# Patent

## Title
Pharmaceutical composition for treating Alzheimer's disease

## Abstract

A pharmaceutical composition for treating Alzheimer's disease containing a compound represented by the general formula (I);




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

    E is lower alkylene, etc.;
    X is S, O, or NR1;
    R1 is a hydrogen atom or lower alkyl;
    R2a, R2b, R3a, R3b, R4a and R4b are each independently a hydrogen atom, halogen, hydroxy, etc.;
    n and m are each independently an integer of 0 to 3;
    n+m is an integer of 1 to 3; and
    R5 is a hydrogen atom, optionally substituted lower alkyl, etc.;
    its pharmaceutically acceptable salt, or a solvate thereof as an active ingredient.

## Background
TECHNICAL FIELD
The present invention relates to a pharmaceutical composition 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, especially Alzheimer's disease.
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 βprecursor 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 compounds contained in the pharmaceutical composition of the present invention, and the compounds have NO synthase enzyme inhibitory activity and are useful for dementia.
Patent. Literature 2 to 10 describes the compounds which are known as BACE 1 inhibitor, however, have different structures from the compounds contained in the pharmaceutical composition of the present invention.

    [Patent Literature 1] International Patent Application Publication WO96/014842
    [Patent Literature 2] International Patent Application Publication WO02/96897
    [Patent Literature 3] International Patent Application Publication WO04/043916
    [Patent Literature 4] International Patent Application Publication WO2005/058311
    [Patent Literature 5] international Patent Application Publication WO2005/097767
    [Patent Literature 6] International Patent Application Publication WO2006/041404
    [Patent Literature 7] International Patent Application Publication WO2006/041405
    [Patent Literature 8] US Patent Application Publication US2007/0004786
    [Patent Literature 9] US Patent Application Publication US2007/0004730
    [Patent Literature 10] US Patent Application Publication US2007/27199
    [Patent Literature 11] International Patent Application Publication WO2007/049532


DISCLOSURE OF INVENTION
Problems to be Solved by the Invention
The present invention provides pharmaceutical compositions which have reducing effects to produce amyloid β protein, especially BACE 1 inhibitory activity, and which 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 pharmaceutical composition for treating Alzheimer's disease containing a compound represented by the general formula (I):






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






    wherein 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, 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 as an active ingredient,
    (a1) a pharmaceutical composition for treating Alzheimer's disease containing a compound represented by the general formula (I):






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






    wherein 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; R3 is a hydrogen atom; and
    ring A is non-substituted phenyl is excluded,
    its pharmaceutically acceptable salt, or a solvate thereof as an active ingredient,
    (b) the pharmaceutical composition for treating Alzheimer's disease according to (a), wherein X is S,
    (c) the pharmaceutical composition for treating Alzheimer's disease according to (a), wherein n is 2, and m is 0,
    (d) the pharmaceutical composition for treating Alzheimer's disease according to (a), wherein E is a bond,
    (e) a pharmaceutical composition for treating Alzheimer's disease containing 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, R3 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, in 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, and
    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 as an active ingredient,
    (f) the pharmaceutical composition for treating Alzheimer's disease according to (e), wherein X is S,
    (g) the pharmaceutical composition for treating Alzheimer's disease according to (e) or (f), wherein n is 2, and m is 0,
    (h) the pharmaceutical composition for treating Alzheimer's disease 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,
    (i) the pharmaceutical composition for treating Alzheimer's disease according to any one of (e) to (h), wherein R1a is a hydrogen atom; R2b is a hydrogen atom, optionally substituted lower alkyl, optionally substituted acyl, optionally substituted lower alkylsulfonyl, or optionally substituted amidino,
    (j) the pharmaceutical composition for treating Alzheimer's disease according to any one of (e) to (h), wherein NR2aR2b is represented by the formula:






wherein 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;
    (k) the pharmaceutical composition for treating Alzheimer's disease according to any one of (e) to (j), wherein ring A is substituted phenyl,
    (l) the pharmaceutical composition for treating Alzheimer's disease 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,
    (m) the pharmaceutical composition for treating Alzheimer's disease according to (l),
    wherein G is represented by the 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 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,
    (n) the pharmaceutical composition for treating Alzheimer's disease 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 and 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 and an optionally substituted heterocyclic group,
    (o) the pharmaceutical composition for treating Alzheimer's disease according to (m), wherein G is represented by the formula:






wherein, each symbols are the same as described above,

    (p) the pharmaceutical composition for treating Alzheimer's disease according to any one of (e) to (o), wherein R5 is C1 to C3 alkyl,
    (q) the pharmaceutical composition for treating Alzheimer's disease according to any one of (e) to (o), wherein R5 is methyl,
    (r) the pharmaceutical composition for treating Alzheimer's disease according to any one of (e) to (q), wherein
    R3a and R3b are each independently a hydrogen atom, halogen, hydroxy, optionally substituted lower a optionally substituted lower alkoxy or optionally substituted aryl,
    (s) the pharmaceutical composition for treating Alzheimer's disease according to any one of (e) to (q), wherein
    R3a and R3b are both hydrogen atoms,
    (t) the pharmaceutical composition according to any one of (a) to (d) which is the composition for reducing amyloid β production,
    its pharmaceutically acceptable salt, or a solvate thereof as an active ingredient,
    (u) the pharmaceutical composition according to any one of (a) to (d) or (d) which is the composition for treating disease induced by production, secretion and/or deposition of amyloid β protein,
    (v) a method for treating disease induced by production, secretion and/or deposition of amyloid β protein (for example, Alzheimer's disease) comprising administering the compound as defined in any one of formula (I) in above (a),
    its pharmaceutically acceptable salt, or a solvate thereof,
    (w) use of the 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 (for example, Alzheimer's disease),
    (x) 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,
    (y) use of the 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 composition of the present invention is useful as an agent for treating disease such as Alzheimer's disease induced by production, secretion and/or deposition of amyloid β protein.
Additionally, because the pharmaceutical composition of the present invention comprises the compound which has the characteristics: it has high inhibitory activity against BACE-1, it has high selectivity against other enzymes, and the like; as an active ingredient, it can be a medicament whose side effects are reduced. The pharmaceutical composition of the present invention can be a medicament which possess a great safety margin in side effect by comprising an optical active compound which has a suitable conformation as an active ingredient. The pharmaceutical composition of the present invention can be an excellent medicament because it comprises the compound which has the following characteristics as an active ingredient: high metabolic stability, high dissolubility, high oral absorbability, high bioavailability, preferable clearance, high transfer to brain, long half-life, high protein-unbound fraction, low inhibitory activity to hERG channel, low inhibitory activity to CYPs, and/or negative activity in Ames assay.


BEST MODE FOR CARRYING OUT THE INVENTION
As used herein, the “halogen” includes fluorine, chlorine, bromine, and iodine. A halogeno 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 “halogeno lower alkoxy”, the “halogeno lower alkylthio”, the “hydroxy lower alkyl”, the “lower alkoxycarbonyl”, the “halogeno 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), (iv), (vi), (x) (wherein each Q1 is optionally substituted lower alkylene); the group defined as (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; (v), (vii) or (ix), wherein Q2is 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 alkoxyl carbonyl, 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 Q2is 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 acyloxyl” 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, naphthyridinyl, purinyl, pteridinyl, benzopyranyl, benzimidazolyl, benzioxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, pyrazolopyridyl, triazolopyridyl, itnidazothiazolyl, 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, pyrrolinyi, 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 optionally 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 optionally substituted with one or more substituents selected from the group of substituent α, wherein preferable is lower alkoxycarbonyl, halogen and /or halogeno lower alkoxycarbonyl, and the like;
    lower alkynyl optionally substituted with one or more substituents selected from the group of substituent α, wherein preferable is for example, lower alkoxycarbonyl,
    lower alkoxy optionally 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 optionally 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 optionally substituted with one or more substituents selected from the group of substituent α,
    aryl lower alkoxycarbonyl optionally 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 optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl,
    lower alkylsulfinyl optionally substituted with one or more substituents selected from the group of substituent α, sulfamoyl,
    aryl optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl,
    heterocyclic optionally group substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl,
    aryloxy optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl,
    heterocyclicoxy optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl,
    arylthio optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl,
    heterocyclicthio optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl, arylamino optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl,
    heterocyclicamino optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl, aryl lower alkylamino optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl,
    heterocyclic lower alkylamino optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl,
    lower alkyl sulfamoyl optionally substituted with one or more substituents selected from the group of substituent α,
    aryl sulfamoyl optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl,
    heterocyclic sulfamoyl optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl,
    arylsulfonyl optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl,
    heterocyclic sulfomyl optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl,
    aryl carbamoyl optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl,
    heterocyclic carbamoyl optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl,
    aryl lower alkylcarbamoyl optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl,
    heterocyclic lower alkylcarbamoyl optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl,
    aryloxycarbonyl optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl,
    heterocyclicoxycarbonyl optionally 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 optionally 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 substituted with one or more substituents selected from the group of substituent α,
    hydroxyimino lower alkyl;
    lower alkoxyimino lower alkyl;
    lower alkenyl optionally substituted with one or more substituents selected from the group of substituent α;
    lower alkynyl optionally substituted with one or more substituents selected from the group of substituent α;
    lower alkoxy optionally substituted with one or more substutuents selected from the group of substituent α, wherein preferable is halogen, hydroxy, and the like;
    lower alkylthio optionally 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 optionally substituted with one or more substituents selected from the group of substituent α;
    aryl lower alkoxycarbonyl optionally 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 optionally substituted with one or more substituents selected from the group of substituent α;
    sulfamoyl;
    lower alkyl sulfamoyl optionally substituted with one or more substituents selected from the group of substituent α;
    cycloalkyl optionally substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
    aryl optionally substituted with one or more substituents selected from the group of substituent αazido and lower alkyl;
    heterocyclic group optionally 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 optionally substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
    heterocyclicoxy optionally substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
    arylthio optionally 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, and the like;
    heterocyclic thio optionally substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
    arylamino optionally 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 optionally substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
    aryl lower alkylamino optionally 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 optionally substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
    arylsulfamoyl optionally substituted with one or more substituents selected from the group of substituent αazido and lower alkyl;
    heterocyclic sulfamoyl optionally substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
    arylsulfonyl optionally substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
    heterocyclic sulfonyl optionally substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
    arylcarbamoyl optionally substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
    heterocyclic carbamoyl optionally substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
    aryl lower alkylcarbamoyl optionally substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
    heterocyclic lower alkylcarbamoyl optionally substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
    aryloxy carbonyl optionally substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
    heterocyclicoxycarbonyl optionally 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, tetramethylene, 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 in 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 R3c 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 50° C. 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.
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 dihydorgen 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 0) 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 lease 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 hour 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 150° 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 (O-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 are 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, 1,2dimethoxyethane, 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).
Production of optical active compounds
For example, Optical active compound aq, one embodiment of the pharmaceutical composition of the present invention can be synthesized in the following method.
1) n=2
1-1) X=S




wherein R5 is hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, lower alkoxycarbonyl, optionally substituted carbamoyl, an optionally substituted cabocyclic group or an optionally substituted heterocyclic group, R25 is a chiral sulfoxide having optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted carbocyclic group or optionally substituted hetererocyclic group, R3a and R3b are each independently hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxycarbonyl, optionally substituted carbamoyl, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group, optionally substituted acyl, carboxy or optionally substituted amino, R27 is optionally substituted lower alkyl, optionally substituted lower alkenyl, R2a and R2b are each independently hydrogen, 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, L is an leaving group such as halogen, methanesulfonyloxy, trifluoromethylsulfonyloxy and the like, and other symbols are the same as described above.

The above compounds ak and al can be synthesized according to the method described in (1)T, Fujisawa et al., Tetrahedron Lett., 37, 3881-3884 (1996), (2)D. H. Hua et al, Sulfur Reports, vol. 21, pp. 211-239 (1999), (3)Y. Koriyama et al., Tetrahedron, 58, 9621-9628 (2002), (4)T. Vilavan et al, Cuuent Organic Chemistry, 9, 1315-1392 (2005) and the like, or by optical resolution of each intermediate or final compound, or by the method described below. Examples of methods for optical resolution are separation of optical isomers using an optically active column, kinetic resolution by an enzyme reaction or the like, crystallization of diastereomers by salt formulation using a chiral acid or a chiral base, and a preferential crystallization etc.
Step 1
Compound ak can be obtained by reacting Compound aj, which is commercially available or can be prepared by a known method, with a chiral reagent having a substituent corresponding to the target compound such as para-toluene, tert-butylsulfine amide or the like at 60° C. to 120° C., preferably 80° C. to 100° C. in a solvent such as ether, tetrahydrofuran, toluene, benzene or the like or a mixed solvent such as ether-tetrahydrofuran or the like for 0.5 to 24 hours, preferably 0.5 to 5 hours in the presence of moleculer sieves or magnesium sulfate or the like, under continuous evaporation by Dean-Stark apparatus, or in the presence of a chiral reagent having a substituent corresponding to the target compound such as para-toluene, tert-butylsulfine amide ane the like according to the method described in the above literatures.
Step 2
Compound al can be diastereoselectively obtained by reacting compound ak with a metal, which is lithium, aluminum, zinc, titanium or the like, enolate of acetate ester or the like possessing a substituent corresponding to the target compound which is commercially available or prepared by a known method, at −100° C. to 0° C., preferably −80° C. to −50° C. for 0.5 to 24 hours, preferably 0.5 hours in a solvent such as ether, tetrahydrofuran, toluene, methylene chloride or a mixed solvent of ethertetrahydrofuran or the like, or obtained according to the method described in the above literature (1) or (3). Alternatively, ketenesilyl acetate of acetate ester which is prepared from ester acetate or the like possessing a substituent corresponding to the target compound can be used.
Step 3
Compound am can be obtained by reacting Compound al in a solvent such as methanol, ethanol ether, tetrahydrofuran, 1,4-dioxane, methylene chloride, ethyl acetate or the like, which contains hydrogen chloride, trifluoroacetic acid or the like, or in trifluoroacetcic acid without a solvent, or at −30° C. to 100° C., preferably −10° C. to 90° C. for 0.5 to 12 hours, preferably 0.5 to 5 hours.
Step 4
To a solution of Compound am in a solvent such as ether, tetrahydrofuran, toluene or the like or a mixed solvent such as ether-tetrahydrofuran is added a reductant such as a boran-tetrahydrofuran complex, a boran-dimethylsulfide complex, a boran-triethylamine complex, a boran-pyridine complex or the like, or ether of tetrahydrofuran solution of them at −30° C. to 30° C., preferably −10° C. to 20° C. and the mixture is reacted for 0.5 to 12 hours, preferably 0.5 to 5 hours to obtain Compound an.
Step 5
To a solution of Compound an in a solvent such as methylene chloride, toluene or the like or a mixed solvent of methylene chloride-water or the like is added calcium carbonate, potassium carbonate or the like, and added thiophosgene at −30° C. to 50° C., preferably −10° C. to 25° C., followed by reacting for 0.5 to 12 hours, preferably 0.5 to 5 hours to obtain Compound ao.
Step 6
To a solution of Compound ao in a solvent such as methylene chloride, tetrahydrofuran, toluene or the like are added oxalyl chloride, thionyl chloride or the like and a catalytic amount of N,N-dimethylformamide at −30° C. to 50° C., preferably −10° C. to 20° C. The mixture is reacted at 0° C. to 100° C., preferably 20° C. to 90° C. for 0.5 to 12 hours, preferably 0.5 to 5 hours to obtain Compound ap. Alternatively, Compound ap can be obtained by halogenation according to the method described in Comprehensive Organic Transformations, Richard C Larock (Mcgraw-Hill) or by reacting Compound ao with a sulfonylation reagent such as methanesulfonyl chloride, p-toluene sulfonyl chloride or the like in the presence of a base such as diisopropylethylamine, triethylamine or the like in a solvent such as toluene, dichloromethane or 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.
Step 7
To a solution of Compound ap in a solvent such as ethyl acetate, methylene chloride, tetrahydrofuran, toluene or the like is added 15 to 30% aqueous ammonia or a reagent having a substituent corresponding to the target compound such as tert-butyl amine at −30° C. to 50° C., preferably −10° C. to 30° C. The mixture is reacted at −10° C. to 30° C., preferably 0° C. to 30° C. for 0.5 to 72 hours to obtain Compound aq-i or Compound aq-ii.
In the case that thus-obtained Compound aq-i or Compound aq-ii is a compound wherein R2a and/or R2b is hydrogen, the target substituent R2a or R2b can be introduced by the usual method, if necessary.
1-2) Introduction of R3a and R3b 




wherein each symbols are the same as described above.

To obtain Compound aq-iii or aq-iv wherein R3a and R3b are substituted at the carbon atom neighboring to X, R3a and R3b may be introduced by conducting Step 3′ and Step 4′ instead of Step 3 and Step4.
Step 3′
To a solution of Compound al in a solvent such as ether, tetrahydrofuran or the like or a mixed solvent such as ether-tetrahydrofuran or the like is added a Grignard reagent having a substituent corresponding to the target compound such as methyl magnesium chloride, ethyl magnesium bromide or the like at −100° C. to 50° C., preferably −80° C. to 30° C. to obtain Compound am′. Alternatively, after conversion of Compound al to Weinreb amide thereof, the compound is reacted sequentially with a Grignard reagent having a substituent corresponding to the target compound such as R3 a MgBr, R3 b MgBr or the like to obtain Compound am′, The reaction may be conducted for 0.2 to 24 hours, preferably 0.2 to 5 hours.
Step 4′
Compound an′ can be synthesized according to the above-mentioned Step 3. Compound an can be obtained by reacting Compound am′ in a solvent such as methanol, ethanol, ether, tetrahydrofuran, 1,4-dioxane, methylene chloride, ethyl acetate or the like which includes hydrogen chloride, trifluoroacetic acid or the like, without a solvent, or in trifluoroacetic acid without a solvent at −30° C. to 100° C., preferably −10° C. to 90° C. for 0.5 to 12 hours, preferably 0.5 to 5 hours.
Then, the target Compound aq-iii or aq-iv can be obtained by conducting the similar methods to Steps 5 to 7 mentioned in the above 1-1),
1-3) X═O




wherein R28 is alkyl or optionally substituted alkylsulfonyl, optionally substituted carbocyclic sulfonyl or optionally substituted heterocyclic sulfonyl and other symbols are the same as described above.

The target compound can be obtained by conducting the following steps instead of Steps 5 to 7 described in the above 1-1).
Step 5′
Compound ao′ can be obtained by reacting Compound an′ with an isothiocyanate having the substituent corresponding to the target compound such as ally isothiocyanate, tert-butylisothiocyanate or the like or a thiocarbamoyl halide having the substituent corresponding to the target compound such as N,N-dimethylthiocarbamoyl chloride, N,N-diethylthiocarbamoyl chloride or the like in a solvent such as toluene, chloroform, tetrahydrofuran or 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.
Step 6′
Compound ap′′ can be obtained by reacting Compound ao′ with an alkylating agent such as methyl iodide, diethyl sulfate, benzylbromide or the like or a sulfonating agent such as p-toluensulfonyl chloride in the presence or absence of a base such as diisopropylethylamine, triethylamine, pyridine, sodium hydroxide or the like in a solvent such as methanol, ethanol, dimethylformamide, tetrahydrofuran or 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.
Step 7
Compound aq-v or aq-vi can be obtained by reacting Compound ap′ in the presence or absence of a base such as diisopropylethylamine, triethylamine, pyridine, sodium hydroxide or the like, in the presence or absence of a metallic oxide such as silver oxide, mercury oxide, manganese dioxide or the like, in a solvent such as dimethylformamide, tetrahydrofuran, dichloromethane or 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.
1-4) X═N




wherein each symbols are the same as described above.

Step 6′′

Compound ap′′′ can be obtained by reacting Compound ao′ with an azidation agent such as sodium azide, trimethylsillylazide or the like in the presence or absence of an acid such as trifluoroacetic acid or the like in a solvent such as chloroform, tetrahydrofuran or the like at −10° C. to 200° C., preferably 0° C. to 100° C. for 0.1 to 48 hours, preferably 0.5 to 24 hours.
Step 7′
Compound ar can be obtained by reacting Compound ap′′′ with an alkylating agent such as methyl iodide, diethyl sulfate, benzylbromide or the like or a sulfonating agent such as p-toluensulfonyl chloride in the presence or absence of a base such as diisopropylethylamine, triethylamine, pyridine, sodium hydroxide or the like in a solvent such as methanol, ethanol, dimethylformamide, tetrahydrofuran or 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.
Step 8′′
To a solution of Compound ar in a solvent such as tetrahydrofuran, ethyl acetate, methanol or the like is added a catalytic reduction catalyst such as 10% Pd/C, and the mixture is reacted under hydrogen atmosphere at normal pressures to 5 atm, preferably at normal pressure to 2 atm at 10° C. to 100° C., preferably 20° C. to 80° C. for 0.5 to 48 hours, preferably 6 to 20 hours to obtain Cyclized Compound aq-vii or aq-viii. Alternatively, Cyclized Compound aq-vii or aq-viii can be obtained by reducing a azide group of Compound or by the method described in “Comprehensive Organic Transformations, Richard C Larock (Mcgraw-Hill)”. If necessary, the compound obtained by reduction may be treated with a base such as triethylamine, sodium hydroxide or the like to obtain Compound aq-vii or aq-viii.
2) n=3




wherein the each symbols are the same as defined above.

Step 2′′

Compound al′ can be obtained by reacting Compound ak with a Grignard reagent having a substituent corresponding to the target compound such as an allyl Grignard reagent in a solvent such as ether, tetrahydrofuran, toluene or the like or a mixed solvent such as ether-tetrahydrofuran at −80° C. to 50° C., preferably −40° C. to 30° C. for 0.5 to 12 hours, preferably 0.5 to 8 hours.
Step 3′′
Compound an′′ can be obtained by hydroboration, wherein Compound al′ is reacted with a reductant such as a boran-tetrahydrofuran complex, a boran-dimethylsulfide complex, a boran-triethylamine complex, a boran-pyridine complex or the like or an ether or tetrahydrofuran solution of them in a solvent such as ether, tetrahydrofuran, toluene or the like or a mixed solvent such as ether-tetrahydrofuran or the like at −30° C. to 30° C., preferably −15° C. to 20° C. for 0.5 to 12 hours, preferably 0.5 to 5 hours.
Substituents R3a and R3b can be introduced into thus-obtained Compound an′′ by the method according to the above-mentioned 1-2).
3) Conversion of Substituents (1)




wherein R13a and R13b are amino-protecting groups and the other symbols are the same as defined above.

Synthesis of Compound as-1

To a solution of Compound aq-1 in a solvent such as tetrahydrofuran, toluene, xylene or the like are added trisdibenzyliden acetone dipalladium, palladium acetate or palladium(0) prepared in situ and a phosphine ligand such as tri-tert-butylphosphine, dicyclohexylbiphenyl phosphine or the like, and further added a reagent having the substituent corresponding to the target compound such as lithium hexamethyl disilazide at −10° C. to 30° C., followed by reacting at 30° C. to 120° C., preferably 50° C. to 100° C. for 0.5 to 48 hours, preferably 3 to 20 hours to obtain Compound as-1.
An amino protecting group may be a group which is deprotected by the method described in “Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons)” etc. and the examples are lower alkoxy-carbonyl, lower alkenyloxycarbonyl, trialkylsillyl, acyl, methansulfonyl, trifiuoroethansulfonyl, toluensulfonyl and the like.
4) Conversion of Substituent (2)




Synthesis of Compound as-2

To a solution of aq-2 in a solvent such as tetrahydrofuran, ethyl acetate, methanol or the like is added a catalytic reduction catalyst such as 10% Pd/C, and then the mixture is reacted at normal pressure to 5 atm, preferably normal pressure to 2 atm under hydrogen atmosphere for 0.5 to 48 hours, preferably 6 to 20 hours to obtain Compound as-2. Alternatively. Compound as-2 can be obtained by the method described in “Comprehensive Organic Transformations, Richard C Larock (McGraw-Hill)”.
5) Conversion of Substituent (3)




wherein R14 is hydroxy, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkylthio, optionally substituted lower amino, optionally substituted aromatic carbocyclicoxy or heterocyclic oxy, optionally substituted aromatic carbocyclicamino or heterocyclic amino, optionally substituted aromatic carbocyclicthio or heterocyclicthio, cyano, azide, optionally substituted carbocyclic group, optionally substituted heterocyclic group, optionally substituted carbamoyl or the like and the other symbols are the same as defined above.

Synthesis of Compound as-3

To a solution of Compound aq-3 in a solvent such as tetrahydrofuran, ethanol or the like is added a reagent having the substituent corresponding to the target compound such as ethanol, methanethiol, dimethyl amine or the like at −10° C. to 30° C. and the mixture is reacted for 0.5 to 12 hours, preferably 1 to 8 hours to obtain Compound as-3.
Then, the similar reaction described in the above “4) Conversion of substituent (2)” may be conducted, and further a coupling reaction may be conducted according to the above-mentioned method for producing Compound (I-19), if necessary.
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′),




    wherein, 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 non-substituted phenyl;
    ii) wherein n is 2, no 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 are phenyl;
    v) wherein n is 2, m is 0, R2a and R2b are a hydrogen atom, R5 and ring A are taken together to form






    and
    vi) wherein n+m is 1 or 2; R5 is a hydrogen atom; and 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 carbocyclic 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 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
    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;






    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:






    wherein 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:






    wherein 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:






    wherein G is defined in 16), ring B is optionally substituted phenyl, optionally substituted 5- to 6-membered heteroaryl, optionally substituted benzothiazolyl or optionally substituted benzothienyl, and 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:






    wherein 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): and 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, R3a 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(s) 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, 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,R 2-1,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,R2-1,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,A5,R 5-2,R3-2),(nm-1,R2-1,A-5,R5-3,R3-1),(nm-1,R2-1,A-5,R5-3,R3-2),(nm1,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,R5-2,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,R3-1), (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-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-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,R5-2,R3-1),(nm-1,R2-1,A-10,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-10,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,R5-2,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,R 3-2),(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,R5-2,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,R5-3,R3-1),(nm-1,R2-2,A-4,R5-3,R3-2),(nm-1,R2-2,A-5,R5-1,R3-1),(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,R5-1,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-R2,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-8R5-3,R3-2,(nm-1,R2-2,A-9,R5-1),R3-1),(nm-1,R2-2,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-10,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,R2-2,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-1 1,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,R3-2),(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,R3-2),(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,R3-1),(nm-1,R2-3,A-5,R5-3,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,R2-3,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,R5-3,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),(nm-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,R2-3,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-1 4,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,R2-4,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,R5-1,R3-2),(nm-1,R2-4,A-7,R5-2,R3-1),(nm-1,R2-4A-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,R3-1),(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-1 0,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 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    (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,R2-1,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,R5-2,R3-2),(nm-2,R2-1,A-6,R5-3,R3-1),(nm-2,R2-1,A-6,R5-3,R3-2),(nm-2,R2-1,A-7,R5-1,R3-1),(nm-2,R2-1,A-7,R5-1,R3-2),(nm-2,R2-1,A-7,R5-2,R3-1),(nm-2,R2-1,A-7,R5-2,R3-2),(nm-2,R2-1,A-7,R5-3,R3-1),(nm-2,R2-1,A-7,R5-3,R3-2),(nm-2,R2-1,A-8,R5-1,R3-1), (nm-2,R2-1,A-8,R5-1,R3-2),(nm-2,R2-1,A-8,R5-2,R3-1),(nm-2,R2-1,A-8,R5-2,R3-2),(nm-2,R2-1,A-8,R5-3,R3-1),(nm-2,R2-1,A-8,R5-3,R3-2),(nm-2,R2-1,A-9,R5-1,R3-1),(nm-2,R2-1,A-9,R5-1,R3-2),(nm-2,R2-1,A-9,R5-2,R3-1),(nm-2,R2-1,A-9,R5-2,R3-2),(nm -2,R2-1,A-9,R5-3,R3-1),(nm-2,R2-1,A-9,R5-3,R3-2),(nm-2,R2-1,A-10,R5-1,R3-1),(nm-2,R2-1,A-10,R5-1,R3-2),(nm-2,R2-1,A-10,R5-2,R3-1),(nm-2,R2-1,A-10,R5-2,R3-1),(nm-2,R2-1,A-10,R5-3,R3-1),(nm-2,R2-1,A-10,R5-3,R3-2),(nm-2,R2-1,A-11,R5-1,R3-1),(nm-2,R2-1,A-11,R5-1,R3-2),(nm-2,R2-1,A-11,R5-2,R3-1),(nm-2,R2-1,A-11,R5-2,R3-2), (nm-2,R2-1,A-11,R5-3,R3-1),(nm-2,R2-1,A-11,R5-3,R3-2),(nm-2,R2-1,A-12,R5-1,R3-1),(nm-2,R2-1,A-12,R5-1,R3-2),(nm-2,R2-1,A-12,R5-2),(R3-1),(nm-2,R2-1,A-12,R5-2,R3-2),(nm-2,R2-1,A-12,R5-3,R3-1),(nm-2,R2-1,A-12,R5-3,R3-2),(nm-2,R2-1,A-13,R5-1,R3-1),(nm-2,R2-1,A-13,R5-1,R3-2),(nm-2,R2-1,A-13,R5-2,R3-1),(nm-2,R2-1,A-13,R5-2,R3-2),(nm-2,R2-1,A-13,R5-3,R3-1),(nm-2,R2-1,A-13,R5-3,R3-2),(nm-2,R2-1,A-14,R5-1,R3-1),(nm-2,R2-1,A-14,R5-1,R3-2),(nm-2,R2-1,A-14,R5-2,R3-1),(nm-2,R2-1,A-14,R5-2,R3-2),(nm-2,R2-1,A-14,R5-3,R3-1),(nm-2,R2-1,A-14,R5-3,R3-2),(nm-2,R2-2,A-1,R5-1,R3-1),(nm-2,R2-2,A-1,R5-1,R3-2),(nm-2,R2-2,A-1,R5-2,R3-1),(nm-2,R2-2,A-1,R5-2,R3-2),(nm-2,R2-2,A-1,R5-3,R3-1),(nm-2,R2-2,A-1,R5-3,R3-2),(nm-2,R2-2,A-2,R5-1,R3-1),(nm-2,R2-2,A-2,R5-1,R3-2),(nm-2,R2-2,A-2,R5-2,R3-1),(nm-2,R2-2,A-2,R5-2,R3-2),(nm-2,R2-2,A-2,R5-3,R3-1),(nm-2,R2-2,A-2,R5-3,R3-2),(nm-2,R2-2,A-3,R5-1,R3-1),(nm-2,R2-2,A-3,R5-1,R3-2),(nm-2,R2-2,A-3,R5-2,R3-1),(nm-2,R2-2,A-3,R5-2,R3-2),(nm-2,R2-2,A-3,R5-3,R3-1),(nm-2,R2-2,A-3,R5-3,R3-2),(nm-2,R2-2,A-4,R5-1,R3-1), (nm-2,R2-2,A-4,R5-1,R3-2),(nm-2,R2-2,A-4,R5-2,R3-1),(nm-2,R2-2,A-4,R5-2,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,R3-1),(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,R2-2,A-9,R5-1,R3-2),(nm-2,R2-2,A-9,R5-2,R3-1),(nm-2,R2-2,A-9,R5-2,R2-2),(nm-2,R2-2,A-9,R3,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,R2-2,A-10,R5-3,R3-1),(nm-2,R2-2,A-10,R5-3,R3-2),(nm-2,R2-2,A-11,R5-1,R3-1),(nm-2,R2-2,A-1 1,R5-1,R3-2),(nm-2,R2-2,A-11,R5-2,R3-1),(nm-2,R2-2,A-11,R5-2,R3-2),(nm-2,R2-2,A 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(nm-2,R2-3,A-8,R5-2,R3-1),(nm-2,R2-3,A-8,R5-2,R3-2),(nm-2,R2-3,A-8,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,R5-3,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,R2-3,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),(mn-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-1 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    (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,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 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(nm-3,R2-1,A-8,R5-1,R3-2),(nm-3,R2-1,A-8,R5-2,R3-1),(nm-3,R2-1,A-8,R5-2,R3-2),(nm-3,R2-1,A-8,R5-3,R3-1),(nm-3,R2-1,A-8,R5-3,R3-2),(nm-3,R2-1,A-9,R5-1,R3-1),(n m-3,R2-1,A-9,R5-1,R3-2),(nm-3,R2-1,A-9,R5-2,R3-1),(nm-3,R2-1,A-9,R5-2,R3-2),(nm -3,R2-1,A-9,R5-3,R3-1),(nm-3,R2-1,A-9,R5-3,R3-2),(nm-3,R2-1,A-10,R5-1,R3-1),(nm-3,R2-1,A-10,R5-1,R3-2),(nm-3,R2-1,A-10,R5-2,R3-1),(nm-3,R2-1,A-10,R5-2,R3-2),(nm-3,R2-1,A-10,R5-3,R3-1),(nm-3,R2-1,A-10,R5-3,R3-2),(nm-3,R2-1,A-11,R5-1,A-11,R5-1,R3-1),(nm3,R2-1,A-11,R5-1,R3-2),(nm-3,R2-1,A-11,R5-2,R3-1),(nm-3,R2-1,A-11,R5-2,R3-2), (nm-3,R2-1,A-11,R5-3,R3-1),(nm-3,R2-1,A-11,R5-3,R3-2),(nm-3,R2-1,A-12,R5-1,R3-1),(nm-3,R2-1,A-12,R5-1,R3-2),(nm-3,R2-1,A-12,R5-2,R3-1),(nm-3,R2-1,A-12,R5-2,R3-2),(nm-3,R2-1,A-12,R5-3,R3-1),(nm-3,R2-1,A-12,R5-3,R3-2),(nm-3,R2-1,A-13,R5-1,R3-1),(nm-3,R2-1,A-13,R5-1,R3-2),(nm-3,R2-1,A-13,R5-2,R3-1),(nm-3,R2-1,A-13,R5-2,R3-2),(nm-3,R2-1,A-13,R5-3,R3-1),(nm-3,R2-1,A-13,R5-3,R3-2),(nm-3,R2-1,A-14,R5-1,R3-1),(nm-3,R2-1,A-14,R5-1,R3-2),(nm-3,R2-1,A-14,R5-2,R3-1),(nm-3,R2-1,A-14,R5-2,R3-2),(nm-3,R2-1,A-14,R5-3,R3-1),(nm-3,R2-1,A-14,R5-3,R3-2),(nm-3,R2-2,A-1,R5-1,R3-1),(nm-3,R2-2,A-1,R5-1,R3-2),(nm-3,R2-2,A-1,R5-2,R3-1),(nm-3,R2-2,A-1,R5-2,R3-2),(nm-3,R2-2,A-1,R5-3,R3-1),(nm-3,R2-2,A-1,R5-3,R3-2),(nm-3,R2-2,A-2,R5-1,R3-1),(nm-3,R2-2,A-2,R5-1,R3-2),(nm-3,R2-2,A-2,R5-2,R3-1),(nm-3,R2-2,A-2,R5-2,R3-2),(nm-3,R2-2,A-2,R5-3,R3-1),(nm-3,R2-2,A-2,R5-3,R3-2),(nm-3,R2-2,A-3,R5-1,R3-1),(nm-3,R2-2,A-3,R5-1,R3-2),(nm-3,R2-2,A-3,R5-2,R3-1),(nm-3,R2-2,A-3,R5-2,R3-2),(nm-3,R2-2,A-3,R5-3,R3-1),(nm-3,R2-2,A-3,R5-3,R3-2),(nm-3,R2-2,A-4,R5-1,R3-1), (nm-3,R2-2,A-4,R5-1,R3-2),(nm-3,R2-2,A-4,R5-2,R3-1),(nm-3,R2-2,A-4,R5-2,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,R3-1),(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,R5-3-1),(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,R2-2,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,R2-2,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-1 1,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,R3-2),(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),(n m-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,R3-2),(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,R3-1),(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),(mn-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,R2-3,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,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,R5-3,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,R3-3,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,R2-3,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-1 4,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,R2-4A-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,R2-4,A-4,R5-1,R3-2),(nm-3,R2-4,A-4,R5-2,R3-1),(nm-3,R2-4,A-4,R5-2),(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,R5-1,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-8R5-1,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,R3-1),(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-1 0,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,R5-1,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), and (nm-3,R2-4,A-14,R5-3,R3-3).


In the 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
Reference 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 dry ice-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 35 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, filtrate was evaporated under reduced pressure, and the compound (1-3)(3,00 g) was obtained as a 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 a 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 (1-4)(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)
Reference 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 thiocyanate (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 thiocyanate (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 bicarbonate 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), 7.82-7.95 (2H, m)
Step 2
The compound (2-2)(842 mg) was dissolved into ethano (8.4 ml), sodium dihydrogen phosphate and an aqueous solution of sodium borohydride (113.2 mg) in 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 a crude product.
Step 3
To a solution of compound (23)(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 with stirring, and then stirred for 1 hour at the same temperature. 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 a 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 a crude product.
Reference Example 3
The Synthesis of Compound 561




Step 1

To tetrahydrofuran (30 ml) under cooling with ice-water bath with stirring, lithium aluminum 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(1H, t, J=7.6 Hz), 7.40(2H, t, J=7.6 Hz), 7.48(2H, t, J=7.6 Hz).
Reference 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 a crude product.
Step 2
To a solution of the compound (4-2)(0.71 g) in tetrahydrofuran (10 ml), lithium aluminum 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 a 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 5 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 (4-5)(0.06 g),
1H-NMR(CDCl3): 1.35(9H, s), 1.59(3H, s), 1.91(1H, ddd, J=13.5, 8.8, 5.0 Hz), 2.06(1H, dt, J=13.5, 5.0 Hz), 3.00(1H, ddd, J=15.1, 8.8, 5.0 Hz), 3.30(1H, dt, J=15.1, 5.0 Hz), 7.24-7.38(5H, m).
Step 5
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,), 6.12(1H, br), 6,65(1H, br), 7.21-7.24(1H, m), 7.31-7,37(4H, m).
Reference Example 5
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, 5), 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-dry ice 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, s), 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).
Reference 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 a 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).
Reference Example 7
The Synthesis of Compound 69




Step 1

A solution of the compound (7-1)(1.93 g), diphenylphosploryl 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,), 3.48-3.56(1H, 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-NM(CDCl3): 1.79(3H, s), 1.82-2.20(2H, 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 a 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).
Reference 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 a crude product.
Step 2
To the suspension of lithium aluminum 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 filtrate 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 a 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 TLC), 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, 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 a 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 the filtrate 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)
Reference 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).
Reference 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 a 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, 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,) 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)
Reference 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,), 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,), 3.84 (3H, s), 7.10-7.27 (3H, m), 7.76 (3H, br s), 8.26 (1H, br s), 9.42 (1H, s)
Reference 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-azahenzotriazo-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 (6H, m), 1.87-1.98 (1H, m), 2.09-2.19(1H, m), 2.91-2.97 (2H, m), 3.64-3.68 (4H,), 6.73 (1H, d, J=4.05 Hz), 7.14(1H, d, J=4.05 Hz)
Reference 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), 2.76(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-d6): 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)
Reference 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).
Reference 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, s), 10.72(1H, s).
Reference 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 s)
Reference Example 17
The Synthesis of Compound 597




Step 1

The solution of compound (17-1)(135 mg), O-metbxylhydroxylamine 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).
Reference Example 18
The Synthesis of Compounds 134 and 135







Step 1

The compound (18-1) (2020 mg) was dissolved into chloroform (20 ml), and water (4 ml) and sodium thiocyanate(1470 mg) were added to the solution with stirring at room temperature. Sulfuric acid (1.94 ml) was added dropwise to the reaction mixture under cooling with ice-water bath. After the addition was completed, the reaction mixture was warmed to room temperature and then stirred for 345 minutes, then stirred at 60° C. for overnight. Because the compound (18-1) was remained (checked by TLC), the reaction mixture was cooled to room temperature, then sodium thiocyanate (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. A saturated sodium bicarbohydrate 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 under reduced pressure and the obtained residue was subjected to silica gel chromatography to afford the compound (18-2) (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 m), 7.82-7.95 (2H, m)
Step 2
The compound (18-2) (842 mg) was dissolved into ethanol (8.4 ml). Sodium dihydrogen phosphate(1600 mg) and sodium borohydride (113.2 mg) in water (2.8 ml) were added to the solution successively under cooling with ice-water bath with stirring, and the mixture was stirred for 30 minutes at the same temperature. After the consumption of the compound (18-2) (checked by TLC), ethyl acetate and water were added to the 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 and brine successively, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford the compound (18-3) (904.8 mg) as a crude product.
Step 3
To a stirring solution of the compound (18-3) (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 stirred for 1 hour at the same temperature. After the consumption of the compound (18-3)(checked by TLC), the reaction solution was concentrated under reduced pressure to afford the compound (18-4)(1076.8 mg) as a crude product.
Step 4
The compound (18-4) (1070 mg) was dissolved into ca. 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 (18-4)(checked by TLC), the reaction solution was concentrated under reduced pressure to afford the compound (18-5) (2633 mg) as a crude product.
Step 5
The compound (18-5)(2633 mg) was dissolved into tetrahydrofuran (10 ml), and 4-dimethylaminopyridine (43.2 mg) and di-t-butyl dicarbonate (0.976 ml) were added to the solution successively under cooling with ice-water bath with stirring. The reaction mixture was warmed to room temperature and then stirred for 260 minutes. Because the compound (18-5) was remained (checked by TLC) in the reaction solution, di-t-butyl dicarbonate (0.488 ml) was added to the reaction mixture at room temperature and then stirred at the same temperature for overnight. After, addition of water, 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 under reduced pressure and the obtained residue was subjected to silica gel column chromatography to afford the compound (18-6a) (99.6 mg) and the compound (18-6b) (183.2 mg).
18-6a: 1H-NMR(CDCl3, 400 MHz): 1.49 (9H, s), 1.80 (3H, s), 2.22 (1H, t, J=13.6 Hz), 2.36 (1H, dd, J=14.2, 3.4 Hz), 4.63 (1H, dd, J=12.6, 3.4 Hz), 7.27-7.47 (10H, m)
18-6b: 1H-NMR(CDCl3, 400 MHz): 1.53 (9H, s), 1.72 (3H, s), 2.34 (1H, t, J=13.0 Hz), 2.66 (1H, dd, J=14.0, 2.5 Hz), 3.86 (1H, dd, J=12.4, 2.5 Hz), 7.20-7.45 (10H, m)
Step 6
The compound (18-6a) (99.6 mg) was dissolved into a 4 mol/L hydrogen chloride in 1,4-dioxane solution (4 ml) on ice bath, and the mixture was warmed to room temperature and then stirred for 6 days. After the consumption of the compound (18-6a) (checked by LC-MS), the reaction mixture was concentrated under reduced pressure. The obtained residue was crystallized from dichloromethane-ethyl acetate, and the crystals were collected by filtration and washed with ethyl acetate to afford the compound (441) (52.4 mg).
1H-NMR(DMSO-d6, 400 MHz): 1.83 (3H, s), 2.43 (1H, t, J=13.2 Hz), 2.55 (1H, dd, J=14.0, 2.8 Hz), 5.10 (1H, dd, J=12.4, 2.8 Hz), 7.34-7.48 (6H, m), 7.53-7.57 (4H,
Step 7
The compound (18-6b) (183 mg) was dissolved into a 4 mol/L of hydrogen chloride in 1,4-dioxane solution (8 ml) on ice bath, and the mixture was warmed to room temperature and then stirred for 6 days. Because the compound (18-6b) was remained. (checked by LC-MS), 4 mol/L of hydrogen chloride in 1,4-dioxanesolution (2 ml) was added to the reaction mixture at room temperature, and then the mixture was stirred at 40° C. for overnight. The reaction mixture was concentrated under reduced pressure, a saturated sodium bicarbonate aqueous solution was added to be basic condition, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the obtained residue was subjected to silica gel column chromatography and crystallized from dichloromethane-diisopropyl ether. The crystals were collected by filtration and washed with diisopropyl ether to afford the compound (835) (32,2. mg).
1H-NMR(CDCl3, 400 MHz): 1.64 (3H, s), 1.95 (1H, t, J=13.2 Hz), 2.52 (1H, dd, J=13.8, 3.0 Hz), 3.84 (1H, dd, J=12.6, 3.0 Hz), 4.16-4.76 (2H, br), 7.20-7.39 (10H, m)
Reference Example 19







Step 1

After the compound (19-1) was added dropwise to sulfuric acid (279 ml) under cooling on acetonitrile/dry ice bath with stirring, the mixture of fuming nitric acid (42 ml) and sulfuric acid (98 ml) was added dropwise to the mixture. After stirred for 16 minutes, the reaction mixture was gradually added into ice. The precipitated crystals were collected by filtration and dried to afford the compound (19-2) (77.79 g).
1H-NMR (CDCl3) δ: 2.71 (3H, d, J=4.9 Hz), 7.34 (1H, t, J=9.3 Hz), 8.40 (1H, ddd, J=9.3, 6.2, 3.0 Hz), 8.78 (1H, dd, J=6.2, 3.0 Hz).
Step 2
After the mixed solution of the compound (19-2) (73.94 g), (R)-(+)-2-methyl-2-propane sulfinamide (53.82 g) and tetraethyl orthotitanate (230.20 g) in tetrahydrofuran (500 ml) was heated and refluxed for 2.5 hours. The reaction mixture was gradually poured into ice and the precipitated insoluble was removed by filtration. The filtrate was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was crystallized from ethyl acetate/ n-hexane to afford the compound (19-3) (85.44 g).
1H-NMR. (CDCl3) δ: 1.34 (9H, s), 2.81 (3H, d, J=3.5 Hz), 7.29 (1H, t, J=8.9 Hz), 8.31 (1H, dt, J=8.9, 2.9 Hz), 8.55 (1H, dd, J=6.3, 2.9 Hz).
Step 3
A solution of t-butyl acetate (6.08 g) in tetrahydrofuran (10 ml) was added dropwise to a solution of 2M lithium diisopropylamide in tetrahydrofuran/n-heptane/ethyl benzene (27.9 ml) under cooling on acetone/dry ice bath with stirring. After stirred for 20 minutes, a solution of chlorotitanium triisopropoxide (17.5 ml) in tetrahydrofuran (30 ml) was added dropwise to the mixture. The mixture was stirred for 1 hour and a solution of the compound (19-3) (5.00 g) in tetrahydrofuran (10 ml) was added dropwise to the mixture. After reacted for 1 hour, the mixture was gradually poured into an aqueous solution of ammonium chloride under cooling on ice-water bath with stirring, and the precipitated insoluble was removed by filtration. The filtrate was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel chromatography to afford the compound (19-4) (5.49 g).
1H-NMR (CDCl3) δ: 1.30 (9H, s), 1.35 (9H, s), 1.86 (3H, s), 3.11 (1H, dd, J=16.2, 2.1 Hz), 3.26 (1H, dd, J=16.2, 2.1 Hz), 5.55 (1H, s), 7.18 (1H, dd, J=11.1, 8.9 Hz), 8.18 (1H, ddd, J=8.9, 4.0, 2.9 Hz), 8.53 (1H, dd, J=7.0, 2.9 Hz).

    Ration of diastereomers: S:R97/3, HPLC Column: AS-RH, Detection: 254 nm: Column temp.: 25° C., Mobile phase: 40% MeCNaq., Flow rate: 0.5 ml/min.
    
        It is known that stereochemistry of the obtained compound (19-4) is preferentially afforded (S) isomer as described in Literature A, and each of diastereomers can be arbitrarily synthesized by using appropriate metal species or reaction conditions.

Literature A

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

Step 4



To the compound (19-4) (12.74 g) was added a solution of 4M hydrochloric acid in 1,4-dioxane (50 ml). After the mixture was stirred at 80° C. for 1 hour, diethyl ether (50 ml) was added to the mixture. The precipitated crystals were collected by filtration, and dried to afford the compound (19-5) (7.67 g),
1H-NMR (DMSO-d6) δ: 1.76 (3H, s), 3.25 (2H, s), 7.62 (1H, dd, J=11.4, 9.4 Hz),
Step 5
To a stirred solution of the compound (19-5) (141.32 g) in tetrahydrofuran (707 ml) was added dropwise a solution of 1M boran tetrahydrofuran complex in tetrahydrofuran (2029 ml) under cooling on ice-water bath. After reacted for 3 hours 6 minutes, the mixture was added into the mixture of sodium bicarbonate (511 g), ice (1500 g) and ethyl acetate (3000 ml) at room temperature with stirring. The mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to afford the compound (19-6) (115.46 g) as a crude product.
Step 6
To the compound (19-6) (3.76 g) obtained in Step 5 was added toluene (25 ml) and water (12.5 ml), Potassium carbonate (7.97 g) and thiophosgene (2.85 g) was added to the stirring mixture subsequently under cooling on ice-water bath After reacted for 3 hours, water was added to the mixture and extracted with toluene, and the organic layer was dried over anhydrous magnesium sulfate, and a part of the solvent was removed under reduced pressure to afford the compound (19-7) as a crude product.
Step 7
To a stirred solution of the compound (19-7) obtained in Step 6 in toluene (17.4 ml) was added thionyl chloride (6.67 g) and N,N-dimethylformamide (0.128 ml) at room temperature. After stirred for 2 hours at 80° C., water was added to the mixture and extracted with toluene. Solvent was evaporated under reduced pressure to afford the compound (19-8) (4.03 g).
Step 8
To a stirred solution of the compound (19-8) (4.03 g) from Step 7 in tetrahydrofuran (23.8 ml) was added,28% aqueous ammonia (23.8 ml) on ice bath, and the mixture was stirred at room temperature for 3 days. The solvent of the reaction mixture was evaporated under reduced pressure, and then ethyl acetate was added. Hydrochloric acid (6 ml) was added to the stirred mixture under cooling with ice-water bath, and the precipitated crystals were washed with ethyl acetate and water, then dried to afford the compound (19-9) (2.14 g).
1H-NMR. (DMSO-d6) δ: 1.76 (3H, s), 2.13-2.24 (1H, m), 2.68-2.74 (2H, m), 3.19-3.25 (1H, m), 7.63 (1H, dd, 11.4, 8.9 Hz), 8.07 (1H, dd, J=7.0, 3.5 Hz), 8.36 (1H, dt, J=8.9, 3.5 Hz), 11.22 (1H, s).
Step 9
The compound (19-9) (100 mg) was dissolved into methanol (2 ml), 10% palladium carbon powder (50 mg) was added and then stirred at room temperature for 18 hours. The insoluble was removed by filtration, the solvent of the filtrate was removed under reduced pressure. Sodium carbonate and water were added to the mixture. The mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate, and a solvent was evaporated under reduced pressure to afford the compound (19-10) (68 mg).
Reference Example 20







Step 1

The compound (20-1) (9.13 g) and 3′-bromoacetopherione (15.0 g) were dissolved into tetrahydrofuran (250 ml), and tetraethoxy titanium (39.5 ml) was added to the solution at room temperature with stirring and then stirred at 75° C. for 5 hours. After the consumption of the compound (20-1), brine was added to the mixture. The precipitated titanium oxide was removed by filtration, and the filtrate was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography to afford the compound (20-2) (20.1 g).
1H-NMR(CDCl3): 1.33 (9H, s), 2.75 (3H, s), 7.30 (1H, t. J=7.8) 7.59-7.63 (1H, m), 7.79 (1H, d, J=7.8) 8.0 (1H, s).
Step 2
To a solution of diisopropylamine (42.1 ml) tetrahydrofuran (100 ml) was added dropwise n-butyl lithium in hexane solution (2.64 M, 79.5 ml) at −78° C. under nitrogen atmosphere. After stirred at. 0° C. for 30 minutes, the mixture was cooled to −78° C. again and a solution of t-butyl acetate (26.9 ml) in tetrahydrofuran (100 ml) was added dropwise to the mixture. After stirred −78° C. for 30 minutes, chloro(triisopropoxy)titanium in tetrahydrofuran (150 ml) was added dropwise to the mixture. The mixture was stirred at the same temperature for 70 minutes, the compound (2) (20.1 g) in tetrahydrofuran (100 ml) was added dropwise to the mixture and stirred at −78° C. for 3 hours. After the consumption of the compound (20-2), an aqueous solution of ammonium chloride was added. The precipitated titanium oxide was removed by filtration and the filtrate was extracted with ethyl acetate. The organic layer was washed with brine, then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to afford the compound (20-3) as a crude product (26.4 g).
Step 3
The crude product of the compound (20-3) (26.4 g) was dissolved into toluene (80 ml) and added dropwise to a 1.0 M diisobuty aluminum hydride in toluene (253 ml) with stirring at 0° C. The reaction mixture was stirred at room temperature for 1.5 hours. After the consumption of the compound (20-3), a 1M hydrochloric acid aqueous solution was added. The mixture was extracted with ethyl acetate, the organic layer was washed with brine, then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by crystallization to afford the compound (20-4) (18.1 g),
1H-NMR(CDCl3):1.28(9H,s,),1.71(3H,s),2.19-2.24(2H,m),3.27-3.32(1H,m),3.54-3.66(1H, m), 3.87-3.97 (1H, m), 5.10-5.11(1H, m), 7.22 (1H, t, 7.32-7.41 (2H, m), 7.56-7.58 (1H, m)
Step 4
The compound (20-4) (18.1 g) was dissolved into methanol (130 ml) and a 10% hydrochloric acid-methanol solution (130 ml) was added to the solution with stirring at room temperature. Then, the reaction mixture was stirred at room temperature for 4 hours. After consumption of the compound (20-4), a 1M hydrochloric acid aqueous solution was added. The mixture was washed with ethyl acetate, the aqueous layer was neutralized with a 2M sodium hydroxide aqueous solution and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to afford the crude product of the compound (20-5) (14.1 g).
Step 5
The crude product of the compound (20-5) (32.8 g) and potassium carbonate (37.1 g) were dissolved into a mixed solvent of toluene (450 ml) and water (225 ml), and thiophosgene (15.3 ml) was added dropwise to the mixture with stirring at 0° C. The reaction mixture was stirred at 0° C. for 1 hour. After consumption of the compound (20-5), water was added. After the mixture was extracted with ethyl acetate, the organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford the crude product of the compound (20-6) (38.4 g).
Step 6
The crude product of the compound (20-6) (38.4 g) was dissolved into toluene (384 ml), and thionyl chloride (29.4 ml) and N,N-dimethylformamide (1.04 ml) were added dropwise to the solution with stirring at 0° C. The reaction mixture was stirred at 80° C. for 5 hours. After consumption of the compound (6), the solvent was evaporated under reduced pressure to afford the crude product of the compound (20-7) (40.9 g).
Step 7
The crude product of the compound (20-7) (40.9 g) was dissolved into tetrahydrofuran (250 ml), and 25% aqueous ammonia (250 ml) was added dropwise to the solution at 0° C. The reaction mixture was stirred at room temperature for 16 hours. After consumption of the compound (6), a saturated solution of sodium hydrogencarbonate was added. The organic layer was separated and the aqueous solution was extracted with dichloromethane. The combined organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to afford the crude product of the compound (20-8) (38.3 g).
Step 8
The crude product of the compound (20-8) (38.3 g) was dissolved into tetrahydrofuran (383 ml), and di-t-butyl dicarbonate (61.5 g) and N,N-dimethylaminopyridine (1.64 g) were added to the solution, and the mixture was stirred at room temperature for 72 hours. After consumption of the compound (20-8), the solvent was evaporated under reduced pressure and the residue was subjected to silica gel chromatography to afford the compound (20-9) (45.3 g).
1H-NMR(CDCl3): 1.54 (9H, s,), 1.57 (3H, s), 1.96 (2H, t, 2.80-2.92(1H, m), 3.00-3.13 (1H, m), 7.21 (1H, t, J=8.1) 7.28-7.41 (2H, m), 7.52-7.55 (1H, m).
Step 9
The compound (20-9) (12.1 g), tris dibenzylidene acetone dipalladium (1.14 g) and dicyclohexyl biphenyl phosphine (0.88 g) were dissolved into toluene (125 ml) under nitrogen atmosphere, and a solution of 1.6M lithium hexamethyl disilazide in tetrahydrofuran (46.9 ml) was added with stirring at room temperature. The reaction mixture was warmed to 80° C. and then stirred for 16 hours. After consumption of the compound (20-9), the mixture was cooled to 0° C. and diethyl ether and a 1M hydrochloric acid aqueous solution were added. After stirring at 0° C. for 10 minutes, the mixture was neutralized by the addition of a saturated aqueous solution of sodium carbonate. The mixture was extracted with ethyl acetate, the organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was subjected to silica gel chromatography to afford the compound (20-10) (6.84 g).
1H-NMR(CDCl3): 1.51 (9H, s,), 1.69 (3H, s), 2.01-2.12 (1H, m), 2.40-2.51(1H, m), 2.67-2.76 (2H, m), 6.55-6.67 (3H, m), 7.15 (1H, t, J=8.1)
Reference Example
The Synthesis of Compound 241




Indazole-3-carboxylic acid (71 mg) and the compound (19-10) (100 mg) were dissolved into methanol (5 ml), and 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylnmorpholinium chloride (173 mg) was added to the mixture with stirring at room temperature. The mixture was stirred for 5 hours. The reaction was quenched by the addition of brine, and the reaction mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and then concentrated. The crude product was purified by silica gel chromatography (NH2-silica gel, 2-8% MeOH/CHCl3) to afford the compound (241) (66 mg).
1H-NMR (DMSO-d6) δ: 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).
Reference Example 22
The Synthesis of Compound 702




1-methylpyrazole-5-carboxylic acid (80 mg) and the compound (19-10) (145 mg) were dissolved into methanol (3 ml), and 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride (251 mg) was added to the mixture with stirring at room temperature, and the mixture was stirred for 5 hours. The reaction was quenched by addition of brine, and the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and concentrated. The crude product was purified by silica gel chromatography (NH2-silica gel, 0-4% MeOH/CHCl3) to afford the compound (702) (146 mg).
1H-NMR (CDCl3) δ: 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).
Reference Example 23
The Synthesis of the Compound 737




3-chloro-1-methylpyrazole-5-carboxylic acid (102 mg) and the compound (19-10) (145 mg) were dissolved into methanol (3 ml), and 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride (251 mg) was added to the mixture with stirring at room temperature, and the mixture was stirred for 5 hours. The reaction was quenched by addition of brine, and the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and concentrated to afford crude product. The crude product was purified by silica gel chromatography (NH2-silica gel, 33-78% AcOEt/Hexane) to afford the compound (737) (51 mg).

1H-NMR (CDCl3) δ: 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, s).
Reference Example 24
The Synthesis of the Compound 949




5-fluoro-2-pyridine carboxylic acid (70.7 mg) was dissolved into methanol (2 ml), and 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride (180.1 mg) was added to the mixture with stirring at room temperature. The mixture was stirred for 5 minutes and a solution of the compound (19-10) (119.9 mg) in methanol (2 ml) was added to the reaction solution with stirring under cooling with ice-water bath. After stirred for 3 hours, a 0.5M aqueous solution of sodium hydroxide was added to the mixture with stirring under cooling with ice-water bath, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to silica gel chromatography to afford the compound (949) (149.4 mg).
1H-NMR (CDCl3) δ: 1.63 (3H, s), 1.82-2.00 (1H, m), 2.43-2.58 (1H, m), 2.72-2.82 (1H, m), 2.95-3.02 (1H, m), 7.06 (1H, dd, J=11,7, 9.0 Hz), 7.43-7.48 (1H, m), 7.97-8.03 (1H, m), 8.15-8.18 (1H, m), 8.42 (1H, d, J=8.1 Hz),8.72 (1H, s), 9.91 (1H, br s)
Reference Example 25
The Synthesis of the Compound 943




5-trifluoromethyl-2-pyridine carboxylic acid (95.7 mg) was dissolved into methanol (2 ml), and 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride (180.1 mg) was added to the solution with stirring at room temperature. After stirring for 5 minutes, a solution of the compound (19-10) (119.9 mg) in methanol (2 ml) was added to the reaction mixture with stirring under cooling with ice-water bath. After stirring for 3 hours, a 0.5N aqueous solution of sodium hydroxide was added with stirring under cooling with ice-water bath, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel chromatography to afford the compound (943) (174.5 mg).
1H-NMR (CDCl3) δ: 1.63 (3H, s), 1.82-2.00 (1H, m), 2.36-2.52 (1H, m), 2.72-2.82 (1H, m), 2.95-3.02 (1H, m), 7.07 (1H, dd, J=11.7, 8.1 Hz), 7.39-7.42 (1H, m), 7.55-7.63 (1H, m), 7.96-8.02 (1H,), 8.33 (1H, dd, J=4.8, 9.0 Hz),8.45 (1H, d, J=2.4 Hz), 9.78 (1H, s).
Reference Example 26
The Synthesis of the Compound 578




Step 1

To a stirred solution of 2,5-dimethylfuran carboxylic acid (115 mg) and the compound (20-10) (290 mg) in methanol (2 ml) was added 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride (273 mg) at room temperature. After stirring for 2 hours, the reaction was quenched by addition of a saturated aqueous solution of sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The mixture was washed with water and brine successively, dried and concentrated to afford crude product (300 mg). The crude product was purified by silica gel chromatography (silica gel, 50-66% AcOEt/hexane) to afford the compound (26-1) (221 mg).
1H-NMR (CDCl3) δ: 7.64-7.60 (1.0H, m), 7.43-7.41 (2.0H, m), 7.35 (1.0H, t, J=7.93 Hz), 7.04-7.02 (1.0H, m), 6.17 (1.0H, s), 2.80-2.61 (2.0H, m), 2.59(3.0H, s), 2.56-2.52 (1.0H, m), 2.30 (3.0H, s), 2.19-2.06 (1.0H, m), 1.71 (3.0H, s), 1.52 (9.0H, s).
Step 2
The compound (26-1) (221 mg) was dissolved into dichloroethane (1 ml) and trifluoroacetic acid (1 ml) was added to the solution with stirring at room temperature. After stirring for 1 hour 10 minutes, the solvent was evaporated. Ethyl acetate and an aqueous solution of sodium carbonate were added to the residue and the mixture was stirred for 1 hour. The mixture was extracted with ethyl acetate and washed with an aqueous solution of sodium carbonate, water and brine successively. The organic layer was dried, and concentrated to afford crude product (154 mg). The crude product was purified by recrystallization (hexane/AcOEt) to afford the compound (578) (24 mg).
(1H-NMR (CDCl3) δ: 7.79 (1.0H, br s), 7.65-7.64 (1.0H, m), 7.48-7.41 (1.0H, m), 7.31 (1.0H, t, J=8.01 Hz), 7.04-7.01 (1.0H, m), 6.23 (1.0H, br s), 2.93-2.65 (2.0H, m), 2.57 (3.0H, br s), 2.40 (1.0H, ddd, J=14.11, 5.34, 3.43 Hz), 2.27 (3.0H, br s), 2.09-1.92 (1.0H, m), 1.67 (3.01H, s).
Reference Example 27
The Synthesis of the Compound 472




The compound (27-1) (256 mg) and 3-amino-5-chloropicolinic acid hydrochloride (266 mg) were suspended in methanol (2.6 ml), and N-methylmorpholine (153 μl) was added to the suspension, and the mixture was stirred at room temperature. After stirred for 6 minutes, 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride (385 mg) was added to the mixture, and stirred for 1 hour 10 minutes, and left to stand for 13 hours 20 minutes additionally. The solvent was evaporated, and ethyl acetate, methanol and an aqueous solution of sodium carbonate were added to the residue and stirred for 40 minutes. The aqueous layer was removed, the organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over magnesium sulfate. The magnesium sulfate was removed by filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (Yamazen HI-FLASH column NH2-40W-M, ethyl acetate:hexane=1:1). The obtained fraction was concentrated and the residue was crystallized from ethyl acetate. The crystals were collected by filtration, washed with diethyl ether and dried to afford the compound (472) (82.0 mg).
1H-NMR (DMSO-d6) δ: 1.41 (3H, s), 1.72 (1H, ddd, J=13.7, 10.2, 3.6 Hz), 2.02 (1H, m), 2.58 (1H, m), 2.90 (1H, ddd, J=11.9, 6,6, 3.6 Hz), 5.77 (2H, brs), 7.09 (1H, dt, J=7.9, 1.3 Hz), 7.13 (2H, brs), 7.27 (1H, t, J=8.0 Hz), 7.33 (1H, d, J=2.2 Hz), 7.68-7.72 (2H, m), 7.85 (1H, d, J=2.0 Hz), 10.23 (1H, s).
The other compounds were synthesized in the same way. The structural formulas and physical constants are shown below.










TABLE 1







No.
Structure









1







 



2







 



3







 



4







 



5







 



6







 



7







 



8







 



9






















TABLE 2





No.
Structure
















10






 


11






 


12






 


13






 


14






 


15






 


16






 


17






 


18





















TABLE 3





No.
Structure
















19






 


20






 


21






 


22






 


23






 


24






 


25






 


26






 


27






 


28





















TABLE 4





No.
Structure
















29






 


30






 


31






 


32






 


33






 


34






 


35






 


36






 


37






 


38






 


39





















TABLE 5





No.
Structure
















40






 


41






 


42






 


43






 


44






 


45






 


46






 


47





















TABLE 6





No.
Structure
















48






 


49






 


50






 


51






 


52






 


53






 


54






 


55





















TABLE 7





No.
Structure
















56






 


57






 


58






 


59






 


60






 


61






 


62






 


63






 


64






 


65





















TABLE 8





No.
Structure
















66






 


67






 


68






 


69






 


70






 


71






 


72






 


73






 


74





















TABLE 9





No.
Structure
















75






 


76






 


77






 


78






 


79






 


80






 


81






 


82





















TABLE 10





No.
Structure
















83






 


84






 


85






 


86






 


87






 


88






 


89






 


90






 


91





















TABLE 11





No.
Structure
















92






 


93






 


94






 


95






 


96






 


97






 


98






 


99






 


100






 


101





















TABLE 12





No.
Structure
















102






 


103






 


104






 


105






 


106






 


107






 


108






 


109





















TABLE 13





No.
Structure
















110






 


111






 


112






 


113






 


114






 


115






 


116






 


117






 


118






 


119





















TABLE 14





No.
Structure
















120






 


121






 


122






 


123






 


124






 


125






 


126






 


127






 


128






 


129





















TABLE 15





No.
Structure
















130






 


131






 


132






 


133






 


134






 


135






 


136






 


137






 


138






 


139





















TABLE 16





No.
Structure
















140






 


141






 


142






 


143






 


144






 


145






 


146






 


147





















TABLE 17





No.
Structure
















148






 


149






 


150






 


151






 


152






 


153






 


154






 


155






 


156






 


157





















TABLE 18





No.
Structure
















158






 


159






 


160






 


161






 


162






 


163





















TABLE 19





No.
Structure
















164






 


165






 


166






 


167






 


168






 


169






 


170






 


171






 


172






 


173






 


174





















TABLE 20





No.
Structure
















175






 


176






 


177






 


178






 


179






 


180






 


181






 


182






 


183






 


184






 


185





















TABLE 21 





No.
Structure
















186






 


187






 


188






 


189






 


190






 


191






 


192






 


193






 


194





















TABLE 22





No.
Structure
















195






 


196






 


197






 


198






 


199






 


200






 


201






 


202






 


203






 


204





















TABLE 23





No.
Structure
















205






 


206






 


207






 


208






 


209






 


210






 


211






 


212





















TABLE 24





No.
Structure
















213






 


214






 


215






 


216






 


217






 


218






 


219






 


220






 


221






 


222





















TABLE 25





No.
Structure
















223






 


224






 


225






 


226






 


227






 


228






 


229






 


230






 


231






 


232





















TABLE 26





No.
Structure
















233






 


234






 


235






 


236






 


237






 


238






 


239






 


240






 


241






 


242






 


243





















TABLE 27





No.
Structure
















244






 


245






 


246






 


247






 


248






 


249






 


250






 


251






 


252






 


253





















TABLE 28





No.
Structure
















254






 


255






 


256






 


257






 


258






 


259






 


260






 


261






 


262






 


263






 


264





















TABLE 29





No.
Structure
















265






 


266






 


267






 


268






 


269






 


270






 


271






 


272






 


273





















TABLE 30





No.
Structure
















274






 


275






 


276






 


277






 


278






 


279






 


280






 


281





















TABLE 31





No.
Structure
















282






 


283






 


284






 


285






 


286






 


287






 


288






 


289






 


290






 


291





















TABLE 32





No.
Structure
















292






 


293






 


294






 


295






 


296






 


297






 


298






 


299





















TABLE 33





No.
Structure
















300






 


301






 


302






 


303






 


304






 


305






 


306






 


307






 


308






 


309





















TABLE 34





No.
Structure
















310






 


311






 


312






 


313






 


314






 


315






 


316






 


317





















TABLE 35





No.
Structure
















318






 


319






 


320






 


321






 


322






 


323






 


324






 


325






 


326






 


327






 


328





















TABLE 36





No.
Structure
















329






 


330






 


331






 


332






 


333






 


334






 


335






 


336






 


337






 


338






 


339





















TABLE 37





No.
Structure
















340






 


341






 


342






 


343






 


344






 


345






 


346






 


347






 


348





















TABLE 38





No.
Structure
















349






 


350






 


351






 


352






 


353






 


354






 


355






 


356






 


357





















TABLE 39





No.
Structure
















358






 


359






 


360






 


361






 


362






 


363






 


364






 


365






 


366






 


367






 


368






 


369





















TABLE 40





No.
Structure
















370






 


371






 


372






 


373






 


374






 


375






 


376






 


377






 


378





















TABLE 41





No.
Structure
















379






 


380






 


381






 


382






 


383






 


384






 


385






 


386






 


387






 


388






 


389





















TABLE 42





No.
Structure
















390






 


391






 


392






 


393






 


394






 


395






 


396






 


397





















TABLE 43





No.
Structure
















398






 


399






 


400






 


401






 


402






 


403






 


404






 


405






 


406






 


407





















TABLE 44





No.
Structure
















408






 


409






 


410






 


411






 


412






 


413






 


414






 


415






 


416





















TABLE 45





No.
Structure
















417






 


418






 


419






 


420






 


421






 


422






 


423






 


424





















TABLE 46





No.
Structure
















425






 


426






 


427






 


428






 


429






 


430






 


431






 


432






 


433





















TABLE 47





No.
Structure







434






 


435






 


436






 


437






 


438






 


439






 


440






 


441 (race mate)






 


442





















TABLE 48





No.
Structure
















443






 


444






 


445






 


446






 


447






 


448






 


449






 


450






 


451






 


452






 


453





















TABLE 49





No.
Structure
















454






 


455






 


456






 


457






 


458






 


459






 


460






 


461






 


462






 


463






 


464





















TABLE 50





No.
Structure
















465






 


466






 


467






 


468






 


469






 


470






 


471






 


472






 


473






 


474





















TABLE 51





No.
Structure
















475






 


476






 


477






 


478






 


479






 


480






 


481






 


482






 


483





















TABLE 52





No.
Structure
















484






 


485






 


486






 


487






 


488






 


489






 


490






 


491






 


492





















TABLE 53





No.
Structure
















493






 


494






 


495






 


496






 


497






 


498






 


499






 


500






 


501






 


502






 


503





















TABLE 54





No.
Structure
















504






 


505






 


506






 


507






 


508






 


509






 


510






 


511






 


512






 


513






 


514





















TABLE 55





No.
Structure
















515






 


516






 


517






 


518






 


519






 


520






 


521






 


522






 


523






 


524





















TABLE 56





No.
Structure
















525






 


526






 


527






 


528






 


529






 


530






 


531






 


532






 


533






 


534






 


535





















TABLE 57





No.
Structure
















536






 


537






 


538






 


539






 


540






 


541






 


542






 


543






 


544






 


545






 


546





















TABLE 58





No.
Structure
















547






 


548






 


549






 


550






 


551






 


552






 


553






 


554






 


555





















TABLE 59





No.
Structure
















556






 


557






 


558






 


559






 


560






 


561






 


562






 


563






 


564






 


565






 


566





















TABLE 60





No.
Structure
















567






 


568






 


569






 


570






 


571






 


572






 


573






 


574





















TABLE 61





No.
Structure
















575






 


576






 


577






 


578






 


579






 


580






 


581






 


582






 


583






 


584





















TABLE 62





No.
Structure
















585






 


586






 


587






 


588






 


589






 


590






 


591





















TABLE 63





No.
Structure
















592






 


593






 


594






 


595






 


596






 


597






 


598






 


599






 


600






 


601






 


602





















TABLE 64





No.
Structure
















603






 


604






 


605






 


606






 


607






 


608






 


609






 


610






 


611






 


612






 


613





















TABLE 65





No.
Structure
















614






 


615






 


616






 


617






 


618






 


619






 


620






 


621






 


622






 


623






 


624





















TABLE 66





No.
Structure
















625






 


626






 


627






 


628






 


629






 


630






 


631






 


632






 


633






 


634






 


635





















TABLE 67





No.
Structure
















636






 


637






 


638






 


639






 


640






 


641






 


642






 


643





















TABLE 68





No.
Structure
















644






 


645






 


646






 


647






 


648






 


649






 


650






 


651






 


652






 


653






 


654






 


655






 


656





















TABLE 69





No.
Structure
















657






 


658






 


659






 


660






 


661






 


662






 


663






 


664






 


665





















TABLE 70





No.
Structure
















666






 


667






 


668






 


669






 


670






 


671






 


672






 


673






 


674





















TABLE 71





No.
Structure
















675






 


676






 


677






 


678






 


679






 


680






 


681






 


682






 


683





















TABLE 72





No.
Structure
















684






 


685






 


686






 


687






 


688






 


689






 


690






 


691






 


692





















TABLE 73





No.
Structure
















693






 


694






 


695






 


696






 


697






 


698






 


699






 


700






 


701






 


702





















TABLE 74





No.
Structure
















703






 


704






 


705






 


706






 


707






 


708






 


709






 


710






 


711






 


712





















TABLE 75





No.
Structure
















713






 


714






 


715






 


716






 


717






 


718






 


719





















TABLE 76





No.
Structure
















720






 


721






 


722






 


723






 


724






 


725






 


726






 


727






 


728






 


729





















TABLE 77





No.
Structure
















730






 


731






 


732






 


733






 


734






 


735






 


736






 


737






 


738






 


739





















TABLE 78





No.
Structure
















740






 


741






 


742






 


743






 


744






 


745






 


746






 


747






 


748






 


749





















TABLE 79





No.
Structure
















750






 


751






 


752






 


753






 


754






 


755






 


756






 


757






 


758






 


759





















TABLE 80





No.
Structure
















760






 


761






 


762






 


763






 


764






 


765






 


766






 


767






 


768






 


769





















TABLE 81





No.
Structure
















770






 


771






 


772






 


773






 


774






 


775






 


776






 


777





















TABLE 82





No.
Structure
















778






 


779






 


780






 


781






 


782






 


783






 


784






 


785






 


786






 


787






 


788






 


789





















TABLE 83





No.
Structure
















790






 


791






 


792






 


793






 


794






 


795






 


796






 


797






 


798





















TABLE 84





No.
Structure
















799






 


800






 


801






 


802






 


803






 


804






 


805






 


806






 


807






 


808






 


809





















TABLE 85





No.
Structure
















810






 


811






 


812






 


813






 


814






 


815






 


816






 


817






 


818





















TABLE 86





No.
Structure
















819






 


820






 


821






 


822






 


823






 


824






 


825






 


826






 


827





















TABLE 87





No.
Structure







828






 


829






 


830






 


831






 


832






 


833






 


834






 


835 (race mate)






 


836





















TABLE 88





No.
Structure
















837






 


838






 


839






 


840






 


841






 


842






 


843






 


844






 


845





















TABLE 89





No.
Structure
















846






 


847






 


848






 


849






 


850






 


851






 


852






 


853






 


854






 


855





















TABLE 90





No.
Structure
















856






 


857






 


858






 


859






 


860






 


861






 


862






 


863






 


864





















TABLE 91





No.
Structure
















865






 


866






 


867






 


868






 


869






 


870






 


871






 


872






 


873






 


874





















TABLE 92





No.
Structure
















875






 


876






 


877






 


878






 


879






 


880






 


881






 


882





















TABLE 93





No.
Structure
















883






 


884






 


885






 


886






 


887






 


888






 


889






 


890






 


891





















TABLE 94





No.
Structure
















892






 


893






 


894






 


895






 


896






 


897






 


898






 


899






 


900






 


901





















TABLE 95





No.
Structure
















902






 


903






 


904






 


905






 


906






 


907






 


908






 


909






 


910






 


911






 


912





















TABLE 96





No.
Structure
















913






 


914






 


915






 


916






 


917






 


918






 


919






 


920





















TABLE 97





No.
Structure
















921






 


922






 


923






 


924






 


925






 


926






 


927






 


928






 


929






 


930





















TABLE 98





No.
Structure
















931






 


932






 


933






 


934






 


935






 


936






 


937






 


938





















TABLE 99





No.
Structure
















939






 


940






 


941






 


942






 


943






 


944






 


945






 


946






 


947





















TABLE 100 





No.
Structure
















948






 


949






 


950






 


951






 


952






 


953






 


954






 


955





















TABLE 101





No.
Structure
















956






 


957






 


958






 


959






 


960






 


961






 


962






 


963





















TABLE 102





No.
Structure
















964






 


965






 


966






 


967






 


968






 


969






 


970





















TABLE 103





No.
Structure
















971






 


972






 


973






 


974






 


975






 


976






 


977





















TABLE 104





No.
Structure
















978






 


979






 


980






 


981






 


982






 


983






 


984






 


985






 


986





















TABLE 105





No.
Structure
















987






 


988






 


989






 


990






 


991






 


992






 


993






 


994






 


995





















TABLE 106





No.
Structure
















996






 


997






 


998






 


999






 


1000






 


1001






 


1002






 


1003






 


1004





















TABLE 107





No.
Structure
















1005






 


1006






 


1007






 


1008






 


1009






 


1010






 


1011






 


1012






 


1013





















TABLE 108





No.
Structure
















1014






 


1015






 


1016






 


1017






 


1018






 


1019






 


1020






 


1021





















TABLE 109





No.
Structure
















1022






 


1023






 


1024






 


1025






 


1026






 


1027






 


1028






 


1029






 


1030





















TABLE 110





No.
Structure
















1031






 


1032






 


1033






 


1034






 


1035






 


1036






 


1037






 


1038






 


1039





















TABLE 111





No.
Structure
















1040






 


1041






 


1042






 


1043






 


1044






 


1045






 


1046






 


1047






 


1048





















TABLE 112





No.
Structure
















1049






 


1050






 


1051






 


1052






 


1053






 


1054






 


1055






 


1056






 


1057





















TABLE 113





No.
Structure
















1058






 


1059






 


1060






 


1061






 


1062






 


1063






 


1064






 


1065






 


1066






 


1067





















TABLE 114





No.
Structure
















1068






 


1069






 


1070






 


1071






 


1072






 


1073






 


1074






 


1075





















TABLE 115





No.
Structure
















1076






 


1077






 


1078






 


1079






 


1080






 


1081






 


1082






 


1083






 


1084






 


1085





















TABLE 116





No.
Structure
















1086






 


1087






 


1088






 


1089






 


1090






 


1091






 


1092






 


1093






 


1094





















TABLE 117





No.
Structure
















1095






 


1096






 


1097






 


1098






 


1099






 


1100






 


1101






 


1102





















TABLE 118





No.
Structure
















1103






 


1104






 


1105






 


1106






 


1107






 


1108






 


1109






 


1110






 


1111





















TABLE 119





No.
Structure
















1112






 


1113






 


1114






 


1115






 


1116






 


1117






 


1118





















TABLE 120





No.
Structure
















1119






 


1120






 


1121






 


1122






 


1123






 


1124






 


1125






 


1126






 


1127






 


1128





















TABLE 121





No.
Structure
















1129






 


1130






 


1131






 


1132






 


1133






 


1134






 


1135






 


1136





















TABLE 122





No.
Structure
















1137






 


1138






 


1139






 


1140






 


1141






 


1142






 


1143






 


1144






 


1145






 


1146





















TABLE 123





No.
Structure
















1147






 


1148






 


1149






 


1150






 


1151






 


1152






 


1153






 


1154






 


1155






 


1156





















TABLE 124





No.
Structure
















1157






 


1158






 


1159






 


1160






 


1161






 


1162






 


1163






 


1164





















TABLE 125





No.
Structure
















1165






 


1166






 


1167






 


1168






 


1169






 


1170






 


1171






 


1172






 


1173





















TABLE 126





No.
Structure
















1174






 


1175






 


1176






 


1177






 


1178






 


1179






 


1180






 


1181






 


1182






 


1183





















TABLE 127





No.
Structure
















1184






 


1185






 


1186






 


1187






 


1188






 


1189






 


1190






 


1191






 


1192






 


1193






 


1194





















TABLE 128





No.
Structure
















1195






 


1196






 


1197






 


1198






 


1199






 


1200






 


1201






 


1202






 


1203





















TABLE 129





No.
Structure
















1204






 


1205






 


1206






 


1207






 


1208






 


1209






 


1210






 


1211






 


1212





















TABLE 130





No.
Structure
















1213






 


1214






 


1215






 


1216






 


1217






 


1218






 


1219






 


1220






 


1221





















TABLE 131





No.
Structure
















1222






 


1223






 


1224






 


1225






 


1226






 


1227






 


1228






 


1229






 


1230






 


1231





















TABLE 132





No.
Structure
















1232






 


1233






 


1234






 


1235






 


1236






 


1237






 


1238






 


1239






 


1240






 


1241






 


1242





















TABLE 133





No.
Structure
















1243






 


1244






 


1245






 


1246






 


1247






 


1248






 


1249






 


1250






 


1251






 


1252





















TABLE 134





No.
Structure
















1253






 


1254






 


1255






 


1256






 


1257






 


1258






 


1259






 


1260






 


1261





















TABLE 135





No.
Structure
















1262






 


1263






 


1264






 


1265






 


1266






 


1267






 


1268






 


1269






 


1270






 


1271






 


1272






 


1273





















TABLE 136





No.
Structure
















1274






 


1275






 


1276






 


1277






 


1278






 


1279






 


1280






 


1281






 


1282




























TABLE 137








MS
UV


No.
mp (° C.)
1H-NMR(δ)
(m/z)
(λ max: 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

δ 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) δ: 1.76 (3H, s), 2.02 (1H, s), 2.58
365[M + 1]




(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 138








MS
UV


No.
mp (° C.)
1H-NMR(δ)
(m/z)
(λ max: 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





298
206






216


96



309


97

δ 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

δ 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 =
344[M + 1]




13.85, 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 139








MS
UV


No.
mp (° C.)
1H-NMR(δ)
(m/z)
(λ max: 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

δ 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

δ 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 140








MS
UV


No.
mp (° C.)
1H-NMR(δ)
(m/z)
(λ max: 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




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),


224
oil
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) δ: 1.59 (3H, s), 1.83-1.90 (1H,
378[M + 1]




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




m), 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) δ: 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 141








MS
UV


No.
mp (° C.)
1H-NMR(δ)
(m/z)
(λ max: 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), 2.46-

229




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


383[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 =

301




12.2, 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 142








MS
UV


No.
mp (° C.)
1H-NMR(δ)
(m/z)
(λ max: 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
167-188


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), 2.65-

267




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 143








MS
UV


No.
mp (° C.)
1H-NMR(δ)
(m/z)
(λ max: 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 144








MS
UV


No.
mp (° C.)
1H-NMR(δ)
(m/z)
(λ max: 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
181-165


443

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




m), 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 145








MS
UV


No.
mp (° C.)
1H-NMR(δ)
(m/z)
(λ max: 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




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


446
oil
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

δ 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 146








MS
UV


No.
mp (° C.)
1H-NMR(δ)
(m/z)
(λ max: nm)



















494

δ 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

δ 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, 60, 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 147








MS
UV


No.
mp (° C.)
1H-NMR(δ)
(m/z)
(λ max: 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

δ 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

δ 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

δ 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 148








MS
UV


No.
mp (° C.)
1H-NMR(δ)
(m/z)
(λ max: 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

δ 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 149








MS
UV


No.
mp (° C.)
1H-NMR(δ)
(m/z)
(λ max: 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

δ 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

δ 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

δ 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 150








MS
UV


No.
mp (° C.)
1H-NMR(δ)
(m/z)
(λ max: 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) δ: 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
187-169




















TABLE 151








MS
UV


No.
mp (° C.)
1H-NMR(δ)
(m/z)
(λ max: nm)



















730



211.0






289.9


731
91-94


732
amorphous


211


735
166-168


737

1H-NMR (CDCl3) δ: 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

δ 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
362[M + 1]
213




(3H, s), 2.37-2.42 (1H, m), 2.70-2.75 (1H, m), 2.96-

263




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) δ: 1.77 (3H, s), 2.11-2.21 (1H,
400[M + 1]




m), 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








MS
UV


No.
mp (° C.)
1H-NMR(δ)
(m/z)
(λ max: 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

δ 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








MS
UV


No.
mp (° C.)
1H-NMR(δ)
(m/z)
(λ max: 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, 287


835
139-140


836



221.6






279.3


840
223-225


848
oil


223, 254


849
143-145


850

δ 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








MS
UV


No.
mp (° C.)
1H-NMR(δ)
(m/z)
(λ max: nm)







875
oil


222, 271


876
oil


222


878
oil


211


881
141-144


887



262.7


892
251 (dec.)


893

δ 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

δ 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








MS
UV


No.
mp (° C.)
1H-NMR(δ)
(m/z)
(λ max: 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

δ 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








MS
UV


No.
mp (° C.)
1H-NMR(δ)
(m/z)
(λ max: 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
262-287


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








MS
UV


No.
mp (° C.)
1H-NMR(δ)
(m/z)
(λ max: 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 =

318




12.3, 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 =

284




12.2, 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
187-170
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








MS
UV


No.
mp (° C.)
1H-NMR(δ)
(m/z)
(λ max: 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








MS
UV


No.
mp (° C.)
1H-NMR(δ)
(m/z)
(λ max: 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

δ 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

δ 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








MS
UV


No.
mp (° C.)
1H-NMR(δ)
(m/z)
(λ max: nm)







1263

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





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




1.77(1H, 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) δ: 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(δ in d6-DMSO): 1.43(3H, s), 1.70-
369[M + 1]




1.81(1H, 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) δ: 1.82-1.91 (1H, m), 2.04 (3H,
338[M + 1]




s), 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) δ: 1.62 (3H, s), 1.89 (1H, t, J =
327[M + 1]




12.3 Hz), 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) δ: 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(δ in d6-DMSO): 1.41(3H, s), 1.65-
397[M + 1]




1.75(1H, 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








MS
UV


No.
mp (° C.)
1H-NMR(δ)
(m/z)
(λ max: 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) δ: 1.58 (3H, s), 1.89 (1H, t, J =
395[M + 1]




11.2 Hz), 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) δ: 1.61 (3H, s), 1.84-1.93 (1H,
327[M + 1]




m), 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) δ: 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) δ: 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) δ: 1.73 (3H, s), 2.04 (1H, dt, J =
328[M + 1]




18.2, 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(δ in d6-DMSO): 1.42(3H, s), 1.68-
426[M + 1]




1.82(1H, 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(δ in d6-DMSO): 1.40(3H, s), 1.30-
427[M + 1]




1.50(2H, 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





 
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
378[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 + 1]



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]


298
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]



464[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 + 3]


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]



396[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]


746
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
366[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
363[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
318[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, R3c, 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,NHCOPh),(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),(NHMe,H,H,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-2furyl),(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,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),(NHMe,H,Ph,Me,CONHPh),(NHMe,H,Ph,Me,CONH-3-pyridyl),(NHMe,H,Ph,Me,NHCOPh),(NHMe,H,Ph,Me,NHCO-2furyl),(NHMe,H,Ph,Me,NHCONHPh),(NHMe,H,Ph,Me,NHCOCONHPh),(NHMe,H,Ph,Et,CONHPh),(NHMe,H,Ph,Et,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,NHCONPh),(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,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-3pyridyl),(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,H,OH,Me,CONHPh),(NHCH2CH2OH,H,OH,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,H,OH,Et,CONH-3-pyridyl),(NHCH2CH2OH,H,OH,Et,NHCOPh),(NHCH2CH2OH,H,OH,Et,NHCO-2-furyl),(NHCH2CH2OH,H,OH,Et,NHCONHPh),(NHCH2CH2OH,H,OH,Et,NHCOCONHPh),(NHCH2CH2OH,H,OH,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),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,NRCOPh),(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),(NRCH2CH2OH,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,H,OH,Me,CONHPh),(NHCH2CONH2,H,Me,CONH-3-pyridyl),(NHCH2CONH2,H,OH,Me,NHCOPh),(NHCH2CONH2,H,OH,Me,NHCO-2-furyl),(NHCH2CONH2,H,OH,Me,NHCONHPh),(NHCH2CONH2,H,OH,Me,NHCOCONHPh),(NHCH2CONH2,H,OH,Et,CONHPh),(NHCH2CONH2,H,OH,Et,CONH-3-pyridyl),(NHCH2CONH2,H,OH,Et,NHCOPh),(NHCH2CONH2,H,OH,Et,NHCO-2-furyl),(NHCH2CONH2,H,OH,Et,NHCONHPh),(NHCH2CONH2,H,OH,Et,NHCOCONHPh),(NHCH2CONH2,H,OH,CH2OH,CONHPh),(NHCH2CONH2,H,OH,CH2OH,CONH-3-pyridyl),(NHCH2CONH2,H,OH,CH2OH,NHCOPh),(NHCH2CONH2,H,OH,CH2OH,NHCO-2-furyl),(NHCH2CONH2,H,OH,CH2OH,NHCONHPh),(NHCH2CONH2,H,OH,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),(NHCH2CONH2,1Me,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,H,OH,Me,CONHPh),(NHCH(Bn)CONH2,H,OH,Me,CONH-3-pyridyl),(NHCH(Bn)CONH2,H,OH,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,H,OH,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,H,OH,Et,NHCOCONHPh),(NHCH(Bn)CONH2,H,OH,CH2OH,CONHPh),(NHCH(Bn)CONH2,H,OH,CH2OH,CONH-3-pyridyl),(NHCH(Bn)CONH2,H,OH,CH2OH,NHCOPh),(NHCH(Bn)CONH2,H,OH,CH2OH,NHCO-2-furyl),(NHCH(Bn)CONH2,H,OH,CH2OH,NHCONHPh),(NHCH(Bn)CONH2,H,OH,CH2OH,NHCOCONHPh),(NHCH(Bn)CONH2,Me,H,Me,CONHPh),(NHCH(Bn)CONH2,Me,H,Me,CONH-3-pyridyl),(NHCH(Bn)CONH2,Me,H,Me,NHCOPh),(NHCH(Bn)CONH2,Me,H,Me,NHCO-2-furyl),(NHCH(Bn)CONH2,Me,H,Me,NHCONHPh),(NHCH(Bn)CONH2,Me,Me,NHCOCONHPh),(NHCH(Bn)CONH2,Me,H,Et,CONHPh),(NHCH(Bn)CONH2,Me,H,Et,CONH-3-pyridyl),(NHCH(Bn)CONH2,Me,H,Et,NHCOPh),(NHCH(Bn)CONH2,Me,H,Et,NHCO-2-furyl,(NHCH(Bn)CONH2,Me,H,Et,NHCONHPh),(NHCH(Bn)CONH2,Me,H,Et,NHCOCONHPh),(NHCH(Bn)CONH2,Me,H,CH2OH,CONHPh),(NHCH(Bn)CONH2,Me,H,CH2OH,CONH-3-pyridyl),(NHCH(Bn)CONH2,Me,H,CH2OH,NHCOPh),(NHCH(Bn)CONH2,Me,H,CH2OH,NHCO-2-furyl),(NHCH(Bn)CONH2,Me,H,CH2OH,NHCONHPh),(NHCH(Br)CONH2,Me,H,CH2OH,NHCOCONHPh),(NHCH(Bn)CONH2,Me,Me,Me,CONHPh),(NHCH(Bn)CONH2,Me,Me,Me,CONH-3-pyridyn,(NHCH(Bn)CONH2,Me,Me,Me,NHCOPh),(NHCH(Bn)CONH2,Me,Me,Me,NHCO-2-furyl),(NHCH(Bn)CONH2,Me,Me,Me,NHCONHPh),(NHCH(Bn)CONH2,Me,Me,Me,NHCOCONHPh),(NHCH(Bn)CONH2,Me,Me,Et,CONHPh),(NHCH(Bn)CONH2,Me,Me,Et,CONH-3-pyridyl),(NHCH(Bn)CONH2,Me,Me,Et,NHCOPh),(NHCH(Br)CONH2,Me,Me,Et,NHCO-2-furyl),(NRCH(Bn)CONH2,Me,Me,Et,NHCONHPh),(NHCH(Bn)CONH2,Me,Me,Et,NHCOCONHPh),(NHCH(Bn)CONH2,Me,Me,CH2OH,CONHPh),(NHCH(Bn)CONH2,Me,Me,CH2OH,CONH-3-pyridyl),(NHCH(Bn)CONH2,Me,Me,CH2OH,NHCOPh),(NHCH(Bn)CONH2,Me,Me,CH2OH,NHCO-2-furyl),(NHCH(Bn)CONH2,Me,Me,CH2OH,NHCONHPh),(NHCH(Bn)CONH2,Me,Me,CH2OH,NHCOCONHPh),(NHCH(Bn)CONH2,Me,Ph,Me,CONHPh),(NHCH(Bn)CONH2,Me,Ph,Me,CONH-3-pyridyl),(NHCH(Bn)CONH2,Me,Ph,Me,NHCOPh),(NHCH(Bn)CONH2,Me,Ph,Me,NHCO-2-furyl),(NHCH(Bn)CONH2,Me,Ph,Me,NHCONHPh),(NHCH(Bn)CONH2,Me,Ph,Me,NHCOCONHPh),(NHCH(Bn)CONH2,Me,Ph,Et,CONHPh),(NHCH(Bn)CONH2,Me,Ph,Et,CONH-3-pyridyl),(NHCH(Bn)CONH2,Me,Ph,Et,NHCOPh),(NHCH(Bn)CONH2,Me,Ph,Et,NHCO-2-furyl),(NHCH(Bn)CONH2,Me,Ph,Et,NHCONHPh),(NHCH(Bn)CONH2,Me,Ph,Et,NHCOCO NHPh),(NHCH(Bn)CONH2,Me,Ph,CH2OH,CONHPh),(NHCH(Bn)CONH2,Me,Ph,CH2OH,CONH-3-pyridyl),(NHCH(Bn)CONH2,Me,Ph,CH2OH,NHCOPh),(NHCH(Bn)CONH2,Me,Ph,CH2OH,NHCO-2-furyl),(NHCH(Bn)CONH2,Me,Ph,CH2OH,NHCONHPh),(NHCH(Bn)CONH2,Me,Ph,CH2OH,NHCOCONHPh),(NHCH(Bn)CONH2,Me,OH,Me,CONHPh),(NHCH(Bn)CONH2,Me,OH,Me,CONH-3-pyridyl),(NHCH(Bn)CONH2,Me,OH,Me,NHCOPh),(NHCH(Bn)CONH2,Me,OH,Me,NHCO-2-furyl,(NHCH(Bn)CONH2,Me,OH,NHCONHPh),(NHCH(Bn)CONH2,Me,OH,Me,NHCOCONHPh),(NHCH(Bn)CONH2,Me,OH,Et,CONHPh),(NHCH(Bn)CONH2,Me,OH,Et,CONH-3-pyridyl),(NHCH(Bn)CONH2,Me,OH,Et,NHCOPh),(NHCH(Bn)CONH2,Me,OH,Et,NHCO-2-furyl),(NHCH(Bn)CONH2,Me,OH,Et,NHCONHPh),(NHCH(Bn)CONH2,Me,OH,Et,NHCOCONHPh),(NHCH(Bn)CONH2,Me,OH,CH2OH,CONHPh),(NHCH(Bn)CONH2,Me,OH,CH2OH,CONH-3-pyridyl),(NHCH(Bn)CONH2,Me,OH,CH2OH,NHCOPh),(NHCH(Bn)CONH2,Me,OH,CH2OH,NHCO-2-furyl),(NHCH(Bn)CONH2,Me,OH,CH2OH,NHCONHPh),(NHCH(Bn)CONH2,Me,OH,CH2OH,NHCOCONHPh),(NHCH(Bn)CONH2,Ph,H,Me,CONHPh),(NHCH(Bn)CONH2,Ph,H,Me,CONH-3-pyridyl),(NHCH(Bn)CONH2,Ph,H,Me,NHCOPh),(NHCH(Bn)CONH2,Ph,H,Me,NHCO-2-furyl),(NHCH(Bn)CONH2,Ph,H,Me,NHCONHPh),(NHCH(Bn)CONH2,Ph,H,Me,NHCOCONHPh),(NHCH(Bn)CONH2,Ph,H,Et,CONHPh),(NHCH(Bn)CONH2,Ph,H,Et,CONH-3-pyridyl,(NHCH(Bn)CONH2,Ph,H,Et,NHCOPh),(NHCH(Bn)CONH2,Ph,H,Et,NHCO-2-furyl),(NHCH(Bn)CONH2,Ph,H,Et,NHCONHPh),(NHCH(Bn)CONH2,Ph,H,Et,NHCOCONHPh),(NHCH(Bn)CONH2,Ph,H,CH2OH,CONHPh),(NHCH(Bn)CONH2,Ph,H,CH2OH,CONH-3-pyridyl),(NHCH(Bn)CONH2,Ph,H,CH2OH,NHCOPh),(NHCH(Bn)CONH2,Ph,H,CH2OH,NHCO-2-furyl),(NHCH(Bn)CONH2,Ph,H,CH2OH,NHCONHPh),(NHCH(Bn)CONH2,Ph,H,CH2OH,NHCOCONHPh),(NHCH(Bn)CONH2,Ph,Me,Me,CONHPh),(NHCH(Bn)CONH2,Ph,Me,Me,CONH-3-pyridyl),(NHCH(Bn)CONH2,Ph,Me,Me,NHCOPh),(NHCH(Bn)CONH2,Ph,Me,Me,NHCO-2-furyl),(NHCH(Bn)CONH2,Ph,Me,Me,NHCONHPh),(NHCH(Bn)CONH2,Ph,Me,Me,NHCOCONHPh),(NHCH(Bn)CONH2,Ph,Me,Et,CONHPh),(NHCH(Bn)CONH2,Ph,Me,Et,CONH-3-pyridyl),(NHCH(Bn)CONH2,Ph,Me,Et,NHCOPh),(NHCH(Bn)CONH2,Ph,Me,Et,NHCO-2-furyl),(NHCH(Bn)CONH2,Ph,Me,Et,NHCONHPh),(NHCH(Bn)CONH2,Ph,Me,Et,NHCOCONHPh),(NHCH(Bn)CONH2,Ph,Me,CH2OH,CONHPh),(NHCH(Bn)CONH2,Ph,Me,CH2OH,CONH-3-pyridyl),(NHCH(Bn)CONH2,Ph,Me,CH2OH,NHCOPh),(NHCH(Bn)CONH2,Ph,Me,CH2OH,NHCO-2-furyl),(NHCH(Bn)CONH2,Ph,Me,CH2OH,NHCONHPh),(NHCH(Bn)CONH2,Ph,Me,CH2OH,NHCOCONHPh),(NHCH(Bn)CONH2,Ph,Ph,Me,CONHPh),(NHCH(Bn)CONH2,Ph,Ph,Me,CONH-3-pyridyl),(NHCH(Bn)CONH2,Ph,Ph,Me,NHCOPh),(NHCH(Bn)CONH2,Ph,Ph,Me,NHCO-2-furyl),(NHCH(Bn)CONH2,Ph,Ph,Me,NHCONHPh),(NHCH(Bn)CONH2,Ph,Ph,Me,NHCOCONHPh),(NHCH(Bn)CONH2,Ph,Ph,Et,CONHPh),(NHCH(Bn)CONH2,Ph,Ph,Et,CONH-3-pyridyl),(NHCH(Bn)CONH2,Ph,Ph,Et,NHCOPh),(NHCH(Bn)CONH2,Ph,Ph,Et,NHCO-2-furyl),(NHCH(Bn)CONH2,Ph,Ph,Et,NHCONHPh),(NHCH(Bn)CONH2,Ph,Ph,Et,NHCOCONHPh),(NHCH(Bn)CONH2,Ph,Ph,CH2OH,CONHPh),(NHCH(Bn)CONH2,Ph,Ph,CH2OH,CONH-3-pyridyl),(NHCH(Bn)CONH2,Ph,Ph,CH2OH,NHCOPh),(NHCH(Bn)CONH2,Ph,Ph,CH2OH,NHCO-2-furyl),(NHCH(Bn)CONH2,Ph,Ph,CH2OH,NHCONHPh),(NHCH(Bn)CONH2,Ph,Ph,CH2OH,NHCOCONHPh),(NHCH(Bn)CONH2,Ph,OH,Me,CONHPh),(NHCH(Bn)CONH2,Ph,OH,Me,CONH-3-pyridyl),(NHCH(Bn)CONH2,Ph,OH,Me,NHCOPh),(NHCH(Br)CONH2,Ph,OH,Me,NHCO-2-furyl),(NHCH(Bn)CONH2,Ph,OH,Me,NHCONHPh),(NHCH(Bn)CONH2,Ph,OH,Me,NHCOCONHPh),(NHCH(Bn)CONH2,Ph,OH,Et,CONHPh),(NHCH(Bn)CONH2,Ph,OH,Et,CONH-3-pyridyl),(NHCH(Bn)CONH2,Ph,OH,Et,NHCOPh),(NHCH(Bn)CONH2,Ph,OH,Et,NHCO-2-furyl),(NHCH(Bn)CONH2,Ph,OH,Et,NHCONHPh),(NHCH(Bn)CONH2,Ph,OH,Et,NHCOCONHPh),(NHCH(Bn)CONH2,Ph,OH,CH2OH,CONHPh),(NHCH(Bn)CONH2,Ph,OH,CH2OH,CONH-3-pyridyl),(NHCH(Bn)CONH2,Ph,OH,CH2OH,NHCOPh),(NHCH(Bn)CONH2,Ph,OH,CH2OH,NHCO-2-furyl),(NHCH(Bn)CONH2,Ph,OH,CH2OH,NHCONHPh),(NHCH(Bn)CONH2,Ph,OH,CH2OH,NHCOCONHPh),
    (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,Me,Me,CONH-3-pyridyl),(NHCH(Me)CH2OH,H,Me,Me,NHCOPh),(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,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,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,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,H,OH,Me,NHCONHPh),(NHCH(Me)CH2OH,H,OH,Me,NHCOCONHPh),(NHCH(Me)CH2OH,H,OH,Et,CONHPh),(NHCH(Me)CH2OH,H,OH,Et,CONH-3-pyridyl),(NHCH(Me)CH2OH,H,OH,Et,NHCOPh),(NHCH(Me)CH2OH,H,OH,Et,NHCO-2-furyl),(NHCH(Me)CH2OH,H,OH,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,NH COPh),(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,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)OCH2OH,Ph,B,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,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,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,EtNHCO-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,H,OH,Me,CONHPh),(NHCH(Me)CONHMe,H,OH,Me,CONH-3-pyridyl),(NHCH(Me)CONHMe,H,OH,Me,NHCOPh),(NHCH(Me)CONHMe,H,Me,NHCO-2-furyl),(NHCH(Me)CONHMe,H,OH,Me,NHCONHPh),(NHCH(Me)CONHMe,H,OH,Me,NHCOCONHPh),(NHCH(Me)CONHMe,H,OH,Et,CONHPh),(NHCH(Me)CONHMe,H,OH,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),(NHCH(Me)CONHMe,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),(NHCH(Me)CONHMe,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),(NHCH(Me)CONHMe,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,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)NHMe,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,CO NHPh),(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,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,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,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,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,Ph,CH2OH,CONHPh),(NHCOCH(iPr)OH,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,H,OH,Me,CONHPh),(NHCOCH(iPr)OH,H,OH,Me,CONH-3-pyridyl),(NHCOCH(iPr)OH,H,OH,Me,NHCOPh),(NHCOCH(iPr)OH,H,OH,Me,NHCO-2-furyl),(NHCOCH(iPr)OH,H,OH,Me,NHCONHPh),(NHCOCH(iPr)OH,H,OH,Me,NHCOCONHPh),(NHCOCH(iPr)OH,H,OH,Et,CONHPh),(NHCOCH(iPr)OH,H,OH,Et,CONH-3-pyridyl),(NHCOCH(iPr)OH,H,OH,Et,NHCOPh),(NHCOCH(iPr)OH,H,OH,Et,NHCO-2-furyl),(NHCOCH(iPr)OH,H,OH,Et,NHCONHPh),(NHCOCH(iPr)OH,H,OH,Et,NHCOCONHPh),(NHCOCH(iPr)OH,H,OH,CH2OH,CONHPh),(NHCOCH(iPr)OH,H,OH,CH2OH,CONH-3-pyridyl),(NHCOCH(iPr)OH,H,OH,CH2OH,NHCOPh),(NHCOCH(iPr)OH,H,OH,CH2OH,NHCO-2-furyl),(NHCOCH(iPr)OH,H,OH,CH2OH,NHCONHPh),(NHCOCH(iPr)OH,H,OH,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),(NHCOH(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)OOH,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),(NHCOC(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),(NHCO(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,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,NHCONHPh),(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,NH,CONHPh),(NHS2Me,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,H,OH,Me,CONHPh),(NHSO2Me,H,OH,Me,CONH-3-pyridyl),(NHSO2Me,H,OH,Me,NHCOPh),(NHSO2Me,H,OH,Me,NHCO-2-furyl),(NHSO2Me,H,OH,Me,NHCONHPh),(NHSO2Me,H,OH,Me,NHCOCONHPh),(NHSO2Me,H,OH,Et,CONHPh),(NHSO2Me,H,OH,Et,CONH-3-pyridyl),(NHSO2Me,H,OH,Et,NHCOPh),(NHSO2Me,H,OH,Et,NHCO-2-furyl),(NHSO2Me,H,OH,Et,NHCONHPh),(NHSO2Me,H,OH,Et,NHCOCONHPh),(NHSO2Me,H,OH,CH2OH,CONHPh),(NHSO2Me,H,OH,CH2H,CONH-3-pyridyl),(NHSO2Me,H,OH,CH2OH,NHCOPh),(NHSO2Me,H,OH,CH2OH,NHCO-2-furyl),(NHSO2Me,H,OH,CH2OH,NHCONHPh),(NHSO2Me,H,OH,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,CONHPh),(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-furyl),(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,NHCONHPR(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,H,OH,Me,CONH-3-pyridyl),(NH2,H,OH,Me,NHCONHPh),(NH2,H,OH,Me,NHCOCONHPh),(NH2,H,OH,Et,CONHPh),(NH2,H,OH,Et,CONH-3-pyridyl),(NH2,H,OH,Et,NHCOPh),(NH2,H,OH,Et,NHCO-2-furyl),(NH2,H,OH,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),(NH2Me,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,(H2OH,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,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,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(O)NH2,H,Me,NHCOPh),(NHC(O)C(O)NH2,H,H,Me,NHCO-2-furyl),(NHC(O)C(O)NH2,H,H,Me,NHCONHPh),(NHC(O)C(O)NH2,H,H,Me,NHCOCONHPh),(NHC(O)C(O)NHMe,H,H,Me,CONHPh),(NHC(O)C(O)NHMe,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(O)NHMe,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≡CMe


 


B4
cHex-
L4




A4




R54
—CF3


 


B5
cHex-CH2—
L5




A5




R55
—CH2Cl


 








R56
CHCl2









    (B, Linker, A, R5)=(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,A 1,R52),(B1,L2,A 1,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,R56),(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,A 1,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),(B53),(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,L5A3,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,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,A3R55),(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,R51),(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,L5A2,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),(B3,1,3,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,A 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1,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,R51),(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,R51),(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,R51),(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 Example 1
Lowering Effect on Brain β Amyloid in Rats
A test compound was suspended in 0.5% methylcellulose, the final concentration was adjusted to 2 mg/mL, and this was orally administered to male Crg:SD rat (7 to 9 week old) at 10 mg/kg. In a vehicle control group, only 0.5% methylcellulose was administered, and an administration test was performed at 3 to 8 animals per group. A brain was isolated 3 hours after administration, a cerebral hemisphere was isolated, a weight thereof was measured, the hemisphere was rapidly frozen in liquid nitrogen, and stored at −80° C. until the day for extraction. The frozen cerebral hemisphere was transferred to a homogenizer manufactured by Teflon (registered trade mark) under ice cooling, a 5-fold volume of a weight of an extraction buffer (containing 1% CHAPS ({3-[(3-chloroamidopropyl)dimethylammonio]-1-propanesulfonate}), 20 mM Tris-HCl (pH 8.0), 150 mM NaCl, Complete (Roche) protease inhibitor) was added, up and down movement was repeated, and this was homogenized to solubilize for 2 minutes. The suspension was transferred to a centrifugation tube, allowed to stand on an ice for 3 hours or more and, thereafter centrifuged at 100,000×g and 4° C. for 20 minutes. After centrifugation, the supernatant was transferred to an ELISA plate (product No. 27730, Immuno-Biological Laboratories) for measuring β amyloid 1-40. ELISA measurement was performed according to the attached instruction. The lowering effect was calculated as a ratio compared to the brain b amyloid 1-40 level of vehicle control group.










TABLE 170







Compound No.
% of vehicle control group









634
21.1



622
50.1










Compound No. 733, 359, 39, 212, 793, 204, 243, 482 and 1282 also lowered the brain β amyloid 1-40 with approximately 60 to 90% reduction compared to those of a vehicle control group.
Therefore, it is shown that Compound (I) lowers the brain β amyloid 1-40 in rats.
Test Example 2
Lowering Effect on Brain β Amyloid in Mice
A test compound was suspended in 0.5% methylcellulose, the final concentration was adjusted to 10 mg/mL, and this was subcutaneously administered to back of male Crlj:CD-1(ICR) mouse (7 to 8 week old) at 100 mg/kg. In a vehicle control group, only 0.5% methylcellulose was administered. A test was performed at 4 to 8 animals per group. A brain was isolated 3 hours after administration. The subsequent operations were the same as in the above test in rat.










TABLE 171







Compound No.
% of vehicle control group









1199
14.1



1043
15.0



1100
20.2



 127
25.2



 605
36.5



 396
38.4



1244
50.1



 651*
52.3










(*3 hours after 30 mg/kg of subcutaneous administration)

Compounds 309, 165, 739, 1266, 900, 220, 964, 1262 and 1014 also lowered the brain β amyloid 1-40 with approximately 60 to 90% reduction compared to those of vehicle control group.
Therefore, it is shown that Compound (I) lowers the brain β amyloid 1-40 in mice.
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 Mowing 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 pharmaceutical composition of the present invention can be a useful medicament for treating disease induced by production, secretion and/or deposition o β amyloid, especially Alzheimer's disease.

## Claims

1. A method for treating Alzheimer's disease, comprising:
administering a composition in an amount effective for treating Alzheimer's disease to a subject in need thereof, wherein the composition contains a compound represented by the general formula (I):




wherein ring A is




R9 and R10 are each independently a hydrogen atom, 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 lower 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 alkyl sulfinyl, 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;
G is




wherein Q1 and Q2 are each independently a bond, optionally substituted lower alkylene, or optionally substituted lower alkenylene;
W1 is O or S;
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 an optionally substituted carbocyclic group or an optionally substituted heterocyclic group,




wherein 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;
each of R2a and R2b is a hydrogen atom,
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 is 2 and m is 0;
each R3a, each R3b, each R4a, and each R4b may be independently different;
R5 is optionally substituted lower alkyl;
its pharmaceutically acceptable salt, or a solvate thereof as an active ingredient.

2. The method for treating Alzheimer's disease according to claim 1, wherein X is S.

3. The method for treating Alzheimer's disease according to claim 1, wherein E is a bond.

4. The method for treating Alzheimer's disease according to claim 1, wherein ring B is aryl optionally substituted with one or more substituents selected from the group consisting 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, and an optionally substituted heterocyclic group or heteroaryl optionally substituted with one or more substituents selected from the group consisting 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, and an optionally substituted heterocyclic group.

5. The method for treating Alzheimer's disease according to claim 1, wherein G is represented by the formula:

6. The method for treating Alzheimer's disease according to claim 1, wherein R5 is C1 to C3 alkyl.

7. The method for treating Alzheimer's disease according to claim 1, wherein R5 is methyl.

8. The method for treating Alzheimer's disease 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.

9. The method for treating Alzheimer's disease according to claim 1, wherein all of R3a and all of R3b are hydrogen atoms.