s), 7.37 (1H, d, J=8.0 Hz), 7.48 (1H, d, J=8.0 Hz), 7.56 (1H, s), 7.62 (1H, d, J=8.0 Hz).
The other compounds were synthesized in the same way. The structural formulas and physical constants are shown below.








TABLE 1





Compound



No.
Chemical structure







1






 


2






 


3






 


4






 


5






 


6






 


7






 


8






 


9





















TABLE 2







10






 


11






 


12






 


13






 


14






 


15






 


16






 


17






 


18























TABLE 3









19







 



20







 



21







 



22







 



23







 



24







 



25







 



26







 



27







 



28






















TABLE 4







29






 


30






 


31






 


32






 


33






 


34






 


35






 


36






 


37






 


38






 


39





















TABLE 5







40






 


41






 


42






 


43






 


44






 


45






 


46






 


47























TABLE 6









48







 



49







 



50







 



51







 



52







 



53







 



54







 



55






















TABLE 7







56






 


57






 


58






 


59






 


60






 


61






 


62






 


63






 


64






 


65





















TABLE 8







66






 


67






 


68






 


69






 


70






 


71






 


72






 


73






 


74























TABLE 9









75







 



76







 



77







 



78







 



79







 



80







 



81







 



82






















TABLE 10







83






 


84






 


85






 


86






 


87






 


88






 


89






 


90






 


91





















TABLE 11







92






 


93






 


94






 


95






 


96






 


97






 


98






 


99






 


100






 


101























TABLE 12









102







 



103







 



104







 



105







 



106







 



107







 



108







 



109






















TABLE 13







110






 


111






 


112






 


113






 


114






 


115






 


116






 


117






 


118






 


119





















TABLE 14







120






 


121






 


122






 


124






 


125






 


126






 


127






 


128






 


129






 


130





















TABLE 15







131






 


132






 


133






 


134






 


135






 


136






 


137






 


138






 


139






 


140






 


141





















TABLE 16







142






 


143






 


144






 


145






 


146






 


147






 


148






 


149






 


150





















TABLE 17







151






 


152






 


153






 


154






 


155






 


156






 


157






 


158






 


159






















TABLE 18








160






 



161






 



162






 



163






 



164






 



165






 



166





















TABLE 19







167






 


168






 


169






 


170






 


171






 


172






 


173






 


174






 


175






 


176





















TABLE 20







177






 


178






 


179






 


180






 


181






 


182






 


183






 


184






 


185






 


186






 


187






 


188






















TABLE 21








189






 



190






 



191






 



192






 



193






 



194






 



195






 



196





















TABLE 22







197






 


198






 


199






 


200






 


201






 


202






 


203






 


204






 


205






 


206






















TABLE 23








207






 



208






 



209






 



210






 



211






 



212






 



213






 



214






 



215





















TABLE 24







216






 


217






 


218






 


219






 


220






 


221






 


222






 


223






 


224





















TABLE 25







225






 


226






 


227






 


228






 


229






 


230






 


231






 


232






 


233






 


234





















TABLE 26







235






 


236






 


237






 


238






 


239






 


240






 


241






 


242






 


243






 


244






 


245






 


246





















TABLE 27







247






 


248






 


249






 


250






 


251






 


252






 


253






 


254






 


255





















TABLE 28







256






 


257






 


258






 


259






 


260






 


261






 


262






 


263






 


264






 


265






 


266





















TABLE 29







267






 


268






 


269






 


270






 


271






 


272






 


273






 


274






 


275























TABLE 30









276







 



277







 



278







 



279







 



280







 



281







 



282







283







 



284






















TABLE 31







285






 


286






 


287






 


288






 


289






 


290






 


291






 


292






 


293





















TABLE 32







294






 


295






 


296






 


297






 


298






 


299






 


300






 


301






 


302























TABLE 33









303







 



304







 



305







 



306







 



307







 



308







 



309






















TABLE 34







310






 


311






 


312






 


313






 


314






 


315






 


316






 


317





















TABLE 35







318 






 


319






 


320






 


321






 


322






 


323






 


324






 


325






 


326






 


327






 


328





















TABLE 36







329






 


330






 


331






 


332






 


333






 


334






 


335






 


336






 


337






 


338






 


339





















TABLE 37







340






 


341






 


342






 


343






 


344






 


345






 


346






 


347






 


348























TABLE 38









349







 



350







 



351







 



352







 



353







 



354







 



355







 



356







 



357






















TABLE 39







358






 


359






 


360






 


361






 


362






 


363






 


364






 


365






 


366






 


367






 


368






 


369























TABLE 40









370







 



371







 



372







 



373







 



374







 



375







 



376







 



377







 



378






















TABLE 41







379






 


380






 


381






 


382






 


383






 


384






 


385






 


386






 


387






 


388






 


389





















TABLE 42







390






 


391






 


392






 


393






 


394






 


395






 


396






 


397





















TABLE 43







398






 


399






 


400






 


401






 


402






 


403






 


404






 


405






 


406






 


407























TABLE 44









408







 



409







 



410







 



411







 



412







 



413







 



414







 



415







 



416
























TABLE 45









417







 



418







 



419







 



420







 



421







 



422







 



423







 



424
























TABLE 46









425







 



426







 



427







 



428







 



429







 



430







 



431







 



432







 



433
























TABLE 47









434







 



435







 



436







 



437







 



438







 



439







 



440







 



441







 



442






















TABLE 48







443






 


444






 


445






 


446






 


447






 


448






 


449






 


450






 


451






 


452






 


453





















TABLE 49







454






 


455






 


456






 


457






 


458






 


459






 


460






 


461






 


462






 


463






 


464























TABLE 50









465







 



466







 



467







 



468







 



469







 



470







 



471







 



472







 



473







 



474
























TABLE 51









475







 



476







 



477







 



478







 



479







 



480







 



481







 



482







 



483






















TABLE 52







484






 


485






 


486






 


487






 


488






 


489






 


490






 


491






 


492























TABLE 53









493







 



494







 



495







 



496







 



497







 



498







 



499







 



500







 



501







 



502







 



503
























TABLE 54









504







 



505







 



506







 



507







 



508







 



509







 



510







 



511







 



512







 



513







 



514
























TABLE 55









515







 



516







 



517







 



518







 



519







 



520







 



521







 



522







 



523







 



524
























TABLE 56









525







 



526







 



527







 



528







 



529







 



530







 



531







 



532







 



533







 



534







 



535






















TABLE 57







536






 


537






 


538






 


539






 


540






 


541






 


542






 


543






 


544






 


545






 


548























TABLE 58









547







 



548







 



549







 



550







 



551







 



552







 



553







 



554







 



555






















TABLE 59







556






 


557






 


558






 


559






 


560






 


561






 


562






 


563






 


564






 


565






 


566





















TABLE 60







567






 


568






 


569






 


570






 


571






 


572






 


573






 


574





















TABLE 61







575






 


576






 


577






 


578






 


579






 


580






 


581






 


582






 


583






 


584





















TABLE 62







585






 


586






 


587






 


588






 


589






 


590






 


591





















TABLE 63







592






 


593






 


594






 


595






 


596






 


597






 


598






 


599






 


600






 


601






 


602





















TABLE 64







603






 


604






 


605






 


606






 


607






 


608






 


609






 


610






 


611






 


612






 


613





















TABLE 65







614






 


615






 


616






 


617






 


618






 


619






 


620






 


621






 


623






 


624





















TABLE 66







625






 


626






 


627






 


628






 


629






 


630






 


631






 


632






 


633






 


634






 


635





















TABLE 67







636






 


637






 


638






 


639






 


640






 


641






 


642






 


643





















TABLE 68







644






 


645






 


646






 


647






 


648






 


649






 


650






 


651






 


652






 


653






 


654






 


655






 


656





















TABLE 69







657






 


658






 


659






 


660






 


661






 


662






 


663






 


664






 


665





















TABLE 70







666






 


667






 


668






 


669






 


670






 


671






 


672






 


673






 


674





















TABLE 71







675






 


676






 


677






 


678






 


679






 


680






 


681






 


682






 


683





















TABLE 72







684






 


685






 


686






 


687






 


688






 


689






 


690






 


691






 


692





















TABLE 73







693






 


694






 


695






 


696






 


697






 


698






 


699






 


700






 


701






 


702





















TABLE 74











703


 






704


 






705


 






706


 






707


 






708


 






709


 






710


 






711


 






712

















TABLE 75











713


 






714


 






715


 






716


 






717


 






718


 






719

















TABLE 76











720


 






721


 






722


 






723


 






724


 






725


 






726


 






727


 






728


 






729

















TABLE 77











730


 






731


 






732


 






734


 






735


 






736


 






737


 






738


 






739


 






740

















TABLE 78











741


 






742


 






743


 






744


 






745


 






746


 






747


 






748


 






749

















TABLE 79











750


 






751


 






752


 






753


 






754


 






755


 






756


 






757


 






758


 






759

















TABLE 80











760


 






761


 






762


 






763


 






764


 






765


 






766


 






767


 






768


 






769

















TABLE 81











770


 






771


 






772


 






773


 






774


 






775


 






776


 






777

















TABLE 82











778


 






779


 






780


 






781


 






782


 






783


 






784


 






785


 






786


 






787


 






788


 






789

















TABLE 83











790


 






791


 






792


 






793


 






794


 






795


 






796


 






797


 






798

















TABLE 84











799


 






800


 






801


 






802


 






803


 






804


 






805


 






806


 






807


 






808


 






809

















TABLE 85











810


 






811


 






812


 






813


 






814


 






815


 






816


 






817


 






818

















TABLE 86











819


 






820


 






821


 






822


 






823


 






824


 






825


 






828


 






827

















TABLE 87











828


 






829


 






830


 






831


 






832


 






833


 






834


 






835


 






836

















TABLE 88











837


 






838


 






839


 






840


 






841


 






842


 






843


 






844


 






845

















TABLE 89







846






 


847






 


848






 


849






 


850






 


851






 


852






 


853






 


854






 


855





















TABLE 90







856






 


857






 


858






 


859






 


860






 


861






 


862






 


863






 


864






 


865





















TABLE 91







866






 


867






 


868






 


869






 


870






 


871






 


872






 


873






 


874






 


875























TABLE 92









876







 



877







 



878







 



879







 



880







 



881







 



882







 



883






















TABLE 93











884


 






885


 






886


 






887


 






888


 






889


 






890


 






891


 






892


 






893


 






894

















TABLE 94







895






 


896






 


897






 


898






 


899






 


900






 


901






 


902






 


903






 


904





















TABLE 95







905






 


906






 


907






 


908






 


909






 


910






 


911






 


912






 


913






 


914























TABLE 96









915







 



916







 



917







 



918







 



919







 



920







 



921







 



922






















TABLE 97







923






 


924






 


925






 


926






 


927






 


928






 


929






 


930






 


931






 


932





















TABLE 98







933






 


934






 


935






 


936






 


937






 


938






 


939






 


940























TABLE 99









941







 



942







 



943







 



944







 



945







 



946







 



947







 



948







 



949
























TABLE 100









950







 



951







 



952







 



953







 



954







 



955







 



956







 



957
























TABLE 101









958







 



959







 



960







 



961







 



962







 



963







 



964
























TABLE 102









965







 



966







 



967







 



968







 



969







 



970







 



971







 



972






















TABLE 103











973


 






974


 






975


 






976


 






977


 






978


 






979


 






980



















TABLE 104









981







 



982







 



983







 



984







 



985







 



986







 



987







 



988







 



989
























TABLE 105









990







 



991







 



992







 



993







 



994







 



995







 



996







 



997







 



998






















TABLE 106







 999






 


1000






 


1001






 


1002






 


1003






 


1004






 


1005






 


1006






 


1007





















TABLE 107







1008






 


1009






 


1010






 


1011






 


1012






 


1013






 


1014






 


1015






 


1016






 


1017





















TABLE 108







1018






 


1019






 


1020






 


1021






 


1022






 


1023






 


1024






 


1025





















TABLE 109







1026






 


1027






 


1028






 


1029






 


1030






 


1031






 


1032






 


1033






 


1034






 


1035





















TABLE 110







1036






 


1037






 


1038






 


1039






 


1040






 


1041






 


1042






 


1043






 


1044





















TABLE 111







1045






 


1046






 


1047






 


1048






 


1049






 


1050






 


1051






 


1052





















TABLE 112











1053


 






1054


 






1055


 






1056


 






1057


 






1058


 






1059


 






1060


 






1061


 






1062

















TABLE 113







1063






 


1064






 


1065






 


1066






 


1067






 


1068






 


1069






 


1070






 


1071





















TABLE 114







1072






 


1073






 


1074






 


1075






 


1076






 


1077






 


1078






 


1079






 


1080





















TABLE 115







1081






 


1082






 


1083






 


1084






 


1085






 


1086






 


1087






 


1088






 


1089






 


1090





















TABLE 116







1091






 


1092






 


1093






 


1094






 


1095






 


1096






 


1097






 


1098





















TABLE 117







1099






 


1100






 


1101






 


1102






 


1103






 


1105






 


1106






 


1107























TABLE 118









1108







 



1109







 



1110







 



1111







 



1112







 



1113







 



1114







 



1115






















TABLE 119







1116






 


1117






 


1118






 


1119






 


1120






 


1121






 


1122






 


1123






 


1124





















TABLE 120







1125






 


1126






 


1127






 


1128






 


1129






 


1130






 


1131






 


1132





















TABLE 121







1133






 


1134






 


1135






 


1136






 


1137






 


1138






 


1139






 


1140





















TABLE 122











1141


 






1142


 






1143


 






1144


 






1145


 






1146


 






1147


 






1148


 






1149


 






1150


 






1151


 






1152

















TABLE 123











1153


 






1154


 






1155


 






1156


 






1157


 






1158


 






1159


 






1160

















TABLE 124











1161


 






1162


 






1163


 






1164


 






1165


 






1166


 






1167


 






1168

















TABLE 125











1169


 






1170


 






1171


 






1172


 






1173


 






1174


 






1175


 






1176


 






1177

















TABLE 126











1178


 






1179


 






1180


 






1181


 






1182


 






1183


 






1184


 






1185


 






1186


 






1187


 






1188

















TABLE 127











1189


 






1190


 






1191


 






1192


 






1193


 






1194


 






1195


 






1196


 






1197


 






1198

















TABLE 128











1199


 






1200


 






1201


 






1202


 






1203


 






1204


 






1205


 






1206


 






1207

















TABLE 129











1208


 






1209


 






1210


 






1211


 






1212


 






1213


 






1214


 






1215


 






1216


 






1217

















TABLE 130











1218


 






1219


 






1220


 






1221


 






1222


 






1223


 






1224


 






1225


 






1226

















TABLE 131











1227


 






1228


 






1229


 






1230


 






1231


 






1232


 






1233


 






1234


 






1235


 






1236

















TABLE 132











1237


 






1238


 






1239


 






1240


 






1241


 






1242


 






1243


 






1244


 






1245


 






1246

















TABLE 133











1247


 






1248


 






1249


 






1250


 






1251


 






1252


 






1253


 






1254


 






1255


 






1256


 






1257

















TABLE 134











1258


 






1259


 






1260


 






1261


 






1262


 






1263


 






1264


 






1265


 






1266


 






1267


 






1268


 






1269

















TABLE 135











1270


 






1271


 






1272


 






1273


 






1274


 






1275


 






1276


 






1277


 






1279


 






1280


 






1281


 






1282
























TABLE 136





Compound
Melting Point

MS
UV


No.
(° C.)
1H-NMR (d)
(m/z)
(λmax: nm)



















1



213.4






305.3


3
285 (dec.)


4
amorphous


219


5



215, 262


6
147-148


8
214-217


9
oil


220


18
181-183


23



213.4






272.2






305.3


24
116-117


26
182-184


30



267.4


33



253.3






305.3


37
amorphous


219, 275


38
240-244



(dec.)


39



285.2


42
187-188


43



218.1






275.7


48



230






275


57
197-198


58
234-240


62
198-201


69
194-195


71



216.9






268.6


73
266-269


77

d in d20-DMSO: 1.67 (3H, s), 2.13-2.06 (1H, m),

422.543




2.63-2.55 (2H, m), 3.16-3.13 (4H, m), 3.65-3.63 (2H, m),




4.76-4.73 (2H, m), 7.15-7.08 (2H, m), 7.30 (1H, t, J = 8.0 Hz),




7.35 (1H, s), 7.42 (1H, t, J = 8.0 Hz), 7.60 (1H,




d, J = 8.0 Hz), 7.69 (1H, d, J = 8.0 Hz), 7.73 (1H, brs),




7.86 (1H, d, J = 8.0 Hz), 10.52 (1H, s)


78

1H-NMR (CDCl3) d: 1.76 (3H, s), 2.02 (1H, s),
365 [M + 1]




2.58 (1H, d, J = 14.1 Hz), 2.78 (2H, d, J = 6.9 Hz),




3.80 (3H, d, J = 13.1 Hz), 4.54 (2H, s), 6.45 (1H, s),




6.55-6.57 (2H, m), 6.66 (1H, d, J = 8.7 Hz), 7.10 (1H, t, J = 7.0 Hz),




7.22 (2H, td, J = 7.7, 1.4 Hz), 7.34 (1H, d, J = 9.1 Hz),




7.56 (1H, d, J = 7.7 Hz).


80



220.4






280.4




















TABLE 137





Compound
Melting Point

MS
UV


No.
(° C.)
1H-NMR (d)
(m/z)
(λmax: nm)



















85
147-148
1.54 (3H, s), 1.75-1.86 (1H, m), 2.08-2.18 (1H, m),






2.33 (3H, s), 2.63-2.74 (1H, m), 2.81-2.90 (1H, m),




4.36 (2H, br), 7.13 (2H, d, J = 8.6 Hz), 7.20 (2H, d, J = 8.6 Hz)




(solvent: CDCl3)


86
141-142


91


372 [M + 1]
201





296
206






216


96



309


97

d in d13-DMSO: 1.64 (3H, s), 2.03-1.97 (1H, m),




2.63-2.57 (2H, m), 3.28-3.25 (1H, m), 7.22 (1H, q, J = 12.4,




9.0 Hz), 7.82-7.77 (2H, m), 8.60 (1H, s), 8.79 (1H, s),




10.37 (1H, s).


99
221-224


101
264-265


104
amorphous


229, 280


113

1.58 (s, 3H), 1.88 (ddd, J = 14.1, 10.9, 3.7 Hz, 1H),




2.24 (ddd, J = 14.1, 5.9, 3.5 Hz, 1H), 2.73 (ddd,




J = 12.3, 10.9, 3.5 Hz, 1H), 2.88 (ddd, J = 12.3, 5.9,




3.7 Hz, 1H), 3.83 (d, J = 15.4 Hz, 1H), 3.87 (d,




J = 15.4 Hz, 1H), 7.02-7.04 (m, 1H), 7.25-7.31 (m, 2H),




7.36 (d, J = 2.0 Hz, 1H), 7.45-7.50 (m, 2H), 8.52 (d,




J = 5.2 Hz, 1H), 9.43 (s, 1H) (solvent: CDCl3)


114



214.5






306.5


115

d in d6-DMSO: 1.47 (3H, s), 1.80-1.74 (1H, m,




2.22-2.18 (1H, m), 2.60-2.55 (1H, m), 2.96-2.93 (1H, m),




6.14 (1H, s), 6.93 (1H, s), 7.09-7.04 (2H, m),




7.63-7.61 (1H, m), 7.68-7.66 (1H, m), 9.85 (1H, s),




11.63 (1H, brs)


120
amorphous


213


121
166-167


125
>300


126
amorphous


229, 271


127
280-285


128
159-163


129
219-222


130
128-131
1.56 (3H, s), 1.83-1.93 (1H, m), 2.16 (1H, dq, J = 13.85,
344 [M + 1]




3.41 Hz), 2.29 (3H, s), 2.72-2.77 (1H, m),




2.90-2.94 (1H, m), 4.13 (3H, s), 6.42 (1H, s),




7.10-7.14 (1H, m), 7.32 (1H, d, J = 7.91 Hz),




7.37-7.38 (1H, m), 7.60-7.63 (1H, m). (solvent: CDCl3)


132
147-150


134



228.5




















TABLE 138





Compound
Melting Point

MS
UV


No.
(° C.)
1H-NMR (d)
(m/z)
(λmax: nm)



















139
287-290
1.77 (s, 3H), 2.10 (ddd, J = 14.0, 10.8, 3.6 Hz, 1H),






2.64-2.70 (4H, m), 2.76 (td, J = 12.8, 3.6 Hz, 1H),




2.90 (dt, J = 12.8, 3.6 Hz, 1H), 7.05 (ddd, J = 8.0,




2.0, 0.8 Hz, 1H), 7.41 (t, J = 8.0 Hz, 1H),




7.69-7.72 (m, 2H), 8.32 (dd, J = 8.0, 0.8 Hz, 1H), 8.40 (dd, J = 8.0,




2.0 Hz, 1H), 9.14 (dd, J = 2.0, 0.8 Hz, 1H)




(solvent: CDCl3 + CD3OD)


141

d in d17-DMSO: 1.41 (3H, s), 1.75-1.70 (1H, m),




2.03-1.99 (1H, m), 2.62-2.56 (1H, m), 2.94-2.89 (1H, m),




3.89 (3H, s), 6.88 (1H, d, J = 8.8 Hz), 7.05 (1H, d, J = 7.6 Hz),




7.24 (1H, t, J = 8.0 Hz), 7.66-7.63 (3H, m),




8.45-8.44 (1H, m), 9.90 (1H, s)


148


362 [M + 1]
200





286
208






212






218






262


149
143-145


157

d in d6-DMSO: 1.20 (6H, d, J = 6.6 Hz), 1.41 (3H, s),




1.65-1.77 (1H, m), 1.96-2.07 (1H, m), 2.55-2.63 (1H,




m), 2.85-2.95 (1H, m), 4.04-4.16 (1H, m), 5.79 (2H,




bs), 7.07 (1H, d, J = 8.1 Hz), 7.25 (1H, t, J = 8.1 Hz),




7.72-7.78 (3H, m), 7.93 (1H, s), 8.64 (1H, s), 9.96 (1H, s).


159
amorphous


285


161
247-251


163
amorphous


164
91-96
1.68 (s, 3H), 2.07-2.15 (m, 1H), 3.13-3.20 (m, 1H),




7.12 (d, J = 7.6 Hz, 1H), 7.46 (t, J = 7.6 Hz, 1H),




7.90-7.94 (m, 2H), 8.83 (br s, 1H), 8.96 (br s, 1H), 9.31 (br s,




1H), 10.36 (s, 1H), 10.86 (s, 1H)


165
246-248


166
amorphous


220, 275


176
amorphous


217, 278


178
224-225


181



261.5


189



259


193
266-268


196



212


202
117-118
0.85 (3H, t, J = 7.3 Hz), 1.02-1.19 (1H, m),




1.34-1.54 (1H, m), 1.72-1.89 (3H, m), 2.04-2.15 (1H, m),




2.61-2.82 (2H, m), 3.80 (3H, s), 4.32 (2H, br), 6.85 (2H,




d, J = 8.9 Hz), 7.18 (2H, d, J = 8.9 Hz)




(solvent: CDCl3)




















TABLE 139





Compound
Melting Point

MS
UV


No.
(° C.)
1H-NMR (d)
(m/z)
(λmax: nm)







204
205-208
1.64 (d, J = 1.2 Hz, 3H), 1.95 (ddd, J = 14.0, 10.8,






3.6 Hz, 1H), 2.45 (ddd, J = 14.0, 6.4, 3.6 Hz, 1H),




2.75 (ddd, J = 12.4, 10.8, 3.6 Hz, 1H), 2.99 (ddd, J = 12.4,




6.4, 3.6 Hz, 1H), 7.09 (dd, J = 11.6, 8.8 Hz,




1H), 7.47 (dd, J = 7.2, 2.8 Hz, 1H), 8.03 (ddd, J = 8.8,




4.4, 2.8 Hz, 1H), 8.89 (s, 2H), 9.75 (s, 1H)




(solvent: CDCl3)


213
oil


216, 272


214



212.2






292.3






356.5


216



242.7


220
191-193

363 [M + 3]





361 [M + 1]





287





285


224
oil
1.58 (3H, s), 1.87 (1H, ddd, J = 13.9, 10.5, 3.7),

222




2.13 (1H, ddd, J = 13.9, 6.3, 3.7), 2.25 (3H, s),




2.68 (1H, ddd, J = 12.1, 10.5, 6.2), 2.89 (1H, ddd, J = 12.1,




6.3, 3.7), 5.23 (2H, s), 7.28-7.48 (4H, m),




7.60 (1H, s), 7.75 (1H, d, J = 8.0), 8.56 (1H, dd, J = 5.0,




1.4), 8.70 (1H, d, J = 1.4)




(solvent: CDCl3)


227



213


232

1H-NMR (CDCl3) d: 1.59 (3H, s), 1.83-1.90 (1H, m),
378 [M + 1]




2.35-2.47 (4H, m), 2.60-2.67 (1H, m), 2.87-2.92 (1H,




m), 4.70 (2H, br s), 6.87-6.98 (2H, m), 7.16 (1H, d, J = 6.6 Hz),




7.27 (2H, d, J = 7.8 Hz), 7.61 (2H, d, J = 8.1 Hz).


233
oil


224, 272


235
196-200


238

1H-NMR (CDCl3) d: 1.68 (3H, s), 1.97-2.00 (1H, m),
362 [M + 1]




2.53 (1H, dt, J = 14.4, 3.7 Hz), 2.63-2.79 (2H, m),




4.52 (2H, s), 6.56-6.66 (3H, m), 7.17 (1H, t, J = 8.0 Hz),




7.43-7.52 (3H, m), 7.81 (4H, dd, J = 11.6, 5.7 Hz).


241
187-190
1H-NMR (DMSO-d6) d: 1.49 (3H, s), 1.78-1.86 (1H,




m), 2.13-2.21 (1H, m), 2.59-2.67 (1H, m),




2.96-3.02 (1H, m), 7.11 (1H, t, J = 10.7 Hz), 7.29 (1H, t, J = 7.8 Hz),




7.45 (1H, t, J = 7.5 Hz), 7.66 (1H, d, J = 8.8 Hz),




7.74-7.78 (1H, m), 7.80-7.83 (1H, m), 8.21 (1H, d, J = 8.6 Hz),




10.25 (1H, s).


243
182-184
1.46 (s, 3H), 1.75-1.83 (m, 1H), 2.08-2.16 (m, 1H),




2.55-2.63 (m, 1H), 2.92-2.98 (m, 1H), 4.02 (s, 3H),




7.11 (d, J = 8.0 Hz, 1H), 7.31 (t, J = 8.0 Hz, 1H),




7.77 (d, J = 8.0 Hz, 1H), 7.82 (br s, 1H), 8.41 (d, J = 1.2 Hz,




1H), 8.90 (d, J = 1.2 Hz, 1H), 10.38 (s, 1H)




(solvent: CDCl3)




















TABLE 140





Compound
Melting Point

MS
UV


No.
(° C.)
1H-NMR (d)
(m/z)
(λmax: nm)



















244
222-224





251


351 [M + 1]
200





311
204





275
215






285


255
238-239


256
oil


215, 257


259
amorphous
1.58 (3H, s), 2.01 (1H, ddd, J = 15.2, 12.2, 3.4),

229




2.46-2.56 (2H, m), 3.07 (1H, ddd, J = 13.3, 5.7, 3.5),

298




4.24 (2H, s), 6.53 (1H, d, J = 7.6), 6.59-6.61 (2H, m),




7.09-7.12 (1H, m), 7.11 (2H, d, J = 7.6), 7.24 (2H, d, J = 7.6),




8.82 (2H, br) (solvent: DMSO-d6)


263


363 [M + 1]
200





287
284


267
114-115


268



214.5






298.2


271
oil


229, 276


275

(CDCl3) 1.66 (3H, d, J = 1.2 Hz), 1.98 (1H, ddd, J = 14.0,




10.4, 3.7 Hz), 2.47 (1H, ddd, J = 14.0, 6.7, 3.5 Hz),




2.79 (1H, ddd, J = 12.0, 10.4, 3.5 Hz), 3.02 (1H, ddd,




J = 12.0, 6.7, 3.7 Hz), 4.45 (2H, br), 6.16 (2H, br),




7.04-7.11 (2H, m), 7.38 (1H, dd, J = 7.2, 2.9 Hz), 7.88 (1H, d,




J = 2.0 Hz), 7.96 (1H, ddd, J = 8.9, 4.2, 2.9 Hz),




9.88 (1H, s)


277



216






228






281


279



214.5






292.3


281
amorphous
1.55 (3H, s), 1.83 (1H, ddd, J = 13.9, 10.6, 3.9),

233




2.10 (1H, ddd, J = 13.9, 6.5, 3.6), 2.67 (1H, ddd, J = 12.2,

301




10.6, 3.6), 2.87 (1H, ddd, J = 12.2, 6.5, 3.9),




4.49 (2H, d, J = 5.6), 4.85 (1H, br), 6.38 (1H, dt, J = 8.5,




0.9), 6.59 (1H, ddd, J = 7.2, 5.2, 0.9),




7.21-7.24 (2H, m), 7.28-7.32 (2H, m), 7.40 (1H, ddd, J = 8.5,




7.2, 1.8), 8.11 (1H, ddd, J = 5.2, 1.8, 0.8)




(solvent: CDCl3)


282
146-147


284
181.5


293

1.57 (s, 3H), 1.78-1.89 (m, 1H), 2.10-2.19 (m, 1H),




2.69 (ddd, J = 11.9, 10.8, 3.5 Hz, 1H), 2.83-2.91 (m,




1H), 7.15-7.35 (m, 5H)




(solvent: CDCl3)


299



293.5




















TABLE 141





Compound
Melting Point

MS
UV


No.
(° C.)
1H-NMR (d)
(m/z)
(λmax: nm)







301

(CDCl3) 1.53 (3H, s), 1.80 (1H, ddd, J = 14.0, 10.4, 3.6 Hz),






2.12 (1H, ddd, J = 14.0, 6.0, 3.6 Hz), 2.75 (1H,




ddd, J = 12.0, 10.4, 3.6 Hz), 2.85 (1H, ddd, J = 12.0,




6.0, 3.6 Hz), 3.64 (2H, s), 4.32 (2H, br), 6.55 (1H, ddd,




J = 8.0, 2.0, 0.8 Hz), 6.66 (1H, t, J = 2.0 Hz), 6.70 (1H,




ddd, J = 8.0, 2.0, 0.8 Hz), 7.11 (1H, t, J = 8.0 Hz)


302
122-126
1.41 (s, 3H), 1.67-1.76 (m, 1H), 1.98-2.06 (m, 1H),




2.55-2.63 (m, 1H), 2.86-2.94 (m, 1H), 3.19 (s, 6H),




5.75 (s, 2H), 7.08 (d, J = 8.0 Hz, 1H), 7.26 (t, J = 8.0 Hz,




1H), 7.73 (d, J = 8.0 Hz, 1H), 7.76 (br s, 1H),




8.16 (s, 1H), 8.73 (s, 1H), 10.00 (s, 1H)(solvent:




CDCl3)


306



231, 258,






289


307

1.83 (ddd, J = 13.9, 10.3, 3.6 Hz, 1H), 2.13 (ddd, J = 13.6,




6.2, 3.5 Hz, 1H), 2.53 (s, 3H), 2.66-2.75 (m,




1H), 2.90 (ddd, J = 12.2, 6.3, 3.8 Hz, 1H), 7.09 (d, J = 7.8 Hz,




1H), 7.32 (t, J = 8.0 Hz, 1H), 7.37 (s, 1H),




7.63 (d, J = 7.8 Hz, 1H), 8.79 (s, 1H) (solvent:




CDCl3)


308
167-168


309
241-244


319



308.9


329
238-239


330



213.4






263.9


332



212.2


333
154-158


339
217-218


341
amorphous


216






249


342
184-187


344

(DMSO) 1.49 (3H, s), 1.73-1.85 (1H, m),




2.15-2.28 (1H, m), 2.54-2.66 (1H, m), 2.92-3.04 (1H, m),




5.86 (2H, s), 7.03-7.25 (3H, m), 7.40-7.48 (2H, m),




7.64-7.78 (3H, m), 10.31 (1H, s), 11.74 (1H, s)


353



279.3






364.5


354
102-103


356
amorphous
1.73 (s, 3H), 2.09-2.17 (m, 1H), 2.40 (s, 3H),

267




2.65-2.73 (m, 2H), 3.15-3.23 (m, 1H), 3.81 (s, 3H),




7.07 (d, J = 7.2 Hz, 2H), 7.29 (br s, 1H), 7.36 (d, J = 8.0 Hz,




2H), 7.61 (d, J = 8.0 Hz, 2H), 7.78 (br s, 1H),




7.90 (d, J = 7.2 Hz, 2H), 8.00 (br s, 1H), 10.32 (s,




1H) (solvent: DMSO-d6)


357
amorphous


224, 298




















TABLE 142





Compound
Melting Point

MS
UV


No.
(° C.)
1H-NMR (d)
(m/z)
(λmax: nm)



















358

1.57 (3H, s), 1.80-1.91 (1H, m), 2.15-2.18 (1H, m),
360 [M + 1]





2.70-2.94 (2H, m), 3.94 (3H, s), 4.67 (2H, s),




6.75 (1H, s), 7.05-7.08 (1H, m), 7.31 (1H, t, J = 7.91 Hz),




7.53 (1H, t, J = 1.98 Hz), 7.64-7.67 (1H, m),




8.64 (1H, s). (solvent: CDCl3)


359
212-214
1.46 (s, 3H), 1.73-1.83 (m, 1H), 2.13-2.20 (m, 1H),




2.54-2.61 (m, 1H), 2.62 (s, 3H), 2.93-3.00 (m, 1H),




5.84 (br s, 2H), 7.12 (dd, J = 12.0, 8.8 Hz, 1H),




7.73-7.78 (m, 1H), 7.81 (dd, J = 7.2, 2.4 Hz, 1H), 8.68 (s,




1H), 9.13 (s, 1H), 10.59 (s, 1H) (solvent: CDCl3)


360
amorphous


222


361



280.4


364
oil

344 [M + 1]
227, 271


367

(CDCl3) 1.78 (3H, s), 2.07 (1H, ddd, J = 14.0, 12.4, 3.6 Hz),




2.61 (1H, br d, J = 14.0 Hz), 2.84 (1H, td, J = 12.4,




3.2 Hz), 2.94 (1H, td, J = 12.4, 3.6 Hz), 4.08 (3H, s),




7.07 (1H, ddd, J = 8.0, 2.0, 0.8 Hz), 7.40 (1H, t, J = 8.0 Hz),




7.63 (1H, ddd, J = 8.0, 2.0, 0.8 Hz), 7.74 (1H, t,




J = 2.0 Hz), 8.18 (1H, d, J = 1.2 Hz), 9.02 (1H, d, J = 1.2 Hz),




9.56 (1H, s)


375



217


380
181-182
0.86 (t, J = 7.2 Hz, 3H), 1.82-1.98 (m, 3H), 2.24 (br,




1H), 2.74 (td, J = 12.0, 3.6 Hz, 1H), 2.84 (dt, J = 12.0,




4.0 Hz, 1H), 7.08 (ddd, J = 8.0, 2.0, 0.8 Hz,




1H), 7.37 (t, J = 8.0 Hz, 1H), 7.58 (t, J = 2.0 Hz, 2H),




7.76 (ddd, J = 8.0, 2.0, 0.8 Hz, 1H), 7.88 (dd, J = 8.4,




2.4 Hz, 1H), 8.25 (dd, J = 8.4, 0.8 Hz, 1H), 8.57 (dd,




J = 2.4, 0.8 Hz, 1H), 9.84 (s, 1H)




(solvent: CDCl3)


383
oil


225, 269,






288


389
amorphous


292


393



213.4






316.0


395
amorphous


217, 269


396
211-213
1.64 (s, 3H), 1.96 (ddd, J = 14.0, 10.4, 4.0 Hz, 1H),




2.44 (ddd, J = 14.0, 6.8, 3.6 Hz, 1H), 2.75 (ddd, J = 12.4,




10.4, 3.6 Hz, 1H),, 2.99 (ddd, J = 12.4, 6.8, 4.0 Hz,




1H), 4.50 (2H, br), 7.08 (dd, J = 11.6, 8.8 Hz,




1H), 7.45 (dd, J = 6.8, 2.8 Hz, 1H), 8.01 (ddd, J = 8.8,




4.4, 2.8 Hz, 1H), 8.16 (ddd, J = 8.0, 2.0, 0.8 Hz,




1H), 8.43 (d, J = 8.0 Hz, 1H), 8.89 (dd, J = 2.0, 0.8 Hz,




1H), 9.91 (s, 1H)




(solvent: CDCl3)


401
106-107




















TABLE 143





Compound
Melting Point

MS
UV


No.
(° C.)
1H-NMR (d)
(m/z)
(λmax: nm)



















405
192-194
1.41 (s, 3H), 1.68-1.77 (m, 1H), 1.96-2.05 (m, 1H),






2.55-2.63 (m, 1H), 2.88-2.95 (m, 1H), 4.15 (s, 3H),




5.74 (s, 2H), 7.13 (d, J = 8.0 Hz, 1H), 7.29 (t, J = 8.0 Hz,




1H), 7.44 (d, J = 8.8 Hz, 1H), 7.75 (d, J = 8.0 Hz,




1H), 7.86 (br s, 1H), 8.20 (d, J = 8.8 Hz, 1H), 10.73 (s,




1H) (solvent: CDCl3)


406



276.9


408
221-224
1.74 (3H, s), 2.28 (2H, m), 2.67 (2H, m), 2.91 (3H, s),




3.82 (3H, s), 6.90 (2H, d, J = 9.0), 7.19 (2H, d, J = 9.0)




(solvent: CDCl3)


409
oil


215


410
178-182
1.37 (d, J = 6.0 Hz, 6H), 1.42 (s, 3H), 1.70-1.78 (m,




1H), 2.00-2.08 (m, 1H), 2.53-2.61 (m, 1H),




2.88-2.95 (m, 1H), 5.36 (quintet, J = 6.0 Hz, 1H), 7.11 (d, J = 8.0 Hz,




1H), 7.29 (t, J = 8.0 Hz, 1H), 7.75 (d, J = 8.0 Hz,




1H), 7.80 (br s, 1H), 8.32 (d, J = 1.2 Hz, 1H),




8.87 (d, J = 1.2 Hz, 1H), 10.32 (s, 1H)




(solvent: CDCl3)


411



218, 264


413
251-254


415
amorphous


226, 290


417
137-139


422

(CDCl3) 1.45 (3H, s), 1.70-1.84 (1H, m),




1.96-2.04 (1H, m), 2.88-2.96 (1H, m), 3.04-3.14 (1H, m),




6.86 (1H, d, J = 15.9 Hz), 6.42 (1H, d, J = 15.9 Hz),




7.22-7.41 (5H, m)


426



211.0






312.4


427



216


429
oil


211






259


430

(DMSO) 1.07 (3H, s), 1.53-1.66 (4H, m),




2.50-2.70 (2H, m), 2.92-3.10 (2H, m), 5.48 (1H, s),




7.11-7.21 (3H, m), 7.23-7.29 (2H, m)


432
oil


216, 272


436
254-256


441
161-165


443

1H-NMR (CDCl3) d: 1.55 (4H, s), 1.74-1.80 (1H, m),
362 [M + 1]




2.13-2.17 (1H, m), 2.68-2.73 (2H, m), 4.33 (1H, br s),




4.48 (2H, d, J = 4.0 Hz), 4.76 (2H, t, J = 20.1 Hz),




6.52 (1H, dd, J = 7.9, 1.8 Hz), 6.63-6.65 (2H, m),




7.13 (1H, t, J = 7.8 Hz), 7.45-7.51 (2H, m),




7.79-7.82 (4H, m).




















TABLE 144





Compound
Melting Point

MS
UV


No.
(° C.)
1H-NMR (d)
(m/z)
(λmax: nm)







444
214-215
1.41 (s, 3H), 1.66-1.76 (m, 1H), 1.97-2.05 (m, 1H),






2.53-2.62 (m, 1H), 2.62 (s, 3H), 2.86-2.93 (m, 1H),




5.79 (br s, 2H), 7.12 (d, J = 8.0 Hz, 1H), 7.28 (t, J = 8.0 Hz,




1H), 7.74 (d, J = 8.0 Hz, 1H), 7.81 (br s, 1H),




8.68 (s, 1H), 9.14 (s, 1H), 10.52 (s, 1H)




(solvent: CDCl3)


445
92-93


446
oil
1.57 (3H, s), 1.86 (1H, ddd, J = 13.9, 10.4, 3.7),

219




2.13 (1H, ddd, J = 13.9, 6.5, 3.6), 2.25 (3H, s),

252




2.35 (3H, s), 2.70 (1H, ddd, J = 12.2, 10.4, 3.6),




2.89 (1H, ddd, J = 12.2, 6.5, 3.7), 4.35 (2H, br),




5.19 (2H, s), 7.17 (2H, d, J = 8.0), 7.31-7.34 (4H, m),




7.50 (1H, ddd, J = 5.8, 3.0, 1.8), 7.55-7.60 (1H, m)




(solvent: CDCl3)


448

d in d6-DMSO: 1.41 (3H, s), 1.67-1.75 (1H, m),




1.98-2.05 (1H, m), 2.52-2.61 (1H, m), 2.86-2.94 (1H, m),




5.79 (2H, bs), 7.14 (1H, d, J = 7.8 Hz), 7.30 (1H, t,




J = 7.8 Hz), 7.73 (1H, bd, J = 7.8 Hz), 7.81 (1H, t,




J = 1.8 Hz), 8.94 (1H, m), 9.11 (1H, m), 10.63 (1H, bs).


452
132-134


456
147-149


457
153-155


465
194.6


466



211


470
281 (dec.)


482

1.60 (s, 3H), 1.91 (ddd, J = 14.0, 10.8, 4.0 Hz, 1H),




2.23 (ddd, J = 14.0, 6.4, 3.6 Hz, 1H), 2.77 (ddd, J = 12.0,




10.8, 3.6 Hz, 1H), 2.93 (ddd, J = 12.0, 6.4, 4.0 Hz,




1H), 7.16 (ddd, J = 8.0, 2.0, 0.8 Hz, 1H), 7.37 (t,




J = 8.0 Hz, 1H), 7.61 (t, J = 2.0 Hz, 1H), 7.75 (ddd, J = 8.0,




2.0, 0.8 Hz, 1H), 8.14 (d, J = 1.6 Hz, 1H),




8.80 (d, J = 1.6 Hz, 1H), 9.79 (s, 1H)




(solvent: CDCl3)


483
224-227


211, 289


490

1.64 (3H, s) 2.03-2.12 (1H, m) 2.49-2.62 (m)




3.12-3.16 (1H m) 7.22 (1H, dd, J = 4.2 Hz) 7.27 (1H, bs)




7.75 (1H bs) 7.87 (1H, dd, J = 4.2 Hz) 8.04 (1H, s)




8.12 (1H, dd, J = 4.2 Hz) 10.64 (1H, s) 10.72 (1H,




s)(solvent: DMSO-d6)


491

1.58 (s, 3H), 1.85-1.96 (m, 1H), 2.15-2.24 (m, 1H),




2.50 (s, 3H), 2.67 (s, 3H), 2.71-2.81 (m, 1H),




2.90-2.98 (m, 1H), 7.13 (d, J = 6.2 Hz, 1H), 7.35 (t, J = 8.0 Hz,




1H), 7.40 (s, 1H), 7.55 (d, J = 7.6 Hz, 1H)




(solvent: CDCl3)


493



216




















TABLE 145





Compound
Melting Point

MS
UV


No.
(° C.)
1H-NMR (d)
(m/z)
(λmax: nm)



















494

d in d6-DMSO: 1.37 (3H, s), 1.62-1.70 (1H, m),
366 [M + 1]





2.0-2.12 (1H, m), 2.40-2.50 (1H, m), 2.79-2.83 (1H, m),




3.82 (3H, s), 4.52 (2H, d, J = 5.4 Hz), 6.19 (1H, m),




6.54 (1H, d, J = 7.8 Hz), 6.62 (1H, d, J = 8.1 Hz), 6.75 (1H,




s), 7.01 (1H, t, J = 8.1 Hz), 7.14-7.25 (2H, m), 7.51 (1H,




d, J = 8.1 Hz), 7.60 (1H, d, J = 7.5 Hz).


496
152-154


497

d in d6-DMSO: 1.48 (3H, s), 1.83-1.77 (1H, m),




2.61-2.56 (1H, m), 2.99-2.95 (1H, m), 3.86 (3H, s), 6.07 (1H,




s), 6.95 (1H, s), 7.03-7.02 (1H, m), 7.09-7.06 (1H, m),




7.58-7.57 (1H, m), 7.64-7.62 (1H, m), 9.83 (1H, s)


498
122-125


500
181-184


501
155-156


502
137-138


504
209-219


511
211-214
1.58 (s, 3H), 1.90 (ddd, J = 14.0, 10.0, 3.6 Hz, 1H),




2.15 (ddd, J = 14.0, 6.8, 3.6 Hz, 1H), 2.77 (ddd, J = 12.4,




10.0, 3.6 Hz, 1H), 2.94 (ddd, J = 12.4, 6.8, 3.6 Hz,




1H), 4.34 (2H, br), 7.17 (ddd, J = 8.0, 2.0, 0.8 Hz,




1H), 7.38 (t, J = 8.0 Hz, 1H), 7.50 (d, J = 2.0 Hz,




1H), 7.56 (td, J = 2.0 Hz, 1H), 7.70 (ddd, J = 8.0, 2.0,




0.8 Hz, 1H), 8.08 (d, J = 1.6 Hz), 9.70 (s, 1H)




(solvent: CDCl3)


515
204-206
1.61 (s, 3H), 1.90 (ddd, J = 14.0, 10.8, 3.6 Hz, 1H),




2.22 (ddd, J = 14.0, 6.0, 3.6 Hz, 1H), 2.77 (ddd, J = 12.4,




10.8, 3.6 Hz, 1H), 2.93 (ddd, J = 12.4, 6.0, 3.6 Hz,




1H), 7.15 (ddd, J = 8.0, 2.0, 0.8 Hz, 1H), 7.39 (t,




J = 8.0 Hz, 1H), 7.65 (t, J = 2.0 Hz, 1H), 7.80 (ddd, J = 8.0,




2.0, 0.8 Hz, 1H), 8.89 (s, 2H), 9.77 (s, 1H)




(solvent: CDCl3)


516



292.3


525
105-106


528
173-174
1.60 (s, 3H), 1.89 (ddd, J = 14.0, 10.8, 3.6 Hz, 1H),




2.22 (ddd, J = 14.0, 6.4, 3.2 Hz, 1H), 2.44 (s, 3H),




2.77 (ddd, J = 12.4, 10.8, 3.2 Hz, 1H), 2.91 (ddd, J = 12.4,




6.4, 3.6 Hz, 1H), 4.50 (br, 2H), 7.11 (ddd, J = 8.0,




2.0, 0.8 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H),




7.67-7.71 (m, 2H), 7.74 (ddd, J = 8.0, 2.0, 0.8 Hz, 1H),




8.18 (d, J = 8.4 Hz, 1H), 8.44 (d, J = 1.6 Hz, 1H),




9.98 (s, 1H) (solvent: CDCl3)


532



305.3


533
180-181


534
201-204


549
100-101


551
139-141


554



216




















TABLE 146





Compound
Melting Point

MS
UV


No.
(° C.)
1H-NMR (d)
(m/z)
(λmax: nm)







556

(CDCl3) 1.67 (3H, d, J = 1.2 Hz), 1.98 (1H, ddd, J = 14.0,






10.4, 3.7 Hz), 2.47 (1H, ddd, J = 14.0, 6.7, 3.5 Hz),




2.79 (1H, ddd, J = 12.0, 10.4, 3.5 Hz), 3.02 (1H, ddd,




J = 12.0, 6.7, 3.7 Hz), 4.11 (3H, s), 4.45 (2H, br),




7.10 (1H, dd, J = 11.7, 8.8 Hz), 7.41 (1H, dd, J = 6.9, 2.8 Hz),




8.04 (1H, ddd, J = 8.8, 4.0, 2.8 Hz), 8.20 (1H, d,




J = 1.4 Hz), 9.06 (1H, d, J = 1.4 Hz), 9.51 (1H, s)


558


358 [M + 1]
200





282


559



224


560

d in d10-DMSO: 1.72 (3H, s), 2.12-2.05 (1H, m),




2.71-2.61 (2H, m), 3.22-3.19 (1H, m), 6.52 (1H, s), 7.26 (1H,




q, J = 11.6, 9.2 Hz), 7.55 (1H, s), 7.66-7.62 (2H, m),




7.79-7.77 (1H, m), 7.90-7.88 (1H, m), 8.07 (1H, s),




10.42 (1H, s), 11.55 (1H, s)


561
235-240


567
oil


212


570
186-187


573
112-114


577

d in d19-DMSO: 2.14-2.07 (1H, m), 2.88-2.70 (3H, m),




3.07, 3.26 (2H, abq, J = 12.0 Hz), 3.73 (3H, s),




5.40 (2H, s), 6.51 (1H, s), 6.85 (1H, d, J = 12.0 Hz),




7.34 (1H, d, J = 8.0 Hz)


584
152-153


586

d in d7-DMSO: 1.71 (3H, s), 2.10-2.04 (1H, m),




2.69-2.59 (2H, m), 3.20-3.17 (1H, m), 4.00 (3H, s), 7.13 (1H,




d, J = 7.4 Hz), 7.33-7.23 (3H, m), 7.55 (1H, d, J = 8.4 Hz),




7.72-7.68 (1H, m), 7.92-7.90 (1H, m),




10.60 (1H, s)


588
155-156


593
oil


226


595
oil
1.56 (3H, s), 1.86 (1H, ddd, J = 13.9, 10.1, 3.7),

220




2.11 (1H, ddd, J = 13.9, 6.6, 3.6), 2.32 (3H, s),




2.70 (1H, ddd, J = 12.3, 10.1, 3.6), 2.90 (1H, ddd, J = 12.3,




6.6, 3.7), 5.25 (2H, s), 7.29-7.35 (4H, m),




7.47 (1H, dt, J = 6.8, 2.0), 7.56-7.58 (1H, m), 8.59 (2H,




d, J = 6.0) (solvent: CDCl3)


596



215


597
192-194


600
178-180


601
181-192
1.59 (3H, s), 1.85-1.95 (1H, m), 2.15-2.22 (1H, m),
375 [M + 1]




2.72-2.78 (1H, m), 2.88-2.96 (1H, m), 4.31 (3H, s),




7.13 (1H, d, J = 7.25 Hz), 7.33 (1H, t, J = 7.91 Hz),




7.59 (1H, s), 7.68 (1H, d, J = 7.91 Hz), 7.75 (1H,




s). (solvent: CDCl3)


602
272-285



(dec.)




















TABLE 147





Compound
Melting Point

MS
UV


No.
(° C.)
1H-NMR (d)
(m/z)
(λmax: nm)







605
230-233
1.63 (s, 3H), 1.94 (ddd, J = 14.0, 10.4, 3.6 Hz, 1H),






2.44 (ddd, J = 14.0, 6.4, 3.6 Hz, 1H), 2.75 (ddd, J = 12.4,




10.4, 3.6 Hz, 1H),, 2.98 (ddd, J = 12.4, 6.4, 3.6 Hz,




1H), 4.50 (2H, br), 7.06 (dd, J = 11.6, 8.8 Hz,




1H), 7.40 (dd, J = 7.2, 2.8 Hz, 1H), 7.59 (ddd, J = 8.8,




8.0, 2.8 Hz, 1H), 7.99 (ddd, J = 8.8, 4.4, 2.8 Hz,




1H), 8.33 (dd, J = 8.8, 4.4 Hz, 1H), 8.45 (d, J = 2.8 Hz,




1H), 9.78 (s, 1H) (solvent: CDCl3)


608



213.4






304.1


611
200-202


613



238  


618

1.74 (s, 3H), 1.97-2.07 (m, 1H), 2.45-2.55 (m, 1H),




2.77-2.85 (m, 1H), 2.84 (s, 3H), 2.90-2.96 (m, 1H),




7.11 (d, J = 8.0 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H),




7.57 (d, J = 8.8 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H),




7.74 (br s, 1H), 8.29 (d, J = 8.8 Hz, 1H), 10.12 (s, 1H)




(solvent: CDCl3)


620



212, 253


625
107-109


629

d in d14-DMSO: 1.66 (3H, s), 2.11-2.05 (1H, m),




2.37 (3H, s), 2.63-2.53 (2H, m), 3.14-3.11 (1H, m),




7.08-7.04 (2H, t, J = 7.0 Hz), 7.43-7.35 (4H, m),




7.83-7.80 (2H, m), 10.39 (1H, s), 11.69 (1H, s)


630

1.28 (3H, t, J = 7.7 Hz), 1.96 (1H, ddd, J = 3.8, 9.9,
301 [M + 1]




13.7 Hz), 2.19 (1H, ddd, J = 3.5, 7.0, 13.7 Hz),




2.74 (1H, ddd, J = 3.6, 9.9, 12.2 Hz), 2.93 (1H, ddd, J = 3.8,




7.0, 12.1 Hz), 4.05-4.49 (4H, m), 7.40-7.50 (3H, m),




7.77-7.86 (1H, m) (solvent: CDCl3)


634

(CDCl3) 1.67 (3H, d, J = 1.2 Hz), 1.98 (1H, ddd, J = 14.0,




10.4, 3.7 Hz), 2.47 (1H, ddd, J = 14.0, 6.7, 3.5 Hz),




2.79 (1H, ddd, J = 12.0, 10.4, 3.5 Hz), 3.02 (1H, ddd,




J = 12.0, 6.7, 3.7 Hz), 4.11 (3H, s), 4.45 (2H, br),




7.10 (1H, dd, J = 11.7, 8.8 Hz), 7.41 (1H, dd, J = 6.9, 2.8 Hz),




8.04 (1H, ddd, J = 8.8, 4.0, 2.8 Hz), 8.20 (1H, d,




J = 1.4 Hz), 9.06 (1H, d, J = 1.4 Hz), 9.51 (1H, s)


636
118-119


637



229, 275


643
155-157
1.60 (s, 3H), 1.90 (ddd, J = 14.0, 10.4, 3.6 Hz, 1H),




2.20 (ddd, J = 14.0, 6.8, 3.6 Hz, 1H), 2.77 (ddd, J = 12.0,




10.4, 3.6 Hz, 1H),, 2.93 (ddd, J = 12.0, 6.8, 3.6 Hz,




1H), 4.59 (brs, 1H), 7.16 (ddd, J = 8.0, 2.0, 0.8 Hz,




1H), 7.37 (t, J = 8.0 Hz, 1H), 7.67 (t, J = 2.0 Hz,




1H), 7.71 (ddd, J = 8.0, 2.0, 0.8 Hz, 1H), 7.87 (dd, J = 10.0,




1.2 Hz, 1H), 8.73 (d, J = 1.2 Hz, 1H), 9.74 (s,




1H) (solvent: CDCl3)


644
201-203




















TABLE 148





Compound
Melting Point

MS
UV


No.
(° C.)
1H-NMR (d)
(m/z)
(λmax: nm)







645
oil
1.58 (3H, s), 1.87 (1H, ddd, J = 14.0, 10.4, 3.6),

222




2.16 (1H, ddd, J = 14.0, 6.3, 3.5), 2.34 (3H, s),




2.70 (1H, ddd, J = 12.3, 10.4, 3.5), 2.90 (1H, ddd, J = 12.3,




6.3, 3.6), 5.38 (2H, s), 7.18-7.33 (3H, m),




7.43 (1H, d, J = 8.0), 7.49-7.60 (2H, m), 7.69 (1H, dt, J = 7.7,




1.9), 8.59 (1H, ddd, J = 4.9, 1.9, 1.1) (solvent:




CDCl3)


649
161-162


651
193-196
1.59 (s, 3H), 1.90 (ddd, J = 14.0, 10.4, 3.6 Hz, 1H),




2.18 (ddd, J = 14.0, 6.4, 3.6 Hz, 1H), 2.76 (ddd, J = 12.4,




10.4, 3.6 Hz, 1H),, 2.93 (ddd, J = 12.4, 6.4, 3.6 Hz,




1H), 4.42 (br, 2 H), 7.17 (ddd, J = 8.0, 2.0, 0.8 Hz,




1H), 7.38 (t, J = 8.0 Hz, 1H), 7.64 (t, J = 2.0 Hz,




1H), 7.77 (ddd, J = 8.0, 2.0, 0.8 Hz, 1H), 8.20 (dd, J = 8.0,




2.0 Hz, 1H), 8.44 (dd, J = 8.0, 0.8 Hz, 1H),




8.91 (dd, J = 2.0, 0.8 Hz, 1H), 9.87 (s, 1H)




(solvent: CDCl3)


652

d in d21-DMSO: 1.67 (3H, s), 2.14-2.07 (1H, m),




2.62-2.57 (2H, m), 3.17-3.14 (1H, m), 5.74 (1H, s),




7.14 (1H, d, J = 8.0 Hz), 7.44 (1H, t, J = 8.0 Hz),




7.85-7.81 (2H, m), 8.01 (1H, d, J = 12.0 Hz), 8.16 (1H, d, J = 8.0 Hz),




8.77 (1H, s), 10.95 (1H, s)


653
193-194


654
oil


257


657
199-203


660
amorphous


223, 266


661

d in d9-DMSO: 1.30 (3H, t, J = 7.0 Hz), 1.69 (3H, s),




2.10-2.04 (1H, m), 2.20 (3H, s), 2.67-2.62 (2H, m),




3.20-3.17 (1H, m), 4.40 (2H, q, J = 14.0, 7.0 Hz),




6.83 (1H, s), 7.25 (1H, q, J = 12.0, 9.0 Hz),




7.62-7.61 (1H, m), 7.85-7.83 (1H, m), 10.42 (1H, s)


664
amorphous


225, 267


667
amorphous


226


673
oil


224


677
amorphous


216


680
159-160
1.63 (3H, s), 1.65-1.80 (1H, m), 2.53-2.64 (1H, m),




2.75-2.88 (2H, m), 3.83 (3H, s), 4.32 (2H, br),




6.87-6.96 (2H, m), 7.19-7.33 (2H, m) (solvent: CDCl3)


681

d in d6-DMSO: 1.43 (3H, s), 1.66-1.74 (1H, m),
338 [M + 1]




2.02-2.07 (1H, m), 2.56-2.63 (1H, m), 2.85-2.90 (1H, m),




5.80 (2H, bs), 6.91 (1H, d, J = 7.8 Hz), 6.96-6.98 (2H,




m), 7.25 (1H, t, J = 7.8 Hz), 7.2-7.36 (2H, m), 7.40 (1H,




m), 7.89-7.92 (1H, m), 9.42 (1H, bs), 10.78 (1H, bs).


683
166-168




















TABLE 149





Compound
Melting Point

MS
UV


No.
(° C.)
1H-NMR (d)
(m/z)
(λmax: nm)







687
164-167
1.60 (3H, s), 1.84-1.95 (1H, m), 2.21-2.26 (1H, m),
388 [M + 1]





2.73-2.94 (2H, m), 3.92 (3H, s), 4.25 (3H, s),




7.10 (1H, d, J = 7.58 Hz), 7.34 (1H, t, J = 7.91 Hz),




7.40 (1H, s), 7.57 (1H, br s), 7.66 (1H, d, J = 7.91 Hz),




8.67 (1H, s). (solvent: CDCl3)


692

(CDCl3) 1.50 (3H, s), 1.75-1.88 (1H, m),




2.00-2.10 (1H, m), 2.91-2.99 (1H, m), 3.08-3.18 (1H, m),




6.21 (1H, d, J = 15.9 Hz), 6.59 (1H, d, J = 15.9 Hz),




7.42-7.47 (3H, m), 7.59 (1H, dd, J = 8.6, 2.0 Hz),




7.74-7.83 (4H, m)


698



269


700
177-178


701

1.61 (s, 3H), 1.90 (m, 1H), 2.25 (m, 1H), 2.81 (m, 1H),




2.92 (m, 1H), 3.86 (s, 3H), 6.71 (t-like, J = 1.8 Hz, 1H),




7.12 (t-like, J = 1.8 Hz, 1H), 7.53 (t-like, J = 1.8 Hz, 1H),




7.89 (dd, J = 8.3 Hz, 2.4 Hz, 1H), 8.24 (d, J = 8.3 Hz,




1H), 8.58 (d, J = 2.4 Hz, 1H), 9.85 (br, 1H)




(solvent: CDCl3)


702

1H-NMR (CDCl3) d: 1.65 (3H, s), 1.91-1.98 (1H, m),




2.57-2.62 (1H, m), 2.68-2.75 (1H, m), 2.92-2.97 (1H,




m), 4.18 (3H, s), 6.82 (1H, br s), 7.02-7.08 (1H, m),




7.28-7.32 (1H, m), 7.44 (1H, s), 7.92-7.96 (1H, m).


707
167-174


709
 99-100
0.82 (3H, t, J = 7.3 Hz), 1.72-1.90 (3H, m),




2.06-2.15 (1H, m), 2.61-2.82 (2H, m), 3.80 (3H, s), 4.36 (2H,




br), 6.86 (2H, d, J = 8.9 Hz), 7.17 (2H, d, J = 8.9 Hz)




(solvent: CDCl3)


717
157-162
1.58 (s, 3H), 1.90 (ddd, J = 14.0, 10.4, 3.6 Hz, 1H),




2.15 (ddd, J = 14.0, 6.8, 3.6 Hz, 1H), 2.76 (ddd, J = 12.4,




10.4, 3.6 Hz, 1H), 2.94 (ddd, J = 12.4, 6.8, 3.6 Hz,




1H), 3.49 (1H, S), 3.76 (2H, br), 7.17 (ddd, J = 8.0,




2.0, 0.8 Hz, 1H), 7.36 (t, J = 8.0 Hz, 1H), 7.38 (d,




J = 1.6 Hz, 1H), 7.50 (t, J = 2.0 Hz, 1H), 7.73 (ddd, J = 8.0,




2.0, 0.8 Hz, 1H), 8.22 (d, J = 2.4 Hz), 9.26 (d,




J = 2.4 Hz, 1H), 10.12 (s, 1H)




(solvent: CDCl3)


719
oil


226






254


720
133-138


725
amorphous
1.62 (s, 3H), 1.96-2.03 (m, 1H), 2.38-2.49 (m, 1H),

265




2.63-2.71 (m, 1H), 3.05-3.12 (m, 1H), 6.73 (dd, J = 3.2,




1.6 Hz, 2H), 7.35 (d, J = 3.2 Hz, 1H), 7.37 (br s,




1H), 7.57 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 8.4 Hz,




2H), 7.77 (br s, 1H), 7.96 (br s, 1H), 8.01 (br s, 1H),




10.35 (s, 1H) (solvent: DMSO-d6)


728
179-182


729
167-169




















TABLE 150





Compound
Melting Point

MS
UV


No.
(° C.)
1H-NMR (d)
(m/z)
(λmax: nm)



















730



211.0






289.9


731
91-94


732
amorphous


211


735
166-168


737

1H-NMR (CDCl3) d: 1.59 (3H, s), 1.87-1.94 (1H, m),




2.47-2.53 (1H, m), 2.67-2.73 (1H, m), 2.93-2.99 (1H,




m), 4.10 (3H, s), 6.62 (1H, s), 7.04 (1H, t, J = 10.2 Hz),




7.33 (1H, d, J = 4.3 Hz), 7.85 (1H, br s).


738
181-183


739



285


740
250 (dec.)


743
148-150
1.60 (s, 3H), 179-2.93 (m, 4H), 4.46 (2H, br),




7.09 (d, J = 2.0 Hz, 1H), 7.12 (ddd, J = 7.6, 2.0, 0.8 Hz,




1H), 7.18 (t, J = 2.0 Hz, 1H), 7.36 (d, J = 7.6, 2.0, 0.8 Hz,




1H), 7.43 (t, J = 7.6 Hz, 1H), 8.21 (d, J = 2.0 Hz)




(solvent: CDCl3)


744

d in d8-DMSO: 1.47 (3H, s), 1.82-1.78 (1H, m),




2.22-2.18 (1H, m), 2.62-2.56 (1H, m), 3.00-2.96 (1H, m),




6.79 (1H, s), 6.63 (1H, s), 7.08-7.03 (1H, m), 7.51 (1H,




s), 7.64-7.57 (2H, m), 9.57 (1H, s), 11.25 (1H, s)


753
amorphous


225, 299


756
110-111
1.55 (3H, s), 1.76-1.87 (1H, m), 2.08-2.17 (1H, m),




2.35 (3H, s), 2.65-2.76 (1H, m), 2.82-2.92 (1H, m),




4.35 (2H, br), 7.01-7.25 (4H, m)




(solvent: CDCl3)


758
156-157


766


336 [M + 1]
203





260
212


767
 98-100


768

1.60 (3H, d, J = 1.3 Hz), 1.89-1.99 (1H, m), 2.29 (3H,
362 [M + 1]
213




s), 2.37-2.42 (1H, m), 2.70-2.75 (1H, m),

263




2.96-3.00 (1H, m), 4.12 (3H, s), 6.39 (1H, s), 7.04 (1H, dd, J = 11.5,




8.9 Hz), 7.18 (1H, dd, J = 6.9, 2.6 Hz),




7.60 (1H, s), 7.82-7.86 (1H, m). (solvent: CDCl3)


771


417 [M + 1]
201





341


774

1H-NMR (CDCl3) d: 1.77 (3H, s), 2.11-2.21 (1H, m),
400 [M + 1]




2.71-2.80 (1H, m), 2.87-2.99 (2H, m), 6.91 (1H, d, J = 6.9 Hz),




7.28 (2H, s), 7.47 (1H, t, J = 8.1 Hz),




7.75 (1H, t, J = 8.6 Hz), 8.04 (1H, dd, J = 8.6, 2.3 Hz),




8.29 (1H, d, J = 8.2 Hz), 8.46 (1H, d, J = 2.2 Hz).




















TABLE 151





Compound
Melting Point

MS
UV


No.
(° C.)
1H-NMR (d)
(m/z)
(λmax: nm)







781

1.63 (s, 3H), 1.92 (ddd, J = 14.0, 10.8, 4.0 Hz, 1H),






2.29 (m, 1H), 2.78 (ddd, J = 12.4, 10.8, 3.6 Hz, 1H),,




2.91 (ddd, J = 12.4, 6.4, 4.0 Hz, 1H), 3.94 (3H, s),




7.09 (ddd, J = 8.0, 2.0, 0.8 Hz, 1H), 7.34 (dd, J = 8.8,




2.8 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.68 (t, J = 2.0 Hz,




1H), 7.71 (ddd, J = 8.0, 2.0, 0.8 Hz, 1H), 8.24 (d,




J = 8.8 Hz, 1H), 8.28 (d, J = 2.8, Hz, 1H), 9.86 (s, 1H)




(solvent: CDCl3)


783
205-206


786

1.66 (3H, s), 2.10 (1H, m), 2.57-2.64 (2H, m), 3.16 (1H,




m), 6.74 (1H, s), 7.30 (1H, s), 7.36 (1H, s), 7.74 (1H, s),




7.98 (1H, s), 8.06 (1H, s), 10.33 (1H, s), 10.47 (1H, s)




(solvent: DMSO-d6)


790
amorphous


223, 290


791

d in d18-DMSO: 1.41 (3H, s), 1.76-1.69 (1H, m),




2.02-1.98 (1H, m), 2.62-2.55 (1H, m), 2.92-2.89 (1H, m),




7.13 (1H, d, J = 7.6 Hz), 7.29 (1H, t, J = 7.6 Hz),




7.62-7.59 (2H, m), 8.71 (1H, s), 9.28 (1H, s), 10.46 (1H, brs)


792



299.4


793
269 (dec.)


797



213.4






312.4


799



215, 240


800



225, 275


802

1.63 (s, 3H), 1.92 (ddd, J = 14.0, 11.2, 3.6 Hz, 1H),




2.28 (br, 1H), 2.78 (ddd, J = 12.4, 11.2, 3.6 Hz, 1H),




2.81 (s, 3H), 2.92 (ddd, J = 12.4, 6.4, 4.0 Hz, 1H),




7.10 (ddd, J = 8.0, 2.0, 0.8 Hz, 1H), 7.35 (t, J = 8.0 Hz,




1H), 7.56 (t, J = 2.0 Hz, 1H), 7.65 (d, J = 2.4 Hz,




1H), 7.74 (ddd, J = 8.0, 2.0, 0.8 Hz, 1H), 8.41 (d, J = 2.4 Hz,




1H), 10.03 (s, 1H) (solvent: CDCl3)


803



271  


804
135-136


810
47-48


811
138-139


813
204-205
182 (s, 3H), 1.89-1.94 (m, 1H), 2.78 (ddd, J = 12.4,




6.4, 3.6 Hz, 1H), 4.50 (2H, br), 7.06 (dd, J = 11.6, 8.8 Hz,




1H), 7.40 (dd, J = 7.2, 2.8 Hz, 1H), 7.59 (ddd, J = 8.8,




8.0, 2.8 Hz, 1H), 7.99 (ddd, J = 8.8, 4.4, 2.8 Hz,




1H), 8.33 (dd, J = 8.8, 4.4 Hz, 1H), 8.45 (d, J = 2.8 Hz,




1H), 9.78 (s, 1H)(solvent: CDCl3)


814
oil


218, 272


816



214.5




















TABLE 152





Compound
Melting Point

MS
UV


No.
(° C.)
1H-NMR (d)
(m/z)
(λmax: nm)



















820

(CDCl3) 1.66 (3H, d, J = 1.2 Hz), 1.98 (1H, ddd, J = 14.0,






10.4, 3.7 Hz), 2.47 (1H, ddd, J = 14.0, 6.7, 3.5 Hz),




2.79 (1H, ddd, J = 12.0, 10.4, 3.5 Hz), 3.02 (1H, ddd,




J = 12.0, 6.7, 3.7 Hz), 4.45 (2H, br), 6.16 (2H, br),




7.04-7.11 (2H, m), 7.38 (1H, dd, J = 7.2, 2.9 Hz), 7.88 (1H, d,




J = 2.0 Hz), 7.96 (1H, ddd, J = 8.9, 4.2, 2.9 Hz),




9.88 (1H, s)


822



279


827
134-137


214.5






284.0


832



212, 299


833
oil


212, 273


834



217, 267


835
139-140


836



221.6






279.3


840
223-225


848
oil


223, 254


849
143-145


850

d in d16-DMSO: 1.41 (3H, s), 1.75-1.70 (1H, m),




2.02-1.99 (1H, m), 2.61-2.56 (1H, m), 2.93-2.88 (1H, m),




7.13 (1H, d, J = 8.0), 7.29 (1H, t, J = 7.8 Hz), 7.35 (1H,




q, J = 8.4, 2.4 Hz), 7.66-7.63 (2H, m), 8.52-8.47 (1H,




m), 8.81 (1H, s), 10.44 (1H, s)


851
82-83
1.55 (3H, s), 1.76-1.88 (1H, m), 2.10-2.18 (1H, m),




2.66-2.77 (1H, m), 2.82-2.91 (1H, m), 3.81 (3H, s),




6.73-6.78 (1H, m), 6.88-6.92 (2H, m), 7.21-7.29 (1H,




m) (solvent: CDCl3)


855
oil


219


859


350 [M + 1]
200





274
208






254


863
192-194
1.39 (t, J = 7.2 Hz, 3H), 1.42 (s, 3H), 1.71-1.79 (m,




1H), 2.02-2.10 (m, 1H), 2.55-2.62 (m, 1H),




2.88-2.96 (m, 1H), 4.47 (q, J = 7.2 Hz, 2H), 5.70-6.20 (br s,




2H), 7.11 (d, J = 8.0 Hz, 1H), 7.29 (t, J = 8.0 Hz, 1H),




7.75 (d, J = 8.0 Hz, 1H), 7.80 (br s, 1H), 8.38 (d, J = 1.2 Hz,




1H), 8.87 (d, J = 1.2 Hz, 1H), 10.34 (s, 1H)




(solvent: CDCl3)


866



293.5


869

1.65 (s, 3H), 1.90-2.01 (m, 3H), 2.32 (br, 1H),




2.80 (td, J = 12.0, 3.6 Hz, 1H), 2.85 (t, J = 8.0 Hz, 2H),




2.92 (ddd, J = 12.0, 5.6, 3.6, 1H), 3.75 (t, J = 8.0 Hz,




2H), 7.11 (ddd, J = 8.0, 2.0, 0.8 Hz, 1H), 7.37 (t, J = 8.0 Hz,




1H), 7.70 (t, J = 2.0 Hz, 1H), 7.73-7.76 (m,




2H), 8.22 (d, J = 7.6 Hz, 1H), 8.48 (d, J = 2.0 Hz,




1H), 10.00 (s, 1H) (solvent: CDCl3)


871
212-213




















TABLE 153





Compound
Melting Point

MS
UV


No.
(° C.)
1H-NMR (d)
(m/z)
(λmax: nm)







875
oil


222, 271


876
oil


222


878
oil


211


881
141-144


887



262.7


892
251 (dec.)


893

d in d12-DMSO: 1.70 (3H, s), 2.10-2.04 (1H, m),




2.69-2.59 (2H, m), 3.20-3.17 (1H, m), 6.80 (1H, brs),




7.26-7.20 (1H, m), 7.88-7.81 (3H, m), 10.35 (1H,




s)13.53 (1H, brs)


895


378 [M + 1]
202





302
208






216






221






265


896
amorphous


219, 264


897
212-214


900
205-207
1.61 (s, 3H), 1.91 (ddd, J = 14.0, 10.8, 4.0 Hz, 1H),




2.23 (ddd, J = 14.0, 6.4, 3.6 Hz, 1H), 2.77 (ddd, J = 12.4,




10.8, 3.6 Hz, 1H), 2.92 (ddd, J = 12.4, 6.4, 4.0 Hz,




1H), 7.15 (ddd, J = 8.0, 2.0, 0.8 Hz, 1H), 7.38 (t,




J = 8.0 Hz, 1H), 7.65 (t, J = 2.0 Hz, 1H), 7.79 (ddd, J = 8.0,




2.0, 0.8 Hz, 1H), 8.99 (s, 2H), 9.78 (s, 1H)




(solvent: CDCl3)


906



212.2






273.4






350.5


908

d in d15-DMSO: 1.66 (3H, s), 2.11-2.05 (1H, m),




2.37 (3H, s), 2.63-2.54 (2H, m), 3.16-3.11 (1H, m),




3.16 (3H, s), 7.08-6.96 (3H, m), 7.49-7.41 (3H, m),




7.85-7.81 (2H, m), 10.52 (1H, s)11.69 (1H, s)


910
oil


211, 276


916
131-132


926

1.89 (3H, s), 2.15 (1H, m), 2.71-2.82 (2H, m), 2.96 (1H,




m), 3.04 (3H, d, J = 4.9), 7.35 (1H, dd, J = 8.7, 1.8),




7.50-7.55 (2H, m), 7.74 (1H, s), 7.82-7.90 (3H, s),




10.40 (1H, br), 11.36 (1H, Br) (solvent: CDCl3)


928

1.20 (t, J = 7.6 Hz, 3H), 1.53 (br s, 3H), 1.82-1.97 (m,




1H), 2.39 (s, 3H), 2.61 (q, J = 7.6 Hz, 2H),




2.99-3.07 (m, 1H), 6.93 (br s, 1H), 7.33 (d, J = 8.4 Hz, 2H),




7.54-7.58 (m, 2H), 7.87 (d, J = 8.4 Hz, 2H), 10.13 (s,




1H) (solvent: CDCl3)


930
132.1-134.4

328 [M + 1]


931



299


933
amorphous


212, 259




















TABLE 154





Compound
Melting Point

MS
UV


No.
(° C.)
1H-NMR (d)
(m/z)
(λmax: nm)



















935
161-165
1.62 (s, 3H), 1.91 (ddd, J = 14.0, 10.4, 4.0 Hz, 1H),






2.24 (ddd, J = 14.0, 6.4, 3.6 Hz, 1H), 2.80 (ddd, J = 12.0,




10.4, 3.6 Hz, 1H), 2.93 (ddd, J = 12.0, 6.4, 4.0 Hz,




1H), 7.15 (ddd, J = 8.0, 2.0, 1.2 Hz, 1H), 7.39 (t,




J = 8.0 Hz, 1H), 7.66 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H),




7.75 (t, J = 2.0 Hz, 1H), 7.80-7.84 (m, 2H), 7.93 (ddd,




J = 8.0, 2.0, 1.2 Hz), 8.21 (d, J = 8.4 Hz, 1H),




8.38 (d, J = 8.0 Hz, 1H), 8.41 (d, J = 8.0 Hz, 1H), 10.25 (s,




1H) (solvent: CDCl3)


936
169-170


939

d in d6-DMSO: 1.72 (3H, s), 2.11-2.05 (1H, m),




2.70-2.60 (2H, m), 3.21-3.18 (1H, m), 7.20 (1H, d, J = 9.2 Hz),




7.28 (1H, q, J = 11.6, 9.2 Hz), 8.56-7.54 (2H,




m), 7.69 (1H, s), 7.90-7.85 (2H, m), 10.69 (1H, s),




12.17 (1H, brs)


941



220


944
amorphous


219, 256


946

1.61 (s, 3H), 1.91 (ddd, J = 14.0, 10.8, 3.6 Hz, 1H),




2.26 (ddd, J = 14.0, 6.4, 3.6 Hz, 1H), 2.77 (ddd, J = 12.4,




10.8, 3.6 Hz, 1H),, 2.92 (ddd, J = 12.4, 6.4, 3.6 Hz,




1H), 7.13 (ddd, J = 8.0, 2.0, 1.2 Hz, 1H), 7.36 (t,




J = 8.0 Hz, 1H), 7.61 (t, J = 2.0 Hz, 1H), 7.72 (ddd, J = 8.0,




2.0, 1.2 Hz, 1H), 7.91 (d, J = 2.4 Hz, 1H),




8.49 (d, J = 2.4 Hz, 1H), 9.75 (s, 1H)(solvent: CDCl3)


947



215.7






276.9


960



261.5


964
185-187


966
oil


216


968
107-109


970

1.57 (s, 3H), 1.78-1.89 (m, 1H), 2.10-2.19 (m, 1H),




2.69 (ddd, J = 11.9, 10.8, 3.5 Hz, 1H), 2.83-2.91 (m,




1H), 7.15-7.35 (m, 5H) (solvent: CDCl3)


971

(DMSO) 1.49 (3H, s), 1.73-1.86 (1H, m),




2.16-2.30 (1H, m), 2.54-2.65 (1H, m), 2.92-3.03 (1H, m),




5.86 (2H, s), 7.04-7.18 (2H, m), 7.38-7.50 (3H, m),




7.66-7.78 (2H, m), 10.35 (1H, s), 11.84 (1H, s)


972

1.51 (3H, s) 1.91-1.95 (1H, m) 2.37 (3H, s)




3.00-3.05 (1H, m) 7.24 (1H s) 7.33 (2H, d J = 9.0 Hz)




7.66 (1H, s) 7.85 (2H, d J = 9.0 Hz) 8.03 (1H, s) 10.37 (1H,




s) (solvent: DMSO-d6)


974
amorphous


219


978
oil


222


984



255.7






318.4


990
126-129


994
130-131




















TABLE 155





Compound
Melting Point

MS
UV


No.
(° C.)
1H-NMR (d)
(m/z)
(λmax: nm)



















998
amorphous


229, 290


1005
191-193


1006
88-90
2.42-2.47 (2H, m), 2.80-2.86 (2H, m), 7.78 (6H, s),




6.83 (4H, d, J = 8.9 Hz), 7.22 (4H, d, J = 8.9 Hz)




(solvent: CDCl3)


1008
125-126


1010
90-91


1014
206-210


1020



216.9






245.1


1028
105-106


1034



212.2






286.4


1035
247-251



(dec.)


1037
amorphous


224, 272


1039
amorphous


217






249


1043
277-281


1044

(DMSO) 1.12 (3H, s), 1.60 (2H, d, J = 6.2 Hz), 1.73 (2H,




d, J = 8.6 Hz), 2.65-2.90 (2H, m), 2.93-3.13 (2H, m),




5.55 (1H, s), 7.34-7.52 (3H, m), 7.68 (1H, s),




7.79-7.90 (3H, m)


1052

1.75 (s, 3H), 2.12-2.21 (m, 1H), 2.40 (s, 3H),




2.65-2.73 (m, 2H), 3.17-3.23 (m, 1H), 7.37 (d, J = 8.4 Hz,




2H), 7.40-7.44 (m, 1H), 7.77 (br s, 1H), 7.92-7.99 (m,




5H), 8.47 (br s, 1H), 8.70 (d, J = 4.8 Hz, 1H), 10.37 (s,




1H), 10.41 (s, 1H) (solvent: CDCl3)


1055
169-170
1.56 (3H, s), 1.78-1.89 (1H, m), 2.04-2.15 (1H, m),




2.68-2.79 (1H, m), 2.86-2.95 (1H, m), 4.32 (2H, br),




6.94-7.02 (4H, m), 7.05-7.12 (1H, m), 7.25-7.37 (4H,




m)(solvent: CDCl3)


1056



219


1059
262-267


1061



216


1062
136-137
1.53 (3H, s), 1.76-1.88 (1H, m), 2.03-2.13 (1H, m),




2.63-2.73 (1H, m), 2.85-2.94 (1H, m), 4.35 (2H, br),




7.23-7.32 (4H, m) (solvent: CDCl3)


1064
84-85
1.52 (3H, s), 1.73-1.89 (1H, m), 1.97-2.07 (1H, m),




2.64-2.81 (1H, m), 2.82-2.91 (1H, m), 2.87 (3H, s),




3.77 (3H, s), 4.10 (1H, brs), 6.84 (2H, d, J = 8.9 Hz),




7.28 (2H, d, J = 8.6 Hz) (solvent: CDCl3)


1067
162-165


1068
132-134


230


1069
194-196


1074


324 [M + 1]
200





248
207


1076
amorphous


217




















TABLE 156





Compound
Melting Point

MS
UV


No.
(° C.)
1H-NMR (d)
(m/z)
(λmax: nm)



















1084
146-149





1087



  311.2


1088
amorphous
1.55 (3H, s), 1.83 (1H, ddd, J = 13.9, 10.5, 3.7),

229




2.09 (1H, ddd, J = 13.9, 6.6, 3.6), 2.67 (1H, ddd, J = 12.3,

318




10.5, 3.6), 2.88 (1H, ddd, J = 12.3, 6.6, 3.7),




4.48 (2H, d, J = 6.0), 4.91 (1H, br), 6.33 (1H, dd, J = 8.8,




0.8), 7.19 (1H, d, J = 7.3, 7.23-7.30 (2H, m),




7.35 (1H, dd, J = 8.8, 2.8), 8.05 (1H, dd, J = 2.8, 0.8)




(solvent: CDCl3)


1094



216, 322


1100
278 (dec.)


1107
oil
1.58 (3H, s), 1.90 (1H, ddd, J = 13.9, 10.1, 3.7),

226




2.14 (1H, ddd, J = 13.9, 6.8, 3.6), 2.69 (1H, ddd, J = 12.2,

284




10.1, 3.6), 2.94 (1H, ddd, J = 12.2, 6.8, 3.7),




3.81 (3H, s), 4.62 (2H, s), 6.90 (2H, d, J = 8.8),




7.30 (2H, d, J = 8.8), 7.43 (1H, t, J = 7.4), 7.57 (1H,




ddd, J = 7.4, 1.6, 1.2), 7.81 (1H, ddd, J = 7.6, 1.6,




1.2), 7.95 (1H, t, J = 1.6) (solvent: CDCl3)


1109
134-140


1110
109-110


1111
118-119


1114
121-124


1115
167-170
1.63 (s, 3H), 1.93 (ddd, J = 14.0, 10.4, 4.0 Hz, 1H),




2.24 (ddd, J = 14.0, 6.4, 3.6 Hz, 1H), 2.81 (ddd, J = 12.4,




10.4, 3.6 Hz, 1H), 2.96 (ddd, J = 12.4, 6.4, 4.0 Hz,




1H), 4.49 (br, 2 H), 7.19 (ddd, J = 8.0, 2.0, 0.8 Hz,




1H), 7.42 (t, J = 8.0 Hz, 1H), 7.74 (t, J = 2.0 Hz,




1H), 7.84 (ddd, J = 8.0, 2.0, 0.8 Hz, 1H),




7.88-7.95 (m, 2H), 8.22-8.26 (m, 2H), 9.80 (s, 1H), 9.89 (s, 1H)




(solvent: CDCl3)


1116
oil


220, 255,






307


1119
153-157


1120
213-214


1124
169-172


225


1125
195-198


222






256






289


1131
189-191


1132
175-180



(dec)


1133
amorphous


219, 292


1135
255-260



(dec.)


1139
140-141


1140
oil


218


1142
182-186



(dec.)




















TABLE 157





Compound
Melting Point

MS
UV


No.
(° C.)
1H-NMR (d)
(m/z)
(λmax: nm)



















1147



214.5






275.7


1150



221.6






279.3


1153
156-159


1160

1.64 (3H, s) 2.02-2.12 (1H, m) 2.54-2.63 (1H, m)




3.11-3.16 (1H, m) 7.28 (1H, s) 7.70 (1H, dd J = 8.1 Hz)




7.85 (1H, s) 8.04-8.17 (2H, m) 8.28 (1H s)




8.74 (1H d J = 5.1 Hz) 10.81 (1H, s) 10.96 (1H, s)




(solvent: DMSO-d6)


1161
192-193


1166
290-295

444 [M + 3]





442 [M + 1]





368





366


1172

1.55 (3H, s) 1.94-2.03 (1H, m) 2.18-2.27 (1H, m)




2.32 (3H, s) 3.03-3.07 (1H, m) 7.05 (1H, s) 7.09 (1H, s)




7.14 (1H, s) 7.37 (2H, d J = 9.0 Hz) 7.66 (2H, d




J = 9.0 Hz) 10.65 (1H, s) 10.70 (1H, s)




(solvent: DMSO-d6)


1181
194-195
1.60 (3H, s), 1.81-1.93 (1H, m), 2.13-2.22 (1H, m),




2.70-2.81 (1H, m), 2.86-2.96 (1H, m), 4.36 (2H, br),




7.29-7.46 (5H, m), 7.53-7.61 (4H, m) (solvent:




CDCl3)


1184
149-150


1185



225.1






280.4


1193
182-183


1194


344 [M + 1]
209





268
214






261


1197
250-255



(dec.)


1199
274-283


1205
oil


E 213, 273






Z 219, 275


1207
106-108


1211

1.77 (s, 3H), 1.98-2.54 (m, 2H), 2.81 (s, 3H),




2.81-2.94 (m, 2H), 3.93 (s, 3H), 7.03 (ddd, J = 8.0, 2.0,




0.8 Hz, 1H), 7.08 (d, J = 2.4 Hz, 1H), 7.36 (t, J = 8.0 Hz,




1H), 7.63 (t, J = 2.0 Hz, 1H), 7.69 (ddd, J = 8.0,




2.0, 0.8 Hz, 1H), 8.14 (d, J = 2.4 Hz, 1H), 10.13 (s,




1H) (solvent: CDCl3)


1213


406 [M + 1]
20





330
209






213




















TABLE 158





Compound
Melting Point

MS
UV


No.
(° C.)
1H-NMR (d)
(m/z)
(λmax: nm)



















1215
amorphous
1.64 (s, 3H), 2.07 (ddd, J = 14.1, 11.5, 3.8 Hz, 1H),






2.17 (s, 3H), 2.39 (ddd, J = 14.1, 5.3, 3.5 Hz, 1H),




2.72 (ddd, J = 12.6, 11.5, 3.5 Hz, 1H), 2.80 (ddd, J = 12.6,




5.3, 3.8 Hz, 1H), 3.21 (t, J = 8.9 Hz, 2H), 4.58 (t,




J = 8.9 Hz, 2H), 6.76 (d, J = 8.4 Hz, 1H), 6.97-7.02 (m,




1H), 7.08-7.11 (m, 1H) (solvent: CDCl3)


1216



305.3


1217
263-266


1221
amorphous


220, 253


1223



226.3






280.4


1224

d in d11-DMSO: 1.46 (3H, s), 1.83-1.77 (1H, m),




2.18-2.15 (1H, m), 2.61-2.56 (1H, m), 2.99-2.95 (1H, m),




7.08 (1H, q, J = 12.0, 8.4 Hz), 7.72-7.66 (2H, m),




7.79 (2H, d, J = 9.2)9.67 (1H, s)


1228
oil


224


1230
232-234


1240



216.9






285.2


1241
194-195


1242

d in d21-DMSO: 1.41 (3H, m), 1.75-1.68 (1H, m),




2.04-1.99 (1H, m), 2.61-2.56 (1H, m), 2.89 (4H, s), 5.75 (2H,




brs), 7.07 (1H, d, J = 4.0 Hz), 7.25 (1H, t, J = 8.0 Hz),




7.72 (1H, d, J = 8.0 Hz), 7.75 (1H, s), 7.83 (1H, brs),




7.96 (1H, s), 8.67 (1H, s), 9.96 (1H, s)


1243
amorphous
1.58 (3H, s), 2.00 (1H, ddd, J = 14.3, 11.5, 3.1),

223




2.53 (1H, m), 2.56 (1H, m), 3.07 (1H, dt, J = 12.5,

299




3.1), 4.26 (2H, s), 6.47-6.56 (3H, m), 7.07-7.15 (1H,




m), 7.12 (2H, t, J = 8.8), 7.39 (2H, dd, J = 8.8, 5.6),




8.76 (2H, br) (solvent: DMSO-d6)


1244
268-288
1.68 (s, 3H), 2.11 (ddd, J = 15.2, 12.0, 4.0 Hz, 1H),

219




2.57-2.64 (m, 2H), 3.16 (dt, J = 12.0, 4.0 Hz, 1H),

288




7.13 (ddd, J = 8.0, 2.0, 0.8 Hz, 1H), 7.46 (t, J = 8.0 Hz,




1H), 7.89 (t, J = 2.0 Hz, 1H), 7.97 (ddd, J = 8.0, 2.0,




0.8 Hz, 1H), 8.35 (d, J = 8.0 Hz, 1H), 8.52 (dd, J = 8.0,




2.4 Hz, 1H), 9.12 (d, J = 2.4 Hz, 1H), 10.68 (s, 1H),




10.92 (s, 1H) (solvent: DMSO-d6)


1245
oil


286


1247



211


1255



242.7


1257
amorphous


211


1258


352 [M + 1]
228






276






301


1261
179-180


1262
278-281




















TABLE 159





Compound
Melting Point

MS
UV


No.
(° C.)
1H-NMR (d)
(m/z)
(λmax: nm)







1263

1H-NMR (d in d6-DMSO): 1.41 (3H, s), 1.65-1.77 (1H,
387 [M + 1]





m), 1.95-2.07 (1H, m), 2.54-2.63 (1H, m),




2.84-2.94 (1H, m), 3.39-3.46 (2H, m), 3.53-3.61 (2H, m),




4.83 (1H, t, J = 5.4 Hz), 5.79 (2H, bs), 7.07 (1H, d,




J = 7.5 Hz), 7.25 (1H, t, J = 7.8 Hz), 7.73 (1H, d,




J = 7.8 Hz), 7.76 (1H, m), 7.87-7.93 (1H, m), 8.02 (1H, d,




J = 1.2 Hz), 8.63 (1H, d, J = 1.2 Hz), 9.97 (1H, s).


1264

1H-NMR (d in d6-DMSO): 1.41 (3H, s), 1.65-1.77 (1H,
413 [M + 1]




m), 1.95-2.07 (1H, m), 2.53-2.63 (1H, m),




2.84-2.95 (1H, m), 3.73 (8H, s), 5.79 (2H, bs), 7.09 (1H, d,




J = 7.8 Hz), 7.26 (1H, t, J = 7.8 Hz), 7.72 (1H, d,




J = 7.8 Hz), 7.75-7.78 (1H, m), 8.34 (1H, d, J = 1.2 Hz),




8.76 (1H, d, J = 1.2 Hz), 10.08 (1H, bs).


1265

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




m), 2.02-2.05 (1H, m), 2.56-2.59 (1H, m),




2.87-2.93 (2H, m), 7.07 (1H, d, J = 7.6 Hz), 7.23-7.26 (3H, m),




7.72-7.74 (2H, m), 7.93 (1H, s), 8.60 (1H, s),




9.99 (1H, s).


1266

1H-NMR (d in d6-DMSO): 1.43 (3H, s), 1.70-1.81 (1H,
369 [M + 1]




m), 1.97-2.10 (1H, m), 2.55-2.64 (1H, m),




2.89-2.95 (1H, m), 5.84 (2H, bs), 7.17 (1H, d, J = 7.8 Hz),




7.33 (1H, t, J = 7.8 Hz), 9.98 (1H, d, J = 1.2 Hz),




10.01 (1H, d, J = 1.2 Hz), 10.74 (1H, bs).


1267

1H-NMR (CDCl3) d: 1.82-1.91 (1H, m), 2.04 (3H, s),
338 [M + 1]




2.22 (1H, ddd, J = 13.8, 5.2, 3.6 Hz), 2.67 (1H, dt, J = 16.7,




5.8 Hz), 2.80 (1H, dt, J = 12.4, 4.7 Hz),




6.95 (2H, d, J = 8.1 Hz), 7.06 (2H, td, J = 7.8, 1.2 Hz),




7.18 (1H, td, J = 7.6, 1.1 Hz), 7.27 (1H, d, J = 1.7 Hz),




7.32 (1H, d, J = 7.9 Hz), 7.42-7.44 (2H, m),




7.80 (1H, dd, J = 8.0, 1.9 Hz).


1268

1H-NMR (CDCl3) d: 1.62 (3H, s), 1.89 (1H, t, J = 12.3 Hz),
327 [M + 1]




2.27-2.30 (1H, m), 2.69-2.76 (1H, m),




2.85-2.88 (1H, m), 7.11 (1H, dd, J = 11.4, 7.7 Hz),




7.30-7.53 (2H, m), 7.63 (1H, s), 7.71 (1H, d, J = 6.9 Hz).


1269

1H-NMR (DMSO-d6) d: 1.40 (3H, s), 1.70-1.73 (1H,




m), 1.99-2.02 (1H, m), 2.57-2.60 (1H, m),




2.88-2.90 (1H, m), 3.29 (3H, s), 3.52 (4H, s), 5.75 (2H, br s),




7.07 (1H, d, J = 7.6 Hz), 7.25 (1H, t, J = 7.7 Hz),




7.72 (1H, d, J = 8.3 Hz), 7.75 (1H, s), 7.92 (1H, br s),




8.03 (1H, s), 8.64 (1H, s), 9.96 (1H, s).


1271

1H-NMR (d in d6-DMSO): 1.41 (3H, s), 1.65-1.75 (1H,
397 [M + 1]




m), 1.99-2.06 (5H, m), 2.52-2.61 (1H, m),




2.85-2.93 (1H, m), 3.55 (4H, t, J = 6.6 Hz), 5.79 (2H, bs),




7.05 (1H, d, J = 7.8 Hz), 7.25 (1H, t, J = 7.8 Hz),




7.70-7.75 (1H, m), 7.73-7.77 (1H, m), 7.97 (1H, d, J = 1.2 Hz),




8.72 (1H, d, J = 1.2 Hz), 10.00 (1H, s).




















TABLE 160





Compound
Melting Point

MS
UV


No.
(° C.)
1H-NMR (d)
(m/z)
(λmax: nm)







1272

(CDCl3) 1.61 (3H, s), 1.85-1.96 (1H, m),






2.17-2.27 (1H, m), 2.69-2.79 (1H, m), 2.87-2.97 (1H, m),




7.17 (1H, d, J = 8.1 Hz), 7.38 (1H, t, J = 8.1 Hz),




7.48-7.74 (5H, m), 8.40 (2H, d, J = 7.5 Hz)


1273

1H-NMR (CDCl3) d: 1.58 (3H, s), 1.89 (1H, t, J = 11.2 Hz),
395 [M + 1]




2.27 (1H, s), 2.75-2.82 (2H, m), 6.61 (1H,




dd, J = 20.3, 8.4 Hz), 7.10 (1H, d, J = 7.2 Hz),




7.37 (1H, dd, J = 15.0, 8.8 Hz), 7.90 (1H, d, J = 7.6 Hz),




8.10 (1H, d, J = 3.2 Hz), 9.37 (1H, d, J = 4.9 Hz),




9.69 (1H, s).


1274

1H-NMR (CDCl3) d: 1.61 (3H, s), 1.84-1.93 (1H, m),
327 [M + 1]




2.30 (1H, t, J = 13.1 Hz), 2.77-2.86 (2H, m),




6.64 (1H, dd, J = 20.6, 8.6 Hz), 7.13 (1H, d, J = 7.9 Hz),




7.38-7.43 (1H, m), 7.93 (1H, d, J = 8.1 Hz), 8.13 (1H,




s), 9.40 (1H, d, J = 4.9 Hz), 9.72 (1H, s).


1275

1H-NMR (DMSO-d6) d: 1.40 (3H, s), 1.70-1.72 (1H,




m), 2.01-2.04 (1H, m), 2.18 (6H, s), 2.44 (2H, t, J = 6.3 Hz),




2.56-2.59 (1H, m), 2.86-2.92 (1H, m),




7.06 (1H, d, J = 7.6 Hz), 7.25 (1H, t, J = 7.7 Hz),




7.71-7.73 (3H, m), 8.02 (1H, s), 8.64 (1H, s), 9.95 (1H, s).


1276

1H-NMR (DMSO-d6) d: 1.70-1.73 (1H, m),




1.99-2.02 (1H, m), 2.57-2.60 (1H, m), 2.88-2.91 (1H, m),




3.04 (3H, s), 3.43 (3H, t, J = 6.3 Hz), 3.79-3.81 (2H,




m), 5.75 (3H, br s), 7.08 (1H, d, J = 7.3 Hz),




7.26 (1H, t, J = 7.8 Hz), 7.72 (1H, d, J = 7.8 Hz), 7.76 (1H,




s), 8.04 (1H, s), 8.09 (1H, br s), 8.70 (1H, s),




10.01 (1H, s).


1279

1H-NMR (CDCl3) d: 1.73 (3H, s), 2.04 (1H, dt, J = 18.2,
328 [M + 1]




6.5 Hz), 2.45 (1H, d, J = 13.6 Hz), 2.78 (2H, t, J = 11.8 Hz),




2.89 (2H, t, J = 11.5 Hz), 6.60 (1H, s),




6.99 (1H, d, J = 8.2 Hz), 7.34 (1H, t, J = 8.0 Hz),




7.48 (1H, s), 7.70 (1H, d, J = 8.2 Hz).


1280

1H-NMR (d in d6-DMSO): 1.42 (3H, s), 1.68-1.82 (1H,
426 [M + 1]




m), 2.02-2.09 (1H, m), 2.23 (3H, s), 2.43 (4H, t,




J = 5.1 Hz), 2.53-2.61 (1H, m), 2.87-2.95 (1H, m),




3.73 (4H, t, J = 5.1 Hz), 6.01 (2H, bs), 7.07 (1H, d,




J = 7.8 Hz), 7.26 (1H, t, J = 7.8 Hz), 7.73 (1H, d,




J = 7.8 Hz), 7.73-7.78 (1H, m), 8.33 (1H, d, J = 1.2 Hz),




8.72 (1H, d, J = 1.2 Hz), 10.06 (1H, s).


1281

1H-NMR (d in d6-DMSO): 1.40 (3H, s), 1.30-1.50 (2H,
427 [M + 1]




m), 1.69-1.76 (1H, m), 1.82-1.88 (2H, m),




2.01-2.07 (1H, m), 2.52-2.61 (1H, m), 2.86-2.94 (1H, m),




3.76-3.83 (1H, m), 4.10-4.18 (2H, m), 4.82 (1H, d,




J = 4.2 Hz), 5.91 (2H, bs), 7.07 (1H, d, J = 7.8 Hz),




7.26 (1H, t, J = 7.8 Hz), 7.70-7.77 (2H, m), 8.33 (1H, d,




J = 1.2 Hz), 8.70 (1H, d, J = 1.2 Hz), 10.02 (1H, s).

















TABLE 161





compound No.
MS (m/z)
















2
336 [M + 1]


7
394 [M + 1]


10
431 [M + 3]



429 [M + 1]


11
356 [M + 1]


12
354 [M + 1]


13
363 [M + 3]



361 [M + 1]


14
394 [M + 1]


15
409 [M + 1]


16
425 [M + 1]


17
374 [M + 1]


19
362 [M + 3]



360 [M + 1]


20
438 [M + 1]


21
380 [M + 3]



378 [M + 1]


22
380 [M + 3]



378 [M + 1]


25
354 [M + 1]


27
338 [M + 1]


28
356 [M + 1]


29
372 [M + 1]


31
378 [M + 1]


32
417 [M + 1]


34
358 [M + 1]


35
398 [M + 3]



396 [M + 1]


36
370 [M + 1]


40
416 [M + 1]



340


41
414 [M + 1]


44
362 [M + 3]



360 [M + 1]


45
365 [M + 1]


46
362 [M + 1]


47
416 [M + 3]



414 [M + 1]


49
394 [M + 3]



392 [M + 1]


50
292 [M + 1]


51
388 [M + 1]


52
360 [M + 1]



284


53
380 [M + 1]


54
332 [M + 1]


55
412 [M + 3]



410 [M + 1]


56
397 [M + 1]



395 [M + 1]


59
412 [M + 1]


60
422 [M + 1]



420 [M + 1]


61
394 [M + 1]


63
366 [M + 1]


64
441 [M + 1]



365


65
384 [M + 1]


66
398 [M + 1]


67
386 [M + 1]



310


68
376 [M + 1]


70
372 [M + 1]


72
330 [M + 1]


74
322 [M + 1]


75
412 [M + 1]


76
363 [M + 3]



361 [M + 1]


79
310 [M + 1]


81
386 [M + 1]


82
306 [M + 1]


83
336 [M + 1]


84
380 [M + 1]


87
415 [M + 1]


88
426 [M + 1]


89
370 [M + 1]


90
354 [M + 1]


92
417 [M + 1]


93
407 [M + 1]


94
350 [M + 1]


95
406 [M + 3]



404 [M + 1]


98
398 [M + 3]



396 [M + 1]


100
332 [M + 1]


102
424 [M + 3]



422 [M + 1]


103
444 [M + 1]


105
424 [M + 1]



348


106
490 [M + 1]



414


107
414 [M + 3]



412 [M + 1]


108
332 [M + 1]


109
412 [M + 1]


110
404 [M + 1]


111
469 [M + 1]



393


112
377 [M + 1]


116
408 [M + 1]


117
413 [M + 1]


118
372 [M + 1]


119
424 [M + 1]


122
338 [M + 1]


124
471 [M + 1]


131
412 [M + 3]



410 [M + 1]


133
404 [M + 1]


135
416 [M + 1]


136
380 [M + 1]


137
327 [M + 1]


138
394 [M + 1]


140
456 [M + 1]


142
446 [M + 1]


143
399 [M + 1]


144
432 [M + 1]


145
394 [M + 3]



392 [M + 1]


146
433 [M + 3]



431 [M + 1]


147
324 [M + 1]


150
418 [M + 1]


151
458 [M + 3]



456 [M + 1]


152
371 [M + 1]


153
398 [M + 1]


154
401 [M + 1]


155
322 [M + 1]


156
332 [M + 3]



330 [M + 1]


158
394 [M + 1]

















TABLE 162







160
427 [M + 1]


162
416 [M + 3]



414 [M + 1]


167
392 [M + 3]



390 [M + 1]


168
380 [M + 3]



378 [M + 1]


169
346 [M + 1]


170
356 [M + 1]


171
334 [M + 1]


172
376 [M + 3]



374 [M + 1]


173
424 [M + 3]



422 [M + 1]


174
369 [M + 1]


175
410 [M + 1]


177
357 [M + 1]


179
334 [M + 1]


180
426 [M + 1]


182
396 [M + 3]



394 [M + 1]


183
372 [M + 1]


184
346 [M + 1]


185
330 [M + 1]


186
393 [M + 3]



391 [M + 1]


187
374 [M + 1]


188
423 [M + 1]


190
278 [M + 1]


191
448 [M + 1]


192
436 [M + 3]



434 [M + 1]


194
384 [M + 1]


195
369 [M + 1]


197
382 [M + 1]


198
355 [M + 1]


199
361 [M + 1]


200
356 [M + 1]



280


201
452 [M + 1]


203
397 [M + 1]


205
427 [M + 1]


206
386 [M + 1]



310


207
384 [M + 1]


208
386 [M + 3]



384 [M + 1]


209
371 [M + 1]


210
366 [M + 1]


211
442 [M + 1]



366


212
345 [M + 1]


215
425 [M + 3]



423 [M + 1]


217
362 [M + 1]


218
322 [M + 1]


219
347 [M + 1]


221
444 [M + 1]


222
329 [M + 1]


223
413 [M + 1]


225
402 [M + 1]


226
390 [M + 1]


228
383 [M + 1]


229
366 [M + 1]


230
368 [M + 1]


231
336 [M + 1]


234
376 [M + 1]


236
392 [M + 1]


237
348 [M + 1]


239
384 [M + 1]


240
341 [M + 1]


242
446 [M + 1]


245
374 [M + 1]


246
390 [M + 1]



314


247
374 [M + 1]


248
370 [M + 1]


249
336 [M + 1]


250
366 [M + 1]


252
401 [M + 1]


253
397 [M + 1]


254
434 [M + 1]


257
321 [M + 1]


258
398 [M + 1]


260
440 [M + 1]


261
308 [M + 1]


262
466 [M + 3]



464 [M + 1]


264
336 [M + 1]


265
435 [M + 1]


266
432 [M + 3]



430 [M + 1]


269
372 [M + 1]



296


270
338 [M + 1]


272
349 [M + 1]


273
406 [M + 3]



404 [M + 1]


274
380 [M + 1]


276
398 [M + 3]



396 [M + 1]


278
404 [M + 1]


280
433 [M + 3]



431 [M + 1]


283
322 [M + 1]


285
340 [M + 1]


286
433 [M + 3]



431 [M + 1]


287
440 [M + 1]


288
354 [M + 1]


289
341 [M + 1]


290
363 [M + 3]



361 [M + 1]


291
317 [M + 1]


292
426 [M + 1]


294
424 [M + 3]



422 [M + 1]


295
394 [M + 3]



392 [M + 1]


296
389 [M + 1]


297
448 [M + 3]



446 [M + 1]


299
363 [M + 3]



361 [M + 1]


300
356 [M + 1]


303
366 [M + 1]


304
402 [M + 1]


305
407 [M + 3]



405 [M + 1]


310
411 [M + 1]

















TABLE 163







311
388 [M + 1]


312
428 [M + 1]


313
453 [M + 1]


314
368 [M + 1]


315
322 [M + 1]


316
386 [M + 1]


317
328 [M + 1]


318
362 [M + 1]


320
327 [M + 1]


321
392 [M + 1]


322
404 [M + 1]



328


323
394 [M + 1]


324
384 [M + 1]


325
399 [M + 1]


326
440 [M + 1]



364


327
314 [M + 1]


328
384 [M + 1]


331
360 [M + 1]


334
412 [M + 1]


335
316 [M + 1]


336
356 [M + 1]


337
428 [M + 1]


338
466 [M + 3]



484 [M + 1]


340
344 [M + 1]


343
399 [M + 1]


345
412 [M + 1]


346
384 [M + 1]


347
430 [M + 1]


348
341 [M + 1]


349
335 [M + 1]


350
412 [M + 1]


351
322 [M + 1]


352
327 [M + 1]


355
397 [M + 1]


362
366 [M + 1]


363
376 [M + 3]



374 [M + 1]


365
366 [M + 1]


366
409 [M + 1]


368
384 [M + 1]


369
396 [M + 3]



394 [M + 1]


371
398 [M + 3]



396 [M + 1]


372
348 [M + 1]


373
358 [M + 1]


374
364 [M + 1]


376
412 [M + 1]


377
425 [M + 1]


378
380 [M + 3]



378 [M + 1]


379
377 [M + 1]


381
409 [M + 1]


382
340 [M + 1]


384
388 [M + 1]


385
384 [M + 1]


386
352 [M + 1]


387
376 [M + 1]


388
440 [M + 1]


390
407 [M + 1]



331


391
362 [M + 1]


392
390 [M + 1]


394
363 [M + 3]



361 [M + 1]


397
460 [M + 3]



458 [M + 1]


398
408 [M + 1]


399
372 [M + 1]


400
374 [M + 1]


402
372 [M + 1]



296


403
436 [M + 1]


404
376 [M + 3]



374 [M + 1]


407
449 [M + 3]



447 [M + 1]


412
410 [M + 1]


414
331 [M + 1]


416
282 [M + 1]


418
322 [M + 1]


419
420 [M + 3]



418 [M + 1]


420
332 [M + 1]


421
388 [M + 3]



386 [M + 1]


423
412 [M + 3]



410 [M + 1]


424
370 [M + 1]


425
380 [M + 3]



378 [M + 1]


428
350 [M + 1]


431
391 [M + 1]


433
454 [M + 3]



452 [M + 1]


434
448 [M + 3]



446 [M + 1]


435
431 [M + 3]



429 [M + 1]


437
382 [M + 1]


438
400 [M + 1]



324


439
380 [M + 1]


440
358 [M + 1]


442
394 [M + 1]



318


447
370 [M + 1]


449
336 [M + 1]


450
455 [M + 1]


451
390 [M + 3]



388 [M + 1]


453
358 [M + 1]


454
407 [M + 1]



331


455
296 [M + 1]


458
382 [M + 1]


459
392 [M + 1]


460
431 [M + 1]


461
369 [M + 1]


462
381 [M + 3]



379 [M + 1]


463
440 [M + 3]



438 [M + 1]


464
338 [M + 1]



262


467
387 [M + 1]


468
439 [M + 1]



363


469
360 [M + 1]


471
363 [M + 3]



361 [M + 1]

















TABLE 164







472
376 [M + 1]


473
414 [M + 1]


474
334 [M + 1]


475
317 [M + 1]


476
324 [M + 1]


477
437 [M + 1]


478
379 [M + 1]


479
394 [M + 1]


480
370 [M + 1]


481
431 [M + 1]


484
314 [M + 3]



312 [M + 1]


485
448 [M + 1]


486
350 [M + 1]


487
338 [M + 1]


488
306 [M + 1]


489
335 [M + 1]


492
380 [M + 1]


495
334 [M + 1]


499
370 [M + 1]


503
412 [M + 1]


505
363 [M + 3]



361 [M + 1]


506
386 [M + 1]


507
400 [M + 1]


508
372 [M + 1]


509
414 [M + 1]



338


510
374 [M + 1]


512
320 [M + 1]


513
420 [M + 3]



418 [M + 1]


514
372 [M + 1]


517
369 [M + 1]


518
376 [M + 1]


519
411 [M + 1]


520
395 [M + 1]


521
372 [M + 1]


522
390 [M + 1]


523
414 [M + 1]


524
341 [M + 1]


526
426 [M + 1]


527
381 [M + 3]



379 [M + 1]


529
320 [M + 1]


530
390 [M + 3]



388 [M + 1]


531
410 [M + 1]


535
356 [M + 1]


536
372 [M + 1]


537
377 [M + 1]


538
406 [M + 1]


539
411 [M + 1]


540
354 [M + 1]


541
342 [M + 1]


542
361 [M + 1]


543
344 [M + 1]


544
412 [M + 1]


545
366 [M + 1]


546
383 [M + 1]


547
430 [M + 1]



428 [M + 1]


548
427 [M + 1]


550
340 [M + 1]


552
400 [M + 1]


553
304 [M + 1]


555
383 [M + 1]


557
304 [M + 1]


562
374 [M + 1]


563
366 [M + 1]


564
395 [M + 1]


565
336 [M + 1]


566
427 [M + 1]



351


568
362 [M + 3]



360 [M + 1]


569
356 [M + 1]


571
356 [M + 1]


572
473 [M + 3]



471 [M + 1]


574
381 [M + 3]



379 [M + 1]


575
360 [M + 1]


576
384 [M + 1]


578
344 [M + 1]


579
370 [M + 1]


580
347 [M + 1]


581
409 [M + 1]


582
334 [M + 1]


583
392 [M + 1]


585
358 [M + 1]


587
348 [M + 1]


589
407 [M + 3]



405 [M + 1]


590
410 [M + 3]



408 [M + 1]


591
460 [M + 1]



384


592
380 [M + 3]



378 [M + 1]


594
390 [M + 1]


598
394 [M + 1]


599
377 [M + 1]


603
398 [M + 3]



396 [M + 1]


604
395 [M + 1]


606
358 [M + 1]


607
362 [M + 1]


609
413 [M + 1]


610
409 [M + 1]


612
385 [M + 1]


614
322 [M + 1]


615
441 [M + 1]


616
346 [M + 3]



344 [M + 1]



270



268


617
406 [M + 3]



404 [M + 1]


619
404 [M + 1]


621
366 [M + 1]


623
422 [M + 1]



346


624
370 [M + 1]


626
402 [M + 1]


627
398 [M + 3]



396 [M + 1]


628
413 [M + 1]


631
370 [M + 1]


632
414 [M + 3]



412 [M + 1]

















TABLE 165







633
322 [M + 1]


635
420 [M + 1]


638
408 [M + 1]


639
386 [M + 1]



310


640
370 [M + 1]


641
437 [M + 1]


642
380 [M + 1]


646
395 [M + 1]


647
334 [M + 1]


648
403 [M + 1]


650
370 [M + 1]


655
362 [M + 1]


656
308 [M + 1]


658
430 [M + 1]


659
340 [M + 3]



388 [M + 1]


662
330 [M + 1]


663
334 [M + 1]


665
316 [M + 1]


666
345 [M + 1]


668
430 [M + 1]


669
377 [M + 1]


670
368 [M + 3]



366 [M + 1]


671
334 [M + 1]


672
442 [M + 1]


674
340 [M + 1]


675
306 [M + 1]


676
392 [M + 1]


678
386 [M + 1]


679
426 [M + 1]


682
414 [M + 3]



412 [M + 1]


684
384 [M + 1]


685
389 [M + 1]


686
446 [M + 1]


688
414 [M + 1]


689
306 [M + 1]


690
348 [M + 1]


691
452 [M + 1]


693
371 [M + 1]


694
448 [M + 1]


695
364 [M + 1]


696
392 [M + 3]



390 [M + 1]


697
358 [M + 1]


699
426 [M + 1]


703
451 [M + 3]



449 [M + 1]


704
342 [M + 1]


705
372 [M + 1]


706
368 [M + 1]


708
383 [M + 1]


710
396 [M + 3]



394 [M + 1]


711
351 [M + 1]


712
376 [M + 1]


713
398 [M + 3]



398 [M + 1]


714
366 [M + 1]


715
454 [M + 1]


716
381 [M + 3]



379 [M + 1]


718
386 [M + 1]


721
322 [M + 1]


722
377 [M + 1]


723
440 [M + 1]



364


724
457 [M + 3]



455 [M + 1]


726
362 [M + 1]


727
366 [M + 1]


734
370 [M + 1]


736
338 [M + 1]


741
404 [M + 1]


742
351 [M + 1]


745
386 [M + 1]


748
370 [M + 1]



294


747
336 [M + 1]


748
381 [M + 3]



379 [M + 1]


749
416 [M + 1]



340


750
437 [M + 1]


751
362 [M + 1]


752
352 [M + 3]



350 [M + 1]


754
366 [M + 1]


755
354 [M + 1]


757
425 [M + 1]


759
346 [M + 1]


760
344 [M + 1]


761
402 [M + 1]


762
251 [M + 1]


763
355 [M + 1]


764
362 [M + 3]



360 [M + 1]


765
392 [M + 3]



390 [M + 1]


769
386 [M + 1]


770
372 [M + 1]


772
292 [M + 1]


773
424 [M + 1]


775
396 [M + 3]



394 [M + 1]


776
388 [M + 1]


777
383 [M + 1]


778
404 [M + 1]


779
398 [M + 1]


780
368 [M + 1]


782
368 [M + 1]


784
369 [M + 1]


785
431 [M + 3]



429 [M + 1]


787
473 [M + 1]



397


788
375 [M + 1]


789
467 [M + 1]


794
327 [M + 1]


795
384 [M + 1]


796
370 [M + 1]


798
370 [M + 1]


801
404 [M + 3]



402 [M + 1]


805
376 [M + 1]


806
411 [M + 1]


807
356 [M + 1]

















TABLE 166







808
354 [M + 1]


809
400 [M + 1]



324


812
425 [M + 1]


815
386 [M + 1]


817
377 [M + 1]


818
398 [M + 1]


819
352 [M + 1]


821
336 [M + 1]


823
362 [M + 1]


824
363 [M + 1]



287


825
420 [M + 1]


826
430 [M + 1]


828
377 [M + 1]


829
437 [M + 1]


830
370 [M + 1]


831
327 [M + 1]


837
324 [M + 1]



248


838
377 [M + 1]


839
376 [M + 3]



374 [M + 1]


841
363 [M + 3]



361 [M + 1]


842
386 [M + 1]


843
466 [M + 3]



464 [M + 1]


844
381 [M + 1]


845
324 [M + 1]



248


846
358 [M + 1]


847
373 [M + 1]


852
489 [M + 1]


853
376 [M + 1]


854
448 [M + 1]


856
420 [M + 1]



344


857
341 [M + 1]


858
383 [M + 1]


860
370 [M + 1]


861
334 [M + 3]



332 [M + 1]


862
358 [M + 1]


864
392 [M + 1]


865
398 [M + 3]



396 [M + 1]


867
399 [M + 1]


868
430 [M + 1]


870
362 [M + 3]



360 [M + 1]


872
428 [M + 1]


873
351 [M + 1]


874
341 [M + 1]


877
399 [M + 1]



323


879
332 [M + 1]


880
363 [M + 3]



361 [M + 1]


882
426 [M + 1]


883
360 [M + 1]


884
320 [M + 1]


885
361 [M + 1]


886
380 [M + 1]


888
292 [M + 1]


889
451 [M + 1]



449 [M + 1]


890
400 [M + 1]


891
292 [M + 1]


894
347 [M + 1]


898
412 [M + 3]



410 [M + 1]


899
397 [M + 1]


901
411 [M + 1]


902
377 [M + 1]


903
370 [M + 1]


904
422 [M + 1]


905
392 [M + 1]


907
308 [M + 1]


909
393 [M + 1]


911
415 [M + 1]


912
383 [M + 1]


913
413 [M + 1]


914
400 [M + 1]


915
389 [M + 1]



313


917
358 [M + 1]


918
433 [M + 3]



431 [M + 1]


919
354 [M + 1]


920
381 [M + 3]



379 [M + 1]


921
389 [M + 1]


922
413 [M + 1]



337


923
437 [M + 1]


924
376 [M + 1]


925
390 [M + 1]


927
355 [M + 1]


929
370 [M + 1]


932
380 [M + 3]



378 [M + 1]


934
507 [M + 1]


937
388 [M + 1]


938
366 [M + 1]


940
388 [M + 1]


942
378 [M + 1]


943
413 [M + 1]


945
372 [M + 1]


948
462 [M + 1]


949
363 [M + 1]


950
368 [M + 1]


951
412 [M + 1]


952
378 [M + 1]


953
318 [M + 1]


954
363 [M + 3]



361 [M + 1]


955
406 [M + 3]



404 [M + 1]


956
292 [M + 1]


957
398 [M + 3]



396 [M + 1]


958
310 [M + 1]


959
406 [M + 3]



404 [M + 1]


961
362 [M + 3]



360 [M + 1]


962
327 [M + 1]


963
392 [M + 1]

















TABLE 167







965
438 [M + 3]



436 [M + 1]


967
425 [M + 3]



423 [M + 1]


969
413 [M + 1]


973
386 [M + 1]


975
407 [M + 3]



405 [M + 1]


976
358 [M + 1]


977
369 [M + 1]


979
395 [M + 1]


980
402 [M + 1]


981
392 [M + 3]



390 [M + 1]


982
366 [M + 1]


983
379 [M + 1]


985
408 [M + 1]


986
440 [M + 3]



438 [M + 1]


987
358 [M + 1]


988
294 [M + 1]


989
332 [M + 1]


991
356 [M + 1]


992
477 [M + 1]


993
416 [M + 3]



414 [M + 1]


995
425 [M + 3]



423 [M + 1]


996
416 [M + 3]



414 [M + 1]


997
363 [M + 3]



361 [M + 1]


999
336 [M + 1]


1000
388 [M + 1]



312


1001
374 [M + 1]


1002
400 [M + 1]


1003
394 [M + 1]


1004
397 [M + 1]


1007
448 [M + 1]



372


1009
366 [M + 1]


1011
419 [M + 1]


1012
316 [M + 1]


1013
431 [M + 1]


1015
372 [M + 1]


1016
470 [M + 1]


1017
413 [M + 1]


1018
386 [M + 1]


1019
433 [M + 3]



431 [M + 1]


1021
464 [M + 1]


1022
384 [M + 1]


1023
407 [M + 3]



405 [M + 1]


1024
346 [M + 1]


1025
455 [M + 3]



453 [M + 1]


1026
425 [M + 1]


1027
444 [M + 1]


1029
410 [M + 1]


1030
413 [M + 1]


1031
404 [M + 1]


1032
472 [M + 1]



396


1033
377 [M + 1]


1036
350 [M + 1]


1038
364 [M + 1]


1040
317 [M + 1]


1041
407 [M + 1]


1042
382 [M + 1]


1045
425 [M + 3]



423 [M + 1]


1046
366 [M + 1]


1047
390 [M + 1]


1048
440 [M + 1]


1049
396 [M + 1]


1050
400 [M + 1]


1051
315 [M + 1]


1053
383 [M + 3]



361 [M + 1]


1054
360 [M + 1]


1057
427 [M + 1]


1058
360 [M + 1]


1060
381 [M + 3]



379 [M + 1]


1063
395 [M + 1]


1065
451 [M + 1]



449 [M + 1]


1066
485 [M + 1]


1070
380 [M + 3]



378 [M + 1]


1071
345 [M + 1]


1072
381 [M + 3]



379 [M + 1]


1073
397 [M + 1]


1075
342 [M + 1]


1077
344 [M + 1]


1078
370 [M + 1]


1079
387 [M + 1]


1080
370 [M + 1]



294


1081
355 [M + 1]


1082
398 [M + 3]



396 [M + 1]


1083
316 [M + 1]


1085
439 [M + 3]



437 [M + 1]


1086
428 [M + 1]


1089
399 [M + 1]


1090
398 [M + 1]


1091
434 [M + 3]



432 [M + 1]


1092
398 [M + 3]



396 [M + 1]


1093
401 [M + 1]


1095
400 [M + 1]


1096
409 [M + 1]


1097
384 [M + 1]


1098
395 [M + 1]


1099
511 [M + 4]



510 [M + 3]



509 [M + 2]



508 [M + 1]


1101
350 [M + 1]


1102
442 [M + 1]


1103
397 [M + 1]


1105
372 [M + 1]


1106
346 [M + 1]


1108
383 [M + 1]


1112
445 [M + 1]

















TABLE 168







1113
358 [M + 1]


1117
394 [M + 1]


1118
336 [M + 1]



260


1121
392 [M + 3]



390 [M + 1]


1122
322 [M + 1]


1123
316 [M + 1]


1126
386 [M + 1]


1127
368 [M + 1]


1128
416 [M + 3]



414 [M + 1]


1129
341 [M + 1]


1130
432 [M + 1]


1134
396 [M + 1]


1136
396 [M + 3]



394 [M + 1]


1137
292 [M + 1]


1138
413 [M + 1]


1141
344 [M + 1]


1143
384 [M + 1]


1144
446 [M + 1]


1145
390 [M + 1]



314


1146
405 [M + 1]


1148
380 [M + 1]



304


1149
364 [M + 1]


1151
442 [M + 1]


1152
365 [M + 1]


1154
318 [M + 1]


1155
427 [M + 1]


1156
368 [M + 1]


1157
366 [M + 1]


1158
415 [M + 3]



413 [M + 1]


1159
414 [M + 3]



412 [M + 1]


1162
370 [M + 1]



294


1163
416 [M + 3]



414 [M + 1]


1164
396 [M + 1]



320


1165
361 [M + 1]


1167
424 [M + 1]



348


1168
428 [M + 1]


1169
422 [M + 1]


1170
411 [M + 1]


1171
390 [M + 3]



388 [M + 1]


1173
361 [M + 1]


1174
342 [M + 1]


1175
430 [M + 1]


1176
345 [M + 1]


1177
376 [M + 3]



374 [M + 1]


1178
351 [M + 1]


1179
344 [M + 1]


1180
398 [M + 3]



396 [M + 1]


1182
426 [M + 1]


1183
376 [M + 3]



374 [M + 1]


1186
374 [M + 1]



298


1187
427 [M + 1]


1188
350 [M + 1]


1189
408 [M + 3]



406 [M + 1]


1190
386 [M + 1]


1191
377 [M + 1]


1192
335 [M + 1]


1195
412 [M + 3]



410 [M + 1]


1196
380 [M + 1]


1198
398 [M + 1]



322


1200
352 [M + 1]


1201
424 [M + 3]



422 [M + 1]


1202
369 [M + 1]


1203
420 [M + 1]


1204
398 [M + 3]



396 [M + 1]


1206
416 [M + 1]


1208
344 [M + 1]


1209
422 [M + 1]


1210
408 [M + 1]


1212
391 [M + 1]


1214
360 [M + 1]


1218
372 [M + 1]


1219
470 [M + 1]


1220
264 [M + 1]


1222
362 [M + 3]



360 [M + 1]


1225
413 [M + 1]


1226
374 [M + 1]


1227
425 [M + 1]


1229
455 [M + 3]



453 [M + 1]


1231
413 [M + 1]


1232
340 [M + 1]


1233
394 [M + 1]


1234
416 [M + 3]



414 [M + 1]


1235
427 [M + 1]


1236
348 [M + 1]



272


1237
353 [M + 1]


1238
419 [M + 1]


1239
416 [M + 3]



414 [M + 1]


1246
474 [M + 1]


1248
414 [M + 1]


1249
336 [M + 1]


1250
352 [M + 1]


1251
393 [M + 1]


1252
357 [M + 1]


1253
430 [M + 1]


1254
412 [M + 1]


1256
333 [M + 1]


1259
356 [M + 1]


1260
348 [M + 1]


1270
374 [M + 1]


1282
362 [M + 1]
















In above structural formula (Ia) to (Ih), the combination of NR2aR2b, R8c, R3d, R5 and G (NR2aR2b, R3c, R3d, R5, G) are the following compounds.
(NHMe,H,H,Me,CONHPh),(NHMe,H,H,Me,CONH-3-pyridyl),(NHMe,H,H,Me,NHC OPh),(NHMe,H,H,Me,NHCO-2-furyl),(NHMe,H,H,Me,NHCONHPh),(NHMe,H,H,Me,NHCOCONHPh),(NHMe,H,H,Et,CONHPh),(NHMe,H,H,Et,CONH-3-pyridyl),(NHMe,H,H,Et,NHCOPh),(NHMe,H,H,Et,NHCO-2-furyl),(NHMe,H,H,Et,NHCONHPh),(NHMe,H,H,Et,NHCOCONHPh),(NHMe,H,H,CH2OH,CONHPh),(NHMe,H,H,CH2OH,CONH-3-pyridyl),(NHMe,H,H,CH2OH,NHCOPh),(NHMe,H,H,CH2OH,NHCO-2-furyl),CH2OH,NHCONHPh),(NHMe,H,H,CH2OH,NHCOCONHPh),(NHMe,H,Me,Me,CONHPh),(NHMe,H,Me,Me,CONH-3-pyridyl),(NHMe,H,Me,Me,NHCOPh),(NHMe,H,Me,Me,NHCO-2-furyl),(NHMe,H,Me,Me,NHCONHPh),(NHMe,H,Me,Me,NHCOCONHPh),(NHMe,H,Me,Et,CONHPh),(NHMe,H,Me,Et,CONH-3-pyridyl),(NHMe,H,Me,Et,NHCOPh),(NHMe,H,Me,Et,NHCO-2-furyl),(NHMe,H,Me,Et,NHCONHPh),(NHMe,H,Me,Et,NHCOCONHPh),(NHMe,H,Me,CH2OH,CONHPh),(NHMe,H,Me,CH2OH,CONH-3-pyridyl),(NHMe,H,Me,CH2OH,NHCOPh),(NHMe,H,Me,CH2OH,NHCO-2-furyl),(NHMe,H,Me,CH2OH,NHCONHPh),(NHMe,H,Me,CH2OH,NHCOCONHPh),H,Ph,Me,CONHPh),(NHMe,H,Ph,Me,CONH-3-pyridyl),(NHMe,H,Ph,Me,NHCOPh),H,Ph,Me,NHCO-2-furyl),(NHMe,H,Ph,Me,NHCONHPh),(NHMe,H,Ph,Me,NHCOCONHPh),(NHMe,H,Ph,Et,CONHPh),CONH-3-pyridyl),(NHMe,H,Ph,Et,NHCOPh),(NHMe,H,Ph,Et,NHCO-2-furyl),(NHMe,H,Ph,Et,NHCONHPh),(NHMe,H,Ph,Et,NHCOCONHPh),(NHMe,H,Ph,CH2OH,CONHPh),(NHMe,H,Ph,CH2OH,CONH-3-pyridyl),(NHMe,H,Ph,CH2OH,NHCOPh),(NHMe,H,Ph,CH2OH,NHCO-2-furyl),(NHMe,H,Ph,CH2OH,NHCONHPh),(NHMe,H,Ph,CH2OH,NHCOCONHPh),(NHMe,H,OH,Me,CONHPh),(NHMe,H,OH,Me,CONH-3-pyridyl),(NHMe,H,OH,Me,NHCOPh),(NHMe,H,OH,Me,NHCO-2-furyl),(NHMe,H,OH,Me,NHCONHPh),(NHMe,H,OH,Me,NHCOCONHPh),(NHMe,H,OH,Et,CONHPh),(NHMe,H,OH,Et,CONH-3-pyridyl),(NHMe,H,OH,Et,NHCOPh),(NHMe,H,OH,Et,NHCO-2-furyl),(NHMe,H,OH,Et,NHCONHPh),(NHMe,H,OH,Et,NHCOCONHPh),(NHMe,H,OH,CH2OH,CONHPh),(NHMe,H,OH,CH2OH,CONH-3-pyridyl),(NHMe,H,OH,CH2OH,NHCOPh),(NHMe,H,OH,CH2OH,NHCO-2-furyl),(NHMe,H,OH,CH2OH,NHCONHPh),(NHMe,H,OH,CH2OH,NHCOCONHPh),(NHMe,Me,H,Me,CONHPh),(NHMe,Me,H,Me,CONH-3-pyridyl),(NHMe,Me,H,Me,NHCOPh),(NHMe,Me,H,Me,NHCO-2-furyl),(NHMe,Me,H,Me,NHCONHPh),(NHMe,Me,H,Me,NHCOCONHPh),(NHMe,Me,H,Et,CONHPh),(NHMe,Me,H,Et,CONH-3-pyridyl),(NHMe,Me,H,Et,NHCOPh),(NHMe,Me,H,Et,NHCO-2-furyl),(NHMe,Me,H,Et,NHCONHPh),(NHMe,Me,H,Et,NHCOCONHPh),(NHMe,Me,H,CH2OH,CONHPh),(NHMe,Me,H,CH2OH,CONH-3-pyridyl),(NHMe,Me,H,CH2OH,NHCOPh),(NHMe,Me,H,CH2OH,NHCO-2-furyl),(NHMe,Me,H,CH2OH,NHCONHPh),(NHMe,Me,H,CH2OH,NHCOCONHPh),(NHMe,Me,Me,Me,CONHPh),(NHMe,Me,Me,Me,CONH-3-pyridyl),(NHMe,Me,Me,Me,NHCOPh),(NHMe,Me,Me,Me,NHCO-2-furyl),(NHMe,Me,Me,Me,NHCONHPh),(NHMe,Me,Me,Me,NHCOCONHPh),(NHMe,Me,Me,Et,CONHPh),(NHMe,Me,Me,Et,CONH-3-pyridyl),(NHMe,Me,Me,Et,NHCOPh),(NHMe,Me,Me,Et,NHCO-2-furyl),(NHMe,Me,Me,Et,NHCONHPh),(NHMe,Me,Me,Et,NHCOCONHPh),(NHMe,Me,Me,CH2OH,CONHPh),(NHMe,Me,Me,CH2OH,CONH-3-pyridyl),(NHMe,Me,Me,CH2OH,NHCOPh),(NHMe,Me,Me,CH2OH,NHCO-2-furyl),(NHMe,Me,Me,CH2OH,NHCONHPh),(NHMe,Me,Me,CH2OH,NHCOCONHPh),(NHMe,Me,Ph,Me,CONHPh),(NHMe,Me,Ph,Me,CONH-3-pyridyl),(NHMe,Me,Ph,Me,NHCOPh),(NHMe,Me,Ph,Me,NHCO-2-furyl),(NHMe,Me,Ph,Me,NHCONHPh),(NHMe,Me,Ph,Me,NHCOCONHPh),(NHMe,Me,Ph,Et,CONHPh),(NHMe,Me,Ph,Et,CONH-3-pyridyl),(NHMe,Me,Ph,Et,NHCOPh),(NHMe,Me,Ph,Et,NHCO-2-furyl),(NHMe,Me,Ph,Et,NHCONHPh),(NHMe,Me,Ph,Et,NHCOCONHPh),(NHMe,Me,Ph,CH2OH,CONHPh),(NHMe,Me,Ph,CH2OH,CONH-3-pyridyl),(NHMe,Me,Ph,CH2OH,NHCOPh),(NHMe,Me,Ph,CH2OH,NHCO-2-furyl),(NHMe,Me,Ph,CH2OH,NHCONHPh),(NHMe,Me,Ph,CH2OH,NHCOCONHPh),(NHMe,Me,OH,Me,CONHPh),(NHMe,Me,OH,Me,CONH-3-pyridyl),(NHMe,Me,OH,Me,NHCOPh),(NHMe,Me,OH,Me,NHCO-2-furyl),(NHMe,Me,OH,Me,NHCONHPh),(NHMe,Me,OH,Me,NHCOCONHPh),(NHMe,Me,OH,Et,CONHPh),(NHMe,Me,OH,Et,CONH-3-pyridyl),(NHMe,Me,OH,Et,NHCOPh),(NHMe,Me,OH,Et,NHCO-2-furyl),(NHMe,Me,OH,Et,NHCONHPh),(NHMe,Me,OH,Et,NHCOCONHPh),(NHMe,Me,OH,CH2OH,CONHPh),(NHMe,Me,OH,CH2OH,CONH-3-pyridyl),(NHMe,Me,OH,CH2OH,NHCOPh),(NHMe,Me,OH,CH2OH,NHCO-2-furyl),(NHMe,Me,OH,CH2OH,NHCONHPh),(NHMe,Me,OH,CH2OH,NHCOCONHPh),(NHMe,Ph,H,Me,CONHPh),(NHMe,Ph,H,Me,CONH-3-pyridyl),(NHMe,Ph,H,Me,NHCOPh),(NHMe,Ph,H,Me,NHCO-2-furyl),(NHMe,Ph,H,Me,NHCONHPh),(NHMe,Ph,H,Me,NHCOCONHPh),(NHMe,Ph,H,Et,CONHPh),(NHMe,Ph,H,Et,CONH-3-pyridyl),(NHMe,Ph,H,Et,NHCOPh),(NHMe,Ph,H,Et,NHCO-2-furyl),(NHMe,Ph,H,Et,NHCONHPh),(NHMe,Ph,H,Et,NHCOCONHPh),(NHMe,Ph,H,CH2OH,CONHPh),(NHMe,Ph,H,CH2OH,CONH-3-pyridyl),(NHMe,Ph,H,CH2OH,NHCOPh),(NHMe,Ph,H,CH2OH,NHCO-2-furyl),(NHMe,Ph,H,CH2OH,NHCONHPh),(NHMe,Ph,H,CH2OH,NHCOCONHPh),(NHMe,Ph,Me,Me,CONHPh),(NHMe,Ph,Me,Me,CONH-3-pyridyl),(NHMe,Ph,Me,Me,NHCOPh),(NHMe,Ph,Me,Me,NHCO-2-furyl),(NHMe,Ph,Me,Me,NHCONHPh),(NHMe,Ph,Me,Me,NHCOCONHPh),(NHMe,Ph,Me,Et,CONHPh),(NHMe,Ph,Me,Et,CONH-3-pyridyl),(NHMe,Ph,Me,Et,NHCOPh),(NHMe,Ph,Me,Et,NHCO-2-furyl),(NHMe,Ph,Me,Et,NHCONHPh),(NHMe,Ph,Me,Et,NHCOCONHPh),(NHMe,Ph,Me,CH2OH,CONHPh),(NHMe,Ph,Me,CH2OH,CONH-3-pyridyl),(NHMe,Ph,Me,CH2OH,NHCOPh),(NHMe,Ph,Me,CH2OH,NHCO-2-furyl),(NHMe,Ph,Me,CH2OH,NHCONHPh),(NHMe,Ph,Me,CH2OH,NHCOCONHPh),(NHMe,Ph,Ph,Me,CONHPh),(NHMe,Ph,Ph,Me,CONH-3-pyridyl),(NHMe,Ph,Ph,Me,NHCOPh),(NHMe,Ph,Ph,Me,NHCO-2-furyl),(NHMe,Ph,Ph,Me,NHCONHPh),(NHMe,Ph,Ph,Me,NHCOCONHPh),(NHMe,Ph,Ph,Et,CONHPh),(NHMe,Ph,Ph,Et,CONH-3-pyridyl),(NHMe,Ph,Ph,Et,NHCOPh),(NHMe,Ph,Ph,Et,NHCO-2-furyl),(NHMe,Ph,Ph,Et,NHCONHPh),(NHMe,Ph,Ph,Et,NHCOCONHPh),(NHMe,Ph,Ph,CH2OH,CONHPh),(NHMe,Ph,Ph,CH2OH,CONH-3-pyridyl),(NHMe,Ph,Ph,CH2OH,NHCOPh),(NHMe,Ph,Ph,CH2OH,NHCO-2-furyl),(NHMe,Ph,Ph,CH2OH,NHCONHPh),(NHMe,Ph,Ph,CH2OH,NHCOCONHPh),(NHMe,Ph,OH,Me,CONHPh),(NHMe,Ph,OH,Me,CONH-3-pyridyl),(NHMe,Ph,OH,Me,NHCOPh),(NHMe,Ph,OH,Me,NHCO-2-furyl),(NHMe,Ph,OH,Me,NHCONHPh),(NHMe,Ph,OH,Me,NHCOCONHPh),(NHMe,Ph,OH,Et,CONHPh),(NHMe,Ph,OH,Et,CONH-3-pyridyl),(NHMe,Ph,OH,Et,NHCOPh),(NHMe,Ph,OH,Et,NHCO-2-furyl),(NHMe,Ph,OH,Et,NHCONHPh),(NHMe,Ph,OH,Et,NHCOCONHPh),(NHMe,Ph,OH,CH2OH,CONHPh),(NHMe,Ph,OH,CH2OH,CONH-3-pyridyl),(NHMe,Ph,OH,CH2OH,NHCOPh),(NHMe,Ph,OH,CH2OH,NHCO-2-furyl),(NHMe,Ph,OH,CH2OH,NHCONHPh),(NHMe,Ph,OH,CH2OH,NHCOCONHPh),

(NHCH2CH2OH,H,H,Me,CONHPh),(NHCH2CH2OH,H,H,Me,CONH-3-pyridyl),(NHCH2CH2OH,H,H,Me,NHCOPh),(NHCH2CH2OH,H,H,Me,NHCO-2-furyl),(NHCH2CH2OH,H,H,Me,NHCONHPh),(NHCH2CH2OH,H,H,Me,NHCOCONHPh),(NHCH2CH2OH,H,H,Et,CONHPh),(NHCH2CH2OH,H,H,Et,CONH-3-pyridyl),(NHCH2CH2OH,H,H,Et,NHCOPh),(NHCH2CH2OH,H,H,Et,NHCO-2-furyl),(NHCH2CH2OH,H,H,Et,NHCONHPh),(NHCH2CH2OH,H,H,Et,NHCOCONHPh),(NHCH2CH2OH,H,H,CH2OH,CONHPh),(NHCH2CH2OH,H,H,CH2OH,CONH-3-pyridyl),(NHCH2CH2OH,H,H,CH2OH,NHCOPh),(NHCH2CH2OH,H,H,CH2OH,NHCO-2-furyl),(NHCH2CH2OH,H,H,CH2OH,NHCONHPh),(NHCH2CH2OH,H,H,CH2OH,NHCOCONHPh),(NHCH2CH2OH,H,Me,Me,CONHPh),(NHCH2CH2OH,H,Me,Me,CONH-3-pyridyl),(NHCH2CH2OH,H,Me,Me,NHCOPh),(NHCH2CH2OH,H,Me,Me,NHCO-2-furyl),(NHCH2CH2OH,H,Me,Me,NHCONHPh),(NHCH2CH2OH,H,Me,Me,NHCOCONHPh),(NHCH2CH2OH,H,Me,Et,CONHPh),(NHCH2CH2OH,H,Me,Et,CONH-3-pyridyl),(NHCH2CH2OH,H,Me,Et,NHCOPh),(NHCH2CH2OH,H,Me,Et,NHCO-2-furyl),(NHCH2CH2OH,H,Me,Et,NHCONHPh),(NHCH2CH2OH,H,Me,Et,NHCOCONHPh),(NHCH2CH2OH,H,Me,CH2OH,CONHPh),(NHCH2CH2OH,H,Me,CH2OH,CONH-3-pyridyl),(NHCH2CH2OH,H,Me,CH2OH,NHCOPh),(NHCH2CH2OH,H,Me,CH2OH,NHCO-2-furyl),(NHCH2CH2OH,H,Me,CH2OH,NHCONHPh),(NHCH2CH2OH,H,Me,CH2OH,NHCOCONHPh),(NHCH2CH2OH,H,Ph,Me,CONHPh),(NHCH2CH2OH,H,Ph,Me,CONH-3-pyridyl),(NHCH2CH2OH,H,Ph,Me,NHCOPh),(NHCH2CH2OH,H,Ph,Me,NHCO-2-furyl),(NHCH2CH2OH,H,Ph,Me,NHCONHPh),(NHCH2CH2OH,H,Ph,Me,NHCOCONHPh),(NHCH2CH2OH,H,Ph,Et,CONHPh),(NHCH2CH2OH,H,Ph,Et,CONH-3-pyridyl),(NHCH2CH2OH,H,Ph,Et,NHCOPh),(NHCH2CH2OH,H,Ph,Et,NHCO-2-furyl),(NHCH2CH2OH,H,Ph,Et,NHCONHPh),(NHCH2CH2OH,H,Ph,Et,NHCOCONHPh),(NHCH2CH2OH,H,Ph,CH2OH,CONHPh),(NHCH2CH2OH,H,Ph,CH2OH,CONH-3-pyridyl),(NHCH2CH2OH,H,Ph,CH2OH,NHCOPh),(NHCH2CH2OH,H,Ph,CH2OH,NHCO-2-furyl),(NHCH2CH2OH,H,Ph,CH2OH,NHCONHPh),(NHCH2CH2OH,H,Ph,CH2OH,NHCOCONHPh),(NHCH2CH2OH,H2OH,Me,CONHPh),(NHCH2CH2OH,H2OH,Me,CONH-3-pyridyl),(NHCH2CH2OH,H,OH,Me,NHCOPh),(NHCH2CH2OH,H,OH,Me,NHCO-2-furyl),(NHCH2CH2OH,H,OH,Me,NHCONHPh),(NHCH2CH2OH,H,OH,Me,NHCOCONHPh),(NHCH2CH2OH,H,OH,Et,CONHPh),(NHCH2CH2OH,H2OH,Et,CONH-3-pyridyl),(NHCH2CH2OH,H,OH,Et,NHCOPh),(NHCH2CH2OH,H,OH,Et,NHCO-2-furyl),(NHCH2CH2OH,H2OH,Et,NHCONHPh),(NHCH2CH2OH,H,OH,Et,NHCOCONHPh),(NHCH2CH2OH,H2OH,CH2OH,CONHPh),(NHCH2CH2OH,H,OH,CH2OH,CONH-3-pyridyl),(NHCH2CH2OH,H,OH,CH2OH,NHCOPh),(NHCH2CH2OH,H,OH,CH2OH,NHCO-2-furyl)(NHCH2CH2OH,H,OH,CH2OH,NHCONHPh),(NHCH2CH2OH,H,OH,CH2OH,NHCOCONHPh),(NHCH2CH2OH,Me,H,Me,CONHPh),(NHCH2CH2OH,Me,H,Me,CONH-3-pyridyl),(NHCH2CH2OH,Me,H,Me,NHCOPh),(NHCH2CH2OH,Me,H,Me,NHCO-2-furyl),(NHCH2CH2OH,Me,H,Me,NHCONHPh),(NHCH2CH2OH,Me,H,Me,NHCOCONHPh),(NHCH2CH2OH,Me,H,Et,CONHPh),(NHCH2CH2OH,Me,H,Et,CONH-3-pyridyl),(NHCH2CH2OH,Me,H,Et,NHCOPh),(NHCH2CH2OH,Me,H,Et,NHCO-2-furyl),(NHCH2CH2OH,Me,H,Et,NHCONHPh),(NHCH2CH2OH,Me,H,Et,NHCOCONHPh),(NHCH2CH2OH,Me,H,CH2OH,CONHPh),(NHCH2CH2OH,Me,H,CH2OH,CONH-3-pyridyl),(NHCH2CH2OH,Me,H,CH2OH,NHCOPh),(NHCH2CH2OH,Me,H,CH2OH,NHCO-2-furyl),(NHCH2CH2OH,Me,H,CH2OH,NHCONHPh),(NHCH2CH2OH,Me,H,CH2OH,NHCOCONHPh),(NHCH2CH2OH,Me,Me,Me,CONHPh),(NHCH2CH2OH,Me,Me,Me,CONH-3-pyridyl),(NHCH2CH2OH,Me,Me,Me,NHCOPh),(NHCH2CH2OH,Me,Me,Me,NHCO-2-furyl),(NHCH2CH2OH,Me,Me,Me,NHCONHPh),(NHCH2CH2OH,Me,Me,Me,NHCOCONHPh),(NHCH2CH2OH,Me,Me,Et,CONHPh),(NHCH2CH2OH,Me,Me,Et,CONH-3-pyridyl),(NHCH2CH2OH,Me,Me,Et,NHCOPh),(NHCH2CH2OH,Me,Me,Et,NHCO-2-furyl),(NHCH2CH2OH,Me,Me,Et,NHCONHPh),(NHCH2CH2OH,Me,Me,Et,NHCOCONHPh),(NHCH2CH2OH,Me,Me,CH2OH,CONHPh),(NHCH2CH2OH,Me,Me,CH2OH,CONH-3-pyridyl),(NHCH2CH2OH,Me,Me,CH2OH,NHCOPh),(NHCH2CH2OH,Me,Me,CH2OH,NHCO-2-furyl),(NHCH2CH2OH,Me,Me,CH2OH,NHCONHPh),(NHCH2CH2OH,Me,Me,CH2OH,NHCOCONHPh),(NHCH2CH2OH,Me,Ph,Me,CONHPh),(NHCH2CH2OH,Me,Ph,Me,CONH-3-pyridyl),(NHCH2CH2OH,Me,Ph,Me,NHCOPh),(NHCH2CH2OH,Me,Ph,Me,NHCO-2-furyl),(NHCH2CH2OH,Me,Ph,Me,NHCONHPh),(NHCH2CH2OH,Me,Ph,Me,NHCOCONHPh),(NHCH2CH2OH,Me,Ph,Et,CONHPh),(NHCH2CH2OH,Me,Ph,Et,CONH-3-pyridyl),(NHCH2CH2OH,Me,Ph,Et,NHCOPh),(NHCH2CH2OH,Me,Ph,Et,NHCO-2-furyl),(NHCH2CH2OH,Me,Ph,Et,NHCONHPh),(NHCH2CH2OH,Me,Ph,Et,NHCOCONHPh),(NHCH2CH2OH,Me,Ph,CH2OH,CONHPh),(NHCH2CH2OH,Me,Ph,CH2OH,CONH-3-pyridyl),(NHCH2CH2OH,Me,Ph,CH2OH,NHCOPh),(NHCH2CH2OH,Me,Ph,CH2OH,NHCO-2-furyl),(NHCH2CH2OH,Me,Ph,CH2OH,NHCONHPh),(NHCH2CH2OH,Me,Ph,CH2OH,NHCOCONHPh),(NHCH2CH2OH,Me,OH,Me,CONHPh),(NHCH2CH2OH,Me,OH,Me,CONH-3-pyridyl),(NHCH2CH2OH,Me,OH,Me,NHCOPh),(NHCH2CH2OH,Me,OH,Me,NHCO-2-furyl),(NHCH2CH2OH,Me,OH,Me,NHCONHPh),(NHCH2CH2OH,Me,OH,Me,NHCOCONHPh),(NHCH2CH2OH,Me,OH,Et,CONHPh),(NHCH2CH2OH,Me,OH,Et,CONH-3-pyridyl),(NHCH2CH2OH,Me,OH,Et,NHCOPh),(NHCH2CH2OH,Me,OH,Et,NHCO-2-furyl),(NHCH2CH2OH,Me,OH,Et,NHCONHPh),(NHCH2CH2OH,Me,OH,Et,NHCOCONHPh),(NHCH2CH2OH,Me,OH,CH2OH,CONHPh),(NHCH2CH2OH,Me,OH,CH2OH,CONH-3-pyridyl),(NHCH2CH2OH,Me,OH,CH2OH,NHCOPh),(NHCH2CH2OH,Me,OH,CH2OH,NHCO-2-furyl),(NHCH2CH2OH,Me,OH,CH2OH,NHCONHPh),(NHCH2CH2OH,Me,OH,CH2OH,NHCOCONHPh),(NHCH2CH2OH,Ph,H,Me,CONHPh),(NHCH2CH2OH,Ph,H,Me,CONH-3-pyridyl),(NHCH2CH2OH,Ph,H,Me,NHCOPh),(NHCH2CH2OH,Ph,H,Me,NHCO-2-furyl),(NHCH2CH2OH,Ph,H,Me,NHCONHPh),(NHCH2CH2OH,Ph,H,Me,NHCOCONHPh),(NHCH2CH2OH,Ph,H,Et,CONHPh),(NHCH2CH2OH,Ph,H,Et,CONH-3-pyridyl),(NHCH2CH2OH,Ph,H,Et,NHCOPh),(NHCH2CH2OH,Ph,H,Et,NHCO-2-furyl),(NHCH2CH2OH,Ph,H,Et,NHCONHPh),(NHCH2CH2OH,Ph,H,Et,NHCOCONHPh),(NHCH2CH2OH,Ph,H,CH2OH,CONHPh),(NHCH2CH2OH,Ph,H,CH2OH,CONH-3-pyridyl),(NHCH2CH2OH,Ph,H,CH2OH,NHCOPh),(NHCH2CH2OH,Ph,H,CH2OH,NHCO-2-furyl),(NHCH2CH2OH,Ph,H,CH2OH,NHCONHPh),(NHCH2CH2OH,Ph,H,CH2OH,NHCOCONHPh),(NHCH2CH2OH,Ph,Me,Me,CONHPh),(NHCH2CH2OH,Ph,Me,Me,CONH-3-pyridyl),(NHCH2CH2OH,Ph,Me,Me,NHCOPh),(NHCH2CH2OH,Ph,Me,Me,NHCO-2-furyl),(NHCH2CH2OH,Ph,Me,Me,NHCONHPh),(NHCH2CH2OH,Ph,Me,Me,NHCOCONHPh),(NHCH2CH2OH,Ph,Me,Et,CONHPh),(NHCH2CH2OH,Ph,Me,Et,CONH-3-pyridyl),(NHCH2CH2OH,Ph,Me,Et,NHCOPh),(NHCH2CH2OH,Ph,Me,Et,NHCO-2-furyl),(NHCH2CH2OH,Ph,Me,Et,NHCONHPh),(NHCH2CH2OH,Ph,Me,Et,NHCOCONHPh),(NHCH2CH2OH,Ph,Me,CH2OH,CONHPh),(NHCH2CH2OH,Ph,Me,CH2OH,CONH-3-pyridyl),(NHCH2CH2OH,Ph,Me,CH2OH,NHCOPh),(NHCH2CH2OH,Ph,Me,CH2OH,NHCO-2-furyl),(NHCH2CH2OH,Ph,Me,CH2OH,NHCONHPh),(NHCH2CH2OH,Ph,Me,CH2OH,NHCOCONHPh),(NHCH2CH2OH,Ph,Ph,Me,CONHPh),(NHCH2CH2OH,Ph,Ph,Me,CONH-3-pyridyl),(NHCH2CH2OH,Ph,Ph,Me,NHCOPh),(NHCH2CH2OH,Ph,Ph,Me,NHCO-2-furyl),(NHCH2CH2OH,Ph,Ph,Me,NHCONHPh),(NHCH2CH2OH,Ph,Ph,Me,NHCOCONHPh),(NHCH2CH2OH,Ph,Ph,Et,CONHPh),(NHCH2CH2OH,Ph,Ph,Et,CONH-3-pyridyl),(NHCH2CH2OH,Ph,Ph,Et,NHCOPh),(NHCH2CH2OH,Ph,Ph,Et,NHCO-2-furyl),(NHCH2CH2OH,Ph,Ph,Et,NHCONHPh),(NHCH2CH2OH,Ph,Ph,Et,NHCOCONHPh),(NHCH2CH2OH,Ph,Ph,CH2OH,CONHPh),(NHCH2CH2OH,Ph,Ph,CH2OH,CONH-3-pyridyl),(NHCH2CH2OH,Ph,Ph,CH2OH,NHCOPh),(NHCH2CH2OH,Ph,Ph,CH2OH,NHCO-2-furyl),(NHCH2CH2OH,Ph,Ph,CH2OH,NHCONHPh),(NHCH2CH2OH,Ph,Ph,CH2OH,NHCOCONHPh),(NHCH2CH2OH,Ph,OH,Me,CONHPh),(NHCH2CH2OH,Ph,OH,Me,CONH-3-pyridyl),(NHCH2CH2OH,Ph,OH,Me,NHCOPh),(NHCH2CH2OH,Ph,OH,Me,NHCO-2-furyl),(NHCH2CH2OH,Ph,OH,Me,NHCONHPh),(NHCH2CH2OH,Ph,OH,Me,NHCOCONHPh),(NHCH2CH2OH,Ph,OH,Et,CONHPh),(NHCH2CH2OH,Ph,OH,Et,CONH-3-pyridyl),(NHCH2CH2OH,Ph,OH,Et,NHCOPh),(NHCH2CH2OH,Ph,OH,Et,NHCO-2-furyl),(NHCH2CH2OH,Ph,OH,Et,NHCONHPh),(NHCH2CH2OH,Ph,OH,Et,NHCOCONHPh),(NHCH2CH2OH,Ph,OH,CH2OH,CONHPh),(NHCH2CH2OH,Ph,OH,CH2OH,CONH-3-pyridyl),(NHCH2CH2OH,Ph,OH,CH2OH,NHCOPh),(NHCH2CH2OH,Ph,OH,CH2OH,NHCO-2-furyl),(NHCH2CH2OH,Ph,OH,CH2OH,NHCONHPh),(NHCH2CH2OH,Ph,OH,CH2OH,NHCOCONHPh),

(NHCH2CONH2,H,H,Me,CONHPh),(NHCH2CONH2,H,H,Me,CONH-3-pyridyl),(NHCH2CONH2,H,H,Me,NHCOPh),(NHCH2CONH2,H,H,Me,NHCO-2-furyl),(NHCH2CONH2,H,H,Me,NHCONHPh),(NHCH2CONH2,H,H,Me,NHCOCONHPh),(NHCH2CONH2,H,H,Et,CONHPh),(NHCH2CONH2,H,H,Et,CONH-3-pyridyl),(NHCH2CONH2,H,H,Et,NHCOPh),(NHCH2CONH2,H,H,Et,NHCO-2-furyl),(NHCH2CONH2,H,H,Et,NHCONHPh),(NHCH2CONH2,H,H,Et,NHCOCONHPh),(NHCH2CONH2,H,H,CH2OH,CONHPh),(NHCH2CONH2,H,H,CH2OH,CONH-3-pyridyl),(NHCH2CONH2,H,H,CH2OH,NHCOPh),(NHCH2CONH2,H,H,CH2OH,NHCO-2-furyl),(NHCH2CONH2,H,H,CH2OH,NHCONHPh),(NHCH2CONH2,H,H,CH2OH,NHCOCONHPh),(NHCH2CONH2,H,Me,Me,CONHPh),(NHCH2CONH2,H,Me,Me,CONH-3-pyridyl),(NHCH2CONH2,H,Me,Me,NHCOPh),(NHCH2CONH2,H,Me,Me,NHCO-2-furyl),(NHCH2CONH2,H,Me,Me,NHCONHPh),(NHCH2CONH2,H,Me,Me,NHCOCONHPh),(NHCH2CONH2,H,Me,Et,CONHPh),(NHCH2CONH2,H,Me,Et,CONH-3-pyridyl),(NHCH2CONH2,H,Me,Et,NHCOPh),(NHCH2CONH2,H,Me,Et,NHCO-2-furyl),(NHCH2CONH2,H,Me,Et,NHCONHPh),(NHCH2CONH2,H,Me,Et,NHCOCONHPh),(NHCH2CONH2,H,Me,CH2OH,CONHPh),(NHCH2CONH2,H,Me,CH2OH,CONH-3-pyridyl),(NHCH2CONH2,H,Me,CH2OH,NHCOPh),(NHCH2CONH2,H,Me,CH2OH,NHCO-2-furyl),(NHCH2CONH2,H,Me,CH2OH,NHCONHPh),(NHCH2CONH2,H,Me,CH2OH,NHCOCONHPh),(NHCH2CONH2,H,Ph,Me,CONHPh),(NHCH2CONH2,H,Ph,Me,CONH-3-pyridyl),(NHCH2CONH2,H,Ph,Me,NHCOPh),(NHCH2CONH2,H,Ph,Me,NHCO-2-furyl),(NHCH2CONH2,H,Ph,Me,NHCONHPh),(NHCH2CONH2,H,Ph,Me,NHCOCONHPh),(NHCH2CONH2,H,Ph,Et,CONHPh),(NHCH2CONH2,H,Ph,Et,CONH-3-pyridyl),(NHCH2CONH2,H,Ph,Et,NHCOPh),(NHCH2CONH2,H,Ph,Et,NHCO-2-furyl),(NHCH2CONH2,H,Ph,Et,NHCONHPh),(NHCH2CONH2,H,Ph,Et,NHCOCONHPh),(NHCH2CONH2,H,Ph,CH2OH,CONHPh),(NHCH2CONH2,H,Ph,CH2OH,CONH-3-pyridyl),(NHCH2CONH2,H,Ph,CH2OH,NHCOPh),(NHCH2CONH2,H,Ph,CH2OH,NHCO-2-furyl),(NHCH2CONH2,H,Ph,CH2OH,NHCONHPh),(NHCH2CONH2,H,Ph,CH2OH,NHCOCONHPh),(NHCH2CONH2,H2OH,Me,CONHPh),(NHCH2CONH2,H2OH,Me,CONH-3-pyridyl),(NHCH2CONH2,H2OH,Me,NHCOPh),(NHCH2CONH2,H2OH,Me,NHCO-2-furyl),(NHCH2CONH2,H2OH,Me,NHCONHPh),(NHCH2CONH2,H2OH,Me,NHCOCONHPh),(NHCH2CONH2,H2OH,Et,CONHPh),(NHCH2CONH2,H2OH,Et,CONH-3-pyridyl),(NHCH2CONH2,H2OH,Et,NHCOPh),(NHCH2CONH2,H2OH,Et,NHCO-2-furyl),(NHCH2CONH2,H2OH,Et,NHCONHPh),(NHCH2CONH2,H2OH,Et,NHCOCONHPh),(NHCH2CONH2,H2OH,CH2OH,CONHPh),(NHCH2CONH2,H2OH,CH2OH,CONH-3-pyridyl),(NHCH2CONH2,H2OH,CH2OH,NHCOPh),(NHCH2CONH2,H2OH,CH2OH,NHCO-2-furyl),(NHCH2CONH2,H2OH,CH2OH,NHCONHPh),(NHCH2CONH2,H2OH,CH2OH,NHCOCONHPh),(NHCH2CONH2,Me,H,Me,CONHPh),(NHCH2CONH2,Me,H,Me,CONH-3-pyridyl),(NHCH2CONH2,Me,H,Me,NHCOPh),(NHCH2CONH2,Me,H,Me,NHCO-2-furyl),(NHCH2CONH2,Me,H,Me,NHCONHPh),(NHCH2CONH2,Me,H,Me,NHCOCONHPh),(NHCH2CONH2,Me,H,Et,CONHPh),(NHCH2CONH2,Me,H,Et,CONH-3-pyridyl),(NHCH2CONH2,Me,H,Et,NHCOPh),(NHCH2CONH2,Me,H,Et,NHCO-2-furyl),(NHCH2CONH2,Me,H,Et,NHCONHPh),(NHCH2CONH2,Me,H,Et,NHCOCONHPh),(NHCH2CONH2,Me,H,CH2OH,CONHPh),(NHCH2CONH2,Me,H,CH2OH,CONH-3-pyridyl),(NHCH2CONH2,Me,H,CH2OH,NHCOPh),(NHCH2CONH2,Me,H,CH2OH,NHCO-2-furyl),(NHCH2CONH2,Me,H,CH2OH,NHCONHPh),(NHCH2CONH2,Me,H,CH2OH,NHCOCONHPh),(NHCH2CONH2,Me,Me,Me,CONHPh),(NHCH2CONH2,Me,Me,Me,CONH-3-pyridyl),(NHCH2CONH2,Me,Me,Me,NHCOPh),(NHCH2CONH2,Me,Me,Me,NHCO-2-furyl),(NHCH2CONH2,Me,Me,Me,NHCONHPh),(NHCH2CONH2,Me,Me,Me,NHCOCONHPh),(NHCH2CONH2,Me,Me,Et,CONHPh),(NHCH2CONH2,Me,Me,Et,CONH-3-pyridyl),(NHCH2CONH2,Me,Me,Et,NHCOPh),(NHCH2CONH2,Me,Me,Et,NHCO-2-furyl),(NHCH2CONH2,Me,Me,Et,NHCONHPh),(NHCH2CONH2,Me,Me,Et,NHCOCONHPh),(NHCH2CONH2,Me,Me,CH2OH,CONHPh),(NHCH2CONH2,Me,Me,CH2OH,CONH-3-pyridyl),(NHCH2CONH2,Me,Me,CH2OH,NHCOPh),(NHCH2CONH2,Me,Me,CH2OH,NHCO-2-furyl),(NHCH2CONH2,Me,Me,CH2OH,NHCONHPh),(NHCH2CONH2,Me,Me,CH2OH,NHCOCONHPh),(NHCH2CONH2,Me,Ph,Me,CONHPh),(NHCH2CONH2,Me,Ph,Me,CONH-3-pyridyl),(NHCH2CONH2,Me,Ph,Me,NHCOPh),(NHCH2CONH2,Me,Ph,Me,NHCO-2-furyl),(NHCH2CONH2,Me,Ph,Me,NHCONHPh),(NHCH2CONH2,Me,Ph,Me,NHCOCONHPh),(NHCH2CONH2,Me,Ph,Et,CONHPh),(NHCH2CONH2,Me,Ph,Et,CONH-3-pyridyl),(NHCH2CONH2,Me,Ph,Et,NHCOPh),(NHCH2CONH2,Me,Ph,Et,NHCO-2-furyl),(NHCH2CONH2,Me,Ph,Et,NHCONHPh),(NHCH2CONH2,Me,Ph,Et,NHCOCONHPh),(NHCH2CONH2,Me,Ph,CH2OH,CONHPh),(NHCH2CONH2,Me,Ph,CH2OH,CONH-3-pyridyl),(NHCH2CONH2,Me,Ph,CH2OH,NHCOPh),(NHCH2CONH2,Me,Ph,CH2OH,NHCO-2-furyl),(NHCH2CONH2,Me,Ph,CH2OH,NHCONHPh),(NHCH2CONH2,Me,Ph,CH2OH,NHCOCONHPh),(NHCH2CONH2,Me,OH,Me,CONHPh),(NHCH2CONH2,Me,OH,Me,CONH-3-pyridyl),(NHCH2CONH2,Me,OH,Me,NHCOPh),(NHCH2CONH2,Me,OH,Me,NHCO-2-furyl),(NHCH2CONH2,Me,OH,Me,NHCONHPh),(NHCH2CONH2,Me,OH,Me,NHCOCONHPh),(NHCH2CONH2,Me,OH,Et,CONHPh),(NHCH2CONH2,Me,OH,Et,CONH-3-pyridyl),(NHCH2CONH2,Me,OH,Et,NHCOPh); (NHCH2CONH2,Me,OH,Et,NHCO-2-furyl),(NHCH2CONH2,Me,OH,Et,NHCONHPh),(NHCH2CONH2,Me,OH,Et,NHCOCONHPh),(NHCH2CONH2,Me,OH,CH2OH,CONHPh),(NHCH2CONH2,Me,OH,CH2OH,CONH-3-pyridyl),(NHCH2CONH2,Me,OH,CH2OH,NHCOPh),(NHCH2CONH2,Me,OH,CH2OH,NHCO-2-furyl),(NHCH2CONH2,Me,OH,CH2OH,NHCONHPh),(NHCH2CONH2,Me,OH,CH2OH,NHCOCONHPh),(NHCH2CONH2,Ph,H,Me,CONHPh),(NHCH2CONH2,Ph,H,Me,CONH-3-pyridyl),(NHCH2CONH2,Ph,H,Me,NHCOPh),(NHCH2CONH2,Ph,H,Me,NHCO-2-furyl),(NHCH2CONH2,Ph,H,Me,NHCONHPh),(NHCH2CONH2,Ph,H,Me,NHCOCONHPh),(NHCH2CONH2,Ph,H,Et,CONHPh),(NHCH2CONH2,Ph,H,Et,CONH-3-pyridyl),(NHCH2CONH2,Ph,H,Et,NHCOPh),(NHCH2CONH2,Ph,H,Et,NHCO-2-furyl),(NHCH2CONH2,Ph,H,Et,NHCONHPh),(NHCH2CONH2,Ph,H,Et,NHCOCONHPh),(NHCH2CONH2,Ph,H,CH2OH,CONHPh),(NHCH2CONH2,Ph,H,CH2OH,CONH-3-pyridyl),(NHCH2CONH2,Ph,H,CH2OH,NHCOPh),(NHCH2CONH2,Ph,H,CH2OH,NHCO-2-furyl),(NHCH2CONH2,Ph,H,CH2OH,NHCONHPh),(NHCH2CONH2,Ph,H,CH2OH,NHCOCONHPh),(NHCH2CONH2,Ph,Me,Me,CONHPh),(NHCH2CONH2,Ph,Me,Me,CONH-3-pyridyl),(NHCH2CONH2,Ph,Me,Me,NHCOPh),(NHCH2CONH2,Ph,Me,Me,NHCO-2-furyl),(NHCH2CONH2,Ph,Me,Me,NHCONHPh),(NHCH2CONH2,Ph,Me,Me,NHCOCONHPh),(NHCH2CONH2,Ph,Me,Et,CONHPh),(NHCH2CONH2,Ph,Me,Et,CONH-3-pyridyl),(NHCH2CONH2,Ph,Me,Et,NHCOPh),(NHCH2CONH2,Ph,Me,Et,NHCO-2-furyl),(NHCH2CONH2,Ph,Me,Et,NHCONHPh),(NHCH2CONH2,Ph,Me,Et,NHCOCONHPh),(NHCH2CONH2,Ph,Me,CH2OH,CONHPh),(NHCH2CONH2,Ph,Me,CH2OH,CONH-3-pyridyl),(NHCH2CONH2,Ph,Me,CH2OH,NHCOPh),(NHCH2CONH2,Ph,Me,CH2OH,NHCO-2-furyl),(NHCH2CONH2,Ph,Me,CH2OH,NHCONHPh),(NHCH2CONH2,Ph,Me,CH2OH,NHCOCONHPh),(NHCH2CONH2,Ph,Ph,Me,CONHPh),(NHCH2CONH2,Ph,Ph,Me,CONH-3-pyridyl),(NHCH2CONH2,Ph,Ph,Me,NHCOPh),(NHCH2CONH2,Ph,Ph,Me,NHCO-2-furyl),(NHCH2CONH2,Ph,Ph,Me,NHCONHPh),(NHCH2CONH2,Ph,Ph,Me,NHCOCONHPh),(NHCH2CONH2,Ph,Ph,Et,CONHPh),(NHCH2CONH2,Ph,Ph,Et,CONH-3-pyridyl),(NHCH2CONH2,Ph,Ph,Et,NHCOPh),(NHCH2CONH2,Ph,Ph,Et,NHCO-2-furyl),(NHCH2CONH2,Ph,Ph,Et,NHCONHPh),(NHCH2CONH2,Ph,Ph,Et,NHCOCONHPh),(NHCH2CONH2,Ph,Ph,CH2OH,CONHPh),(NHCH2CONH2,Ph,Ph,CH2OH,CONH-3-pyridyl),(NHCH2CONH2,Ph,Ph,CH2OH,NHCOPh),(NHCH2CONH2,Ph,Ph,CH2OH,NHCO-2-furyl),(NHCH2CONH2,Ph,Ph,CH2OH,NHCONHPh),(NHCH2CONH2,Ph,Ph,CH2OH,NHCOCONHPh),(NHCH2CONH2,Ph,OH,Me,CONHPh),(NHCH2CONH2,Ph,OH,Me,CONH-3-pyridyl),(NHCH2CONH2,Ph,OH,Me,NHCOPh),(NHCH2CONH2,Ph,OH,Me,NHCO-2-furyl),(NHCH2CONH2,Ph,OH,Me,NHCONHPh),(NHCH2CONH2,Ph,OH,Me,NHCOCONHPh),(NHCH2CONH2,Ph,OH,Et,CONHPh),(NHCH2CONH2,Ph,OH,Et,CONH-3-pyridyl),(NHCH2CONH2,Ph,OH,Et,NHCOPh),(NHCH2CONH2,Ph,OH,Et,NHCO-2-furyl),(NHCH2CONH2,Ph,OH,Et,NHCONHPh),(NHCH2CONH2,Ph,OH,Et,NHCOCONHPh),(NHCH2CONH2,Ph,OH,CH2OH,CONHPh),(NHCH2CONH2,Ph,OH,CH2OH,CONH-3-pyridyl),(NHCH2CONH2,Ph,OH,CH2OH,NHCOPh),(NHCH2CONH2,Ph,OH,CH2OH,NHCO-2-furyl),(NHCH2CONH2,Ph,OH,CH2OH,NHCONHPh),(NHCH2CONH2,Ph,OH,CH2OH,NHCOCONHPh),(NHCH(Bn)CONH2,H,H,Me,CONHPh),(NHCH(Bn)CONH2,H,H,Me,CONH-3-pyridyl),(NHCH(Bn)CONH2,H,H,Me,NHCOPh),(NHCH(Bn)CONH2,H,H,Me,NHCO-2-furyl),(NHCH(Bn)CONH2,H,H,Me,NHCONHPh),(NHCH(Bn)CONH2,H,H,Me,NHCOCONHPh),(NHCH(Bn)CONH2,H,H,Et,CONHPh),(NHCH(Bn)CONH2,H,H,Et,CONH-3-pyridyl),(NHCH(Bn)CONH2,H,H,Et,NHCOPh),(NHCH(Bn)CONH2,H,H,Et,NHCO-2-furyl),(NHCH(Bn)CONH2,H,H,Et,NHCONHPh),(NHCH(Bn)CONH2,H,H,Et,NHCOCONHPh),(NHCH(Bn)CONH2,H,H,CH2OH,CONHPh),(NHCH(Bn)CONH2,H,H,CH2OH,CONH-3-pyridyl),(NHCH(Bn)CONH2,H,H,CH2OH,NHCOPh),(NHCH(Bn)CONH2,H,H,CH2OH,NHCO-2-furyl),(NHCH(Bn)CONH2,H,H,CH2OH,NHCONHPh),(NHCH(Bn)CONH2,H,H,CH2OH,NHCOCONHPh),(NHCH(Bn)CONH2,H,Me,Me,CONHPh),(NHCH(Bn)CONH2,H,Me,Me,CONH-3-pyridyl),(NHCH(Bn)CONH2,H,Me,Me,NHCOPh),(NHCH(Bn)CONH2,H,Me,Me,NHCO-2-furyl),(NHCH(Bn)CONH2,H,Me,Me,NHCONHPh),(NHCH(Bn)CONH2,H,Me,Me,NHCOCONHPh),(NHCH(Bn)CONH2,H,Me,Et,CONHPh),(NHCH(Bn)CONH2,H,Me,Et,CONH-3-pyridyl),(NHCH(Bn)CONH2,H,Me,Et,NHCOPh),(NHCH(Bn)CONH2,H,Me,Et,NHCO-2-furyl),(NHCH(Bn)CONH2,H,Me,Et,NHCONHPh),(NHCH(Bn)CONH2,H,Me,Et,NHCOCONHPh),(NHCH(Bn)CONH2,H,Me,CH2OH,CONHPh),(NHCH(Bn)CONH2,H,Me,CH2OH,CONH-3-pyridyl),(NHCH(Bn)CONH2,H,Me,CH2OH,NHCOPh),(NHCH(Bn)CONH2,H,Me,CH2OH,NHCO-2-furyl),(NHCH(Bn)CONH2,H,Me,CH2OH,NHCONHPh),(NHCH(Bn)CONH2,H,Me,CH2OH,NHCOCONHPh),(NHCH(Bn)CONH2,H,Ph,Me,CONHPh),(NHCH(Bn)CONH2,H,Ph,Me,CONH-3-pyridyl),(NHCH(Bn)CONH2,H,Ph,Me,NHCOPh),(NHCH(Bn)CONH2,H,Ph,Me,NHCO-2-furyl),(NHCH(Bn)CONH2,H,Ph,Me,NHCONHPh),(NHCH(Bn)CONH2,H,Ph,Me,NHCOCONHPh),(NHCH(Bn)CONH2,H,Ph,Et,CONHPh),(NHCH(Bn)CONH2,H,Ph,Et,CONH-3-pyridyl),(NHCH(Bn)CONH2,H,Ph,Et,NHCOPh),(NHCH(Bn)CONH2,H,Ph,Et,NHCO-2-furyl),(NHCH(Bn)CONH2,H,Ph,Et,NHCONHPh),(NHCH(Bn)CONH2,H,Ph,Et,NHCOCONHPh),(NHCH(Bn)CONH2,H,Ph,CH2OH,CONHPh),(NHCH(Bn)CONH2,H,Ph,CH2OH,CONH-3-pyridyl),(NHCH(Bn)CONH2,H,Ph,CH2OH,NHCOPh),(NHCH(Bn)CONH2,H,Ph,CH2OH,NHCO-2-furyl),(NHCH(Bn)CONH2,H,Ph,CH2OH,NHCONHPh),(NHCH(Bn)CONH2,H,Ph,CH2OH,NHCOCONHPh),(NHCH(Bn)CONH2,H2OH,Me,CONHPh),(NHCH(Bn)CONH2,H2OH,Me,CONH-3-pyridyl),(NHCH(Bn)CONH2,H2OH,Me,NHCOPh),(NHCH(Bn)CONH2,H,OH,Me,NHCO-2-furyl),(NHCH(Bn)CONH2,H,OH,Me,NHCONHPh),(NHCH(Bn)CONH2,H,OH,Me,NHCOCONHPh),(NHCH(Bn)CONH2,H2OH,Et,CONHPh),(NHCH(Bn)CONH2,H,OH,Et,CONH-3-pyridyl),(NHCH(Bn)CONH2,H,OH,Et,NHCOPh),(NHCH(Bn)CONH2,H,OH,Et,NHCO-2-furyl),(NHCH(Bn)CONH2,H,OH,Et,NHCONHPh),(NHCH(Bn)CONH2,H2OH,Et,NHCOCONHPh),(NHCH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(NHCH(Me)CH2OH,H,H,Me,CONHPh),(NHCH(Me)CH2OH,H,H,Me,CONH-3-pyridyl),(NHCH(Me)CH2OH,H,H,Me,NHCOPh),(NHCH(Me)CH2OH,H,H,Me,NHCO-2-furyl),(NHCH(Me)CH2OH,H,H,Me,NHCONHPh),(NHCH(Me)CH2OH,H,H,Me,NHCOCONHPh),(NHCH(Me)CH2OH,H,H,Et,CONHPh),(NHCH(Me)CH2OH,H,H,Et,CONH-3-pyridyl),(NHCH(Me)CH2OH,H,H,Et,NHCOPh),(NHCH(Me)CH2OH,H,H,Et,NHCO-2-furyl),(NHCH(Me)CH2OH,H,H,Et,NHCONHPh),(NHCH(Me)CH2OH,H,H,Et,NHCOCONHPh),(NHCH(Me)CH2OH,H,H,CH2OH,CONHPh),(NHCH(Me)CH2OH,H,H,CH2OH,CONH-3-pyridyl),(NHCH(Me)CH2OH,H,H,CH2OH,NHCOPh),(NHCH(Me)CH2OH,H,H,CH2OH,NHCO-2-furyl),(NHCH(Me)CH2OH,H,H,CH2OH,NHCONHPh),(NHCH(Me)CH2OH,H,H,CH2OH,NHCOCONHPh),(NHCH(Me)CH2OH,H,Me,Me,CONHPh),(NHCH(Me)CH2OH,H,Me,Me,CONH-3-pyridyl),(NHCH(Me)CH2OH,H,Me,Me,NHCOP(NHCH(Me)CH2OH,H,Me,Me,NHCO-2-furyl),(NHCH(Me)CH2OH,H,Me,Me,NHCONHPh),(NHCH(Me)CH2OH,H,Me,Me,NHCOCONHPh),(NHCH(Me)CH2OH,H,Me,Et,CONHPh),(NHCH(Me)CH2OH,H,Me,Et,CONH-3-pyridyl),(NHCH(Me)CH2OH,H,Me,Et,NHCOPh),(NHCH(Me)CH2OH,H,Me,Et,NHCO-2-furyl),(NHCH(Me)CH2OH,H,Me,Et,NHCONHPh),(NHCH(Me)CH2OH,H,Me,Et,NHCOCONHPh),(NHCH(Me)CH2OH,H,Me,CH2OH,CONHPh),(NHCH(Me)CH2OH,H,Me,CH2OH,CONH-3-pyridyl),(NHCH(Me)CH2OH,H,Me,CH2OH,NHCOPh),(NHCH(Me)CH2OH,H,Me,CH2OH,NHCO-2-furyl),(NHCH(Me)CH2OH,H,Me,CH2OH,NHCONHPh),(NHCH(Me)CH2OH,H,Me,CH2OH,NHCOCONHPh),(NHCH(Me)CH2OH,H,Ph,Me,CONHPh),(NHCH(Me)CH2OH,H,Ph,Me,CONH-3-pyridyl),(NHCH(Me)CH2OH,H,Ph,Me,NHCOPh),(NHCH(Me)CH2OH,H,Ph,Me,NHCO-2-furyl),(NHCH(Me)CH2OH,H,Ph,Me,NHCONHPh),(NHCH(Me)CH2OH,H,Ph,Me,NHCOCONHPh),(NHCH(Me)CH2OH,H,Ph,Et,CONHPh),(NHCH(Me)CH2OH,H,Ph,Et,CONH-3-pyridyl),(NHCH(Me)CH2OH,H,Ph,Et,NHCOPh),(NHCH(Me)CH2OH,H,Ph,Et,NHCO-2-furyl),(NHCH(Me)CH2OH,H,Ph,Et,NHCONHPh),(NHCH(Me)CH2OH,H,Ph,Et,NHCOCONHPh),(NHCH(Me)CH2OH,H,Ph,CH2OH,CONHPh),(NHCH(Me)CH2OH,H,Ph,CH2OH,CONH-3-pyridyl),(NHCH(Me)CH2OH,H,Ph,CH2OH,NHCOPh),(NHCH(Me)CH2OH,H,Ph,CH2OH,NHCO-2-furyl),(NHCH(Me)CH2OH,H,Ph,CH2OH,NHCONHPh),(NHCH(Me)CH2OH,H,Ph,CH2OH,NHCOCONHPh),(NHCH(Me)CH2OH,H,OH,Me,CONHPh),(NHCH(Me)CH2OH,H,OH,Me,CONH-3-pyridyl),(NHCH(Me)CH2OH,H,OH,Me,NHCOPh),(NHCH(Me)CH2OH,H,OH,Me,NHCO-2-furyl),(NHCH(Me)CH2OH,H2OH,Me,NHCONHPh),(NHCH(Me)CH2OH,H2OH,Me,NHCOCONHPh),(NHCH(Me)CH2OH,H2OH,Et,CONHPh),(NHCH(Me)CH2OH,H2OH,Et,CONH-3-pyridyl),(NHCH(Me)CH2OH,H,OH,Et,NHCOPh),(NHCH(Me)CH2OH,H,OH,Et,NHCO-2-furyl),(NHCH(Me)CH2OH,H2OH,Et,NHCONHPh),(NHCH(Me)CH2OH,H,OH,Et,NHCOCONHPh),(NHCH(Me)CH2OH,H,OH,CH2OH,CONHPh),(NHCH(Me)CH2OH,H,OH,CH2OH,CONH-3-pyridyl),(NHCH(Me)CH2OH,H,OH,CH2OH,NHCOPh),(NHCH(Me)CH2OH,H,OH,CH2OH,NHCO-2-furyl),(NHCH(Me)CH2OH,H,OH,CH2OH,NHCONHPh),(NHCH(Me)CH2OH,H,OH,CH2OH,NHCOCONHPh),(NHCH(Me)CH2OH,Me,H,Me,CONHPh),(NHCH(Me)CH2OH,Me,H,Me,CONH-3-pyridyl),(NHCH(Me)CH2OH,Me,H,Me,NHCOPh),(NHCH(Me)CH2OH,Me,H,Me,NHCO-2-furyl),(NHCH(Me)CH2OH,Me,H,Me,NHCONHPh),(NHCH(Me)CH2OH,Me,H,Me,NHCOCONHPh),(NHCH(Me)CH2OH,Me,H,Et,CONHPh),(NHCH(Me)CH2OH,Me,H,Et,CONH-3-pyridyl),(NHCH(Me)CH2OH,Me,H,Et,NHCOPh),(NHCH(Me)CH2OH,Me,H,Et,NHCO-2-furyl),(NHCH(Me)CH2OH,Me,H,Et,NHCONHPh),(NHCH(Me)CH2OH,Me,H,Et,NHCOCONHPh),(NHCH(Me)CH2OH,Me,H,CH2OH,CONHPh),(NHCH(Me)CH2OH,Me,H,CH2OH,CONH-3-pyridyl),(NHCH(Me)CH2OH,Me,H,CH2OH,NHCOPh),(NHCH(Me)CH2OH,Me,H,CH2OH,NHCO-2-furyl),(NHCH(Me)CH2OH,Me,H,CH2OH,NHCONHPh),(NHCH(Me)CH2OH,Me,H,CH2OH,NHCOCONHPh),(NHCH(Me)CH2OH,Me,Me,Me,CONHPh),(NHCH(Me)CH2OH,Me,Me,Me,CONH-3-pyridyl),(NHCH(Me)CH2OH,Me,Me,Me,NHCOPh),(NHCH(Me)CH2OH,Me,Me,Me,NHCO-2-furyl),(NHCH(Me)CH2OH,Me,Me,Me,NHCONHPh),(NHCH(Me)CH2OH,Me,Me,Me,NHCOCONHPh),(NHCH(Me)CH2OH,Me,Me,Et,CONHPh),(NHCH(Me)CH2OH,Me,Me,Et,CONH-3-pyridyl),(NHCH(Me)CH2OH,Me,Me,Et,NHCOPh),(NHCH(Me)CH2OH,Me,Me,Et,NHCO-2-furyl),(NHCH(Me)CH2OH,Me,Me,Et,NHCONHPh),(NHCH(Me)CH2OH,Me,Me,Et,NHCOCONHPh),(NHCH(Me)CH2OH,Me,Me,CH2OH,CONHPh),(NHCH(Me)CH2OH,Me,Me,CH2OH,CONH-3-pyridyl),(NHCH(Me)CH2OH,Me,Me,CH2OH,NHCOPh),(NHCH(Me)CH2OH,Me,Me,CH2OH,NHCO-2-furyl),(NHCH(Me)CH2OH,Me,Me,CH2OH,NHCONHPh),(NHCH(Me)CH2OH,Me,Me,CH2OH,NHCOCONHPh),(NHCH(Me)CH2OH,Me,Ph,Me,CONHPh),(NHCH(Me)CH2OH,Me,Ph,Me,CONH-3-pyridyl),(NHCH(Me)CH2OH,Me,Ph,Me,NHCOPh),(NHCH(Me)CH2OH,Me,Ph,Me,NHCO-2-furyl),(NHCH(Me)CH2OH,Me,Ph,Me,NHCONHPh),(NHCH(Me)CH2OH,Me,Ph,Me,NHCOCONHPh),(NHCH(Me)CH2OH,Me,Ph,Et,CONHPh),(NHCH(Me)CH2OH,Me,Ph,Et,CONH-3-pyridyl),(NHCH(Me)CH2OH,Me,Ph,Et,NHCOPh),(NHCH(Me)CH2OH,Me,Ph,Et,NHCO-2-furyl),(NHCH(Me)CH2OH,Me,Ph,Et,NHCONHPh),(NHCH(Me)CH2OH,Me,Ph,Et,NHCOCONHPh),(NHCH(Me)CH2OH,Me,Ph,CH2OH,CONHPh),(NHCH(Me)CH2OH,Me,Ph,CH2OH,CONH-3-pyridyl),(NHCH(Me)CH2OH,Me,Ph,CH2OH,NHCOPh),(NHCH(Me)CH2OH,Me,Ph,CH2OH,NHCO-2-furyl),(NHCH(Me)CH2OH,Me,Ph,CH2OH,NHCONHPh),(NHCH(Me)CH2OH,Me,Ph,CH2OH,NHCOCONHPh),(NHCH(Me)CH2OH,Me,OH,Me,CONHPh),(NHCH(Me)CH2OH,Me,OH,Me,CONH-3-pyridyl),(NHCH(Me)CH2OH,Me,OH,Me,NHCOPh),(NHCH(Me)CH2OH,Me,OH,Me,NHCO-2-furyl),(NHCH(Me)CH2OH,Me,OH,Me,NHCONHPh),(NHCH(Me)CH2OH,Me,OH,Me,NHCOCONHPh),(NHCH(Me)CH2OH,Me,OH,Et,CONHPh),(NHCH(Me)CH2OH,Me,OH,Et,CONH-3-pyridyl),(NHCH(Me)CH2OH,Me,OH,Et,NHCOPh),(NHCH(Me)CH2OH,Me,OH,Et,NHCO-2-furyl),(NHCH(Me)CH2OH,Me,OH,Et,NHCONHPh),(NHCH(Me)CH2OH,Me,OH,Et,NHCOCONHPh),(NHCH(Me)CH2OH,Me,OH,CH2OH,CONHPh),(NHCH(Me)CH2OH,Me,OH,CH2OH,CONH-3-pyridyl),(NHCH(Me)CH2OH,Me,OH,CH2OH,NHCOPh),(NHCH(Me)CH2OH,Me,OH,CH2OH,NHCO-2-furyl),(NHCH(Me)CH2OH,Me,OH,CH2OH,NHCONHPh),(NHCH(Me)CH2OH,Me,OH,CH2OH,NHCOCONHPh),(NHCH(Me)CH2OH,Ph,H,Me,CONHPh),(NHCH(Me)CH2OH,Ph,H,Me,CONH-3-pyridyl),(NHCH(Me)CH2OH,Ph,H,Me,NHCOPh),(NHCH(Me)CH2OH,Ph,H,Me,NHCO-2-furyl),(NHCH(Me)CH2OH,Ph,H,Me,NHCONHPh),(NHCH(Me)CH2OH,Ph,H,Me,NHCOCONHPh),(NHCH(Me)CH2OH,Ph,H,Et,CONHPh),(NHCH(Me)CH2OH,Ph,H,Et,CONH-3-pyridyl),(NHCH(Me)CH2OH,Ph,H,Et,NHCOPh),(NHCH(Me)CH2OH,Ph,H,Et,NHCO-2-furyl),(NHCH(Me)CH2OH,Ph,H,Et,NHCONHPh),(NHCH(Me)CH2OH,Ph,H,Et,NHCOCONHPh),(NHCH(Me)CH2OH,Ph,H,CH2OH,CONHPh),(NHCH(Me)CH2OH,Ph,H,CH2OH,CONH-3-pyridyl),(NHCH(Me)CH2OH,Ph,H,CH2OH,NHCOPh),(NHCH(Me)CH2OH,Ph,H,CH2OH,NHCO-2-furyl),(NHCH(Me)CH2OH,Ph,H,CH2OH,NHCONHPh),(NHCH(Me)CH2OH,Ph,H,CH2OH,NHCOCONHPh),(NHCH(Me)CH2OH,Ph,Me,Me,CONHPh),(NHCH(Me)CH2OH,Ph,Me,Me,CONH-3-pyridyl),(NHCH(Me)CH2OH,Ph,Me,Me,NHCOPh),(NHCH(Me)CH2OH,Ph,Me,Me,NHCO-2-furyl),(NHCH(Me)CH2OH,Ph,Me,Me,NHCONHPh),(NHCH(Me)CH2OH,Ph,Me,Me,NHCOCONHPh),(NHCH(Me)CH2OH,Ph,Me,Et,CONHPh),(NHCH(Me)CH2OH,Ph,Me,Et,CONH-3-pyridyl),(NHCH(Me)CH2OH,Ph,Me,Et,NHCOPh),(NHCH(Me)CH2OH,Ph,Me,Et,NHCO-2-furyl),(NHCH(Me)CH2OH,Ph,Me,Et,NHCONHPh),(NHCH(Me)CH2OH,Ph,Me,Et,NHCOCONHPh),(NHCH(Me)CH2OH,Ph,Me,CH2OH,CONHPh),(NHCH(Me)CH2OH,Ph,Me,CH2OH,CONH-3-pyridyl),(NHCH(Me)CH2OH,Ph,Me,CH2OH,NHCOPh),(NHCH(Me)CH2OH,Ph,Me,CH2OH,NHCO-2-furyl),(NHCH(Me)CH2OH,Ph,Me,CH2OH,NHCONHPh),(NHCH(Me)CH2OH,Ph,Me,CH2OH,NHCOCONHPh),(NHCH(Me)CH2OH,Ph,Ph,Me,CONHPh),(NHCH(Me)CH2OH,Ph,Ph,Me,CONH-3-pyridyl),(NHCH(Me)CH2OH,Ph,Ph,Me,NHCOPh),(NHCH(Me)CH2OH,Ph,Ph,Me,NHCO-2-furyl),(NHCH(Me)CH2OH,Ph,Ph,Me,NHCONHPh),(NHCH(Me)CH2OH,Ph,Ph,Me,NHCOCONHPh),(NHCH(Me)CH2OH,Ph,Ph,Et,CONHPh),(NHCH(Me)CH2OH,Ph,Ph,Et,CONH-3-pyridyl),(NHCH(Me)CH2OH,Ph,Ph,Et,NHCOPh),(NHCH(Me)CH2OH,Ph,Ph,Et,NHCO-2-furyl),(NHCH(Me)CH2OH,Ph,Ph,Et,NHCONHPh),(NHCH(Me)CH2OH,Ph,Ph,Et,NHCOCONHPh),(NHCH(Me)CH2OH,Ph,Ph,CH2OH,CONHPh),(NHCH(Me)CH2OH,Ph,Ph,CH2OH,CONH-3-pyridyl),(NHCH(Me)CH2OH,Ph,Ph,CH2OH,NHCOPh),(NHCH(Me)CH2OH,Ph,Ph,CH2OH,NHCO-2-furyl),(NHCH(Me)CH2OH,Ph,Ph,CH2OH,NHCONHPh),(NHCH(Me)CH2OH,Ph,Ph,CH2OH,NHCOCONHPh),(NHCH(Me)CH2OH,Ph,OH,Me,CONHPh),(NHCH(Me)CH2OH,Ph,OH,Me,CONH-3-pyridyl),(NHCH(Me)CH2OH,Ph,OH,Me,NHCOPh),(NHCH(Me)CH2OH,Ph,OH,Me,NHCO-2-furyl),(NHCH(Me)CH2OH,Ph,OH,Me,NHCONHPh),(NHCH(Me)CH2OH,Ph,OH,Me,NHCOCONHPh),(NHCH(Me)CH2OH,Ph,OH,Et,CONHPh),(NHCH(Me)CH2OH,Ph,OH,Et,CONH-3-pyridyl),(NHCH(Me)CH2OH,Ph,OH,Et,NHCOPh),(NHCH(Me)CH2OH,Ph,OH,Et,NHCO-2-furyl),(NHCH(Me)CH2OH,Ph,OH,Et,NHCONHPh),(NHCH(Me)CH2OH,Ph,OH,Et,NHCOCONHPh),(NHCH(Me)CH2OH,Ph,OH,CH2OH,CONHPh),(NHCH(Me)CH2OH,Ph,OH,CH2OH,CONH-3-pyridyl),(NHCH(Me)CH2OH,Ph,OH,CH2OH,NHCOPh),(NHCH(Me)CH2OH,Ph,OH,CH2OH,NHCO-2-furyl),(NHCH(Me)CH2OH,Ph,OH,CH2OH,NHCONHPh),(NHCH(Me)CH2OH,Ph,OH,CH2OH,NHCOCONHPh),

(NHCH(Me)CONHMe,H,H,Me,CONHPh),(NHCH(Me)CONHMe,H,H,Me,CONH-3-pyridyl),(NHCH(Me)CONHMe,H,H,Me,NHCOPh),(NHCH(Me)CONHMe,H,H,Me,NHCO-2-furyl),(NHCH(Me)CONHMe,H,H,Me,NHCONHPh),(NHCH(Me)CONHMe,H,H,Me,NHCOCONHPh),(NHCH(Me)CONHMe,H,H,Et,CONHPh),(NHCH(Me)CONHMe,H,H,Et,CONH-3-pyridyl),(NHCH(Me)CONHMe,H,H,Et,NHCOPh),(NHCH(Me)CONHMe,H,H,Et,NHCO-2-furyl),(NHCH(Me)CONHMe,H,H,Et,NHCONHPh),(NHCH(Me)CONHMe,H,H,Et,NHCOCONHPh),(NHCH(Me)CONHMe,H,H,CH2OH,CONHPh),(NHCH(Me)CONHMe,H,H,CH2OH,CONH-3-pyridyl),(NHCH(Me)CONHMe,H,H,CH2OH,NHCOPh),(NHCH(Me)CONHMe,H,H,CH2OH,NHCO-2-furyl),(NHCH(Me)CONHMe,H,H,CH2OH,NHCONHPh),(NHCH(Me)CONHMe,H,H,CH2OH,NHCOCONHPh),(NHCH(Me)CONHMe,H,Me,Me,CONHPh),(NHCH(Me)CONHMe,H,Me,Me,CONH-3-pyridyl),(NHCH(Me)CONHMe,H,Me,Me,NHCOPh),(NHCH(Me)CONHMe,H,Me,Me,NHCO-2-furyl),(NHCH(Me)CONHMe,H,Me,Me,NHCONHPh),(NHCH(Me)CONHMe,H,Me,Me,NHCOCONHPh),(NHCH(Me)CONHMe,H,Me,Et,CONHPh),(NHCH(Me)CONHMe,H,Me,Et,CONH-3-pyridyl),(NHCH(Me)CONHMe,H,Me,Et,NHCOPh),(NHCH(Me)CONHMe,H,Me,Et,NHCO-2-furyl),(NHCH(Me)CONHMe,H,Me,Et,NHCONHPh),(NHCH(Me)CONHMe,H,Me,Et,NHCOCONHPh),(NHCH(Me)CONHMe,H,Me,CH2OH,CONHPh),(NHCH(Me)CONHMe,H,Me,CH2OH,CONH-3-pyridyl),(NHCH(Me)CONHMe,H,Me,CH2OH,NHCOPh),(NHCH(Me)CONHMe,H,Me,CH2OH,NHCO-2-furyl),(NHCH(Me)CONHMe,H,Me,CH2OH,NHCONHPh),(NHCH(Me)CONHMe,H,Me,CH2OH,NHCOCONHPh),(NHCH(Me)CONHMe,H,Ph,Me,CONHPh),(NHCH(Me)CONHMe,H,Ph,Me,CONH-3-pyridyl),(NHCH(Me)CONHMe,H,Ph,Me,NHCOPh),(NHCH(Me)CONHMe,H,Ph,Me,NHCO-2-furyl),(NHCH(Me)CONHMe,H,Ph,Me,NHCONHPh),(NHCH(Me)CONHMe,H,Ph,Me,NHCOCONHPh),(NHCH(Me)CONHMe,H,Ph,Et,CONHPh),(NHCH(Me)CONHMe,H,Ph,Et,CONH-3-pyridyl),(NHCH(Me)CONHMe,H,Ph,Et,NHCOPh),(NHCH(Me)CONHMe,H,Ph,Et,NHCO-2-furyl),(NHCH(Me)CONHMe,H,Ph,Et,NHCONHPh),(NHCH(Me)CONHMe,H,Ph,Et,NHCOCONHPh),(NHCH(Me)CONHMe,H,Ph,CH2OH,CONHPh),(NHCH(Me)CONHMe,H,Ph,CH2OH,CONH-3-pyridyl),(NHCH(Me)CONHMe,H,Ph,CH2OH,NHCOPh),(NHCH(Me)CONHMe,H,Ph,CH2OH,NHCO-2-furyl),(NHCH(Me)CONHMe,H,Ph,CH2OH,NHCONHPh),(NHCH(Me)CONHMe,H,Ph,CH2OH,NHCOCONHPh),(NHCH(Me)CONHMe,H2OH,Me,CONHPh),(NHCH(Me)CONHMe,H,OH,Me,CONH-3-pyridyl),(NHCH(Me)CONHMe,H,OH,Me,NHCOPh),(NHCH(Me)CONHMe,H2OH,Me,NHCO-2-furyl),(NHCH(Me)CONHMe,H2OH,Me,NHCONHPh),(NHCH(Me)CONHMe,H2OH,Me,NHCOCONHPh),(NHCH(Me)CONHMe,H,OH,Et,CONHPh),(NHCH(Me)CONHMe,H2OH,Et,CONH-3-pyridyl),(NHCH(Me)CONHMe,H,OH,Et,NHCOPh),(NHCH(Me)CONHMe,H,OH,Et,NHCO-2-furyl),(NHCH(Me)CONHMe,H,OH,Et,NHCONHPh),(NHCH(Me)CONHMe,H,OH,Et,NHCOCONHPh),(NHCH(Me)CONHMe,H,OH,CH2OH,CONHPh),(NHCH(Me)CONHMe,H,OH,CH2OH,CONH-3-pyridyl),(NHCHCONHMe,H,OH,CH2OH,NHCOPh),(NHCH(Me)CONHMe,H,OH,CH2OH,NHCO-2-furyl),(NHCH(Me)CONHMe,H,OH,CH2OH,NHCONHPh),(NHCH(Me)CONHMe,H,OH,CH2OH,NHCOCONHPh),(NHCH(Me)CONHMe,Me,H,Me,CONHPh),(NHCHNOCONHMe,Me,H,Me,CONH-3-pyridyl),(NHCH(Me)CONHMe,Me,H,Me,NHCOPh),(NHCH(Me)CONHMe,Me,H,Me,NHCO-2-furyl),(NHCH(Me)CONHMe,Me,H,Me,NHCONHPh),(NHCH(Me)CONHMe,Me,H,Me,NHCOCONHPh),(NHCH(Me)CONHMe,Me,H,Et,CONHPh),(NHCH(Me)CONHMe,Me,H,Et,CONH-3-pyridyl),(NHCH(Me)CONHMe,Me,H,Et,NHCOPh),(NHCH(Me)CONHMe,Me,H,Et,NHCO-2-furyl),(NHCH(Me)CONHMe,Me,H,Et,NHCONHPh),(NHCH(Me)CONHMe,Me,H,Et,NHCOCONHPh),(NHCHCONHMe,Me,H,CH2OH,CONHPh),(NHCH(Me)CONHMe,Me,H,CH2OH,CONH-3-pyridyl),(NHCH(Me)CONHMe,Me,H,CH2OH,NHCOPh),(NHCH(Me)CONHMe,Me,H,CH2OH,NHCO-2-furyl),(NHCH(Me)CONHMe,Me,H,CH2OH,NHCONHPh),(NHCH(Me)CONHMe,Me,H,CH2OH,NHCOCONHPh),(NHCH(Me)CONHMe,Me,Me,Me,CONHPh),(NHCH(Me)CONHMe,Me,Me,Me,CONH-3-pyridyl),(NHCH(Me)CONHMe,Me,Me,Me,NHCOPh),(NHCH(Me)CONHMe,Me,Me,Me,NHCO-2-furyl),(NHCH(Me)CONHMe,Me,Me,Me,NHCONHPh),(NHCH(Me)CONHMe,Me,Me,Me,NHCOCONHPh),(NHCH(Me)CONHMe,Me,Me,Et,CONHPh),(NHCH(Me)CONHMe,Me,Me,Et,CONH-3-pyridyl),(NHCH(Me)CONHMe,Me,Me,Et,NHCOPh),(NHCH(Me)CONHMe,Me,Me,Et,NHCO-2-furyl),(NHCH(Me)CONHMe,Me,Me,Et,NHCONHPh),(NHCH(Me)CONHMe,Me,Me,Et,NHCOCONHPh),(NHCH(Me)CONHMe,Me,Me,CH2OH,CONHPh),(NHCH(Me)CONHMe,Me,Me,CH2OH,CONH-3-pyridyl),(NHCH(Me)CONHMe,Me,Me,CH2OH,NHCOPh),(NHCH(Me)CONHMe,Me,Me,CH2OH,NHCO-2-furyl),(NHCH(Me)CONHMe,Me,Me,CH2OH,NHCONHPh),(NHCH(Me)CONHMe,Me,Me,CH2OH,NHCOCONHPh),(NHCH(Me)CONHMe,Me,Ph,Me,CONHPh),(NHCH(Me)CONHMe,Me,Ph,Me,CONH-3-pyridyl),(NHCH(Me)CONHMe,Me,Ph,Me,NHCOPh),(NHCH(Me)CONHMe,Me,Ph,Me,NHCO-2-furyl),(NHCH(Me)CONHMe,Me,Ph,Me,NHCONHPh),(NHCH(Me)CONHMe,Me,Ph,Me,NHCOCONHPh),(NHCH(Me)CONHMe,Me,Ph,Et,CONHPh),(NHCH(Me)CONHMe,Me,Ph,Et,CONH-3-pyridyl),(NHCH(Me)CONHMe,Me,Ph,Et,NHCOPh),(NHCH(Me)CONHMe,Me,Ph,Et,NHCO-2-furyl),(NHCH(Me)CONHMe,Me,Ph,Et,NHCONHPh),(NHCH(Me)CONHMe,Me,Ph,Et,NHCOCONHPh),(NHCH(Me)CONHMe,Me,Ph,CH2OH,CONHPh),(NHCH(Me)CONHMe,Me,Ph,CH2OH,CONH-3-pyridyl),(NHCH(Me)CONHMe,Me,Ph,CH2OH,NHCOPh),(NHCH(Me)CONHMe,Me,Ph,CH2OH,NHCO-2-furyl),(NHCH(Me)CONHMe,Me,Ph,CH2OH,NHCONHPh),(NHCH(Me)CONHMe,Me,Ph,CH2OH,NHCOCONHPh),(NHCH(Me)CONHMe,Me,OH,Me,CONHPh),(NHCH(Me)CONHMe,Me,OH,Me,CONH-3-pyridyl),(NHCH(Me)CONHMe,Me,OH,Me,NHCOPh),(NHCH(Me)CONHMe,Me,OH,Me,NHCO-2-furyl),(NHCH(Me)CONHMe,Me,OH,Me,NHCONHPh),(NHCH(Me)CONHMe,Me,OH,Me,NHCOCONHPh),(NHCH(Me)CONHMe,Me,OH,Et,CONHPh),(NHCH(Me)CONHMe,Me,OH,Et,CONH-3-pyridyl),(NHCH(Me)CONHMe,Me,OH,Et,NHCOPh),(NHCH(Me)CONHMe,Me,OH,Et,NHCO-2-furyl),(NHCH(Me)CONHMe,Me,OH,Et,NHCONHPh),(NHCH(Me)CONHMe,Me,OH,Et,NHCOCONHPh),(NHCH(Me)CONHMe,Me,OH,CH2OH,CONHPh),(NHCH(Me)CONHMe,Me,OH,CH2OH,CONH-3-pyridyl),(NHCH(Me)CONHMe,Me,OH,CH2OH,NHCOPh),(NHCH(Me)CONHMe,Me,OH,CH2OH,NHCO-2-furyl),(NHCH(Me)CONHMe,Me,OH,CH2OH,NHCONHPh),(NHCH(Me)CONHMe,Me,OH,CH2OH,NHCOCONHPh),(NHCH(Me)CONHMe,Ph,H,Me,CONHPh),(NHCH(Me)CONHMe,Ph,H,Me,CONH-3-pyridyl),(NHCH(Me)CONHMe,Ph,H,Me,NHCOPh),(NHCH(Me)CONHMe,Ph,H,Me,NHCO-2-furyl),(NHCH(Me)CONHMe,Ph,H,Me,NHCONHPh),(NHCH(Me)CONHMe,Ph,H,Me,NHCOCONHPh),(NHCH(Me)CONHMe,Ph,H,Et,CONHPh),(NHCH(Me)CONHMe,Ph,H,Et,CONH-3-pyridyl),(NHCH(Me)CONHMe,Ph,H,Et,NHCOPh),(NHCH(Me)CONHMe,Ph,H,Et,NHCO-2-furyl),(NHCH(Me)CONHMe,Ph,H,Et,NHCONHPh),(NHCH(Me)CONHMe,Ph,H,Et,NHCOCONHPh),(NHCH(Me)CONHMe,Ph,H,CH2OH,CONHPh),(NHCH(Me)CONHMe,Ph,H,CH2OH,CONH-3-pyridyl),(NHCH(Me)CONHMe,Ph,H,CH2OH,NHCOPh),(NHCH(Me)CONHMe,Ph,H,CH2OH,NHCO-2-furyl),(NHCH(Me)CONHMe,Ph,H,CH2OH,NHCONHPh),(NHCH(Me)CONHMe,Ph,H,CH2OH,NHCOCONHPh),(NHCH(Me)CONHMe,Ph,Me,Me,CONHPh),(NHCH(Me)CONHMe,Ph,Me,Me,CONH-3-pyridyl),(NHCH(Me)CONHMe,Ph,Me,Me,NHCOPh),(NHCH(Me)CONHMe,Ph,Me,Me,NHCO-2-furyl),(NHCH(Me)CONHMe,Ph,Me,Me,NHCONHPh),(NHCH(Me)CONHMe,Ph,Me,Me,NHCOCONHPh),(NHCH(Me)CONHMe,Ph,Me,Et,CONHPh),(NHCH(Me)CONHMe,Ph,Me,Et,CONH-3-pyridyl),(NHCH(Me)CONHMe,Ph,Me,Et,NHCOPh),(NHCH(Me)CONHMe,Ph,Me,Et,NHCO-2-furyl),(NHCH(Me)CONHMe,Ph,Me,Et,NHCONHPh),(NHCH(Me)CONHMe,Ph,Me,Et,NHCOCONHPh),(NHCH(Me)CONHMe,Ph,Me,CH2OH,CONHPh),(NHCH(Me)CONHMe,Ph,Me,CH2OH,CONH-3-pyridyl),(NHCH(Me)CONHMe,Ph,Me,CH2OH,NHCOPh),(NHCH(Me)CONHMe,Ph,Me,CH2OH,NHCO-2-furyl),(NHCH(Me)CONHMe,Ph,Me,CH2OH,NHCONHPh),(NHCH(Me)CONHMe,Ph,Me,CH2OH,NHCOCONHPh),(NHCH(Me)CONHMe,Ph,Ph,Me,CONHPh),(NHCH(Me)CONHMe,Ph,Ph,Me,CONH-3-pyridyl),(NHCH(Me)CONHMe,Ph,Ph,Me,NHCOPh),(NHCH(Me)CONHMe,Ph,Ph,Me,NHCO-2-furyl),(NHCH(Me)CONHMe,Ph,Ph,Me,NHCONHPh),(NHCH(Me)CONHMe,Ph,Ph,Me,NHCOCONHPh),(NHCH(Me)CONHMe,Ph,Ph,Et,CONHPh),(NHCH(Me)CONHMe,Ph,Ph,Et,CONH-3-pyridyl),(NHCH(Me)CONHMe,Ph,Ph,Et,NHCOPh),(NHCH(Me)CONHMe,Ph,Ph,Et,NHCO-2-furyl),(NHCH(Me)CONHMe,Ph,Ph,Et,NHCONHPh),(NHCH(Me)CONHMe,Ph,Ph,Et,NHCOCONHPh),(NHCH(Me)CONHMe,Ph,Ph,CH2OH,CONHPh),(NHCH(Me)CONHMe,Ph,Ph,CH2OH,CONH-3-pyridyl),(NHCH(Me)CONHMe,Ph,Ph,CH2OH,NHCOPh),(NHCH(Me)CONHMe,Ph,Ph,CH2OH,NHCO-2-furyl),(NHCH(Me)CONHMe,Ph,Ph,CH2OH,NHCONHPh),(NHCH(Me)CONHMe,Ph,Ph,CH2OH,NHCOCONHPh),(NHCH(Me)CONHMe,Ph,OH,Me,CONHPh),(NHCH(Me)CONHMe,Ph,OH,Me,CONH-3-pyridyl),(NHCH(Me)CONHMe,Ph,OH,Me,NHCOPh),(NHCH(Me)CONHMe,Ph,OH,Me,NHCO-2-furyl),(NHCH(Me)CONHMe,Ph,OH,Me,NHCONHPh),(NHCH(Me)CONHMe,Ph,OH,Me,NHCOCONHPh),(NHCH(Me)CONHMe,Ph,OH,Et,CONHPh),(NHCH(Me)CONHMe,Ph,OH,Et,CONH-3-pyridyl),(NHCH(Me)CONHMe,Ph,OH,Et,NHCOPh),(NHCH(Me)CONHMe,Ph,OH,Et,NHCO-2-furyl),(NHCH(Me)CONHMe,Ph,OH,Et,NHCONHPh),(NHCH(Me)CONHMe,Ph,OH,Et,NHCOCONHPh),(NHCH(Me)CONHMe,Ph,OH,CH2OH,CONHPh),(NHCH(Me)CONHMe,Ph,OH,CH2OH,CONH-3-pyridyl),(NHCH(Me)CONHMe,Ph,OH,CH2OH,NHCOPh),(NHCH(Me)CONHMe,Ph,OH,CH2OH,NHCO-2-furyl),(NHCH(Me)CONHMe,Ph,OH,CH2OH,NHCONHPh),(NHCH(Me)CONHMe,Ph,OH,CH2OH,NHCOCONHPh),

(NHCOCH(iPr)OH,H,H,Me,CONHPh),(NHCOCH(iPr)OH,H,H,Me,CONH-3-pyridyl),(NHCOCH(iPr)OH,H,H,Me,NHCOPh),(NHCOCH(iPr)OH,H,H,Me,NHCO-2-furyl),(NHCOCH(iPr)OH,H,H,Me,NHCONHPh),(NHCOCH(iPr)OH,H,H,Me,NHCOCONHPh),(NHCOCH(iPr)OH,H,H,Et,CONHPh),(NHCOCH(iPr)OH,H,H,Et,CONH-3-pyridyl),(NHCOCH(iPr)OH,H,H,Et,NHCOPh),(NHCOCH(iPr)OH,H,H,Et,NHCO-2-furyl),(NHCOCH(iPr)OH,H,H,Et,NHCONHPh),(NHCOCH(iPr)OH,H,H,Et,NHCOCONHPh),(NHCOCH(iPr)OH,H,H,CH2OH,CONHPh),(NHCOCH(iPr)OH,H,H,CH2OH,CONH-3-pyridyl),(NHCOCH(iPr)OH,H,H,CH2OH,NHCOPh),(NHCOCH(iPr)OH,H,H,CH2OH,NHCO-2-furyl),(NHCOCH(iPr)OH,H,H,CH2OH,NHCONHPh),(NHCOCH(iPr)OH,H,H,CH2OH,NHCOCONHPh),(NHCOCH(iPr)OH,H,Me,Me,CONHPh),(NHCOCH(iPr)OH,H,Me,Me,CONH-3-pyridyl),(NHCOCH(iPr)OH,H,Me,Me,NHCOPh),(NHCOCH(iPr)OH,H,Me,Me,NHCO-2-furyl),(NHCOCH(iPr)OH,H,Me,Me,NHCONHPh),(NHCOCH(iPr)OH,H,Me,Me,NHCOCONHPh),(NHCOCH(iPr)OH,H,Me,Et,CONHPh),(NHCOCH(iPr)OH,H,Me,Et,CONH-3-pyridyl),(NHCOCH(iPr)OH,H,Me,Et,NHCOPh),(NHCOCH(iPr)OH,H,Me,Et,NHCO-2-furyl),(NHCOCH(iPr)OH,H,Me,Et,NHCONHPh),(NHCOCH(iPr)OH,H,Me,Et,NHCOCONHPh),(NHCOCH(iPr)OH,H,Me,CH2OH,CONHPh),(NHCOCH(iPr)OH,H,Me,CH2OH,CONH-3-pyridyl),(NHCOCH(iPr)OH,H,Me,CH2OH,NHCOPh),(NHCOCH(iPr)OH,H,Me,CH2OH,NHCO-2-furyl),(NHCOCH(iPr)OH,H,Me,CH2OH,NHCONHPh),(NHCOCH(iPr)OH,H,Me,CH2OH,NHCOCONHPh),(NHCOCH(iPr)OH,H,Ph,Me,CONHPh),(NHCOCH(iPr)OH,H,Ph,Me,CONH-3-pyridyl),(NHCOCH(iPr)OH,H,Ph,Me,NHCOPh),(NHCOCH(iPr)OH,H,Ph,Me,NHCO-2-furyl),(NHCOCH(iPr)OH,H,Ph,Me,NHCONHPh),(NHCOCH(iPr)OH,H,Ph,Me,NHCOCONHPh),(NHCOCH(iPr)OH,H,Ph,Et,CONHPh),(NHCOCH(iPr)OH,H,Ph,Et,CONH-3-pyridyl),(NHCOCH(iPr)OH,H,Ph,Et,NHCOPh),(NHCOCH(iPr)OH,H,Ph,Et,NHCO-2-furyl),(NHCOCH(iPr)OH,H,Ph,Et,NHCONHPh),(NHCOCH(iPr)OH,H,Ph,Et,NHCOCONHPh),(NHCOCH(iPr)OH,H,Ph,CH2OH,CONHPh),(NHCOCH(iPr)OH,H,Ph,CH2OH,CONH-3-pyridyl),(NHCOCH(iPr)OH,H,Ph,CH2OH,NHCOPh),(NHCOCH(iPr)OH,H,Ph,CH2OH,NHCO-2-furyl),(NHCOCH(iPr)OH,H,Ph,CH2OH,NHCONHPh),(NHCOCH(iPr)OH,H,Ph,CH2OH,NHCOCONHPh),(NHCOCH(iPr)OH,H2OH,Me,CONHPh),(NHCOCH(iPr)OH,H,OH,Me,CONH-3-pyridyl),(NHCOCH(iPr)OH,H2OH,Me,NHCOPh),(NHCOCH(iPr)OH,H,OH,Me,NHCO-2-furyl),(NHCOCH(iPr)OH,H2OH,Me,NHCONHPh),(NHCOCH(iPr)OH,H2OH,Me,NHCOCONHPh),(NHCOCH(iPr)OH,H2OH,Et,CONHPh),(NHCOCH(iPr)OH,H2OH,Et,CONH-3-pyridyl),(NHCOCH(iPr)OH,H2OH,Et,NHCOPh),(NHCOCH(iPr)OH,H2OH,Et,NHCO-2-furyl),(NHCOCH(iPr)OH,H2OH,Et,NHCONHPh),(NHCOCH(iPr)OH,H2OH,Et,NHCOCONHPh),(NHCOCH(iPr)OH,H2OH,CH2OH,CONHPh),(NHCOCH(iPr)OH,H2OH,CH2OH,CONH-3-pyridyl),(NHCOCH(iPr)OH,H,OH,CH2OH,NHCOPh),(NHCOCH(iPr)OH,H2OH,CH2OH,NHCO-2-furyl),(NHCOCH(iPr)OH,H2OH,CH2OH,NHCONHPh),(NHCOCH(iPr)OH,H2OH,CH2OH,NHCOCONHPh),(NHCOCH(iPr)OH,Me,H,Me,CONHPh),(NHCOCH(iPr)OH,Me,H,Me,CONH-3-pyridyl),(NHCOCH(iPr)OH,Me,H,Me,NHCOPh),(NHCOCH(iPr)OH,Me,H,Me,NHCO-2-furyl),(NHCOCH(iPr)OH,Me,H,Me,NHCONHPh),NHCOCH(iPr)OH,Me,H,Me,NHCOCONHPh),(NHCOCH(iPr)OH,Me,H,Et,CONHPh),(NHCOCH(iPr)OH,Me,H,Et,CONH-3-pyridyl),(NHCOCH(iPr)OH,Me,H,Et,NHCOPh),(NHCOCH(iPr)OH,Me,H,Et,NHCO-2-furyl),(NHCOCH(iPr)OH,Me,H,Et,NHCONHPh),(NHCOCH(iPr)OH,Me,H,Et,NHCOCONHPh),(NHCOCH(iPr)OH,Me,H,CH2OH,CONHPh),(NHCOCH(iPr)OH,Me,H,CH2OH,CONH-3-pyridyl),(NHCOCH(iPr)OH,Me,H,CH2OH,NHCOPh),(NHCOCH(iPr)OH,Me,H,CH2OH,NHCO-2-furyl),(NHCOCH(iPr)OH,Me,H,CH2OH,NHCONHPh),(NHCOCH(iPr)OH,Me,H,CH2OH,NHCOCONHPh),(NHCOCH(iPr)OH,Me,Me,Me,CONHPh),(NHCOCH(iPr)OH,Me,Me,Me,CONH-3-pyridyl),(NHCOCH(iPr)OH,Me,Me,Me,NHCOPh),(NHCOCH(iPr)OH,Me,Me,Me,NHCO-2-furyl),(NHCOCH(iPr)OH,Me,Me,Me,NHCONHPh),(NHCOCH(iPr)OH,Me,Me,Me,NHCOCONHPh),(NHCOCH(iPr)OH,Me,Me,Et,CONHPh),(NHCOCH(iPr)OH,Me,Me,Et,CONH-3-pyridyl),(NHCOCH(iPr)OH,Me,Me,Et,NHCOPh),(NHCOCH(iPr)OH,Me,Me,Et,NHCO-2-furyl),(NHCOCH(iPr)OH,Me,Me,Et,NHCONHPh),(NHCOCH(iPr)OH,Me,Me,Et,NHCOCONHPh),(NHCOCH(iPr)OH,Me,Me,CH2OH,CONHPh),(NHCOCH(iPr)OH,Me,Me,CH2OH,CONH-3-pyridyl),(NHCOCH(iPr)OH,Me,Me,CH2OH,NHCOPh),(NHCOCH(iPr)OH,Me,Me,CH2OH,NHCO-2-furyl),(NHCOCH(iPr)OH,Me,Me,CH2OH,NHCONHPh),(NHCOCH(iPr)OH,Me,Me,CH2OH,NHCOCONHPh),(NHCOCH(iPr)OH,Me,Ph,Me,CONHPh),(NHCOCH(iPr)OH,Me,Ph,Me,CONH-3-pyridyl),(NHCOCH(iPr)OH,Me,Ph,Me,NHCOPh),(NHCOCH(iPr)OH,Me,Ph,Me,NHCO-2-furyl),(NHCOCH(iPr)OH,Me,Ph,Me,NHCONHPh),(NHCOCH(iPr)OH,Me,Ph,Me,NHCOCONHPh),(NHCOCH(iPr)OH,Me,Ph,Et,CONHPh),(NHCOCH(iPr)OH,Me,Ph,Et,CONH-3-pyridyl),(NHCOCH(iPr)OH,Me,Ph,Et,NHCOPh),(NHCOCH(iPr)OH,Me,Ph,Et,NHCO-2-furyl),(NHCOCH(iPr)OH,Me,Ph,Et,NHCONHPh),(NHCOCH(iPr)OH,Me,Ph,Et,NHCOCONHPh),(NHCOCH(iPr)OH,Me,Ph,CH2OH,CONHPh),(NHCOCH(iPr)OH,Me,Ph,CH2OH,CONH-3-pyridyl),(NHCOCH(iPr)OH,Me,Ph,CH2OH,NHCOPh),(NHCOCH(iPr)OH,Me,Ph,CH2OH,NHCO-2-furyl),(NHCOCH(iPr)OH,Me,Ph,CH2OH,NHCONHPh),(NHCOCH(iPr)OH,Me,Ph,CH2OH,NHCOCONHPh),(NHCOCH(iPr)OH,Me,OH,Me,CONHPh),(NHCOCH(iPr)OH,Me,OH,Me,CONH-3-pyridyl),(NHCOCH(iPr)OH,Me,OH,Me,NHCOPh),(NHCOCH(iPr)OH,Me,OH,Me,NHCO-2-furyl),(NHCOCH(iPr)OH,Me,OH,Me,NHCONHPh),(NHCOCH(iPr)OH,Me,OH,Me,NHCOCONHPh),(NHCOCH(iPr)OH,Me,OH,Et,CONHPh),(NHCOCH(iPr)OH,Me,OH,Et,CONH-3-pyridyl),(NHCOCH(iPr)OH,Me,OH,Et,NHCOPh),(NHCOCH(iPr)OH,Me,OH,Et,NHCO-2-furyl),(NHCOCH(iPr)OH,Me,OH,Et,NHCONHPh),(NHCOCH(iPr)OH,Me,OH,Et,NHCOCONHPh),(NHCOCH(iPr)OH,Me,OH,CH2OH,CONHPh),(NHCOCH(iPr)OH,Me,OH,CH2OH,CONH-3-pyridyl),(NHCOCH(iPr)OH,Me,OH,CH2OH,NHCOPh),(NHCOCH(iPr)OH,Me,OH,CH2OH,NHCO-2-furyl),(NHCOCH(iPr)OH,Me,OH,CH2OH,NHCONHPh),(NHCOCH(iPr)OH,Me,OH,CH2OH,NHCOCONHPh),(NHCOCH(iPr)OH,Ph,H,Me,CONHPh),(NHCOCH(iPr)OH,Ph,H,Me,CONH-3-pyridyl),(NHCOCH(iPr)OH,Ph,H,Me,NHCOPh),(NHCOCH(iPr)OH,Ph,H,Me,NHCO-2-furyl),(NHCOCH(iPr)OH,Ph,H,Me,NHCONHPh),(NHCOCH(iPr)OH,Ph,H,Me,NHCOCONHPh),(NHCOCH(iPr)OH,Ph,H,Et,CONHPh),(NHCOCH(iPr)OH,Ph,H,Et,CONH-3-pyridyl),(NHCOCH(iPr)OH,Ph,H,Et,NHCOPh),(NHCOCH(iPr)OH,Ph,H,Et,NHCO-2-furyl),(NHCOCH(iPr)OH,Ph,H,Et,NHCONHPh),(NHCOCH(iPr)OH,Ph,H,Et,NHCOCONHPh),(NHCOCH(iPr)OH,Ph,H,CH2OH,CONHPh),(NHCOCH(iPr)OH,Ph,H,CH2OH,CONH-3-pyridyl),(NHCOCH(iPr)OH,Ph,H,CH2OH,NHCOPh),(NHCOCH(iPr)OH,Ph,H,CH2OH,NHCO-2-furyl),(NHCOCH(iPr)OH,Ph,H,CH2OH,NHCONHPh),(NHCOCH(iPr)OH,Ph,H,CH2OH,NHCOCONHPh),(NHCOCH(iPr)OH,Ph,Me,Me,CONHPh),(NHCOCH(iPr)OH,Ph,Me,Me,CONH-3-pyridyl),(NHCOCH(iPr)OH,Ph,Me,Me,NHCOPh),(NHCOCH(iPr)OH,Ph,Me,Me,NHCO-2-furyl),(NHCOCH(iPr)OH,Ph,Me,Me,NHCONHPh),(NHCOCH(iPr)OH,Ph,Me,Me,NHCOCONHPh),(NHCOCH(iPr)OH,Ph,Me,Et,CONHPh),(NHCOCH(iPr)OH,Ph,Me,Et,CONH-3-pyridyl),(NHCOCH(iPr)OH,Ph,Me,Et,NHCOPh),(NHCOCH(iPr)OH,Ph,Me,Et,NHCO-2-furyl),(NHCOCH(iPr)OH,Ph,Me,Et,NHCONHPh),(NHCOCH(iPr)OH,Ph,Me,Et,NHCOCONHPh),(NHCOCH(iPr)OH,Ph,Me,CH2OH,CONHPh),(NHCOCH(iPr)OH,Ph,Me,CH2OH,CONH-3-pyridyl),(NHCOCH(iPr)OH,Ph,Me,CH2OH,NHCOPh),(NHCOCH(iPr)OH,Ph,Me,CH2OH,NHCO-2-furyl),(NHCOCH(iPr)OH,Ph,Me,CH2OH,NHCONHPh),(NHCOCH(iPr)OH,Ph,Me,CH2OH,NHCOCONHPh),(NHCOCH(iPr)OH,Ph,Ph,Me,CONHPh),(NHCOCH(iPr)OH,Ph,Ph,Me,CONH-3-pyridyl),(NHCOCH(iPr)OH,Ph,Ph,Me,NHCOPh),(NHCOCH(iPr)OH,Ph,Ph,Me,NHCO-2-furyl),(NHCOCH(iPr)OH,Ph,Ph,Me,NHCONHPh),(NHCOCH(iPr)OH,Ph,Ph,Me,NHCOCONHPh),(NHCOCH(iPr)OH,Ph,Ph,Et,CONHPh),(NHCOCH(iPr)OH,Ph,Ph,Et,CONH-3-pyridyl),(NHCOCH(iPr)OH,Ph,Ph,Et,NHCOPh),(NHCOCH(iPr)OH,Ph,Ph,Et,NHCO-2-furyl),(NHCOCH(iPr)OH,Ph,Ph,Et,NHCONHPh),(NHCOCH(iPr)OH,Ph,Ph,Et,NHCOCONHPh),(NHCOCH(iPr)OH,Ph,Ph,CH2OH,CONHPh),(NHCOCH(iPr)OH,Ph,Ph,CH2OH,CONH-3-pyridyl),(NHCOCH(iPr)OH,Ph,Ph,CH2OH,NHCOPh),(NHCOCH(iPr)OH,Ph,Ph,CH2OH,NHCO-2-furyl),(NHCOCH(iPr)OH,Ph,Ph,CH2OH,NHCONHPh),(NHCOCH(iPr)OH,Ph,Ph,CH2OH,NHCOCONHPh),(NHCOCH(iPr)OH,Ph,OH,Me,CONHPh),(NHCOCH(iPr)OH,Ph,OH,Me,CONH-3-pyridyl),(NHCOCH(iPr)OH,Ph,OH,Me,NHCOPh),(NHCOCH(iPr)OH,Ph,OH,Me,NHCO-2-furyl),(NHCOCH(iPr)OH,Ph,OH,Me,NHCONHPh),(NHCOCH(iPr)OH,Ph,OH,Me,NHCOCONHPh),(NHCOCH(iPr)OH,Ph,OH,Et,CONHPh),(NHCOCH(iPr)OH,Ph,OH,Et,CONH-3-pyridyl),(NHCOCH(iPr)OH,Ph,OH,Et,NHCOPh),(NHCOCH(iPr)OH,Ph,OH,Et,NHCO-2-furyl),(NHCOCH(iPr)OH,Ph,OH,Et,N HCONHPh),(NHCOCH(iPr)OH,Ph,OH,Et,NHCOCONHPh),(NHCOCH(iPr)OH,Ph,OH,CH2OH,CONHPh),(NHCOCH(iPr)OH,Ph,OH,CH2OH,CONH-3-pyridyl),(NHCOCH(iPr)OH,Ph,OH,CH2OH,NHCOPh),(NHCOCH(iPr)OH,Ph,OH,CH2OH,NHCO-2-furyl),(NHCOCH(iPr)OH,Ph,OH,CH2OH,NHCONHPh),(NHCOCH(iPr)OH,Ph,OH,CH2OH,NHCOCONHPh),

(NHSO2Me,H,H,Me,CONHPh),(NHSO2Me,H,H,Me,CONH-3-pyridyl),(NHSO2Me,H,H,Me,NHCOPh),(NHSO2Me,H,H,Me,NHCO-2-furyl),(NHSO2Me,H,H,Me,NHCONHPh),(NHSO2Me,H,H,Me,NHCOCONHPh),(NHSO2Me,H,H,Et,CONHPh),(NHSO2Me,H,H,Et,CONH-3-pyridyl),(NHSO2Me,H,H,Et,NHCOPh),(NHSO2Me,H,H,Et,NHCO-2-furyl),(NHSO2Me,H,H,Et,NHCONHPh),(NHSO2Me,H,H,Et,NHCOCONHPh),(NHSO2Me,H,H,CH2OH,CONHPh),(NHSO2Me,H,H,CH2OH,CONH-3-pyridyl),(NHSO2Me,H,H,CH2OH,NHCOPh),(NHSO2Me,H,H,CH2OH,NHCO-2-furyl),(NHSO2Me,H,H,CH2OH,NHCONHPh),(NHSO2Me,H,H,CH2OH,NHCOCONHPh),(NHSO2Me,H,Me,Me,CONHPh),(NHSO2Me,H,Me,Me,CONH-3-pyridyl),(NHSO2Me,H,Me,Me,NHCOPh),(NHSO2Me,H,Me,Me,NHCO-2-furyl),(NHSO2Me,H,Me,Me,NHCONHPh),(NHSO2Me,H,Me,Me,NHCOCONHPh),(NHSO2Me,H,Me,Et,CONHPh),(NHSO2Me,H,Me,Et,CONH-3-pyridyl),(NHSO2Me,H,Me,Et,NHCOPh),(NHSO2Me,H,Me,Et,NHCO-2-furyl),(NHSO2Me,H,Me,Et,NHCONHPh),(NHSO2Me,H,Me,Et,NHCOCONHPh),(NHSO2Me,H,Me,CH2OH,CONHPh),(NHSO2Me,H,Me,CH2OH,CONH-3-pyridyl),(NHSO2Me,H,Me,CH2OH,NHCOPh),(NHSO2Me,H,Me,CH2OH,NHCO-2-furyl),(NHSO2Me,H,Me,CH2OH,NHCONHPh),(NHSO2Me,H,Me,CH2OH,NHCOCONHPh),(NHSO2Me,H,Ph,Me,CONHPh),(NHSO2Me,H,Ph,Me,CONH-3-pyridyl),(NHSO2Me,H,Ph,Me,NHCOPh),(NHSO2Me,H,Ph,Me,NHCO-2-furyl),(NHSO2Me,H,Ph,Me,NHCONHPh),(NHSO2Me,H,Ph,Me,NHCOCONHPh),(NHSO2Me,H,Ph,Et,CONHPh),(NHSO2Me,H,Ph,Et,CONH-3-pyridyl),(NHSO2Me,H,Ph,Et,NHCOPh),(NHSO2Me,H,Ph,Et,NHCO-2-furyl),(NHSO2Me,H,Ph,Et,NHCONHPh),(NHSO2Me,H,Ph,Et,NHCOCONHPh),(NHSO2Me,H,Ph,CH2OH,CONHPh),(NHSO2Me,H,Ph,CH2OH,CONH-3-pyridyl),(NHSO2Me,H,Ph,CH2OH,NHCOPh),(NHSO2Me,H,Ph,CH2OH,NHCO-2-furyl),(NHSO2Me,H,Ph,CH2OH,NHCONHPh),(NHSO2Me,H,Ph,CH2OH,NHCOCONHPh),(NHSO2Me,H2OH,Me,CONHPh),(NHSO2Me,H,OH,Me,CONH-3-pyridyl),(NHSO2Me,H2OH,Me,NHCOPh),(NHSO2Me,H2OH,Me,NHCO-2-furyl),(NHSO2Me,H2OH,Me,NHCONHPh),(NHSO2Me,H2OH,Me,NHCOCONHPh),(NHSO2Me,H2OH,Et,CONHPh),(NHSO2Me,H2OH,Et,CONH-3-pyridyl),(NHSO2Me,H2OH,Et,NHCOPh),(NHSO2Me,H2OH,Et,NHCO-2-furyl),(NHSO2Me,H,OH,Et,NHCONHPh),(NHSO2Me,H2OH,Et,NHCOCONHPh),(NHSO2Me,H2OH,CH2OH,CONHPh),(NHSO2Me,H2OH,CH2OH,CONH-3-pyridyl),(NHSO2Me,H2OH,CH2OH,NHCOPh),(NHSO2Me,H2OH,CH2OH,NHCO-2-furyl),(NHSO2Me,H2OH,CH2OH,NHCONHPh),(NHSO2Me,H2OH,CH2OH,NHCOCONHPh),(NHSO2Me,Me,H,Me,CONHPh),(NHSO2Me,Me,H,Me,CONH-3-pyridyl),(NHSO2Me,Me,H,Me,NHCOPh),(NHSO2Me,Me,H,Me,NHCO-2-furyl),(NHSO2Me,Me,H,Me,NHCONHPh),(NHSO2Me,Me,H,Me,NHCOCONHPh),(NHSO2Me,Me,H,Et,CONHPh),(NHSO2Me,Me,H,Et,CONH-3-pyridyl),(NHSO2Me,Me,H,Et,NHCOPh),(NHSO2Me,Me,H,Et,NHCO-2-furyl),(NHSO2Me,Me,H,Et,NHCONHPh),(NHSO2Me,Me,H,Et,NHCOCONHPh),(NHSO2Me,Me,H,CH2OH,CONHPh),(NHSO2Me,Me,H,CH2OH,CONH-3-pyridyl),(NHSO2Me,Me,H,CH2OH,NHCOPh),(NHSO2Me,Me,H,CH2OH,NHCO-2-furyl),(NHSO2Me,Me,H,CH2OH,NHCONHPh),(NHSO2Me,Me,H,CH2OH,NHCOCONHPh),(NHSO2Me,Me,Me,Me,CONHPh),(NHSO2Me,Me,Me,Me,CONH-3-pyridyl),(NHSO2Me,Me,Me,Me,NHCOPh),(NHSO2Me,Me,Me,Me,NHCO-2-furyl),(NHSO2Me,Me,Me,Me,NHCONHPh),(NHSO2Me,Me,Me,Me,NHCOCONHPh),(NHSO2Me,Me,Me,Et,CONHPh),(NHSO2Me,Me,Me,Et,CONH-3-pyridyl),(NHSO2Me,Me,Me,Et,NHCOPh),(NHSO2Me,Me,Me,Et,NHCO-2-furyl),(NHSO2Me,Me,Me,Et,NHCONHPh),(NHSO2Me,Me,Me,Et,NHCOCONHPh),(NHSO2Me,Me,Me,CH2OH,CONHPh),(NHSO2Me,Me,Me,CH2OH,CONH-3-pyridyl),(NHSO2Me,Me,Me,CH2OH,NHCOPh),(NHSO2Me,Me,Me,CH2OH,NHCO-2-furyl),(NHSO2Me,Me,Me,CH2OH,NHCONHPh),(NHSO2Me,Me,Me,CH2OH,NHCOCONHPh),(NHSO2Me,Me,Ph,Me,CONHPh),(NHSO2Me,Me,Ph,Me,CONH-3-pyridyl),(NHSO2Me,Me,Ph,Me,NHCOPh),(NHSO2Me,Me,Ph,Me,NHCO-2-furyl),(NHSO2Me,Me,Ph,Me,NHCONHPh),(NHSO2Me,Me,Ph,Me,NHCOCONHPh),(NHSO2Me,Me,Ph,Et,CONHPh),(NHSO2Me,Me,Ph,Et,CONH-3-pyridyl),(NHSO2Me,Me,Ph,Et,NHCOPh),(NHSO2Me,Me,Ph,Et,NHCO-2-furyl),(NHSO2Me,Me,Ph,Et,NHCONHPh),(NHSO2Me,Me,Ph,Et,NHCOCONHPh),(NHSO2Me,Me,Ph,CH2OH,CONHPh),(NHSO2Me,Me,Ph,CH2OH,CONH-3-pyridyl),(NHSO2Me,Me,Ph,CH2OH,NHCOPh),(NHSO2Me,Me,Ph,CH2OH,NHCO-2-furyl),(NHSO2Me,Me,Ph,CH2OH,NHCONHPh),(NHSO2Me,Me,Ph,CH2OH,NHCOCONHPh),(NHSO2Me,Me,OH,Me,CONHPh),(NHSO2Me,Me,OH,Me,CONH-3-pyridyl),(NHSO2Me,Me,OH,Me,NHCOPh),(NHSO2Me,Me,OH,Me,NHCO-2-furyl),(NHSO2Me,Me,OH,Me,NHCONHPh),(NHSO2Me,Me,OH,Me,NHCOCONHPh),(NHSO2Me,Me,OH,Et,CONHPh),(NHSO2Me,Me,OH,Et,CONH-3-pyridyl),(NHSO2Me,Me,OH,Et,NHCOPh),(NHSO2Me,Me,OH,Et,NHCO-2-furyl),(NHSO2Me,Me,OH,Et,NHCONHPh),(NHSO2Me,Me,OH,Et,NHCOCONHPh),(NHSO2Me,Me,OH,CH2OH,CONHPh),(NHSO2Me,Me,OH,CH2OH,CONH-3-pyridyl),(NHSO2Me,Me,OH,CH2OH,NHCOPh),(NHSO2Me,Me,OH,CH2OH,NHCO-2-furyl),(NHSO2Me,Me,OH,CH2OH,NHCONHPh),(NHSO2Me,Me,OH,CH2OH,NHCOCONHPh),(NHSO2Me,Ph,H,Me,CONHPh),(NHSO2Me,Ph,H,Me,CONH-3-pyridyl),(NHSO2Me,Ph,H,Me,NHCOPh),(NHSO2Me,Ph,H,Me,NHCO-2-furyl),(NHSO2Me,Ph,H,Me,NHCONHPh),(NHSO2Me,Ph,H,Me,NHCOCONHPh),(NHSO2Me,Ph,H,Et,CONHPb),(NHSO2Me,Ph,H,Et,CONH-3-pyridyl),(NHSO2Me,Ph,H,Et,NHCOPh),(NHSO2Me,Ph,H,Et,NHCO-2-furyl),(NHSO2Me,Ph,H,Et,NHCONHPh),(NHSO2Me,Ph,H,Et,NHCOCONHPh),(NHSO2Me,Ph,H,CH2OH,CONHPh),(NHSO2Me,Ph,H,CH2OH,CONH-3-pyridyl),(NHSO2Me,Ph,H,CH2OH,NHCOPh),(NHSO2Me,Ph,H,CH2OH,NHCO-2-furyl),(NHSO2Me,Ph,H,CH2OH,NHCONHPh),(NHSO2Me,Ph,H,CH2OH,NHCOCONHPh),(NHSO2Me,Ph,Me,Me,CONHPh),(NHSO2Me,Ph,Me,Me,CONH-3-pyridyl),(NHSO2Me,Ph,Me,Me,NHCOPh),(NHSO2Me,Ph,Me,Me,NHCO-2-furyl),(NHSO2Me,Ph,Me,Me,NHCONHPh),(NHSO2Me,Ph,Me,Me,NHCOCONHPh),(NHSO2Me,Ph,Me,Et,CONHPh),(NHSO2Me,Ph,Me,Et,CONH-3-pyridyl),(NHSO2Me,Ph,Me,Et,NHCOPh),(NHSO2Me,Ph,Me,Et,NHCO-2-furyl),(NHSO2Me,Ph,Me,Et,NHCONHPh),(NHSO2Me,Ph,Me,Et,NHCOCONHPh),(NHSO2Me,Ph,Me,CH2OH,CONHPh),(NHSO2Me,Ph,Me,CH2OH,CONH-3-pyridyl),(NHSO2Me,Ph,Me,CH2OH,NHCOPh),(NHSO2Me,Ph,Me,CH2OH,NHCO-2-furyl),(NHSO2Me,Ph,Me,CH2OH,NHCONHPh),(NHSO2Me,Ph,Me,CH2OH,NHCOCONHPh),(NHSO2Me,Ph,Ph,Me,CONHPh),(NHSO2Me,Ph,Ph,Me,CONH-3-pyridyl),(NHSO2Me,Ph,Ph,Me,NHCOPh),(NHSO2Me,Ph,Ph,Me,NHCO-2-furyl),(NHSO2Me,Ph,Ph,Me,NHCONHPh),(NHSO2Me,Ph,Ph,Me,NHCOCONHPh),(NHSO2Me,Ph,Ph,Et,CONHPh),(NHSO2Me,Ph,Ph,Et,CONH-3-pyridyl),(NHSO2Me,Ph,Ph,Et,NHCOPh),(NHSO2Me,Ph,Ph,Et,NHCO-2-fury % (NHSO2Me,Ph,Ph,Et,NHCONHPh),(NHSO2Me,Ph,Ph,Et,NHCOCONHPh),(NHSO2Me,Ph,Ph,CH2OH,CONHPh),(NHSO2Me,Ph,Ph,CH2OH,CONH-3-pyridyl),(NHSO2Me,Ph,Ph,CH2OH,NHCOPh),(NHSO2Me,Ph,Ph,CH2OH,NHCO-2-furyl),(NHSO2Me,Ph,Ph,CH2OH,NHCONHPh),(NHSO2Me,Ph,Ph,CH2OH,NHCOCONHPh),(NHSO2Me,Ph,OH,Me,CONHPh),(NHSO2Me,Ph,OH,Me,CONH-3-pyridyl),(NHSO2Me,Ph,OH,Me,NHCOPh),(NHSO2Me,Ph,OH,Me,NHCO-2-furyl),(NHSO2Me,Ph,OH,Me,NHCONHPh),(NHSO2Me,Ph,OH,Me,NHCOCONHPh),(NHSO2Me,Ph,OH,Et,CONHPh),(NHSO2Me,Ph,OH,Et,CONH-3-pyridyl),(NHSO2Me,Ph,OH,Et,NHCOPh),(NHSO2Me,Ph,OH,Et,NHCO-2-furyl),(NHSO2Me,Ph,OH,Et,NHCONHPh),(NHSO2Me,Ph,OH,Et,NHCOCONHPh),(NHSO2Me,Ph,OH,CH2OH,CONHPh),(NHSO2Me,Ph,OH,CH2OH,CONH-3-pyridyl),(NHSO2Me,Ph,OH,CH2OH,NHCOPh),(NHSO2Me,Ph,OH,CH2OH,NHCO-2-furyl),(NHSO2Me,Ph,OH,CH2OH,NHCONHPh),(NHSO2Me,Ph,OH,CH2OH,NHCOCONHPh),

(NH2,H,H,Me,CONHPh),(NH2,H,H,Me,CONH-3-pyridyl),(NH2,H,H,Me,NHCOPh),(NH2,H,H,Me,NHCO-2-furyl),(NH2,H,H,Me,NHCONHPh),(NH2,H,H,Me,NHCOCONHPh),(NH2,H,H,Et,CONHPh),(NH2,H,H,Et,CONH-3-pyridyl),(NH2,H,H,Et,NHCOPh),(NH2,H,H,Et,NHCO-2-furyl),(NH2,H,H,Et,NHCONHPh),(NH2,H,H,Et,NHCOCONHPh),(NH2,H,H,CH2OH,CONHPh),(NH2,H,H,CH2OH,CONH-3-pyridyl),(NH2,H,H,CH2OH,NHCONHPh),(NH2,H,H,CH2OH,NHCOCONHPh),(NH2,H,Me,Me,CONHPh),(NH2,H,Me,Me,CONH-3-pyridyl),(NH2,H,Me,Me,NHCONHPh),(NH2,H,Me,Me,NHCOCONHPh),(NH2,H,Me,Et,CONHPh),(NH2,H,Me,Et,CONH-3-pyridyl),(NH2,H,Me,Et,NHCOPh),(NH2,H,Me,Et,NHCO-2-furyl),(NH2,H,Me,Et,NHCONHPh),(NH2,H,Me,Et,NHCOCONHPh),(NH2,H,Me,CH2OH,CONHPh),(NH2,H,Me,CH2OH,CONH-3-pyridyl),(NH2,H,Me,CH2OH,NHCONHPh),(NH2,H,Me,CH2OH,NHCOCONHPh),(NH2,H,Ph,Me,CONHPh),(NH2,H,Ph,Me,CONH-3-pyridyl),(NH2,H,Ph,Me,NHCONHPh),(NH2,H,Ph,Me,NHCOCONHPh),(NH2,H,Ph,Et,CONHPh),(NH2,H,Ph,Et,CONH-3-pyridyl),(NH2,H,Ph,Et,NHCOPh),(NH2,H,Ph,Et,NHCO-2-furyl),(NH2,H,Ph,Et,NHCONHPh),(NH2,H,Ph,Et,NHCOCONHPh),(NH2,H,Ph,CH2OH,CONHPh),(NH2,H,Ph,CH2OH,CONH-3-pyridyl),(NH2,H,Ph,CH2OH,NHCONHPh),(NH2,H,Ph,CH2OH,NHCOCONHPh),(NH2,H,OH,Me,CONHPh),(NH2,H2OH,Me,CONH-3-pyridyl),(NH2,H2OH,Me,NHCONHPh),(NH2,H,OH,Me,NHCOCONHPh),(NH2,H2OH,Et,CONHPh),(NH2,H2OH,Et,CONH-3-pyridyl),(NH2,H,OH,Et,NHCOPh),(NH2,H,OH,Et,NHCO-2-furyl),(NH2,H2OH,Et,NHCONHPh),(NH2,H,OH,Et,NHCOCONHPh),(NH2,H,OH,CH2OH,CONHPh),(NH2,H,OH,CH2OH,CONH-3-pyridyl),(NH2,H,OH,CH2OH,NHCONHPh),(NH2,H,OH,CH2OH,NHCOCONHPh),(NH2,Me,H,Me,CONHPh),(NH2,Me,H,Me,CONH-3-pyridyl),(NH2,Me,H,Me,NHCONHPh),(NH2,Me,H,Me,NHCOCONHPh),(NH2,Me,H,Et,CONHPh),(NH2,Me,H,Et,CONH-3-pyridyl),(NH2,Me,H,Et,NHCOPh),(NH2,Me,H,Et,NHCO-2-furyl),(NH2,Me,H,Et,NHCONHPh),(NH2,Me,H,Et,NHCOCONHPh),(NH2,Me,H,CH2OH,CONHPh),(NH2,Me,H,CH2OH,CONH-3-pyridyl),(NH2,Me,H,CH2OH,NHCONHPh),(NH2,Me,H,CH2OH,NHCOCONHPh),(NH2,Me,Me,Me,CONHPh),(NH2,Me,Me,Me,CONH-3-pyridyl),(NH2,Me,Me,Me,NHCONHPh),(NH2,Me,Me,Me,NHCOCONHPh),(NH2,Me,Me,Et,CONHPh),(NH2,Me,Me,Et,CONH-3-pyridyl),(NH2,Me,Me,Et,NHCOPh),(NH2,Me,Me,Et,NHCO-2-furyl),(NH2,Me,Me,Et,NHCONHPh),(NH2,Me,Me,Et,NHCOCONHPh),(NH2,Me,Me,CH2OH,CONHPh),(NH2,Me,Me,CH2OH,CONH-3-pyridyl),(NH2,Me,Me,CH2OH,NHCONHPh),(NH2,Me,Me,CH2OH,NHCOCONHPh),(NH2,Me,Ph,Me,CONHPh),(NH2,Me,Ph,Me,CONH-3-pyridyl),(NH2,Me,Ph,Me,NHCOPh),(NH2,Me,Ph,Me,NHCO-2-furyl),(NH2,Me,Ph,Me,NHCONHPh),(NH2,Me,Ph,Me,NHCOCONHPh),(NH2,Me,Ph,Et,CONHPh),(NH2,Me,Ph,Et,CONH-3-pyridyl),(NH2,Me,Ph,Et,NHCOPh),(NH2,Me,Ph,Et,NHCO-2-furyl),(NH2,Me,Ph,Et,NHCONHPh),(NH2,Me,Ph,Et,NHCOCONHPh),(NH2,Me,Ph,CH2OH,CONHPh),(NH2,Me,Ph,CH2OH,CONH-3-pyridyl),(NH2,Me,Ph,CH2OH,NHCONHPh),(NH2,Me,Ph,CH2OH,NHCOCONHPh),(NH2,Me,OH,Me,CONHPh),(NH2,Me,OH,Me,CONH-3-pyridyl),(NH2,Me,OH,Me,NHCONHPh),(NH2,Me,OH,Me,NHCOCONHPh),(NH2,Me,OH,Et,CONHPh),(NH2,Me,OH,Et,CONH-3-pyridyl),(NH2,Me,OH,Et,NHCOPh),(NH2,Me,OH,Et,NHCO-2-furyl),(NH2,Me,OH,Et,NHCONHPh),(NH2,Me,OH,Et,NHCOCONHPh),(NH2,Me,OH,CH2OH,CONHPh),(NH2,Me,OH,CH2OH,CONH-3-pyridyl),(NH2,Me,OH,CH2OH,NHCONHPh),(NH2,Me,OH,CH2OH,NHCOCONHPh),(NH2,Ph,H,Me,CONHPh),(NH2,Ph,H,Me,CONH-3-pyridyl),(NH2,Ph,H,Me,NHCONHPh),(NH2,Ph,H,Me,NHCOCONHPh),(NH2,Ph,H,Et,CONHPh),(NH2,Ph,H,Et,CONH-3-pyridyl),(NH2,Ph,H,Et,NHCOPh),(NH2,Ph,H,Et,NHCO-2-furyl),(NH2,Ph,H,Et,NHCONHPh),(NH2,Ph,H,Et,NHCOCONHPh),(NH2,Ph,H,CH2OH,CONHPh),(NH2,Ph,H,CH2OH,CONH-3-pyridyl),(NH2,Ph,H,CH2OH,NHCONHPh),(NH2,Ph,H,CH2OH,NHCOCONHPh),(NH2,Ph,Me,Me,CONHPh),(NH2,Ph,Me,Me,CONH-3-pyridyl),(NH2,Ph,Me,Me,NHCONHPh),(NH2,Ph,Me,Me,NHCOCONHPh),(NH2,Ph,Me,Et,CONHPh),(NH2,Ph,Me,Et,CONH-3-pyridyl),(NH2,Ph,Me,Et,NHCOPh),(NH2,Ph,Me,Et,NHCO-2-furyl),(NH2,Ph,Me,Et,NHCONHPh),(NH2,Ph,Me,Et,NHCOCONHPh),(NH2,Ph,Me,CH2OH,CONHPh),(NH2,Ph,Me,CH2OH,CONH-3-pyridyl),(NH2,Ph,Me,CH2OH,NHCONHPh),(NH2,Ph,Me,CH2OH,NHCOCONHPh),(NH2,Ph,Ph,Me,CONHPh),(NH2,Ph,Ph,Me,CONH-3-pyridyl),(NH2,Ph,Ph,Me,NHCOPh),(NH2,Ph,Ph,Me,NHCO-2-furyl),(NH2,Ph,Ph,Me,NHCONHPh),(NH2,Ph,Ph,Me,NHCOCONHPh),(NH2,Ph,Ph,Et,CONHPh),(NH2,Ph,Ph,Et,CONH-3-pyridyl),(NH2,Ph,Ph,Et,NHCOPh),(NH2,Ph,Ph,Et,NHCO-2-furyl),(NH2,Ph,Ph,Et,NHCONHPh),(NH2,Ph,Ph,Et,NHCOCONHPh),(NH2,Ph,Ph,CH2OH,CONHPh),(NH2,Ph,Ph,CH2OH,CONH-3-pyridyl),(NH2,Ph,Ph,CH2OH,NHCOPh),(NH2,Ph,Ph,CH2OH,NHCO-2-furyl),(NH2,Ph,Ph,CH2OH,NHCONHPh),(NH2,Ph,Ph,CH2OH,NHCOCONHPh),(NH2,Ph,OH,Me,CONHPh),(NH2,Ph,OH,Me,CONH-3-pyridyl),(NH2,Ph,OH,Me,NHCONHPh),(NH2,Ph,OH,Me,NHCOCONHPh),(NH2,Ph,OH,Et,CONHPh),(NH2,Ph,OH,Et,CONH-3-pyridyl),(NH2,Ph,OH,Et,NHCOPh),(NH2,Ph,OH,Et,NHCO-2-furyl),(NH2,Ph,OH,Et,NHCONHPh),(NH2,Ph,OH,Et,NHCOCONHPh),(NH2,Ph,OH,CH2OH,CONHPh),(NH2,Ph,OH,CH2OH,CONH-3-pyridyl),(NH2,Ph,OH,CH2OH,NHCOPh),(NH2,Ph,OH,CH2OH,NHCO-2-furyl),(NH2,Ph,OH,CH2OH,NHCONHPh),(NH2,Ph,OH,CH2OH,NHCOCONHPh),

(NHCH2CH(OH)CH2OH,H,H,Me,CONHPh),(NHCH2CH(OH)CH2OH,H,H,Me,CONH-3-pyridyl),(NHCH2CH(OH)CH2OH,H,H,Me,NHCOPh),(NHCH2CH(OH)CH2OH,H,H,Me,NHCO-2-furyl),(NHCH2CH(Oh)CH2OH,H,H,Me,NHCONHPh),(NHCH2CH(OH)CH2OH,H,H,Me,NHCOCONHPh),(NHCH2CH(Oh)CH2OMe,H,H,Me,CONHPh),(NHCH2CH(OH)CH2OMe,H,H,Me,CONH-3-pyridyl),(NHCH2CH(Oh)CH2OMe,H,H,Me,NHCOPh),(NHCH2CH(OH)CH2OMe,H,H,Me,NHCO-2-furyl),(NHCH2CH(Oh)CH2OMe,H,H,Me,NHCONHPh),(NHCH2CH(Oh)CH2OMe,H,H,Me,NHCOCONHPh),(NHCH2CH(OH)CH2NH2,H,H,Me,CONHPh),(NHCH2CH(OH)CH2NH2,H,H,Me,CONH-3-pyridyl),(NHCH2CH(Oh)CH2NH2,H,H,Me,NHCOPh),(NHCH2CH(OH)CH2NH2,H,H,Me,NHCO-2-furyl),(NHCH2CH(OH)CH2NH2,H,H,Me,NHCONHPh),(NHCH2CH(OH)CH2NH2,H,H,Me,NHCOCONHPh),(NHCH2CH(OH)CH2NHMe,H,H,Me,CONHPh),(NHCH2CH(OH)CH2NHMe,H,H,Me,CONH-3-pyridyl),(NHCH2CH(OH)CH2NHMe,H,H,Me,NHCOPh),(NHCH2CH(OH)CH2NHMe,H,H,Me,NHCO-2-furyl),(NHCH2CH(OH)CH2NHMe,H,H,Me,NHCONHPh),(NHCH2CH(OH)CH2NHMe,H,H,Me,NHCOCONHPh),(NHCH2CH(OH)CH2NHCOMe,H,H,Me,CONHPh),(NHCH2CH(OH)CH2NHCOMe,H,H,Me,CONH-3-pyridyl),(NHCH2CH(OH)CH2NHCOMe,H,H,Me,NHCOPh),(NHCH2CH(OH)CH2NHCOMe,H,H,Me,NHCO-2-furyl),(NHCH2CH(Oh)CH2NHCOMe,H,H,Me,NHCONHPh),(NHCH2CH(OH)CH2NHCOMe,H,H,Me,NHCOCONHPh),(NHCH2CH(OH)CH2N(Me)Me,H,H,Me,CONHPh),(NHCH2CH(OH)CH2N(Me)Me,H,H,Me,CONH-3-pyridyl),(NHCH2CH(OH)CH2N(Me)Me,H,H,Me,NHCOPh),(NHCH2CH(OH)CH2N(Me)Me,H,H,Me,NHCO-2-furyl),(NHCH2CH(Oh)CH2N(Me)Me,H,H,Me,NHCONHPh),(NHCH2CH(OH)CH2N(Me)Me,H,H,Me,NHCOCONHPh),(NHC(O)C(O)NH2,H,H,Me,CONHPh),(NHC(O)C(O)NH2,H,H,Me,CONH-3-pyridyl),(NHC(O)C(ONH2,H,H,Me,NHCOPh),(NHC(O)C(ONH2,H,H,Me,NHCO-2-furyl),(NHC(O)C(O)NH2,H,H,Me,NHCONHPh),(NHC(O)C(ONH2,H,H,Me,NHCOCONHPh),(NHC(O)C(ONHMe,H,H,Me,CONHPh),(NHC(O)C(ONHMe,H,H,Me,CONH-3-pyridyl),(NHC(O)C(O)NHMe,H,H,Me,NHCOPh),(NHC(O)C(O)NHMe,H,H,Me,NHCO-2-furyl),(NHC(O)C(ONHMe,H,H,Me,NHCONHPh),(NHC(O)C(O)NHMe,H,H,Me,NHCOCONHPh),(NHC(O)C(O)N(Me)Me,H,H,Me,CONHPh),(NHC(O)C(O)N(Me)Me,H,H,Me,CONH-3-pyridyl),(NHC(O)C(O)N(Me)Me,H,H,Me,NHCOPh),(NHC(O)C(O)N(Me)Me,H,H,Me,NHCO-2-furyl),(NHC(O)C(O)N(Me)Me,H,H,Me,NHCONHPh),(NHC(O)C(O)N(Me)Me,H,H,Me,NHCOCONHPh).





In above structural formula (II) or (Ij), the combination of B, Linker, A, R5 (B, Linker, A, R5) are the following compounds.













TABLE 169






B
Linker

A

R5






















B1
Ph—
L1




A1




R51
—CN


 


B2
2-pyridyl-
L2




A2




R52
—C≡CH


 


B3
4-Me—Ph—
L3




A3




R53
—C≡OMe


 


B4
xHex—
L4




A4




R54
—CF3


 


B5
cHex—CH2—
L5




A5




R55
—CH2Cl


 








R56
CHCl2









(B, Linker, A, R8)=(B1,L1,A1,R51),(B1,L1,A1,R52),(B1,L1,A1,R53),(B1,L1,A1,R54),(B1,L1,A1,R55),(B1, L1,A1,R56),(B1,L1,A2,R51),(B1,L1,A2,R52),(B1,L1,A2,R53),(B1,L1,A2,R54),(B1,L1, A2,R55),(B1,L1,A2,R56),(B1,L1,A3,R51),(B1,L1,A3,R52),(B1,L1,A3,R53),(B1,L1,A3, R54),(B1,L1,A3,R55),(B1,L1,A3,R56),(B1,L1,A4,R51),(B1,L1,A4,R52),(B1,L1,A4,R53),(B1,L1,A4,R54),(B1,L1,A4,R55),(B1,L1,A4,R56),(B1,L1,A5,R51),(B1,L1,A5,R52),(B1,L1,A5,R53),(B1,L1,A5,R54),(B1,L1,A5,R55),(B1,L1,A5,R56),(B1,L2,A1,R51),(B1, L2,A1,R52),(B1,L2,A1,R53),(B1,L2,A1,R54),(B1,L2,A1,R55),(B1,L2,A1,R56),(B1,L2, A2,R51),(B1,L2,A2,R52),(B1,L2,A2,R53),(B1,L2,A2,R54),(B1,L2,A2,R55),(B1,L2,A2, R56),(B1,L2,A3,R51),(B1,L2,A3,R52),(B1,L2,A3,R53),(B1,L2,A3,R54),(B1,L2,A3,R55),(B1,L2,A3,R56),(B1,L2,A4,R51),(B1,L2,A4,R52),(B1,L2,A4,R53),(B1,L2,A4,R54),(B1,L2,A4,R55),(B1,L2,A4,R56),(B1,L2,A5,R51),(B1,L2,A5,R52),(B1,L2,A5,R53),(B1, L2,A5,R54),(B1,L2,A5,R55),(B1,L2,A5,R56),(B1,L3,A1,R51),(B1,L3,A1,R52),(B1,L3, A1,R53),(B1,L3,A1,R54),(B1,L3,A1,R55),(B1,L3,A1,R56),(B1,L3,A2,R51),(B1,L3,A2, R52),(B1,L3,A2,R53),(B1,L3,A2,R54),(B1,L3,A2,R55),(B1,L3,A2,R56),(B1,L3,A3,R51),(B1,L3,A3,R52),(B1,L3,A3,R53),(B1,L3,A3,R54),(B1,L3,A3,R55),(B1,L3,A3,R56),(B1,L3,A4,R51),(B1,L3,A4,R52),(B1,L3,A4,R53),(B1,L3,A4,R54),(B1,L3,A4,R55),(B1, L3,A4,R66),(B1,L3,A5,R51),(B1,L3,A5,R52),(B1,L3,A5,R53),(B1,L3,A5,R54),(B1,L3, A5,R55),(B1,L3,A5,R56),(B1,L4,A1,R51),(B1,L4,A1,R52),(B1,L4,A1,R53),(B1,L4,A1, R54),(B1,L4,A1,R55),(B1,L4,A1,R56),(B1,L4,A2,R51),(B1,L4,A2,R52),(B1,L4,A2,R53),(B1,L4,A2,R54),(B1,L4,A2,R55),(B1,L4,A2,R56),(B1,L4,A3,R51),(B1,L4,A3,R52),(B1,L4,A3,R53),(B1,L4,A3,R54),(B1,L4,A3,R55),(B1,L4,A3,R56),(B1,L4,A4,R51),(B1, L4,A4,R52),(B1,L4,A4,R53),(B1,L4,A4,R54),(B1,L4,A4,R55),(B1,L4,A4,R56),(B1,L4, A5,R51),(B1,L4,A5,R52),(B1,L4,A5,R53),(B1,L4,A5,R54),(B1,L4,A5,R55),(B1,L4,A5, R56),(B1,L5,A1,R51),(B1,L5,A1,R52),(B1,L5,A1,R53),(B1,L5,A1,R54),(B1,L5,A1,R55),(B1,L5,A1,R56),(B1,L5,A2,R51),(B1,L5,A2,R52),(B1,L5,A2,R53),(B1,L5,A2,R54),(B1,L5,A2,R55),(B1,L5,A2,R56),(B1,L5,A3,R51),(B1,L5,A3,R52),(B1,L5,A3,R53),(B1, L5,A3,R54),(B1,L5,A3,R55),(B1,L5,A3,R56),(B1,L5,A4,R51),(B1,L5,A4,R52),(B1,L5, A4,R53),(B1,L5,A4,R54),(B1,L5,A4,R55),(B1,L5,A4,R56),(B1,L5,A5,R51),(B1,L5,A5, R52),(B1,L5,A5,R53),(B1,L5,A5,R54),(B1,L5,A5,R55),(B1,L5,A5,R56),(B2,L1,A1,R51); (B2,L1,A1,R52),(B2,L1,A1,R53),(B2,L1,A1,R54),(B2,L1,A1,R55),(B2,L1,A1,R56),(B2,L1,A2,R51),(B2,L1,A2,R52),(B2,L1,A2,R53),(B2,L1,A2,R54),(B2,L1,A2,R55),(B2, L1,A2,R56),(B2,L1,A3,R51),(B2,L1,A3,R52),(B2,L1,A3,R53),(B2,L1,A3,R54),(B2,L1, A3,R55),(B2,L1,A3,R56),(B2,L1,A4,R51),(B2,L1,A4,R52),(B2,L1,A4,R53),(B2,L1,A4, R54),(B2,L1,A4,R55),(B2,L1,A4,R56),(B2,L1,A5,R51),(B2,L1,A5,R52),(B2,L1,A5,R53),(B2,L1,A5,R54),(B2,L1,A5,R55),(B2,L1,A5,R56),(B2,L2,A1,R51),(B2,L2,A1,R52),(B2,L2,A1,R53),(B2,L2,A1,R54),(B2,L2,A1,R55),(B2,L2,A1,R56),(B2,L2,A2,R51),(B2, L2,A2,R52),(B2,L2,A2,R53),(B2,L2,A2,R54),(B2,L2,A2,R55),(B2,L2,A2,R56),(B2,L2, A3,R51),(B2,L2,A3,R52),(B2,L2,A3,R53),(B2,L2,A3,R54),(B2,L2,A3,R55),(B2,L2,A3, R56),(B2,L2,A4,R51),(B2,L2,A4,R52),(B2,L2,A4,R53),(B2,L2,A4,R54),(B2,L2,A4,R55),(B2,L2,A4,R56),(B2,L2,A5,R51),(B2,L2,A5,R52),(B2,L2,A5,R53),(B2,L2,A5,R54),(B2,L2,A5,R55),(B2,L2,A5,R56),(B2,L3,A1,R51),(B2,L3,A1,R52),(B2,L3,A1,R53),(B2, L3,A1,R54),(B2,L3,A1,R55),(B2,L3,A1,R56),(B2,L3,A2,R51),(B2,L3,A2,R52),(B2,L3, A2,R53),(B2,L3,A2,R54),(B2,L3,A2,R55),(B2,L3,A2,R56),(B2,L3,A3,R51),(B2,L3,A3, R52),(B2,L3,A3,R53),(B2,L3,A3,R54),(B2,L3,A3,R55),(B2,L3,A3,R56),(B2,L3,A4,R51),(B2,L3,A4,R52),(B2,L3,A4,R53),(B2,L3,A4,R54),(B2,L3,A4,R55),(B2,L3,A4,R56),(B2,L3,A5,R51),(B2,L3,A5,R52),(B2,L3,A5,R53),(B2,L3,A5,R54),(B2,L3,A5,R55),(B2, L3,A5,R56),(B2,L4,A1,R51),(B2,L4,A1,R52),(B2,L4,A1,R53),(B2,L4,A1,R54),(B2,L4, A1,R55),(B2,L4,A1,R56),(B2,L4,A2,R51),(B2,L4,A2,R52),(B2,L4,A2,R53),(B2,L4,A2, R54),(B2,L4,A2,R55),(B2,L4,A2,R56),(B2,L4,A3,R50,(B2,L4,A3,R52),(B2,L4,A3,R53),(B2,L4,A3,R54),(B2,L4,A3,R55),(B2,L4,A3,R56),(B2,L4,A4,R51),(B2,L4,A4,R52),(B2,L4,A4,R53),(B2,L4,A4,R54),(B2,L4,A4,R55),(B2,L4,A4,R56),(B2,L4,A5,R51),(B2, L4,A5,R52),(B2,L4,A5,R53),(B2,L4,A5,R54),(B2,L4,A5,R55),(B2,L4,A5,R56),(B2,L5, A1,R51),(B2,L5,A1,R52),(B2,L5,A1,R53),(B2,L5,A1,R54),(B2,L5,A1,R55),(B2,L5,A1, R56),(B2,L5,A2,R51),(B2,L5,A2,R52),(B2,L5,A2,R53),(B2,L5,A2,R54),(B2,L5,A2,R55),(B2,L5,A2,R56),(B2,L5,A3,R51),(B2,L5,A3,R52),(B2,L5,A3,R53),(B2,L5,A3,R54),(B2,L5,A3,R55),(B2,L5,A3,R56),(B2,L5,A4,R51),(B2,L5,A4,R52),(B2,L5,A4,R53),(B2, L5,A4,R54),(B2,L5,A4,R55),(B2,L5,A4,R56),(B2,L5,A5,R51),(B2,L5,A5,R52),(B2,L5, A5,R53),(B2,L5,A5,R54),(B2,L5,A5,R55),(B2,L5,A5,R56),(B3,L1,A1,R51),(B3,L1,A1, R52),(B3,L1,A1,R53),(B3,L1,A1,R54),(B3,L1,A1,R55),(B3,L1,A1,R56),(B3,L1,A2,R51),(B3,L1,A2,R52),(B3,L1,A2,R53),(B3,L1,A2,R54),(B3,L1,A2,R55),(B3,L1,A2,R56),(B3,L1,A3,R51),(B3,L1,A3,R52),(B3,L1,A3,R53),(B3,L1,A3,R54),(B3,L1,A3,R55),(B3, L1,A3,R56),(B3,L1,A4,R51),(B3,L1,A4,R52),(B3,L1,A4,R53),(B3,L1,A4,R54),(B3,L1, A4,R55),(B3,L1,A4,R56),(B3,L1,A5,R51),(B3,L1,A5,R52),(B3,L1,A5,R53),(B3,L1,A5, R54),(B3,L1,A5,R55),(B3,L1,A5,R56),(B3,L2,A1,R51),(B3,L2,A1,R52),(B3,L2,A1,R53),(B3,L2,A1,R54),(B3,L2,A1,R55),(B3,L2,A1,R56),(B3,L2,A2,R51),(B3,L2,A2,R52),(B3,L2,A2,R53),(B3,L2,A2,R54),(B3,L2,A2,R55),(B3,L2,A2,R56),(B3,L2,A3,R51),(B3, L2,A3,R52),(B3,L2,A3,R53),(B3,L2,A3,R54),(B3,L2,A3,R55),(B3,L2,A3,R56),(B3,L2, A4,R51),(B3,L2,A4,R52),(B3,L2,A4,R53),(B3,L2,A4,R54),(B3,L2,A4,R55),(B3,L2,A4, R56),(B3,L2,A5,R51),(B3,L2,A5,R52),(B3,L2,A5,R53),(B3,L2,A5,R54),(B3,L2,A5,R55),(B3,L2,A5,R56),(B3,L3,A1,R51),(B3,L3,A1,R52),(B3,L3,A1,R53),(B3,L3,A1,R54),(B3,L3,A1,R55),(B3,L3,A1,R56),(B3,L3,A2,R51),(B3,L3,A2,R52),(B3,L3,A2,R53),(B3, L3,A2,R54),(B3,L3,A2,R55),(B3,L3,A2,R56),(B3,L3,A3,R51),(B3,L3,A3,R52),(B3,L3, A3,R53),(B3,L3,A3,R54),(B3,L3,A3,R55),(B3,L3,A3,R56),(B3,L3,A4,R51),(B3,L3,A4, R52),(B3,L3,A4,R53),(B3,L3,A4,R54),(B3,L3,A4,R55),(B3,L3,A4,R56),(B3,L3,A5,R51),(B3,L3,A5,R52),(B3,L3,A5,R53),(B3,L3,A5,R54),(B3,L3,A5,R55),(B3,L3,A5,R56),(B3,L4,A1,R51),(B3,L4,A1,R52),(B3,L4,A1,R53),(B3,L4,A1,R54),(B3,L4,A1,R55),(B3, L4,A1,R56),(B3,L4,A2,R51),(B3,L4,A2,R52),(B3,L4,A2,R53),(B3,L4,A2,R54),(B3,L4, A2,R55),(B3,L4,A2,R56),(B3,L4,A3,R51),(B3,L4,A3,R52),(B3,L4,A3,R53),(B3,L4,A3, R54),(B3,L4,A3,R55),(B3,L4,A3,R56),(B3,L4,A4,R51),(B3,L4,A4,R52),(B3,L4,A4,R53),(B3,L4,A4,R54),(B3,L4,A4,R55),(B3,L4,A4,R56),(B3,L4,A5,R51),(B3,L4,A5,R52),(B3,L4,A5,R53),(B3,L4,A5,R54),(B3,L4,A5,R55),(B3,L4,A5,R56),(B3,L5,A1,R51),(B3, L5,A1,R52),(B3,L5,A1,R53),(B3,L5,A1,R54),(B3,L5,A1,R55),(B3,L5,A1,R56),(B3,L5, A2,R51),(B3,L5,A2,R52),(B3,L5,A2,R53),(B3,L5,A2,R54),(B3,L5,A2,R55),(B3,L5,A2, R56),(B3,L5,A3,R51),(B3,L5,A3,R52),(B3,L5,A3,R53),(B3,L5,A3,R54),(B3,L5,A3,R55),(B3,L5,A3,R56),(B3,L5,A4,R51),(B3,L5,A4,R52),(B3,L5,A4,R53),(B3,L5,A4,R54),(B3,L5,A4,R55),(B3,L5,A4,R56),(B3,L5,A5,R51),(B3,L5,A5,R52),(B3,L5,A5,R53),(B3, L5,A5,R54),(B3,L5,A5,R55),(B3,L5,A5,R56),(B4,L1,A1,R51),(B4,L1,A1,R52),(B4,L1, A1,R53),(B4,L1,A1,R54),(B4,L1,A1,R55),(B4,L1,A1,R56),(B4,L1,A2,R51),(B4,L1,A2, R52),(B4,L1,A2,R53),(B4,L1,A2,R54),(B4,L1,A2,R55),(B4,L1,A2,R56),(B4,L1,A3,R51),(B4,L1,A3,R52),(B4,L1,A3,R53),(B4,L1,A3,R54),(B4,L1,A3,R55),(B4,L1,A3,R56),(B4,L1,A4,R51),(B4,L1,A4,R52),(B4,L1,A4,R53),(B4,L1,A4,R54),(B4,L1,A4,R55),(B4, L1,A4,R56),(B4,L1,A5,R51),(B4,L1,A5,R52),(B4,L1,A5,R53),(B4,L1,A5,R54),(B4,L1, A5,R55),(B4,L1,A5,R56),(B4,L2,A1,R51),(B4,L2,A1,R52),(B4,L2,A1,R53),(B4,L2,A1, R54),(B4,L2,A1,R55),(B4,L2,A1,R56),(B4,L2,A2,R51),(B4,L2,A2,R52),(B4,L2,A2,R53),(B4,L2,A2,R54),(B4,L2,A2,R55),(B4,L2,A2,R56),(B4,L2,A3,R51),(B4,L2,A3,R52),(B4,L2,A3,R53),(B4,L2,A3,R54),(B4,L2,A3,R55),(B4,L2,A3,R56),(B4,L2,A4,R51),(B4, L2,A4,R52),(B4,L2,A4,R53),(B4,L2,A4,R54),(B4,L2,A4,R55),(B4,L2,A4,R56),(B4,L2, A5,R51),(B4,L2,A5,R52),(B4,L2,A5,R53),(B4,L2,A5,R54),(B4,L2,A5,R55),(B4,L2,A5, R56),(B4,L3,A1,R51),(B4,L3,A1,R52),(B4,L3,A1,R53),(B4,L3,A1,R54),(B4,L3,A1,R55),(B4,L3,A1,R56),(B4,L3,A2,R51),(B4,L3,A2,R52),(B4,L3,A2,R53),(B4,L3,A2,R54),(B4,L3,A2,R55),(B4,L3,A2,R56),(B4,L3,A3,R51),(B4,L3,A3,R52),(B4,L3,A3,R53),(B4, L3,A3,R54),(B4,L3,A3,R55),(B4,L3,A3,R56),(B4,L3,A4,R51),(B4,L3,A4,R52),(B4,L3, A4,R53),(B4,L3,A4,R54),(B4,L3,A4,R55),(B4,L3,A4,R56),(B4,L3,A5,R51),(B4,L3,A5, R52),(B4,L3,A5,R53),(B4,L3,A5,R54),(B4,L3,A5,R55),(B4,L3,A5,R56),(B4,L4,A1,R50,(B4,L4,A1,R52),(B4,L4,A1,R53),(B4,L4,A1,R54),(B4,L4,A1,R55),(B4,L4,A1,R56), B4,L4,A2,R51),(B4,L4,A2,R52),(B4,L4,A2,R53),(B4,L4,A2,R54),(B4,L4,A2,R55),(B4, L4,A2,R56),(B4,L4,A3,R50,(B4,L4,A3,R52),(B4,L4,A3,R53),(B4,L4,A3,R54),(B4,L4, A3,R55),(B4,L4,A3,R56),(B4,L4,A4,R51),(B4,L4,A4,R52),(B4,L4,A4,R53),(B4,L4,A4, R54),(B4,L4,A4,R55),(B4,L4,A4,R56),(B4,L4,A5,R51),(B4,L4,A5,R52),(B4,L4,A5,R53),(B4,L4,A5,R54),(B4,L4,A5,R55),(B4,L4,A5,R56),(B4,L5,A1,R51),(B4,L5,A1,R52),(B4,L5,A1,R53),(B4,L5,A1,R54),(B4,L5,A1,R55),(B4,L5,A1,R56),(B4,L5,A2,R51),(B4, L5,A2,R52),(B4,L5,A2,R53),(B4,L5,A2,R54),(B4,L5,A2,R55),(B4,L5,A2,R56),(B4,L5, A3,R50,(B4,L5,A3,R52),(B4,L5,A3,R53),(B4,L5,A3,R54),(B4,L5,A3,R55),(B4,L5,A3, R56),(B4,L5,A4,R51),(B4,L5,A4,R52),(B4,L5,A4,R53),(B4,L5,A4,R54),(B4,L5,A4,R55),(B4,L5,A4,R56),(B4,L5,A5,R5 (B4,L5,A5,R52),(B4,L5,A5,R53),(B4,L5,A5,R54),(B4,L5,A5,R55),(B4,L5,A5,R56),(B5,L1,A1,R51),(B5,L1,A1,R52),(B5,L1,A1,R53),(B5, L1,A1,R54),(B5,L1,A1,R55),(B5,L1,A1,R56),(B5,L1,A2,R51),(B5,L1,A2,R52),(B5,L1, A2,R53),(B5,L1,A2,R54),(B5,L1,A2,R55),(B5,L1,A2,R56),(B5,L1,A3,R51),(B5,L1,A3, R52),(B5,L1,A3,R53),(B5,L1,A3,R54),(B5,L1,A3,R55),(B5,L1,A3,R56),(B5,L1,A4,R51),(B5,L1,A4,R52),(B5,L1,A4,R53),(B5,L1,A4,R54),(B5,L1,A4,R55),(B5,L1,A4,R56),(B5,L1,A5,R51),(B5,L1,A5,R52),(B5,L1,A5,R53),(B5,L1,A5,R54),(B5,L1,A5,R55),(B5, L1,A5,R56),(B5,L2,A1,R51),(B5,L2,A1,R52),(B5,L2,A1,R53),(B5,L2,A1,R54),(B5,L2, A1,R55),(B5,L2,A1,R56),(B5,L2,A2,R51),(B5,L2,A2,R52),(B5,L2,A2,R53),(B5,L2,A2, R54),(B5,L2,A2,R55),(B5,L2,A2,R56),(B5,L2,A3,R51),(B5,L2,A3,R52),(B5,L2,A3,R53),(B5,L2,A3,R54),(B5,L2,A3,R55),(B5,L2,A3,R56),(B5,L2,A4,R51),(B5,L2,A4,R52),(B5,L2,A4,R53),(B5,L2,A4,R54),(B5,L2,A4,R55),(B5,L2,A4,R56),(B5,L2,A5,R50,(B5, L2,A5,R52),(B5,L2,A5,R53),(B5,L2,A5,R54),(B5,L2,A5,R55),(B5,L2,A5,R56),(B5,L3, A1,R51),(B5,L3,A1,R52),(B5,L3,A1,R53),(B5,L3,A1,R54),(B5,L3,A1,R55),(B5,L3,A1, R56),(B5,L3,A2,R51),(B5,L3,A2,R52),(B5,L3,A2,R53),(B5,L3,A2,R54),(B5,L3,A2,R55),(B5,L3,A2,R56),(B5,L3,A3,R50,(B5,L3,A3,R52),(B5,L3,A3,R53),(B5,L3,A3,R54),(B5,L3,A3,R55),(B5,L3,A3,R56),(B5,L3,A4,R51),(B5,L3,A4,R52),(B5,L3,A4,R53),(B5, L3,A4,R54),(B5,L3,A4,R55),(B5,L3,A4,R56),(B5,L3,A5,R51),(B5,L3,A5,R52),(B5,L3, A5,R53),(B5,L3,A5,R54),(B5,L3,A5,R55),(B5,L3,A5,R56),(B5,L4,A1,R51),(B5,L4,A1, R52),(B5,L4,A1,R53),(B5,L4,A1,R54),(B5,L4,A1,R55),(B5,L4,A1,R56),(B5,L4,A2,R51),(B5,L4,A2,R52),(B5,L4,A2,R53),(B5,L4,A2,R54),(B5,L4,A2,R55),(B5,L4,A2,R56),(B5,L4,A3,R51),(B5,L4,A3,R52),(B5,L4,A3,R53),(B5,L4,A3,R54),(B5,L4,A3,R55),(B5, L4,A3,R56),(B5,L4,A4,R51),(B5,L4,A4,R52),(B5,L4,A4,R53),(B5,L4,A4,R54),(B5,L4, A4,R55),(B5,L4,A4,R56),(B5,L4,A5,R51),(B5,L4,A5,R52),(B5,L4,A5,R53),(B5,L4,A5, R54),(B5,L4,A5,R55),(B5,L4,A5,R56),(B5,L5,A1,R51),(B5,L5,A1,R52),(B5,L5,A1,R53),(B5,L5,A1,R54),(B5,L5,A1,R55),(B5,L5,A1,R56),(B5,L5,A2,R51),(B5,L5,A2,R52),(B5,L5,A2,R53),(B5,L5,A2,R54),(B5,L5,A2,R55),(B5,L5,A2,R56),(B5,L5,A3,R50,(B5, L5,A3,R52),(B5,L5,A3,R53),(B5,L5,A3,R54),(B5,L5,A3,R55),(B5,L5,A3,R56),(B5,L5, A4,R51),(B5,L5,A4,R52),(B5,L5,A4,R53),(B5,L5,A4,R54),(B5,L5,A4,R55),(B5,L5,A4, R56),(B5,L5,A5,R51),(B5,L5,A5,R52),(B5,L5,A5,R53),(B5,L5,A5,R54),(B5,L5,A5,R55),(B5,L5,A5,R56).

Test: Measurement of Inhibition of β-Secretase Activity

Zero point five μL of the test compounds (dissolved in N,N′-dimethylsulfoxide) were incubated with 48.5 μL of the fluorescence-quenched peptide substrate solution (Biotin-XSEVNLDAEFRHDSGC-Eu:X=ε-amino-n-capronic acid, Eu=Europium cryptate) and 1 μL of recombinant human BACE-1 protein (R&D systems) for 3 h at 30° C. in the 96 well half-area plate (black color plate, Costar). The substrate peptide was synthesized by reacting with Biotin-XSEVNLDAEFRHDSGC (Peptide Institute) and Cryptate TBPCOOH mono SMP (CIS bio international). The final concentration of the substrate peptide and recombinant human BACE-1 protein were 18 nM and 7.4 nM, respectively. The enzymatic reaction was performed in sodium acetate buffer (50 mM sodium acetate (pH5.0), 0.008% Triton X-100). After the reaction, a 50 μL of 8.0 μg/mL Streptavidin-XL665 (CIS bio international) dissolved in phosphate buffer (150 mM K2HPO4—KH2PO4 (pH7.0), 0.008% Triton X-100, 0.8 M KF) was add to each well and incubated for 1 h at 30° C. Then, the fluorescence intensity (excitation wavelength 320 nm, emission wavelength 620 nM and 665 nM) in each well was measured using Wallac 1420 multilabel counter (Perkin Elmer life sciences). The enzymatic activity was calculated by the each fluorescence intensity ratio ([ratio of fluorescence at 665 nm to that at 620 nm]×10,000). IC50 values of test compounds were indicated in table 170.










TABLE 170







Compound
IC50 value



No.
(μM)



















1186
5.7



639
7.9



1000
8.0



246
2.9



269
7.0



1010
2.8



417
5.0



161
7.7



220
1.5



1207
4.0



998
4.5



1205
8.1



616
5.9



504
2.5



799
6.7



490
5.1



972
0.45



1160
0.72



753
5.6



786
0.156



165
0.0394



1132
2.563



570
0.149



1014
0.165



731
0.278



1262
0.140



964
0.264



793
0.061



625
1.288



498
0.930



26
1.977



465
3.239



1197
0.912



395
1.500



896
8.497



660
4.586



664
3.642



176
1.479



284
0.229



912
0.175



212
0.220



163
2.278



1244
0.130



52
10.0



698
0.165



96
0.163



822
0.243



739
0.049



832
0.222



897
0.816



1100
0.037



740
0.505



436
0.160



1043
0.027



1199
0.032



73
0.435



127
0.054



309
0.833



1135
2.296



1035
0.174










The IC50 value of the following compounds were less than 100 μM by the same test.
3, 4, 6, 8, 12, 17, 18, 30, 31, 35, 36, 38, 39, 42, 43, 57, 61, 67, 67, 71, 77, 78, 80, 85, 97, 99, 106, 106, 113, 114, 115, 117, 120, 121, 125, 128, 129, 130, 134, 139, 144, 154, 157, 159, 164, 172, 176, 178, 181, 182, 186, 189, 200, 200, 201, 204, 207, 209, 211, 214, 215, 216, 228, 232, 240, 241, 243, 243, 243, 251, 256, 259, 267, 273, 276, 278, 279, 281, 282, 293, 298, 299, 300, 302, 303, 307, 314, 319, 321, 322, 326, 328, 330, 333, 336, 339, 341, 344, 345, 346, 348, 362, 353, 367, 368, 359, 359, 369, 360, 361, 363, 369, 370, 373, 378, 380, 383, 389, 390, 393, 396, 397, 402, 406, 406, 409, 410, 413, 415, 426, 442, 443, 444, 461, 452, 454, 466, 463, 467, 469, 472, 472, 479, 480, 482, 482, 483, 491, 493, 497, 500, 501, 502, 609, 511, 615, 516, 517, 627, 528, 632, 542, 544, 549, 550, 661, 558, 660, 568, 569, 675, 578, 684, 586, 588, 691, 600, 607, 608, 611, 613, 618, 620, 629, 634, 634, 637, 643, 646, 662, 657, 661, 671, 677, 681, 687, 691, 708, 711, 719, 720, 723, 725, 728, 729, 730, 732, 735, 743, 746, 766, 758, 761, 770, 775, 781, 787, 788, 790, 791, 792, 796, 797, 802, 803, 804, 808, 809, 813, 816, 819, 820, 824, 833, 835, 836, 847, 850, 861, 865, 866, 871, 876, 887, 893, 894, 900, 905, 906, 908, 910, 919, 922, 928, 932, 933, 935, 936, 939, 941, 943, 944, 946, 947, 949, 959, 966, 971, 984, 986, 988, 990, 1004, 1005, 1007, 1009, 1013, 1020, 1028, 1034, 1039, 1046, 1055, 1062, 1063, 1069, 1074, 1077, 1084, 1089, 1096, 1099, 1108, 1109, 1114, 1124, 1125, 1131, 1140, 1142, 1145, 1147, 1148, 1150, 1164, 1165, 1172, 1174, 1184, 1185, 1193, 1211, 1217, 1221, 1237, 1241, 1243, 1255, 1256, 1257, 1258, 1261, 1263, 1264, 1265, 1266, 1268, 1269, 1270, 1271, 1272, 1274, and so on.
Formulation Example 1
A granule containing the following ingredients is prepared.

















Ingredient
Compound represented by formula (I)
 10 mg




Lactose
700 mg




Corn starch
274 mg




HPC-L
 16 mg





1000 mg 










The compound represented by the formula (I) and lactose are passed through a 60 mesh sieve. Corn starch is passed through a 120 mesh sieve. These are mixed with a V-type mixer. To a mixed powder is added a HPC-L (lower viscosity hydroxypropylcellulose) aqueous solution, the materials are kneaded, granulated (extrusion granulation, pore diameter 0.5 to 1 mm), and dried. The resulting dry granule is passed through a sieve using a vibration sieve (12/60 mesh) to obtain a granule.
Formulation Example 2
A granule for filling into a capsule containing the following ingredients is prepared.

















Ingredient
Compound represented by formula (I)
15 mg




Lactose
90 mg




Corn starch
42 mg




HPC-L
 3 mg





150 mg 










The compound represented by the formula (I) and lactose are passed through a 60 mesh sieve. Corn starch is passed through a 120 mesh sieve. These are mixed, to a mixed powder, is added a HPC-L solution, the materials are kneaded, granulated, and dried. The resulting dry granule is size-adjusted, 150 mg of which is filled into a No. 4 hard gelatin capsule.
Formulation Example 3
A tablet containing the following ingredients is prepared.














Ingredient
Compound represented by the formula (I)
10 mg



Lactose
90 mg



Microcrystalline cellulose
30 mg



CMC-Na
15 mg



Magnesium stearate
 5 mg




150 mg 









The compound represented by the formula (I), lactose, microcrystalline cellulose, CMC-Na (carboxymethylcellulose sodium salt) are passed through a 60 mesh sieve, and mixed. Into a mixed powder is mixed magnesium stearate to obtain a mixed powder for tabletting. The present mixed powder is compressed to obtain 150 mg of a tablet.
Formulation Example 4
The following ingredients are warmed, mixed, and sterilized to obtain an injectable.














Ingredient
Compound represented by the formula (I)
 3 mg



Nonionic surfactant
15 mg



Purified water for injection
 1 ml









INDUSTRIAL APPLICABILITY
The present invention is useful as an agent for treating disease induced by production, secretion and/or deposition of amyloid β.

## Claims

1. A compound represented by the formula (I):



wherein ring A is an optionally substituted heterocyclic group,
the heterocyclic group being substituted optionally with at least one selected from the group consisting of
(A) the substituent α, the substituent a 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, lower alkylthio, carbamoyl, lower alkylcarbamoyl, hydroxy lower alkylcarbamoyl, sulfamoyl, lower alkylsulfamoyl, lower alkylsulfinyl, cyano, nitro, aryl, and heterocyclic group;
(B) lower alkyl optionally substituted with one or more substituents selected from the group of substituent α;
(C) amino lower alkyl substituted with one or more substituents selected from the group of substituent α;
(D) hydroxyimino lower alkyl;
(E) lower alkoxyimino lower alkyl;
(F) lower alkenyl optionally substituted with one or more substituents selected from the group of substituent α;
(G) lower alkynyl optionally substituted with one or more substituents selected from the group of substituent α;
(H) lower alkoxy optionally substituted with one or more substituents selected from the group of substituent α;
(I) lower alkylthio optionally substituted with one or more substituents selected from the group of substituent α;
(J) lower alkylamino substituted with one or more substituents selected from the group of substituent α;
(K) lower alkylsulfonyl optionally substituted with one or more substituents selected from the group of substituent α;
(L) aryl lower alkoxycarbonyl optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl;
(M) acyl substituted with one or more substituents selected from the group of substituent α; and the ring part of the carbocyclic carbonyl and the heterocyclic carbonyl is substituted optionally with at least one selected from the group of lower alkyl; the substituent group α; and lower alkyl substituted with at least one selected from the group of the substituent α;
(N) cycloalkyl optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl;
(O) lower alkylsulfinyl optionally substituted with one or more substituents selected from the group of substituent α;
(P) sulfamoyl;
(Q) aryl optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl;
(R) heterocyclic group optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl;
(S) aryloxy optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl;
(T) heterocyclicoxy optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl;
(U) arylthio optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl;
(V) heterocyclic thio optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl;
(W) arylamino optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl;
(X) heterocyclicamino optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl;
(Y) aryl lower alkylamino optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl;
(Z) heterocyclic lower alkylamino optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl;
(AA) lower alkyl sulfamoyl optionally substituted with one or more substituents selected from the group of substituent α;
(AB) aryl sulfamoyl optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl;
(AC) heterocyclic sulfamoyl optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl;
(AD) arylsulfonyl substituted optionally with one or more substituents selected from the group of substituent α, azido, and lower alkyl;
(AE) heterocyclic sulfonyl optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl;
(AF) aryl carbamoyl optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl;
(AG) heterocyclic carbamoyl optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl;
(AH) aryl lower alkylcarbamoyl optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl;
(AI) heterocyclic lower alkylcarbamoyl optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alky;
(AJ) aryloxycarbonyl optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl;
(AK) heterocyclicoxycarbonyl optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl;
(AL) lower alkylenedioxy substituted optionally with halogen;
(AM) oxo;
(AN) azido; and
(AO) one of the following formulae:







wherein Q1, Q2 and Q3 are each independently a bond, lower alkylene or lower alkenylene, lower alkylene and lower alkenylene being substituted optionally with a substituent α, the substituent 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, lower alkylthio, carbamoyl, lower alkylcarbamoyl, hydroxy lower alkylcarbamoyl, sulfamoyl, lower alkylsulfamoyl, lower alkylsulfinyl, cyano, nitro, aryl, and heterocyclic group;
Q4 is lower alkylene or lower alkenylene, lower alkylene and lower alkenylene being substituted optionally with a substituent α, the substituent 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, lower alkylthio, carbamoyl, lower alkylcarbamoyl, hydroxy lower alkylcarbamoyl, sulfamoyl, lower alkylsulfamoyl, lower alkylsulfinyl, cyano, nitro, aryl, and heterocyclic group;
W1 and W2 are each independently O or S;
W3 is O, S or NR12;
R12 is a hydrogen atom, lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl, lower alkoxycarbonyl lower alkyl, carbocyclic group lower alkyl or acyl;
R14 is a hydrogen atom or lower alkyl;
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 group consisting of
(a) a substituent α, the substituent 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, lower alkylthio, carbamoyl, lower alkylcarbamoyl, hydroxy lower alkylcarbamoyl, sulfamoyl, lower alkylsulfamoyl, lower alkylsulfinyl, cyano, nitro, aryl, and heterocyclic group;
(b) lower alkyl optionally substituted with the substituent α;
(c) amino lower alky substituted with the substituent α;
(d) hydroxyimino lower alkyl;
(e) lower alkoxyimino lower alkyl;
(f) lower alkenyl optionally substituted with the substituent α;
(g) lower alkynyl optionally substituted with the substituent α;
(h) lower alkoxy optionally substituted with the substituent α;
(i) lower alkylthio optionally substituted with the substituent α;
(j) lower alkylamino substituted with the substituent α;
(k) lower alkylsulfonyl optionally substituted with the substituent α;
(l) aryl lower alkoxycarbonyl optionally substituted with one or more substituents selected from the group of substituent α and lower alkyl;
(m) acyl substituted with the substituent α; and the ring part of the carbocyclic carbonyl and the heterocyclic carbonyl is substituted optionally with at least one selected from the group of lower alkyl; the substituent group α; and lower alkyl substituted with at least one selected from the group of the substituent α,
(n) lower alkylsulfonyl optionally substituted with the substituent α;
(o) sulfamoyl;
(p) lower alkyl sulfamoyl optionally substituted with one or more substituents selected from the group of substituent α;
(q) cycloalkyl optionally substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
(r) aryl optionally substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
(s) heterocyclic group optionally substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
(t) aryloxy optionally substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
(u) heterocyclicoxy optionally substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
(v) arylthio optionally substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
(w) heterocyclic thio optionally substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
(x) arylamino optionally substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
(y) heterocyclic amino optionally substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
(z) aryl lower alkylamino optionally substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
(aa) heterocyclic lower alkylamino optionally substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
(ab) arylsulfamoyl optionally substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
(ac) heterocyclic sulfamoyl optionally substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
(ad) arylsulfonyl optionally substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
(ae) heterocyclic sulfonyl optionally substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
(af) arylcarbamoyl optionally substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
(ag) heterocyclic carbamoyl optionally substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
(ah) aryl lower alkylcarbamoyl optionally substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
(ai) heterocyclic lower alkylcarbamoyl optionally substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
(aj) aryloxy carbonyl optionally substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
(ak) heterocyclicoxycarbonyl optionally substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
(al) lower alkylenedioxy substituted optionally with halogen; and
(am) oxo;
Alk2 is lower alkyl, lower alkyl being substituted optionally with at least one selected from the group consisting of a substituent α;
p is an integer of 1 or 2;




Alk1 is lower alkylene or lower alkenylene;
R0 is a hydrogen atom, lower alkyl, or acyl;
X is O;
R2a and R2b are each independently a hydrogen atom, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted amino, optionally substituted amidino, optionally substituted acyl, optionally substituted carbamoyl, optionally substituted carbamoylcarbonyl, optionally substituted lower alkylsulfonyl, optionally substituted arylsulfonyl, an optionally substituted carbocyclic group, or an optionally substituted heterocyclic group;
lower alkyl being substituted optionally with at least one selected from the group consisting of a substituent α, the substituent 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, lower alkylthio, carbamoyl, lower alkylcarbamoyl, hydroxy lower alkylcarbamoyl, sulfamoyl, lower alkylsulfamoyl, lower alkylsulfinyl, cyano, nitro, aryl, and heterocyclic group,
lower alkenyl being substituted optionally with the substituent α,
amino being substituted optionally with at least one selected from the group consisting of lower alkyl, acyl, hydroxy, lower alkoxy, lower alkoxycarbonyl, a carbocyclic group and a heterocyclic group,
amidino being substituted optionally with at least one selected from the group consisting of lower alkyl, acyl, hydroxy, lower alkoxy, lower alkoxycarbonyl, a carbocyclic group and a heterocyclic group,
acyl includes aliphatic acyl of a carbon number of 1 to 10, carbocyclic carbonyl and heterocyclic carbonyl;
acyl being substituted optionally with the substituent α; and the ring part of the carbocyclic carbonyl and the heterocyclic carbonyl is substituted optionally with at least one selected from the group of lower alkyl; the substituent group α; and lower alkyl substituted with at least one selected from the group of the substituent α,
carbamoyl being substituted optionally with at least one selected from the group consisting of lower alkyl, acyl, hydroxy, lower alkoxy, lower alkoxycarbonyl, a carbocyclic group and a heterocyclic group,
carbamoylcarbonyl being substituted optionally with at least one selected from the group consisting of lower alkyl, acyl, hydroxy, lower alkoxy, lower alkoxycarbonyl, a carbocyclic group and a heterocyclic group,
lower alkylsulfonyl being substituted optionally with the substituent α,
arylsulfonyl being substituted optionally with at least one selected from the group consisting of the substituent α and a lower alkyl, and
the carbocyclic group and the heterocyclic group being substituted optionally with at least one selected from the group consisting of the substituent α and lower alkyl;
R3a, R3b, R4a, and R4b are each independently a hydrogen atom, halogen, hydroxy, 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;
lower alkyl being substituted optionally with at least one selected from the group consisting of a substituent α, the substituent 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, lower alkylthio, carbamoyl, lower alkylcarbamoyl, hydroxy lower alkylcarbamoyl, sulfamoyl, lower alkylsulfamoyl, lower alkylsulfinyl, cyano, nitro, aryl, and heterocyclic group,
lower alkenyl being substituted optionally with the substituent α,
acyl being substituted optionally with the substituent α; and the ring part of the carbocyclic carbonyl and the heterocyclic carbonyl is substituted optionally with at least one selected from the group of lower alkyl; the substituent group α; and lower alkyl substituted with at least one selected from the group of the substituent α,
lower alkoxycarbonyl being substituted optionally with the substituent α,
amino being substituted optionally with at least one selected from the group consisting of lower alkyl, acyl, hydroxy, lower alkoxy, lower alkoxycarbonyl, a carbocyclic group and a heterocyclic group,
carbamoyl being substituted optionally with at least one selected from the group consisting of lower alkyl, acyl, hydroxy, lower alkoxy, lower alkoxycarbonyl, a carbocyclic group and a heterocyclic group, and
the carbocyclic group and the heterocyclic group being substituted optionally with at least one selected from the group consisting of the substituent α and a lower alkyl;
n=0, 1, 2 or 3, m=0, 1, 2 or 3,
with the proviso that n+m=3,
each R3a, each R3b, each R4a, and each R4b may be independently different;
R5 is a hydrogen atom, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, an optionally substituted carbocyclic group, an optionally substituted heterocyclic group;
lower alkyl being substituted optionally with at least one selected from the group consisting of a substituent α, the substituent 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, lower alkylthio, carbamoyl, lower alkylcarbamoyl, hydroxy lower alkylcarbamoyl, sulfamoyl, lower alkylsulfamoyl, lower alkylsulfinyl, cyano, nitro, aryl, and heterocyclic group,
lower alkenyl being substituted optionally with the substituent α,
lower alkynyl being substituted optionally with the substituent α, and
the carbocyclic group and the heterocyclic group being substituted optionally with at least one selected from the group consisting of the substituent α and a lower alkyl;
wherein acyl includes aliphatic acyl of a carbon number of 1 to 10, carbocyclic carbonyl and heterocyclic carbonyl;
when




R5 and ring A can be taken together to form




wherein R5a and R5b are each independently a hydrogen atom or lower alkyl;
s is an integer of 1 to 4;
each R5a and each R5b may be different,
its pharmaceutically acceptable salt, or a solvate thereof.

2. The compound according to claim 1, wherein E is a bond, its pharmaceutically acceptable salt or a solvate thereof.

3. The compound according to claim 1, wherein R5 is optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, an optionally substituted carbocyclic group, or an optionally substituted heterocyclic group,
lower alkyl being substituted optionally with at least one selected from the group consisting of a substituent α, the substituent 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, lower alkylthio, carbamoyl, lower alkylcarbamoyl, hydroxy lower alkylcarbamoyl, sulfamoyl, lower alkylsulfamoyl, lower alkylsulfinyl, cyano, nitro, aryl, and heterocyclic group,
lower alkenyl being substituted optionally with the substituent α,
lower alkynyl being substituted optionally with the substituent α, and
the carbocyclic group and the heterocyclic group being substituted optionally with at least one selected from the group consisting of the substituent α and lower alkyl,
its pharmaceutically acceptable salt, or a solvate thereof.

4. The compound according to claim 1, wherein R2a is a hydrogen atom;
R2b is a hydrogen atom, optionally substituted lower alkyl, optionally substituted acyl, optionally substituted lower alkylsulfonyl, or optionally substituted amidino,
lower alkyl being substituted optionally with at least one selected from the group consisting of a substituent α, the substituent 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, lower alkylthio, carbamoyl, lower alkylcarbamoyl, hydroxy lower alkylcarbamoyl, sulfamoyl, lower alkylsulfamoyl, lower alkylsulfinyl, cyano, nitro, aryl, and heterocyclic group,
acyl being substituted optionally with the substituent α, and the ring part of the carbocyclic carbonyl and the heterocyclic carbonyl is substituted optionally with at least one selected from the group of lower alkyl; the substituent group α; and lower alkyl substituted with at least one selected from the group of the substituent α,
lower alkylsulfonyl being substituted optionally with the substituent α, and
amidino being substituted optionally with at least one selected from the group consisting of lower alkyl, acyl, hydroxy, lower alkoxy, lower alkoxycarbonyl, a carbocyclic group and a heterocyclic group,
its pharmaceutically acceptable salt, or a solvate thereof.

5. The compound according to claim 1, wherein NR2aR2b is represented by the formula:



R6, R7, and R8 are each independently a hydrogen atom, lower alkyl, or acyl;
Y is optionally substituted lower alkylene, optionally substituted lower alkenylene, or optionally substituted lower alkynylene;
lower alkylene being substituted optionally with a substituent α, the substituent 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, lower alkylthio, carbamoyl, lower alkylcarbamoyl, hydroxy lower alkylcarbamoyl, sulfamoyl, lower alkylsulfamoyl, lower alkylsulfinyl, cyano, nitro, aryl, and heterocyclic group,
lower alkenylene being substituted optionally with the substituent α, and
lower alkynylene being substituted optionally with the substituent α;
Z is O or S,
its pharmaceutically acceptable salt, or a solvate thereof.

6. The compound according to claim 1, wherein R5 is C1 to C3 alkyl,
its pharmaceutically acceptable salt, or a solvate thereof.

7. The compound according to claim 1, wherein R5 is methyl,
its pharmaceutically acceptable salt, or a solvate thereof.

8. The compound according to claim 1, wherein R3a and R3b are each independently a hydrogen atom, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkoxy, or optionally substituted aryl,
lower alkyl being substituted optionally with at least one selected from the group consisting of a substituent α, the substituent 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, lower alkylthio, carbamoyl, lower alkylcarbamoyl, hydroxy lower alkylcarbamoyl, sulfamoyl, lower alkylsulfamoyl, lower alkylsulfinyl, cyano, nitro, aryl, and heterocyclic group,
lower alkoxy being substituted optionally with the substituent α, and
aryl being substituted optionally with the substituent α or lower alkyl,
its pharmaceutically acceptable salt, or a solvate thereof.

9. The compound according to claim 1, wherein all of R3a and all of R3b are hydrogen atoms,
its pharmaceutically acceptable salt, or a solvate thereof.

10. A pharmaceutical composition comprising the compound as defined in claim 1, a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient, and a pharmaceutically acceptable carrier.

11. The compound according to claim 1, wherein ring A is substituted pyridyl, pyridyl being substituted with at least one selected from the group consisting of the (A) to (AO) as defined in claim 1,
its pharmaceutically acceptable salt, or a solvate thereof.

12. The compound according to claim 1, wherein the heterocyclic group in ring A is



wherein R9 and R10 are each independently a hydrogen atom, halogen, hydroxy, optionally substituted lower alkyl, cyano, nitro, optionally substituted lower alkoxy, optionally substituted acyl, optionally substituted amino, optionally substituted carbamoyl, optionally substituted carbamoyloxy, optionally substituted lower alkylsulfonyl, optionally substituted arylsulfonyl, optionally substituted lower alkylsulfonyloxy, optionally substituted arylsulfonyloxy, an optionally substituted carbocyclic group, optionally substituted carbocyclicoxy, an optionally substituted heterocyclic group or optionally substituted heterocyclicoxy,
lower alkyl being substituted optionally with at least one selected from the group consisting of a substituent α, a hydroxyimino group, and a lower alkoxyimino group, the substituent 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, lower alkylthio, carbamoyl, lower alkylcarbamoyl, hydroxy lower alkylcarbamoyl, sulfamoyl, lower alkylsulfamoyl, lower alkylsulfinyl, cyano, nitro, aryl, and heterocyclic group,
lower alkoxy being substituted optionally with the substituent α,
acyl includes aliphatic acyl of a carbon number of 1 to 10, carbocyclic carbonyl and heterocyclic carbonyl; and
acyl being substituted optionally with the substituent α; and the ring part of the carbocyclic carbonyl and the heterocyclic carbonyl is substituted optionally with at least one selected from the group of lower alkyl; the substituent group α; and lower alkyl substituted with at least one selected from the group of the substituent α,
the amino being substituted optionally with at least one selected from the group consisting of lower alkyl, acyl, hydroxy, lower alkoxy, lower alkoxycarbonyl, a carbocyclic group and a heterocyclic group,
the carbamoyl being substituted optionally with at least one selected from the group consisting of lower alkyl, acyl, hydroxy, lower alkoxy, lower alkoxycarbonyl, a carbocyclic group and a heterocyclic group,
carbamoyloxy being substituted optionally with at least one selected from the group consisting of lower alkyl, acyl, hydroxy, lower alkoxy, lower alkoxycarbonyl, a carbocyclic group and a heterocyclic group,
lower alkylsulfonyl being substituted optionally with the substituent α,
arylsulfonyl being substituted optionally with at least one selected from the group consisting of the substituent α and lower alkyl,
lower alkylsulfonyloxy being substituted optionally with the substituent α,
arylsulfonyloxy being substituted optionally with the substituent α,
the carbocyclic group, carbocyclicoxy, the heterocyclic group, and heterocyclicoxy being substituted optionally with at least one selected from the group consisting of lower alkyl and the substituent α;
G is represented by the following formula:










wherein Q1, Q2 and Q3 are each independently a bond, lower alkylene or lower alkenylene, lower alkylene and lower alkenylene being substituted optionally with a substituent α, the substituent 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, lower alkylthio, carbamoyl, lower alkylcarbamoyl, hydroxy lower alkylcarbamoyl, sulfamoyl, lower alkylsulfamoyl, lower alkylsulfinyl, cyano, nitro, aryl, and heterocyclic group;
Q4 is lower alkylene or lower alkenylene, lower alkylene and lower alkenylene being substituted optionally with a substituent α, the substituent 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, lower alkylthio, carbamoyl, lower alkylcarbamoyl, hydroxy lower alkylcarbamoyl, sulfamoyl, lower alkylsulfamoyl, lower alkylsulfinyl, cyano, nitro, aryl, and heterocyclic group;
W1 and W2 are each independently O or S;
W3 is 0, S or NR12;
R12 is a hydrogen atom, lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl, lower alkoxycarbonyl lower alkyl, carbocyclic lower alkyl or acyl;
R14 is hydrogen atom or lower alkyl;
ring B is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group;
the carbocyclic group and the heterocyclic group being substituted optionally with at least one selected from the group consisting of (a) to (am) as defined in claim 1:
Alk2 is lower alkyl, lower alkyl being substituted optionally with at least one selected from the group consisting of a substituent α, and
p is 1 or 2,
its pharmaceutically acceptable salt, or a solvate thereof.

13. The compound according to claim 1, wherein the heterocyclic group in ring A is pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furyl, thienyl; indolyl, isoindolyl, indazolyl, indolizinyl, indolinyl, isoindolinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzopyranyl, benzimidazolyl, benzoxazolyl, benzoxazolyl, benzoxadiazolyl, benzoisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, pyrazolopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, quinazolinyl, quinolyl, isoquinolyl, naphthyridinyl, dihydrobenzofuryl, tetrahydroquinolyl, tetrahydroisoquinolyl, dihydrobenzoxazine, tetrahydrobenzothienyl, carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, dibenzofuryl, and imidazoquinolyl, dioxanyl, thiiranyl, oxyranyl, oxathioranyl, azetidinyl, thianyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, dihydropyridyl, dihydrobenzoimidazolyl, tetrahydropyridyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, dihydroxazinyl, hexahydroazepinyl or tetrahydroazepinyl,
the heterocyclic group being substituted optionally with at least one selected from the group consisting of (A) to (AO) as defined in claim 1,
its pharmaceutically acceptable salt, or a solvate thereof.

14. The compound according to claim 1, wherein
the heterocyclic group in ring A is substituted optionally with at least one selected from the group consisting of (A) and (B) as defined in claim 1 and the formulas:




Q1 is a bond, optionally substituted lower alkylene, or optionally substituted lower alkenylene, lower alkylene and lower alkenylene being substituted optionally with a substituent α, the substituent 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, lower alkylthio, carbamoyl, lower alkylcarbamoyl, hydroxy lower alkylcarbamoyl, sulfamoyl, lower alkylsulfamoyl, lower alkylsulfinyl, cyano, nitro, aryl, and heterocyclic group;
R12 is a hydrogen atom, lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl, lower alkoxycarbonyl lower alkyl, carbocyclic lower alkyl, or acyl;
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 group consisting of the (a) to (am) as defined in claim 1;
its pharmaceutically acceptable salt, or a solvate thereof.

15. The compound according to claim 1, wherein n=3 and m=0,
its pharmaceutically acceptable salt, or a solvate thereof.