JP3244672B2 - Pharmaceuticals consisting of isoxazole derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to isoxazole derivatives useful as therapeutic agents for autoimmune diseases, inflammatory diseases and the like.

[0002]

2. Description of the Related Art Conventionally, acidic non-steroidal anti-inflammatory drugs, steroid drugs and the like have been used as therapeutic agents for inflammatory diseases, but their use is limited in terms of side effects.
In addition, these treatment methods belong to symptomatic treatment and have no effect of improving the underlying cause of the disease.
As elucidation of the etiology and pathology of autoimmune diseases such as rheumatoid arthritis exhibiting a strong inflammation pattern, it is suggested that abnormalities of the immune system are deeply involved in the onset and chronicity of inflammation. From such a point, drugs that improve the disease state by acting on the immune system, such as gold preparations and D-penicillamine, have been attracting attention as causal treatments. However, it is not always in a satisfactory state due to side effects and lack of sustained effect. On the other hand, isoxazole derivatives having various physiological activities have been reported. For example, JP-A-63-152368 reports an aralkyl-5-membered heterocyclic compound containing an isoxazole derivative as a therapeutic agent for autoimmune diseases, inflammation, allergy, asthma and the like. In German Patent No. 2847792, as anti-inflammatory, analgesic, antipyretic,
Quinolylguanidine derivatives, including isoxazole derivatives, have been reported. J. Med. Chem., 21 , 773 (1978) reports that N-cyano-N'-isoxazolylguanidine derivatives are effective as antihypertensive agents.

[0003]

A therapeutic agent for an autoimmune disease requires a clear effect on chronic inflammation leading to tissue destruction. Furthermore, it is important that the underlying therapy also has an effect of suppressing abnormalities of the immune system existing in the background of the disease. In addition, since therapeutic agents for these diseases often require long-term administration, they are required to have few side effects. An object of the present invention is to provide a compound which has an excellent immunity-improving activity and a chronic inflammation-improving activity and is useful as a therapeutic or prophylactic agent for autoimmune diseases, inflammatory diseases and the like with few side effects.

[0004]

Means for Solving the Problems As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that isoxazole derivatives have a strong effect on both immunological amelioration and chronic inflammation ameliorating effects, and also have side effects. Finding less,
The present invention has been completed. That is, the present invention is as follows. [1] Equation 1:

[Formula 9] [Wherein D is a hydrogen atom, a halogen atom, a hydroxyl group, a mercapto group, a nitro group, a cyano group, a carboxy group, an optionally substituted amino group, an optionally substituted hydroxylamino group, an optionally substituted carbamoyl group , A sulfamoyl group which may be substituted, a sulfo group, -R ⁵ , -OR ⁵ ,-
_{^{CO 2 R 6, -SR 7,}} - (CO) SR 7, - (CS) OR
⁷ or -CS ₂ R ⁷ (wherein, R ⁵ is an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, R ⁶ represents an optionally substituted cycloalkenyl group, an optionally substituted aryl group, an optionally substituted heterocyclic group or an acyl group, and R ⁶ represents an optionally substituted alkyl group, an optionally substituted alkenyl group, R ⁷ represents an optionally substituted alkynyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group, and R ⁷ represents an optionally substituted alkyl group or an optionally substituted aryl group. A and B are one of the formula:

[Formula 10](E represents a single bond or an alkylene group.
Means that one means a double bond together with the solid line, and the other
Both mean a single bond. R¹Is a single bond with a broken line and a solid line
Bond to the nitrogen atom that bonds to the bond that represents R¹, R^Two,
R^ThreeAnd R^FourAre each independently a hydrogen atom, a halogen atom
, Hydroxyl group, mercapto group, nitro group, cyano group,
Boxy group, optionally substituted amino group, optionally substituted
Hydroxylamino group, carbamoy which may be substituted
, A sulfamoyl group which may be substituted, a sulfo group,
NH protecting group, -R^Five, -OR^Five, -CO_TwoR⁶, -SR
⁷,-(CO) SR⁷,-(CS) OR⁷Or -CS _TwoR
⁷(Where R^Five, R⁶And R⁷Is as defined above. )
Represent. Also, R¹, R ^Two, R^ThreeAnd R^FourIs the role of
Two are bonded together to form a nitrogen atom,
It may form a heterocyclic ring which may be substituted. Also, the formula:
NR^ThreeR^FourHas the formula: -N = C (NH_Two) NR⁴³R⁴⁴Represented by
May be represented. R⁴³And R⁴⁴Is the following
(1) or (2). (1) independently a hydrogen atom, an alkyl group having 1 to 4 carbon atoms,
− (CH_Two)_n-COCH _Three(N represents an integer of 1 to 3
You. ),-(CH_Two)_n-CO_TwoR³²(N is as defined above.
is there. R³²Represents an alkyl group having 1 to 3 carbon atoms. ),-
(CH_Two)_n-CONR³³R³⁴(N is as defined above.
R³³And R³⁴Is independently a hydrogen atom or a group having 1 to 3 carbon atoms.
Represents an alkyl group. ),-(CH_Two)_m-OR³⁵(M is
Represents 2 or 3. R³⁵Is a hydrogen atom,
Alkyl group or-(CH_Two)_m-OR³⁶(M is as defined above
It is. R³⁶Is a hydrogen atom or an alkyl having 1 to 3 carbon atoms
Represents a group. ). ),-(CH_Two)_m-NR³⁷R
³⁸(M is as defined above. R³⁷And R³⁸Independently
Represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, or
Or R³⁷And R³⁸Together, together with the nitrogen atom,
Loridine, piperidine, azepan, morpholine or N
-Methylpiperazine (in these, pyrrolidine,
Peridine, azepan, morpholine and N-methylpipe
Razine may be substituted with one or two methyls.
No. ). ), Phenyl, pyridyl, pyrimidini
, Pyridazinyl, pyrazinyl, tetrazolyl, benzyl
, Pyridylmethyl, pyrimidinylmethyl, pyridazini
Methyl, pyrazinylmethyl, tetrazolylmethyl, water
An acid group, an alkoxy group having 1 to 3 carbon atoms or -NR³⁹R⁴⁰
(R³⁹And R⁴⁰Independently represent a hydrogen atom, a carbon number of 1 to 3
Represents an alkyl group, phenyl or pyridyl. )
You. (2) 5-7 member saturated nitrogen containing together with nitrogen atom
A heterocyclic group (a 5- to 7-membered saturated nitrogen-containing heterocyclic group is an alkyl
Group, amino group, hydroxyl group, alkoxy group and oxo group.
Substituted with one or two substituents arbitrarily selected from the group
It may be. ). ). A and
And B are the other of the formula: -JG (where G is substituted
Or an optionally substituted heterocyclic group
Represents J is -C (R⁸R⁹)-Or -C (= CR
⁸R⁹)-. R⁸And R⁹Is each independently hydrogen
Atom, lower alkoxy group which may be substituted, or substituted
Represents a lower alkyl group which may be substituted. Also, R⁸and
R⁹Are bonded together and, together with the carbon atom,
Hydrocarbon ring which may be substituted, 1,3-dio which may be substituted
Xan ring or 1,3-dioxolan which may be substituted
A ring may be formed. ). ]
Isoxazole derivative or its pharmaceutically acceptable
Pharmaceutical consisting of salt.

[2] E is a single bond or a lower alkylene group
The medicament according to [1]. [3] D is hydrogen atom, nitro group, cyano group, carboxy
Group, optionally substituted amino group, optionally substituted hydrid
Roxylamino group, carbamoyl group which may be substituted,
-R^FiveOr -CO_TwoR⁶ (Where R^FiveAnd R⁶Is
It is synonymous. ) The pharmaceutical according to [1] or [2], wherein [4] D is a hydrogen atom, a carboxy group, -R^FiveOr -C
O_TwoR⁶(Where R^FiveAnd R⁶Is as defined above. )so
The pharmaceutical according to [3]. [5] R¹, R^Two, R^ThreeAnd R^FourBut each independently represents hydrogen
Atom, hydroxyl group, amino group which may be substituted, substituted
A hydroxylamino group, an optionally substituted alcohol
An xyl group, an optionally substituted alkyl group, an optionally substituted
Alkenyl group, alkynyl group which may be substituted,
Cycloalkyl group, optionally substituted cycloalkyl group
A loalkenyl group, an optionally substituted aryl group,
Represents an optionally substituted heterocyclic group or an acyl group or has the formula: -N
R^ThreeR^FourHas the formula: -N = C (NH _Two) NR⁴³R⁴⁴(R⁴³You
And R⁴⁴Is as defined above. Represents a group represented by)
Or R¹, R^Two, R^ThreeAnd R^FourAny two of
Are bonded together and, together with the nitrogen atom,
Any one of [1] to [4] which forms a heterocyclic ring which may be
Medicine. [6] R¹, R^Two, R^ThreeAnd R^FourBut each independently represents hydrogen
Atom, hydroxyl group, amino group which may be substituted, substituted
A hydroxylamino group, an optionally substituted alcohol
An xyl group, an optionally substituted alkyl group, an optionally substituted
Alkenyl group, alkynyl group which may be substituted,
An optionally substituted cycloalkyl group, an optionally substituted ant
Represents an aryl group, an optionally substituted heterocyclic group or an acyl group.
The formula: -NR^ThreeR^FourHas the formula: -N = C (NH_Two) NR
⁴³R⁴⁴(R⁴³And R⁴⁴Is as defined above. )
Or a group represented by R¹, R^Two, R^ThreeAnd R^FourHorse
Any two of them are bonded together to form a nitrogen atom
Further forms a heterocyclic ring which may be substituted;
medicine.

[7] G is optionally substituted phenyl, optionally substituted naphthyl, optionally substituted furyl, optionally substituted thienyl, optionally substituted indolyl, optionally substituted isothiazolyl, Optionally substituted benzothienyl, optionally substituted isobenzofuranyl, optionally substituted pyrrolyl, optionally substituted benzofuryl, optionally substituted imidazolyl, optionally substituted pyrazolyl, optionally substituted Good isoxazolyl, optionally substituted isothiazolyl, optionally substituted thiazolyl, optionally substituted oxazolyl, optionally substituted benzimidazolyl, optionally substituted benzothiazolyl, optionally substituted benzoxazolyl, substituted Optionally substituted pyridyl, optionally substituted pyrazinyl, optionally substituted pyrimidinyl 1, optionally substituted pyridazinyl, optionally substituted triazinyl, optionally substituted quinolyl, optionally substituted isoquinolyl, optionally substituted quinazolinyl, optionally substituted quinoxalinyl, optionally substituted 2 , 3-Dihydro-benzo [1,
4] The medicament according to any one of [1] to [6], which is dioxanyl or carbazolyl which may be substituted.

[8] Equation:

[Formula 11] Wherein G ¹ is phenyl, biphenyl-4-yl, 3
-Benzoylphenyl, 4-benzoylphenyl, 1H
-Indol-2-yl, 1H-indol-3-yl, 1-methyl-1H-indol-2-yl, 1-methyl-1H-indol-3-yl, 2,3-dihydro-benzo [1,4 Dioxin-6-yl, 1-benzofuran-5-yl, 1-benzofuran-6-yl, quinolyl, isoquinolyl, phenylpyridyl, phenylpyrimidinyl, phenylpyridazinyl or phenylpyrazinyl (wherein phenyl, biphenyl -4-yl, 3-benzoylphenyl, 4-benzoylphenyl, 1H-indol-2-yl, 1H-indole-
3-yl, 1-methyl-1H-indol-2-yl,
1-methyl-1H-indol-3-yl, 2,3-dihydro-benzo [1,4] dioxin-6-yl, 1-
Benzofuran-5-yl, 1-benzofuran-6-yl, quinolyl, isoquinolyl, phenylpyridyl, phenylpyrimidinyl, phenylpyridazinyl and phenylpyrazinyl represent a fluorine atom, a chlorine atom, a bromine atom, acetyl, cyano,- CO ₂ R ²⁹ (R ²⁹ represents an alkyl group having 1 to 3 carbon atoms) and —CONR ³⁰ R ³¹ (R ³⁰ and R ³¹ independently represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms) ) May be substituted with one or two groups arbitrarily selected from the group consisting of: ). R ²³ and R ²⁴ independently represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, methoxy or ethoxy, or together represent methylene. Formula: = C (NR ²⁵ R ²⁶ ) NR ²⁷ R ²⁸ is represented by the following (1):
(2) or (3). (1) R ²⁵ and R ²⁶ are as shown in the following (a) or (b), and R ²⁷ and R ²⁸ are as shown in the following (c) or (d). (A) independently a hydrogen atom, an alkyl group having 1 to 4 carbon atoms,
— (CH ₂ ) _n —COCH ₃ (n is as defined above), — (CH ₂ ) _n —CO ₂ R ³² (n and R ³² are as defined above), and — (CH ₂ ) _n- CONR ³³ R
³⁴ (n, R ³³ and R ³⁴ are as defined above),-
(CH ₂ ) _m —OR ³⁵ (m and R ³⁵ are as defined above), — (CH ₂ ) _m —NR ³⁷ R ³⁸ (m, R ³⁷ and R
³⁸ is as defined above. ), Phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, tetrazolyl,
Benzyl, pyridylmethyl, pyrimidinylmethyl, pyridazinylmethyl, pyrazinylmethyl, tetrazolylmethyl, hydroxyl group, alkoxy group having 1 to 3 carbon atoms or -NR
³⁹ R ⁴⁰ (R ³⁹ and R ⁴⁰ are as defined above). (B) a 5- to 7-membered saturated nitrogen-containing heterocyclic group together with a nitrogen atom (the 5- to 7-membered saturated nitrogen-containing heterocyclic group is a group consisting of an alkyl group, an amino group, a hydroxyl group, an alkoxy group, and an oxo group; And may be substituted with one or two substituents arbitrarily selected from. (C) independently a hydrogen atom, an alkyl group having 1 to 4 carbon atoms,
— (CH ₂ ) _n —COCH ₃ (n is as defined above), — (CH ₂ ) _n —CO ₂ R ³² (n and R ³² are as defined above), and — (CH ₂ ) _n- CONR ³³ R
³⁴ (n, R ³³ and R ³⁴ are as defined above),-
(CH ₂ ) _m —OR ³⁵ (m and R ³⁵ are as defined above), — (CH ₂ ) _m —NR ³⁷ R ³⁸ (m, R ³⁷ and R
³⁸ is as defined above. ), Phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, tetrazolyl,
Benzyl, pyridylmethyl, pyrimidinylmethyl, pyridazinylmethyl, pyrazinylmethyl, tetrazolylmethyl, hydroxyl group, alkoxy group having 1 to 3 carbon atoms or -NR
³⁹ R ⁴⁰ (R ³⁹ and R ⁴⁰ are as defined above). (D) a 5- to 7-membered saturated nitrogen-containing heterocyclic group together with a nitrogen atom (a 5- to 7-membered saturated nitrogen-containing heterocyclic group is a group consisting of an alkyl group, an amino group, a hydroxyl group, an alkoxy group, and an oxo group; And may be substituted with one or two substituents arbitrarily selected from.

[0008] (2) R²⁶And R²⁷Are two together
5-7 membered saturated nitrogen-containing heterocycle with nitrogen and carbon atoms
Group (where the 5- to 7-membered saturated nitrogen-containing heterocyclic group is an alkyl
Group, amino group, hydroxyl group, alkoxy group and oxo group.
Substituted with one or two substituents arbitrarily selected from the group
It may be. ). R^{twenty five}And R²⁸Is independently water
An element atom, an alkyl group having 1 to 3 carbon atoms, acetyl or-
(CH_Two)_m-OR³⁶(M and R³⁶Is as defined above
You. ). Formula (3): = C (NR^{twenty five}R²⁶) NR²⁷R²⁸Is the formula: = C
(NR⁴¹R⁴²) N = C (NH_Two) NR⁴³R⁴⁴Represents R
⁴¹And R⁴²Is the following (a¹) Or (b)¹) On the street
Yes, R⁴³And R ⁴⁴Is the following (c¹) Or (d¹)
It is as follows. (A¹) Independently a hydrogen atom, an alkyl having 1 to 4 carbon atoms
Group,-(CH_Two)_n-COCH_Three(N is as defined above.
You. ),-(CH_Two)_n-CO_TwoR³²(N and R³²Is before
Synonymous with ),-(CH_Two)_n-CONR³³R
³⁴(N, R³³And R³⁴Is as defined above. ),-
(CH_Two)_m-OR³⁵(M and R³⁵Is as defined above
You. ),-(CH_Two)_m-NR³⁷R³⁸(M, R³⁷And R
³⁸Is as defined above. ), Phenyl, pyridyl, pyri
Midinyl, pyridazinyl, pyrazinyl, tetrazolyl,
Benzyl, pyridylmethyl, pyrimidinylmethyl, pyri
Dazinylmethyl, pyrazinylmethyl, tetrazolylmethyl
, A hydroxyl group, an alkoxy group having 1 to 3 carbon atoms or -NR
³⁹R⁴⁰(R³⁹And R⁴⁰Is as defined above. )
You. (B¹5) together with the nitrogen atom,
A nitrogen heterocyclic group (a 5- to 7-membered saturated nitrogen-containing heterocyclic group is
Group, amino group, hydroxyl group, alkoxy group, oxo group
Substituted with one or two substituents arbitrarily selected from the group consisting of
May be done. ). (C¹) Independently a hydrogen atom, an alkyl having 1 to 4 carbon atoms
Group,-(CH_Two)_n-COCH_Three(N is as defined above.
You. ),-(CH_Two)_n-CO_TwoR³²(N and R³²Is before
Synonymous with ),-(CH_Two)_n-CONR³³R
³⁴(N, R³³And R³⁴Is as defined above. ),-
(CH_Two)_m-OR³⁵(M and R³⁵Is as defined above
You. ),-(CH_Two)_m-NR³⁷R³⁸(M, R³⁷And R
³⁸Is as defined above. ), Phenyl, pyridyl, pyri
Midinyl, pyridazinyl, pyrazinyl, tetrazolyl,
Benzyl, pyridylmethyl, pyrimidinylmethyl, pyri
Dazinylmethyl, pyrazinylmethyl, tetrazolylmethyl
, A hydroxyl group, an alkoxy group having 1 to 3 carbon atoms or -NR
³⁹R⁴⁰(R³⁹And R⁴⁰Is as defined above. )
You. (D¹5) together with the nitrogen atom,
A nitrogen heterocyclic group (a 5- to 7-membered saturated nitrogen-containing heterocyclic group is
Group, amino group, hydroxyl group, alkoxy group, oxo group
Substituted with one or two substituents arbitrarily selected from the group consisting of
May be done. ). ]

Or the formula:

Embedded image [Wherein, G ¹ , R ²³ and R ²⁴ are as defined above. ^{Formula: -N (R 45) C (} NR 46 R 47) = NR 48 is shown in the following (1 ¹⁾ or (2 ^{1). (1 1)} R ⁴⁵ represents an alkyl group or an acetyl having 1 to 3 carbon atoms. R ⁴⁸ represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or acetyl. R ⁴⁶ and R ⁴⁷ are as follows (a ² ) or (b ² ). (A ²⁾ independently represent a hydrogen atom, an alkyl group having 1 to 4 carbon _{atoms, - (CH 2) n -COCH} 3 (n is as defined _{above.), - (CH 2)} n -CO 2 R 32 (N and R ³² are as defined above),-(CH ₂ ) _n -CONR ³³ R
³⁴ (n, R ³³ and R ³⁴ are as defined above),-
(CH ₂ ) _m —OR ³⁵ (m and R ³⁵ are as defined above), — (CH ₂ ) _m —NR ³⁷ R ³⁸ (m, R ³⁷ and R
³⁸ is as defined above. ), Phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, tetrazolyl,
Benzyl, pyridylmethyl, pyrimidinylmethyl, pyridazinylmethyl, pyrazinylmethyl, tetrazolylmethyl, hydroxyl group, alkoxy group having 1 to 3 carbon atoms or -NR
³⁹ R ⁴⁰ (R ³⁹ and R ⁴⁰ are as defined above). (B ² ) a 5- to 7-membered saturated nitrogen-containing heterocyclic group together with a nitrogen atom (the 5- to 7-membered saturated nitrogen-containing heterocyclic group comprises an alkyl group, an amino group, a hydroxyl group, an alkoxy group, and an oxo group; And may be substituted with one or two substituents arbitrarily selected from the group). (2 ¹⁾ R ⁴⁵ and R ^46, together with the nitrogen atom taken together with 5- to 7-membered saturated nitrogen-containing Hajime Tamaki (wherein 5-7 membered saturated nitrogen-containing heterocyclic group, an alkyl group, an amino group , Hydroxyl,
It may be substituted with one or two substituents arbitrarily selected from the group consisting of an alkoxy group and an oxo group. ).
R ⁴⁷ and R ^{48 each} independently represent a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, acetyl or — (CH ₂ ) _m —OR ³⁶ (m
And R ³⁶ are as defined above. ). ] The medicament according to [1], comprising the isoxazole derivative represented by the formula: or a pharmaceutically acceptable salt thereof.

[9] Equation:

Embedded image Wherein G ² is 2-fluoro-biphenyl-4-yl, 2′-fluoro-biphenyl-4-yl or 3-
Represents benzoylphenyl. R ⁴⁹ represents methyl. R
⁵⁰ represents a hydrogen atom, methyl, methoxy or ethoxy. ^{Formula: = C (NR 51 R 52} ) NR 53 R 54 , the following (1 ^2), is as (2 ²⁾ or (3 ^2). (1 ² ) R ⁵¹ and R ⁵² are the following (a ³ ), (b ³ ) or (c ³ ), and R ⁵³ and R ⁵⁴ are the following (d ³ ), (e ³ ) Or (f ³ ). (A ³ ) independently represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. (B ³ ) one represents a hydrogen atom and the other is — (CH ₂ ) _n −
COCH ₃ (n is as defined _{above.), - (CH 2)} n
—CO ₂ R ³² (n and R ³² are as defined above),
— (CH ₂ ) _n —CONR ³³ R ³⁴ (n is as defined above. R ³³ and R ³⁴ independently represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms), and — (CH ₂ ) _m -OR ³⁵
(M and R ³⁵ are as defined above) or-(CH
_{^{2) m -NR 3 7 R 38}} (m, R 37 and R ³⁸ represent the same as defined above.). (C ³ ) together with a nitrogen atom, pyrrolidine, azepane, morpholine, thiazoline, piperidin-2-one, piperidin-4-one, thiamorpholine, carbon number 1
Piperazine which may be substituted at the 4-position with an alkyl group having 1 to 3 carbon atoms, piperidine which may be substituted at the 4-position with an alkoxy group having 1 to 3 carbon atoms, 4-hydroxypiperidine, or 1
Alternatively, piperidine substituted at the 4-position with an amino group which may be substituted with two alkyl groups having 1 to 3 carbon atoms (in these, pyrrolidine, azepane, morpholine, thiazoline, piperidin-2-one, piperidine-4-one) on,
Thiamorpholine, piperazine optionally substituted at the 4-position with an alkyl group having 1 to 3 carbon atoms, piperidine optionally substituted at the 4-position with an alkoxy group having 1 to 3 carbon atoms, 4-hydroxypiperidine, and 1 or 2 The piperidine substituted at the 4-position with an amino group optionally substituted with an alkyl group having 1 to 3 carbon atoms may be substituted with 1 or 2 methyl. ).

(D ³ ) Independently hydrogen or C 1-4
Represents an alkyl group. (E ³ ) one represents a hydrogen atom and the other is — (CH ₂ ) _n −
COCH ₃ (n is as defined _{above.), - (CH 2)} n
—CO ₂ R ³² (n and R ³² are as defined above),
— (CH ₂ ) _n —CONR ³³ R ³⁴ (n, R ³³ and R ³⁴ are as defined above), and — (CH ₂ ) _m —OR ³⁵ (m and R ³⁵ are as defined above) or - (CH _{2) m} -N
R ³⁷ R ³⁸ (m, R ³⁷ and R ³⁸ are as defined above)
Represents (F ³ ) together with a nitrogen atom, pyrrolidine, azepane, morpholine, thiazoline, piperidin-2-one, piperidin-4-one, thiamorpholine, carbon number 1
Piperazine which may be substituted at the 4-position with an alkyl group having 1 to 3 carbon atoms, piperidine which may be substituted at the 4-position with an alkoxy group having 1 to 3 carbon atoms, 4-hydroxypiperidine, or 1
Alternatively, piperidine substituted at the 4-position with an amino group which may be substituted with two alkyl groups having 1 to 3 carbon atoms (in these, pyrrolidine, azepane, morpholine, thiazoline, piperidin-2-one, piperidine-4-one) on,
Thiamorpholine, piperazine optionally substituted at the 4-position with an alkyl group having 1 to 3 carbon atoms, piperidine optionally substituted at the 4-position with an alkoxy group having 1 to 3 carbon atoms, 4-hydroxypiperidine, and 1 or 2 The piperidine substituted at the 4-position with an amino group optionally substituted with an alkyl group having 1 to 3 carbon atoms may be substituted with 1 or 2 methyl. ). (2 ^{2): = C (NR 51 R 52} ) NR 53 R 54 has the formula:

Embedded image (Wherein, R ⁵⁵ is an alkyl group having 1 to 3 carbon atoms, acetyl or — (CH ₂ ) _m —OR ⁵⁶ (m is as defined above).
R ⁵⁶ represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms. ). ) Represents a group represented by (3 ^{2): = C (NR 51 R 52} ) NR 53 R 54 has the formula: =
Represents a ^{C (NR 57 R 58) N} = C (NH 2) NR 59 R 60.
R ⁵⁷ and R ⁵⁸ represent the following (a ⁴ ), (b ⁴ ) or (c
⁴⁾ as, R ^{5 9} and R ⁶⁰ are the following (d ^4),
(E ⁴ ) or (f ⁴ ). (A ⁴ ) independently represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. (B ⁴ ) one represents a hydrogen atom and the other is — (CH ₂ ) _n −
COCH ₃ (n is as defined _{above.), - (CH 2)} n
—CO ₂ R ³² (n and R ³² are as defined above),
— (CH ₂ ) _n —CONR ³³ R ³⁴ (n, R ³³ and R ³⁴ are as defined above), and — (CH ₂ ) _m —OR ³⁵ (m and R ³⁵ are as defined above) or - (CH _{2) m} -N
R ³⁷ R ³⁸ (m, R ³⁷ and R ³⁸ are as defined above)
Represents (C ⁴ ) together with a nitrogen atom, pyrrolidine, azepane, morpholine, thiazoline, piperidin-2-one, piperidin-4-one, thiamorpholine, carbon number 1
Piperazine which may be substituted at the 4-position with an alkyl group having 1 to 3 carbon atoms, piperidine which may be substituted at the 4-position with an alkoxy group having 1 to 3 carbon atoms, 4-hydroxypiperidine, or 1
Alternatively, piperidine substituted at the 4-position with an amino group which may be substituted with two alkyl groups having 1 to 3 carbon atoms (in these, pyrrolidine, azepane, morpholine, thiazoline, piperidin-2-one, piperidine-4-one) on,
Thiamorpholine, piperazine optionally substituted at the 4-position with an alkyl group having 1 to 3 carbon atoms, piperidine optionally substituted at the 4-position with an alkoxy group having 1 to 3 carbon atoms, 4-hydroxypiperidine, and 1 or 2 The piperidine substituted at the 4-position with an amino group optionally substituted with an alkyl group having 1 to 3 carbon atoms may be substituted with 1 or 2 methyl. ). (D ⁴ ) independently represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. (E ⁴ ) one represents a hydrogen atom and the other is — (CH ₂ ) _n −
COCH ₃ (n is as defined _{above.), - (CH 2)} n
—CO ₂ R ³² (n and R ³² are as defined above),
— (CH ₂ ) _n —CONR ³³ R ³⁴ (n, R ³³ and R ³⁴ are as defined above), and — (CH ₂ ) _m —OR ³⁵ (m and R ³⁵ are as defined above) or - (CH _{2) m} -N
R ³⁷ R ³⁸ (m, R ³⁷ and R ³⁸ are as defined above)
Represents (F ⁴ ) together with a nitrogen atom, pyrrolidine, azepane, morpholine, thiazoline, piperidin-2-one, piperidin-4-one, thiamorpholine, carbon number 1
Piperazine which may be substituted at the 4-position with an alkyl group having 1 to 3 carbon atoms, piperidine which may be substituted at the 4-position with an alkoxy group having 1 to 3 carbon atoms, 4-hydroxypiperidine, or 1
Alternatively, piperidine substituted at the 4-position with an amino group which may be substituted with two alkyl groups having 1 to 3 carbon atoms (in these, pyrrolidine, azepane, morpholine, thiazoline, piperidin-2-one, piperidine-4-one) on,
Thiamorpholine, piperazine optionally substituted at the 4-position with an alkyl group having 1 to 3 carbon atoms, piperidine optionally substituted at the 4-position with an alkoxy group having 1 to 3 carbon atoms, 4-hydroxypiperidine, and 1 or 2 The piperidine substituted at the 4-position with an amino group optionally substituted with an alkyl group having 1 to 3 carbon atoms may be substituted with 1 or 2 methyl. ). ] The medicament according to [1], comprising the isoxazole derivative represented by the formula: or a pharmaceutically acceptable salt thereof.

[10] Equation:

Embedded image[Where G^Two, R⁴⁹And R⁵⁰Is as defined above. Formula: = C (NR⁶¹R⁶²) NR⁶³R⁶⁴Is the following
(1^Three), (2^Three) Or (3)^ThreeA). (1^Three) R⁶³And R⁶⁴Both represent a hydrogen atom. R⁶¹
And R⁶²Is the following (a^Five), (B)^Five) Or (c)^Five)
It is as follows. (A^Five) Independently a hydrogen atom or an alkyl having 1 to 3 carbon atoms
Represents a hydroxyl group. (B^FiveOne represents a hydrogen atom and the other represents-(CH_Two)_n−
CO_TwoR³²(N and R ³²Is as defined above. ),-
(CH_Two)_m-OR⁶⁵(M is as defined above. R ⁶⁵Is
Hydrogen atom, alkyl group having 1 to 3 carbon atoms, 2-hydroxy
Represents ethyl or 3-hydroxypropyl. ) Or
− (CH_Two)_m-NR⁶⁶R⁶⁷(M is as defined above. R
⁶⁶And R⁶⁷Is independently a hydrogen atom or a group having 1 to 3 carbon atoms.
Represents an alkyl group of⁶⁶And R⁶⁷Together
Together with the nitrogen atom, pyrrolidine, piperidine,
Holin or N-methylpiperazine (in these,
Pyrrolidine, piperidine, morpholine and N-methyl
Piperazine may be substituted with one or two methyls.
No. ). ). (C^Five) Together with the nitrogen atom, pyrrolidine,
Peridine, morpholine or N-methylpiperazine (this
In these, pyrrolidine, piperidine, morpholine and
And N-methylpiperazine are one or two methyl
It may be replaced. ). (2^ThreeFormula: = C (NR⁶¹R⁶²) NR⁶³R⁶⁴But the formula:

Embedded image (R ⁶⁸ represents an alkyl group having 1 to 3 carbon atoms, 2-hydroxyethyl or 3-hydroxypropyl). ^{(3 3)} R ⁶¹ and R ^62, together with the nitrogen atom together represent morpholine, R ⁶³ and R ^64, taken together, amino - represents a methylene - morpholin-4-yl. ] The medicament according to [1], comprising the isoxazole derivative represented by the formula: or a pharmaceutically acceptable salt thereof.

[11] The medicament according to [1], comprising an isoxazole derivative selected from the following compounds or a pharmaceutically acceptable salt thereof. ({3- [1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylimino}-
Morpholin-4-yl-methyl) -amine [{3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylimino}-
(4-Methyl-piperazin-1-yl) -methyl] -amine N- {3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-yl} -N'-
(2-morpholin-4-yl-ethyl) -guanidine ({3- [1- (2-fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-ylimino} -morpholine-4- Yl-methyl) -amine [{3- [1- (2-fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-ylimino}-(4-methyl-piperazin-1-yl) −
Methyl] -amine N- {3- [1- (2-fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-yl} -N '-(2-morpholin-4-yl- Ethyl)-
Guanidine ({3- [1- (2'-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylimino}-
Morpholin-4-yl-methyl) -amine [{3- [1- (2'-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylimino}-
(4-Methyl-piperazin-1-yl) -methyl] -amine N- {3- [1- (2'-fluoro-biphenyl-4-)
Yl) -ethyl] -isoxazol-5-yl {-N '
-(2-morpholin-4-yl-ethyl) -guanidine ({3- [1- (2'-fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-ylimino} -morpholine- 4-yl-methyl) -amine [{3- [1- (2'-fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-ylimino}-(4-methyl-piperazine-1 -Il)-
Methyl] -amine N- {3- [1- (2'-fluoro-biphenyl-4-
Yl) -1-methyl-ethyl] -isoxazole-5
Yl @ -N '-(2-morpholin-4-yl-ethyl)
-Guanidine (3- {1- [5- (amino-morpholin-4-yl-
Methyleneamino) -isoxazol-3-yl] -ethyl} -phenyl) -phenyl-methanone [3- (1- {5- [amino- (4-methyl-piperazin-1-yl) -methyleneamino] -isoxazole-
3-yl {-ethyl) -phenyl] -phenyl-methanone N- {3- [1- (3-benzoyl-phenyl) -ethyl] -isoxazol-5-yl} -N '-(2-morpholin-4- Yl-ethyl) -guanidine (3- {1- [5- (amino-morpholin-4-yl-
Methyleneamino) -isoxazol-3-yl] -1-
Methyl-ethyl} -phenyl) -phenyl-methanone [3- (1- {5- [amino- (4-methyl-piperazin-1-yl) -methyleneamino] -isoxazole-
3-yl} -1-methyl-ethyl) -phenyl] -phenyl-methanone N- {3- [1- (3-benzoyl-phenyl) -1-]
Methyl-ethyl] -isoxazol-5-yl {-N ′
-(2-morpholin-4-yl-ethyl) -guanidine

[12] The medicament according to any one of [1] to [11], which is a therapeutic or prophylactic agent for an autoimmune disease. [13] The medicament according to any one of [1] to [11], which is a therapeutic or prophylactic agent for an inflammatory disease. [14] The medicament according to any one of [1] to [11], which is an antirheumatic agent. [15] The medicament according to any one of [1] to [11], which is an anti-inflammatory agent.

Examples of the aryl group include an aryl group having 6 to 14 carbon atoms, and specific examples include phenyl, 1-naphthyl, 2-naphthyl, phenanthryl, anthryl and the like. Preferably, phenyl, 1-naphthyl,
2-naphthyl is exemplified. Examples of the heterocyclic group include a 1 to 3 5- to 7-membered saturated or unsaturated heterocyclic group containing 1 to 6 nitrogen, oxygen and / or sulfur atoms. As such a saturated heterocyclic group, specifically, tetrahydrofuryl, pyrrolidinyl,
One to three-membered 5-membered saturated heterocyclic group such as pyrazolidinyl and imidazolidinyl; and one to three-membered 6-membered saturated heterocyclic group such as piperidyl, morpholinyl, thiamorpholinyl, piperazinyl and hexahydro-pyrimidinyl;
And 3 to 7-membered saturated heterocyclic groups. As such unsaturated heterocyclic groups, specifically, furyl, thienyl,
Indolyl, isothiazolyl, benzothienyl, isobenzofuranyl, pyrrolyl, benzofuryl, imidazolyl, 4,5-dihydro-1H-imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, thiazolyl, oxazolyl, benzimidazolyl, benzothiazolyl,
1-3-membered 5-membered unsaturated heterocyclic group such as benzoxazolyl and carbazolyl, pyridyl, pyrazinyl, pyrimidinyl, 1,4,5,6-tetrahydro-pyrimidinyl,
3,6-dihydro-2H- [1,3,5] oxadiazinyl, pyridazinyl, triazinyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, chromenyl,
1-3 ring 6-membered unsaturated heterocyclic group such as 2,3-dihydro-benzo [1,4] dioxanyl, and 1 such as 4,5,6,7-tetrahydro-1H- [1,3] diazepinyl ~ 3
And a 7-membered unsaturated heterocyclic group of a ring.

[0016] Substitution in substituted aryl group and substituted heterocyclic group
Examples of the substituent include each of the following groups a) to g):
And any one or more of these
May be replaced. a): halogen atom, nitro group, cyano group, azide
Group, mercapto group, amino group which may be substituted,
An optionally substituted hydroxylamino group, an optionally substituted low
Secondary alkoxyamino group, hydroxyl group, acyl group, acyloxy
Si group, carboxyl group, carbamoyl which may be substituted
Group, carbamoyloxy group which may be substituted, sulfo
Group, a sulfamoyl group which may be substituted b): -R^Ten, -OR^Ten, -CO_TwoR^Ten, -SO
_ThreeR^Ten, -SR^Ten, -OCH _TwoR^Ten, -SCH_TwoR^Ten, −
C (= NOH) R^Ten  [Wherein, R^TenRepresents a phenyl group or a monocyclic heterocyclic group.
You. A phenyl group or a monocyclic heterocyclic group is, for example, halogen
Atom, lower alkyl group, lower haloalkyl group, cyano
Group, nitro group, azide group, hydroxyl group, lower alkoxy group,
Lower haloalkoxy group, optionally substituted amino group,
A carbamoyl group, a carboxy group, a lower
Alkylcarbonyl group, lower alkoxycarbonyl group, low
Lower alkylthio group, lower alkylsulfinyl group and
Any one selected from the group consisting of a lower alkylsulfonyl group and the like;
Alternatively, it may be substituted with a plurality of groups. ]

C): an alkyl group, an alkoxy group, an alkoxycarbonyl group, an alkoxy (thiocarbonyl) group, an alkylthio group, a (alkylthio) thiocarbonyl group,
(Alkylthio) carbonyl group, alkylcarbonyl group, alkylthioyl group, alkylsulfinyl group, alkylsulfonyl group, alkylcarbonyloxy group, alkylthioyloxy group, alkylsulfonyloxy group [each group in this group is, for example, a halogen atom, a nitro group. , Cyano group, mercapto group, oxo group, thioxo group, optionally substituted amino group, hydroxyl group, acyl group, acyloxy group, carboxy group, optionally substituted carbamoyl group,
Optionally substituted carbamoyloxy group, a sulfo group, an optionally substituted sulfamoyl group, -R ^10, -OR ^{10,
_{-SR 10, -OCH 2 R 10,}} -SCH 2 R 10 ( wherein, R ¹⁰
Is as defined above. ), Lower cycloalkyl group (lower cycloalkyl group is arbitrarily selected from the group of halogen atom, lower alkyl group, lower haloalkyl group, optionally substituted amino group, hydroxyl group, lower alkoxy group, lower haloalkoxy group, etc.) Lower alkoxy group, lower alkoxycarbonyl group and lower alkylthio group (lower alkoxy group, lower alkoxycarbonyl group and lower alkylthio group include, for example, halogen atom, lower cycloalkyl group , A monocyclic heterocyclic group, a phenyl group, a cyano group, a nitro group, a hydroxyl group, a lower alkoxy group, a lower haloalkoxy group, an optionally substituted amino group, an optionally substituted carbamoyl group, a carboxy group, and a lower alkylcarbonyl Group, lower alkoxycarbonyl group, lower alkylthio group Group, lower alkylsulfinyl group, lower alkylsulfonyl group, etc., may be substituted with one or more groups arbitrarily selected from the group consisting of Good. D): alkenyl group [alkenyl group includes, for example, halogen atom, nitro group, cyano group, mercapto group, oxo group, thioxo group, amino group which may be substituted, hydroxyl group, lower alkoxy group, lower haloalkoxy group, lower Alkoxycarbonyl group, lower alkylthio group, acyl group, acyloxy group, carboxy group, carbamoyl group which may be substituted, -R ¹⁰ , -O
_{^{R 10, -SR 10, -OCH 2}} R 10 and -SCH ₂ R
¹⁰ (wherein, R ¹⁰ has the same meaning as described above) and the like. ]

E): Alkynyl group [Alkynyl group is, for example, halogen atom, nitro group, cyano group, mercapto group, oxo group, thioxo group, optionally substituted amino group, hydroxyl group, lower alkoxy group, lower haloalkoxy group A lower alkoxycarbonyl group, a lower alkylthio group, an acyl group, an acyloxy group, a carboxy group, an optionally substituted carbamoyl group, -R ¹⁰ , -O
_{^{R 10, -SR 10, -OCH 2}} R 10 and -SCH ₂ R
¹⁰ (wherein, R ¹⁰ has the same meaning as described above) and the like. F): alkenyloxy group, alkenyloxycarbonyl group, alkenylcarbonyl group, alkenylcarbonyloxy group, alkynyloxy group, alkynyloxycarbonyl group [each group in this group is, for example, a halogen atom, an oxo group, or may be substituted; Amino group, hydroxyl group, lower alkoxy group,
Lower haloalkoxy group, acyl group, acyloxy group, lower alkylthio group, carboxy group, carbamoyl group which may be substituted, lower alkoxycarbonyl group and phenyl group; Is also good. G): lower cycloalkyl group, lower cycloalkyloxy group, lower cycloalkylcarbonyl group, lower cycloalkylcarbonyloxy group, lower cycloalkyloxycarbonyl group, lower cycloalkenyl group, lower cycloalkenyloxy group, lower cycloalkenylcarbonyl Group, lower cycloalkenylcarbonyloxy group, lower cycloalkenyloxycarbonyl group [each group in this group is, for example, a halogen atom, a nitro group, a cyano group, a mercapto group, an oxo group, a thioxo group, a lower alkyl group, a lower haloalkyl group, Optionally substituted amino group, hydroxyl group, lower alkoxy group, lower haloalkoxy group, acyl group, acyloxy group, lower alkylthio group,
It may be substituted with one or more groups arbitrarily selected from a group such as a carboxy group, a carbamoyl group which may be substituted, and a lower alkoxycarbonyl group. ]

Specific examples of the substituent of the substituted aryl group and the substituted heterocyclic group include methyl, 2-methyl-1-propyl, hexyl, 2-methyl-2-propyl, 2-propyl, phenyl, and trifluoromethyl. , 2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl, 6,6,6-trifluorohexyl, hydroxymethyl, hydroxyethyl, methoxymethyl, hexyloxymethyl, cyclopropyl Methoxymethyl, acetoxymethyl, N, N-dimethylcarbamoyloxymethyl, methanesulfonyloxymethyl, N, N-dimethylsulfamoyloxymethyl, 2- (1-pyrrolidinyl) ethoxymethyl, 2-methoxyethyl, carboxymethyl, methoxy Carbonylmethyl, carbamoylmethyl, amidinomethyl, Methylthiomethyl, cyanomethyl, aminomethyl, aminoethyl, N-acetylaminomethyl, ethenyl, 2-propenyl, ethynyl, 2-propynyl, 2-methoxycarbonylethenyl, fluoro, chloro, bromo, nitro, cyano, hydroxy, amino, N, N-dimethylamino, mercapto, sulfo,
Carboxy, amidino, methoxy, cyclopropylmethoxy, 2- (1-pyrrolidinyl) ethoxy, methoxycarbonylmethoxy, 2-acetoxyethoxy, 2-hydroxyethoxy, 2-methoxyethoxy, 4,4,5
5,5-pentafluoropentoxy, 2-methanesulfinylethoxy, phenoxy, benzyloxy, 4-methoxybenzyloxy, methoxycarbonyloxy,
-Pyrrolidinyl, 3-hydroxy-1-pyrrolidinyl,
Acetylamino, N-acetyl-N-methylamino, N
-Methanesulfonylamino, N-methanesulfonyl-N
-Methylamino, methoxycarbonyl, 2-methyl-2
-Propyloxycarbonyl, 2,2,2-trifluoroethoxycarbonyl, carbamoyl, N, N-dimethylcarbamoyl, 2-thiazolidinyl, 2-oxazolidinyl, 5-tetrazolyl, methanesulfinyl, sulfamoyl, N, N-dimethylsulfamoyl , Acetyl, benzoyl, pivaloyl, trifluoroacetyl,
Formyl, ethylenedioxymethyl, imino, methoxyimino and the like can be mentioned.

Preferred examples of the substituent include methyl, 2-methyl-1-propyl, hexyl, 2-methyl-2-propyl, 2-propyl, phenyl, trifluoromethyl, 2,2 , 2-trifluoroethyl, hydroxymethyl, hydroxyethyl, methoxymethyl, cyclopropylmethoxymethyl, acetoxymethyl, N, N-dimethylcarbamoyloxymethyl, methanesulfonyloxymethyl, N, N-dimethylsulfamoyloxymethyl, -(1-pyrrolidinyl) ethoxymethyl, 2-methoxyethyl, carboxymethyl, methoxycarbonylmethyl, carbamoylmethyl, amidinomethyl, methylthiomethyl, cyanomethyl, aminomethyl, aminoethyl, N-acetylaminomethyl, fluoro, chloro, Bromo, nitro, cyano,
Hydroxy, amino, N, N-dimethylamino, methoxy, 2- (1-pyrrolidinyl) ethoxy, methoxycarbonylmethoxy, 2-acetoxyethoxy, 2-hydroxyethoxy, 2-methoxyethoxy, 2-methanesulfinylethoxy, 1-pyrrolidinyl , 3-hydroxy-1-pyrrolidinyl, acetylamino, N-acetyl-
N-methylamino, N-methanesulfonylamino, N-
Methanesulfonyl-N-methylamino, methoxycarbonyl, 2-methyl-2-propyloxycarbonyl,
Examples include 2,2,2-trifluoroethoxycarbonyl, carbamoyl, N, N-dimethylcarbamoyl, methanesulfinyl, acetyl, benzoyl, pivaloyl, trifluoroacetyl and the like. The preferred number of substituents in the aryl group and the heterocyclic group is 1, 2 or 3. Further, the aryl group and the heterocyclic group are preferably unsubstituted.

Examples of the alkyl group include a linear or branched alkyl group having 1 to 10 carbon atoms. Specifically, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methyl-1-propyl, 1,1-dimethylethyl, pentyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-methylbutyl, 3-methylbutyl, hexyl, 2-methylpentyl, 3,3- Examples include dimethylbutyl, heptyl, 1-ethylpentyl, 5-methylhexyl, octyl, 1,5-dimethylhexyl, 2-ethylhexyl, nonyl, decyl and the like. As the lower alkyl group, one having 1 to carbon atoms
And 6 alkyl groups.

Examples of the substituent in the substituted alkyl group include, for example, any of the following groups a) to d), and these groups may be arbitrarily substituted one or more times. a): halogen atom, nitro group, cyano group, mercapto group, oxo group, thioxo group, optionally substituted amino group, optionally substituted hydroxylamino group, optionally substituted lower alkoxyamino group, hydroxyl group, acyl Group,
Acyloxy group, carboxy group, carbamoyl group which may be substituted, carbamoyloxy group which may be substituted,
Sulfo group, sulfamoyl group which may be substituted b): lower cycloalkyl group, lower cycloalkyloxy group, lower cycloalkylcarbonyl group, lower cycloalkylcarbonyloxy group, lower cycloalkyloxycarbonyl group, lower cycloalkenyl group, lower Cycloalkenyloxy group, lower cycloalkenylcarbonyl group, lower cycloalkenylcarbonyloxy group, lower cycloalkenyloxycarbonyl group [each group in this group includes, for example, a halogen atom, a nitro group, a cyano group, a mercapto group, an oxo group, a thioxo group; A lower alkyl group, a lower haloalkyl group, an amino group which may be substituted, a hydroxyl group, a lower alkoxy group, a lower haloalkoxy group, an acyl group, an acyloxy group, a lower alkylthio group,
It may be substituted with one or more groups arbitrarily selected from a group such as a carboxy group, a carbamoyl group which may be substituted, and a lower alkoxycarbonyl group. ]

C): alkoxy, alkoxycarbonyl, alkoxy (thiocarbonyl), alkylthio, (alkylthio) thiocarbonyl, (alkylthio) carbonyl, alkylcarbonyl, alkylthioyl, alkylsulfinyl, alkylsulfonyl Group, alkylcarbonyloxy group, alkylthioyloxy group, alkylsulfonyloxy group [each group in this group is, for example, a halogen atom, a nitro group, a cyano group, a mercapto group, an oxo group, a thioxo group, an optionally substituted amino group; A hydroxyl group, an acyl group, an acyloxy group, a carboxy group, a carbamoyl group which may be substituted,
Optionally substituted carbamoyloxy group, a sulfo group, an optionally substituted sulfamoyl group, -R ^10, -OR ^{10,
_{-SR 10, -OCH 2 R 10,}} -SCH 2 R 10 ( wherein, R ¹⁰
Is as defined above. ), Lower cycloalkyl group (lower cycloalkyl group is arbitrarily selected from the group of halogen atom, lower alkyl group, lower haloalkyl group, optionally substituted amino group, hydroxyl group, lower alkoxy group, lower haloalkoxy group, etc.) Lower alkoxy group, lower alkoxycarbonyl group and lower alkylthio group (lower alkoxy group, lower alkoxycarbonyl group and lower alkylthio group include, for example, halogen atom, lower cycloalkyl group , A monocyclic heterocyclic group, a phenyl group, a cyano group, a nitro group, a hydroxyl group, a lower alkoxy group, a lower haloalkoxy group, an optionally substituted amino group, an optionally substituted carbamoyl group, a carboxy group, and a lower alkylcarbonyl Group, lower alkoxycarbonyl group, lower alkylthio group Group, lower alkylsulfinyl group, lower alkylsulfonyl group, etc., may be substituted with one or more groups arbitrarily selected from the group consisting of Good. ^{] D): -R 10, -OR} 10, -SR 10, -OCH
_{^{2 R 10, -SCH 2 R 10}} ( wherein, R ¹⁰ is as defined above.)

As the substituted alkyl group, specifically, trifluoromethyl, 2-nitroethyl, 2-cyanopropyl,
4-mercaptobutyl, 3-oxobutyl, 2-piperidinoethyl, 2-hydroxyethyl, 3-methoxypropyl, ethoxycarbonylmethyl, cyclopropylmethyl, cyclohexylmethyl, 6-cyclohexylhexyl, 3-cyclohexenylbutyl, 2-phenylbutyl, Benzyl, 2-naphthylmethyl, phenethyl, 2-
Pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-quinolylmethyl, 3-quinolylmethyl, 3-
Thienylpropyl, hydroxymethyl, hydroxyethyl, aminomethyl, aminoethyl, carboxymethyl,
Ethoxycarbonylmethyl, carbamoylmethyl and the like. In addition, a lower haloalkyl group refers to a lower alkyl group substituted with 1 to 5 halogen atoms.

[0025] The alkoxy group refers to an oxy group to which an alkyl group is bonded. Specific examples include methoxy, ethoxy, propoxy, 2-propoxy, butoxy, 1,1-dimethylethoxy, pentoxy, hexoxy and the like. Examples of the substituent of the substituted alkoxy group include the same as the substituent of the substituted alkyl group. Specific examples of the substituted alkoxy group include cyclopropylmethoxy, trifluoromethoxy, 2-pyrrolidinoethoxy, benzyloxy, 2-pyridylmethoxy and the like. In addition, the haloalkoxy group refers to an alkoxy group substituted with 1 to 5 halogen atoms. An alkoxycarbonyl group refers to a carbonyl group to which an alkoxy group is bonded. Specific examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 2-propoxycarbonyl and the like. Examples of the substituent in the substituted alkoxycarbonyl group include the same substituents as those in the substituted alkyl group.

Examples of the alkenyl group include a linear or branched alkenyl group having 2 to 10 carbon atoms and having 1 to 3 double bonds. Specifically, ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 4-pentenyl , 3-methyl-2-butenyl, 1-hexenyl,
2-hexenyl, 1-heptenyl, 2-heptenyl, 1
-Octenyl, 2-octenyl, 1,3-octadienyl, 2-nonenyl, 1,3-nonadienyl, 2-decenyl and the like. Preferred alkenyl groups include, for example, ethenyl, 1-propenyl and 1-butenyl groups. Examples of the lower alkenyl group include alkenyl groups having 2 to 6 carbon atoms. Examples of the substituent of the substituted alkenyl group include a halogen atom, a nitro group, a cyano group, a mercapto group, an oxo group, a thioxo group, an amino group which may be substituted, a hydroxyl group, a lower alkoxy group, a lower haloalkoxy group, and a lower alkoxycarbonyl group. , lower alkylthio group, an acyl group, an acyloxy group, a carboxy group, which may be substituted carbamoyl groups, -R ^10, -OR ^10, -S
_{^{R 10, -OCH 2 R 10,}} -SCH 2 R 10 ( wherein, R ¹⁰ is as defined above.), And the like. Further, an alkenyloxy group refers to an oxy group to which an alkenyl group is bonded.

Examples of the alkynyl group include linear or branched alkynyl groups having 2 to 10 carbon atoms and having 1 to 3 triple bonds. Specifically, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3
-Butynyl, 1-pentynyl, 2-pentynyl, 4-pentynyl, 1-octynyl, 6-methyl-1-heptynyl, 2-decynyl and the like. Preferred alkynyl groups include, for example, 1-propynyl, 1-butynyl and the like. The lower alkynyl group has 2 to 2 carbon atoms.
And 6 alkynyl groups. Examples of the substituent of the substituted alkynyl group include a halogen atom, a nitro group, a cyano group, a mercapto group, an oxo group, a thioxo group, an amino group which may be substituted, a hydroxyl group, a lower alkoxy group, a lower haloalkoxy group, an acyl group, and an acyloxy group. group, a lower alkylthio group, a carboxy group, which may be substituted carbamoyl groups, lower alkoxycarbonyl groups, -R ^10, -OR ^{10,
_{-SR 10, -OCH 2 R 10,}} -SCH 2 R 10 ( wherein, R ¹⁰
Is as defined above. ) And the like. Further, an alkynyloxy group refers to an oxy group to which an alkynyl group is bonded.

Examples of the cycloalkyl group include, for example, those having 3 to 3 carbon atoms.
And 10 cycloalkyl groups, specifically, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Examples of the lower cycloalkyl group include a cycloalkyl group having 3 to 6 carbon atoms. Further, a cycloalkyloxy group refers to an oxy group to which a cycloalkyl group is bonded. Examples of the cycloalkenyl group include those having 3 to 10 carbon atoms, and specific examples include cyclohexenyl. Examples of the lower cycloalkenyl group include cycloalkenyl groups having 3 to 6 carbon atoms. Further, a cycloalkenyloxy group refers to an oxy group to which a cycloalkenyl group is bonded. Examples of the substituent of the substituted cycloalkyl group and the substituted cycloalkenyl group include a halogen atom, a nitro group,
Cyano group, mercapto group, oxo group, thioxo group, lower alkyl group, lower haloalkyl group, optionally substituted amino group, hydroxyl group, lower alkoxy group, lower haloalkoxy group, acyl group, acyloxy group, lower alkylthio group,
Examples thereof include a carboxy group, a carbamoyl group which may be substituted, and a lower alkoxycarbonyl group.

As the acyl group, for example, a group represented by the formula -ZR ¹¹ (where Z is -CO-, -CS-, -SO- or -SO ₂
And R ¹¹ represents an alkyl group which may be substituted, an aryl group which may be substituted, or a heterocyclic group which may be substituted. And the like. Specific examples of the acyl group include formyl, acetyl, propanoyl, 2-propanoyl, pivaloyl, valeryl, pivaloyl, trifluoroacetyl, benzoyl, naphthoyl, nicotinoyl, methanesulfonyl, trifluoromethanesulfonyl, and p-toluenesulfonyl. . Preferred acyl groups include an acetyl group. An acyloxy group refers to an oxy group to which an acyl group is bonded.

[0030] The substituent in the substituted carbamoyl group includes
Examples thereof include an alkyl group which may be substituted with an aryl group or a heterocyclic group, and an aryl group, a heterocyclic group, and the like, or a plurality of identical or different groups may be independently substituted. Specific examples of the substituted carbamoyl group include ethylcarbamoyl, dimethylcarbamoyl, phenylcarbamoyl, 2-pyridylcarbamoyl, benzylcarbamoyl, (3-pyridylmethyl) carbamoyl, and the like. Examples of the substituent in the substituted sulfamoyl group include an alkyl group, an aryl group, and a heterocyclic group. A plurality of the same or different substituents may be independently substituted. Specific examples of the substituted sulfamoyl group include ethylsulfamoyl, dimethylsulfamoyl, phenylsulfamoyl, 2-pyridylsulfamoyl and the like. Examples of the substituent in the substituted amino group include an acyl group and an alkyl group, and a plurality of the same or different substituents may be independently substituted. Specific substituted amino groups include acetamido, propionamido, butylamido, 2-butylamido, methylamino,
2-methyl-1-propylamino, diethylamino and the like. The substituent in the substituted hydroxylamino group may be substituted with any of a nitrogen atom and an oxygen atom, and examples of the substituent include the same substituents as those in the substituted amino group. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like.

Examples of the alkylene group include, for example, those having 1 to 10 carbon atoms.
Or a linear or branched alkylene group. Specifically, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene, decamethylene,
Methyl methylene, ethyl methylene, dimethyl methylene,
1,1-dimethylethylene, 1,2-dimethylethylene, 1-methyltrimethylene, 2-methyltrimethylene, 1,1-dimethyltrimethylene, 1,2-dimethyltrimethylene, 1,3-dimethyltrimethylene, 2,2
-Dimethyltrimethylene, 1-ethyltrimethylene, 2
-Ethyltrimethylene, 1,1-diethyltrimethylene, 1,2-diethyltrimethylene, 1,3-diethyltrimethylene, 2,2-diethyltrimethylene and the like. As the lower alkylene group, for example, having 1 to 1 carbon atoms
And 6 straight-chain or branched alkylene groups. N
As the protecting group for the H group, various types of protecting groups that are commonly used are possible, and preferably, for example, methoxycarbonyl,
Ethoxycarbonyl, tert-butoxycarbonyl,
Carbamate-type protecting groups such as benzyloxycarbonyl; amide-type protecting groups such as acetyl and benzoyl; benzyl, nitro, p-toluenesulfonyl, methanesulfonyl and the like.

Examples of the heterocyclic ring in the optionally substituted heterocyclic ring formed by bonding any ^{two of} R ¹ , R ² , R ³ and R ⁴ together with a nitrogen atom include, for example,
A 5- to 7-membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring containing 6 nitrogen atoms, oxygen atoms and / or sulfur atoms (including at least one nitrogen atom) is exemplified. Specifically, pyrrolidine, imidazolidine,
4,5-dihydro-1H-imidazole, piperidine,
Piperidin-4-one, piperazine, morpholine, thiamorpholine, 1,4,5,6-tetrahydro-pyrimidine, hexahydro-pyrimidine, 3,6-dihydro-2
H- [1,3,5] oxadiazine and the like can be mentioned. Examples of the substituent in the substituted heterocyclic ring include the same substituents as those in the substituted heterocyclic ring. Examples of the optionally substituted hydrocarbon ring in which R ⁸ and R ⁹ are bonded together to form a carbon atom include, for example, an optionally substituted cycloalkane ring having 3 to 8 carbon atoms or an optionally substituted cycloalkane ring. Examples thereof include a cycloalkene ring having 3 to 8 carbon atoms. As such a cycloalkane ring or a cycloalkene ring,
Specific examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, and the like. Examples of the substituent in the substituted hydrocarbon ring include the same substituents as those in the substituted cycloalkyl group.

The compound in which a polar functional group is introduced into the isoxazole ring in the isoxazole derivative of the formula 1 is particularly improved in pharmacokinetics, has few side effects, and can be administered for a long period of time. The present invention includes all stereoisomers, optically active forms and tautomers of the isoxazole derivative of the formula 1. The present invention also encompasses solvates such as hydrates of the isoxazole derivative of the formula 1 or a pharmaceutically acceptable salt thereof, and all forms of the crystalline form.

The pharmaceutically acceptable salts of the isoxazole derivatives of the formula 1 include acid addition salts and base addition salts. Examples of acid addition salts include hydrochloride, hydrobromide,
Inorganic acid salts such as sulfate, hydroiodide, nitrate and phosphate, citrate, oxalate, acetate, formate, propionate, benzoate, trifluoroacetate, fumarate , Maleate, tartrate, aspartate, glutamate, methanesulfonate, benzenesulfonate, camphor-sulfonate, and other organic acid salts. Base addition salts include sodium salts, potassium salts,
Inorganic base salts such as calcium salts, magnesium salts, and ammonium salts; and organic base salts such as triethylammonium salts, triethanolammonium salts, pyridinium salts, and diisopropylammonium salts.

The isoxazole derivative of the formula 1 can be produced, for example, by the following five methods. However,
In the reaction formulas shown below, only the case where A and B in Formula 1 have one definition will be described, but the derivative having the other definition can be similarly produced. Method 1

Embedded image[Where D, E, J, G, R¹, R^Two, R^Three, R^FourAnd break
The lines are as defined above. The isoxazole derivative (1a) of the present invention is a compound of the formula 2a
Compound and a guanidine derivative of formula 3
Of Mitsunobu reaction using fin and azodicarboxylic acid ester
Conditions (Chem. Lett., 1994, 539; Tetrahedron Lett.,Three
Five977 (1994)) in an inert solvent at a reaction temperature of 0 to 25.
It can be produced by reacting at ℃. bird
As the alkylphosphine, for example, triphenylphosphine
Fin, tributylphosphine and the like. Azodi
As the carboxylic acid ester, for example, azodicarboxylic acid
Diethyl, diisopropyl azodicarboxylate, 1, 1'-
(Azodicarbonyl) dipiperidine, N, N, N ', N'-tetra
Lamethylazodicarboxamide, N, N, N ', N'-tetra
Isopropyl azodicarboxamide and the like. Good
Preferred solvents include, for example, tetrahydrofuran,
Zen, toluene and the like. Smell of the compound of formula 1a
And R¹, R^Two, R^ThreeOr R^FourIs a protecting group for the NH group
In such a case, deprotection can be performed if desired. This pro
Protection can be performed according to common methods, for example P
rotective Groups in Organic Synthesis, 2nd Editio
n, T.W.Greene and P.G.M.Wuts, John Wiley and Sons,
 inc., New York (1991), p 315-362.
Can be As the protecting group for the NH group, various types commonly used
Although a protecting group of
Rubonyl, ethoxycarbonyl, tert-butoxyca
Carbamates such as rubonyl and benzyloxycarbonyl
Type protecting groups, amides such as N-acetyl, N-benzoyl
Type of protecting group, benzyl, nitro, p-toluenesulfoni
And methanesulfonyl.

[0036] 1) Preparation of E is a compound of formula 2a is an alkylene (a compound of formula 2a ¹⁾

Embedded image[Wherein, D, J and G are as defined above. E¹Is simply
Represents a bond or an alkylene group. R¹²Is a lower alkyl group
Represents General isoxazole synthesis methods (eg, A. R. Katrit
zky et al., Comprehensive Heteocyclic Chemistry, V
ol.6, Pergamon Press Ltd., New York (1984), p. 61)
Accordingly, the ester derivative of β-diketone of formula 4
Inactivates xyamine or hydroxylamine hydrochloride
Acting in a solvent to produce a compound of formula 5a
be able to. In that case, a compound of the formula 5b is also formed
However, by controlling the reaction conditions, the compound of formula 5a
Alternatively, only one of the compounds of formula 5b may be prepared.
(For example, F. Lepage et al., Eur. J. Med. Chem.,Two
7A. R. Katritzky et al., Compre, supra.
hensive Heteocyclic Chemistry, Vol. 6, Pergamon Pre
ss Ltd., New York (1984), p 62). Compound of formula 5a
By treatment with a reducing agent in an inert solvent, the compound of formula 2a
¹Can be produced. As a reducing agent,
For example, lithium aluminum hydride and the like, and a solvent
Examples thereof include tetrahydrofuran and the like, and the reaction temperature is
A temperature around 0 ° C. is preferred.

2) a compound of formula 2a wherein E is a single bond (formula 2a
^Of compound ² )

Embedded image [Wherein, D, J and G are as defined above. According to a known method (for example, JP-A-63-152368), formula 6
The amine of formula 7a can be prepared by reacting an acyl nitrile of formula 1 with hydroxylamine hydrochloride. Subsequently, a known method (for example, JP-A-62-8406)
According 4) by acid hydrolysis of the amine of the formula 7a, it is possible to produce a compound of formula 2a ^2. The compounds of formula 2a ² a known method (e.g., JP-5
According to 2-106466), it can also be produced by reacting a Meldrum acid derivative of the formula 8 with hydroxylamine hydrochloride.

3) A compound of formula 2b wherein E is a single bond (formula 2b
^Of compound ² )

Embedded image [Wherein, D, J, G and R ¹² are as defined above. According to a known method (for example, JP-A-54-3062), an amine of the formula 7b is produced by treating an acylnitrile of the formula 6 with hydrochloric acid gas in methanol and then reacting with hydroxylamine hydrochloride. Can be. Using an amine of the formula 7b, and an amine of the formula 7a in the same manner as in the preparation of compounds of formula 2a ^2, it is possible to produce a compound of formula 2b ^2. The compounds of the formula 2b ² a known method (for example, N. Jacobsen et al., Can.J. Chem., 62, 19
40 (1984)), by reacting a β-ketoester of formula 9 with hydroxylamine hydrochloride.

Method 2

Embedded image[Wherein, D, E, J, G and the dashed line are as defined above.
You. R¹³, R¹⁴, R^FifteenAnd R¹⁶Are each independently water
Elemental atom, halogen atom, hydroxyl group, mercapto group, nitro
Group, cyano group, carboxy group, optionally substituted amino
Group, an optionally substituted hydroxylamino group, substituted
Carbamoyl group, sulfamo which may be substituted
Yl group, sulfo group, protecting group for NH group, -R^Five, -OR^Five,
-CO_TwoR⁶, -SR⁷,-(CO) SR⁷,-(CS) O
R⁷Or -CS_TwoR⁷(Where R^Five, R ⁶And R⁷Is
Is synonymous with ). Pseudothiourea derivative of formula 10a and amine of formula 11
And if necessary, in the presence of additives, if necessary, inert solution
Reaction at a reaction temperature of 20 to 140 ° C in a medium.
Equation 1a¹Can be produced.
For example, additives such as ammonium acetate and sodium acetate
Sodium, acetic acid, oxalic acid, sodium hydroxide, sodium carbonate
, Sodium bicarbonate, 1,8-diazabicyclo [5.4.
0] undec-7-ene, triethylamine, or these
And the like, and preferred solvents include, for example,
For example, water, methanol, ethanol, isopropanol,
Acetonitrile, N, N-dimethylformamide, tet
Lahydrofuran, 1,4-dioxane, pyridine, tolu
En, chloroform, methylene chloride, or a mixture thereof
Solvents and the like can be mentioned. In addition, silver nitrate is used as an additive.
The method of Web et al. (J. Org. Chem.,56, 3009 (199
According to 1)), a compound of formula 10a and an amine of formula 11 are
Reaction temperature in an inert solvent in the presence of silver nitrate and a base
By reacting at 10 to 50 ° C., formula 1a¹Compound of
Can also be manufactured. As the base, for example, trie
Tilamine and the like, and preferred solvents include, for example,
For example, acetonitrile and the like can be mentioned. Equation 1a¹To the compound
Where R¹³, R¹⁴, R^FifteenOr R¹⁶Is a protecting group for an NH group
In the case where
Can also be performed.

The starting compound in the above-mentioned production method is a compound known per se or a compound which can be produced by a known synthesis method. For example, the compound of formula 10a can be produced by the following method.

Embedded image [Wherein, D, E, J, G, R ¹³ , R ¹⁴ and the broken line are as defined above. One of R ¹⁷ and R ¹⁸ is a hydrogen atom, and the other is a hydrogen atom, a halogen atom, a hydroxyl group, a mercapto group, a nitro group, a cyano group, a carboxy group, an optionally substituted amino group, an optionally substituted hydroxyl group. An amino group, an optionally substituted carbamoyl group, an optionally substituted sulfamoyl group, a sulfo group, a protecting group for an NH group, -R
_{^{5, -OR 5, -CO 2 R}} 6, -SR 7, - (CO) SR 7,
— (CS) OR ⁷ or —CS ₂ R ⁷ (wherein, R ⁵ , R ⁶ and R ⁷ are as defined above). A known method or a known synthesis method (for example, JP-A-63-1
52368) can be prepared by reacting a thiourea derivative of formula 12a with a methyl halide in an inert solvent in the presence of a base,
By reacting at a reaction temperature of 40 to 80 ° C.,
The compound of a can be prepared. Examples of the methyl halide include, for example, methyl iodide, and examples of the base include, for example, potassium carbonate, sodium carbonate, an aqueous solution of potassium hydroxide, and an aqueous solution of sodium hydroxide.
Examples of the solvent include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide and the like.

Method 3

Embedded image Wherein D, E, J, G, R ¹³ , R ¹⁴ , R ¹⁵ and R ¹⁶
Is as defined above. Reaction of the compound of formula 13a with the pseudothiourea derivative of formula 14 in an inert solvent in the presence of a base at a reaction temperature of 20 to 10
By reacting at 0 ° C., it can be prepared a compound of formula 1a ^2. Examples of the base include 1,8-diazabicyclo [5.4.0] undec-7-ene, triethylamine and the like, and examples of preferable solvents include pyridine, acetonitrile, N, N-dimethylformamide and the like. Also, the method of the above-mentioned webs using silver nitrate
(J. Org. Chem., 56 , 3009 (1991)), in the presence of silver nitrate and a base, in an inert solvent, at a reaction temperature of -10 to 50 ° C.
It is also possible to produce a compound of formula 1a ² by in reacting. The base includes, for example, triethylamine and the like, and the preferred solvent includes, for example, acetonitrile and the like. In the compounds of formula 1a ^2,
When R ¹³ , R ¹⁴ , R ¹⁵ or R ¹⁶ is a protecting group for an NH group, deprotection can be carried out if desired in the same manner as described above. The compound of the formula 13a can be produced, for example, by subjecting the compound of the formula 2a to halogenation, azidation and the like (for example, the method of Pey et al. (Y. Pei, et al.,
Tetrahedron Lett., 34 , 7509 (1993)). If necessary, a substituent may be further introduced into the amino group (for example, RC Larock, Comprehensive Organic
Transformations, VCH Publishers, Inc., New York (19
89), p 397).

Method 4

Embedded image [Wherein, D, E, J, G, R ¹³ , R ¹⁵ and R ¹⁶ are as defined above. R ¹⁹ is an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted Represents an aryl group or an optionally substituted heterocyclic group. L ¹ , L ²
Each independently represents a halogen atom or methylthio. The compound of the formula 13a is reacted with a methylene sulfonamide derivative of the formula 15 (for example, Chem. Ber., 99 , 2900 (1966)) in an inert solvent at a reaction temperature of -20 to 80 ° C. By reacting the amine of formula 11, the compound of formula 1a ³
Can be obtained. Preferred solvents include
For example, acetonitrile, diethyl ether, tetrahydrofuran, 1,4-dioxane, benzene, toluene,
Examples include methylene chloride and carbon tetrachloride. When E is a single bond, the compound of the formula 15 is preferably a compound in which both L ¹ and L ² are chlorine atoms. In the compounds of formula 1a ^3, if R ^13, R ¹⁵ or R ¹⁶ is a protecting group for NH group, the same manner as described above, it may be deprotected if desired. Further, in the same manner as described above, if desired,
Elimination of the group represented by SO ₂ R ¹⁹ can also be performed.

Method 5

Embedded image [Wherein, D, E, J, G, R ¹³ , R ¹⁵ and R ¹⁶ are as defined above. ] Compound and cyanoamide derivative of formula 16 of 13a (e.g., commercially available cyano morpholine) and the presence of a base, in an inert solvent, by reacting at a reaction temperature 20 to 130 ° C., the compound of formula 1a ⁴ to Can be manufactured. As the base, for example, sodium hydride, potassium carbonate,
Preferred solvents include, for example, N, N-dimethylformamide, tetrahydrofuran, toluene, acetonitrile, and the like.
tert-butanol and the like. In the compounds of formula 1a ^4, when R ^13, R ¹⁵ or R ¹⁶ is a protecting group for NH group, the same manner as described above, may be deprotected if desired.

The compound of the formula 20a, which is used as a starting compound in the above method, can also be produced as follows.

Embedded image [Wherein, G and J are as defined above. R ²⁰ is -CO
It represents a ₂ R ²¹ or -SO ₂ R ²¹ (R ²¹ represents a lower alkyl group or an aryl group.). Activating the carboxyl group of the compound of formula 17 and, if necessary, treating the compound of formula 18 with a base in an inert solvent at a reaction temperature of −78 to 30 ° C., followed by R ²⁰ The compound of formula 19 can be obtained by removing a group represented by the formula: Preferred examples of the inert solvent include, for example, tetrahydrofuran, methylene chloride, toluene and the like. The carboxyl group can be activated by reacting in an inert solvent in the presence of an additive, if necessary. As the activator, additives and reaction conditions, those commonly used can be used. For example, Reactivity and Structure Concepts in Organic Chlorine
emistry Vol. 21: The Practice of Peptide Synthesi
s, M. Bodanszky and A. Bodanszky, Springer-Verlag,
Berlin (1984), pp. 87-150.
Preferred activators include, for example, 1,1'-carbonyldiimidazole, isobutyl chloroformate, n-butyl chloroformate and the like. Preferred additives include, for example, triethylamine, 4- (dimethylamino) pyridine, N-
And methyl morpholine. Preferred solvents include, for example, N, N-dimethylformamide, tetrahydrofuran, methylene chloride, toluene and the like. Equation 18
Preferred examples of the compound include isopropyl cyanoacetate, tert-butyl cyanoacetate, methylsulfonylacetonitrile, phenylsulfonylacetonitrile and the like. Preferred examples of the base optionally treated with the compound of the formula 18 include, for example, 4- (dimethylamino) pyridine, lithium diisopropylamide, magnesium ethoxide and the like, and more preferably sodium hydride, lithium amide and the like. No. R ²⁰
As a method for removing the group represented by the general method can be used. When R ²⁰ is —CO ₂ R ²¹ ,
For example, it can be carried out by acid treatment in an inert solvent at a reaction temperature of 0 to 100 ° C. Preferred acids include, for example, hydrochloric acid, sulfuric acid, trifluoroacetic acid and the like. Preferred examples of the inert solvent include, for example, tetrahydrofuran,
Examples include methylene chloride and toluene. R ²⁰ is -SO
If it is ₂ R ^{2 1} a known method (for example, KC Santh
osh et al., J. Chem. Soc., Chem. Commun., 1992, 22
4; R. Giovannini et al., Synlett, 1995, 973). The amine of the formula 20a can be produced by reacting the compound of the formula 19 with hydroxylamine according to a known method (for example, JP-A-63-152368). The compound of formula 20a can also be prepared directly from the compound of formula 17 without isolating the compound of formula 19. That is, the resulting compound of formula 19 is directly used as
By adding water or a buffer as necessary in an aqueous solvent and reacting with hydroxylamine at a reaction temperature of 20 to 100 ° C., an amine of the formula 20a can be produced directly from a compound of the formula 17 . Preferred water-soluble solvents include, for example, ethanol, isopropanol, tert-
Butanol, N, N-dimethylformamide and the like. Preferred buffers include, for example, phosphate buffer, acetate buffer and the like. According to this method, when there is an asymmetric carbon at the position of J, the formula 20 is maintained while maintaining its optical purity.
The amine of a can be prepared.

The method for producing the isoxazole derivative of the formula 1 wherein any ^{two of} the substituents R ¹ , R ² , R ³ and R ⁴ are bonded together to form a heterocyclic ring together with a nitrogen atom is as described above. According to 1 to 5, in addition to a method using a material having the ring structure as a raw material, a method of closing a substituent during the above-mentioned production process or at the final stage (for example, a condensation reaction between a carboxyl group and an NH group (for example, J . Gen. Chem.
USSR, 18 , 2023 (1948)), and ring closure reactions using the following reaction reagents). As a reaction reagent used for this ring closure reaction, 1,3-dibromopropane (J.
Chem. Soc. Chem. Commun., 1992 , 507), 1,4-diaminobutane (J. Am. Chem. Soc., 70 , 430 (1948)),
Bis-chloromethyl-methyl-amine (EP 4289)
No. 41), paraformaldehyde (European Patent No. 580553)
No.), butylamine and formaldehyde (J. Org. Che
m., 25 , 147 (1960)), glyoxal (Tetrahedron L
ett., 32 , 5325 (1991)), acrylic acid esters (Heteroc
ycles, 20 , 1769 (1983)), benzylideneacetone (J.
Heterocycl. Chem., 21 , 65 (1984)) and epibromohydrin (Can. J. Chem., 53 , 894 (1975)). As a method for producing an isoxazole derivative of the formula 1 in which the substituent J is -C (= CR ⁸ R ⁹ )-(R ⁸ and R ⁹ are as defined above), for example, J is -C (R ^8a R ^9a). )-
(Wherein R ^8a represents a lower alkoxy group and R ^9a represents a lower alkyl group, etc.)
A method of treating with an acid such as trifluoroacetic acid in an inert solvent such as methylene chloride is exemplified. Substituents R ⁸ and R ⁹
Wherein R ⁸ and R ⁹ are a lower alkoxy group which may be both substituted with an isoxazole derivative of the formula 1, and R ⁸ and R ⁹ may be bonded together and substituted with a carbon atom As a method for producing an isoxazole derivative of the formula 1 forming a 1.3-dioxane ring or a 1.3-dioxolane ring which may be substituted, a 2-ketoalkanoic acid ester is prepared by reacting an alcohol, a tri-orthoformate in the presence of an acid. Reaction with alkyls, ethylene glycols or 1,3-propanediols (for example, Protec
tive Groups in Organic Synthesis, 2ndEdition, TW
Greene and PGMWuts, John Wiley and Sons, inc.,
New York (1991), pp. 185-195), followed by a known method (for example, JP-A-63-152368) to obtain a compound of the formula 6 or the like, followed by a method of producing the compound according to Method 1 or Method 2. Can be

In the isoxazole derivative of the formula 1, when D is an alkoxycarbonyl group or the like, it can be converted to an isoxazole derivative of the formula 1 in which D is a hydrogen atom by hydrolysis and decarboxylation. . In the case where the isoxazole derivative of the formula 1 has one or more asymmetric points, it can be produced by using a raw material having the asymmetric point or by introducing it at an intermediate reaction step according to a usual method. it can. For example, in the case of an optical isomer, it can be obtained by using an optically active raw material or performing optical resolution or the like at an appropriate stage of the production process.

The isoxazole derivative of the present invention or a pharmaceutically acceptable salt thereof is used as a medicament when
It can be administered orally or parenterally (eg, intravenous, subcutaneous, or intramuscular injection, topical, rectal, transdermal, or nasal). Forms for oral administration include, for example, tablets, capsules, pills, granules, powders, solutions, syrups and suspensions, and forms for parenteral administration include, for example, injection Aqueous or oily agents, ointments, creams, lotions,
Aerosols, suppositories, patches and the like can be mentioned. These preparations are prepared using a conventionally known technique, and can contain an acceptable usual carrier, excipient, binder, stabilizer and the like. When the composition is used in the form of an injection, an acceptable buffer, solubilizing agent, isotonic agent and the like can be added. The dose of the isoxazole derivative of the present invention or a pharmaceutically acceptable salt thereof, the number of administrations, symptoms, age, body weight,
Although it depends on the administration form, it is usually about 1 to 2000 per day as an active ingredient of the compound of the present invention for an adult.
mg, preferably 10 to 500 mg, can be administered once or in several divided doses.

Specific examples of the compounds included in the present invention include:
The following compounds are exemplified. However, these compounds are for the purpose of illustration, and the present invention is not limited thereto.

N '-{3- [1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylmethyl} -N, N-dimethyl-guanidine N'-{5- [1- (2-fluoro-biphenyl-4-
Yl) -ethyl] -isoxazol-3-yl} -N,
N-dimethyl-guanidine N '-(2- {3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-yl}
-Ethyl) -N, N-dimethyl-guanidine N '-(3- {3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-yl}
-Propyl) -N, N-dimethyl-guanidine

N '-(2- {5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazole-3
-Yl {-ethyl) -N, N-dimethyl-guanidine N '-(3- {5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-yl}
-Propyl) -N, N-dimethyl-guanidine N '-{3- [1- (2-fluoro-biphenyl-4-
Yl) -ethyl] -4-methyl-isoxazole-5-
Yl} -N, N-dimethyl-guanidine N '-{3- [1- (2-fluoro-biphenyl-4-
Yl) -ethyl] -4-methyl-isoxazole-5-
Ilmethyl {-N, N-dimethyl-guanidine N '-{5- [1- (2-fluoro-biphenyl-4-)
Yl) -ethyl] -4-methyl-isoxazole-3-
Ill} -N, N-dimethyl-guanidine N '-{5- [1- (2-fluoro-biphenyl-4-)
Yl) -ethyl] -4-methyl-isoxazole-3-
Ilmethyl} -N, N-dimethyl-guanidine

5- (N ', N'-dimethyl-guanidino)-
3- [1- (2-fluoro-biphenyl-4-yl)-
Ethyl] -isoxazole-4-carboxylic acid 5- (N ′, N′-dimethyl-guanidinomethyl) -3
-[1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazole-4-carboxylic acid 3- (N ′, N′-dimethyl-guanidino) -5- [1
-(2-Fluoro-biphenyl-4-yl) -ethyl]
-Isoxazole-4-carboxylic acid 3- (N ', N'-dimethyl-guanidinomethyl) -5
-[1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazole-4-carboxylic acid {5- (N ', N'-dimethyl-guanidino) -3-
[1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-4-yl} -acetic acid {5- (N ′, N′-dimethyl-guanidinomethyl)-
3- [1- (2-fluoro-biphenyl-4-yl)-
Ethyl] -isoxazol-4-yl} -acetic acid {3- (N ′, N′-dimethyl-guanidino) -5
[1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-4-yl} -acetic acid {3- (N ′, N′-dimethyl-guanidinomethyl)-
5- [1- (2-fluoro-biphenyl-4-yl)-
Ethyl] -isoxazol-4-yl} -acetic acid

N '-{3- {1- (2-fluoro-biphenyl-4-yl) -ethyl] -4-hydroxymethyl-isoxazol-5-yl} -N, N-dimethyl-guanidine N'-} 3- {1- (2-fluoro-biphenyl-4-
Yl) -ethyl] -4-hydroxymethyl-isoxazol-5-ylmethyl} -N, N-dimethyl-guanidine N ′-{5-} 1- (2-fluoro-biphenyl-4-
Yl) -ethyl] -4-hydroxymethyl-isoxazol-3-yl} -N, N-dimethyl-guanidine N ′-{5-} 1- (2-fluoro-biphenyl-4-
Yl) -ethyl] -4-hydroxymethyl-isoxazol-3-ylmethyl} -N, N-dimethyl-guanidine

N '-{3- [1- (2-Fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-yl} -N, N-dimethyl-guanidine N'-{3 -[1- (2-fluoro-biphenyl-4-
Yl) -1-methyl-ethyl] -isoxazole-5
Ilmethyl {-N, N-dimethyl-guanidine N '-{5- [1- (2-fluoro-biphenyl-4-)
Yl) -1-methyl-ethyl] -isoxazole-3-
Ill} -N, N-dimethyl-guanidine N '-{5- [1- (2-fluoro-biphenyl-4-)
Yl) -1-methyl-ethyl] -isoxazole-3-
Ylmethyl} -N, N-dimethyl-guanidine N ′-[3- (2-fluoro-biphenyl-4-ylmethyl) -isoxazol-5-yl] -N, N-dimethyl-guanidine

N '-[3- (2-fluoro-biphenyl-4
-Ylmethyl) -isoxazol-5-ylmethyl]-
N, N-dimethyl-guanidine N '-[5- (2-fluoro-biphenyl-4-ylmethyl) -isoxazol-3-yl] -N, N-dimethyl-guanidine N'-[5- (2-fluoro- Biphenyl-4-ylmethyl) -isoxazol-3-ylmethyl] -N, N-
Dimethyl-guanidine N '-{3- [1- (2-fluoro-biphenyl-4-)
Yl) -cyclopropyl] -isoxazol-5-yl} -N, N-dimethyl-guanidine N ′-{3- [1- (2-fluoro-biphenyl-4-
Yl) -cyclopropyl] -isoxazol-5-ylmethyl} -N, N-dimethyl-guanidine N ′-{5- [1- (2-fluoro-biphenyl-4-
Yl) -cyclopropyl] -isoxazol-3-yl} -N, N-dimethyl-guanidine N ′-{5- [1- (2-fluoro-biphenyl-4-
Yl) -cyclopropyl] -isoxazol-3-ylmethyl} -N, N-dimethyl-guanidine

N '-{3- [1- (2-Fluoro-biphenyl-4-yl) -vinyl] -isoxazol-5-yl} -N, N-dimethyl-guanidine N'-{3- [1- (2-fluoro-biphenyl-4-
Yl) -vinyl] -isoxazol-5-ylmethyl}
-N, N-dimethyl-guanidine N '-{5- [1- (2-fluoro-biphenyl-4-)
Yl) -vinyl] -isoxazol-3-yl} -N,
N-dimethyl-guanidine N '-{5- [1- (2-fluoro-biphenyl-4-)
Yl) -vinyl] -isoxazol-3-ylmethyl}
-N, N-dimethyl-guanidine N '-{3- [1- (2-fluoro-biphenyl-4-
Yl) -2-methyl-propenyl] -isoxazole-
5-yl} -N, N-dimethyl-guanidine N ′-{3- [1- (2-fluoro-biphenyl-4-
Yl) -2-methyl-propenyl] -isoxazole-
5-ylmethyl} -N, N-dimethyl-guanidine N ′-{5- [1- (2-fluoro-biphenyl-4-
Yl) -2-methyl-propenyl] -isoxazole-
3-yl} -N, N-dimethyl-guanidine

N '-{5- [1- (2-Fluoro-biphenyl-4-yl) -2-methyl-propenyl] -isoxazol-3-ylmethyl} -N, N-dimethyl-guanidine N'-{3 -[1- (3-benzoyl-phenyl) -ethyl] -isoxazol-5-yl} -N, N-dimethyl-guanidine N '-{3- [1- (3-benzoyl-phenyl) -ethyl] -isoxazole -5-ylmethyl} -N, N-
Dimethyl-guanidine N '-{5- [1- (3-benzoyl-phenyl) -ethyl] -isoxazol-3-yl} -N, N-dimethyl-guanidine N'-{5- [1- (3-benzoyl) -Phenyl) -ethyl] -isoxazol-3-ylmethyl} -N, N-
Dimethyl-guanidine N '-{3- [1- (4-isobutyl-phenyl) -ethyl] -isoxazol-5-yl} -N, N-dimethyl-guanidine N'-{3- [1- (4-isobutyl -Phenyl) -ethyl] -isoxazol-5-ylmethyl} -N, N-
Dimethyl-guanidine

N '-{5- [1- (4-isobutyl-phenyl) -ethyl] -isoxazol-3-yl} -N, N
-Dimethyl-guanidine N '-{5- [1- (4-isobutyl-phenyl) -ethyl] -isoxazol-3-ylmethyl} -N, N-
Dimethyl-guanidine N '-{3- [1- (6-methoxy-naphthalene-2-)
Yl) -ethyl] -isoxazol-5-yl} -N,
N-dimethyl-guanidine N '-{3- [1- (6-methoxy-naphthalene-2-
Yl) -ethyl] -isoxazol-5-ylmethyl}
-N, N-dimethyl-guanidine N '-{5- [1- (6-methoxy-naphthalene-2-
Yl) -ethyl] -isoxazol-3-yl} -N,
N-dimethyl-guanidine N '-{5- [1- (6-methoxy-naphthalene-2-
Yl) -ethyl] -isoxazol-3-ylmethyl}
-N, N-dimethyl-guanidine ({3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylmethylimino} -piperidin-1-yl-methyl) -amine ( {5- [1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-ylimino}-
Piperidin-1-yl-methyl) -amine

[(2- {3- [1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-yl} -ethylimino) -piperidin-1-yl-methyl] -amine [( 3- {3- [1- (2-fluoro-biphenyl-4)
-Yl) -ethyl] -isoxazol-5-yl} -propylimino) -piperidin-1-yl-methyl] -amine [(2- {5- [1- (2-fluoro-biphenyl-4)
-Yl) -ethyl] -isoxazol-3-yl} -ethylimino) -piperidin-1-yl-methyl] -amine [(3- {5- [1- (2-fluoro-biphenyl-4)
-Yl) -ethyl] -isoxazol-3-yl} -propylimino) -piperidin-1-yl-methyl] -amine ({3- [1- (2-fluoro-biphenyl-4-yl) -ethyl]- 4-methyl-isoxazol-5-ylimino} -piperidin-1-yl-methyl) -amine

(｛3- [1- (2-fluoro-biphenyl-
4-yl) -ethyl] -4-methyl-isoxazole-
5-ylmethylimino {-piperidin-1-yl-methyl) -amine ({5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -4-methyl-isoxazol-3-ylimino}- Piperidin-1-yl-methyl) -amine ({5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -4-methyl-isoxazol-3-ylmethylimino} -piperidin-1-yl -Methyl)-
Amine 5- (amino-piperidin-1-yl-methyleneamino) -3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazole-4-carboxylic acid 5- (amino-piperidin-1 -Yl-methyleneamino-methyl) -3- [1- (2-fluoro-biphenyl-
4-yl) -ethyl] -isoxazole-4-carboxylic acid

3- (amino-piperidin-1-yl-methyleneamino) -5- [1- (2-fluoro-biphenyl-
4-yl) -Ethyl] -isoxazole-4-carboxylic acid 3- (amino-piperidin-1-yl-methyleneamino-methyl) -5- [1- (2-fluoro-biphenyl-
4-yl) -ethyl] -isoxazole-4-carboxylic acid {5- (amino-piperidin-1-yl-methyleneamino) -3- [1- (2-fluoro-biphenyl-4-yl) -ethyl]- Isoxazol-4-yl} -acetic acid {5- (amino-piperidin-1-yl-methyleneamino-methyl) -3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazole-4- Il
-Acetic acid {3- (amino-piperidin-1-yl-methyleneamino) -5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-4-yl} -acetic acid

{3- (amino-piperidin-1-yl-methyleneamino-methyl) -5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazole-4
-Yl} -acetic acid {5- (amino-piperidin-1-yl-methyleneamino) -3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-4-yl} -methanol 5- (amino-piperidin-1-yl-methyleneamino-methyl) -3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-4-yl}
-Methanol {3- (amino-piperidin-1-yl-methyleneamino) -5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-4-yl} -methanol {3- ( Amino-piperidin-1-yl-methyleneamino-methyl) -5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-4-yl}
-Methanol

(｛3- [1- (2-fluoro-biphenyl-
4-yl) -1-methyl-ethyl] -isoxazole-
5-ylimino} -piperidin-1-yl-methyl)-
Amine ({3- [1- (2-Fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-ylmethylimino} -piperidin-1-yl-methyl)-
Amine ({5- [1- (2-Fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-3-ylimino} -piperidin-1-yl-methyl) -amine ({5- [1 -(2-Fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-3-ylmethylimino} -piperidin-1-yl-methyl)-
Amine {[3- (2-fluoro-biphenyl-4-ylmethyl) -isoxazol-5-ylimino] -piperidin-1-yl-methyl} -amine {[3- (2-fluoro-biphenyl-4-ylmethyl)- Isoxazol-5-ylmethylimino] -piperidin-1-yl-methyl} -amine

{[5- (2-Fluoro-biphenyl-4-ylmethyl) -isoxazol-3-ylimino] -piperidin-1-yl-methyl} -amine {[5- (2-fluoro-biphenyl-4-ylmethyl) -amine} ) -Isoxazol-3-ylmethylimino] -piperidin-1-yl-methyl} -amine ({3- [1- (2-fluoro-biphenyl-4-yl) -cyclopropyl] -isoxazol-5-ylimino} -Piperidin-1-yl-methyl) -amine ({3- [1- (2-fluoro-biphenyl-4-yl) -cyclopropyl] -isoxazol-5-ylmethylimino} -piperidin-1-yl-methyl ) -Amine ({5- [1- (2-fluoro-biphenyl-4-yl) -cyclopropyl] -isoxazol-3-ylimino} Piperidin-1-yl-methyl) -amine ({5- [1- (2-fluoro-biphenyl-4-yl) -cyclopropyl] -isoxazol-3-ylmethylimino} -piperidin-1-yl-methyl) -Amine

(｛3- [1- (2-fluoro-biphenyl-
4-yl) -Vinyl] -isoxazol-5-ylimino} -piperidin-1-yl-methyl) -amine ({3- [1- (2-fluoro-biphenyl-4-yl) -vinyl] -isoxazole-5 -Ylmethylimino} -piperidin-1-yl-methyl) -amine ({5- [1- (2-fluoro-biphenyl-4-yl) -vinyl] -isoxazol-3-ylimino}-
Piperidin-1-yl-methyl) -amine ({5- [1- (2-fluoro-biphenyl-4-yl) -vinyl] -isoxazol-3-ylmethylimino} -piperidin-1-yl-methyl)- Amine ({3- [1- (2-Fluoro-biphenyl-4-yl) -2-methyl-propenyl] -isoxazole-5
-Ilimino} -piperidin-1-yl-methyl) -amine ({3- [1- (2-Fluoro-biphenyl-4-yl) -2-methyl-propenyl] -isoxazole-5
-Ylmethylimino} -piperidin-1-yl-methyl) -amine ({5- [1- (2-fluoro-biphenyl-4-yl) -2-methyl-propenyl] -isoxazole-3
-Ilimino} -piperidin-1-yl-methyl) -amine

(｛5- [1- (2-fluoro-biphenyl-
4-yl) -2-methyl-propenyl] -isoxazol-3-ylmethylimino} -piperidin-1-yl-
Methyl) -amine (3- {1- [5- (amino-piperidin-1-yl-
Methyleneamino) -isoxazol-3-yl] -ethyl} -phenyl) -phenyl-methanone (3- {1- [5- (amino-piperidin-1-yl-
Methyleneamino-methyl) -isoxazol-3-yl] -ethyl} -phenyl) -phenyl-methanone (3- {1- [3- (amino-piperidin-1-yl-
Methyleneamino) -isoxazol-5-yl] -ethyl} -phenyl) -phenyl-methanone (3- {1- [3- (amino-piperidin-1-yl-
Methyleneamino-methyl) -isoxazol-5-yl] -ethyl} -phenyl) -phenyl-methanone ({3- [1- (4-isobutyl-phenyl) -ethyl] -isoxazol-5-ylimino} -piperidine-1 -Yl-methyl) -amine ({3- [1- (4-isobutyl-phenyl) -ethyl] -isoxazol-5-ylmethylimino} -piperidin-1-yl-methyl) -amine

(｛5- [1- (4-isobutyl-phenyl)
-Ethyl] -isoxazol-3-ylimino} -piperidin-1-yl-methyl) -amine ({5- [1- (4-isobutyl-phenyl) -ethyl] -isoxazol-3-ylmethylimino} -piperidine- 1-yl-methyl) -amine ({3- [1- (6-methoxy-naphthalen-2-yl) -ethyl] -isoxazol-5-ylimino}-
Piperidin-1-yl-methyl) -amine ({3- [1- (6-methoxy-naphthalen-2-yl) -ethyl] -isoxazol-5-ylmethylimino} -piperidin-1-yl-methyl)- Amine ({5- [1- (6-methoxy-naphthalen-2-yl) -ethyl] -isoxazol-3-ylimino}-
Piperidin-1-yl-methyl) -amine ({5- [1- (6-methoxy-naphthalen-2-yl) -ethyl] -isoxazol-3-ylmethylimino} -piperidin-1-yl-methyl)- Amine ({3- [1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylmethylimino} -morpholin-4-yl-methyl) -amine ({5- [1- ( 2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-ylimino}-
Morpholin-4-yl-methyl) -amine

[(2- {3- [1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-yl} -ethylimino) -morpholin-4-yl-methyl] -amine [( 3- {3- [1- (2-fluoro-biphenyl-4)
-Yl) -ethyl] -isoxazol-5-yl} -propylimino) -morpholin-4-yl-methyl] -amine [(2- {5- [1- (2-fluoro-biphenyl-4)
-Yl) -ethyl] -isoxazol-3-yl} -ethylimino) -morpholin-4-yl-methyl] -amine [(3- {5- [1- (2-fluoro-biphenyl-4)
-Yl) -ethyl] -isoxazol-3-yl} -propylimino) -morpholin-4-yl-methyl] -amine ({3- [1- (2-fluoro-biphenyl-4-yl) -ethyl]- 4-methyl-isoxazol-5-ylimino} -morpholin-4-yl-methyl) -amine ({3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -4-methyl-isoxazole-5 -Ylmethylimino} -morpholin-4-yl-methyl)-
Amine

(｛5- [1- (2-fluoro-biphenyl-
4-yl) -ethyl] -4-methyl-isoxazole-
3-ylimino} -morpholin-4-yl-methyl)-
Amine ({5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -4-methyl-isoxazol-3-ylmethylimino} -morpholin-4-yl-methyl)-
Amine 5- (amino-morpholin-4-yl-methyleneamino) -3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazole-4-carboxylic acid 5- (amino-morpholine-4 -Yl-methyleneamino-methyl) -3- [1- (2-fluoro-biphenyl-
4-yl) -ethyl] -isoxazole-4-carboxylic acid 3- (amino-morpholin-4-yl-methyleneamino) -5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazole 4-Carboxylic acid 3- (amino-morpholin-4-yl-methyleneamino-methyl) -5- [1- (2-fluoro-biphenyl-
4-yl) -ethyl] -isoxazole-4-carboxylic acid

{5- (amino-morpholin-4-yl-methyleneamino) -3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-4-yl}
-Acetic acid {5- (amino-morpholin-4-yl-methyleneamino-methyl) -3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-4-yl}
-Acetic acid {3- (amino-morpholin-4-yl-methyleneamino) -5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-4-yl} -acetic acid {3- ( Amino-morpholin-4-yl-methyleneamino-methyl) -5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-4-yl}
-Acetic acid {5- (amino-morpholin-4-yl-methyleneamino) -3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-4-yl} -methanol {5- ( Amino-morpholin-4-yl-methyleneamino-methyl) -3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-4-yl}
-Methanol

{3- (amino-morpholin-4-yl-methyleneamino) -5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-4-yl}
-Methanol {3- (amino-morpholin-4-yl-methyleneamino-methyl) -5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-4-yl}
-Methanol ({3- [1- (2-fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-ylmethylimino} -morpholin-4-yl-methyl)-
The amine ({5- [1- (2-fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-3-ylimino} -morpholin-4-yl-methyl) -amine ({5- [1 -(2-Fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-3-ylmethylimino} -morpholin-4-yl-methyl)-
Amine

[3- (2-Fluoro-biphenyl-4-ylmethyl) -isoxazol-5-ylmethylimino]
-Morpholin-4-yl-methyl} -amine {[5- (2-fluoro-biphenyl-4-ylmethyl) -isoxazol-3-ylimino] -morpholin-4-yl-methyl} -amine {[5- (2 -Fluoro-biphenyl-4-ylmethyl) -isoxazol-3-ylmethylimino] -morpholin-4-yl-methyl} -amine ({3- [1- (2-fluoro-biphenyl-4-yl) -cyclopropyl ] -Isoxazol-5-ylmethylimino {-morpholin-4-yl-methyl) -amine ({5- [1- (2-fluoro-biphenyl-4-yl) -cyclopropyl] -isoxazol-3-ylimino} -Morpholin-4-yl-methyl) -amine

(｛5- [1- (2-fluoro-biphenyl-
4-yl) -cyclopropyl] -isoxazole-3-
Ylmethylimino} -morpholin-4-yl-methyl
-Amine ({3- [1- (2-fluoro-biphenyl-4-yl) -vinyl] -isoxazol-5-ylimino}-
Morpholin-4-yl-methyl) -amine ({3- [1- (2-fluoro-biphenyl-4-yl) -vinyl] -isoxazol-5-ylmethylimino} -morpholin-4-yl-methyl)- Amine ({5- [1- (2-fluoro-biphenyl-4-yl) -vinyl] -isoxazol-3-ylimino}-
Morpholin-4-yl-methyl) -amine ({5- [1- (2-fluoro-biphenyl-4-yl) -vinyl] -isoxazol-3-ylmethylimino} -morpholin-4-yl-methyl)- Amine ({3- [1- (2-Fluoro-biphenyl-4-yl) -2-methyl-propenyl] -isoxazole-5
-Ilimino} -morpholin-4-yl-methyl) -amine ({3- [1- (2-Fluoro-biphenyl-4-yl) -2-methyl-propenyl] -isoxazole-5
-Ylmethylimino} -morpholin-4-yl-methyl) -amine

(｛5- [1- (2-fluoro-biphenyl-
4-yl) -2-methyl-propenyl] -isoxazol-3-ylimino} -morpholin-4-yl-methyl) -amine ({5- [1- (2-fluoro-biphenyl-4-yl) -2-) Methyl-propenyl] -isoxazole-3
-Ylmethylimino} -morpholin-4-yl-methyl) -amine (3- {1- [5- (amino-morpholin-4-yl-
Methyleneamino-methyl) -isoxazol-3-yl] -ethyl} -phenyl) -phenyl-methanone (3- {1- [3- (amino-morpholin-4-yl-
Methyleneamino) -isoxazol-5-yl] -ethyl} -phenyl) -phenyl-methanone (3- {1- [3- (amino-morpholin-4-yl-
Methyleneamino-methyl) -isoxazol-5-yl] -ethyl} -phenyl) -phenyl-methanone

(｛3- [1- (4-isobutyl-phenyl)
-Ethyl] -isoxazol-5-ylmethylimino}
-Morpholin-4-yl-methyl) -amine ({5- [1- (4-isobutyl-phenyl) -ethyl] -isoxazol-3-ylimino} -morpholin-4-yl-methyl) -amine ({5- [1- (4-Isobutyl-phenyl) -ethyl] -isoxazol-3-ylmethylimino} -morpholin-4-yl-methyl) -amine ({3- [1- (6-methoxy-naphthalen-2-yl) ) -Ethyl] -isoxazol-5-ylmethylimino} -morpholin-4-yl-methyl) -amine ({5- [1- (6-methoxy-naphthalen-2-yl) -ethyl] -isoxazole-3- Il Imino
Morpholin-4-yl-methyl) -amine ({5- [1- (6-methoxy-naphthalen-2-yl) -ethyl] -isoxazol-3-ylmethylimino} -morpholin-4-yl-methyl)- Amine

N- {3- [1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylmethyl} -guanidine N- {5- [1- (2-fluoro-biphenyl-4) -Yl) -ethyl] -isoxazol-3-yl} -guanidine N- {3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylmethyl}-
N'-methyl-guanidine N- {5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-yl} -N'-
Methyl-guanidine N-ethyl-N '-{3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazole-5-
Ylmethyl} -guanidine N-ethyl-N ′-{5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazole-3-
Ill} -guanidine N-ethyl-N '-{5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazole-3-
Ilmethyl｝ -guanidine

N- {3- [1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylmethyl} -N'-phenyl-guanidine N- {5- [1- (2- Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-yl {-N′-
Phenyl-guanidine N- {5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-ylmethyl}-
N'-phenyl-guanidine N- {3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-yl} -N'-
p-Toluyl-guanidine N- {3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylmethyl}-
N'-p-toluyl-guanidine N- {5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-yl} -N'-
p-Toluyl-guanidine N- {5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-ylmethyl}-
N'-p-toluyl-guanidine N- {3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-yl} -N'-
(4-methoxy-phenyl) -guanidine

N- {3- [1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylmethyl} -N '-(4-methoxy-phenyl) -guanidine N- {5- [1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-yl} -N'-
(4-methoxy-phenyl) -guanidine N- {5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-ylmethyl}-
N '-(4-methoxy-phenyl) -guanidine N-benzyl-N'-{3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazole-5
-Yl} -guanidine N-benzyl-N '-{3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazole-5
-Ylmethyl} -guanidine N-benzyl-N '-{5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazole-3
-Yl} -guanidine N-benzyl-N '-{5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazole-3
-Ylmethyl｝ -guanidine

N- {3- [1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-yl}
-N'-phenethyl-guanidine N- {3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylmethyl}-
N'-phenethyl-guanidine N- {5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-yl} -N'-
Phenethyl-guanidine N- {5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-ylmethyl}-
N'-phenethyl-guanidine N- (2-amino-ethyl) -N '-{3- [1- (2
-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-yl} -guanidine N- (2-amino-ethyl) -N '-{3- [1- (2
-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylmethyl} -guanidine N- (2-amino-ethyl) -N '-{5- [1- (2
-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-yl} -guanidine N- (2-amino-ethyl) -N '-{5- [1- (2
-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-ylmethyl} -guanidine

[｛3- [1- (2-Fluoro-biphenyl-)
4-yl) -ethyl] -isoxazol-5-ylimino}-(4-methyl-piperidin-1-yl) -methyl] -amine [{3- [1- (2-fluoro-biphenyl-4-yl)-] Ethyl] -isoxazol-5-ylmethylimino}-(4-methyl-piperidin-1-yl) -methyl] -amine [{5- [1- (2-fluoro-biphenyl-4-yl) -ethyl]- Isoxazol-3-ylimino｝-
(4-Methyl-piperidin-1-yl) -methyl] -amine [{5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-ylmethylimino}-(4- Methyl-piperidin-1-yl) -methyl] -amine ((2,6-dimethyl-piperidin-1-yl)-{3
-[1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylimino} -methyl)
-Amine ((2,6-dimethyl-piperidin-1-yl)-{3
-[1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylmethylimino} -methyl) -amine

((2,6-Dimethyl-piperidin-1-yl)-{5- [1- (2-fluoro-biphenyl-4-)
Yl) -ethyl] -isoxazol-3-ylimino}
-Methyl) -amine ((2,6-dimethyl-piperidin-1-yl)-{5
-[1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-ylmethylimino} -methyl) -amine 1- (amino- {3- [1- (2-fluoro-biphenyl-) 4-yl) -ethyl] -isoxazol-5-ylmethylimino} -methyl) -piperidin-4-ol 1- (amino- {5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -Isoxazol-3-ylimino {-methyl) -piperidin-4-ol 1- (amino- {5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-ylmethylimino} -Methyl) -piperidin-4-ol [{3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylimino}-
(4-methoxy-piperidin-1-yl) -methyl]-
Amine

[{3- [1- (2-Fluoro-biphenyl-)
4-yl) -ethyl] -isoxazol-5-ylmethylimino}-(4-methoxy-piperidin-1-yl)
-Methyl] -amine [{5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-ylimino}-
(4-methoxy-piperidin-1-yl) -methyl]-
Amine [{5- [1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-ylmethylimino}-(4-methoxy-piperidin-1-yl) -methyl] -amine (( 4-amino-piperidin-1-yl)-{3- [1
-(2-Fluoro-biphenyl-4-yl) -ethyl]
-Isoxazol-5-ylimino} -methyl) -amine ((4-amino-piperidin-1-yl)-{3- [1
-(2-Fluoro-biphenyl-4-yl) -ethyl]
-Isoxazol-5-ylmethylimino} -methyl)
-Amine

((4-amino-piperidin-1-yl)-
{5- [1- (2-fluoro-biphenyl-4-yl)]
-Ethyl] -isoxazol-3-ylimino} -methyl) -amine ((4-amino-piperidin-1-yl)-{5- [1
-(2-Fluoro-biphenyl-4-yl) -ethyl]
-Isoxazol-3-ylmethylimino} -methyl)
-Amine ((4-dimethylamino-piperidin-1-yl)-
{3- [1- (2-Fluoro-biphenyl-4-yl)]
-Ethyl] -isoxazol-5-ylimino} -methyl) -amine ((4-dimethylamino-piperidin-1-yl)-
{3- [1- (2-Fluoro-biphenyl-4-yl)]
-Ethyl] -isoxazol-5-ylmethylimino}
-Methyl) -amine ((4-dimethylamino-piperidin-1-yl)-
{5- [1- (2-fluoro-biphenyl-4-yl)]
-Ethyl] -isoxazol-3-ylimino} -methyl) -amine ((4-dimethylamino-piperidin-1-yl)-
{5- [1- (2-fluoro-biphenyl-4-yl)]
-Ethyl] -isoxazol-3-ylmethylimino}
-Methyl) -amine

1- (amino- {3- [1- (2-fluoro-
Biphenyl-4-yl) -ethyl] -isoxazole-
5-ylimino} -methyl) -piperidine-4-carboxylic acid 1- (amino- {3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylmethylimino} -methyl ) -Piperidine-4-carboxylic acid 1- (amino- {5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-ylimino} -methyl) -piperidine-4-carboxylic acid 1- (amino- {5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-ylmethylimino} -methyl) -piperidine-4-carboxylic acid 1- (amino- ｛ 3- [1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylimino} -methyl) -piperidine-4-carboxylic acid amide 1- ( Mino - {3- [1- (2-fluoro - biphenyl-4-yl) - ethyl] - isoxazol-5 Irumechiruimino} - methyl) - piperidine-4-carboxylic acid amide

1- (amino- {5- [1- (2-fluoro-
Biphenyl-4-yl) -ethyl] -isoxazole-
3-ylimino {-methyl) -piperidine-4-carboxylic acid amide 1- (amino- {5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-ylmethylimino}- Methyl) -piperidine-4-carboxylic acid amide 1- (amino- {3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylimino} -methyl) -piperidine-3- Carboxylic acid 1- (amino- {3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylmethylimino} -methyl) -piperidine-3-carboxylic acid 1- (amino -{5- [1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-ylimino} -methyl) -piperidine-3-carboxylic acid - (amino - {5- [1- (2-fluoro - biphenyl-4-yl) - ethyl] - isoxazole-3-Irumechiruimino} - methyl) - piperidine-3-carboxylic acid

1- (amino- {3- [1- (2-fluoro-
Biphenyl-4-yl) -ethyl] -isoxazole-
5-ylimino {-methyl) -piperidine-3-carboxylic acid amide 1- (amino- {3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylmethylimino}- Methyl) -piperidine-3-carboxylic acid amide 1- (amino- {5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-ylimino} -methyl) -piperidine-3- Carboxamide 1- (amino- {5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-ylmethylimino} -methyl) -piperidine-3-carboxyamide

1- (amino- {3- [1- (2-fluoro-
Biphenyl-4-yl) -ethyl] -isoxazole-
5-ylmethylimino {-methyl) -piperidine-4-
On 1- (amino- {5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-ylimino} -methyl) -piperidin-4-one 1- (amino- {5- [1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-ylmethylimino} -methyl) -piperidin-4-one ((3,5-dimethyl-morpholin-4-yl)- $ 3
-[1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylimino} -methyl)
-Amine ((3,5-dimethyl-morpholin-4-yl)-{3
-[1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylmethylimino} -methyl) -amine

((3,5-dimethyl-morpholin-4-yl)-{5- [1- (2-fluoro-biphenyl-4-yl)
Yl) -ethyl] -isoxazol-3-ylimino}
-Methyl) -amine ((3,5-dimethyl-morpholin-4-yl)-{5
-[1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-ylmethylimino {-methyl) -amine ((2,6-dimethyl-morpholin-4-yl)-{3
-[1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylimino} -methyl)
-Amine ((2,6-dimethyl-morpholin-4-yl)-{3
-[1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylmethylimino} -methyl) -amine ((2,6-dimethyl-morpholin-4-yl)-{5
-[1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-ylimino} -methyl)
-Amine ((2,6-dimethyl-morpholin-4-yl)-{5
-[1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-ylmethylimino} -methyl) -amine

(｛3- [1- (2-fluoro-biphenyl-
4-yl) -ethyl] -isoxazol-5-ylmethylimino} -thiamorpholin-4-yl-methyl) -amine ({5- [1- (2-fluoro-biphenyl-4-yl) -ethyl]- Isoxazol-3-ylimino｝-
Thiamorpholin-4-yl-methyl) -amine ({5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-ylmethylimino} -thiamorpholin-4-yl-methyl ) -Amine ({3- [1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylmethylimino} -piperazin-1-yl-methyl) -amine ({5- [1 -(2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-ylimino}-
Piperazin-1-yl-methyl) -amine

(｛5- [1- (2-fluoro-biphenyl-
4-yl) -ethyl] -isoxazol-3-ylmethylimino} -piperazin-1-yl-methyl) -amine [{3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazole -5-ylmethylimino}-(4-methyl-piperazin-1-yl) -methyl] -amine [{5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazole-3- Il Imino
(4-Methyl-piperazin-1-yl) -methyl] -amine [{5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-ylmethylimino}-(4- Methyl-piperazin-1-yl) -methyl] -amine 2- [4- (amino- {3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazole-5
-Ilimino {-methyl) -piperazin-1-yl]-
ethanol

2- [4- (amino- {3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylmethylimino} -methyl) -piperazin-1-yl] -Ethanol 2- [4- (amino- {5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazole-3 "
-Ilimino {-methyl) -piperazin-1-yl]-
Ethanol 2- [4- (amino- {5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazole-3
-Ylmethylimino} -methyl) -piperazin-1-yl] -ethanol ([4- (2-amino-ethyl) -piperazin-1-yl]-{3- [1- (2-fluoro-biphenyl-4) −
Yl) -ethyl] -isoxazol-5-ylimino}
-Methyl) -amine ([4- (2-amino-ethyl) -piperazin-1-yl]-{3- [1- (2-fluoro-biphenyl-4-
Yl) -ethyl] -isoxazol-5-ylmethylimino} -methyl) -amine ([4- (2-amino-ethyl) -piperazin-1-yl]-{5- [1- (2-fluoro-biphenyl) -4-
Yl) -ethyl] -isoxazol-3-ylimino}
-Methyl) -amine

([4- (2-Amino-ethyl) -piperazin-1-yl]-{5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-ylmethylimino ｝ -Methyl) -amine 1- [4- (amino- ｛3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazole-5
-Ilimino {-methyl) -piperazin-1-yl]-
Ethanone 1- [4- (amino- {3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazole-5
-Ylmethylimino} -methyl) -piperazin-1-yl] -ethanone 1- [4- (amino- {5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazole-3
-Ilimino {-methyl) -piperazin-1-yl]-
Ethanone 1- [4- (amino- {5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazole-3
-Ylmethylimino} -methyl) -piperazin-1-yl] -ethanone (N '-{3- [1- (2-fluoro-biphenyl-4)
-Yl) -ethyl] -isoxazol-5-ylmethyl} -guanidino) -acetic acid

(N ′-{5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-yl} -guanidino) -acetic acid (N ′-{5- [1- ( 2-fluoro-biphenyl-4
-Yl) -ethyl] -isoxazol-3-ylmethyl} -guanidino) -acetic acid (N ′-{3- [1- (2-fluoro-biphenyl-4)
-Yl) -ethyl] -isoxazol-5-yl} -N
-Methyl-guanidino) -acetic acid (N '-{3- [1- (2-fluoro-biphenyl-4)
-Yl) -ethyl] -isoxazol-5-ylmethyl} -N-methyl-guanidino) -acetic acid (N ′-{5- [1- (2-fluoro-biphenyl-4)
-Yl) -ethyl] -isoxazol-3-yl} -N
-Methyl-guanidino) -acetic acid (N '-{5- [1- (2-fluoro-biphenyl-4)
-Yl) -ethyl] -isoxazol-3-ylmethyl} -N-methyl-guanidino) -acetic acid (N ′-{3- [1- (2-fluoro-biphenyl-4)
-Yl) -ethyl] -isoxazol-5-ylmethyl} -guanidino) -acetic acid ethyl ester (N ′-{5- [1- (2-fluoro-biphenyl-4)
-Yl) -ethyl] -isoxazol-3-yl} -guanidino) -acetic acid ethyl ester (N '-{5- [1- (2-fluoro-biphenyl-4)
-Yl) -ethyl] -isoxazol-3-ylmethyl} -guanidino) -acetic acid ethyl ester

2- (N '-{3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazole-5
-Yl} -guanidino) -acetamide 2- (N '-{3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylmethyl} -guanidino) -acetamide 2- (N '-{5- [1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-yl}
-Guanidino) -acetamide 2- (N '-{5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-ylmethyl} -guanidino) -acetamide 2- (N'-} 3- [1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-yl}
-Guanidino) -propionic acid 2- (N '-{3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylmethyl} -guanidino) -propionic acid 2- (N' -{5- [1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-yl}
-Guanidino) -propionic acid 2- (N '-{5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-ylmethyl} -guanidino) -propionic acid 2- (N' -{3- [1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-yl}
-Guanidino) -succinic acid

2- (N '-{3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazole-5
-Ylmethyl {-guanidino) -succinic acid 2- (N '-{5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-yl}
-Guanidino) -succinic acid 2- (N '-{5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-ylmethyl} -guanidino) -succinic acid 1- (amino- {3- [1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylimino} -methyl) -pyrrolidine-2-carboxylic acid 1- (amino- {3- [1- (2 -Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylmethylimino} -methyl) -pyrrolidine-2-carboxylic acid 1- (amino- {5- [1- (2-fluoro-biphenyl-4) -Yl) -ethyl] -isoxazol-3-ylimino {-methyl) -pyrrolidine-2-carboxylic acid

1- (amino- {5- [1- (2-fluoro-
Biphenyl-4-yl) -ethyl] -isoxazole-
3-ylmethylimino {-methyl) -pyrrolidine-2-
Carboxylic acid N- {3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-yl} -N ′,
N "-dimethyl-guanidine N- {3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylmethyl}-
N ', N "-dimethyl-guanidine N- {5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-yl} -N',
N "-dimethyl-guanidine N- {5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-ylmethyl}-
N ', N "-dimethyl-guanidine N- {3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-yl} -N'-
Methyl-N "-phenyl-guanidine N- {3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylmethyl}-
N'-methyl-N "-phenyl-guanidine N- {5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-yl} -N'-
Methyl-N "-phenyl-guanidine

N- {5- [1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-ylmethyl} -N'-methyl-N "-phenyl-guanidine N"-{3- [1- (2-Fluoro-biphenyl-4-
Yl) -ethyl] -isoxazol-5-yl} -N,
N, N ', N'-tetramethyl-guanidine N "-{3- [1- (2-fluoro-biphenyl-4-
Yl) -ethyl] -isoxazol-5-ylmethyl}
-N, N, N ', N'-tetramethyl-guanidine N "-{5- [1- (2-fluoro-biphenyl-4-)
Yl) -ethyl] -isoxazol-3-yl} -N,
N, N ', N'-tetramethyl-guanidine N "-{5- [1- (2-fluoro-biphenyl-4-
Yl) -ethyl] -isoxazol-3-ylmethyl}
-N, N, N ', N'-tetramethyl-guanidine (di-piperidin-1-yl-methylene)-{3- [1
-(2-Fluoro-biphenyl-4-yl) -ethyl]
-Isoxazol-5-yl} -amine (di-piperidin-1-yl-methylene)-{3- [1
-(2-Fluoro-biphenyl-4-yl) -ethyl]
-Isoxazol-5-ylmethyl} -amine

(Di-piperidin-1-yl-methylene)-
{5- [1- (2-fluoro-biphenyl-4-yl)]
-Ethyl] -isoxazol-3-yl} -amine (di-piperidin-1-yl-methylene)-{5- [1
-(2-Fluoro-biphenyl-4-yl) -ethyl]
-Isoxazol-3-ylmethyl} -amine (di-morpholin-4-yl-methylene)-{3- [1
-(2-Fluoro-biphenyl-4-yl) -ethyl]
-Isoxazol-5-yl} -amine (di-morpholin-4-yl-methylene)-{3- [1
-(2-Fluoro-biphenyl-4-yl) -ethyl]
-Isoxazol-5-ylmethyl} -amine (di-morpholin-4-yl-methylene)-{5- [1
-(2-Fluoro-biphenyl-4-yl) -ethyl]
-Isoxazol-3-yl} -amine (di-morpholin-4-yl-methylene)-{5- [1
-(2-Fluoro-biphenyl-4-yl) -ethyl]
-Isoxazol-3-ylmethyl} -amine (di-piperazin-4-yl-methylene)-{3- [1
-(2-Fluoro-biphenyl-4-yl) -ethyl]
-Isoxazol-5-yl} -amine (di-piperazin-4-yl-methylene)-{3- [1
-(2-Fluoro-biphenyl-4-yl) -ethyl]
-Isoxazol-5-ylmethyl} -amine (di-piperazin-4-yl-methylene)-{5- [1
-(2-Fluoro-biphenyl-4-yl) -ethyl]
-Isoxazol-3-yl} -amine

(Di-piperazin-4-yl-methylene)-
{5- [1- (2-fluoro-biphenyl-4-yl)]
-Ethyl] -isoxazol-3-ylmethyl} -amine (4,5-dihydro-1H-imidazol-2-yl)
-{3- [1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-yl} -amine (4,5-dihydro-1H-imidazol-2-yl)
-{3- [1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylmethyl}-
Amine (4,5-dihydro-1H-imidazol-2-yl)
-{5- [1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-yl} -amine (4,5-dihydro-1H-imidazol-2-yl)
-{5- [1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-ylmethyl}-
Amine 1- {3- [1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-yl} -4,5
-Dihydro-1H-imidazol-2-ylamine

1- {3- [1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylmethyl} -4,5-dihydro-1H-imidazole-2-
Iylamine 1- {5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-yl} -4,5
-Dihydro-1H-imidazol-2-ylamine 1- {5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-ylmethyl}-
4,5-dihydro-1H-imidazol-2-ylamine {3- [1- (2-fluoro-biphenyl-4-yl)
-Ethyl] -isoxazol-5-yl}-(1,4,
5,6-tetrahydro-pyrimidin-2-yl) -amine {3- [1- (2-fluoro-biphenyl-4-yl)
-Ethyl] -isoxazol-5-ylmethyl}-
(1,4,5,6-tetrahydro-pyrimidin-2-yl) -amine {5- [1- (2-fluoro-biphenyl-4-yl)]
-Ethyl] -isoxazol-3-yl}-(1,4,
5,6-tetrahydro-pyrimidin-2-yl) -amine

[0100] {5- [1- (2-Fluoro-biphenyl-4)
-Yl) -ethyl] -isoxazol-3-ylmethyl}-(1,4,5,6-tetrahydro-pyrimidine-
2-yl) -amine 1- {3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-yl} -1,
4,5,6-tetrahydro-pyrimidin-2-ylamine 1- {3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylmethyl}-
1,4,5,6-tetrahydro-pyrimidin-2-ylamine 1- {5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-yl} -1,
4,5,6-tetrahydro-pyrimidin-2-ylamine 1- {5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-ylmethyl}-
1,4,5,6-tetrahydro-pyrimidin-2-ylamine

(3,6-Dihydro-2H- [1,3,5] oxadiazin-4-yl)-{3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazole-5 -Yl} -amine (3,6-dihydro-2H- [1,3,5] oxadiazin-4-yl)-{3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazole −5-
Ylmethyl} -amine (3,6-dihydro-2H- [1,3,5] oxadiazin-4-yl)-{5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazole- 3-
Ill} -amine (3,6-dihydro-2H- [1,3,5] oxadiazin-4-yl)-{5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazole- 3-
Ylmethyl} -amine 3- {3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-yl} -3,6
-Dihydro-2H- [1,3,5] oxadiazine-4
-Ylamine 3- {3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylmethyl}-
3,6-dihydro-2H- [1,3,5] oxadiazin-4-ylamine

3- {5- [1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-yl}
-3,6-Dihydro-2H- [1,3,5] oxadiazin-4-ylamine 3- {5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-ylmethyl} −
3,6-dihydro-2H- [1,3,5] oxadiazin-4-ylamine {3- [1- (2-fluoro-biphenyl-4-yl)
-Ethyl] -isoxazol-5-yl}-(1,4,
5,6-tetrahydro- [1,3,5] triazine-2
-Yl) -amine {3- [1- (2-fluoro-biphenyl-4-yl)
-Ethyl] -isoxazol-5-ylmethyl}-
(1,4,5,6-tetrahydro- [1,3,5] triazin-2-yl) -amine {5- [1- (2-fluoro-biphenyl-4-yl)]
-Ethyl] -isoxazol-3-yl}-(1,4,
5,6-tetrahydro- [1,3,5] triazine-2
-Yl) -amine {5- [1- (2-fluoro-biphenyl-4-yl)]
-Ethyl] -isoxazol-3-ylmethyl}-
(1,4,5,6-tetrahydro- [1,3,5] triazin-2-yl) -amine

{3- [1- (2-Fluoro-biphenyl-4)
-Yl) -ethyl] -isoxazol-5-yl}-
(5-methyl-1,4,5,6-tetrahydro- [1,
3,5] Triazin-2-yl) -amine {3- [1- (2-fluoro-biphenyl-4-yl)
-Ethyl] -isoxazol-5-ylmethyl}-(5
-Methyl-1,4,5,6-tetrahydro- [1,3
5] triazin-2-yl) -amine {5- [1- (2-fluoro-biphenyl-4-yl)]
-Ethyl] -isoxazol-3-yl}-(5-methyl-1,4,5,6-tetrahydro- [1,3,5] triazin-2-yl) -amine {5- [1- (2- Fluoro-biphenyl-4-yl)
-Ethyl] -isoxazol-3-ylmethyl}-(5
-Methyl-1,4,5,6-tetrahydro- [1,3
5] triazin-2-yl) -amine 1- {3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-yl} -1,
4,5,6-tetrahydro- [1,3,5] triazin-2-ylamine

1- {3- [1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylmethyl} -1,4,5,6-tetrahydro- [1,3
5] triazin-2-ylamine 1- {5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-yl} -1,
4,5,6-tetrahydro- [1,3,5] triazin-2-ylamine 1- {5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-ylmethyl}-
1,4,5,6-tetrahydro- [1,3,5] triazin-2-ylamine 1- {3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-yl {-5-methyl-1,4,5,6-tetrahydro- [1,3,5]
Triazin-2-ylamine 1- {3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-yl} -5-methyl-1,4,5,6-tetrahydro- [ 1,3,5]
Triazin-2-ylamine

1- {5- [1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-yl}
-5-methyl-1,4,5,6-tetrahydro- [1,
3,5] Triazin-2-ylamine 1- {5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-yl} -5-methyl-1,4,5,6 -Tetrahydro- [1,3,5]
Triazin-2-ylamine 2- {3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylamino}-
1,4,5,6-tetrahydro-pyrimidin-5-ol 2-({3- [1- (2-fluoro-biphenyl-4-)
Yl) -ethyl] -isoxazol-5-ylmethyl}
-Amino) -1,4,5,6-tetrahydro-pyrimidin-5-ol 2- {5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-ylamino}-
1,4,5,6-tetrahydro-pyrimidin-5-ol 2-({5- [1- (2-fluoro-biphenyl-4-
Yl) -ethyl] -isoxazol-3-ylmethyl}
-Amino) -1,4,5,6-tetrahydro-pyrimidin-5-ol

[0106] {3- [1- (2-Fluoro-biphenyl-4)
-Yl) -ethyl] -isoxazol-5-yl}-
(5-methoxy-1,4,5,6-tetrahydro-pyrimidin-2-yl) -amine {3- [1- (2-fluoro-biphenyl-4-yl)
-Ethyl] -isoxazol-5-ylmethyl}-(5
-Methoxy-1,4,5,6-tetrahydro-pyrimidin-2-yl) -amine {5- [1- (2-fluoro-biphenyl-4-yl)]
-Ethyl] -isoxazol-3-yl}-(5-methoxy-1,4,5,6-tetrahydro-pyrimidine-2
-Yl) -amine {5- [1- (2-fluoro-biphenyl-4-yl)]
-Ethyl] -isoxazol-3-ylmethyl}-(5
-Methoxy-1,4,5,6-tetrahydro-pyrimidin-2-yl) -amine 2-amino-1- {3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazole- 5-yl} -1,4,5,6-tetrahydro-pyrimidine-5
-All 2-amino-1- {3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylmethyl} -1,4,5,6-tetrahydro-pyrimidine-5- Oar

2-Amino-1- {5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-yl} -1,4,5,6-tetrahydro-pyrimidine-5 -All 2-amino-1- {5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-ylmethyl} -1,4,5,6-tetrahydro-pyrimidine-5- All 1- {3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-yl} -5-methoxy-1,4,5,6-tetrahydro-pyrimidine-
2-ylamine 1- {3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylmethyl}-
5-methoxy-1,4,5,6-tetrahydro-pyrimidin-2-ylamine 1- {5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-yl} -5 -Methoxy-1,4,5,6-tetrahydro-pyrimidine-
2-ylamine

1- {5- [1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-ylmethyl} -5-methoxy-1,4,5,6-tetrahydro-pyrimidine-2 -Ylamine {3- [1- (2-fluoro-biphenyl-4-yl)]
-Ethyl] -isoxazol-5-yl}-(4,5
6,7-tetrahydro-1H- [1,3] diazepine-
2-yl) -amine {3- [1- (2-fluoro-biphenyl-4-yl)
-Ethyl] -isoxazol-5-ylmethyl}-
(4,5,6,7-tetrahydro-1H- [1,3] diazepin-2-yl) -amine {5- [1- (2-fluoro-biphenyl-4-yl)]
-Ethyl] -isoxazol-3-yl}-(4,5
6,7-tetrahydro-1H- [1,3] diazepine-
2-yl) -amine {5- [1- (2-fluoro-biphenyl-4-yl)
-Ethyl] -isoxazol-3-ylmethyl}-
(4,5,6,7-tetrahydro-1H- [1,3] diazepin-2-yl) -amine 1- {3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazole −5-yl｝ -4,
5,6,7-tetrahydro-1H- [1,3] diazepin-2-ylamine

1- {3- [1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylmethyl} -4,5,6,7-tetrahydro-1H- [1,
3] Diazepin-2-ylamine 1- {5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-yl} -4,
5,6,7-tetrahydro-1H- [1,3] diazepin-2-ylamine 1- {5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-ylmethyl}-
4,5,6,7-tetrahydro-1H- [1,3] diazepin-2-ylamine ({3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylmethyl Imino {-pyrrolidin-1-yl-methyl) -amine ({5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-ylimino}-
Pyrrolidin-1-yl-methyl) -amine ({5- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-3-ylmethylimino} -pyrrolidin-1-yl-methyl)- Amine

(Azepan-1-yl- {3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylimino} -methyl) -amine ({3- [1- ( 2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylimino}-
Thiazolidine-3-yl-methyl) -amine 1- (amino- {3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylimino} -methyl) -piperidin-2- ON N- {3- [1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-yl} -N'-
(2-oxo-propyl) -guanidine 3- (N '-{3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-yl}
-Guanidino) -propionic acid ethyl ester 2- (N '-{3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-yl}
-Guanidino) -N, N-dimethyl-acetamide

3- (N ′-{3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazole-5
-Yl} -guanidino) -N, N-dimethyl-propionamide N- {3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-yl} -N'-
(3-Hydroxy-propyl) -guanidine N- {3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-yl} -N'-
(2-pyrrolidin-1-yl-ethyl) -guanidine N- {3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-yl} -N'-
(2-piperidin-1-yl-ethyl) -guanidine N- {3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-yl} -N'-
[2- (4-Methyl-piperazin-1-yl) -ethyl] -guanidine N- {3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-yl} -N '-
(3-morpholin-4-yl-propyl) -guanidine

N- {3- [1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-yl}
-N '-[2- (2-methoxy-ethoxy) -ethyl]
-Guanidine N- {3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-yl} -N'-
[2- (3-hydroxy-propoxy) -ethyl] -guanidine 2- {3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylimino}-
1- (2-methoxy-ethyl) -imidazolidin-4-
ON N-({3- [1- (2-fluoro-biphenyl-4-
Yl) -ethyl] -isoxazol-5-ylimino}
-Methylamino-methyl) -N'-methyl-guanidine N '-(dimethylamino- {3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylimino} -methyl) -N, N-dimethyl-guanidine

[[{3- [1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylimino}-(4-methyl-piperazin-1-yl) -methylimino]-(4 -Methyl-piperazin-1-yl)-
Methyl] -amine N-[{3- [1- (2-fluoro-biphenyl-4-)
Yl) -ethyl] -isoxazol-5-ylimino}
-(2-morpholin-4-yl-ethylamino) -methyl] -N '-(2-morpholin-4-yl-ethyl)-
Guanidine N-[{3- [1- (2-fluoro-biphenyl-4-)
Yl) -ethyl] -isoxazol-5-ylimino}
-(2-hydroxy-ethylamino) -methyl] -N '
-(2-hydroxy-ethyl) -guanidine N- {3- [1- (2-fluoro-biphenyl-4-)
Yl) -ethyl] -isoxazol-5-ylimino}
-[2- (2-hydroxy-ethoxy) -ethylamino] -methyl} -N '-[2- (2-hydroxy-ethoxy) -ethyl] -guanidine [bis- (4-methyl-piperazin-1-yl) ) -Methylene]-{3- [1- (2-fluoro-biphenyl-4)
-Yl) -ethyl] -isoxazol-5-yl} -amine

N- {3- [1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-yl}
-N ', N "-bis- (2-morpholin-4-yl-ethyl) -guanidine N- {3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-yl ｝ -N ',
N "-bis- (2-hydroxy-ethyl) -guanidine N- {3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-yl} -N ',
N "-bis- [2- (2-hydroxy-ethoxy) -ethyl] -guanidine

N- {3- [1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-yl}
-N '-(methylamino) -guanidine N- {3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-yl} -N'-
(Dimethylamino) -guanidine N- {3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-yl} -N'-
(Pyridin-2-yl-amino) -guanidine N- {3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-yl} -N'-
Pyridin-2-yl-guanidine N- {3- [1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-yl} -N'-
Pyridin-4-yl-guanidine

N- {3- [1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-yl}
-N'-pyrimidin-2-yl-guanidine N- {3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-yl} -N'-
(1H-tetrazol-5-yl) -guanidine {3- [1- (2-fluoro-biphenyl-4-yl)
-Ethyl] -isoxazol-5-yl}-(imino-
Morpholin-4-yl-methyl) -methyl-amine N- {3- [1- (2-fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-yl} -N'-methyl -Guanidine

N-ethyl-N '-{3- [1- (2-fluoro-biphenyl-4-yl) -1-methyl-ethyl]-
Isoxazol-5-yl} -guanidine N, N-diethyl-N '-{3- [1- (2-fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-yl} -guanidine ({3- [1- (2-Fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-ylimino} -pyrrolidin-1-yl-methyl) -amine (azepan-1-yl- {3- [1- (2-fluoro-
Biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-ylimino} -methyl) -amine [{3- [1- (2-fluoro-biphenyl-4-yl) -1-methyl-ethyl] -Isoxazol-5-ylimino}-(4-methyl-piperazin-1-yl)-
Methyl] -amine ({3- [1- (2-Fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-ylimino} -thiazolidine-3-yl-methyl) -amine

[{3- [1- (2-Fluoro-biphenyl-)
4-yl) -1-methyl-ethyl] -isoxazole-
5-ylimino {-(4-methyl-piperidin-1-yl) -methyl] -amine ((2,6-dimethyl-morpholin-4-yl)-{3
-[1- (2-fluoro-biphenyl-4-yl) -1
-Methyl-ethyl] -isoxazol-5-ylimino} -methyl) -amine ((4-dimethylamino-piperidin-1-yl)-
{3- [1- (2-Fluoro-biphenyl-4-yl)]
-1-Methyl-ethyl] -isoxazol-5-ylimino} -methyl) -amine 1- (amino- {3- [1- (2-fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazole -5-ylimino {-methyl) -piperidin-4-one 1- (amino- {3- [1- (2-fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-ylimino} -Methyl) -piperidin-2-one

1- (amino- {3- [1- (2-fluoro-
Biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-ylimino} -methyl) -piperidin-4-ol [{3- [1- (2-fluoro-biphenyl-4-yl) -1-] Methyl-ethyl] -isoxazol-5-ylimino}-(4-methoxy-piperidin-1-yl)
-Methyl] -amine ({3- [1- (2-Fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-ylimino}-[1,4] thiazinan-4-yl-methyl ) -Amine 1- [4- (amino- {3- [1- (2-fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-ylimino} -methyl) -piperazine-
1-yl] -ethanone N- {3- [1- (2-fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-yl} -N '-(2-oxo-propyl) -Guanidine

(N ′-{3- [1- (2-Fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-yl} -guanidino) -acetic acid ethyl ester 3- (N ′ -{3- [1- (2-Fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-yl} -guanidino) -propionic acid ethyl ester 2- (N '-{3- [ 1- (2-fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-yl} -guanidino) -N, N-dimethyl-acetamide 3- (N ′-{3- [1- (2-Fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-yl} -guanidino) -N, N-dimethyl-propionamide N- {3- [1- (2-fluoro- Biphenyl-4 Yl) -1-methyl - ethyl] - isoxazol-5-yl} -N '- (2-hydroxy-ethyl) - - guanidine

N- {3- [1- (2-Fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-yl} -N '-(3-hydroxy-propyl)-
Guanidine N- {3- [1- (2-fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-yl} -N '-(2-methoxy-ethyl) -guanidine N- ( 2-dimethylamino-ethyl) -N '-{3-
[1- (2-Fluoro-biphenyl-4-yl) -1-
Methyl-ethyl] -isoxazol-5-yl} -guanidine N- {3- [1- (2-fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-yl} -N'- (2-pyrrolidin-1-yl-ethyl)-
Guanidine N- {3- [1- (2-fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-yl} -N '-(2-piperidin-1-yl-ethyl)-
Guanidine

N- {3- [1- (2-Fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-yl} -N '-(2-morpholin-4-yl-ethyl ) -Guanidine N- {3- [1- (2-fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-yl} -N '-[2- (4-methyl-piperazine- 1-yl) -ethyl] -guanidine N- {3- [1- (2-fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-yl} -N '-(3-morpholine -4-yl-propyl)
-Guanidine N- {3- [1- (2-fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-yl} -N '-[2- (2-hydroxy-ethoxy)- Ethyl] -guanidine N- {3- [1- (2-fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-yl} -N '-[2- (2-methoxy-ethoxy) ) -Ethyl] -guanidine

N- {3- [1- (2-Fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-yl} -N '-[2- (3-hydroxy-propoxy) -Ethyl] -guanidine 2- {3- [1- (2-fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-ylimino} -1-methyl-imidazolidin-4-one 2 -{3- [1- (2-Fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-ylimino} -1- (2-hydroxy-ethyl) -imidazolidin-4-one 2 -{3- [1- (2-Fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-ylimino} -1- (2-methoxy-ethyl) -imidazolidin-4-one N − ( 3- [1- (2-fluoro - biphenyl-4
Yl) -1-methyl-ethyl] -isoxazole-5
Ilimino {-methylamino-methyl) -N'-methyl-guanidine

N ′-(dimethylamino- {3- [1- (2-
Fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-ylimino {-methyl)-
N, N-dimethyl-guanidine [({3- [1- (2-fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-ylimino} -morpholin-4-yl-methylimino)-
Morpholin-4-yl-methyl] -amine [[{3- [1- (2-fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-ylimino}-(4-methyl-piperazine) -1-yl)-
Methylimino]-(4-methyl-piperazin-1-yl) -methyl] -amine N-[{3- [1- (2-fluoro-biphenyl-4-)
Yl) -1-methyl-ethyl] -isoxazole-5
Ilimino {-(2-morpholin-4-yl-ethylamino) -methyl] -N '-(2-morpholin-4-yl-ethyl) -guanidine

N-[{3- [1- (2-Fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-ylimino}-(2-hydroxy-ethylamino) -methyl]- N '-(2-hydroxy-ethyl)-
Guanidine N- {3- [1- (2-fluoro-biphenyl-4-)
Yl) -1-methyl-ethyl] -isoxazole-5
Ilimino}-[2- (2-hydroxy-ethoxy)-
Ethylamino] -methyl} -N ′-[2- (2-hydroxy-ethoxy) -ethyl] -guanidine N- {3- [1- (2-fluoro-biphenyl-4-yl) -1-methyl-ethyl ] -Isoxazol-5-yl} -N ', N "-dimethyl-guanidine N"-{3- [1- (2-fluoro-biphenyl-4-
Yl) -1-methyl-ethyl] -isoxazole-5
Ill} -N, N, N ', N'-tetramethyl-guanidine (di-morpholin-4-yl-methylene)-{3- [1
-(2-Fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-yl} -amine

[Bis- (4-methyl-piperazin-1-yl) -methylene]-{3- [1- (2-fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazole-5- Yl} -amine N- {3- [1- (2-fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-yl} -N ', N "-bis- (2-morpholine -4-yl-ethyl) -guanidine N- {3- [1- (2-fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-yl} -N ', N "-bis -(2-hydroxy-ethyl)
-Guanidin N- {3- [1- (2-fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-yl} -N ', N "-bis- [2- (2- (Hydroxy-ethoxy) -ethyl] -guanidine N- {3- [1- (2′-fluoro-biphenyl-4-)
Yl) -ethyl] -isoxazol-5-yl {-N '
-Methyl-guanidine

N ′-{3- [1- (2′-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-yl} -N, N-dimethyl-guanidine N-ethyl-N ′-｛ 3- [1- (2′-fluoro-biphenyl-4-yl) -ethyl] -isoxazole-5
-Yl} -guanidine N, N-diethyl-N '-{3- [1- (2'-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-yl} -guanidine ({3- [1 -(2'-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylimino}-
Pyrrolidin-1-yl-methyl) -amine ({3- [1- (2'-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylimino}-
Piperidin-1-yl-methyl) -amine (azepan-1-yl- {3- [1- (2'-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylimino} -methyl) -amine [{3- [1- (2'-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylimino}-
(4-Methyl-piperazin-1-yl) -methyl] -amine ({3- [1- (2'-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylimino}-
Thiazolidin-3-yl-methyl) -amine

[{3- [1- (2'-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylimino}-(4-methyl-piperidin-1-yl) -methyl] -amine ( (2,6-dimethyl-morpholin-4-yl)-{3
-[1- (2'-fluoro-biphenyl-4-yl)-
[Ethyl] -isoxazol-5-ylimino} -methyl) -amine ((4-dimethylamino-piperidin-1-yl)-
{3- [1- (2'-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylimino}-
Methyl) -amine 1- (amino- {3- [1- (2′-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylimino} -methyl) -piperidin-4-one 1- (amino -{3- [1- (2'-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylimino} -methyl) -piperidin-2-one 1- (amino- {3- [1- ( 2′-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylimino} -methyl) -piperidin-4-ol

[{3- [1- (2'-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylimino}-(4-methoxy-piperidin-1-yl) -methyl] -amine ( {3- [1- (2'-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylimino}-
[1,4] thiazin-4-yl-methyl) -amine 1- [4- (amino- {3- [1- (2′-fluoro-
Biphenyl-4-yl) -ethyl] -isoxazole-
5-ylimino {-methyl) -piperazin-1-yl]
-Ethanone N- {3- [1- (2'-fluoro-biphenyl-4-
Yl) -ethyl] -isoxazol-5-yl {-N '
-(2-oxo-propyl) -guanidine (N '-{3- [1- (2'-fluoro-biphenyl-
4-yl) -ethyl] -isoxazol-5-yl}-
Guanidino) -acetic acid ethyl ester 3- (N '-{3- [1- (2'-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-yl} -guanidino) -propionic acid ethyl ester

2- (N '-{3- [1- (2'-fluoro-
Biphenyl-4-yl) -ethyl] -isoxazole-
5-yl} -guanidino) -N, N-dimethyl-acetamide 3- (N ′-{3- [1- (2′-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-yl}- Guanidino) -N, N-dimethyl-propionamide N- {3- [1- (2'-fluoro-biphenyl-4-)
Yl) -ethyl] -isoxazol-5-yl {-N '
-(2-hydroxy-ethyl) -guanidine N- {3- [1- (2'-fluoro-biphenyl-4-
Yl) -ethyl] -isoxazol-5-yl {-N '
-(3-hydroxy-propyl) -guanidine N- {3- [1- (2'-fluoro-biphenyl-4-
Yl) -ethyl] -isoxazol-5-yl {-N '
-(2-methoxy-ethyl) -guanidine N- (2-dimethylamino-ethyl) -N '-{3-
[1- (2′-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-yl} -guanidine

N- {3- [1- (2'-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-yl} -N '-(2-pyrrolidin-1-yl-ethyl)-
Guanidine N- {3- [1- (2'-fluoro-biphenyl-4-)
Yl) -ethyl] -isoxazol-5-yl {-N '
-(2-piperidin-1-yl-ethyl) -guanidine N- {3- [1- (2'-fluoro-biphenyl-4-
Yl) -ethyl] -isoxazol-5-yl {-N '
-(2-morpholin-4-yl-ethyl) -guanidine N- {3- [1- (2'-fluoro-biphenyl-4-
Yl) -ethyl] -isoxazol-5-yl {-N '
-[2- (4-methyl-piperazin-1-yl) -ethyl] -guanidine N- {3- [1- (2'-fluoro-biphenyl-4-
Yl) -ethyl] -isoxazol-5-yl {-N '
-(3-morpholin-4-yl-propyl) -guanidine N- {3- [1- (2'-fluoro-biphenyl-4-
Yl) -ethyl] -isoxazol-5-yl {-N '
-[2- (2-hydroxy-ethoxy) -ethyl] -guanidine

N- {3- [1- (2'-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-yl} -N '-[2- (2-methoxy-ethoxy) -ethyl] -Guanidine N- {3- [1- (2'-fluoro-biphenyl-4-
Yl) -ethyl] -isoxazol-5-yl {-N '
-[2- (3-hydroxy-propoxy) -ethyl]-
Guanidine 2- {3- [1- (2'-fluoro-biphenyl-4-)
Yl) -ethyl] -isoxazol-5-ylimino}
-1-methyl-imidazolidin-4-one 2- {3- [1- (2′-fluoro-biphenyl-4-)
Yl) -ethyl] -isoxazol-5-ylimino}
-1- (2-hydroxy-ethyl) -imidazolidine-
4-one 2- {3- [1- (2'-fluoro-biphenyl-4-
Yl) -ethyl] -isoxazol-5-ylimino}
-1- (2-methoxy-ethyl) -imidazolidine-4
-ON

N-({3- [1- (2'-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylimino} -methylamino-methyl) -N'-methyl-
Guanidine N '-(dimethylamino- {3- [1- (2'-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylimino} -methyl) -N, N-dimethyl-
Guanidine [({3- [1- (2′-fluoro-biphenyl-4-
Yl) -ethyl] -isoxazol-5-ylimino}
-Morpholin-4-yl-methylimino) -morpholin-4-yl-methyl] -amine [[{3- [1- (2'-fluoro-biphenyl-4-
Yl) -ethyl] -isoxazol-5-ylimino}
-(4-Methyl-piperazin-1-yl) -methylimino]-(4-methyl-piperazin-1-yl) -methyl] -amine N-[{3- [1- (2'-fluoro-biphenyl-4)
-Yl) -ethyl] -isoxazol-5-ylimino}-(2-morpholin-4-yl-ethylamino)-
Methyl] -N '-(2-morpholin-4-yl-ethyl) -guanidine

N-[{3- [1- (2'-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylimino}-(2-hydroxy-ethylamino) -methyl] -N'- (2-hydroxy-ethyl) -guanidine N- {3- [1- (2'-fluoro-biphenyl-4)
-Yl) -ethyl] -isoxazol-5-ylimino}-[2- (2-hydroxy-ethoxy) -ethylamino] -methyl} -N '-[2- (2-hydroxy-ethoxy) -ethyl] -guanidine N- {3- [1- (2'-fluoro-biphenyl-4-
Yl) -ethyl] -isoxazol-5-yl}-
N ', N "-dimethyl-guanidine N"-{3- [1- (2'-fluoro-biphenyl-4)
-Yl) -ethyl] -isoxazol-5-yl}-
N, N, N ', N'-tetramethyl-guanidine (di-morpholin-4-yl-methylene)-{3- [1
-(2'-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-yl} -amine [bis- (4-methyl-piperazin-1-yl) -methylene]-{3- [1- ( 2'-fluoro-biphenyl-
4-yl) -ethyl] -isoxazol-5-yl}-
Amine

N- {3- [1- (2'-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-yl} -N ', N "-bis- (2-morpholin-4-yl -Ethyl) -guanidine N- {3- [1- (2'-fluoro-biphenyl-4-
Yl) -ethyl] -isoxazol-5-yl}-
N ', N "-bis- (2-hydroxy-ethyl) -guanidine N- {3- [1- (2'-fluoro-biphenyl-4-
Yl) -ethyl] -isoxazol-5-yl}-
N ', N "-bis- [2- (2-hydroxy-ethoxy) -ethyl] -guanidine N- {3- [1- (2'-fluoro-biphenyl-4-
Yl) -1-methyl-ethyl] -isoxazole-5
Ill} -N'-methyl-guanidine N '-{3- [1- (2'-fluoro-biphenyl-4)
-Yl) -1-methyl-ethyl] -isoxazole-5
-Yl {-N, N-dimethyl-guanidine N-ethyl-N '-{3- [1- (2'-fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-yl} -Guanidine N, N-diethyl-N '-{3- [1- (2'-fluoro-biphenyl-4-yl) -1-methyl-ethyl]-
Isoxazol-5-yl} -guanidine

({3- [1- (2′-Fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-ylimino} -pyrrolidin-1-yl-methyl)
-Amine ({3- [1- (2'-fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-ylimino} -piperidin-1-yl-methyl) -amine (azepan-1 -Yl- {3- [1- (2'-fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-ylimino} -methyl) -amine ({3- [1- (2 ' -Fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-ylimino} -morpholin-4-yl-methyl) -amine [{3- [1- (2′-fluoro-biphenyl-4) -Yl) -1-methyl-ethyl] -isoxazol-5-ylimino}-(4-methyl-piperazin-1-yl)-
Methyl] -amine ({3- [1- (2′-fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-ylimino} -thiazolidine-3-yl-methyl) -amine

[{3- [1- (2'-Fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-ylimino}-(4-methyl-piperidin-1-
Yl) -methyl] -amine ((2,6-dimethyl-morpholin-4-yl)-{3
-[1- (2'-fluoro-biphenyl-4-yl)-
1-methyl-ethyl] -isoxazol-5-ylimino} -methyl) -amine ((4-dimethylamino-piperidin-1-yl)-
{3- [1- (2′-Fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-ylimino} -methyl) -amine 1- (amino- {3- [1- (2 '-Fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-ylimino} -methyl) -piperidine-4-
On 1- (amino- {3- [1- (2'-fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-ylimino} -methyl) -piperidine-2-
On 1- (amino- {3- [1- (2'-fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-ylimino} -methyl) -piperidine-4-
Oar

[{3- [1- (2'-Fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-ylimino}-(4-methoxy-piperidine-1
-Yl) -methyl] -amine ({3- [1- (2'-fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-ylimino}-[1,4] thiazinan-4 -Yl-methyl) -amine 1- [4- (amino- {3- [1- (2'-fluoro-
Biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-ylimino} -methyl) -piperazin-1-yl] -ethanone N- {3- [1- (2'-fluoro-biphenyl-4-
Yl) -1-methyl-ethyl] -isoxazole-5
Yl @ -N '-(2-oxo-propyl) -guanidine (N'-{3- [1- (2'-fluoro-biphenyl-
4-yl) -1-methyl-ethyl] -isoxazole-
5-yl} -guanidino) -acetic acid ethyl ester

[0139] 3- (N '-{3- [1- (2'-fluoro-
Biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-yl} -guanidino) -propionic acid ethyl ester 2- (N ′-{3- [1- (2′-fluoro-biphenyl-4-) Yl) -1-methyl-ethyl] -isoxazol-5-yl} -guanidino) -N, N-dimethyl-acetamido 3- (N ′-{3- [1- (2′-fluoro-biphenyl-4-yl) ) -1-Methyl-ethyl] -isoxazol-5-yl} -guanidino) -N, N-dimethyl-propionamide N- {3- [1- (2′-fluoro-biphenyl-4-)
Yl) -1-methyl-ethyl] -isoxazole-5
Ill} -N '-(2-hydroxy-ethyl) -guanidine N- {3- [1- (2'-fluoro-biphenyl-4-
Yl) -1-methyl-ethyl] -isoxazole-5
Yl @ -N '-(3-hydroxy-propyl) -guanidine

N- {3- [1- (2′-Fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-yl} -N ′-(2-methoxy-ethyl) -guanidine N- (2-dimethylamino-ethyl) -N '-{3-
[1- (2′-Fluoro-biphenyl-4-yl) -1
-Methyl-ethyl] -isoxazol-5-yl} -guanidine N- {3- [1- (2'-fluoro-biphenyl-4-)
Yl) -1-methyl-ethyl] -isoxazole-5
Yl @ -N '-(2-pyrrolidin-1-yl-ethyl)
-Guanidine N- {3- [1- (2'-fluoro-biphenyl-4-
Yl) -1-methyl-ethyl] -isoxazole-5
Yl @ -N '-(2-piperidin-1-yl-ethyl)
-Guanidine N- {3- [1- (2'-fluoro-biphenyl-4-
Yl) -1-methyl-ethyl] -isoxazole-5
Yl @ -N '-(2-morpholin-4-yl-ethyl)
-Guanidine

N- {3- [1- (2'-Fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-yl} -N '-[2- (4-methyl-piperazine -1-yl) -ethyl] -guanidine N- {3- [1- (2'-fluoro-biphenyl-4-
Yl) -1-methyl-ethyl] -isoxazole-5
Ill} -N '-(3-morpholin-4-yl-propyl) -guanidine N- {3- [1- (2'-fluoro-biphenyl-4-
Yl) -1-methyl-ethyl] -isoxazole-5
Yl @ -N '-[2- (2-hydroxy-ethoxy)-
Ethyl] -guanidine N- {3- [1- (2'-fluoro-biphenyl-4-
Yl) -1-methyl-ethyl] -isoxazole-5
Ill} -N '-[2- (2-methoxy-ethoxy) -ethyl] -guanidine N- {3- [1- (2'-fluoro-biphenyl-4-)
Yl) -1-methyl-ethyl] -isoxazole-5
Yl @ -N '-[2- (3-hydroxy-propoxy)
-Ethyl] -guanidine

2- {3- [1- (2′-Fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-ylimino} -1-methyl-imidazolidin-
4-one 2- {3- [1- (2'-fluoro-biphenyl-4-
Yl) -1-methyl-ethyl] -isoxazole-5
Ilimino} -1- (2-hydroxy-ethyl) -imidazolidin-4-one 2- {3- [1- (2′-fluoro-biphenyl-4-)
Yl) -1-methyl-ethyl] -isoxazole-5
Ilimino} -1- (2-methoxy-ethyl) -imidazolidin-4-one N-({3- [1- (2′-fluoro-biphenyl-4)
-Yl) -1-methyl-ethyl] -isoxazole-5
-Ilimino} -methylamino-methyl) -N'-methyl-guanidine N '-(dimethylamino- {3- [1- (2'-fluoro-biphenyl-4-yl) -1-methyl-ethyl]-
Isoxazol-5-ylimino} -methyl) -N, N
-Dimethyl-guanidine

[({3- [1- (2′-Fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-ylimino} -morpholin-4-yl-methylimino) -morpholin-4 -Yl-methyl] -amine [[{3- [1- (2'-fluoro-biphenyl-4-
Yl) -1-methyl-ethyl] -isoxazole-5
Ilimino}-(4-methyl-piperazin-1-yl)
-Methylimino]-(4-methyl-piperazin-1-yl) -methyl] -amine N-[{3- [1- (2'-fluoro-biphenyl-4)
-Yl) -1-methyl-ethyl] -isoxazole-5
-Ilimino}-(2-morpholin-4-yl-ethylamino) -methyl] -N '-(2-morpholin-4-yl-ethyl) -guanidine N-[{3- [1- (2'-fluoro) -Biphenyl-4
-Yl) -1-methyl-ethyl] -isoxazole-5
-Ilimino}-(2-hydroxy-ethylamino)-
Methyl] -N '-(2-hydroxy-ethyl) -guanidine

N- {3- [1- (2'-Fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-ylimino}-[2- (2-hydroxy-ethoxy)- Ethylamino] -methyl} -N '-[2-
(2-Hydroxy-ethoxy) -ethyl] -guanidine N- {3- [1- (2'-fluoro-biphenyl-4-)
Yl) -1-methyl-ethyl] -isoxazole-5
Yl @ -N ', N "-dimethyl-guanidine N"-{3- [1- (2'-fluoro-biphenyl-4)
-Yl) -1-methyl-ethyl] -isoxazole-5
-Yl} -N, N, N ', N'-tetramethyl-guanidine (di-morpholin-4-yl-methylene)-{3- [1
-(2'-Fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-yl} -amine [bis- (4-methyl-piperazin-1-yl) -methylene]-{3- [1- (2'-fluoro-biphenyl-
4-yl) -1-methyl-ethyl] -isoxazole-
5-yl} -amine

N- {3- [1- (2'-Fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-yl} -N ', N "-bis- (2-morpholine -4-yl-ethyl) -guanidine N- {3- [1- (2'-fluoro-biphenyl-4-
Yl) -1-methyl-ethyl] -isoxazole-5
Yl {-N ', N "-bis- (2-hydroxy-ethyl) -guanidine N- {3- [1- (2'-fluoro-biphenyl-4-
Yl) -1-methyl-ethyl] -isoxazole-5
Yl @ -N ', N "-bis- [2- (2-hydroxy-
Ethoxy) -ethyl] -guanidine N- {3- [1- (3-benzoyl-phenyl) -ethyl] -isoxazol-5-yl} -N'-methyl-guanidine N- {3- [1- (3- Benzoyl-phenyl) -ethyl] -isoxazol-5-yl} -N′-ethyl-guanidine N ′-{3- [1- (3-benzoyl-phenyl) -ethyl] -isoxazol-5-yl} -N, N-diethyl-guanidine

[0146] (3- {1- [5- (amino-pyrrolidine-1)
-Yl-methyleneamino) -isoxazol-3-yl] -ethyl} -phenyl) -phenyl-methanone (3- {1- [5- (amino-azepan-1-yl-methyleneamino) -isoxazol-3-yl] ] -Ethyl} -phenyl) -phenyl-methanone [3- (1- {5- [amino- (4-methyl-piperazin-1-yl) -methyleneamino] -isoxazole-
3-yl {-ethyl) -phenyl] -phenyl-methanone (3- {1- [5- (amino-thiazolidine-3-yl-methyleneamino) -isoxazol-3-yl] -ethyl} -phenyl) -phenyl -Methanone [3- (1- {5- [amino- (4-methyl-piperidin-1-yl) -methyleneamino] -isoxazole-]
3-yl {-ethyl) -phenyl] -phenyl-methanone [3- (1- {5- [amino- (2,6-dimethyl-morpholin-4-yl) -methyleneamino] -isoxazol-3-yl} -Ethyl) -phenyl] -phenyl-
Methanone

[3- (1- {5- [amino- (4-dimethylamino-piperidin-1-yl) -methyleneamino]-
Isoxazol-3-yl} -ethyl) -phenyl]-
Phenyl-methanone 1- (amino- {3- [1- (3-benzoyl-phenyl) -ethyl] -isoxazol-5-ylimino}-
Methyl) -piperidin-4-one 1- (amino- {3- [1- (3-benzoyl-phenyl) -ethyl] -isoxazol-5-ylimino}-
Methyl) -piperidin-2-one [3- (1- {5- [amino- (4-hydroxy-piperidin-1-yl) -methyleneamino] -isoxazol-3-yl} -ethyl) -phenyl] -phenyl -Methanone [3- (1- {5- [amino- (4-methoxy-piperidin-1-yl) -methyleneamino] -isoxazol-3-yl} -ethyl) -phenyl] -phenyl-methanone (3- { 1- [5- (amino- [1,4] thiazinane-
4-yl-methyleneamino) -isoxazol-3-yl] -ethyl} -phenyl) -phenyl-methanone 1- [4- (amino- {3- [1- (3-benzoyl-
Phenyl) -ethyl] -isoxazol-5-ylimino} -methyl) -piperazin-1-yl] -ethanone

N- {3- [1- (3-benzoyl-phenyl) -ethyl] -isoxazol-5-yl} -N'-
(2-oxo-propyl) -guanidine (N ′-{3- [1- (3-benzoyl-phenyl)-
Ethyl] -isoxazol-5-yl} -guanidino)
-Acetic acid ethyl ester 3- (N '-{3- [1- (3-benzoyl-phenyl) -ethyl] -isoxazol-5-yl} -guanidino) -propionic acid ethyl ester 2- (N'-{3- [1- (3-benzoyl-phenyl) -ethyl] -isoxazol-5-yl} -guanidino) -N, N-dimethyl-acetamide 3- (N ′-{3- [1- (3-benzoyl-phenyl) -Ethyl] -isoxazol-5-yl} -guanidino) -N, N-dimethyl-propionamide N- {3- [1- (3-benzoyl-phenyl) -ethyl] -isoxazol-5-yl} -N ' -(2-hydroxy-ethyl) -guanidine N- {3- [1- (3-benzoyl-phenyl) -ethyl] -isoxazol-5-yl} -N '-(3-hydroxy-propyl Le) -guanidine

N- {3- [1- (3-benzoyl-phenyl) -ethyl] -isoxazol-5-yl} -N'-
(2-Methoxy-ethyl) -guanidine N- {3- [1- (3-benzoyl-phenyl) -ethyl] -isoxazol-5-yl} -N '-(2-dimethylamino-ethyl) -guanidine N- {3- [1- (3-benzoyl-phenyl) -ethyl] -isoxazol-5-yl} -N '-(2-pyrrolidin-1-yl-ethyl) -guanidine N- {3- [1- (3 -Benzoyl-phenyl) -ethyl] -isoxazol-5-yl} -N '-(2-piperidin-1-yl-ethyl) -guanidine N- {3- [1- (3-benzoyl-phenyl) -ethyl] -Isoxazol-5-yl} -N '-(2-morpholin-4-yl-ethyl) -guanidine N- {3- [1- (3-benzoyl-phenyl) -ethyl] -isoxazol-5-yl}- N ' − [2- (4
-Methyl-piperazin-1-yl) -ethyl] -guanidine N- {3- [1- (3-benzoyl-phenyl) -ethyl] -isoxazol-5-yl} -N '-(3-morpholine-4- Yl-propyl) -guanidine

N- {3- [1- (3-benzoyl-phenyl) -ethyl] -isoxazol-5-yl} -N'-
[2- (2-hydroxy-ethoxy) -ethyl] -guanidine N- {3- [1- (3-benzoyl-phenyl) -ethyl] -isoxazol-5-yl} -N '-[2- (2
-Methoxy-ethoxy) -ethyl] -guanidine N- {3- [1- (3-benzoyl-phenyl) -ethyl] -isoxazol-5-yl} -N '-[2- (3
-Hydroxy-propoxy) -ethyl] -guanidine 2- {3- [1- (3-benzoyl-phenyl) -ethyl] -isoxazol-5-ylimino} -1-methyl-imidazolidin-4-one 2- {3 -[1- (3-benzoyl-phenyl) -ethyl] -isoxazol-5-ylimino} -1- (2-
(Hydroxy-ethyl) -imidazolidin-4-one

2- {3- [1- (3-benzoyl-phenyl) -ethyl] -isoxazol-5-ylimino}-
1- (2-methoxy-ethyl) -imidazolidin-4-
ON N-({3- [1- (3-benzoyl-phenyl) -ethyl] -isoxazol-5-ylimino} -methylamino-methyl) -N'-methyl-guanidine N '-({3- [1- (3-benzoyl-phenyl)-
Ethyl] -isoxazol-5-ylimino} -dimethylamino-methyl) -N, N-dimethyl-guanidine [3- (1- {5-[(amino-morpholin-4-yl-methyleneamino) -morpholin-4-] Yl-methyleneamino] -isoxazol-3-yl} -ethyl) -phenyl] -phenyl-methanone [3- (1- {5-[[amino- (4-methyl-piperazin-1-yl) -methyleneamino]] -(4-methyl-
Piperazin-1-yl) -methyleneamino] -isoxazol-3-yl} -ethyl) -phenyl] -phenyl-methanone

N-[{3- [1- (3-benzoyl-phenyl) -ethyl] -isoxazol-5-ylimino}-
(2-morpholin-4-yl-ethylamino) -methyl] -N '-(2-morpholin-4-yl-ethyl)-
Guanidine N-[{3- [1- (3-benzoyl-phenyl) -ethyl] -isoxazol-5-ylimino}-(2-hydroxy-ethylamino) -methyl] -N '-(2-hydroxy-ethyl) -Guanidine N- {3- [1- (3-benzoyl-phenyl) -ethyl] -isoxazol-5-ylimino}-[2-
(2-hydroxy-ethoxy) -ethylamino] -methyl} -N ′-[2- (2-hydroxy-ethoxy) -ethyl] -guanidine N- {3- [1- (3-benzoyl-phenyl) -ethyl ] -Isoxazol-5-yl} -N ', N "-dimethyl-guanidine N"-{3- [1- (3-benzoyl-phenyl) -ethyl] -isoxazol-5-yl} -N, N, N ',
N'-tetramethyl-guanidine

(3- {1- [5- (di-morpholin-4-yl-methyleneamino) -isoxazol-3-yl]-
Ethyl {-phenyl) -phenyl-methanone [3- (1- {5- [bis- (4-methyl-piperazin-1-yl) -methyleneamino] -isoxazole-3]
-Yl} -ethyl) -phenyl] -phenyl-methanone N- {3- [1- (3-benzoyl-phenyl) -ethyl] -isoxazol-5-yl} -N ', N "-bis- (2- Morpholin-4-yl-ethyl) -guanidine N- {3- [1- (3-benzoyl-phenyl) -ethyl] -isoxazol-5-yl} -N ', N "-bis- (2-hydroxy-ethyl ) -Guanidine N- {3- [1- (3-benzoyl-phenyl) -ethyl] -isoxazol-5-yl} -N ', N "-bis- [2- (2-hydroxy-ethoxy) -ethyl] -Guanidine

N- {3- [1- (3-benzoyl-phenyl) -1-methyl-ethyl] -isoxazol-5-yl} -N'-methyl-guanidine N '-{3- [1- (3 -Benzoyl-phenyl) -1
-Methyl-ethyl] -isoxazol-5-yl}-
N, N-dimethyl-guanidine N- {3- [1- (3-benzoyl-phenyl) -1-]
Methyl-ethyl] -isoxazol-5-yl {-N ′
-Ethyl-guanidine N '-{3- [1- (3-benzoyl-phenyl) -1
-Methyl-ethyl] -isoxazol-5-yl}-
N, N-diethyl-guanidine (3- {1- [5- (amino-pyrrolidin-1-yl-
Methyleneamino) -isoxazol-3-yl] -1-
Methyl-ethyl} -phenyl) -phenyl-methanone (3- {1- [5- (amino-piperidin-1-yl-
Methyleneamino) -isoxazol-3-yl] -1-
Methyl-ethyl {-phenyl) -phenyl-methanone

(3- {1- [5- (amino-azepan-1-
Yl-methyleneamino) -isoxazol-3-yl]
-1-Methyl-ethyl} -phenyl) -phenyl-methanone [3- (1- {5- [amino- (4-methyl-piperazin-1-yl) -methyleneamino] -isoxazole-
3-yl} -1-methyl-ethyl) -phenyl] -phenyl-methanone (3- {1- [5- (amino-thiazolidin-3-yl-methyleneamino) -isoxazol-3-yl] -1
-Methyl-ethyl} -phenyl) -phenyl-methanone [3- (1- {5- [amino- (4-methyl-piperidin-1-yl) -methyleneamino] -isoxazole-
3-yl {-1-methyl-ethyl) -phenyl] -phenyl-methanone

[3- (1- {5- [amino- (2,6-dimethyl-morpholin-4-yl) -methyleneamino] -isoxazol-3-yl} -1-methyl-ethyl) -phenyl]- Phenyl-methanone [3- (1- {5- [amino- (4-dimethylamino-
Piperidin-1-yl) -methyleneamino] -isoxazol-3-yl {-1-methyl-ethyl) -phenyl] -phenyl-methanone 1- (amino- {3- [1- (3-benzoyl-phenyl)-] 1-methyl-ethyl] -isoxazol-5-ylimino} -methyl) -piperidin-4-one 1- (amino- {3- [1- (3-benzoyl-phenyl) -1-methyl-ethyl] -isoxazole- 5-ylimino} -methyl) -piperidin-2-one [3- (1- {5- [amino- (4-hydroxy-piperidin-1-yl) -methyleneamino] -isoxazol-3-yl} -1-] Methyl-ethyl) -phenyl]-
Phenyl-methanone

[3- (1- {5- [amino- (4-methoxy-piperidin-1-yl) -methyleneamino] -isoxazol-3-yl} -1-methyl-ethyl) -phenyl] -phenyl- Methanone (3- {1- [5- (amino- [1,4] thiazinan-
4-yl-methyleneamino) -isoxazol-3-yl] -1-methyl-ethyl} -phenyl) -phenyl-
Methanone 1- [4- (amino- {3- [1- (3-benzoyl-
Phenyl) -1-methyl-ethyl] -isoxazole-
5-ylimino {-methyl) -piperazin-1-yl]
-Ethanone N- {3- [1- (3-benzoyl-phenyl) -1-]
Methyl-ethyl] -isoxazol-5-yl {-N ′
-(2-oxo-propyl) -guanidine (N '-{3- [1- (3-benzoyl-phenyl)-]
1-methyl-ethyl] -isoxazol-5-yl}-
Guanidino) -acetic acid ethyl ester 3- (N ′-{3- [1- (3-benzoyl-phenyl) -1-methyl-ethyl] -isoxazol-5-yl} -guanidino) -propionic acid ethyl ester

2- (N '-{3- [1- (3-benzoyl-
Phenyl) -1-methyl-ethyl] -isoxazole-
5-yl} -guanidino) -N, N-dimethyl-acetamide 3- (N ′-{3- [1- (3-benzoyl-phenyl) -1-methyl-ethyl] -isoxazol-5-yl} -guanidino ) -N, N-Dimethyl-propionamide N- {3- [1- (3-benzoyl-phenyl) -1-]
Methyl-ethyl] -isoxazol-5-yl {-N ′
-(2-hydroxy-ethyl) -guanidine N- {3- [1- (3-benzoyl-phenyl) -1-]
Methyl-ethyl] -isoxazol-5-yl {-N ′
-(3-hydroxy-propyl) -guanidine N- {3- [1- (3-benzoyl-phenyl) -1-]
Methyl-ethyl] -isoxazol-5-yl {-N ′
-(2-methoxy-ethyl) -guanidine N- {3- [1- (3-benzoyl-phenyl) -1-]
Methyl-ethyl] -isoxazol-5-yl {-N ′
-(2-dimethylamino-ethyl) -guanidine

N- {3- [1- (3-benzoyl-phenyl) -1-methyl-ethyl] -isoxazol-5-yl} -N '-(2-pyrrolidin-1-yl-ethyl)-
Guanidine N- {3- [1- (3-benzoyl-phenyl) -1-]
Methyl-ethyl] -isoxazol-5-yl {-N ′
-(2-piperidin-1-yl-ethyl) -guanidine N- {3- [1- (3-benzoyl-phenyl) -1-]
Methyl-ethyl] -isoxazol-5-yl {-N ′
-(2-morpholin-4-yl-ethyl) -guanidine N- {3- [1- (3-benzoyl-phenyl) -1-]
Methyl-ethyl] -isoxazol-5-yl {-N ′
-[2- (4-Methyl-piperazin-1-yl) -ethyl] -guanidine N- {3- [1- (3-benzoyl-phenyl) -1-]
Methyl-ethyl] -isoxazol-5-yl {-N ′
-(3-morpholin-4-yl-propyl) -guanidine

N- {3- [1- (3-benzoyl-phenyl) -1-methyl-ethyl] -isoxazol-5-yl} -N ′-[2- (2-hydroxy-ethoxy) -ethyl]- Guanidine N- {3- [1- (3-benzoyl-phenyl) -1-]
Methyl-ethyl] -isoxazol-5-yl {-N ′
-[2- (2-methoxy-ethoxy) -ethyl] -guanidine N- {3- [1- (3-benzoyl-phenyl) -1-]
Methyl-ethyl] -isoxazol-5-yl {-N ′
-[2- (3-hydroxy-propoxy) -ethyl]-
Guanidine 2- {3- [1- (3-benzoyl-phenyl) -1-]
Methyl-ethyl] -isoxazol-5-ylimino}
-1-Methyl-imidazolidin-4-one 2- {3- [1- (3-benzoyl-phenyl) -1-]
Methyl-ethyl] -isoxazol-5-ylimino}
-1- (2-hydroxy-ethyl) -imidazolidine-
4-on

2- {3- [1- (3-benzoyl-phenyl) -1-methyl-ethyl] -isoxazol-5-ylimino} -1- (2-methoxy-ethyl) -imidazolidin-4-one N -(｛3- [1- (3-benzoyl-phenyl) -1
-Methyl-ethyl] -isoxazol-5-ylimino} -methylamino-methyl) -N'-methyl-guanidine N '-({3- [1- (3-benzoyl-phenyl)-
1-methyl-ethyl] -isoxazol-5-ylimino} -dimethylamino-methyl) -N, N-dimethyl-
Guanidine [3- (1- {5-[(amino-morpholin-4-yl-methyleneamino) -morpholin-4-yl-methyleneamino] -isoxazol-3-yl} -1-methyl-
Ethyl) -phenyl] -phenyl-methanone [3- (1- {5-[[amino- (4-methyl-piperazin-1-yl) -methyleneamino]-(4-methyl-
Piperazin-1-yl) -methyleneamino] -isoxazol-3-yl {-1-methyl-ethyl) -phenyl] -phenyl-methanone

N-[{3- [1- (3-benzoyl-phenyl) -1-methyl-ethyl] -isoxazol-5-ylimino}-(2-morpholin-4-yl-ethylamino) -methyl]- N '-(2-morpholin-4-yl-
Ethyl) -guanidine N-[{3- [1- (3-benzoyl-phenyl) -1]
-Methyl-ethyl] -isoxazol-5-ylimino}-(2-hydroxy-ethylamino) -methyl]-
N '-(2-hydroxy-ethyl) -guanidine N- {3- [1- (3-benzoyl-phenyl) -1
-Methyl-ethyl] -isoxazol-5-ylimino {-[2- (2-hydroxy-ethoxy) -ethylamino] -methyl} -N '-[2- (2-hydroxy-ethoxy) -ethyl] -guanidine N -{3- [1- (3-benzoyl-phenyl) -1-]
Methyl-ethyl] -isoxazol-5-yl}-
N ', N "-dimethyl-guanidine N"-{3- [1- (3-benzoyl-phenyl) -1
-Methyl-ethyl] -isoxazol-5-yl}-
N, N, N ', N'-tetramethyl-guanidine (3- {1- [5- (di-morpholin-4-yl-methyleneamino) -isoxazol-3-yl] -1-methyl-ethyl}- Phenyl) -phenyl-methanone

[3- (1- {5- [bis- (4-methyl-piperazin-1-yl) -methyleneamino] -isoxazol-3-yl} -1-methyl-ethyl) -phenyl]
-Phenyl-methanone N- {3- [1- (3-benzoyl-phenyl) -1-]
Methyl-ethyl] -isoxazol-5-yl}-
N ', N "-bis- (2-morpholin-4-yl-ethyl) -guanidine N- {3- [1- (3-benzoyl-phenyl) -1-]
Methyl-ethyl] -isoxazol-5-yl}-
N ', N "-bis- (2-hydroxy-ethyl) -guanidine N- {3- [1- (3-benzoyl-phenyl) -1-]
Methyl-ethyl] -isoxazol-5-yl}-
N ', N "-bis- [2- (2-hydroxy-ethoxy) -ethyl] -guanidine ({3- [1-ethoxy-1- (2'-fluoro-biphenyl-4-yl) -ethyl]- Isoxazole-5
Ilimino {-morpholin-4-yl-methyl) -amine

(3- {1- [5- (amino-morpholine-4)
-Yl-methyleneamino) -isoxazol-3-yl] -1-ethoxy-ethyl} -phenyl) -phenyl-methanone ({3-[(2-fluoro-biphenyl-4-yl)-
Dimethoxy-methyl] -isoxazol-5-ylimino} -morpholin-4-yl-methyl) -amine {[3- (1-biphenyl-4-yl-vinyl) -isoxazol-5-ylimino] -morpholin-4-yl -Methyl} -amine ({3- [1- (1-methyl-1H-indole-2-
Yl) -vinyl] -isoxazol-5-ylimino}
-Morpholin-4-yl-methyl) -amine

(Morpholin-4-yl- {3- [1- (6-
Phenyl-pyridazin-3-yl) -ethyl] -isoxazol-5-ylimino} -methyl) -amine (morpholin-4-yl- {3- [1- (5-phenyl-pyrimidin-2-yl) -ethyl] -Isoxazol-5-ylimino} -methyl) -amine (morpholin-4-yl- {3- [1- (4-phenyl-pyrimidin-2-yl) -ethyl] -isoxazol-5-ylimino} -methyl)- Amine {morpholin-4-yl- [3- (1-quinolin-6-
Yl-ethyl) -isoxazol-5-ylimino]-
Methyl｝ -amine

[0166]

The present invention will be described below with reference to examples and reference examples, but the present invention is not limited to these examples. The abbreviations used in the examples and the like have the following meanings. Boc: tert-butoxycarbonyl Tos: p-toluenesulfonyl Me: methyl Et: ethyl Pr ^n: n-propyl Bu ^t: tert-butyl Ph: phenyl Ac: Acetyl TFA: Trifluoroacetic acid TMS: Trimethylsilyl

Example 1 N ′-(tert-butoxycarbonyl) -N ″-{3
-[1- (2-fluoro-biphenyl-4-yl) -d
Tyl] -isoxazol-5-yl} -N, N-dimethyl
Le-guanidine

Embedded image The compound (2.10 g) obtained in Reference Example 2 was dissolved in acetonitrile (100 ml), and triethylamine (1.77) was dissolved.
g) was added thereto, and a 40% aqueous dimethylamine solution (1.04 g) was added dropwise under ice cooling, and a solution of silver nitrate (1.33 g) in acetonitrile (20 ml) was added dropwise over 30 minutes, followed by stirring at room temperature for 18 hours. After filtering the insoluble matter and washing with acetonitrile, the mother liquor was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the desired product (1.76 g). 108-111 ° C (decomposition) ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.43 (s, 9H), 1.66 (d, 3H, J = 7.1Hz), 3.07 (s, 6H), 4.
16 (q, 1H, J = 7.1Hz), 5.24 (s, 1H), 6.74 (s, 1H), 7.07
-7.17 (m, 2H), 7.32-7.54 (m, 6H) IR (KBr) [cm ^-1 ]: 3383, 2975, 1733, 1614,
1482, 1403 MS (FD) [m / e]: 452 (M ⁺ ) Elemental analysis: Calculated: C, 66.35; H, 6.46; N, 12.38, Found: C, 66.22; H, 6.45; N, 12.46

Example 2 N- (tert-butoxycarbonyl) -N ′-{3-
[1- (2-Fluoro-biphenyl-4-yl) -ethyl]
] -Isoxazol-5-yl} -N "-ethyl-g
Anidine

Embedded image The desired product was obtained in the same manner as in Example 1. Melting point 87-92 ° C ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.21 (t, 3H, J = 7.3Hz), 1.49 (s, 9H), 1.67 (d, 3H, J = 7.
3Hz), 3.40 (m, 2H), 4.14 (q, 1H, J = 7.3Hz), 5.32 (s, 1
H), 7.07-7.17 (m, 2H), 7.31-7.54 (m, 6H), 7.94 (br, 1
H), 8.48 (br, 1H) IR (KBr) [cm ^-1 ]: 3410, 3340, 2980, 1730,
1628, 1603, 1556, 1445, 1240, 1152

Example 3(Tert-butoxycarbonyl)-({3- [1-
(2-Fluoro-biphenyl-4-yl) -ethyl]-
Isoxazol-5-ylimino} -piperidine-1-
Yl-methyl) -amine

Embedded image The desired product was obtained in the same manner as in Example 1. ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.42 (s, 9H), 1.65 (br-s, 6H), 1.66 (d, 3H, J = 6.3H
z), 3.40-3.60 (br, 4H), 4.15 (q, 1H, J = 6.3Hz), 5.24
(s, 1H), 6.60-6.80 (br, 1H), 7.06-7.17 (m, 2H), 7.32
-7.54 (m, 6H) IR (KBr) [cm ^-1 ]: 3390, 2940, 1726, 1600,
1483, 1435, 1365, 1152

Example 4(Tert-butoxycarbonyl)-({3- [1-
(2-Fluoro-biphenyl-4-yl) -ethyl]-
Isoxazol-5-ylimino} -morpholine-4-
Yl-methyl) -amine

Embedded image The desired product was obtained in the same manner as in Example 1. 152-153 ° C ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.44 (s, 9H), 1.67 (d, 3H, J = 7.2Hz), 3.57 (m, 4H), 3.
75 (m, 4H), 4.16 (q, 1H, J = 7.2Hz), 5.28 (s, 1H), 6.86
(s, 1H), 7.06-7.16 (m, 2H), 7.32-7.53 (m, 6H) IR (KBr) [cm ^-1 ]: 3374, 2976, 1726, 1609,
1482, 1431, 1115 MS (FD) [m / e]: 495 (M + 1) Elemental analysis: Calculated: C, 65.57; H, 6.32; N, 11.33, Found: C, 65.45; H, 6.39; N, 11.36

Example 5(N '-(tert-butoxycarbonyl) -N "-
{3- [1- (2-fluoro-biphenyl-4-yl)]
-Ethyl] -isoxazol-5-yl} -guanidinium
G) -acetic acid tert-butyl ester

Embedded image The desired product was obtained in the same manner as in Example 1. Melting point 101.5-103.5 ° C. ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.48 (s, 9H), 1.50 (s, 9H), 1.66 (d, 3H, J = 7.3Hz), 4.
03 (d, 2H, J = 4.6Hz), 4.14 (q, 1H, J = 7.3Hz), 5.31 (s,
1H), 7.06-7.16 (m, 2H), 7.32-7.54 (m, 6H), 8.50-8.52
(br-m, 2H) IR (KBr) [cm ^-1 ]: 3407, 3351, 2980, 1743,
1643, 1560, 1485, 1452 MS (FD) [m / e]: 538 (M ⁺ ) Elemental analysis: Calculated: C, 64.67; H, 6.55; N, 10.40, Found: C, 64.36; H, 6.57 ; N, 10.35

Example 6(N '-(tert-butoxycarbonyl) -N "-
{3- [1- (2-fluoro-biphenyl-4-yl)]
-Ethyl] -isoxazol-5-yl} -N-methyl
-Guanidino) -acetic acid tert-butyl ester

Embedded image The desired product was obtained in the same manner as in Example 1. 190-198 ° C (decomposition) ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.42 (s, 9H), 1.47 (s, 9H), 1.65 (d, 3H, J = 7.2Hz), 3.
12 (s, 3H), 4.00 (s, 2H), 4.12 (q, 1H, J = 7.2Hz), 5.29
(s, 1H), 6.87 (br-s, 1H), 7.06-7.16 (m, 2H), 7.32-7.
54 (m, 6H) IR (KBr) [cm ^-1 ]: 3388, 2984, 1744, 1733,
1608, 1483, 1413 MS (FD) [m / e]: 552 (M ⁺ ) Elemental analysis: Calculated: C, 65.20; H, 6.75; N, 10.14, Found: C, 64.90; H, 6.74; N , 9.93

Example 7(N '-(tert-butoxycarbonyl) -N "-
{3- [1- (2-fluoro-biphenyl-4-yl)]
-Ethyl] -isoxazol-5-yl} -guanidinium
G) -acetic acid ethyl ester

Embedded image The desired product was obtained in the same manner as in Example 1. ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.28 (t, 3H, J = 7.1Hz), 1.50 (s, 9H), 1.66 (d, 3H, J = 7.
3Hz), 4.12 (d, 2H, J = 5.0Hz), 4.16 (q, 1H, J = 7.3Hz),
4.23 (q, 2H, J = 7.1Hz), 5.33 (s, 1H), 7.07-7.16 (m, 2
H), 7.35-7.54 (m, 6H), 8.54 (br-m, 2H) IR (neat) [cm ^-1 ]: 3398, 2981, 1732, 163
4, 1608, 1557, 1486, 1455

Example 8 N′-benzoyl-N- {3- [1- (2-fluoro-
Biphenyl-4-yl) -ethyl] -isoxazole-
5-yl {-N-methyl-N "-propyl-guanidine

Embedded image The desired product was obtained in the same manner as in Example 1. ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
0.90 (t, 3H, J = 7.3Hz), 1.56 (sext., 2H, J = 7.3Hz), 1.7
0 (d, 3H, J = 7.3Hz), 2.85-2.97 (m, 2H), 3.51 (s, 3H),
4.21 (q, 1H, J = 7.3Hz), 5.50 (s, 1H), 7.02-7.27 (m, 3
H), 7.32-7.52 (m, 8H), 8.17-8.22 (m, 2H), 10.30-10.60
(m, 1H)

Example 9 N′-benzoyl-N- {3- [1- (2-fluoro-
Biphenyl-4-yl) -ethyl] -isoxazole-
5-yl} -N, N "-dimethyl-guanidine

Embedded image The desired product was obtained in the same manner as in Example 1. ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.70 (d, 3H, J = 7.3Hz), 2.74-2.76 (m, 3H), 3.51 (s, 3
H), 4.21 (q, 1H, J = 7.3Hz), 5.49 (s, 1H), 7.04-7.16
(m, 2H), 7.33-7.55 (m, 9H), 8.16-8.22 (m, 2H), 10.20
-10.55 (br, 1H) IR (neat) [cm ^-1 ]: 3260, 3070, 2980, 162
2, 1495, 1453, 1418, 1396, 1362

Example 10N, N'-di- (tert-butoxycarbonyl)-
N "-{5- [1- (2-fluoro-biphenyl-4-
Yl) -ethyl] -isoxazol-3-ylmethyl}
-Guanidine

Embedded image Compound (1.12 g) obtained in Reference Example 10 and 1,3-di-
(Tert-Butoxycarbonyl) -2-methyl-isothiourea (Japanese Patent Application Laid-Open No. 2-3661) (2.20 g) was dissolved in pyridine (5 ml), and 1,8-diazabicyclo [5.
4.0] Undec-7-ene (636 mg) was added, and the mixture was stirred at room temperature for 24 hours. Water was added to the reaction solution, extracted with ethyl acetate, and the extract was washed with water and dried. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the desired product (1.24 g). ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.49 (s, 9H), 1.50 (s, 9H), 1.69 (d, 3H, J = 7.1Hz), 4.
26 (q, 1H, J = 7.1Hz), 4.67 (d, 2H, J = 5.3Hz), 6.05 (s,
1H), 7.03-7.12 (m, 2H), 7.33-7.55 (m, 6H), 8.84 (br-
s, 1H), 11.47 (br-s, 1H)

Example 11N, N "-di- (tert-butoxycarbonyl) -N
-{5- [1- (2-fluoro-biphenyl-4-i)
Ru) -ethyl] -isoxazol-3-ylmethyl}-
N ', N'-dimethyl-guanidine

Embedded image The compound (2.38 g) obtained in Reference Example 7, the compound (2.18 g) obtained in Reference Example 11, and tributylphosphine (3.49 g) were dissolved in tetrahydrofuran, and the mixture was dissolved at 0 ° C. in 1,1 ′-(azodiamine). Carbonyl) dipiperidine (4.3
6 g), and the mixture was returned to room temperature and stirred for 24 hours. Water was added to the reaction solution, extracted with ethyl acetate, and the extract was washed with water and dried. After filtering the insolubles, the mother liquor was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the desired product (3.02 g). ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.46 (s, 9H), 1.49 (s, 9H), 1.68 (d, 3H, J = 7.1Hz), 2.
98 (br-s, 6H), 4.25 (q, 1H, J = 7.1Hz), 4.26 (br-s, 1H
H), 4.85 (br-s, 1H), 6.09 (s, 1H), 6.98-7.23 (m, 2H),
7.28-7.54 (m, 6H) IR (neat) [cm ^-1 ]: 2978, 1722, 1680, 160
2, 1485, 1417 MS (FD) [m / e]: 566 (M ⁺ )

Example 12 (tert-Butoxycarbonyl)-{5- [1- (2
-Fluoro-biphenyl-4-yl) -ethyl] -iso
Xazol-3-ylmethyl}-{morpholin-1-i
Ru-[(tert-butoxycarbonyl) -imino]-
Methyl｝ -amine

Embedded image By a method similar to that in Example 11, the target compound was obtained from the compound obtained in Reference Example 7 and the compound obtained in Reference Example 13. ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.46 (s, 9H), 1.48 (s, 9H), 1.68 (d, 3H, J = 7.2Hz), 3.
41-3.80 (br-m, 8H), 4.23 (br-s, 1H), 4.24 (q, 1H, J =
7.2Hz), 4.87 (br-s, 1H), 6.06 (s, 1H), 6.98-7.10 (m,
2H), 7.30-7.63 (m, 6H) IR (neat) [cm ^-1 ]: 2978, 1723, 1683, 159
5, 1484, 1111 MS (FD) [m / e]: 608 (M ⁺ )

Example 13 (tert-butoxycarbonyl)-{5- [1- (2
-Fluoro-biphenyl-4-yl) -ethyl] -iso
Xazol-3-ylmethyl}-{piperidin-1-i
Ru-[(tert-butoxycarbonyl) -imino]-
Methyl｝ -amine

Embedded image Tributylphosphine and 1, 1 '-(azodicarbonyl)
The target compound was obtained from the compound obtained in Reference Example 7 and the compound obtained in Reference Example 12 in the same manner as in Example 11 using triphenylphosphine and diethyl azodicarboxylate instead of dipiperidine. ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.41-1.54 (m, 6H), 1.46 (s, 9H), 1.49 (s, 9H), 1.68
(d, 3H, J = 7.3Hz), 3.19 (br-s, 1H), 3.35 (br-s, 2H),
3.77 (br-s, 1H), 4.22 (br-s, 1H), 4.26 (q, 1H, J = 7.3H
z), 4.90 (br-s, 1H), 6.12 (s, 1H), 6.99-7.11 (m, 2H),
7.33-7.54 (m, 6H)

Example 14N, N'-di- (tert-butoxycarbonyl)-
N "-{5- [1- (2-fluoro-biphenyl-4-
Yl) -ethyl] -isoxazol-3-ylmethyl}
-N-methyl-guanidine

Embedded image The compound (1.50 g) obtained in Reference Example 10 and the compound (2.00 g) obtained in Reference Example 14 were acetonitrile (5
0 ml), triethylamine (1.54 g) was added, and a solution of silver nitrate (2.58 g) in acetonitrile (20 ml) was added dropwise over 30 minutes under ice cooling, followed by stirring at room temperature for 2 days. After filtering the insoluble matter and washing with acetonitrile,
The mother liquor was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the desired product (2.54 g). ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.46 (s, 9H), 1.48 (s, 9H), 1.69 (d, 3H, J = 7.1Hz), 3.
10 (s, 3H), 4.26 (q, 1H, J = 7.1Hz), 4.49 (s, 2H), 6.04
(s, 1H), 7.01-7.11 (m, 2H), 7.32-7.53 (m, 6H)

Example 151- (tert-butoxycarbonyl) -2-[(te
rt-butoxycarbonyl) -imino] -3- {5-
[1- (2-Fluoro-biphenyl-4-yl) -ethyl]
] -Isoxazol-3-ylmethyl} -imidazoli
Gin-4-one

Embedded image By a method similar to that in Example 14, the target compound was obtained from the compound obtained in Reference Example 10 and the compound obtained in Reference Example 15. ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.51 (s, 9H), 1.52 (s, 9H), 1.67 (d, 3H, J = 7.3Hz), 4.
24 (q, 1H, J = 7.3Hz), 4.25 (s, 2H), 4.81 (s, 2H), 6.08
(d, 1H, J = 1.0Hz), 7.02-7.11 (m, 2H), 7.33-7.55 (m, 6
H) IR (KBr) [cm ^-1 ]: 2980, 1740, 1708, 1659,
1368 Elemental analysis: Calcd: C, 64.35; H, 6.10; N, 9.68, Found: C, 64.02; H, 6.24; N, 9.60

Example 16 N-({5- [1- (2-fluoro-biphenyl-4-)
Yl) -ethyl] -isoxazol-3-ylamino}
-Methylamino-methylene) -4-methyl-benzenes
Rufonamide

Embedded image N-dichloromethylene-4-methyl-benzenesulfonamide (Chem. Ber., 99 , 2900 (1966)) (1.33 g)
Of a known compound 5- [1- (2-fluoro-biphenyl-4) was added to an acetonitrile solution (40 ml) under ice-cooling.
-Yl) -ethyl] -isoxazol-3-ylamine (1.41 g) was added. After 30 minutes, triethylamine (0.73 ml) was slowly added dropwise, and the mixture was further stirred for 1 hour under ice cooling. Methylamine (2 ml of a 40% ethanol solution) was added dropwise thereto, and the mixture was stirred for 1 hour, and then an extraction operation was performed. Purification by silica gel column chromatography gave the desired product (735 mg). 125-127 ° C ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.70 (d, 3H, J = 7.3Hz), 2.39 (s, 3H), 2.95 (d, 3H, J = 4.
6Hz), 4.22 (q, 1H, J = 7.3Hz), 5.87 (d, 1H, J = 0.7Hz),
7.01-7.11 (m, 2H), 7.25 (d, 2H, J = 8.4Hz), 7.34-7.55
(m, 6H), 7.80 (d, 2H, J = 8.4Hz), 7.97 (m, 1H), 10.12
(s, 1H)

Example 17 N- {3- [1- (2-fluoro-biphenyl-4-i)
Ru) -ethyl] -isoxazol-5-yl} -guani
gin

Embedded image The compound (500 mg) obtained in Reference Example 1 was dissolved in N, N-dimethylformamide (2 ml), ammonium acetate (5.00 g) was added, the mixture was stirred while heating at 120 ° C., and ammonia gas was introduced for 1.5 hours. . A saturated saline solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the desired product (316 mg). ¹ H-NMR (270 MHz, d ₆ -DMSO) δ pp
m: 1.54 (d, 3H, J = 7.1Hz), 4.08 (q, 1H, J = 7.1Hz), 5.
32 (s, 1H), 6.02 (br-s, 4H), 7.21-7.25 (m, 2H), 7.38-
7.54 (m, 6H) IR (KBr) [cm ^-1 ]: 3449, 3345, 3106, 1657,
1614, 1562, 1472, 1414

Example 18 N- {3- [1- (2-fluoro-biphenyl-4-i)
Ru) -ethyl] -isoxazol-5-yl} -N'-
Methyl-guanidine hydrochloride

Embedded image The compound (600 mg) obtained in Reference Example 1 was dissolved in N, N-dimethylformamide (5 ml), and a methylamine-water-acetic acid solution prepared from a 40% aqueous solution of methylamine (1.31 g) and acetic acid (10 ml) was added. In addition, 30
The mixture was heated and stirred for minutes. Chloroform (50 ml) and a 5 M aqueous solution of sodium hydroxide (300 ml) were added to the reaction solution, extracted with chloroform, and the extract was washed with water and dried. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography and treated with hydrochloric acid-isopropanol solution to obtain the desired product (367 mg). ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.64 (d, 3H, J = 7.2Hz), 2.85 (s, 3H), 4.12 (q, 1H, J = 7.
2Hz), 5.19 (s, 1H), 5.30 (br-s, 2H), 5.59 (br-s, 1H),
7.06-7.15 (m, 2H), 7.33-7.53 (m, 6H) IR (KBr) [cm ^-1 ]: 3144, 1680, 1637, 1484,
1417

Example 19 N ′-{3- [1- (2-fluoro-biphenyl-4-)
Yl) -ethyl] -isoxazol-5-yl} -N,
N-dimethyl-guanidine hydrochloride

Embedded image The compound (1.68 g) obtained in Example 1 was dissolved in methylene chloride (20 ml), and trifluoroacetic acid (12 ml) was dissolved.
After stirring at room temperature for 2 hours, the solvent was distilled off under reduced pressure.
The residue was dissolved in methylene chloride and treated with hydrochloric acid-diethyl ether solution to obtain the desired product (1.39 g). 73-81 ° C (decomposition) ¹ H-NMR (270 MHz, d ₆ -DMSO) δ pp
m: 1.61 (d, 3H, J = 7.0Hz), 3.08 (s, 6H), 4.29 (q, 1H,
J = 7.0Hz), 6.04 (s, 1H), 7.26-7.34 (m, 2H), 7.37-7.5
5 (m, 6H), 8.27 (br-s, 2H) IR (KBr) [cm ^-1 ]: 3132, 1673, 1634, 1484,
1417

Example 20 N-ethyl-N ′-{3- [1- (2-fluoro-bif
Enyl-4-yl) -ethyl] -isoxazole-5-
Ill-guanidine hydrochloride

Embedded image Using the compound obtained in Example 2, the same procedure was performed as in Example 19 to obtain the desired product. ¹ H-NMR (270 MHz, d ₆ -DMSO) δ pp
m: 1.13 (t, 3H, J = 7.1Hz), 1.60 (d, 3H, J = 7.3Hz), 3.
31 (q, 2H, J = 7.1Hz), 4.29 (q, 1H, J = 7.3Hz), 6.17 (s,
1H), 7.24-7.52 (m, 8H), 8.10-8.70 (br, 2H), 8.45-8.6
5 (br, 1H), 11.30-11.65 (br, 1H) IR (KBr) [cm ^-1 ]: 3600-2400, 2980, 1675, 1
623, 1580, 1482, 1415,1131

Example 21({3- [1- (2-fluoro-biphenyl-4-i)
Ru) -ethyl] -isoxazol-5-ylimino}-
Piperidin-1-yl-methyl) -amine hydrochloride

Embedded image Using the compound obtained in Example 3, the same procedure was performed as in Example 19 to obtain the desired product. ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.55-1.75 (m, 9H), 3.52 (br, 4H), 4.15 (q, 1H, J = 7.3H
z), 5.71 (s, 1H), 7.02-7.12 (m, 2H), 7.31-7.50 (m, 6
H), 8.30 (br, 2H), 11.20 (br, 1H) IR (KBr) [cm ^-1 ]: 3600-2500, 2945, 1660, 1
633, 1538, 1484, 1447,1418

Example 22({3- [1- (2-fluoro-biphenyl-4-i)
Ru) -ethyl] -isoxazol-5-ylimino}-
Morpholin-4-yl-methyl) -amine hydrochloride

Embedded image Using the compound obtained in Example 4, the same procedures as in Example 19 were carried out to give the desired product. 174-176 ° C (decomposition) ¹ H-NMR (270 MHz, d ₆ -DMSO) δ pp
m: 1.60 (d, 3H, J = 7.1Hz), 3.56 (m, 4H), 3.67 (m, 4
H), 4.28 (q, 1H, J = 7.1Hz), 6.02 (s, 1H), 7.26-7.37
(m, 2H), 7.38-7.54 (m, 6H), 8.51 (br-s, 2H)

Example 23 (N ′-{3- [1- (2-fluoro-biphenyl-4)
-Yl) -ethyl] -isoxazol-5-yl｝ -g
Anidino) -acetic acid hydrochloride

Embedded image Using the compound obtained in Example 5, the same procedure as in Example 19 was performed to obtain the desired product. Melting point 62 ° C (decomposition) ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.54 (d, 3H, J = 7.1Hz), 3.85 (d, 2H, J = 5.6Hz), 4.10 (q,
1H, J = 7.1Hz), 5.40 (s, 1H), 6.19 (br-s, 2H), 6.41 (t,
1H, J = 5.6Hz), 7.21-7.24 (m, 2H), 7.36-7.54 (m, 6H) IR (KBr) [cm ^-1 ]: 3142, 2978, 1684, 1624,
1484, 1411

Example 24 2- {3- [1- (2-fluoro-biphenyl-4-i)
Ru) -ethyl] -isoxazol-5-ylimino}-
1-methyl-imidazolidin-4-one hydrochloride

Embedded image Using the compound obtained in Example 6, the same procedure was performed as in Example 19 to obtain the desired product. 158-160 ° C (decomposition) ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.66 (d, 3H, J = 7.1Hz), 3.07 (s, 3H), 3.97 (s, 2H), 4.1
6 (q, 1H, J = 7.1Hz), 5.41 (s, 1H), 7.05-7.15 (m, 2H),
7.32-7.54 (m, 6H), 8.91 (br-s, 1H) IR (KBr) [cm ^-1 ]: 3153, 2972, 1761, 1668,
1603, 1578, 1484, 1452, 1418

Example 25 (N ′-{3- [1- (2-fluoro-biphenyl-4)
-Yl) -ethyl] -isoxazol-5-yl｝ -g
Anidino) -acetic acid ethyl ester hydrochloride

Embedded image Using the compound obtained in Example 7, the same procedure was performed as in Example 19 to obtain the desired product. 144-146 ° C (decomposition) ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.26 (t, 3H, J = 7.1Hz), 1.65 (d, 3H, J = 7.3Hz), 4.16-4.
28 (m, 3H), 4.38 (s, 2H), 5.78 (s, 1H), 7.02-7.10 (m,
2H), 7.32-7.56 (m, 6H), 8.00-8.30 (m, 2H) IR (KBr) [cm ^-1 ]: 3088, 2981, 1736, 1684,
1650, 1589, 1485, 1413

Example 26 N- {5- [1- (2-fluoro-biphenyl-4-i)
Ru) -ethyl] -isoxazol-3-ylmethyl}-
Guanidine

Embedded image The compound (1.24 g) obtained in Example 10 was dissolved in trifluoroacetic acid (10 ml), and the mixture was stirred at room temperature for 2 hours, and then the solvent was distilled off under reduced pressure. The residue is dissolved in ethyl acetate and 1N
-Neutralized with aqueous sodium hydroxide solution, the organic layer was separated, washed with water, dried and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give the desired product (562).
mg). ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.50 (d, 3H, J = 6.9Hz), 4.12 (q, 1H, J = 6.9Hz), 4.42 (br
-s, 2H), 6.08 (s, 1H), 6.90-6.97 (m, 2H), 7.19-7.57
(m, 9H), 8.21 (br-s, 1H)

Example 27 N ′-{5- [1- (2-fluoro-biphenyl-4-)
Yl) -ethyl] -isoxazol-3-ylmethyl}
-N, N-dimethyl-guanidine hydrochloride

Embedded image The compound (2.69 g) obtained in Example 11 was dissolved in a trifluoroacetic acid (10 ml) -water (10 ml) solution, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure. The residue was dissolved in methylene chloride and treated with hydrochloric acid-diethyl ether solution to obtain the desired product (897 mg). ¹ H-NMR (270 MHz, d ₆ -DMSO) δ pp
m: 1.62 (d, 3H, J = 7.0Hz), 3.00 (s, 6H), 4.47 (q, 1H,
J = 7.0Hz), 4.53 (d, 2H, J = 5.9Hz), 6.40 (s, 1H), 7.22
-7.28 (m, 2H), 7.37-7.54 (m, 6H), 7.69 (br-s, 2H), 8.
06 (t, 1H, J = 5.9Hz) IR (KBr) [cm ^-1 ]: 3422, 3228, 1658, 1630,
1562, 1485, 1418

Embodiment 28({5- [1- (2-fluoro-biphenyl-4-i)
Ru) -ethyl] -isoxazol-3-ylmethylimi
No-morpholin-4-yl-methyl) -amine hydrochloride

Embedded image Using the compound obtained in Example 12, the desired product was obtained in the same manner as in Example 27. Melting point 161 to 163 ° C. ¹ H-NMR (270 MHz, d ₆ -DMSO) δ pp
m: 1.63 (d, 3H, J = 7.3Hz), 3.46 (m, 4H), 3.64 (m, 4
H), 4.48 (q, 1H, J = 7.3Hz), 4.55 (d, 2H, J = 5.8Hz), 6.
42 (s, 1H), 7.22-7.29 (m, 2H), 7.37-7.54 (m, 6H), 8.0
0 (br-s, 2H), 8.43 (t, 1H, J = 5.8 Hz) IR (KBr) [cm ^-1 ]: 3393, 3356, 1655, 1612,
1561, 1485, 1418, 1116

Example 29({5- [1- (2-fluoro-biphenyl-4-i)
Ru) -ethyl] -isoxazol-3-ylmethylimi
No-piperidin-1-yl-methyl) -amine hydrochloride

Embedded image Using the compound obtained in Example 13, the same procedure as in Example 27 was performed to obtain the desired product. ¹ H-NMR (270 MHz, d ₆ -DMSO) δ pp
m: 1.52 (br-s, 6H), 1.62 (d, 3H, J = 7.3Hz), 3.50 (br-s
s, 4H), 4.47 (q, 1H, J = 7.3Hz), 4.53 (d, 2H, J = 5.6H
z), 6.37 (s, 1H), 7.21-7.27 (m, 2H), 7.39-7.53 (m, 6
H), 7.81 (br-s, 2H), 8.25 (br-s, 1H)

Example 30 N- {5- [1- (2-fluoro-biphenyl-4-i)
Ru) -ethyl] -isoxazol-3-ylmethyl}-
N'-methyl-guanidine hydrochloride

Embedded image Using the compound obtained in Example 14, the same procedures were performed as in Example 27 to give the desired product. Melting point 71-74 ° C (decomposition) ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.68 (d, 3H, J = 7.3Hz), 2.89 (d, 3H, J = 4.6Hz), 4.25 (q,
1H, J = 7.3Hz), 4.42 (br-s, 2H), 6.17 (s, 1H), 7.00-7.
10 (m, 2H), 7.36-7.54 (m, 6H) IR (KBr) [cm ^-1 ]: 3338, 1646, 1602, 1484,
1418

Example 31 2-amino-3- {5- [1- (2-fluoro-biphene)
Nil-4-yl) -ethyl] -isoxazol-3-i
Methyl-3,5-dihydro-imidazole-4-o
Hydrochloride

Embedded image Using the compound obtained in Example 15, the same procedure as in Example 27 was performed to obtain the desired product. Melting point 210-232 ° C (decomposition) ¹ H-NMR (270 MHz, d ₆ -DMSO) δ pp
m: 1.62 (d, 3H, J = 7.1Hz), 4.31 (s, 2H), 4.47 (q, 1H,
J = 7.1Hz), 4.94 (s, 2H), 6.45 (s, 1H), 7.21-7.29 (m,
2H), 7.37-7.55 (m, 6H), 9.53 (br-s, 3H) IR (KBr) [cm ^-1 ]: 3061, 2983, 1778, 1706,
1689, 1604, 1544, 1485, 1419

Example 32[2- (N '-(tert-butoxycarbonyl)-
N "-{3- [1- (2-fluoro-biphenyl-4-
Yl) -ethyl] -isoxazol-5-yl} -gua
Nidino) -ethoxy] -acetic acid methyl ester

Embedded image Using 2- (amino-ethoxy) -acetic acid methyl ester trifluoroacetate, the desired product was obtained in the same manner as in Example 1. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.49 (s, 9H), 1.67 (d, 3H, J = 7.3Hz), 3.59-3.64 (m, 2
H), 3.70-3.76 (m, 2H), 3.79 (s, 3H), 4.11-4.18 (m, 1
H), 4.14 (s, 2H), 5.30 (s, 1H), 7.07-7.17 (m, 2H), 7.
32-7.46 (m, 4H), 7.51-7.54 (m, 2H), 8.28 (br-s, 1H),
8.49 (br-s, 1H) IR (neat) [cm ^-1 ]: 3399, 3349, 2978, 175
0, 1732, 1634, 1606, 1556, 1486, 1455, 1416, 1370,
1241, 1151, 770, 670

Example 33 N- (tert-butoxycarbonyl) -N ′-{3-
[1- (2-Fluoro-biphenyl-4-yl) -ethyl]
L] -isoxazol-5-yl {-N "-[2- (2
-Hydroxy-ethoxy-ethyl)]-guanidine

Embedded image Using 2- (2-amino-ethoxy) -ethanol, the desired product was obtained in the same manner as in Example 1. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.49 (s, 9H), 1.67 (d, 3H, J = 7.1Hz), 2.40 (br-s, 1H),
3.55-3.70 (m, 6H), 3.70-3.80 (m, 2H), 4.15 (q, 1H, J =
7.1Hz), 5.32 (s, 1H), 7.07-7.16 (m, 2H), 7.32-7.54
(m, 6H), 8.36 (br-s, 1H), 8.51 (s, 1H)

Example 34 N- (tert-butoxycarbonyl) -N ′-{3-
[1- (2-Fluoro-biphenyl-4-yl) -ethyl]
L] -isoxazol-5-yl} -N "-(2-hydr
Roxy-ethyl) -guanidine

Embedded image Using 2-amino-ethanol, the desired product was obtained in the same manner as in Example 1. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.50 (s, 9H), 1.67 (d, 3H, J = 7.1Hz), 3.56-3.60 (m, 3
H), 3.77-3.82 (m, 2H), 4.14 (q, 1H, J = 7.1Hz), 5.34
(s, 1H), 7.06-7.16 (m, 2H), 7.32-7.46 (m, 4H), 7.51-
7.54 (m, 2H), 8.41 (br-s, 1H), 8.59 (br-s, 1H)

[0201] Example 35[N '-(tert-butoxycarbonyl) -N "-
{3- [1- (2-fluoro-biphenyl-4-yl)]
-Ethyl] -isoxazol-5-yl} -N- (2-
Hydroxy-ethyl) -guanidino] -acetic acid tert-
Butyl ester

Embedded image Using 3- (2-hydroxy-ethylamino) -propionic acid tert-butyl ester, the desired product was obtained in the same manner as in Example 1. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.33 (s, 9H), 1.44 (s, 9H), 1.64 (d, 3H, J = 7.1Hz), 3.
55-3.65 (m, 2H), 3.74-3.82 (m, 2H), 3.86-3.94 (m, 1
H), 4.02-4.17 (m, 3H), 5.30 (s, 1H), 7.04-7.15 (m, 2
H), 7.32-7.46 (m, 4H), 7.50-7.53 (m, 2H) IR (KBr) [cm ^-1 ]: 3254, 2979, 2936, 1738,
1614, 1484, 1459, 1418, 1369, 1249, 1152, 1060, 76
9, 699

Example 364-[(tert-butoxycarbamoyl)-{3-
[1- (2-Fluoro-biphenyl-4-yl) -ethyl]
] -Isoxazol-5-ylimino} -methyl]-
Morpholin-3-ol

Embedded image Using piperidin-2-ol, the desired product was obtained in the same manner as in Example 1. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.48 (s, 9H), 1.66 (d, 3H, J = 7.0Hz), 3.44-4.00 (m, 6
H), 4.10-4.25 (m, 1H), 5.32 (s, 1H), 6.47 (br-s, 0.5
H), 6.66 (br-s, 0.5H), 6.91-6.96 (m, 1H), 7.07-7.16
(m, 2H), 7.32-7.53 (m, 6H)

Example 37(Tert-butoxycarbonyl)-({3- [1-
(4-isobutyl-phenyl) -ethyl] -isoxazo
5-ylimino} -morpholin-4-yl-methyl
Le) -amine

Embedded image Using the compound obtained in Reference Example 18, the desired product was obtained in the same manner as in Example 1. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
0.89 (d, 6H, J = 6.6Hz), 1.44 (s, 9H), 1.62 (d, 3H, J = 7.
3Hz), 1.83 (m, 1H, J = 6.6Hz), 2.42 (d, 2H, J = 7.3Hz),
3.54-3.58 (m, 4H), 3.72-3.77 (m, 4H), 4.09 (q, 1H, J
= 7.2Hz), 5.23 (s, 1H), 7.05-7.09 (m, 2H), 7.17-7.20
(m, 2H)

Example 38(Tert-butoxycarbonyl)-({3- [1-
(6-Methoxy-naphthalen-2-yl) -ethyl]-
Isoxazol-5-ylimino} -morpholine-4-
Yl-methyl) -amine

Embedded image Using the compound obtained in Reference Example 19, the desired product was obtained in the same manner as in Example 1. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.35 (s, 9H), 1.72 (d, 3H, J = 7.2Hz), 3.54-3.56 (m, 4
H), 3.71-3.75 (m, 4H), 3.91 (s, 3H), 4.25 (q, 1H, J =
7.1Hz), 5.21 (s, 1H), 7.10-7.14 (m, 2H), 7.37 (dd, 1
(H, J = 8.2, 1.5Hz), 7.66-7.70 (m, 3H)

Example 39 N ′-{3- [1- (2-fluoro-biphenyl-4-)
Yl) -ethyl] -isoxazol-5-yl} -N,
N-diethyl-guanidine methanesulfonate

Embedded image The compound (5.0 g) obtained in Reference Example 2 was dissolved in acetonitrile (100 ml), and triethylamine (3.8 m) was dissolved.
l), and a 40% aqueous dimethylamine solution (2.
84 ml), and a solution of silver nitrate (2.05 g) in acetonitrile (10 ml) was added dropwise, followed by stirring at room temperature for 18 hours. After filtering the insoluble matter and washing with chloroform, the mother liquor was concentrated under reduced pressure. The residue was dissolved in an aqueous 83% (V / V) trifluoroacetic acid solution (100 ml), stirred at room temperature for 8 hours, and then azeotropically distilled off with toluene. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (hexane / ethyl acetate = 4 /
Purified in 1). This product was dissolved in 1,4-dioxane and treated with methanesulfonic acid (0.56 ml) to obtain the desired product (3.42 g). Melting point: 154 to 155 ° C ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.21 (t, 6H, J = 7.1Hz), 1.66 (d, 3H, J = 7.1Hz), 2.70 (s,
3H), 3.42 (q, 4H, J = 7.1Hz), 4.17 (q, 1H, J = 7.1Hz),
5.69 (s, 1H), 7.02-7.13 (m, 2H), 7.26-7.54 (m, 6H),
8.24 (br-s, 2H), 10.83 (br-s, 1H)

Example 40 N ′-{3- [1- (2-fluoro-biphenyl-4-)
Yl) -ethyl] -isoxazol-5-yl} -N,
N-bis- (2-methoxy-ethyl) -guanidine
Tansulfonate

Embedded image Using bis- (2-methoxy-ethyl) -amine, the desired product was obtained in the same manner as in Example 39. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.68 (d, 3H, J = 7.1Hz), 2.80 (s, 3H), 3.43 (s, 6H), 3.6
5-3.75 (m, 8H), 4.23 (q, 1H, J = 7.1Hz), 6.04 (s, 1H),
7.07-7.25 (m, 2H), 7.32-7.54 (m, 6H), 7.76 (br-s, 1
H), 8.00 (br-s, 2H)

Example 41({3- [1- (2-fluoro-biphenyl-4-i)
Ru) -ethyl] -isoxazol-5-ylimino}-
Pyrrolidin-1-yl-methyl) -amine methanesul
Fonate

Embedded image Using pyrrolidine, the desired product was obtained in the same manner as in Example 39. Melting point 182-183 ° C (decomposition) ¹ H-NMR (300 MHz, CD ₃ OD) δ ppm:
1.68 (d, 3H, J = 7.1Hz), 2.04-2.15 (m, 4H), 2.67 (s, 3
H), 3.50-3.65 (m, 4H), 4.28 (q, 1H, J = 7.1Hz), 6.03
(s, 1H), 7.14-7.26 (m, 2H), 7.35-7.57 (m, 6H)

Example 42({3- [1- (2-fluoro-biphenyl-4-i)
Ru) -ethyl] -isoxazol-5-ylimino}-
Piperazin-1-yl-methyl) -amine methanesul
Fonate

Embedded image Using piperazine, the desired product was obtained in the same manner as in Example 39. Melting point 185 ° C (decomposition) ¹ H-NMR (300 MHz, CD ₃ OD) δ ppm:
1.68 (d, 3H, J = 7.1Hz), 2.69 (s, 6H), 3.40 (t, 4H, J = 5.
3Hz), 3.86 (t, 4H, J = 5.3Hz), 4.28 (q, 1H, J = 7.1Hz),
5.99 (s, 1H), 7.13-7.25 (m, 2H), 7.35-7.51 (m, 6H)

Example 43[{3- [1- (2-fluoro-biphenyl-4-i)
Ru) -ethyl] -isoxazol-5-ylimino}-
(4-methyl-piperazin-1-yl) -methyl] -a
Min methanesulfonate

Embedded image Using 1-methyl-piperazine, the desired product was obtained in the same manner as in Example 39. 186-187 ° C (decomposition) ¹ H-NMR (300 MHz, CD ₃ OD) δ ppm:
1.68 (d, 3H, J = 7.1Hz), 2.69 (s, 9H), 2.98 (s, 3H), 3.3
1 (br-s, 2H), 3.64 (br-s, 4H), 4.15 (br-s, 2H), 4.28
(q, 1H, J = 7.1Hz), 6.00 (s.1H), 7.13-7.25 (m, 2H),
7.32-7.52 (m, 6H)

Example 44 N- {3- [1- (2-fluoro-biphenyl-4-i)
Ru) -ethyl] -isoxazol-5-yl} -N'-
(2-morpholin-4-yl-ethyl) -guanidine

Embedded image Using 2-morpholin-4-yl-ethylamine, the desired product was obtained in the same manner as in Example 39. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.64 (d, 3H, J = 7.3Hz), 2.49-2.57 (m, 6H), 3.30-3.31
(m, 2H), 3.69 (t, 4H, J = 4.3Hz), 4.41 (q, 1H, J = 7.3H
z), 5.18 (s.1H), 5.70 (s.1H), 6.13 (s.2H), 7.07-7.
17 (m, 2H), 7.32-7.54 (m, 6H)

Example 45 N- {3- [1- (2-fluoro-biphenyl-4-i)
Ru) -ethyl] -isoxazol-5-yl} -N'-
(2-methoxy-ethyl) -guanidine

Embedded image Using 2-methoxy-ethylamine, the desired product was obtained in the same manner as in Example 39. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.65 (d, 3H, J = 7.3Hz), 3.38 (s, 3H), 3.41 (m, 2H), 3.5
2 (t, 2H, J = 4.3Hz), 4.14 (q, 1H, J = 7.3Hz), 5.19 (s. 1
H), 5.50-5.70 (m.3H), 7.08-7.16 (m, 2H), 7.33-7.54
(m, 6H)

Example 46({3- [1- (4-isobutyl-phenyl) -ethyl)
] -Isoxazol-5-ylimino} -morpholine
-4-yl-methyl) -amine hydrochloride

Embedded image Using the compound obtained in Example 37, the desired product was obtained in the same manner as in Example 19. Melting point 94-99 ° C ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
0.89 (d, 6H, J = 6.6Hz), 1.60 (d, 3H, J = 7.1Hz), 1.78-
1.88 (m, 1H), 2.43 (d, 2H, J = 7.1Hz), 3.55-3.62 (m, 4
H), 3.72-3.80 (m, 4H), 4.09 (q, 1H, J = 7.1Hz), 5.65
(s, 1H), 7.08 (d, 2H, J = 8.3Hz), 7.14 (d, 2H, J = 8.1H
z), 8.38 (br-s, 1H)

[0213] Embodiment 47({3- [1- (6-Methoxy-naphthalene-2-i)
Ru) -ethyl] -isoxazol-5-ylimino}-
Morpholin-4-yl-methyl) -amine hydrochloride

Embedded image Using the compound obtained in Example 38, the desired product was obtained in the same manner as in Example 19. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.70 (d, 3H, J = 7.1Hz), 3.44-3.48 (m, 4H), 3.69-3.73
(m, 4H), 3.91 (s, 3H), 4.24 (q, 1H, J = 7.2Hz), 5.21 (s,
1H), 5.31 (br-s, 1H), 7.10-7.13 (m, 2H), 7.39 (d, 1
H, J = 8.6Hz), 7.66-7.70 (m, 3H)

Example 48[2- (N '-{3- [1- (2-fluoro-biphenyl)
Ru-4-yl) -ethyl] -isoxazol-5-i
Ru-guanidino) -ethoxy] -methyl acetate
Le

Embedded image Trifluoroacetic acid (15.0 ml) was added to the compound (5.74 g) obtained in Example 32, and the mixture was stirred at room temperature for 1 hour.
After adding a saturated aqueous sodium hydrogen carbonate solution to the reaction solution, extraction with ethyl acetate was performed,
The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (chloroform only → chloroform / methanol = 99/1 → 39/1) to obtain the desired product (4.32 g). ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.65 (d, 3H, J = 7.1Hz), 3.44-3.51 (m, 2H), 3.64-3.67
(m, 2H), 3.74 (s, 3H), 4.10 (s, 2H), 4.10-4.16 (m, 1
H), 5.20 (s, 1H), 5.60 (br-s, 2H), 6.07 (br-s, 1H),
7.07-7.17 (m, 2H), 7.32-7.46 (m, 4H), 7.50-7.54 (m, 2
H) IR (neat) [cm ^-1 ]: 3374, 2952, 1749, 162
4, 1572, 1483, 1457, 1222, 1132, 969, 915, 769, 72
9, 699

Example 49 N- {3- [1- (2-Fluoro-biphenyl-4-i)
Ru) -ethyl] -isoxazol-5-yl} -N'-
[2- (2-hydroxy-ethoxy-ethyl)]-gua
Nijin

Embedded image Trifluoroacetic acid (10 ml) was added to the compound (5.09 g) obtained in Example 33, and the mixture was stirred at room temperature for 1 hour. After azeotropically distilling off the reaction solution using toluene, the residue
It was dissolved in 4-dioxane, treated with 4N hydrochloric acid-diethyl ether solution, and then concentrated under reduced pressure. After dilution with chloroform, the mixture was neutralized with an aqueous sodium hydroxide solution and extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (chloroform only → chloroform / methanol = 30 /
Purification in 1) gave the desired product (3.34 g). ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.65 (d, 3H, J = 7.0Hz), 3.42-3.48 (m, 2H), 3.57-3.66
(m, 4H), 3.73-3.78 (m, 2H), 4.13 (q, 1H, J = 7.1Hz),
5.55 (s, 1H), 5.69 (br-s, 2H), 7.07-7.16 (m, 2H), 7.3
1-7.55 (m, 6H)

Example 50 N- {3- [1- (2-Fluoro-biphenyl-4-i)
Ru) -ethyl] -isoxazol-5-yl} -N'-
(2-hydroxy-ethyl) -guanidine

Embedded image Using the compound obtained in Example 34, the desired product was obtained in the same manner as in Example 49. ¹ H-NMR (300 MHz, CD ₃ OD) δ ppm:
1.62 (d, 3H, J = 7.1Hz), 3.28-3.36 (m, 2H), 3.62-3.66
(m, 2H), 4.13 (q, 1H, J = 7.3Hz), 5.33 (s, 1H), 7.10-7.
21 (m, 2H), 7.30-7.44 (m, 6H), 7.49-7.52 (m, 2H) IR (KBr) [cm ^-1 ]: 3433, 1639, 1572, 1478,
1456, 1417, 1068, 786,695 MS (FD) [m / e]: 368 (M ⁺ )

Example 51({3- [1- (2-fluoro-biphenyl-4-i)
L) -1-Methyl-ethyl] -isoxazole-5-i
Limino {-morpholin-4-yl-methyl) -amine

Embedded image The compound (4.57 g) obtained in Reference Example 20 was dissolved in cyanomorpholine (8.64 g) and potassium carbonate (4.26) was dissolved.
g) was added and the mixture was refluxed at 130 ° C. for 8 hours. After cooling to room temperature, saturated saline was added, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate = 2/1 → 1/2) to obtain the desired product (1.53 g). ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.71 (s, 6H), 3.47-3.50 (m, 4H), 3.71-3.74 (m, 4H),
5.19 (s, 1H), 5.39 (s, 2H), 7.11-7.20 (m, 2H), 7.32-
7.46 (m, 4H), 7.50-7.54 (m, 2H)

Example 52 (morpholin-4-yl- {3- [1- (3-phenoxy)
C-phenyl) -ethyl] -isoxazol-5-yl
Imino {-methyl) -amine

Embedded image Using the compound obtained in Reference Example 25, the desired product was obtained in the same manner as in Example 51. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.61 (d, 3H, J = 7.3Hz), 3.48 (t, 4H, J = 4.9Hz), 3.72 (t,
4H, J = 4.9Hz), 4.08 (q, 1H, J = 7.3Hz), 5.21 (s, 1H),
5.37 (br-s, 2H), 6.80-6.84 (m, 1H), 6.97-7.12 (m, 5
H), 7.21-7.35 (m, 3H)

Example 53 ({3- [1-ethoxy-1- (2-fluoro-biphene)
Nil-4-yl) -ethyl] -isoxazol-5-i
Limino {-morpholin-4-yl-methyl) -amine
Methanesulfonate

Embedded image The compound (5.0 g) obtained in Reference Example 21 was dissolved in cyanomorpholine (7.75 g), and potassium carbonate (4.24) was dissolved.
g) was added and the mixture was refluxed at 130 ° C. for 8 hours. After cooling to room temperature, saturated saline was added, followed by extraction with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate = 2/1 → 1/2). This purified product was 1.4
-Dissolved in dioxane, added with methanesulfonic acid (0.34 ml) under ice cooling, and concentrated under reduced pressure. The crude product was purified from isopropanol by a recrystallization method to obtain the desired product (85
0 mg). 158-160 ° C ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.71 (t, 3H, J = 6.7Hz), 1.90 (s, 3H), 2.71 (s, 3H), 3.
32-3.57 (m, 6H), 3.73-3.75 (m, 4H), 5.68 (s, 1H), 7.2
2-7.54 (m, 8H), 8.69 (br-s, 2H), 11.16 (br-s, 1H)

Example 54 (R)-({3- [1- (2-Fluoro-biphenyl-)
4-yl) -ethyl] -isoxazol-5-ylimi
No-morpholin-4-yl-methyl) -amine

Embedded image 1) Sodium hydride (25 mg, 60%) was added to a tetrahydrofuran solution (4 ml) of the compound (118 mg, 93% ee) obtained in Reference Example 26 under ice-cooling under a nitrogen atmosphere.
(Oil-based), followed by stirring at 40 ° C. for 10 minutes. After cooling again under ice cooling, cyanomorpholine (0.084 m
l) was added and the temperature was raised to room temperature over 6 hours with stirring.
The reaction solution was diluted with ethyl acetate, and then neutralized with a saturated aqueous solution of ammonium chloride. After extraction with ethyl acetate, the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (hexane / ethyl acetate = 1 /
1 → 1/4) to purify the desired product (137 mg, 93% e.
e.). 2) ({3- [1- (2-fluoro-biphenyl-4-)
Yl) -ethyl] -isoxazol-5-ylimino}
-Morpholin-4-yl-methyl) -amine (3 g) was fractionated on an optically active column (Daicel Chemical Industries, CHIRA).
Separation using LCEL OD (registered trademark) 2 cmφ × 25 cm) to obtain the desired product (1.5 g). ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.66 (d, 3H, J = 7.1Hz), 3.45-3.60 (m, 4H), 3.70-3.80
(m, 4H), 4.15 (q, 1H, J = 7.1Hz), 5.25 (s, 1H), 5.37 (b
rs, 2H), 7.05-7.17 (m, 2H), 7.33-7.54 (m, 6H) [α] _D ²² = -20.0 ° (c: 1.00, CHCl ₃ )

Example 55 (S)-({3- [1- (2-fluoro-biphenyl-)
4-yl) -ethyl] -isoxazol-5-ylimi
No-morpholin-4-yl-methyl) -amine

Embedded image 1) Using the compound obtained in Reference Example 27, the desired product was obtained in the same manner as in Example 54. 2) Separation was performed in the same manner as in Example 54 to obtain the desired product. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.66 (d, 3H, J = 7.1Hz), 3.45-3.55 (m, 4H), 3.65-3.75
(m, 4H), 4.15 (q, 1H, J = 7.1Hz), 5.25 (s, 1H), 5.38 (b
rs, 2H), 7.05-7.17 (m, 2H), 7.33-7.54 (m, 6H) [α] _D ²² = + 19.8 ° (c: 1.00, CHCl ₃ )

Example 56({3- [1- (2-fluoro-2 ′, 3 ′, 4 ′,
5 ', 6'-pentadeuterio-biphenyl-4-i
Ru) -ethyl] -isoxazol-5-ylimino}-
Morpholin-4-yl-methyl) -amine

Embedded image Using the compound obtained in Reference Example 29, the desired product was obtained in the same manner as in Example 54. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.66 (d, 3H, J = 7.1Hz), 3.47-3.51 (m, 4H), 3.71-3.75
(m, 4H), 4.15 (q, 1H, J = 7.1Hz), 5.25 (s, 1H), 5.37 (br
-s, 2H), 7.07-7.17 (m, 2H), 7.37 (t, 1H, J = 8.1 Hz) IR (KBr) [cm ^-1 ]: 3454, 3360, 2971, 1629,
1578, 1548, 1444, 1277, 1124, 1110, 975, 872

Example 57 ({3- [1- (2-fluoro-2′-methoxy-biph)
Enyl-4-yl) -ethyl] -isoxazole-5-
Ilimino {-morpholin-4-yl-methyl) -ami
N

Embedded image Using the compound obtained in Reference Example 30, the desired product was obtained in the same manner as in Example 54. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.66 (d, 3H, J = 7.2Hz), 3.47-3.50 (m, 4H), 3.71-3.75
(m, 4H), 3.80 (s, 3H), 4.15 (q, 1H, J = 7.2Hz), 5.27 (s,
1H), 5.34 (br-s, 2H), 6.97-7.13 (m, 4H), 7.23-7.38
(m, 3H)

Example 58 ({3- [1- (2′-fluoro-biphenyl-4-i)
Ru) -ethyl] -isoxazol-5-ylimino}-
Morpholin-4-yl-methyl) -amine

Embedded image Using the compound obtained in Reference Example 31, the desired product was obtained in the same manner as in Example 54. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.67 (d, 3H, J = 7.1Hz), 3.48 (t, 4H, J = 4.8Hz), 3.72 (t,
4H, J = 4.8Hz), 4.16 (q, 1H, J = 7.1Hz), 5.25 (s, 1H),
5.34 (br-s, 2H), 7.10-7.51 (m, 8H)

Example 59({3- [1- (2-fluoro-biphenyl-4-i)
-Cyclopropyl] -isoxazol-5-yli
Mino-morpholin-4-yl-methyl) -amine

Embedded image Using the compound obtained in Reference Example 22, the desired product was obtained in the same manner as in Example 54. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.31-1.34 (m, 2H), 1.46-1.51 (m, 2H), 3.47 (t, 4H, J =
4.8Hz), 3.73 (t, 4H, J = 4.8Hz), 5.17 (s, 1H), 5.35 (br
-s, 2H), 7.14-7.25 (m, 2H), 7.33-7.55 (m, 6H)

Example 60 [(3-biphenyl-4-ylmethyl-isoxazole)
-5-ylimino) -morpholin-4-yl-methyl]
-Amine

[Chemical Formula 86] Using the compound obtained in Reference Example 28, the desired product was obtained in the same manner as in Example 54. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
3.48 (t, 4H, J = 5.3Hz), 3.72 (t, 4H, J = 5.3Hz), 3.94 (s,
2H), 5.24 (s, 1H), 5.34 (s, 2H), 7.34-7.58 (m, 9H)

Example 61 {[3- (1-Biphenyl-4-yl-ethyl) -iso]
Xazol-5-ylimino] -morpholin-4-yl
-Methyl｝ -amine

Embedded image Using the compound obtained in Reference Example 23, the desired product was obtained in the same manner as in Example 54. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.67 (d, 3H, J = 7.3Hz), 3.48 (t, 4H, J = 4.3Hz), 3.72 (t,
4H, J = 4.3Hz), 4.16 (q, 1H, J = 7.3Hz), 5.24 (s, 1H),
5.35 (s, 2H), 7.30-7.58 (m, 9H)

Example 62 {[3- (1-Biphenyl-4-yl-1-methyl-e)
Tyl) -isoxazol-5-ylimino] -morpholy
N-4-yl-methyl} -amine

Embedded image Using the compound obtained in Reference Example 24, the desired product was obtained in the same manner as in Example 54. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.72 (s, 6H), 3.47 (t, 4H, J = 5.3Hz), 3.72 (t, 4H, J =
5.3Hz), 5.18 (s, 1H), 5.38 (s, 2H), 7.32-7.58 (m, 9H)

Example 63 ({3- [1- (2-Fluoro-4′-methoxy-bifu)
Enyl-4-yl) -ethyl] -isoxazole-5-
Ilimino {-morpholin-4-yl-methyl) -ami
N

Embedded image Using the compound obtained in Reference Example 32, the desired product was obtained in the same manner as in Example 54. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.65 (d, 3H, J = 7.2Hz), 3.46-3.50 (m, 4H), 3.70-3.74
(m, 4H), 3.85 (s, 3H), 4.13 (q, 1H, J = 7.2Hz), 5.25
(s, 1H), 5.36 (br-s, 2H), 6.94-7.00 (m, 2H), 7.05-7.
14 (m, 2H), 7.33 (t, 1H, J = 8.0Hz), 7.43-7.49 (m, 2H)

Example 64 4 ′-{1- [5- (Amino-morpholin-4-yl-
Methyleneamino) -isoxazol-3-yl] -ethyl
Ru-2'-fluoro-biphenyl-4-ol

[Formula 90] Compound obtained in Example 63 (5.16 g) under a nitrogen atmosphere
Was dissolved in tetrahydrofuran (100 ml), and -78 was added.
After adding a solution of boron tribromide (1.6 ml) in methylene chloride (40 ml) at ℃, the temperature was raised to room temperature over 1 hour and further stirred at room temperature for 3 hours. The reaction solution was neutralized with a 15% aqueous sodium hydroxide solution, and then extracted with ethyl acetate and methanol. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (chloroform only → chloroform / methanol = 50/1 →
33/1) to give the desired product (2.67 g). ¹ H-NMR (300 MHz, d ₆ -DMSO) δ pp
m: 1.52 (d, 3H, J = 7.2Hz), 3.38-3.44 (m, 4H), 3.54-
3.59 (m, 4H), 4.06 (q, 1H, J = 7.2Hz), 5.39 (s, 1H), 6.
43 (br-s, 2H), 6.83 (d, 2H, J = 8.3Hz), 7.13-7.20 (m, 2
H), 7.30-7.40 (m, 3H), 9.61 (br-s, 1H) IR (KBr) [cm ^-1 ]: 3335, 3190, 1660, 1568,
1497, 1448, 1274, 1114, 983, 827

Example 65 4 ′-{1- [5- (Amino-morpholin-4-yl-
Methyleneamino) -isoxazol-3-yl] -ethyl
Ru-2'-fluoro-biphenyl-2-ol

Embedded image Using the compound obtained in Example 57, the desired product was obtained in the same manner as in Example 64. ¹ H-NMR (300 MHz, d ₆ -DMSO) δ pp
m: 1.57 (d, 3H, J = 7.1Hz), 3.21-3.22 (m, 2H), 3.46-
3.51 (m, 4H), 3.79-3.84 (m, 2H), 4.21 (q, 1H, J = 7.1H
z), 6.15 (s, 1H), 6.84 (t, 1H, J = 7.5Hz), 6.91 (d, 1H,
J = 7.9Hz), 7.12-7.21 (m, 4H), 7.26-7.31 (m, 1H), 9.5
3 (br-s, 1H) IR (KBr) [cm ^-1 ]: 3275, 2964, 1659, 1605,
1493, 1451, 1419, 1358

Example 66 N- {3- [1- (2-Fluoro-biphenyl-4-i)
Ru) -ethyl] -isoxazol-5-yl} -N'-
[2- (2-hydroxy-ethoxy-ethyl)]-gua
Niidine hydrochloride

Embedded image The compound (3.34 g) obtained in Example 49 was dissolved in 1,4-dioxane and treated with 4N hydrochloric acid to give the desired compound (521 m).
g) was obtained. 127-128 ° C ¹ H-NMR (300 MHz, CD ₃ OD) δ ppm:
1.68 (d, 3H, J = 7.3Hz), 3.48-3.54 (m, 2H), 3.54-3.62
(m, 2H), 3.63-3.70 (m, 4H), 4.27 (q, 1H, J = 7.1Hz),
5.98 (s, 1H), 7.12-7.24 (m, 2H), 7.31-7.52 (m, 6H) IR (KBr) [cm ^-1 ]: 3223, 3121, 2934, 1684,
1644, 1616, 1582, 1532, 1484, 1418, 1353, 1267, 1
137, 1108, 1064, 698 MS (FD) [m / e]: 413 (M-HCl)

Example 67 N- {3- [1- (2-Fluoro-biphenyl-4-i)
Ru) -ethyl] -isoxazol-5-yl} -N'-
(2-hydroxy-ethyl) -guanidine hydrochloride

Embedded image Using the compound obtained in Example 50, the desired product was obtained in the same manner as in Example 66. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.59 (d, 3H, J = 7.1Hz), 3.47-3.58 (m, 2H), 3.70-3.83
(m, 2H), 4.13 (q, 1H, J = 7.0Hz), 5.78 (s, 1H), 7.00-7.
07 (m, 2H), 7.31-7.49 (m, 6H), 7.98 (br-s, 1H)

Example 68 4 ′-{1- [5- (amino-morpholin-4-yl-
Methyleneamino) -isoxazol-3-yl] -ethyl
Ru-2'-fluoro-biphenyl-4-ol hydrochloride

Embedded image Using the compound obtained in Example 64, the desired product was obtained in the same manner as in Example 66. 195-210 ° C (decomposition) ¹ H-NMR (300 MHz, d ₆ -DMSO) δ pp
m: 1.58 (d, 3H, J = 7.2Hz), 3.40-3.67 (m, 8H), 4.24
(q, 1H, J = 7.3Hz), 5.99 (s, 1H), 6.84 (d, 2H, J = 8.4H
z), 7.19-7.45 (m, 5H), 8.49 (br-s, 2H), 9.67 (br-s, 1
H) IR (KBr) [cm ^-1 ]: 3215, 3114, 1647, 1614,
1532, 1495, 1418, 1272, 1116, 820 Elemental analysis: Calculated: C, 59.13; H, 5.41; N, 12.54, Found: C, 59.05; H, 5.26; N, 12.47

Example 69 N- {3- [1- (2-fluoro-biphenyl-4-i)
Ru) -ethyl] -isoxazol-5-yl} -N'-
(2-morpholin-4-yl-ethyl) -guanidine
Hydrochloride

Embedded image Using the compound obtained in Example 44, the desired product was obtained in the same manner as in Example 66. ¹ H-NMR (300 MHz, CD ₃ OD) δ ppm:
1.69 (d, 3H, J = 7.3Hz), 3.43-3.48 (m, 6H), 3.86 (t, 2H,
J = 7.3Hz), 3.90-4.10 (br-s, 6H), 4.30 (q, 1H, J = 7.3H
z), 6.08 (s, 1H), 7.15-7.25 (m, 2H), 7.36-7.53 (m, 6
H)

Example 70 N- {3- [1- (2-fluoro-biphenyl-4-i)
Ru) -ethyl] -isoxazol-5-yl} -N'-
(2-methoxy-ethyl) -guanidine hydrochloride

Embedded image Using the compound obtained in Example 45, the desired compound was obtained in the same manner as in Example 66. ¹ H-NMR (300 MHz, CD ₃ OD) δ ppm:
1.65 (d, 3H, J = 7.3Hz), 3.39 (s, 3H), 3.52 (t, 2H, J = 4.
6Hz), 3.62 (t, 2H, J = 4.6Hz), 4.28 (q, 1H, J = 7.3Hz),
5.98 (s, 1H), 7.15-7.35 (m, 2H), 7.38-7.52 (m, 6H)

Example 71 2- {3- [1- (2-Fluorobiphenyl-4-i)
L) -ethyl] -isoxazol-5-ylimino}
-1- (2-hydroxy-ethyl) -imidazolidin-
4-one hydrochloride

Embedded image The compound (3.3 g) obtained in Example 35 was dissolved in tetrahydrofuran (30 ml), and concentrated hydrochloric acid was added.
Minutes. The reaction solution was concentrated under reduced pressure, and purified by recrystallization from toluene to obtain the desired product (1.4 g). 159-167 ° C (decomposition) ¹ H-NMR (300 MHz, CD ₃ OD) δ pp
m: 1.73 (d, 3H, J = 7.3Hz), 3.71-3.76 (m, 2H), 3.82-3.
86 (m, 2H), 4.39 (q, 1H, J = 7.1Hz), 4.53 (s, 2H), 6.65
(s, 1H), 7.18-7.27 (m, 2H), 7.35-7.52 (m, 6H) IR (KBr) [cm ^-1 ]: 3452, 3192, 2939, 1807,
1707, 1616, 1526, 1485, 1450, 1417, 1147, 1051, 69
7 MS (FD) [m / e]: 444 (M ⁺ ), 409 (M-HC
l)

Example 72({3- [1- (2-fluoro-biphenyl-4-i)
L) -1-Methyl-ethyl] -isoxazole-5-i
Limino {-morpholin-4-yl-methyl) -amine
Methanesulfonate

Embedded image The compound (1.53 g) obtained in Example 51 was dissolved in 1.4-dioxane and methanesulfonic acid (0.27 g) was added under ice cooling.
ml) and stirred for 30 minutes. Subsequently, the product was purified by recrystallization from 1.4-dioxane to obtain the desired product (1.89 g). ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.71 (s, 6H), 2.71 (s, 3H), 3.45-3.52 (m, 4H), 3.71-
3.78 (m, 4H), 5.51 (s, 1H), 7.07 (dd, 1H, J = 12.3, 1.8
Hz), 7.13 (dd, 1H, J = 8.3, 1.8Hz), 7.34-7.46 (m, 4H),
7.50-7.54 (m, 2H), 8.64 (br-s, 2H), 11.10 (br-s, 1H)

Example 73 (morpholin-4-yl- {3- [1- (3-phenoxy)
C-phenyl) -ethyl] -isoxazol-5-yl
Imino {-methyl) -amine methanesulfonate

[Formula 99] Using the compound obtained in Example 52, the desired product was obtained in the same manner as in Example 72. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.62 (d, 3H, J = 7.2Hz), 2.72 (s, 3H), 3.43-3.47 (m, 4
H), 3.72-3.76 (m, 4H), 4.11 (q, 1H, J = 7.2Hz), 5.53
(s, 1H), 6.83-7.01 (m, 5H), 7.09-7.15 (m, 1H), 7.23-
7.37 (m, 3H), 8.63 (br-s, 2H), 11.10 (br-s, 1H)

Example 74 ({3- [1- (2′-fluoro-biphenyl-4-i)
Ru) -ethyl] -isoxazol-5-ylimino}-
Morpholin-4-yl-methyl) -amine methanesul
Fonate

[Formula 100] Using the compound obtained in Example 58, the desired product was obtained in the same manner as in Example 72. ¹ H-NMR (300 MHz, d ₆ -DMSO) δ pp
m: 1.67 (d, 3H, J = 7.1Hz), 2.73 (s, 3H), 3.46-3.50
(m, 4H), 3.72-3.76 (m, 4H), 4.18 (q, 1H, J = 7.1Hz),
5.58 (s, 1H), 7.11-7.61 (m, 8H), 8.56 (br-s, 2H)

[0241] Example 75({3- [1- (2-fluoro-biphenyl-4-i)
-Cyclopropyl] -isoxazol-5-yli
Mino-morpholin-4-yl-methyl) -amine meta
Sulfonic acid salt

Embedded image Using the compound obtained in Example 59, the desired product was obtained in the same manner as in Example 72. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.36-1.41 (m, 2H), 1.47-1.52 (m, 2H), 2.74 (s, 3H),
3.46-3.50 (m, 4H), 3.73-3.78 (m, 4H), 5.50 (s, 1H),
7.12-7.23 (m, 2H), 7.33-7.48 (m, 4H), 7.51-7.56 (m, 2
H), 8.61 (br-s, 2H), 11.10 (br-s, 1H)

Example 76 [(3-Biphenyl-4-ylmethyl-isoxazole)
-5-ylimino) -morpholin-4-yl-methyl]
-Amine methanesulfonate

Embedded image Using the compound obtained in Example 60, the desired product was obtained in the same manner as in Example 72. ¹ H-NMR (300 MHz, CD ₃ OD) δ ppm:
2.69 (s, 3H), 3.60 (t, 4H, J = 5.3Hz), 3.77 (t, 4H, J =
5.3Hz), 4.02 (s, 2H), 5.92 (s, 1H), 7.32-7.45 (m, 5
H), 7.56-7.60 (m, 4H)

Example 77 {[3- (1-Biphenyl-4-yl-ethyl) -iso]
Xazol-5-ylimino] -morpholin-4-yl
-Methyl｝ -amine methanesulfonate

Embedded image Using the compound obtained in Example 61, the desired product was obtained in the same manner as in Example 72. ¹ H-NMR (300 MHz, CD ₃ OD) δ ppm:
1.68 (d, 3H, J = 7.3Hz), 2.69 (s, 3H), 3.57 (t, 4H, J = 4.
3Hz), 3.76 (t, 4H, J = 4.3Hz), 4.23 (q, 1H, J = 7.3Hz),
5.91 (s, 1H), 7.29-7.44 (m, 5H), 7.57-7.60 (m, 4H)

Example 78 {[3- (1-Biphenyl-4-yl-1-methyl-e)
Tyl) -isoxazol-5-ylimino] -morpholy
N-4-yl-methyl} -amine methanesulfonate

Embedded image Using the compound obtained in Example 62, the desired product was obtained in the same manner as in Example 72. ¹ H-NMR (300 MHz, CD ₃ OD) δ ppm:
1.75 (s, 6H), 2.68 (s, 3H), 3.58 (t, 4H, J = 5.3Hz), 3.
76 (t, 4H, J = 5.3Hz), 5.83 (s, 1H), 7.32-7.45 (m, 5H),
7.56-7.60 (m, 4H)

Example 79 ({3- [1- (2-fluoro-4′-methoxy-biph)
Enyl-4-yl) -ethyl] -isoxazole-5-
Ilimino {-morpholin-4-yl-methyl) -ami
Methanesulfonate

Embedded image Using the compound obtained in Example 63, the desired product was obtained in the same manner as in Example 72. 187-189 ° C (decomposition) ¹ H-NMR (300 MHz, d ₆ -DMSO) δ pp
m: 1.59 (d, 3H, J = 7.0Hz), 2.29 (s, 3H), 3.40-3.53
(m, 4H), 3.63-3.67 (m, 4H), 3.78 (s, 3H), 4.26 (q, 1
H, J = 7.2Hz), 6.00 (s, 1H), 7.02 (d, 2H, J = 8.4Hz), 7.
19-7.30 (m, 2H), 7.41-7.48 (m, 3H), 8.40 (br-s, 2H) IR (KBr) [cm ^-1 ]: 3098, 1674, 1634, 1614,
1496, 1456, 1251, 1182, 1116, 1048, 825 Elemental analysis: Calculated: C, 55.37; H, 5.62; N, 10.76, Found: C, 55.32; H, 5.60; N, 10.77

Example 80[2- (N '-(tert-butoxycarbonyl)-
N "-{3- [1- (2-fluoro-biphenyl-4-
Yl) -ethyl] -isoxazol-5-yl} -gua
Nidino) -ethoxy] -acetic acid

Embedded image The compound (52 mg) obtained in Example 32 was dissolved in tetrahydrofuran (1 ml), a 5% aqueous sodium hydroxide solution (1 ml) was added, and the mixture was stirred at room temperature for 3 hours. After adding a saturated aqueous solution of ammonium chloride to the reaction solution, the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (chloroform / methanol = 9/1) to give the desired product (25 mg).
I got ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.42 (s, 9H), 1.62 (d, 3H, J = 7.1Hz), 3.50-3.64 (m, 2
H), 3.65-3.75 (m, 2H), 4.06 (s, 2H), 4.06-4.14 (m, 1
H), 5.31 (s, 1H), 7.05-7.13 (m, 2H), 7.30-7.42 (m, 4
H), 7.48-7.51 (m, 2H), 8.18 (br-s, 1H), 8.44 (br-s, 1
H) IR (neat) [cm ^-1 ]: 3397, 3348, 2980, 2
934, 1731, 1634, 1606,1562, 1486, 1455, 1418, 137
0, 1242, 1150, 912, 770, 733, 699

Example 81[2- (N '-{3- [1- (2-fluoro-biphenyl)
Ru-4-yl) -ethyl] -isoxazol-5-i
Ru-guanidino) -ethoxy] -sodium acetate

Embedded image The compound (4.32 g) obtained in Example 48 was dissolved in tetrahydrofuran (80 ml), a 5% aqueous sodium hydroxide solution (80 ml) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and after filtration, the solid was washed with ethyl acetate and water. After concentrating the filtrate, the solid was filtered again and washed with ethyl acetate and water. The combined crude crystals were purified from water by a recrystallization method to obtain the desired product (3.08 g). ¹ H-NMR (300 MHz, CD ₃ OD) δ ppm:
1.63 (d, 3H, J = 7.1Hz), 3.38-3.42 (m, 2H), 3.56-3.60
(m, 2H), 3.87 (s, 2H), 4.13 (q, 1H, J = 7.2Hz), 5.35 (s,
1H), 7.11-7.21 (m, 2H), 7.30-7.43 (m, 4H), 7.49-7.5
2 (m, 2H) IR (neat) [cm ^-1 ]: 3429, 1573, 1453, 143
0, 1330, 694 Elemental analysis: Calculated: C, 57.77; H, 5.07; N, 12.25, Found: C, 57.86; H, 5.15; N, 12.19

Example 82 (R)-({3- [1- (2-Fluoro-biphenyl-)
4-yl) -ethyl] -isoxazol-5-ylimi
No-morpholin-4-yl-methyl) -amine hydrochloride

Embedded image Using the compound obtained in Example 54, the desired product was obtained in the same manner as in Example 66. 134-136 ° C ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.64 (d, 3H, J = 7.1Hz), 3.45-3.65 (m, 4H), 3.70-3.80
(m, 4H), 4.15 (q, 1H, J = 7.1Hz), 5.69 (s, 1H), 7.03-
7.11 (m, 2H), 7.33-7.52 (m, 6H), 8.45 (br-s, 2H), 11.
31 (br-s, 1H) [α] _D ²² = 16.0 ° (c: 1.00, CHCl ₃ )

Example 83 (S)-({3- [1- (2-Fluoro-biphenyl-)
4-yl) -ethyl] -isoxazol-5-ylimi
No-morpholin-4-yl-methyl) -amine hydrochloride

Embedded image Using the compound obtained in Example 55, the desired product was obtained in the same manner as in Example 66. 134-136 ° C ¹ H-NMR (300 MHz, DCl ₃ ) δ ppm: 1.
64 (d, 3H, J = 7.3Hz), 3.45-3.60 (m, 4H), 3.60-3.80 (m,
4H), 4.15 (q, 1H, J = 7.3Hz), 5.69 (s, 1H), 7.02-7.12
(m, 2H), 7.32-7.52 (m, 6H), 8.44 (br-s, 2H) [α] _D ²² = + 14.4 ° (c: 1.00, CHCl ₃ )

Example 84 (R)-({3- [1- (2-Fluoro-biphenyl-)
4-yl) -ethyl] -isoxazol-5-ylimi
Roh} - morpholin-4-yl - methyl) - amine phosphate

Embedded image The compound obtained in Example 54 was treated with phosphoric acid to obtain the desired product. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.54 (d, 3H, J = 7.3Hz), 3.40-3.43 (m, 4H), 3.55-3.58
(m, 4H), 4.11 (q, 1H, J = 7.3Hz), 5.42 (s, 1H), 6.46 (b
rs, 2H), 7.21-7.26 (m, 2H), 7.38-7.53 (m, 6H) IR (neat) [cm ^-1 ]: 3381, 2973, 2361, 168
2, 1618, 1552, 1484, 1456, 1411, 1274, 1113 [α] _D ²⁰ = −27.2 ° (c: 0.60, MeOH)

Example 85 (S)-({3- [1- (2-Fluoro-biphenyl-)
4-yl) -ethyl] -isoxazol-5-ylimi
Roh} - morpholin-4-yl - methyl) - amine phosphate

Embedded image Using the compound obtained in Example 55, the desired product was obtained in the same manner as in Example 84. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
Same as Example 84. IR (neat) [cm ^-1 ]: Same as in Example 84. [Α] _D ²⁰ = + 27.7 ° (c: 0.52, MeOH)

Example 86 (R)-({3- [1- (2-fluoro-biphenyl-)
4-yl) -ethyl] -isoxazol-5-ylimi
No-morpholin-4-yl-methyl) -amine methanesulfonate

Embedded image Using the compound obtained in Example 54, the desired product was obtained in the same manner as in Example 72. 166-167 ° C ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.66 (d, 3H, J = 7.1Hz), 2.72 (s, 3H), 3.46-3.51 (m, 4
H), 3.71-3.77 (m, 4H), 4.17 (q, 1H, J = 7.2Hz), 5.59
(s, 1H), 7.02-7.12 (m, 2H), 7.33-7.46 (m, 4H), 7.50-
7.53 (m, 2H), 8.62 (br-s, 2H), 11.14 (br-s, 1H) IR (neat) [cm ^-1 ]: 2974, 1668, 1634, 154
8, 1484, 1446, 1270, 1194, 1117, 1043, 776, 699 [α] _D ²² = 14.0 ° (c: 1.00, CHCl ₃ )

Example 87 (S)-({3- [1- (2-fluoro-biphenyl-)
4-yl) -ethyl] -isoxazol-5-ylimi
No-morpholin-4-yl-methyl) -amine methanesulfonate

Embedded image Using the compound obtained in Example 55, the desired product was obtained in the same manner as in Example 72. Melting point: 162 to 165 ° C. ¹ H-NMR (300 MHz,
CDCl ₃ ) δ ppm: 1.66 (d, 3H, J = 7.3 Hz), 2.72 (s, 3H), 3.46-3.51 (m, 4H), 3.71-3.78 (m, 4H),
4.17 (q, 1H, J = 7.1Hz), 5.59 (s, 1H), 7.02-7.12 (m, 2
H), 7.33-7.46 (m, 4H), 7.50-7.53 (m, 2H), 8.62 (br-s,
2H), 11.13 (br-s, 1H) IR (neat) [cm ^-1 ]: 2972, 1668, 1634, 154
8, 1484, 1446, 1418, 1198, 1116, 1062, 1010, 768,
699 [α] _D ²² = + 12.0 ° (c: 0.80, CHCl ₃ )

Example 88 (R)-({3- [1- (2-Fluoro-biphenyl-)
4-yl) -ethyl] -isoxazol-5-ylimi
No-morpholin-4-yl-methyl) -aminebenzenesulfonate

Embedded image The compound obtained in Example 54 was treated with benzenesulfonic acid to obtain the desired product. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.59 (d, 3H, J = 7.1Hz), 3.50 (m, 4H), 3.66 (m, 4H), 4.2
6 (q, 1H, J = 7.1Hz), 5.98 (s, 1H), 7.25-7.59 (m, 13H) IR (neat) [cm ^-1 ]: 3135, 1679, 1630, 155
2, 1484, 1445, 1418 [α] _D ²⁰ = −16.9 ° (c: 0.53, MeOH)

Example 89 (S)-({3- [1- (2-fluoro-biphenyl-)
4-yl) -ethyl] -isoxazol-5-ylimi
No-morpholin-4-yl-methyl) -aminebenzenesulfonate

Embedded image Using the compound obtained in Example 55, the desired product was obtained in the same manner as in Example 88. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
Same as in Example 88. IR (neat) [cm ^-1 ]: Same as in Example 88. [Α] _D ²⁰ = + 16.8 ° (c: 0.51, MeOH)

Example 90 (R)-({3- [1- (2-fluoro-biphenyl-)
4-yl) -ethyl] -isoxazol-5-ylimi
No-morpholin-4-yl-methyl) -amine sulfate

Embedded image The compound obtained in Example 54 was treated with sulfuric acid to obtain the desired product. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.53 (d, 3H, J = 7.3Hz), 3.30-3.80 (m, 8H), 4.07 (q, 1H,
J = 6.8Hz), 5.72 (s, 1H), 6.97-7.05 (m, 2H), 7.28-7.4
4 (m, 6H), 7.95 (br-s, 2H) [α] _D ²² = -20.2 ° (c: 1.00, THF)

Example 91 (S)-({3- [1- (2-Fluoro-biphenyl-)
4-yl) -ethyl] -isoxazol-5-ylimi
No-morpholin-4-yl-methyl) -amine sulfate

Embedded image The target compound was obtained by the same procedure as in the compound obtained in Example 55 and Example 90. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.53 (d, 3H, J = 6.8Hz), 3.30-3.80 (m, 8H), 4.05-4.10
(m, 1H), 5.72 (s, 1H), 6.97-7.05 (m, 2H), 7.28-7.44
(m, 6H), 7.95 (br-s, 1H) [α] _D ²² = + 20.2 ° (c: 1.00, THF)

Example 92 (R)-({3- [1- (2-Fluoro-biphenyl-)
4-yl) -ethyl] -isoxazol-5-ylimi
No-morpholin-4-yl-methyl) -amine D-camphor-sulfonate

Embedded image The compound obtained in Example 54 was treated with D-camphor-sulfonic acid to obtain a desired product. 167-169 ° C ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
0.76 (s, 3H), 0.95 (s, 3H), 1.23-1.32 (m, 1H), 1.53-
1.62 (m, 1H), 1.66 (d, 3H, J = 7.3Hz), 1.79 (d, 1H, J = 1
8.1Hz), 1.82-1.88 (m, 1H), 1.96-2.00 (m, 1H), 2.21-
2.28 (m, 1H), 2.35-2.47 (m, 1H), 2.76 (d, 1H, J = 14.6H
z), 3.26 (d, 1H, J = 14.6Hz), 3.48-3.52 (m, 4H), 3.73-
3.76 (m, 4H), 4.17 (q, 1H, J = 7.1Hz), 5.63 (s, 1H), 7.
03-7.53 (m, 8H), 8.35 (br-s, 2H), 11.12 (br-s, 2H)

Example 93 (S)-({3- [1- (2-fluoro-biphenyl-)
4-yl) -ethyl] -isoxazol-5-ylimi
No-morpholin-4-yl-methyl) -amine D-camphor-sulfonate

Embedded image Using the compound obtained in Example 55, the desired product was obtained in the same manner as in Example 92. 167-168 ° C ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
0.76 (s, 3H), 0.95 (s, 3H), 1.24-1.32 (m, 1H), 1.54-
1.65 (m, 1H), 1.66 (d, 3H, J = 7.1Hz), 1.79 (d, 1H, J = 1
8.1Hz), 1.82-1.91 (m, 1H), 1.96-2.00 (m, 1H), 2.21-
2.30 (m, 1H), 2.35-2.47 (m, 1H), 2.75 (d, 1H, J = 14.6H
z), 3.26 (d, 1H, J = 14.7Hz), 3.48-3.52 (m, 4H), 3.73-
3.76 (m, 4H), 4.17 (q, 1H, J = 7.1Hz), 5.66 (s, 1H), 7.
04-7.14 (m, 2H), 7.33-7.52 (m, 6H), 8.53 (br-s, 2H),
11.11 (br-s, 1H)

Example 94 (R)-({3- [1- (2-Fluoro-biphenyl-)
4-yl) -ethyl] -isoxazol-5-ylimi
No-morpholin-4-yl-methyl) -amine 3-bromo-(+)-camphor-10-sulfonate

Embedded image The compound obtained in Example 54 was treated with 3-bromo-(+)-camphor-10-sulfonic acid to obtain a desired product. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
0.97 (s, 3H), 1.25 (s, 3H), 1.47-1.54 (m, 1H), 1.68
(d, 3H, J = 7.1Hz), 1.85-2.00 (m, 1H), 2.00-2.10 (m, 1
H), 2.23-2.26 (m, 1H), 2.65-2.69 (m, 1H), 2.83 (d, 1
H, J = 14.8Hz), 3.23-3.28 (m, 1H), 3.55-3.59 (m, 4H),
3.74-3.78 (m, 4H), 4.27 (q, 1H, J = 7.1Hz), 4.76-4.79
(m, 1H), 5.91 (s, 1H), 7.13-7.23 (m, 2H), 7.34-7.51
(m, 6H)

Example 95 (S)-({3- [1- (2-Fluoro-biphenyl-)
4-yl) -ethyl] -isoxazol-5-ylimi
No-morpholin-4-yl-methyl) -amine 3-bromo-(+)-camphor-10-sulfonate

Embedded image Using the compound obtained in Example 55, ¹ to obtain the compound of interest by the same procedure as in Example 94 H-NMR (300MHz, CDCl 3) δ ppm:
0.95 (s, 3H), 1.23 (s, 3H), 1.49-1.59 (m, 1H), 1.67
(d, 3H, J = 7.4Hz), 1.80-2.15 (m, 2H), 2.21-2.24 (m, 1
H), 2.62-2.66 (m, 1H), 2.83 (d, 1H, J = 15.0Hz), 3.23-
3.28 (m, 1H), 3.53-3.60 (m, 4H), 3.73-3.77 (m, 4H),
4.21 (q, 1H, J = 7.3Hz), 4.62-4.65 (m, 1H), 5.79 (s, 1
H), 7.06-7.17 (m, 2H), 7.30-7.49 (m, 6H)

Example 96 (R)-({3- [1- (2-Fluoro-biphenyl-)
4-yl) -ethyl] -isoxazol-5-ylimi
No-morpholin-4-yl-methyl) -amine 3-bromo-(+)-camphor-8-sulfonate

Embedded image The compound obtained in Example 54 was treated with 3-bromo-(+)-camphor-8-sulfonic acid to obtain the desired product. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
0.90 (s, 3H), 1.22 (s, 3H), 1.37-1.43 (m, 1H), 1.50-
1.63 (m, 1H), 1.67 (d, 3H, J = 7.1Hz), 1.90-2.15 (m, 2
H), 2.76 (d, 1H, J = 14.3Hz), 2.94 (s, 1H), 3.15 (d, 1
H, J = 14.6Hz), 3.40-3.52 (m, 4H), 3.72-3.77 (m, 4H),
4.17 (q, 1H, J = 7.1Hz), 4.50 (d, 1H, J = 4.7Hz), 5.50
(s, 1H), 7.01-7.12 (m, 2H), 7.34-7.53 (m, 6H)

Example 97 (S)-({3- [1- (2-Fluoro-biphenyl-)
4-yl) -ethyl] -isoxazol-5-ylimi
No-morpholin-4-yl-methyl) -amine 3-bromo-(+)-camphor-8-sulfonate

Embedded image Using the compound obtained in Example 54, the desired product was obtained in the same manner as in Example 96. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
0.90 (s, 3H), 1.11 (s, 3H), 1.37-1.48 (m, 1H), 1.50-
1.63 (m, 1H), 1.67 (d, 3H, J = 7.1Hz), 1.95-2.15 (m, 2
H), 2.76 (d, 1H, J = 14.3Hz), 2.94 (s, 1H), 3.15 (d, 1
H, J = 14.5Hz), 3.40-3.52 (m, 4H), 3.72-3.77 (m, 4H),
4.18 (q, 1H, J = 7.1Hz), 4.49 (d, 1H, J = 4.8Hz), 5.52
(s, 1H), 7.02-7.12 (m, 2H), 7.36-7.53 (m, 6H)

Example 98 ({3- [1- (9H-carbazol-2-yl) -d)
Tyl] -isoxazol-5-ylimino} -morpholy
4-N-yl-methyl) -amine

Embedded image Using the compound obtained in Reference Example 34, the desired product was obtained in the same manner as in Example 54. 113 ° C. (decomposition) ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.71 (d, 3H, J = 7.1Hz), 3.42-3.46 (m, 4H), 3.66-3.71
(m, 4H), 4.27 (q, 1H, J = 7.1Hz), 5.26 (s, 1H), 5.35 (b
rs, 2H), 7.16-7.23 (m, 2H), 7.33-7.42 (m, 3H), 7.96
-8.04 (m, 2H), 8.15 (s, 1H)

Example 99{[3- (2-Fluoro-biphenyl-4-ylmethyi)
-Isoxazol-5-ylimino] -morpholine
-4-yl-methyl} -amine

Embedded image Using the compound obtained in Reference Example 35, the desired product was obtained in the same manner as in Example 54. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
3.47-3.51 (m, 4H), 3.71-3.75 (m, 4H), 3.92 (s, 2H), 5.
26 (s, 1H), 5.38 (br-s, 2H), 7.04-7.14 (m, 2H), 7.33
7.47 (m, 4H), 7.50-7.55 (m, 2H)

Example 100{[3- (2-Fluoro-biphenyl-4-ylmethyi)
-Isoxazol-5-ylimino] -morpholine
-4-yl-methyl} -amine methanesulfonate

Embedded image Using the compound obtained in Example 99, the desired product was obtained in the same manner as in Example 72. Melting point 71-74 ° C (decomposition) ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
2.73 (s, 3H), 3.47-3.51 (m, 4H), 3.69-3.73 (m, 4H), 3.
96 (s, 2H), 5.63 (s, 1H), 7.01-7.11 (m, 2H), 7.34-7.4
7 (m, 4H), 7.50-7.54 (m, 2H), 8.63 (br-s, 2H), 11.2 (b
rs, 1H)

Example 101 ({3- [1- (2,3-dihydro-benzo [1,4]]
Dioxin-6-yl) -ethyl] -isoxazole-
5-ylimino} -morpholin-4-yl-methyl)-
Amine

Embedded image Using the compound obtained in Reference Example 37, the desired product was obtained in the same manner as in Example 54. ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.58 (d, 3H, J = 7.3Hz), 3.47 (t, 4H, J = 4.6Hz), 3.72
(t, 4H, J = 4.6Hz), 4.00 (q, 1H, J = 7.3Hz), 4.22 (s, 4
H), 5.20 (s, 1H), 5.35 (br-s, 2H), 6.77-6.80 (m, 3H)

Example 102 ({3- [1- (1-methyl-1H-indole-3-
Yl) -ethyl] -isoxazol-5-ylimino}
-Morpholin-4-yl-methyl) -amine

Embedded image Using the compound obtained in Reference Example 38, the desired product was obtained in the same manner as in Example 54. ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.72 (d, 3H, J = 7.3Hz), 3.43 (t, 4H, J = 4.6Hz), 3.68
(t, 4H, J = 4.6Hz), 3.73 (s, 3H), 4.40 (q, 1H, J = 7.3H
z), 5.24 (s, 1H), 5.31 (br-s, 2H), 6.92 (s, 1H), 7.03
-7.28 (m, 3H), 7.61 (d, 1H, J = 7.9Hz)

Example 103 ({3- [1- (1H-Indol-3-yl) -ethyl)
] -Isoxazol-5-ylimino} -morpholine
-4-yl-methyl) -amine

Embedded image Using the compound obtained in Reference Example 39, the desired product was obtained in the same manner as in Example 54. ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.72 (d, 3H, J = 7.3Hz), 3.44 (t, 4H, J = 5.0Hz), 3.69
(t, 4H, J = 5.0Hz), 4.41 (q, 1H, J = 7.3Hz), 5.23 (s, 1
H), 5.28 (br-s, 2H), 7.04-7.19 (m, 3H), 7.33 (d, 1H,
J = 7.9Hz), 7.63 (d, 1H, J = 7.9Hz), 8.03 (br-s, 1H)

Example 104 ({3- [1- (1-methyl-1H-indole-2-
Yl) -ethyl] -isoxazol-5-ylimino}
-Morpholin-4-yl-methyl) -amine

Embedded image Using the compound obtained in Reference Example 41, the desired product was obtained in the same manner as in Example 54. ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.73 (d, 3H, J = 7.3Hz), 3.44 (t, 4H, J = 4.6Hz), 3.64
(s, 3H), 3.70 (t, 4H, J = 4.6Hz), 4.34 (q, 1H, J = 7.3H
z), 5.12 (s, 1H), 5.26 (br-s, 2H), 6.45 (s, 1H), 7.04
-7.26 (m, 3H), 7.56 (d, 1H, J = 7.3Hz)

Example 105 {[3- (1-benzofuran-5-yl-ethyl) -i
Soxazol-5-ylimino] -morpholin-4-i
Ru-methyl} -amine

[Of 131] Using the compound obtained in Reference Example 43, the desired product was obtained in the same manner as in Example 54. ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.67 (d, 3H, J = 7.3Hz), 3.46 (t, 4H, J = 4.6Hz), 3.71
(t, 4H, J = 4.6Hz), 4.19 (q, 1H, J = 7.3Hz), 5.20 (s, 1
H), 5.34 (br-s, 2H), 6.71 (d, 1H, J = 2.3Hz), 7.21-7.2
6 (m, 1H), 7.42 (d, 1H, J = 8.6Hz), 7.51 (d, 1H, J = 1.7H
z), 7.59 (d, 1H, J = 2.3Hz)

Example 106 {[3- (1-benzofuran-6-yl-ethyl) -i
Soxazol-5-ylimino] -morpholin-4-i
Ru-methyl} -amine

Embedded image Using the compound obtained in Reference Example 45, the desired product was obtained in the same manner as in Example 54. ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.68 (d, 3H, J = 7.3Hz), 3.46 (t, 4H, J = 4.6Hz), 3.71
(t, 4H, J = 4.6Hz), 4.23 (q, 1H, J = 7.3Hz), 5.21 (s, 1
H), 5.33 (br-s, 2H), 6.72 (d, 1H, J = 2.3Hz), 7.19 (dd,
1H, J = 8.3, 1.7Hz), 7.45-7.52 (m, 2H), 7.58 (d, 1H,
(J = 2.3Hz)

Example 107 (3- {1- [5- (amino-morpholin-4-yl-
Methyleneamino) -isoxazol-3-yl] -ethyl
(Phenyl-phenyl) -phenyl-methanone methanesulfo
Phosphate

Embedded image Example 54 and Example 72 using {3- [1- (5-amino-isoxazol-3-yl) -ethyl] -phenyl} -phenyl-methanone (JP-A-63-152368).
The desired product was obtained by the same operation method as in. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.67 (d, 3H, J = 7.1Hz), 2.72 (s, 3H), 3.45-3.51 (m, 4
H), 3.72-3.76 (m, 4H), 4.22 (q, 1H, J = 7.1Hz), 5.57
(s, 1H), 7.40-7.51 (m, 4H), 7.57-7.65 (m, 2H), 7.71
(s, 1H), 7.77-7.79 (m, 2H), 8.61 (br-s, 2H), 11.13 (b
rs, 1H)

Example 108 [({3- [1- (2-fluoro-biphenyl-4-i)
Ru) -ethyl] -isoxazol-5-ylimino}-
Morpholin-4-yl-methylimino) -morpholine-
4-yl-methyl] -amine

Embedded image Free form of the compound obtained in Example 22 (2.20 g), 4
-A mixture of morpholinecarbonitrile (2.8 ml) and sodium amide (0.44 g) was stirred at room temperature for 5 hours. The reaction solution was poured into a saturated aqueous solution of ammonium chloride and extracted with chloroform. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the desired product (1.62 g). ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.62 (d, 3H, J = 7.3Hz), 3.26-3.29 (m, 4H), 3.54-3.57
(m, 4H), 3.63-3.66 (m, 8H), 4.11 (q, 1H, J = 7.2Hz),
4.63 (br-s, 2H), 5.01 (s, 1H), 7.05-7.17 (m, 2H), 7.3
3-7.54 (m, 6H)

Example 109 [({3- [1- (2-Fluoro-biphenyl-4-i)
Ru) -ethyl] -isoxazol-5-ylimino}-
Morpholin-4-yl-methylimino) -morpholine-
4-yl-methyl] -amine hydrochloride

[Of 135] The compound (1.66 g) obtained in Example 108 was dissolved in 1,4-dioxane (20 ml), and 4N-hydrochloric acid / 1,4-
A dioxane solution (1.00 ml) was added, and the mixture was stirred at room temperature for 2 hours to precipitate a white precipitate. Reaction mixture at 100 ° C
To dissolve the precipitate, and then slowly cooled while stirring. The precipitated white precipitate was collected by filtration to obtain the desired product (1.19).
g) was obtained. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.66 (d, 3H, J = 7.1Hz), 3.44-3.56 (m, 4H), 3.60-3.68
(m, 4H), 3.68-3.83 (m, 8H), 4.16 (q, 1H, J = 7.0Hz),
5.52 (s, 1H), 7.03-7.15 (m, 4H), 7.35-7.55 (m, 6H)

[0276] Example 110({3- [1- (2-fluoro-biphenyl-4-i)
Ru) -vinyl] -isoxazol-5-ylimino}-
Morpholin-4-yl-methyl) -amine

Embedded image To a solution of the compound obtained in Example 53 (30.0 mg) in methylene chloride (1 ml) was added trifluoroacetic acid (4 ml), and the mixture was stirred at room temperature for 8 hours. After adding saturated saline,
After extraction with ethyl acetate, the organic layer was washed with saturated aqueous sodium bicarbonate and saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified on a silica gel column to give the desired product (20 m
g) was obtained. Melting point 167.5 ° C (decomposition) ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
3.51-3.55 (m, 4H), 3.74-3.78 (m, 4H), 5.42 (br-s, 2
H), 5.54 (s, 1H), 5.69 (s, 1H), 5.84 (s, 1H), 7.26-7.
59 (m, 8H)

Example 111 {morpholin-4-yl- [3- (1-quinoline-3-
Yl-ethyl) -isoxazol-5-ylimino]-
Methyl｝ -amine

Embedded image Using the compound obtained in Reference Example 47, the desired product was obtained in the same manner as in Example 54. ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.76 (d, 3H, J = 7.3Hz), 3.48 (t, 4H, J = 4.6Hz), 3.72
(t, 4H, J = 4.6Hz), 4.34 (q, 1H, J = 7.3Hz), 5.24 (s, 1
H), 5.33 (br-s, 2H), 7.50-7.79 (m, 3H), 8.02-8.09 (m,
2H), 8.89 (d, 1H, J = 2.3Hz)

Example 112 {[3- (1-Isoquinolin-4-yl-ethyl) -i]
Soxazol-5-ylimino] -morpholin-4-i
Ru-methyl} -amine

Embedded image Using the compound obtained in Reference Example 48, the desired product was obtained in the same manner as in Example 54. ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.83 (d, 3H, J = 7.3Hz), 3.45 (t, 4H, J = 4.6Hz), 3.68
(t, 4H, J = 4.6Hz), 4.79 (q, 1H, J = 7.3Hz), 5.13 (s, 1
H), 5.40 (br-s, 2H), 7.56-7.72 (m, 2H), 7.97 (d, 1H,
J = 7.6Hz), 8.14 (d, 1H, J = 8.6Hz), 8.52 (s, 1H), 9.15
(s, 1H)

Example 113 {{3- (1-Biphenyl-4-yl-dimethoxy-meth)
Tyl) -isoxazol-5-ylimino] -morpholy
N-4-yl-methyl} -amine

Embedded image Using the compound obtained in Reference Example 50, the desired product was obtained in the same manner as in Example 54. ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
3.28 (s, 6H), 3.47 (t, 4H, J = 4.6Hz), 3.71 (t, 4H, J =
4.6Hz), 5.32 (s, 1H), 5.36 (br-s, 2H), 7.33-7.45 (m,
3H), 7.54-7.67 (m, 6H)

Example 114 ({3- [dimethoxy- (1-methyl-1H-indole)
Ru-2-yl) -methyl] -isoxazol-5-yl
Imino} -morpholin-4-yl-methyl) -amine

[Formula 140] Using the compound obtained in Reference Example 52, the desired product was obtained in the same manner as in Example 54. ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
3.27 (s, 6H), 3.44 (t, 4H, J = 4.6Hz), 3.66 (s, 3H), 3.
69 (t, 4H, J = 4.6Hz), 5.26 (s, 1H), 5.30 (br-s, 2H), 6.
87 (s, 1H), 7.06-7.28 (m, 3H), 7.62 (d, 1H, J = 7.6Hz)

Example 115 N- (tert-butoxycarbonyl) -N ′-{3-
[1- (2-Fluoro-biphenyl-4-yl) -ethyl]
] -Isoxazol-5-yl} -N "-phenyl-
Guanidine

Embedded image The desired product was obtained in the same manner as in Example 1. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.54 (s, 9H), 1.68 (d, 3H, J = 7.1Hz), 4.16 (q, 1H, J =
7.1Hz), 5.45 (s, 1H), 7.07-7.17 (m, 3H), 7.27-7.46
(m, 6H), 7.51-7.61 (m, 4H), 8.63 (br-s, 1H), 10.10 (b
rs, 1H)

Example 116 N- (tert-Butoxycarbonyl) -N ′-{3-
[1- (2-Fluoro-biphenyl-4-yl) -ethyl]
] -Isoxazol-5-yl} -N "-pyridine-
3-yl-guanidine

Embedded image The desired product was obtained in the same manner as in Example 1. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.55 (s, 9H), 1.69 (d, 3H, J = 7.1Hz), 4.18 (q, 1H, J =
7.1Hz), 5.45 (s, 1H), 7.07-7.25 (m, 2H), 7.27-7.46
(m, 4H), 7.51-7.55 (m, 2H), 8.14-8.18 (m, 1H), 8.32-
8.35 (m, 1H), 8.69-8.71 (m, 2H), 10.22 (br-s, 1H)

Example 117(Tert-butoxycarbonyl)-({3- [1-
(2-Fluoro-biphenyl-4-yl) -ethyl]-
Isoxazol-5-ylimino} -thiamorpholine-
4-yl-methyl) -amine

Embedded image The desired product was obtained in the same manner as in Example 1. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.43 (s, 9H), 1.66 (d, 3H, J = 7.3Hz), 2.68-2.74 (m, 4
H), 3.84 (br-s, 4H), 4.16 (q, 1H, J = 7.1Hz), 5.28 (s,
1H), 6.81 (br-s, 1H), 7.07-7.16 (m, 2H), 7.34-7.46
(m, 4H), 7.50-7.54 (m, 2H)

Example 1181-([(tert-butoxycarbonyl) -amino]
-{3- [1- (2-fluoro-biphenyl-4-i)
Ru) -ethyl] -isoxazol-5-ylimino}-
Methyl) -piperidin-4-one

Embedded image The desired product was obtained in the same manner as in Example 1. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.46 (s, 9H), 1.68 (d, 3H, J = 7.3Hz), 2.60 (t, 4H, J =
6.2Hz), 3.84 (t, 4H, J = 6.2Hz), 4.18 (q, 1H, J = 7.0H
z), 5.34 (s, 1H), 7.06 (br-s, 1H), 7.07-7.17 (m, 2H),
7.33-7.46 (m, 4H), 7.50-7.55 (m, 2H)

[0285] Example 1191-([(tert-butoxycarbonyl) -amino]
-{3- [1- (2-fluoro-biphenyl-4-i)
Ru) -ethyl] -isoxazol-5-ylimino}-
Methyl) -piperidin-4-ol

Embedded image The desired product was obtained in the same manner as in Example 1. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.43 (s, 9H), 1.55-1.68 (m, 3H), 1.66 (d, 3H, J = 7.3H
z), 1.85-1.99 (m, 2H), 3.25-3.40 (m, 2H), 3.84-3.99
(m, 3H), 4.12 (q, 1H, J = 7.1Hz), 5.25 (s, 1H), 6.75 (b
rs, 1H), 7.07-7.16 (m, 2H), 7.32-7.46 (m, 4H), 7.50
-7.54 (m, 2H)

Example 120 N- (tert-butoxycarbonyl) -N ′-{3-
[1- (2-Fluoro-biphenyl-4-yl) -ethyl]
] -Isoxazol-5-yl} -N "-hydroxy
-Guanidine

Embedded image The desired product was obtained in the same manner as in Example 1. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.51 (s, 9H), 1.66 (d, 3H, J = 7.1Hz), 4.16 (q, 1H, J =
7.1Hz), 5.79 (s, 1H), 6.20 (br-s, 1H), 7.06-7.14 (m,
2H), 7.32-7.46 (m, 4H), 7.50-7.54 (m, 2H), 7.78 (br-
s, 1H), 9.89 (br-s, 1H)

Example 121 N- (tert-butoxycarbonyl) -N ′-{3-
[1- (2-Fluoro-biphenyl-4-yl) -ethyl]
] -Isoxazol-5-yl} -N "-methoxy-
Guanidine

Embedded image The desired product was obtained in the same manner as in Example 1. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.51 (s, 9H), 1.68 (d, 3H, J = 7.1Hz), 3.78 (s, 3H), 4.
19 (q, 1H, J = 7.1Hz), 5.87 (s, 1H), 7.08-7.17 (m, 2H),
7.32-7.46 (m, 4H), 7.50-7.54 (m, 2H), 7.70 (br-s, 1
H), 9.86 (br-s, 1H)

Example 122 N- (tert-butoxycarbonyl) -N ′-(2-
Dimethylamino-ethyl) -N "-{3- [1- (2-
Fluoro-biphenyl-4-yl) -ethyl] -isoalkyl
Sasol-5-yl} -guanidine

Embedded image The desired product was obtained in the same manner as in Example 1. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.49 (s, 9H), 1.67 (d, 3H, J = 7.1Hz), 2.26 (s, 6H), 2.
49 (t, 2H, J = 6.2Hz), 3.42-3.49 (m, 2H), 4.14 (q, 1H,
J = 7.1Hz), 5.31 (br-s, 1H), 7.07-7.17 (m, 2H), 7.32-
7.46 (m, 4H), 7.50-7.54 (m, 2H), 8.18 (br-s, 1H), 8.4
8 (br-s, 1H)

Example 123 N- {3- [1- (2-Fluoro-biphenyl-4-i)
Ru) -ethyl] -isoxazol-5-yl} -N'-
Phenyl-guanidine

Embedded image Using the compound obtained in Example 115, the desired product was obtained in the same manner as in Example 48. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.64 (d, 3H, J = 7.1Hz), 4.14 (q, 1H, J = 7.1Hz), 5.18 (s,
1H), 5.48 (br-s, 2H), 7.05-7.15 (m, 2H), 7.23-7.47
(m, 3H), 7.32-7.47 (m, 6H), 7.51-7.55 (m, 3H)

Example 124 N- {3- [1- (2-Fluoro-biphenyl-4-i)
Ru) -ethyl] -isoxazol-5-yl} -N'-
Pyridin-3-yl-guanidine

Embedded image Using the compound obtained in Example 116, the desired product was obtained in the same manner as in Example 48. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.64 (d, 3H, J = 7.1Hz), 4.14 (q, 1H, J = 7.1Hz), 5.33 (s,
1H), 5.75 (br-s, 2H), 7.04-7.11 (m, 2H), 7.13-7.26
(m, 1H), 7.31-7.45 (m, 5H), 7.49-7.52 (m, 2H), 7.90
(d, 1H, J = 8.3Hz), 8.28 (d, 1H, J = 4.2Hz), 8.46 (br-s, 1
H)

Example 125({3- [1- (2-fluoro-biphenyl-4-i)
Ru) -ethyl] -isoxazol-5-ylimino}-
Thiamorpholin-4-yl-methyl) -amine

Embedded image Using the compound obtained in Example 117, the desired product was obtained in the same manner as in Example 48. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.65 (d, 3H, J = 7.1Hz), 2.62-2.66 (m, 4H), 3.80-3.85
(m, 4H), 4.14 (q, 1H, J = 7.1Hz), 5.24 (s, 1H), 5.35 (b
rs, 1H), 7.07-7.20 (m, 2H), 7.32-7.46 (m, 4H), 7.50
-7.54 (m, 2H)

Example 126 1- (Amino- {3- [1- (2-fluoro-biphenyl)
Ru-4-yl) -ethyl] -isoxazol-5-yl
Imino {-methyl) -piperidin-4-one

Embedded image Using the compound obtained in Example 118, the desired product was obtained in the same manner as in Example 48. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.67 (d, 3H, J = 7.1Hz), 2.55 (t, 4H, J = 6.2Hz), 3.83 (t,
4H, J = 6.2Hz), 4.16 (q, 1H, J = 7.1Hz), 5.28 (s, 1H),
5.47 (br-s, 2H), 7.07-7.18 (m, 2H), 7.32-7.46 (m, 4
H), 7.50-7.54 (m, 2H)

Example 127 1- (Amino- {3- [1- (2-fluoro-biphenyl)
Ru-4-yl) -ethyl] -isoxazol-5-yl
Imino {-methyl) -piperidin-4-ol

Embedded image Using the compound obtained in Example 119, the desired product was obtained in the same manner as in Example 48. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.50-1.64 (m, 3H), 1.65 (d, 3H, J = 7.1Hz), 1.81-1.94
(m, 2H), 3.18-3.28 (m, 2H), 3.81-3.96 (m, 3H), 4.14
(q, 1H, J = 7.1Hz), 5.22 (s, 1H), 5.34 (br-s, 2H), 7.0
7-7.17 (m, 2H), 7.33-7.45 (m, 4H), 7.50-7.54 (m, 2H)

Example 128 N- {3- [1- (2-Fluoro-biphenyl-4-i)
Ru) -ethyl] -isoxazol-5-yl} -N'-
Hydroxy-guanidine

Embedded image Using the compound obtained in Example 120, the desired product was obtained in the same manner as in Example 48. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.63 (d, 3H, J = 7.1Hz), 4.12 (q, 1H, J = 7.1Hz), 5.34 (s,
1H), 5.59 (br-s, 2H), 7.04-7.12 (m, 2H), 7.33-7.45
(m, 6H), 7.49-7.54 (m, 2H)

Example 129 N- {3- [1- (2-Fluoro-biphenyl-4-i)
Ru) -ethyl] -isoxazol-5-yl} -N'-
Methoxy-guanidine

Embedded image Using the compound obtained in Example 121, the desired product was obtained in the same manner as in Example 48. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.65 (d, 3H, J = 7.1Hz), 3.73 (s, 3H), 4.14 (q, 1H, J = 7.
1Hz), 5.32 (br-s, 2H), 5.41 (s, 1H), 7.06-7.15 (m, 2
H), 7.32-7.46 (m, 4H), 7.50-7.54 (m, 2H)

Example 130N- (2-dimethylamino-ethyl) -N '-{3-
[1- (2-Fluoro-biphenyl-4-yl) -ethyl]
] -Isoxazol-5-yl} -guanidine

Embedded image Using the compound obtained in Example 122, the desired product was obtained in the same manner as in Example 48. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.65 (d, 3H, J = 7.1Hz), 2.29 (s, 6H), 2.50-2.55 (m, 2
H), 3.26-3.32 (m, 2H), 4.14 (q, 1H, J = 7.1Hz), 5.19
(s, 1H), 5.98 (br-s, 1H), 6.34 (br-s, 1H), 7.07-7.17
(m, 2H), 7.33-7.46 (m, 4H), 7.50-7.54 (m, 2H)

[0297] Example 131[(3- {1-methyl-1- [3- (2-phenyl-
[1,3] dioxolan-2-yl) -phenyl] -d
Tyl {-isoxazol-5-ylimino) -morpholy
4-N-yl-methyl] -amine

Embedded image Using the compound obtained in Reference Example 53, the desired product was obtained in the same manner as in Example 54. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.66 (s, 6H), 3.44-3.48 (m, 4H), 3.70-3.73 (m, 4H),
4.05 (s, 4H), 5.07 (s, 1H), 5.31 (br-s, 2H), 7.20-7.3
5 (m, 6H), 7.47-7.58 (m, 3H)

Example 132 (3- {1- [5- (amino-morpholin-4-yl-
Methyleneamino) -isoxazol-3-yl] -1-
Methyl-ethyl {-phenyl) -phenyl-methanone

Embedded image 90% of the compound (8.8 mg) obtained in Example 131
It was dissolved in aqueous acetic acid (2 ml) and stirred for 40 hours. The reaction solution was extracted with ethyl acetate, washed with saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the desired product (8.3 mg). ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.72 (s, 6H), 3.46-3.50 (m, 4H), 3.70-3.74 (m, 4H),
5.14 (s, 1H), 5.39 (br-s, 2H), 7.35-7.61 (m, 6H), 7.7
6-7.84 (m, 3H)

Example 133 (Morpholin-4-yl- {3- [1- (6-phenyl)
-Pyridin-3-yl) -ethyl] -isoxazole-
5-ylimino {-methyl) -amine

Embedded image Using the compound obtained in Reference Example 55, the desired product was obtained in the same manner as in Example 54. ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.69 (d, 3H, J = 7.3Hz), 3.48 (t, 4H, J = 5.0Hz), 3.72
(t, 4H, J = 5.0Hz), 4.18 (q, 1H, J = 7.3Hz), 5.23 (s, 1
H), 5.36 (br-s, 2H), 7.39-7.50 (m, 3H), 7.67 (m, 2H),
7.95 (dd, 2H, J = 8.3, 1.7Hz), 8.64 (s, 1H)

Example 134 (morpholin-4-yl- {3- [1- (5-phenyl)
-Pyridin-2-yl) -ethyl] -isoxazole-
5-ylimino {-methyl) -amine

Embedded image Using the compound obtained in Reference Example 57, the desired product was obtained in the same manner as in Example 54. ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.74 (d, 3H, J = 7.3Hz), 3.48 (t, 4H, J = 5.3Hz), 3.72
(t, 4H, J = 5.3Hz), 4.34 (q, 1H, J = 7.3Hz), 5.20-5.45
(m, 3H), 7.32-7.57 (m, 6H), 7.80 (dd, 1H, J = 7.9, 2.3
Hz,), 8.78 (d, 1H, J = 2.3Hz)

Example 135 (3- {1- [5- (amino-morpholin-4-yl-
Methyleneamino) -isoxazol-3-yl] -1-
Methyl-ethyl {-phenyl) -phenyl-methanone
Oxime

Embedded image Using the compound obtained in Reference Example 58, the desired product was obtained in the same manner as in Example 54. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.66 (s, 4.8H), 1.69 (s, 1.2H), 3.45-3.49 (m, 4H),
3.69-3.74 (m, 4H), 5.12 (s, 0.8H), 5.15 (s, 0.2H), 5.
38 (br-s, 2H), 7.09-7.46 (m, 9H), 7.64 (br-s, 1H)

Example 136 (3- {1- [5- (amino-morpholin-4-yl-
Methyleneamino) -isoxazol-3-yl] -1-
Methyl-ethyl {-phenyl) -phenyl-methanone
Methanesulfonate

Embedded image To a solution of the compound (1.06 g) obtained in Example 135 in tetrahydrofuran (5 ml) was added 3N hydrochloric acid (15 ml).
Was added and stirred for 60 hours. The reaction mixture was basified by adding saturated aqueous layer water, extracted with ethyl acetate, washed with saturated saline, dried over sodium sulfate, and concentrated under reduced pressure.
The residue was dissolved in 1,4-dioxane (20 ml), methanesulfonic acid (0.17 ml) was added, and the mixture was stirred for 30 minutes. After concentrating the reaction solution, the residue was recrystallized from toluene to obtain the desired product (0.79 g). ¹ H-NMR (300 MHz, CD ₃ OD) δ ppm:
1.75 (s, 6H), 2.68 (s, 3H), 3.55-3.59 (m, 4H), 3.74-
3.78 (m, 4H), 5.86 (s, 1H), 7.49-7.76 (m, 9H)

[0303] Example 137(Tert-butoxycarbonyl)-[{3- [1-
(2-Fluoro-biphenyl-4-yl) -ethyl]-
Isoxazol-5-ylimino}-(1-oxo-
[1,4] thiazin-4-yl) -methyl] -amine

Embedded image The compound (2.55 g) obtained in Example 117 was dissolved in chloroform (20 ml), and sodium hydrogencarbonate (0.8
4 g), and added with meta-chloroperbenzoic acid (1.3 under ice cooling).
0 g) and stirred for 30 minutes under ice-cooling. A saturated aqueous solution of sodium hydrogen carbonate (20 ml) was added, and excess peroxide was crushed with sodium sulfite, followed by extraction with chloroform.
The extract was washed with a saturated aqueous sodium hydrogen carbonate solution and dried. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the desired product (2.62 g). ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.44 (s, 9H), 1.67 (d, 3H, J = 7.3Hz), 2.81-2.99 (m, 4
H), 3.95-4.22 (m, 5H), 5.33 (s, 1H), 7.06-7.17 (m, 3
H), 7.31-7.48 (m, 4H), 7.49-7.54 (m, 2H)

Example 138 (tert-Butoxycarbonyl)-((1,1-dio)
Oxo- [1,4] thiazin-4-yl)-{3- [1
-(2-Fluoro-biphenyl-4-yl) -ethyl]
-Isoxazol-5-ylimino} -methyl) -amido
N

Embedded image The compound (2.55 g) obtained in Example 117 was dissolved in chloroform (20 ml), and sodium hydrogencarbonate (0.8
4g), and add metachloroperbenzoic acid (1.30 at room temperature).
g) was added and the mixture was stirred at room temperature for 1.5 hours. A saturated aqueous solution of sodium hydrogen carbonate (20 ml) was added, and excess peroxide was crushed with sodium sulfite, followed by extraction with chloroform.
The extract was washed with a saturated aqueous sodium hydrogen carbonate solution and dried. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the desired product (1.29 g). ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.44 (s, 9H), 1.67 (d, 3H, J = 7.1Hz), 3.15-3.21 (m, 4
H), 4.00-4.07 (m, 4H), 4.18 (q, 1H, J = 7.1Hz), 5.38
(s, 1H), 7.04-7.17 (m, 2H), 7.22 (br, 1H), 7.32-7.47
(m, 4H), 7.48-7.54 (m, 2H)

Example 139 N- (tert-butoxycarbonyl) -N ′-{3-
[1- (2-Fluoro-biphenyl-4-yl) -ethyl]
] -Isoxazol-5-yl} -N "-pyridine-
3-ylmethyl-guanidine

Embedded image The desired product was obtained in the same manner as in Example 1. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.48 (s, 9H), 1.67 (d, 3H, J = 7.3Hz), 4.14 (q, 1H, J =
7.3Hz), 4.57 (d, 2H, J = 5.7Hz), 5.35 (s, 1H), 7.07-7.
17 (m, 2H), 7.24-7.29 (m, 1H), 7.32-7.45 (m, 4H), 7.5
0-7.54 (m, 2H), 7.64-7.71 (m, 1H), 8.41 (br, 1H), 8.5
0-8.54 (m, 1H), 8.57-8.61 (m, 2H),

Example 140[{3- [1- (2-fluoro-biphenyl-4-i)
Ru) -ethyl] -isoxazol-5-ylimino}-
(1-oxo- [1,4] thiazin-4-yl) -me
Tyl] -amine

Embedded image Using the compound obtained in Example 137, the desired product was obtained in the same manner as in Example 48. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.68 (d, 3H, J = 7.1Hz), 2.80 (t, 4H, J = 5.0Hz), 4.02-4.
10 (m, 4H), 4.15 (q, 1H, J = 7.1Hz), 5.28 (s, 1H), 5.45
(br, 2H), 7.07-7.17 (m, 2H), 7.33-7.46 (m, 4H), 7.50
-7.54 (m, 2H)

Example 141 ((1,1-dioxo- [1,4] thiazinan-4-i
)-{3- [1- (2-fluoro-biphenyl-4-)
Yl) -ethyl] -isoxazol-5-ylimino}
-Methyl) -amine

Embedded image Using the compound obtained in Example 138, the desired product was obtained in the same manner as in Example 48. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.67 (d, 3H, J = 7.1Hz), 3.10 (t, 4H, J = 5.2Hz), 4.00 (t,
4H, J = 5.2Hz), 4.16 (q, 1H, J = 7.1Hz), 5.33 (s, 1H),
5.48 (br, 2H), 7.06-7.17 (m, 2H), 7.33-7.46 (m, 4H),
7.50-7.54 (m, 2H)

Example 142 N- {3- [1- (2-Fluoro-biphenyl-4-i)
Ru) -ethyl] -isoxazol-5-yl} -N'-
Pyridin-3-ylmethyl-guanidine

Embedded image Using the compound obtained in Example 139, the desired product was obtained in the same manner as in Example 48. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.63 (d, 3H, J = 7.1Hz), 4.11 (q, 1H, J = 7.1Hz), 4.46 (d,
2H, J = 4.4Hz), 5.25 (s, 1H), 5.48 (br, 2H), 5.71 (br,
1H), 7.04-7.14 (m, 2H), 7.21-7.25 (m, 1H), 7.32-7.4
6 (m, 4H), 7.49-7.53 (m, 2H), 7.65 (d, 1H, J = 7.9Hz),
8.44-8.49 (m, 2H)

[0309] Reference Example 11- {3- [1- (2-fluoro-biphenyl-4-i
Ru) -ethyl] -isoxazol-5-yl} -2-me
Cyl-isothiourea

[Formula 169] 3- [1- (2-fluoro-biphenyl-4-yl)-
Ethyl] -isoxazol-5-yl-thiourea (JP-A-63-152368) (3.03 g) was dissolved in N, N-dimethylformamide (90 ml), and methyl iodide (1.
51g) and potassium carbonate (0.86g).
The mixture was heated and stirred at 0 ° C. for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the desired product (2.67 g). ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.67 (d, 3H, J = 7.2Hz), 2.44 (s, 3H), 4.17 (q, 1H, J = 7.
2Hz), 5.50 (s, 1H), 5.92 (br-s, 2H), 7.06-7.15 (m, 2
H), 7.32-7.54 (m, 6H)

[0310] Reference Example 21- (tert-butoxycarbonyl) -3- {3-
[1- (2-Fluoro-biphenyl-4-yl) -ethyl]
] -Isoxazol-5-yl} -2-methyl-iso
Thiourea

[Formula 170] 60% sodium hydride (4.22 g) was suspended in tetrahydrofuran (80 ml), and the compound (25.0 g) obtained in Reference Example 1 (25.0 g) was suspended in ice under ice cooling.
l) The solution was added dropwise and then tert-butyl azide formate (Organic Syntheses Coll. Vol. 5, John Wiley and
Sons, Inc., New York (1973), p 157) (15.1 g)
Of tetrahydrofuran (50 ml) was slowly added dropwise over 65 minutes, and the mixture was returned to room temperature under ice cooling for 1 hour and stirred overnight. Water was added to the reaction solution, extracted with diethyl ether,
The extract was washed with water and dried. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the desired product (21.1 g). 124-126 ° C (decomposition) ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.49 (s, 9H), 1.68 (d, 3H, J = 7.1Hz), 2.37 (s, 3H), 4.
18 (q, 1H, J = 7.1Hz), 5.63 (s, 1H), 7.06-7.15 (m, 2H),
7.35-7.53 (m, 6H), 8.93 (br-s, 1H) IR (KBr) [cm ^-1 ]: 3382, 2980, 1750, 1588

Reference Example 3 3-benzoyl-1- {3- [1- (2-fluoro-bi
Phenyl-4-yl) -ethyl] -isoxazole-5
-Yl} -1-methyl-thiourea

Embedded image {3- [1- (2-Fluoro-biphenyl-4-yl)]
-Ethyl] -isoxazol-5-yl} -methyl-amine (4.06 g), pyridine (40 ml) and benzoylisothiocyanate (2.5 g) were stirred overnight at room temperature. After concentration, the residue was purified by silica gel chromatography to obtain the desired product (5.28 g). 115-116 ° C ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.59 (d, 3H, J = 7.3Hz), 3.79 (s, 3H), 4.14 (q, 1H, J = 7.
3Hz), 5.83 (s, 1H), 6.92-6.97 (m, 2H), 7.16 (t, 1H, J
= 8.2Hz), 7.34-7.52 (m, 8H), 7.68-7.73 (m, 2H), 8.79
(s, 1H) IR (KBr) [cm ^-1 ]: 3440, 3275, 3125, 2980,
1690, 1612, 1515, 1488, 1424, 1360, 1266, 1230, 11
68

Reference Example 4 3-benzoyl-1- {3- [1- (2-fluoro-bi
Phenyl-4-yl) -ethyl] -isoxazole-5
-Yl} -1,2-dimethyl-isothiourea

Embedded image To a solution of 5.22 g of the compound obtained in Reference Example 3 in N, N-dimethylformamide (60 ml) was added potassium carbonate (4.1).
g) and methyl iodide (1.25 ml).
Stirred for hours. The reaction solution was diluted with ethyl acetate, water was added, and liquid separation extraction was performed. Purification by silica gel column chromatography gave the desired product (4.87 g). 124-126 ° C (decomposition) ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.66 (d, 3H, J = 7.3Hz), 2.28 (s, 3H), 3.56 (s, 3H), 4.1
9 (q, 1H, J = 7.3Hz), 6.06 (s, 1H), 7.00-7.10 (m, 2H),
7.33-7.52 (m, 9H), 9.03 (d, 2H, J = 7.7Hz)

Reference Example 5 5- (2-fluoro-biphenyl-4-yl) -2-h
Ethyl droxy-4-oxo-hex-2-enoate
Steal

Embedded image 3- (2-Fluoro-biphenyl-4-yl) -butan-2-one (JP-A-54-144347) (116 mg) was dissolved in toluene (2 ml), and the solution was dissolved in 60% sodium hydride (2%).
9 mg), and stirred at room temperature for 1 hour. Then, diethyl oxalate (105 mg) was added, and the mixture was heated and stirred at 40 ° C. for 3 hours. Water was added to the reaction solution, extracted with ethyl acetate, and the extract was washed with water and dried. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the desired compound (16).
3 mg). ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.35 (t, 3H, J = 7.2Hz), 1.54 (d, 3H, J = 7.1Hz), 3.86 (q,
1H, J = 7.1Hz), 4.32 (q, 2H, J = 7.2Hz), 6.37 (s, 1H),
7.04-7.12 (m, 2H), 7.31-7.55 (m, 7H) IR (KBr) [cm ^-1 ]: 2925, 1734, 1636, 1484

Reference Example 6 5- [1- (2-fluoro-biphenyl-4-yl)-
Ethyl] -isoxazole-3-carboxylate
Tell

Embedded image The compound (163 mg) obtained in Reference Example 5 and hydroxylamine hydrochloride (40 mg) were dissolved in ethanol (2 ml), and the mixture was heated and stirred at 60 ° C. for 9 hours. Water was added to the reaction solution, extracted with ethyl acetate, and the extract was washed with water and dried. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the desired product (143 mg). ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.41 (t, 3H, J = 7.1Hz), 1.73 (d, 3H, J = 7.3Hz), 4.34 (q,
1H, J = 7.3Hz), 4.43 (q, 2H, J = 7.1Hz), 6.45 (s, 1H),
7.02-7.12 (m, 2H), 7.33-7.55 (m, 6H) IR (KBr) [cm ^-1 ]: 2983, 1733, 1625, 1584,
1484, 1418

Reference Example 7 {5- [1- (2-fluoro-biphenyl-4-yl)
-Ethyl] -isoxazol-3-yl} -methanol

Embedded image The compound (2.45 g) obtained in Reference Example 6 was dissolved in tetrahydrofuran (20 ml), lithium aluminum hydride (300 mg) was added at 0 ° C, and the mixture was stirred for 1.5 hours.
Water was added to the reaction solution, methylene chloride extraction was performed, and the extract was washed with water and dried. The solvent was distilled off under reduced pressure, and the residue was recrystallized from methylene chloride to obtain the desired product (2.09 g). Melting point: 127 to 127.5 ° C. ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.70 (d, 3H, 7.3Hz), 4.28 (q, 1H, J = 7.3Hz), 4.74 (s,
2H), 6.09 (s, 1H), 7.03-7.13 (m, 2H), 7.33-7.55 (m, 6
H) IR (KBr) [cm ^-1 ]: 3308, 1603, 1485, 1418 Elemental analysis [%]: Calculated: C, 72.71; H, 5.42; N 4.7
1, found: C, 72.61; H, 5.45; N, 4.88

Reference Example 8 3-bromomethyl-5- [1- (2-fluoro-biphene)
Nil-4-yl) -ethyl] -isoxazole

Embedded image The compound (2.03 g) obtained in Reference Example 7 was dissolved in methylene chloride (80 ml), carbon tetrabromide (3.40 g) and triphenylphosphine (2.69 g) were added, and the mixture was stirred for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with methylene chloride. The extract was washed with water and dried. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the desired product (6.83 g). Melting point: 102 to 103 ° C. ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.71 (d, 3H, J = 7.3Hz), 4.27 (q, 1H, J = 7.3Hz), 4.39 (s,
2H), 6.12 (d, 1H, J = 0.7Hz), 7.03-7.13 (m, 2H), 7.33
-7.55 (m, 6H) IR (KBr) [cm ^-1 ]: 1600, 1484, 1417 Elemental analysis: Calculated: C, 60.02; H, 4.20; N: 3.89, Found: C, 59.86; H, 4.17 ; N, 4.04

Reference Example 9 3-azidomethyl-5- [1- (2-fluoro-biphe
Nil-4-yl) -ethyl] -isoxazole

Embedded image Compound (2.08 g) obtained in Reference Example 8 and sodium azide (749 mg) were added to N, N-dimethylformamide (2
0 ml) and stirred with heating at 50 ° C for 3 hours. Water was added to the reaction solution, extracted with ethyl acetate, and the extract was washed with water and dried. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the desired product (1.85 g).
I got ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.71 (d, 3H, J = 7.3Hz), 4.28 (q, 1H, J = 7.3Hz), 4.39 (s,
2H), 6.07 (s, 1H), 7.02-7.12 (m, 2H), 7.33-7.55 (m,
6H) IR (neat) [cm ^-1 ]: 2978, 2933, 2104, 159
6, 1485 Elemental analysis: Calcd: C, 67.07; H, 4.69; N, 17.38, Found: C, 66.93; H, 4.78; N, 17.56

Reference Example 10 {5- [1- (2-fluoro-biphenyl-4-yl)]
-Ethyl] -isoxazol-3-ylmethyl} -amido
N

Embedded image The compound (1.82 g) obtained in Reference Example 9 was dissolved in tetrahydrofuran (15 ml), sodium borohydride (641 mg) was added, and the mixture was heated and stirred under reflux conditions. Methanol (3 ml) was added dropwise over 1 hour, and after stirring for 3 hours, the temperature was returned to room temperature, a 1N-HCl aqueous solution (6 ml) was added, and the mixture was separated. Extracted with methylene chloride to pH 11,
The extract was washed with water and dried. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the desired product (1.13 g). ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.70 (d, 3H, J = 7.2Hz), 3.91 (s, 2H), 4.26 (q, 1H, J = 7.
2Hz), 6.01 (s, 1H), 7.03-7.13 (m, 2H), 7.33-7.55 (m,
6H)

Reference Example 11 N ′, N ″ -di- (tert-butoxycarbonyl)-
N, N-dimethylguanidine

Embedded image 1,3-di- (tert-butoxycarbonyl) -2-
Methyl-isothiourea (JP-A 2-3661) (3.00)
g) was dissolved in a 50% aqueous dimethylamine solution (40 ml) and stirred at room temperature for 18 hours. The solvent was distilled off from the reaction solution under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the desired product (2.58 g). ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.50 (s, 18H), 3.07 (s, 6H)

[0320] Reference Example 12 (tert-butoxycarbonyl)-[(tert-butyl
Toxicarbonyl) -imino-piperidin-1-yl-
Methyl] -amine

[Formula 180] The desired product was obtained in the same manner as in Reference Example 11. ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.49 (s, 18H), 1.64 (br-s, 6H), 3.52 (br-s, 4H), 10.1
3 (br-s, 1H) Elemental analysis: Calcd: C, 58.69; H, 8.93; N, 12.83, Found: C, 58.46; H, 8.86; N, 12.79

Reference Example 13 (tert-butoxycarbonyl)-[(tert-butyl
Toxicarbonyl) -imino-morpholin-4-yl-
Methyl] -amine

Embedded image The desired product was obtained in the same manner as in Reference Example 11. ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.48 (s, 9H), 1.50 (s, 9H), 3.59 (br-s, 4H), 3.72-3.7
6 (m, 4H), 10.21 (br-s, 1H)

Reference Example 14 1,3-Di- (tert-butoxycarbonyl) -1,
2-dimethyl-isothiourea

Embedded image 1,3-di- (tert-butoxycarbonyl) -2-
Methyl-isothiourea (JP-A-2-6611) (2.00
g) was dissolved in N, N-dimethylformamide (20 ml), and 60% sodium hydride (331 mg) was added.
The mixture was heated and stirred at 50 ° C. for 2 hours. After cooling to 0 ° C., methyl iodide (1.96 g) was added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, extracted with ethyl acetate, and the extract was washed with water and dried. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the desired product (2.07).
g) was obtained. ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.48 (s, 9H), 1.51 (s, 9H), 2.39 (s, 3H), 3.12 (s, 3H) IR (neat) [cm ^-1 ]: 2979, 1720, 1624 Elemental analysis: Calculated: C, 51.29; H, 7.95; N, 9.20, Found: C, 51.06; H, 8.08; N, 9.31.

Reference Example 15 [1,3-di- (tert-butoxycarbonyl) -2
-Methyl-isothioureido] -acetic acid ethyl ester

Embedded image The desired product was obtained in the same manner as in Reference Example 14. ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.29 (t, 3H, J = 7.1Hz), 1.48 (s, 9H), 1.51 (s, 9H), 2.4
5 (s, 3H), 4.22 (q, 2H, J = 7.1Hz), 4.30 (s, 2H) IR (neat) [cm ^-1 ]: 2981, 1725, 1615, 136
9, 1315 Elemental analysis: Calcd: C, 51.05; H, 7.50; N, 7.44, Found: C, 50.76; H, 7.56; N, 7.50

Reference Example 16 1- {3- [1- (4-isobutyl-phenyl) -ethyl]
] -Isoxazol-5-yl} -2-methyl-iso
Thiourea

Embedded image Under a nitrogen atmosphere, 2- (4-isobutyl-phenyl) -propionic acid (15.0 g) was added to ethanol (200 ml).
And concentrated sulfuric acid (1 ml) was added thereto, followed by stirring under heating and refluxing for 15 hours. After cooling the reaction solution to room temperature, it was concentrated under reduced pressure.
After dilution with ethyl acetate, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate. After extraction with ethyl acetate, the organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain ethyl 2- (4-isobutyl-phenyl) -propionate. Sodium hydride (4.
34 g, 60% oily) in tetrahydrofuran (100
After addition of the ester (approximately 17.
0g) and acetonitrile (7.56 ml) were dissolved in tetrahydrofuran (150 ml) and added dropwise over 1 hour. After stirring for 6 hours while heating under reflux, the mixture was cooled to room temperature, a small amount of water was added, and the mixture was diluted with ethyl acetate and saturated aqueous sodium hydrogen carbonate was added. After extraction with ethyl acetate, the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified from hexane by a recrystallization method to obtain 4- (4-isobutyl-phenyl) -3-oxo-pentanitrile (10.2 g). After dissolving the cyanoketone (10.2 g) in ethanol (150 ml), pyridine (30 ml) and hydroxylamine hydrochloride (6.17 g) were added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer is dried over sodium sulfate and concentrated under reduced pressure to give 3- [1- (4-isobutyl-phenyl) -ethyl] -isoxazole-5.
-Ylamine (11.35 g) was obtained. This isoxazole (11.35 g) was mixed with ethylene dichloride (200 m
l) and benzoyl isothiocyanate (11.
9 ml) and stirred at 60 ° C. for 5 hours. The reaction solution was concentrated under reduced pressure, a small amount of water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure.
The residue was isolated by silica gel chromatography (hexane / ethyl acetate = 2/1), and then purified by recrystallization from toluene to give 1-benzoyl-3- {3- [1- (4-isobutyl-phenyl)-]. Ethyl] -isoxazole-5
-Ill-thiourea (4.65 g) was obtained. This thiourea (4.65 g) was added to tetrahydrofuran (50 m
l), methanol (50 ml) and potassium carbonate (3.15 g) were added, and the mixture was stirred at 50 ° C for 5 hours. After adding a small amount of water to the reaction solution, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate and concentrated under reduced pressure to give 3- [1- (4-isobutyl-phenyl)-.
Ethyl] -isoxazol-5-yl-thiourea (1
5.52 g). Reference Example 1 using this thiourea
The desired product was obtained by the same operation method as in. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
0.89 (d, 6H, J = 6.6Hz), 1.63 (d, 3H, J = 7.3Hz), 1.83
(m, 1H), 2.43 (d, 2H, J = 6.1Hz), 2.44 (s, 3H), 4.11
(q, 1H, J = 7.2Hz), 5.45 (s, 1H), 5.91 (br-s, 2H), 7.0
6-7.09 (m, 2H), 7.17-7.20 (m, 2H)

Reference Example 17 1- {3- [1- (6-Methoxy-naphthalene-2-i)
Ru) -ethyl] -isoxazol-5-yl} -2-me
Cyl-isothiourea

Embedded image Using 2- (6-methoxy-naphthalen-2-yl) -propionic acid, the desired product was obtained in the same manner as in Reference Example 16. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.72 (d, 3H, J = 7.2Hz), 2.42 (s, 3H), 3.91 (s, 3H), 4.
27 (q, 1H, J = 7.2Hz), 5.46 (s, 1H), 5.90 (br-s, 2H), 7.
10-7.15 (m, 2H), 7.37 (dd, 1H, J = 8.4, 1.8Hz), 7.65-
7.71 (m, 3H)

Reference Example 18 1- (tert-butylcarbonyl) -3- {3- [1
-(4-isobutyl-phenyl) -ethyl] -isoxa
Zol-5-yl {-2-methyl-isothiourea

[Formula 186] Using the compound obtained in Reference Example 16, the desired product was obtained in the same manner as in Reference Example 2. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
0.89 (d, 6H, J = 6.6Hz), 1.50 (s, 9H), 1.65 (d, 3H, J =
7.3Hz), 1.84 (m ,, 1H, J = 6.6Hz), 2.36 (s, 3H), 2.44 (d,
2H, J = 7.1Hz), 4.12 (q, 1H, J = 7.3Hz), 5.58 (s, 1H),
7.08-7.11 (m, 2H), 7.17-7.20 (m, 2H), 8.95 (br-s, 1H)

[0327] Reference Example 191- (tert-butoxycarbonyl) -3- {3-
[1- (6-Methoxy-naphthalen-2-yl) -ethyl]
] -Isoxazol-5-yl} -2-methyl-iso
Thiourea

Embedded image Using the compound obtained in Reference Example 17, the desired product was obtained in the same manner as in Reference Example 2. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.50 (s, 9H), 1.74 (d, 3H, J = 7.2Hz), 2.34 (s, 3H), 3.
91 (s, 3H), 4.29 (q, 1H, J = 7.3Hz), 5.59 (s, 1H), 7.10
-7.16 (m, 2H), 7.36 (dd, 1H, J = 8.4, 1.6Hz), 7.65 (s,
1H), 7.68-7.71 (m, 2H), 8.95 (br-s, 1H)

Reference Example 20 3- [1- (2-Fluoro-biphenyl-4-yl)-
1-methyl-ethyl] -isoxazol-5-ylami
N

Embedded image Under a nitrogen atmosphere, 2- (2-fluoro-biphenyl-4-
Yl) -propionic acid (15.0 g) was dissolved in N, N-dimethylformamide (150 ml), sodium hydride (6.14 g, 60% oily) was added, and the mixture was stirred for 1 hour. Subsequently, iodomethane (9.5 ml) was added and 12
Stirred for hours. After adding a small amount of water to the reaction solution, the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified from hexane by a recrystallization method.
-(2-Fluoro-biphenyl-4-yl) -2-methyl-propionic acid methyl ester (14.2 g) was obtained. After adding tetrahydrofuran (100 ml) to sodium hydride (2.70 g, 60% oily), the ester (12.2 g) and acetonitrile (4.66 ml) were added to tetrahydrofuran (100 ml) under reflux with heating.
And added dropwise over 1 hour. After stirring for 8 hours while heating under reflux, the mixture was cooled to room temperature, a small amount of water was added, and the mixture was diluted with ethyl acetate and saturated aqueous sodium hydrogen carbonate was added. After extraction with ethyl acetate, the organic layer was dried over sodium sulfate and concentrated under reduced pressure.
The residue was purified from ethanol by a recrystallization method to obtain 4- (2-fluoro-biphenyl-4-yl) -4-methyl-3-oxo-pentanitrile (6.27 g). After dissolving the cyanoketone (9.98 g) in ethanol (200 ml), pyridine (40 ml) and hydroxylamine hydrochloride (2.47 g) were added, and the mixture was stirred at 50 ° C. for 5 hours. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by recrystallization from ethanol to obtain the desired product (7.00 g). ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.69 (s, 6H), 4.37 (br-s, 2H), 4.86 (s, 1H), 7.10-7.3
4 (m, 2H), 7.32-7.46 (m, 4H), 7.50-7.55 (m, 2H)

Reference Example 21 3- [1-ethoxy-1- (2-fluoro-biphenyl)
-4-yl) -ethyl] -isoxazol-5-ylua
Min

Embedded image Under a nitrogen atmosphere, 2- (2-fluoro-biphenyl-4-
Yl) -2-hydroxy-propionic acid ethyl ester (JP-A-52-105144) (15.0 g) was converted to N, N
-Dissolved in dimethylformamide (300 ml), added sodium hydride (4.16 g, 60% oily) under ice cooling, and stirred for 1 hour. Then iodoethane (10.4
ml) and stirred for 12 hours. After adding a small amount of water and ethanol to the reaction solution, the solvent was azeotropically removed with toluene. After adding ethyl acetate to the residue, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain ethyl 2-ethoxy-2- (2-fluoro-biphenyl-4-yl) -propionate. Sodium hydride (4.16 g, 60%
Oily), tetrahydrofuran (100 ml) was added, and this ester and acetonitrile (5.4) were heated under reflux.
3 ml) was dissolved in tetrahydrofuran (200 ml) and added dropwise over 1 hour. After stirring for 4 hours while heating under reflux, the mixture was cooled to room temperature, a small amount of ethanol was added, and the mixture was diluted with ethyl acetate and saturated aqueous sodium hydrogen carbonate was added. After extraction with ethyl acetate, the organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain a cyanoketone derivative, 4-ethoxy-4- (2-fluoro-biphenyl-4-yl) -3-oxo-pentanenitrile. This cyanoketone is converted to ethanol (300
pyridine (60 ml) and hydroxylamine hydrochloride (5.42 g) were added, and the mixture was stirred at 50 ° C. for 5 hours. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, neutralized with aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (hexane / ethyl acetate = 3 /
Purification in 1) gave the desired product (11.3 g). ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.26 (t, 3H, J = 7.0Hz), 1.86 (s, 3H), 3.35-3.60 (m, 2
H), 4.39 (br-s, 2H), 5.03 (s, 1H), 7.25-7.46 (m, 6H),
7.51-7.55 (m, 2H)

Reference Example 22 3- [1- (2-Fluoro-biphenyl-4-yl)-
Cyclopropyl] -isoxazol-5-ylamine

Embedded image Under a nitrogen atmosphere, (2-fluoro-biphenyl-4-yl) -acetic acid methyl ester (5.0 g) was dissolved in tetrahydrofuran (50 ml), and sodium hydride (8.29 g, 60% oil) was added under ice cooling. Stir for 30 minutes. Subsequently, N, N-dimethylformamide (100 m
l), 1,2-dibromoethane (17.6 m
l) was added and stirred for 1.5 hours. 4N hydrochloric acid-
After adding a 1,4-dioxane solution (60 ml), the mixture was neutralized with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure.
The residue was purified by silica gel chromatography (hexane / ethyl acetate = 20/1) to obtain 1- (2-fluoro-biphenyl-4-yl) -cyclopropanecarboxylic acid methyl ester (4.28 g). From this ester, the target product was obtained in the same manner as in the latter half of Reference Example 20. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.30 (q, 2H, J = 3.7Hz), 1.48 (q, 2H, J = 3.7Hz), 4.34 (br
-s, 2H), 4.88 (s, 1H), 7.13-7.23 (m, 2H), 7.35-7.47
(m, 4H), 7.52-7.55 (m, 2H)

Reference Example 23 3- (1-Biphenyl-4-yl-ethyl) -isoxa
Zol-5-ylamine

Embedded image After performing monomethylation using 4-biphenyl-acetoacetic acid ethyl ester, the target product was obtained via the corresponding cyanoketone by the same operating method as in the latter half of Reference Example 20. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.65 (d, 3H, J = 7.3Hz), 4.12 (q, 1H, J = 7.3Hz), 4.40 (s,
2H), 4.92 (s, 1H), 7.30-7.45 (m, 5H), 7.52-7.59 (m,
4H)

[0332] Reference Example 243- (1-biphenyl-4-yl-1-methyl-ethyl
Ru) -isoxazol-5-ylamine

Embedded image After dimethylation using 4-biphenyl-acetoacetic acid ethyl ester, the target compound was obtained via the corresponding cyanoketone in the same manner as in the latter half of Reference Example 20. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.70 (s, 6H), 4.32 (s, 2H), 4.84 (s, 1H), 7.33-7.59
(m, 9H)

Reference Example 25 3- [1- (3-phenoxy-phenyl) -ethyl]-
Isoxazol-5-ylamine

[Chemical Formula 193] Using calcium 2- (3-phenoxy-phenyl) -propionate and the corresponding ester in the same manner as in the latter half of Reference Example 20, followed by the cyanoketone, the desired product was obtained. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.59 (d, 3H, J = 7.1Hz), 4.12 (q, 1H, J = 7.1Hz), 4.41 (br
-s, 2H), 4.87 (s, 1H), 6.81-6.86 (m, 1H), 6.96-7.11
(m, 5H), 7.21-7.36 (m, 3H)

Reference Example 26 (R) -3- [1- (2-Fluoro-biphenyl-4-)
Yl) -ethyl] -isoxazol-5-ylamine

Embedded image Sodium hydride (160m
g, 60% oily) in tetrahydrofuran (5 m
To 1), tert-butyl cyanoacetate (0.57 ml) was added dropwise with stirring. After stirring for 10 minutes under ice-cooling, the mixture was stirred at room temperature for 20 minutes and again at 0 ° C. On the other hand, (R)-
A solution of 2- (2-fluoro-biphenyl-4-yl) -propionic acid (449 mg, 93% ee) and N-methylmorpholine (0.22 ml) in tetrahydrofuran (2
0 ml), isobutyl chloroformate (0.
26 ml) was added dropwise. After 5 minutes, the solution was added dropwise to the cyanoacetic acid tert-butyl ester solution. Twenty minutes later, the mixture was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained viscous residue was added with hydroxylamine hydrochloride (278 m
g) and ethanol (10 ml).
Stirred for hours. After cooling to room temperature, ethanol was distilled off, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel (hexane / ethyl acetate =
3/2) to purify the desired product (226 mg, 93% ee)
I got ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.63 (d, 3H, J = 7.1Hz), 4.09 (q, 1H, J = 7.1Hz), 4.46 (br
-s, 2H), 4.91 (s, 1H), 7.05-7.18 (m, 2H), 7.31-7.47
(m, 4H), 7.50-7.76 (m, 2H)

Reference Example 27 (S) -3- [1- (2-Fluoro-biphenyl-4-)
Yl) -ethyl] -isoxazol-5-ylamine

Embedded image (S) -2- (2-fluoro-biphenyl-4-yl)
Using -propionic acid, the desired product was obtained in the same manner as in Reference Example 26. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.61 (d, 3H, J = 7.1Hz), 4.08 (q, 1H, J = 7.1Hz), 4.55 (br
-s, 2H), 4.89 (s, 1H), 7.05-7.17 (m, 2H), 7.31-7.44
(m, 4H), 7.50-7.76 (m, 2H)

Reference Example 28 3-Biphenyl-4-ylmethyl-isoxazole-5
-Ylamine

Embedded image Using 4-biphenyl-acetoacetic acid, the desired product was obtained via the corresponding cyanoketone in the same manner as in the latter half of Reference Example 20. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
3.89 (s, 2H), 4.36 (s, 2H), 4.94 (s, 1H), 7.31-7.59
(m, 9H)

Reference Example 29 3- [1- (2-Fluoro-2 ′, 3 ′, 4 ′, 5 ′,
6'-pentadeuterio-biphenyl-4-yl)-
Ethyl] -isoxazol-5-ylamine

[Chemical Formula 197] Under a nitrogen atmosphere, deuterated benzene (56 ml) and water (6 ml) were added to sodium nitrite (4.87 g),
Stirred at ° C. Under stirring, dimethyl 2- (4-
Amino-3-fluorophenyl) -2-methylmalonate (JP-A-2-223542) (10.0 g) and glacial acetic acid (4.24 g) were dissolved in deuterated benzene (19 ml) and added dropwise over 3 hours. After stirring for 2 hours, the mixture was washed with an aqueous sodium sulfate solution and concentrated under reduced pressure. The residue was dissolved in an 85% aqueous sulfuric acid solution (17.7 ml) and extracted with toluene-hexane. The extract was washed with a 1N aqueous sodium carbonate solution and subsequently with a saturated saline solution, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (hexane / ethyl acetate = 13 /
Purification in 1), 2- (2-fluoro-2 ′, 3 ′,
4 ', 5', 6'-pentadeuterio-biphenyl-
4-yl) -2-Methyl-malonic acid diethyl ester (5.99 g) was obtained. This ester (5.98 g) was dissolved in ethanol (39 ml), a 50% aqueous sodium hydroxide solution (3.42 ml) was added at −15 ° C., and the mixture was stirred at room temperature for 6 hours. After adding a small amount of water to the reaction solution, the pH was adjusted to 8 with 3N hydrochloric acid and extracted with chloroform. After adjusting the pH of the aqueous layer to 1, the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. Glacial acetic acid (4.24 g) was added to the residue, and the mixture was heated under reflux for 17 hours. After cooling under ice cooling, water (12 ml) was added, and the furnace was removed.
After washing with acetic acid, 2- (2-fluoro-2 ′, 3 ′,
4 ', 5', 6'-pentadeuterio-biphenyl-
4-yl) -Propionic acid (3.84 g) was obtained. This carboxylic acid (3.84 g) was dissolved in ethanol (20 ml), toluene (10 ml) and concentrated sulfuric acid (50 mg) were added, and the mixture was stirred at 60 to 80 ° C for 4 hours. The reaction solution was diluted with ethyl acetate, neutralized with sodium carbonate, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure.
2- (2-fluoro-2 ', 3', 4 ', 5', 6'-
There was obtained ethyl pentadeuterio-biphenyl-4-yl) -propionate (4.26 g). After adding tetrahydrofuran (30 ml) to sodium hydride (1.11 g, 60% oily), this ester (4.26 g) and acetonitrile (1.14 g) are dissolved in tetrahydrofuran (10 ml) under reflux with heating, and the mixture is taken for 40 minutes. And dropped. After stirring for 2 hours while heating under reflux, the mixture was cooled to room temperature, added with isopropanol (15 ml), neutralized with 3N hydrochloric acid under ice cooling, and extracted with chloroform.
The organic layer was dried over sodium sulfate and concentrated under reduced pressure. After the residue was dissolved in ethanol (20 ml), pyridine (7
ml) and hydroxylamine hydrochloride (2.13 g) were added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure,
After adding a small amount of water, the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by recrystallization from chloroform to obtain the desired product (3.24 g). ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.64 (d, 3H, J = 7.1Hz), 4.11 (q, 1H, J = 7.1Hz), 4.39 (br
-s, 2H), 4.94 (s, 1H), 7.06-7.19 (m, 2H), 7.38 (t, 1
(H, J = 7.9Hz)

Reference Example 30 3- [1- (2-Fluoro-2′-methoxy-biphenyl)
Ru-4-yl) -ethyl] -isoxazol-5-yl
Amine

Embedded image Using methoxybenzene, the target compound was obtained in the same manner as in Reference Example 29. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.64 (d, 3H, J = 7.1Hz), 3.81 (s, 3H), 4.11 (q, 1H, J = 7.
1Hz), 4.37 (br-s, 2H), 4.95 (s, 1H), 6.96-7.13 (m, 5
H), 7.23-7.48 (m, 2H)

Reference Example 31 3- [1- (2′-fluoro-biphenyl-4-yl)
-Ethyl] -isoxazol-5-ylamine

Embedded image Under a nitrogen atmosphere, methylene chloride (100 ml) was added to aluminum chloride (20.1 g), and 2-fluorobiphenyl (20.0 g) and acetyl chloride (10.7 ml) were added.
Was dissolved in methylene chloride (100 ml) and added dropwise at room temperature. After stirring for 4 hours, a small amount of water was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by recrystallization from ethanol to give 1- (2′-fluoro-biphenyl-4-yl)-
Ethanone (17.53 g) was obtained. This ketone (17.
53 g) was dissolved in morpholine (130 ml), sulfur (5.25 g) was added, and the mixture was stirred under reflux for 10 hours. After cooling to room temperature, 1N hydrochloric acid (500 ml) was added,
Extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified from ethanol by a recrystallization method to give 2- (2'-fluoro-biphenyl-4-yl)
-1-morpholin-4-yl-ethanethione (21.6
9 g) were obtained. Add this compound to ethanol (200ml)
And 15% aqueous sodium hydroxide solution (50 ml)
Was added, and the mixture was stirred for 4 hours while heating under reflux. After cooling to room temperature,
The solvent was concentrated under reduced pressure, diluted hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by recrystallization from ethanol, and (2'-
Fluoro-biphenyl-4-yl) -acetic acid (13.46
g) was obtained. Diisopropylamine (16.4 ml) was dissolved in tetrahydrofuran (100 ml), and n-butyllithium in hexane (30.3 ml,
1.66M) and stirred for 15 minutes. Subsequently, after dissolving this carboxylic acid (13.44 g) in tetrahydrofuran (100 ml) under ice-cooling, hexamethylphosphorustriamide (40 ml) was added thereto, and the mixture was stirred for 1 hour under ice-cooling, and further added with iodomethane (100 ml). 3.63 ml) and add 3
Stirred for hours. After adding 10% hydrochloric acid (500 ml) to the reaction mixture, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate and concentrated under reduced pressure.
(2′-Fluoro-biphenyl-4-yl) -propionic acid (16.64 g) was obtained. This carboxylic acid was dissolved in ethanol (100 ml), concentrated sulfuric acid (2 ml) was added, and the mixture was stirred under heating and reflux for 4 hours. The reaction solution was diluted with ethyl acetate, neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate = 4/1) to give 2- (2′-fluoro-biphenyl-4-yl) -propionic acid ethyl ester (9.2).
6 g) were obtained. Sodium hydride (2.12 g, 60%
After adding tetrahydrofuran (100 ml) to the mixture (oil-based), the ester (9.62 g) and acetonitrile (3.67 ml) were added to tetrahydrofuran (100 ml) under reflux with heating.
ml) and added dropwise over 1 hour. After stirring for 5 hours under reflux while heating, the mixture was cooled to room temperature, a small amount of water was added, and the mixture was diluted with ethyl acetate and added with aqueous sodium bicarbonate. After extraction with ethyl acetate, the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel (hexane /
Purification with ethyl acetate = 3/1) gave 4- (2′-fluoro-biphenyl-4-yl) -3-oxo-pentanitrile (7.33 g). After dissolving this cyanoketone in ethanol (120 ml), pyridine (20 ml)
And hydroxylamine hydrochloride (2.86 g) were added, and 6
Stirred at 0 ° C. for 8 hours. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, neutralized with aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure.
The residue was purified by silica gel chromatography (hexane / ethyl acetate = 4/1) to obtain the desired product (6.31 g). ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1,65 (d, 3H, J = 7.1Hz), 4.12 (q, 1H, J = 7.1Hz), 4.36 (br
-s, 2H), 4.92 (s, 1H), 7.10-7.53 (m, 8H)

Reference Example 32 3- [1- (2-Fluoro-4′-methoxy-biphenyl)
Ru-4-yl) -ethyl] -isoxazol-5-yl
Amine

[Chemical Formula 200] 2- (2-Fluoro-biphenyl-4-yl) -propionic acid (104.2 g) was dissolved in methanol (410 ml), concentrated sulfuric acid (60.2 g) was added, and the mixture was stirred at 40 ° C for 2.5 hours. The mixture was cooled to room temperature, diluted with toluene, neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with toluene. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give 2- (2-fluoro-
Biphenyl-4-yl) -propionic acid methyl ester (110.2 g) was obtained. In a nitrogen atmosphere, ethylene dichloride (700 m) was added to aluminum chloride (125.1 g).
1) and then 2-fluorobiphenyl (20.0
g) was added. Acetyl chloride (73.7) under ice cooling
g) was dissolved in ethylene dichloride (300 ml) and added dropwise over 2 hours. After stirring at 20-30 ° C for 2 hours, 40
The temperature was raised to ６０60 ° C., and the mixture was stirred for 3 hours. After cooling to room temperature, a small amount of ice water was added to the reaction solution, hydrochloric acid was added, and the mixture was extracted with ethylene dichloride. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate = 10/1 → 7/1), and 2- (4′-acetyl-2-fluoro-biphenyl-4-yl) -propionic acid methyl ester (107.
6 g) were obtained. This ester (109.6 g) was dissolved in methylene chloride (670 ml), m-chloroperbenzoic acid (110.3 g) was added at room temperature, and the mixture was stirred with heating under reflux for 20 hours. After cooling to room temperature, m-chloroperbenzoic acid was removed by filtration, and a 20% aqueous sodium thiosulfate solution was added.
Subsequently, it was washed with saturated aqueous sodium hydrogen carbonate. After extracting the mother liquor with chloroform, the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by a recrystallization method from hexane-ethyl acetate (130/1) to obtain 2- (4′-acetoxy-2-fluoro-biphenyl-4-yl) -propionic acid methyl ester (97.0 g). . This compound was dissolved in methanol (1000 ml), a 20% aqueous sodium hydroxide solution (200 ml) was added, and the mixture was stirred at 35 ° C. for 3 hours.
After cooling to room temperature, the solvent was concentrated under reduced pressure, and water (1500 m
After addition of 1), 4N hydrochloric acid was added to adjust the pH to 1.
The precipitate was washed with water and dried in vacuo at 60 ° C. to obtain 2- (2-fluoro-4′-hydroxy-biphenyl-4-yl) -propionic acid (68.6 g). This carboxylic acid (6
7.6 g) was dissolved in acetone (1300 ml), and potassium carbonate (100.9 g) and dimethyl sulfate (92.1 g) were dissolved.
g) was added and the mixture was stirred for 5 hours while heating under reflux. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Methanol (1000 ml) was added to the residue, a 20% aqueous sodium hydroxide solution (150 ml) was added, and the mixture was stirred at 35 ° C. for 2 hours. After cooling to room temperature, the solvent was concentrated under reduced pressure, and water (1000 m
After 1) was added, the pH was adjusted to 1 by adding 4N hydrochloric acid, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. This residue is ethanol (300m
1), concentrated sulfuric acid (34.4 g) was added, and the mixture was stirred under reflux for 2 hours. The reaction solution was cooled to room temperature, diluted with toluene, neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with toluene.
The organic layer was dried over sodium sulfate and concentrated under reduced pressure.
(2-Fluoro-4'-methoxy-biphenyl-4-yl) -propionic acid ethyl ester (82.9 g) was obtained. After adding tetrahydrofuran (300 ml) to sodium hydride (19.7 g, 60% oily), the ester (82.9 g) and acetonitrile (2
0.3 g) was dissolved in tetrahydrofuran (100 ml) and added dropwise over 45 minutes. After stirring under reflux for 1.5 hours, the mixture was cooled to room temperature, and isopropanol (50 m
After adding l), the mixture was neutralized with 3N hydrochloric acid and extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give 4- (2-fluoro-4'-methoxy-biphenyl-4-yl) -3-oxo-pentanitrile (89.1).
g) was obtained. This cyanoketone is converted to ethanol (200 m
After dissolving in 1), pyridine (60 ml) and hydroxylamine hydrochloride (38.1 g) were added, and the mixture was stirred at 70 ° C for 4 hours. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer is dried over sodium sulfate and concentrated under reduced pressure to give the desired product (7
9.36 g). ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.63 (d, 3H, J = 7.3Hz), 3.85 (s, 3H), 4.09 (q, 1H, J = 7.
3Hz), 4.38 (br-s, 2H), 4.93 (s, 1H), 6.94-7.00 (m, 2
H), 7.04-7.13 (m, 2H), 7.31-7.38 (m, 2H), 7.44-7.49
(m, 2H)

Reference Example 33 2- (9H-carbazol-2-yl) -propionic acid
Methyl ester

[Formula 201] Using carbazole, a known method (PS Manchand et
al., Heterocycles, 39 , 833 (1994)). ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.59 (d, 3H, J = 7.1Hz), 3.67 (s, 3H), 3.89 (q, 1H, J = 7.
1Hz), 7.15-7.25 (m, 2H), 7.36-7.43 (m, 3H), 7.98-8.1
0 (m, 3H)

[0342] Reference Example 343- [1- (9H-carbazol-2-yl) -ethyl
] -Isoxazol-5-ylamine

Embedded image Using the compound obtained in Reference Example 33, the desired product was obtained in the same manner as in the latter half of Reference Example 20. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.71 (d, 3H, J = 7.1Hz), 4.24 (q, 1H, J = 7.1Hz), 4.90 (s,
1H), 7.15-7.25 (m, 2H), 7.34-7.44 (m, 3H), 7.98-8.0
5 (m, 3H)

Reference Example 35 3- (2-Fluoro-biphenyl-4-ylmethyl)-
Isoxazol-5-ylamine

Embedded image Using (2-fluoro-biphenyl-4-yl) -acetic acid, the desired product was obtained in the same manner as in Reference Example 26. ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
3.88 (s, 2H), 4.97 (s, 1H), 7.04-7.14 (m, 2H), 7.33-
7.47 (m, 4H), 7.51-7.55 (m, 2H)

Reference Example 36 2- (2,3-dihydro-benzo [1,4] dioxin
-6-yl) -propionic acid ethyl ester

Embedded image 3,4-Ethylenedioxyphenylacetic acid ethyl ester (M. Sasamoto, Chem.
Pharm. Bull., 8 , 324 (1960)) (6.00 g) of N,
60% in N-dimethylformamide (65 ml) solution
Sodium hydride (1.13 g) was added. afterwards,
Methyl iodide (1.76 ml) was added dropwise, and the mixture was stirred for 4 hours under ice cooling. 1N-hydrochloric acid was added to the reaction solution, extracted with diethyl ether, and the extract was washed with water and dried. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the desired product (5.57 g). ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.22 (t, 3H, J = 7.3Hz), 1.44 (d, 3H, J = 7.3Hz), 3.59 (q,
1H, J = 7.3Hz), 4.05-4.17 (m, 2H), 4.24 (s, 4H), 6.74
(m, 3H)

Reference Example 37 3- [1- (2,3-dihydro-benzo [1,4] dio
Xin-6-yl) -ethyl] -isoxazole-5-
Ilamine

Embedded image Using the compound obtained in Reference Example 36, the desired product was obtained in the same manner as in the latter half of Reference Example 20. ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.56 (d, 3H, J = 7.3Hz), 3.97 (q, 1H, J = 7.3Hz), 4.23
(s, 4H), 4.33 (br-s, 2H), 4.88 (s, 1H), 6.73-6.82 (m,
3H)

[0346] Reference Example 383- [1- (1-methyl-1H-indole-3-i
Ru) -ethyl] -isoxazol-5-ylamine

Embedded image 2- (1-Methyl-1H-indol-3-yl) -propionic acid ethyl ester (LK Mehta et al., J. Am.
Chem. Soc. Perkin Trans. 2, 1488 (1997))
The target compound was obtained in the same manner as in the latter half of Reference Example 20. ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.69 (d, 3H, J = 7.3Hz), 3.74 (s, 3H), 4.26 (br-s, 2H),
4.36 (q, 1H, J = 7.3Hz), 4.88 (s, 1H), 6.91 (s, 1H), 7.
04-7.29 (m, 3H), 7.62 (d, 1H, J = 7.9Hz)

Reference Example 39 3- [1- (1H-Indol-3-yl) -ethyl]
-Isoxazol-5-ylamine

Embedded image 2- (1H-Indol-3-yl) -propionic acid ethyl ester (M. Julia et al., Bull. Soc. Chim. F.
r., 2291 (1966)) to obtain the desired product in the same manner as in the latter half of Reference Example 20. ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.70 (d, 3H, J = 7.3Hz), 4.25 (br-s, 2H), 4.37 (q, 1H,
J = 7.3Hz), 4.87 (s, 1H), 7.05-7.21 (m, 3H), 7.34 (d, 1
H, J = 8.2), 7.62 (d, 1H, J = 7.9Hz), 8.04 (br-s, 1H)

Reference Example 40 2- (1-Methyl-1H-indol-2-yl) -p
Lopionic acid methyl ester

Embedded image 1-methyl-2- (2'-carbomethoxyvinyl) indole (FE Ziegler et al., J. Am. Chem. Soc., 9
5 , 7146 (1973)) (335 mg), 10% palladium /
A mixture of activated carbon (50 mg) and tetrahydrofuran (4 ml) was hydrogenated at room temperature for 30 minutes. After filtering the reaction mixture to remove the catalyst, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the desired product (168 mg). ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.65 (d, 3H, J = 7.3Hz), 3.69 (s, 3H), 3.72 (s, 3H), 3.
97 (q, 1H, J = 7.3Hz), 6.43 (s, 1H), 7.05-7.31 (m, 3H),
7.57 (d, 1H, J = 7.9Hz)

[0349] Reference Example 413- [1- (1-methyl-1H-indole-2-i
Ru) -ethyl] -isoxazol-5-ylamine

Embedded image Using the compound obtained in Reference Example 40, the desired product was obtained in the same manner as in the latter half of Reference Example 20. ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.72 (d, 3H, J = 7.3Hz), 3.64 (s, 3H), 4.30-4.33 (m, 3
H), 4.81 (s, 1H), 6.44 (s, 1H), 7.05-7.28 (m, 3H), 7.
57 (d, 1H, J = 7.9Hz)

Reference Example 42 Ethyl 2-benzofuran-5-yl-propionate
Tell

Embedded image 5-benzofurancarbonitrile (JP-A-9-24631)
To a solution of (1.30 g) in tetrahydrofuran (5 ml) was added a 0.87 M solution of methylmagnesium bromide in tetrahydrofuran (21 ml), and the mixture was refluxed for 4 hours under a nitrogen atmosphere. The reaction mixture was acidified with concentrated hydrochloric acid, added with water, extracted with diethyl ether, and the extract was washed with water and dried. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give 1-benzofuran-5.
-Yl-ethanone (1.21 g) was obtained. ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
2.67 (s, 3H), 6.86 (d, 1H, J = 2.3Hz), 7.55 (d, 1H, J =
8.9Hz), 7.70 (d, 1H, J = 2.3Hz), 7.97 (dd, 1H, J = 8.9,
1.7Hz), 8.26 (d, 1H, J = 1.7Hz) 1-benzofuran-5-yl-ethanone (850m
g), trimethylsilyl cyanide (0.85 ml), zinc iodide (34 mg) and chloroform (21 ml)
Was heated and refluxed under a nitrogen atmosphere for 3.5 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the desired cyano compound (1.21).
g) was obtained. ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
0.18 (s, 9H), 1.91 (s, 3H), 6.80 (m, 1H), 7.45-7.54
(m, 2H), 7.67 (d, 1H, J = 2.0 Hz), 7.81 (s, 1H) To a solution of this cyano compound (1.21 g) in acetic acid (10 ml) was added tin (II) chloride dihydrate. After stirring for 10 minutes at room temperature, concentrated hydrochloric acid (20 ml) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was further heated and stirred at 100 ° C. for 2.5 hours, added with water, extracted with diethyl ether, and the extract was washed with water and dried. The solvent was distilled off under reduced pressure, and ethanol (4 ml) and concentrated sulfuric acid (0.05 ml) were added to the residue.
The mixture was heated and stirred at 0 ° C. for 2.5 hours. The solvent was distilled off under reduced pressure, water was added to the residue, extracted with diethyl ether, and the extract was washed with water and dried. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the desired product (601 mg). ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.20 (t, 3H, J = 7.3Hz), 1.54 (d, 3H, J = 7.3Hz), 3.80
(q, 1H, J = 7.3Hz), 4.05-4.19 (m, 2H), 6.74 (d, 1H, J =
2.3Hz), 7.24 (d, 1H, J = 8.6Hz), 7.45 (d, 1H, J = 8.6H
z), 7.54 (s, 1H), 7.61 (d, 1H, J = 2.3Hz)

Reference Example 43 3- (1-Benzofuran-5-yl-ethyl) -isoki
Sasol-5-ylamine

Embedded image Using the compound obtained in Reference Example 42, the target compound was obtained in the same manner as in the latter half of Reference Example 20. ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.66 (d, 3H, J = 7.3Hz), 4.17 (q, 1H, J = 7.3Hz), 4.32 (b
rs, 2H), 4.86 (s, 1H), 6.72 (d, 1H, J = 2.3Hz), 7.22
(dd, 1H, J = 8.6, 1.7Hz), 7.43 (d, 1H, J = 8.6Hz), 7.51
(d, 1H, J = 1.7Hz), 7.60 (d, H, J = 2.3Hz)

Reference Example 44 Ethyl 2-benzofuran-6-yl-propionate
Tell

Embedded image The desired product was obtained in the same manner as in Reference Example 42. ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.21 (t, 3H, J = 7.3Hz), 1.55 (d, 3H, J = 7.3Hz), 3.82
(q, 1H, J = 7.3Hz), 4.06-4.18 (m, 2H), 6.74 (d, 1H, J =
2.3Hz), 7.20 (d, 1H, J = 7.9Hz), 7.47 (s, 1H), 7.53 (d,
1H, J = 7.9Hz), 7.6 (d, 1H, J = 2.3Hz)

Reference Example 45 3- (1-benzofuran-6-yl-ethyl) -isoki
Sasol-5-ylamine

Embedded image Using the compound obtained in Reference Example 44, the desired product was obtained in the same manner as in the latter half of Reference Example 20. ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.66 (d, 3H, J = 7.3Hz), 4.19 (q, 1H, J = 7.3Hz), 4.32 (b
rs, 2H), 4.87 (s, 1H), 6.73 (d, 1H, J = 2.3Hz), 7.18
(d, 1H, J = 8.3Hz), 7.44 (s, 1H), 7.52 (d, 1H, J = 8.3H
z), 7.59 (1H, d, J = 2.3Hz)

Reference Example 46 (S) -3- [1- (2-Fluoro-biphenyl-4-)
Yl) -ethyl] -isoxazol-5-ylamine

Embedded image As an alternative to the preparation of the compound of Reference Example 27, a solution of lithium amide (1.61 g) in tetrahydrofuran (73 ml) was heated to 68 ° C. under a nitrogen atmosphere, and cyanoacetic acid te was obtained.
rt-Butyl (11.1 g) was added dropwise. Thereafter, while blowing nitrogen into the solution, the solution was concentrated until the content became 30 g, and cooled to room temperature. The content was made up to 50 g with tetrahydrofuran and cooled to -10 ° C. On the other hand, a solution of isobutyl chloroformate (5.57 g) in tetrahydrofuran (27
ml) contains (S) -2- (2-fluoro-biphenyl-
4-yl) -propionic acid (10.1 g, 99% ee)
And a solution of N-methylmorpholine (5.2 ml) in tetrahydrofuran (27 ml) was added dropwise. After 10 minutes, this solution was added dropwise to the above tert-butyl cyanoacetate solution, and 1
After an hour, water (202 ml) was added and stirred overnight at room temperature. The precipitated crystals were filtered and dried under reduced pressure to obtain the desired lithium salt (13.4 g). ¹ H-NMR (300 MHz, d ₆ -DMSO) δ pp
m: 1.31 (d, 3H, J = 6.8Hz), 1.37 (s, 9H), 4.21 (q, 1H,
J = 6.8 Hz), 7.15-7.22 (m, 2H), 7.35-7.52 (m, 6H) Na ₂ HPO ₄ (826 mg) was dissolved in water (11.6 g), and the pH was adjusted to 8.0 with 1N phosphoric acid. , Hydroxylamine hydrochloride (78.1 g) was added thereto, and at 80 ° C.,
A solution of the lithium salt (1.40 g) obtained above in isopropanol (11.7 ml) was added dropwise, and after stirring for 1 hour, the temperature was returned to room temperature, and water (27 ml) was added to crystallize the desired product.
This was filtered and dried under reduced pressure to give the desired amine (875 m
g, 98% ee).

Reference Example 47 3- (1-quinolin-3-yl-ethyl) -isoxazo
5-ylamine

Embedded image 2-quinolin-3-yl-propionic acid methyl ester (T. Sakamoto et al., Heterocycles, 36, 2509 (199
Using 7)), the target compound was obtained in the same manner as in the latter half of Reference Example 20. ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.71 (d, 3H, J = 7.3Hz), 4.27 (q, 1H, J = 7.3Hz), 4.61 (b
rs, 2H), 4.87 (s, 1H), 7.49-7.79 (m, 3H), 8.01-8.09
(m, 2H), 8.84 (d, 1H, J = 2.0Hz)

Reference Example 48 3- (1-Isoquinolin-4-yl-ethyl) -isoki
Sasol-5-ylamine

Embedded image 2-isoquinolin-4-yl-propionic acid methyl ester (T. Sakamoto et al., Heterocycles, 36 (11), 250
9 (1997)) to obtain the desired product in the same manner as in the latter half of Reference Example 20. ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.81 (d, 3H, J = 7.3Hz), 4.52 (br-s, 2H), 4.71-4.78 (m,
2H), 7.57-7.74 (m, 2H), 7.98 (d, 1H, J = 7.6Hz), 8.14
(d, 1H, J = 8.2Hz), 8.50 (s, 1H), 9.16 (s, 1H)

Reference Example 49 Biphenyl-4-yl-dimethoxy-methyl acetate
Le

Embedded image Biphenyl-4-yl-glyoxylic acid methyl ester
(AT Jeffries, etal., J. Org.Chem., 46, 2885 (19
81)) (10 g), trimethyl orthoformate (43 m
l), a mixture of methanol (60 ml) and concentrated sulfuric acid (3 ml) was heated and refluxed for 8.5 hours under a nitrogen atmosphere. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogen carbonate and extracted with ether. The organic layer was washed with saturated saline and dried over sodium sulfate, and the solvent was distilled off under reduced pressure.
0.5 g). ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
3.31 (s, 6H), 3.75 (s, 3H), 7.35-7.47 (m, 3H), 7.58-
7.69 (m, 6H)

Reference Example 50 3- (biphenyl-4-yl-dimethoxy-methyl)-
Isoxazol-5-ylamine

Embedded image Using the compound obtained in Reference Example 49, the desired product was obtained in the same manner as in the latter half of Reference Example 20. ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
3.27 (s, 6H), 4.38 (br-s, 2H), 5.02 (s, 1H), 7.31-7.
46 (m, 3H), 7.56-7.67 (m, 6H)

Reference Example 51 dimethoxy- (1-methyl-1H-indole-2-i
M-acetic acid methyl ester

Embedded image (1-Methyl-1H-indol-2-yl) -glyoxylic acid methyl ester (FE Ziegler, et al., J. Mol.
Using Amer. Chem. Soc., 95, 7146 (1973)), the target compound was obtained in the same manner as in Reference Example 49. ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
3.32 (s, 6H), 3.77 (s, 3H), 3.78 (s, 3H), 6.85 (s, 1
H), 7.10-7.35 (m, 3H), 7.63 (d, 1H, J = 7.9Hz)

Reference Example 52 3- [Dimethoxy- (1-methyl-1H-indole-
2-yl) -methyl] -isoxazol-5-ylia
Min

Embedded image Using the compound obtained in Reference Example 50 and the corresponding cyanoketone, the desired product was obtained in the same manner as in Example 21. ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
3.27 (s, 6H), 3.68 (s, 3H), 4.38 (br-s, 2H), 4.92 (s,
1H), 6.86 (s, 1H), 7.08-7.31 (m, 3H), 7.63 (d, 1H, J =
(7.9Hz)

Reference Example 53 3- {1-methyl-1- [3- (2-phenyl- [1,
3] dioxolan-2-yl) -phenyl] -ethyl}
-Isoxazol-5-ylamine

Embedded image Under a nitrogen atmosphere, ketoprofen (10 g) was dissolved in N, N-dimethylformamide (50 ml), 60% sodium hydride (3.95 g) was added, and the mixture was stirred. After 30 minutes, methyl iodide (6.1 ml) was added, and the mixture was stirred for 10 hours. Ice water and saturated aqueous sodium hydrogen carbonate were added to the reaction solution, and the mixture was extracted with ethyl acetate.The extract was washed with brine, dried over sodium sulfate, and dried.
After concentration under reduced pressure, a residue (12.78 g) was obtained. A part (7.78 g) of this residue was dissolved in benzene (100 ml), ethylene glycol (10 ml) and p-toluenesulfonic acid (10 g) were added, and the mixture was dehydrated and refluxed for 200 hours. After adding a saturated aqueous sodium hydrogen carbonate solution, the mixture was extracted with ethyl acetate, washed with saturated saline, dried over sodium sulfate, and concentrated under reduced pressure to obtain a residue (9.30 g). Part of this residue (1.
0 g) was dissolved in methanol (10 ml), a 10% aqueous potassium hydroxide solution (10 ml) was added, and the mixture was stirred for 10 hours. After concentrating the reaction solution and distilling off methanol, 2N hydrochloric acid was added and the mixture was extracted with ethyl acetate, washed with saturated saline, dried over sodium sulfate, and concentrated under reduced pressure to give a residue (0.56 g).
I got Sodium hydride (2
20 mg) in tetrahydrofuran (10 ml) solution,
Under stirring, tert-butyl cyanoacetate (0.76 ml) was added dropwise. The mixture was stirred for 30 minutes under ice cooling. On the other hand, in a separate reaction vessel under a nitrogen atmosphere at −15 ° C., a solution of the residue (0.56 g) and N-methylmorpholine (0.24 ml) was added to a solution of isobutyl chloroformate (0.26 ml) in tetrahydrofuran (5 ml). A tetrahydrofuran (5 ml) solution was added dropwise with stirring. After 30 minutes, this solution was added dropwise to the tert-butyl cyanoacetate solution. One hour later, the mixture was poured into saturated aqueous sodium hydrogen carbonate, extracted with ethyl acetate, dried over sodium sulfate, and concentrated under reduced pressure. Hydroxylamine hydrochloride (500 mg) and ethanol (1
6 ml) and pyridine (4 ml) were added, and the mixture was stirred at 50 ° C. for 4 hours. After cooling to room temperature, ethanol was distilled off, a saturated aqueous sodium hydrogen carbonate solution was added to the residue, extracted with ethyl acetate, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the desired product (37.9 mg). ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm:
1.66 (s, 6H), 4.05 (s, 4H), 4.26 (br-s, 2H), 4.73 (s,
1H), 7.21-7.60 (m, 9H)

Reference Example 54 2- (6-Phenyl-pyridin-3-yl) -propio
Acid methyl ester

Embedded image 5-bromo-2-phenylpyridine (JW Tilley, et.
al., J. Org. Chem., 53, 386 (1988)) and a known method (T. Sakamoto, et al., Heterocycles, 36, 2509 (19)
The target product was obtained in the same manner as in 93)). ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.57 (d, 3H, J = 7.3Hz), 3.67 (s, 3H), 3.80 (q, 1H, J =
7.3Hz), 7.41-7.50 (m, 3H), 7.71-7.72 (m, 2H), 7.97 (d,
2H, J = 6.6Hz), 8.61 (s, 1H)

Reference Example 55 3- [1- (6-Phenyl-pyridin-3-yl) -e
Tyl] -isoxazol-5-ylamine

Embedded image Using the compound obtained in Reference Example 54, the desired product was obtained in the same manner as in the latter half of Reference Example 20. ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.67 (d, 3H, J = 7.3Hz), 4.14 (q, 1H, J = 7.3Hz), 4.43 (b
rs, 2H), 4.91 (s, 1H), 7.40-7.49 (m, 3H), 7.70 (m, 2
H), 7.96 (dd, 2H, J = 8.3, 1.7Hz), 8.63 (s, 1H)

Reference Example 56 2- (5-phenyl-pyridin-2-yl) -propio
Acid methyl ester

Embedded image 2-Bromo-5-phenylpyridine (MG Knize, et a
l., Heterocycles, 24, 1815 (1986)) and known methods (T. Sakamoto, et al., Heterocycles, 36, 2509 (199).
The target product was obtained in the same manner as in 3)). ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.61 (d, 3H, J = 7.3Hz), 3.72 (s, 3H), 4.01 (q, 1H, J =
7.3Hz), 7.34-7.59 (m, 6H), 7.85 (dd, 1H, J = 8.2Hz, 2.
3Hz), 8.78 (d, 1H, J = 2.3Hz)

Reference Example 57 3- [1- (5-Phenyl-pyridin-2-yl) -d
Tyl] -isoxazol-5-ylamine

Embedded image Using the compound obtained in Reference Example 56, the desired product was obtained in the same manner as in the latter half of Reference Example 20. ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm:
1.71 (d, 3H, J = 7.3Hz), 4.30 (q, 1H, J = 7.3Hz), 4.39 (b
rs, 2H), 5.08 (s, 1H), 7.32-7.57 (m, 6H), 7.81 (dd,
1H, J = 8.3Hz, J = 2.3Hz), 8.79 (d, 1H, J = 2.3Hz)

[0366] Reference Example 58{3- [1- (5-amino-isoxazole-3-i]
L) -1-methyl-ethyl] -phenyl} -phenyl-
Methanone oxime

Embedded image Under a nitrogen atmosphere, ketoprofen (10 g) was dissolved in N, N-dimethylformamide (50 ml), and sodium hydride (4.72 g, 60% oil) was added and stirred. 3
0 minutes later, methyl iodide (6.1 ml) was added, and the mixture was stirred for 10 hours. Ice water and saturated aqueous layer were added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, dried over sodium sulfate, and concentrated under reduced pressure to obtain a residue (10.28 g). This residue was dissolved in MeOH (70 ml), a 10% aqueous potassium hydroxide solution (70 ml) was added, and the mixture was stirred for 24 hours. After concentrating the reaction solution, 4N hydrochloric acid was added to make the reaction solution acidic, extracted with ethyl acetate, washed with saturated saline, dried over sodium sulfate, and concentrated under reduced pressure to give a residue (9.31).
g) was obtained. Sodium hydride (4.2 g, 60% oily) was added to tetrahydrofuran (1
Tert-butyl cyanoacetate (14.8 ml) was added dropwise with stirring, and the mixture was stirred under ice cooling for 30 minutes to obtain a sodium salt of tert-butyl cyanoacetate. On the other hand, in another reaction vessel under a nitrogen atmosphere,
To a solution of isobutyl chloroformate (5.40 ml) in tetrahydrofuran (100 ml) at 15 ° C. was added the residue (9.31 g) and N-methylmorpholine (4.57 m).
A solution of l) in tetrahydrofuran (100 ml) was added dropwise with stirring. After 30 minutes, the solution was added to the previous cyanoacetic acid ter
It was added dropwise to the sodium salt of t-butyl ester. One hour later, the mixture was poured into saturated saline and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The obtained mucous residue was washed with hexane,
A residue (19.73 g) was obtained. This was dissolved in 1,4-dioxane (150 ml) and methanesulfonic acid (20 m
A solution of l) in water (10 ml) was added and the mixture was heated under reflux. After 4 hours, the reaction solution was concentrated, saturated saline was added, extracted with ethyl acetate, washed with saturated saline, and concentrated under reduced pressure to obtain a residue (10.58 g). To this, hydroxylamine hydrochloride (8.2 g), ethanol (150 m
l) and pyridine (30 ml) were added, and the mixture was stirred at 50 ° C for 8 hours and then at room temperature for 60 hours. Ethanol was distilled off, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the desired product (7.63 g) as a 4: 1 mixture of regioisomers. ¹ H-NMR (300 MHz, CD ₃ OD) δ ppm:
1.57 (s, 4.8H), 1.61 (s, 1.2H), 4.71 (s, 0.2H), 4.76
(s, 0.8H), 7.18-7.46 (m, 10H)

[0367] Test example 1Suppress adjuvant arthritis  Male SD rats were used as experimental animals. Mycobacteriu
The dead cells of m butyricum should be fluidized to a concentration of 0.5%.
Inject the suspension in raffin subcutaneously into the right hind footpad of the rat.
Entered. 17 days later, clear secondary inflammation on the left hind limb
Select an approved animal and suspend it in a 0.5% methylcellulose solution.
The turbid compound of the present invention was orally administered for 5 consecutive days, and the administration was terminated.
Volume of hind limb 5 hours after completion of administration
The swelling inhibitory effect was evaluated based on this difference. So
Are shown in Tables 1, 2 and 3.

[Table 1] Compound administered Oral dose Number of animals Increase in edema (ml) (mg / kg) Injectable foot Non-injectable foot ―――――――――――――――――――――― ―――――――――――― Control-8 0.29 0.39 Compound of Example 19 258 -1.05 -0.55 Compound of Example 20 259 -0.63 -0.40 Indomethacin 0.59 -1.19 -0.77

[Table 2] Compound administered Oral dose Number of animals Increase in edema (ml) (mg / kg) Injectable foot Non-injectable foot ―――――――――――――――――――――― ―――――――――――― Control -9 0.86 0.33 Compound of Example 17 259 -0.01 -0.24 Compound of Example 18 259 -0.48 -0.49 Indomethacin 0.5 9 -1.51 -1.05

[Table 3] Compound administered Oral dose Number of animals Increase in edema (ml) (mg / kg) Injectable foot Non-injectable foot ―――――――――――――――――――――― ―――――――――――― Control-10 0.01 0.00 Compound of Example 87 25 10 -0.35 -0.24 Indomethacin 0.5 10 -0.45 -0.40

[0368] Test Example 2Suppression of type III allergic reaction  BALB / c male mice were used as experimental animals. Physiological salt
Sheep red blood cells were suspended in water to a concentration of 20%
The solution was injected into the tail vein of the mouse, and the same procedure was repeated 14 days later.
The animals were immunized again. 100% sheep red after another 5 days
Blood cell suspension was injected subcutaneously into the right hind footpad of the mouse.
Induces type I allergy and after 3 hours the thickness of the left and right feet
It was measured. The difference in thickness between the right and left feet is used as the amount of edema to evaluate the efficacy
I did it. The compound of the present invention is a 0.5% methylcellulose solution
Orally administered 24 hours before and 1 hour after induction of the inflammatory response.
Gave. Compared to the control group, the amount of edema in the compound administration group was
Table 4 shows the edema suppression rates calculated as described above.

[Table 4] Compound administered Oral dose Number of animals Edema suppression rate (%) (mg / kg) ―――――――――――――――――――――――――――― ―――――― Compound of Example 17 10 13 13.6 Compound of Example 18 50 13 18.4 Levamisole 50 13 28.9

[0369] Test example 3Effects on experimental allergic encephalomyelitis  Experimental allergic brain is an animal model of multiple sclerosis
The drug efficacy of the compound was evaluated using myelitis mice. Real
Experimental allergic encephalomyelitis was induced by the method of Bell et al. (J. Im.
munology, 150: 4085-4092, 1993). Sand
8-week-old female (PL x SJL) F1 mice (Jackson Labor
atories, Bar Harbor, ME)
Myelin basic protein mixed with adjuvant (Husa
200 μg) were injected. Date of sensitization and after sensitization
On the second day, pertussis toxin (List Biological Laboratories, C
ampbell, CA) 200 ng was injected intraperitoneally. Severity of symptoms
The degree of was indicated by a score according to the following criteria. 1: Paralysis of the tail only 2: Mild hind limb paralysis 3: Moderate hind limb paralysis or mild forelimb paralysis 4: Severe hind limb paralysis or severe forelimb paralysis 5: General paralysis 6: Death. The compound of the present invention is suspended in a 0.5% methylcellulose solution,
The mouse was orally administered 0.1 ml per 10 g of body weight. In the control group
Was orally administered only a 0.5% methylcellulose solution. Administration
Starts on the day of sensitization and runs once a day for 42 days
Was. The result is shown in FIG. Control mice are severe
Experimental allergic cerebrospinal cord developed, all cases during the study
(10 animals) died from nerve palsy. On the other hand, Example 22
Mice given the compound (50 mg / kg) also developed symptoms
However, his symptoms were mild, and 3 of 10 animals died.

[0370] As described above, the medicament comprising the isoxazole derivative of the present invention or a pharmaceutically acceptable salt thereof can be used as an animal model for chronic inflammation (rat adjuvant arthritis, etc.) or an animal model for immune abnormality (mouse type III allergic reaction, etc.). ) And experimental allergic encephalomyelitis mice (e.g., multiple sclerosis). Therefore, the isoxazole derivative and the like of the present invention, in addition to a clear effect on chronic inflammation, also acts on immune abnormalities in the background, and is effective against autoimmune diseases and inflammatory diseases such as rheumatoid arthritis. Even so, the isoxazole derivative of the present invention is effective.

[0371] Formulation Example 1Tablet manufacturing  After mixing the ingredients, granulating if necessary,
Thus, a tablet can be produced. Amount (mg / tablet) Compound of Example 85 20 Lactose 70 Maize starch 17 Low substituted hydroxypropylcellulose 8 Hydroxypropylcellulose 4 Magnesium stearate 1 Total 120 mg

[0372] Formulation Example 2Tablet manufacturing  After mixing the ingredients, granulating if necessary,
Thus, a tablet can be produced. Amount (mg / tablet) Compound of Example 43 20 D-mannitol 60 Calcium hydrogen phosphate 25 Carmellose calcium 8 Hydroxypropyl methylcellulose 4 Talc 3 Total 120 mg

[0373] Formulation Example 3Manufacture of capsules  After mixing each component and granulating as necessary, capsule
By filling, a capsule can be produced. Amount (mg / capsule) Compound of Example 69 20 Lactose 150 Maize starch 40 Low-substituted hydroxypropylcellulose 8 Magnesium stearate 2 Total 220 mg

[0374] Formulation Example 4Manufacture of capsules  After mixing each component and granulating as necessary, capsule
By filling, a capsule can be produced. Amount (mg / capsule) Compound of Example 72 20 D-mannitol 123.5 Carmellose calcium 5 Magnesium stearate 1.5 Total 150 mg

[0375] Formulation Example 5Manufacture of powder  By mixing each component and granulating as necessary, powder
Can be manufactured. Amount (mg / 1 g) Compound of Example 74 40 Lactose 750 Maize starch 200 Magnesium stearate 10 Total 1000 mg

[0376] Formulation Example 6Manufacture of powder  By mixing each component and granulating as necessary, powder
Can be manufactured. Amount (mg / 1 g) Compound of Example 107 40 D-mannitol 700 Corn starch 200 Magnesium stearate 10 Total 1000 mg

[0377]

The medicament comprising the isoxazole derivative of the present invention and a pharmaceutically acceptable salt thereof is useful for autoimmune diseases (eg, rheumatoid arthritis, systemic lupus erythematosus, systemic scleroderma, Sjogren's syndrome, Hashimoto) Disease, myasthenia gravis, Basedow's disease, Addison's disease, juvenile diabetes (type I diabetes), autoimmune bloody diseases (eg, aplastic anemia, hemolytic anemia, idiopathic thrombocytopenia, etc.), ulcerative Diseases such as colitis, chronic active hepatitis, glomerulonephritis, interstitial pulmonary fibrosis, multiple sclerosis, and inflammatory diseases (eg, osteoarthritis, gout, atopic dermatitis, psoriasis, etc.) It is useful as a therapeutic or prophylactic agent for

[0378]

[Brief description of the drawings]

FIG. 1 is a graph showing the results of testing a compound of the present invention using an experimental allergic encephalomyelitis mouse, which is an animal model for multiple sclerosis.

Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61K 31/4545 A61K 31/4545 31/4709 31/4709 31/4725 31/4725 31/496 31/496 31/5377 31/5377 31/541 31/541 A61P 29/00 A61P 29/00 101 101 37/02 37/02 // C07D 261/08 C07D 261/08 261/14 261/14 413/06 413/06 413/10 413/10 413/12 413/12 (72) Inventor Fumio Nishikaku 3-1-198 Kasuganaka, Konohana-ku, Osaka-Sumitomo Pharmaceutical Co., Ltd. (58) Field surveyed (Int. Cl. ⁷ , DB name) A61K 31/42- 31/541 A61P 1/00-43/00 C07D 261/00-261/20 C07D 275/00-275/06 C07D 413/00-413/14 CA (STN) REGISTRY (STN) WPI (DIALOG)

Claims (15)

(57) [Claims] [Claim 1] Formula:[Wherein, D represents a hydrogen atom, a halogen atom, a hydroxyl group,
Substituted, nitro, cyano, carboxy, substituted
Amino group which may be substituted, hydroxylamino which may be substituted
Group, an optionally substituted carbamoyl group, an optionally substituted
Good sulfamoyl group, sulfo group, -R^Five, -OR^Five, −
CO_TwoR⁶, -SR⁷,-(CO) SR⁷,-(CS) OR
⁷Or -CS_TwoR⁷(Where R^FiveIs an optionally substituted al
A kill group, an optionally substituted alkenyl group, an optionally substituted
Good alkynyl group, cycloalkyl which may be substituted
Group, an optionally substituted cycloalkenyl group,
An aryl group, an optionally substituted heterocyclic group or
Represents a sil group. R⁶Is an alkyl group which may be substituted,
Alkenyl group which may be substituted, alkyl which may be substituted
Nyl group, optionally substituted aryl group or substituted
Represents a good heterocyclic group. R⁷Is an optionally substituted alk
Represents an aryl group or an optionally substituted aryl group. )
You. A and B each have the formula:(E represents a single bond or an alkylene group.
Means that one means a double bond together with the solid line, and the other
Both mean a single bond. R¹Is a single bond with a broken line and a solid line
Bond to the nitrogen atom that bonds to the bond that represents R¹, R^Two,
R^ThreeAnd R^FourAre each independently a hydrogen atom, a halogen atom
, Hydroxyl group, mercapto group, nitro group, cyano group,
Boxy group, optionally substituted amino group, optionally substituted
Hydroxylamino group, carbamoy which may be substituted
, A sulfamoyl group which may be substituted, a sulfo group,
NH protecting group, -R^Five, -OR^Five, -CO_TwoR⁶, -SR
⁷,-(CO) SR⁷,-(CS) OR⁷Or -CS _TwoR
⁷(Where R^Five, R⁶And R⁷Is as defined above. )
Represent. Also, R¹, R ^Two, R^ThreeAnd R^FourIs the role of
Two are bonded together to form a nitrogen atom,
It may form a heterocyclic ring which may be substituted. Also, the formula:
NR^ThreeR^FourHas the formula: -N = C (NH_Two) NR⁴³R⁴⁴Represented by
May be represented. R⁴³And R⁴⁴Is the following
(1) or (2). (1) independently a hydrogen atom, an alkyl group having 1 to 4 carbon atoms,
− (CH_Two)_n-COCH _Three(N represents an integer of 1 to 3
You. ),-(CH_Two)_n-CO_TwoR³²(N is as defined above.
is there. R³²Represents an alkyl group having 1 to 3 carbon atoms. ),-
(CH_Two)_n-CONR³³R³⁴(N is as defined above.
R³³And R³⁴Is independently a hydrogen atom or a group having 1 to 3 carbon atoms.
Represents an alkyl group. ),-(CH_Two)_m-OR³⁵(M is
Represents 2 or 3. R³⁵Is a hydrogen atom,
Alkyl group or-(CH_Two)_m-OR³⁶(M is as defined above
It is. R³⁶Is a hydrogen atom or an alkyl having 1 to 3 carbon atoms
Represents a group. ). ),-(CH_Two)_m-NR³⁷R
³⁸(M is as defined above. R³⁷And R³⁸Independently
Represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, or
Or R³⁷And R³⁸Together, together with the nitrogen atom,
Loridine, piperidine, azepan, morpholine or N
-Methylpiperazine (in these, pyrrolidine,
Peridine, azepan, morpholine and N-methylpipe
Razine may be substituted with one or two methyls.
No. ). ), Phenyl, pyridyl, pyrimidini
, Pyridazinyl, pyrazinyl, tetrazolyl, benzyl
, Pyridylmethyl, pyrimidinylmethyl, pyridazini
Methyl, pyrazinylmethyl, tetrazolylmethyl, water
An acid group, an alkoxy group having 1 to 3 carbon atoms or -NR³⁹R⁴⁰
(R³⁹And R⁴⁰Independently represent a hydrogen atom, a carbon number of 1 to 3
Represents an alkyl group, phenyl or pyridyl. )
You. (2) 5-7 member saturated nitrogen containing together with nitrogen atom
A heterocyclic group (a 5- to 7-membered saturated nitrogen-containing heterocyclic group is an alkyl
Group, amino group, hydroxyl group, alkoxy group and oxo group.
Substituted with one or two substituents arbitrarily selected from the group
It may be. ). ). A and
And B are the other of the formula: -JG (wherein G is an optionally substituted aryl group or
Represents a heterocyclic group which may be substituted. J is -C (R⁸R⁹)-
Or -C (= CR⁸R⁹)-. R⁸And R⁹Is
Each independently a hydrogen atom, an optionally substituted lower alcohol
Represents an xy group or an optionally substituted lower alkyl group.
You. Also, R⁸And R⁹Are bonded together to form a carbon
Optionally substituted hydrocarbon ring, substituted with atoms
1,3-dioxane ring or may be substituted
A 1,3-dioxolane ring may be formed. )
Represents a group. An isoxazole derivative represented by
A medicament comprising the pharmaceutically acceptable salt thereof. 2. The medicament according to claim 1, wherein E is a single bond or a lower alkylene group. 3. D is a hydrogen atom, a nitro group, a cyano group, a carboxy group, an optionally substituted amino group, an optionally substituted hydroxylamino group, an optionally substituted carbamoyl group, —R ⁵ or —CO. ₂ R ⁶ (wherein R ⁵ and R ⁶
Has the same meaning as in claim 1. The pharmaceutical according to claim 1 or 2, wherein 4. The method according to claim 3, wherein D is a hydrogen atom, a carboxy group, —R ⁵ or —CO ₂ R ⁶ (wherein, R ⁵ and R ⁶ have the same meanings as in claim 1). Medicine. 5. R ¹ , R ² , R ³ and R ⁴ are each independently a hydrogen atom, a hydroxyl group, an optionally substituted amino group, an optionally substituted hydroxylamino group, or an optionally substituted Alkoxy group, optionally substituted alkyl group, optionally substituted alkenyl group, optionally substituted alkynyl group, optionally substituted cycloalkyl group, optionally substituted cycloalkenyl group, optionally substituted Represents an aryl group, a heterocyclic group which may be substituted or an acyl group, or a compound represented by the formula: —NR ³ R ⁴ having a formula: —N ＝ C (NH ₂ ) NR ⁴³
R represents a group represented by R ⁴⁴ (R ⁴³ and R ⁴⁴ have the same meanings as in claim 1), or R ¹ , R ² ,
R ³ and together any two members to one of R ^4, together with the nitrogen atom, a medicament according to any one of the four claims 1 to form a heterocyclic ring which may be substituted. 6. R ¹ , R ² , R ³ and R ⁴ are each independently a hydrogen atom, a hydroxyl group, an optionally substituted amino group, an optionally substituted hydroxylamino group, or an optionally substituted Alkoxy group, optionally substituted alkyl group, optionally substituted alkenyl group, optionally substituted alkynyl group, optionally substituted cycloalkyl group, optionally substituted aryl group, optionally substituted hetero group Represents a ring group or an acyl group, or the formula: —NR ³ R ⁴ is represented by the formula: —N−C (NH
_{^{2) NR 43 R 44 (R}} 43 and R ^{4 4} is or represents a group represented by the same meaning and significance in claim 1.), Or,
R ^1, R ^2, R ³ and together any two members to one of R ^4, together with the nitrogen atom, according to claim 5 medicament according to form a heterocyclic ring which may be substituted. 7. G is optionally substituted phenyl, optionally substituted naphthyl, optionally substituted furyl, optionally substituted thienyl, optionally substituted indolyl, optionally substituted isothiazolyl, substituted Optionally substituted benzothienyl, optionally substituted isobenzofuranyl, optionally substituted pyrrolyl, optionally substituted benzofuryl, optionally substituted imidazolyl, optionally substituted pyrazolyl, optionally substituted Isoxazolyl, optionally substituted isothiazolyl, optionally substituted thiazolyl, optionally substituted oxazolyl, optionally substituted benzimidazolyl, optionally substituted benzothiazolyl, optionally substituted benzoxazolyl, substituted Optionally substituted pyridyl, optionally substituted pyrazinyl, optionally substituted pyrimidi 1, optionally substituted pyridazinyl, optionally substituted triazinyl, optionally substituted quinolyl, optionally substituted isoquinolyl, optionally substituted quinazolinyl, optionally substituted quinoxalinyl, optionally substituted 2 , 3-Dihydro-benzo [1,
4] The medicament according to any one of claims 1 to 6, which is dioxinyl or carbazolyl which may be substituted. 8. The formula: embedded image[Where G¹Is phenyl, biphenyl-4-yl, 3
-Benzoylphenyl, 4-benzoylphenyl, 1H
-Indol-2-yl, 1H-indole-3-i
1-methyl-1H-indol-2-yl, 1-methyl
Tyl-1H-indol-3-yl, 2,3-dihydro
-Benzo [1,4] dioxin-6-yl, 1-benzo
Furan-5-yl, 1-benzofuran-6-yl, quino
Ryl, isoquinolyl, phenylpyridyl, phenylpyridyl
Midinyl, phenylpyridazinyl or phenylpyrazi
Nil (in these, phenyl, biphenyl-4-i
, 3-benzoylphenyl, 4-benzoylphenyi
1H-indole-2-yl, 1H-indole-
3-yl, 1-methyl-1H-indol-2-yl,
1-methyl-1H-indol-3-yl, 2,3-di
Hydro-benzo [1,4] dioxin-6-yl, 1-
Benzofuran-5-yl, 1-benzofuran-6-i
Quinolyl, isoquinolyl, phenylpyridyl,
Nilpyrimidinyl, phenylpyridazinyl and phenyl
Lupyrazinyl is a fluorine, chlorine, bromine,
Cetyl, cyano, -CO_TwoR²⁹(R²⁹Has 1 to 3 carbon atoms
Represents an alkyl group. ) And -CONR³⁰R³¹(R³⁰You
And R³¹Independently represent a hydrogen atom or an atom having 1 to 3 carbon atoms.
Represents a alkyl group. ) Arbitrarily selected from the group consisting of
Or two substituents. ). R^{twenty three}And
And R^{twenty four}Is independently a hydrogen atom, an alkyl having 1 to 4 carbon atoms
Represents, together with, the group methoxy or ethoxy
Represents methylene. Formula: = C (NR^{twenty five}R²⁶) NR²⁷R
²⁸Is as in the following (1), (2) or (3)
You. (1) R^{twenty five}And R²⁶Of the following (a) or (b)
And R²⁷And R²⁸Is the following (c) or
(D). (A) independently a hydrogen atom, an alkyl group having 1 to 4 carbon atoms,
− (CH_Two)_n-COCH_Three(N is the meaning in claim 1)
Is synonymous with ),-(CH_Two)_n-CO_TwoR³²(N and
And R³²Has the same meaning as in claim 1. ),-
(CH_Two)_n-CONR³³R³⁴(N, R³³And R³⁴Ha
It has the same meaning as in claim 1. ),-(CH_Two)_m−
OR³⁵(M and R³⁵Has the same meaning as in claim 1.
is there. ),-(CH_Two)_m-NR³⁷R³⁸(M, R³⁷and
R³⁸Has the same meaning as in claim 1. ), Pheni
, Pyridyl, pyrimidinyl, pyridazinyl, pyrazini
, Tetrazolyl, benzyl, pyridylmethyl, pirimi
Dinylmethyl, pyridazinylmethyl, pyrazinylmethi
, Tetrazolylmethyl, hydroxyl group, C 1-3 alkyl
Coxy group or -NR³⁹R⁴⁰(R³⁹And R⁴⁰Is the claim
Synonymous with the meaning in 1. ). (B) 5-7 membered saturated nitrogen containing together with nitrogen atoms
A heterocyclic group (a 5- to 7-membered saturated nitrogen-containing heterocyclic group is an alkyl
Group, amino group, hydroxyl group, alkoxy group and oxo group.
Substituted with one or two substituents arbitrarily selected from the group
It may be. ). (C) independently a hydrogen atom, an alkyl group having 1 to 4 carbon atoms,
− (CH_Two)_n-COCH_Three(N is as defined above.
You. ),-(CH_Two)_n-CO_TwoR³²(N and R³²Is before
Synonymous with ),-(CH_Two)_n-CONR³³R
³⁴(N, R³³And R³⁴Is as defined above. ),-
(CH_Two)_m-OR³⁵(M and R³⁵Is as defined above
You. ),-(CH_Two)_m-NR³⁷R³⁸(M, R³⁷And R
³⁸Is as defined above. ), Phenyl, pyridyl, pyri
Midinyl, pyridazinyl, pyrazinyl, tetrazolyl,
Benzyl, pyridylmethyl, pyrimidinylmethyl, pyri
Dazinylmethyl, pyrazinylmethyl, tetrazolylmethyl
, A hydroxyl group, an alkoxy group having 1 to 3 carbon atoms or -NR
³⁹R⁴⁰(R³⁹And R⁴⁰Is as defined above. )
You. (D) 5-7 membered saturated nitrogen containing together with nitrogen atoms
An elementary heterocyclic group (where the 5- to 7-membered saturated nitrogen-containing heterocyclic group is
Alkyl group, amino group, hydroxyl group, alkoxy group, oxo
One or two substituents arbitrarily selected from the group consisting of groups
May be substituted. ). (2) R²⁶And R²⁷Are two nitrogen sources together
Together with a carbon atom and a 5 to 7-membered saturated nitrogen-containing heterocyclic group (this
Here, the 5- to 7-membered saturated nitrogen-containing heterocyclic group is an alkyl group,
A group consisting of a mino group, a hydroxyl group, an alkoxy group, and an oxo group
Substituted with one or two substituents arbitrarily selected from
Good). R^{twenty five}And R²⁸Is independently a hydrogen atom,
An alkyl group having 1 to 3 carbon atoms, acetyl or-(C
H_Two)_m-OR³⁶(M is as defined above. R³⁶Is the claim
Synonymous with the meaning in 1. ). Formula (3): = C (NR^{twenty five}R²⁶) NR²⁷R²⁸Is the formula: = C
(NR⁴¹R⁴²) N = C (NH_Two) NR⁴³R⁴⁴Represents R
⁴¹And R⁴²Is the following (a¹) Or (b)¹) On the street
Yes, R⁴³And R ⁴⁴Is the following (c¹) Or (d¹)
It is as follows. (A¹) Independently a hydrogen atom, an alkyl having 1 to 4 carbon atoms
Group,-(CH_Two)_n-COCH_Three(N is as defined above.
You. ),-(CH_Two)_n-CO_TwoR³²(N and R³²Is before
Synonymous with ),-(CH_Two)_n-CONR³³R
³⁴(N, R³³And R³⁴Is as defined above. ),-
(CH_Two)_m-OR³⁵(M and R³⁵Is as defined above
You. ),-(CH_Two)_m-NR³⁷R³⁸(M, R³⁷And R
³⁸Is as defined above. ), Phenyl, pyridyl, pyri
Midinyl, pyridazinyl, pyrazinyl, tetrazolyl,
Benzyl, pyridylmethyl, pyrimidinylmethyl, pyri
Dazinylmethyl, pyrazinylmethyl, tetrazolylmethyl
, A hydroxyl group, an alkoxy group having 1 to 3 carbon atoms or -NR
³⁹R⁴⁰(R³⁹And R⁴⁰Is as defined above. )
You. (B¹5) together with the nitrogen atom,
A nitrogen heterocyclic group (a 5- to 7-membered saturated nitrogen-containing heterocyclic group is
Group, amino group, hydroxyl group, alkoxy group, oxo group
Substituted with one or two substituents arbitrarily selected from the group consisting of
May be done. ). (C¹) Independently a hydrogen atom, an alkyl having 1 to 4 carbon atoms
Group,-(CH_Two)_n-COCH_Three(N is as defined above.
You. ),-(CH_Two)_n-CO_TwoR³²(N and R³²Is before
Synonymous with ),-(CH_Two)_n-CONR³³R
³⁴(N, R³³And R³⁴Is as defined above. ),-
(CH_Two)_m-OR³⁵(M and R³⁵Is as defined above
You. ),-(CH_Two)_m-NR³⁷R³⁸(M, R³⁷And R
³⁸Is as defined above. ), Phenyl, pyridyl, pyri
Midinyl, pyridazinyl, pyrazinyl, tetrazolyl,
Benzyl, pyridylmethyl, pyrimidinylmethyl, pyri
Dazinylmethyl, pyrazinylmethyl, tetrazolylmethyl
, A hydroxyl group, an alkoxy group having 1 to 3 carbon atoms or -NR
³⁹R⁴⁰(R³⁹And R⁴⁰Is as defined above. )
You. (D¹5) together with the nitrogen atom,
A nitrogen heterocyclic group (a 5- to 7-membered saturated nitrogen-containing heterocyclic group is
Group, amino group, hydroxyl group, alkoxy group, oxo group
Substituted with one or two substituents arbitrarily selected from the group consisting of
May be done. ). Or the formula:[Where G¹, R^{twenty three}And R^{twenty four}Is as defined above. Formula: -N (R⁴⁵) C (NR⁴⁶R⁴⁷) = NR⁴⁸Is the following
(1¹) Or (2)¹A). (1¹) R⁴⁵Is an alkyl group having 1 to 3 carbon atoms or
Represents chill. R⁴⁸Is a hydrogen atom, an alkyl having 1 to 3 carbon atoms.
Represents acetyl or acetyl. R⁴⁶And R⁴⁷Is the following
(A^Two) Or (b)^TwoA). (A^Two) Independently a hydrogen atom, an alkyl having 1 to 4 carbon atoms
Group,-(CH_Two)_n-COCH_Three(N is as defined above.
You. ),-(CH_Two)_n-CO_TwoR³²(N and R³²Is before
Synonymous with ),-(CH_Two)_n-CONR³³R
³⁴(N, R³³And R³⁴Is as defined above. ),-
(CH_Two)_m-OR³⁵(M and R³⁵Is as defined above
You. ),-(CH_Two)_m-NR³⁷R³⁸(M, R³⁷And R
³⁸Is as defined above. ), Phenyl, pyridyl, pyri
Midinyl, pyridazinyl, pyrazinyl, tetrazolyl,
Benzyl, pyridylmethyl, pyrimidinylmethyl, pyri
Dazinylmethyl, pyrazinylmethyl, tetrazolylmethyl
, A hydroxyl group, an alkoxy group having 1 to 3 carbon atoms or -NR
³⁹R⁴⁰(R³⁹And R⁴⁰Is as defined above. )
You. (B^Two5) together with the nitrogen atom,
A nitrogen heterocyclic group (a 5- to 7-membered saturated nitrogen-containing heterocyclic group is
Group, amino group, hydroxyl group, alkoxy group, oxo group
Substituted with one or two substituents arbitrarily selected from the group consisting of
May be done. ). (2¹) R⁴⁵And R⁴⁶Together with the nitrogen atom
And a 5- to 7-membered saturated nitrogen-containing heterocyclic group (here, a 5- to 7-membered saturated
The nitrogen-containing heterocyclic group is an alkyl group, an amino group, a hydroxyl group,
Arbitrarily selected from the group consisting of an alkoxy group and an oxo group
It may be substituted with one or two substituents. ).
R⁴⁷And R⁴⁸Is independently a hydrogen atom, a group having 1 to 3 carbon atoms.
An alkyl group, acetyl or-(CH_Two)_m-OR³⁶(M
And R³⁶Is as defined above. ). ]
Isoxazole derivative or pharmaceutically acceptable salt thereof
The medicament according to claim 1, which comprises: 9. The formula: embedded image[Where G^TwoIs 2-fluoro-biphenyl-4-i
, 2'-fluoro-biphenyl-4-yl or 3-
Represents benzoylphenyl. R⁴⁹Represents methyl. R
⁵⁰Represents a hydrogen atom, methyl, methoxy or ethoxy
You. Formula: = C (NR⁵¹R⁵²) NR⁵³R⁵⁴Is (1^Two),
(2^Two) Or (3)^TwoA). (1^Two) R⁵¹And R⁵²Is the following (a^Three), (B)^Three)
Or (c^Three) And R⁵³And R⁵⁴Is the following
(D^Three), (E^Three) Or (f^ThreeA). (A^Three) Independently a hydrogen atom or an alkyl having 1 to 4 carbon atoms
Represents a hydroxyl group. (B^ThreeOne represents a hydrogen atom and the other represents-(CH_Two)_n−
COCH_Three(N has the same meaning as in claim 1)
You. ),-(CH_Two)_n-CO_TwoR³²(N and R³²Ha
It has the same meaning as in claim 1. ),-(CH_Two)_n−
CONR³³R³⁴(N, R³³And R³⁴Is in claim 1
This is synonymous with meaning. ),-(CH_Two)_m-OR ³⁵(M
And R³⁵Has the same meaning as in claim 1. )Also
Is-(CH_Two)_m-NR³⁷R³⁸(M, R³⁷And R³⁸Ha
It has the same meaning as in claim 1. ). (C^Three) Together with the nitrogen atom, pyrrolidine,
Zepan, morpholine, thiazoline, piperidine-2-o
, Piperidin-4-one, thiamorpholine, carbon number 1
Piperazines optionally substituted at the 4-position with alkyl groups
Even if the 4-position is substituted with an alkoxy group having 1 to 3 carbon atoms.
Good piperidine, 4-hydroxypiperidine, or 1
Or substituted by two alkyl groups having 1 to 3 carbon atoms
Piperidine substituted at the 4-position with a good amino group (these
, Pyrrolidine, azepane, morpholine, thiazo
Phosphorus, piperidin-2-one, piperidin-4-one,
Thiamorpholine, C1-C3 alkyl group at 4-position
Piperazine which may be exchanged, alkoxy having 1 to 3 carbon atoms
Piperidine, 4-hydroxy optionally substituted at the 4-position with a group
Sipiperidine, and 1 or 2 carbon atoms having 1 to 3 carbon atoms.
Substituted at the 4-position with an amino group which may be substituted with a alkyl group
Piperidine may be substituted with one or two methyl
Good. ). (D^Three) Independently a hydrogen atom or an alkyl having 1 to 4 carbon atoms
Represents a hydroxyl group. (E^ThreeOne represents a hydrogen atom and the other represents-(CH_Two)_n−
COCH_Three(N is as defined above),-(CH_Two)_n
-CO_TwoR³²(N and R³²Is as defined above. ),
− (CH_Two)_n-CONR³³R³⁴(N, R³³And R³⁴Is
It is as defined above. ),-(CH_Two)_m-OR³⁵(M and
And R³⁵Is as defined above. ) Or-(CH_Two)_m-N
R³⁷R³⁸(M, R³⁷And R³⁸Is as defined above. )
Represents (F^Three) Together with the nitrogen atom, pyrrolidine,
Zepan, morpholine, thiazoline, piperidine-2-o
, Piperidin-4-one, thiamorpholine, carbon number 1
Piperazines optionally substituted at the 4-position with alkyl groups
Even if the 4-position is substituted with an alkoxy group having 1 to 3 carbon atoms.
Good piperidine, 4-hydroxypiperidine, or 1
Or substituted by two alkyl groups having 1 to 3 carbon atoms
Piperidine substituted at the 4-position with a good amino group (these
, Pyrrolidine, azepane, morpholine, thiazo
Phosphorus, piperidin-2-one, piperidin-4-one,
Thiamorpholine, C1-C3 alkyl group at 4-position
Piperazine which may be exchanged, alkoxy having 1 to 3 carbon atoms
Piperidine, 4-hydroxy optionally substituted at the 4-position with a group
Sipiperidine, and 1 or 2 carbon atoms having 1 to 3 carbon atoms.
Substituted at the 4-position with an amino group which may be substituted with a alkyl group
Piperidine may be substituted with one or two methyl
Good. ). (2^TwoFormula: = C (NR⁵¹R⁵²) NR⁵³R⁵⁴Has the formula:(Where R⁵⁵Is an alkyl group having 1 to 3 carbon atoms, acetyl
Or-(CH_Two)_m-OR⁵⁶(M is as defined above.
R⁵⁶Represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.
You. ). ). (3^TwoFormula: = C (NR⁵¹R⁵²) NR⁵³R⁵⁴But the formula: =
C (NR⁵⁷R⁵⁸) N = C (NH_Two) NR⁵⁹R⁶⁰Represents
R⁵⁷And R⁵⁸Is the following (a^Four), (B)^Four) Or (c)
^Four) And R^{Five 9}And R⁶⁰Is the following (d^Four),
(E^Four) Or (f^FourA). (A^Four) Independently a hydrogen atom or an alkyl having 1 to 4 carbon atoms
Represents a hydroxyl group. (B^FourOne represents a hydrogen atom and the other represents-(CH_Two)_n−
COCH_Three(N is as defined above),-(CH_Two)_n
-CO_TwoR³²(N and R³²Is as defined above. ),
− (CH_Two)_n-CONR³³R³⁴(N, R³³And R³⁴Is
It is as defined above. ),-(CH_Two)_m-OR³⁵(M and
And R³⁵Is as defined above. ) Or-(CH_Two)_m-N
R³⁷R³⁸(M, R³⁷And R³⁸Is as defined above. )
Represents (C^Four) Together with the nitrogen atom, pyrrolidine,
Zepan, morpholine, thiazoline, piperidine-2-o
, Piperidin-4-one, thiamorpholine, carbon number 1
Piperazines optionally substituted at the 4-position with alkyl groups
Even if the 4-position is substituted with an alkoxy group having 1 to 3 carbon atoms.
Good piperidine, 4-hydroxypiperidine, or 1
Or substituted by two alkyl groups having 1 to 3 carbon atoms
Piperidine substituted at the 4-position with a good amino group (these
, Pyrrolidine, azepane, morpholine, thiazo
Phosphorus, piperidin-2-one, piperidin-4-one,
Thiamorpholine, C1-C3 alkyl group at 4-position
Piperazine which may be exchanged, alkoxy having 1 to 3 carbon atoms
Piperidine, 4-hydroxy optionally substituted at the 4-position with a group
Sipiperidine, and 1 or 2 carbon atoms having 1 to 3 carbon atoms.
Substituted at the 4-position with an amino group which may be substituted with a alkyl group
Piperidine may be substituted with one or two methyl
Good. ). (D^Four) Independently a hydrogen atom or an alkyl having 1 to 4 carbon atoms
Represents a hydroxyl group. (E^FourOne represents a hydrogen atom and the other represents-(CH_Two)_n−
COCH_Three(N is as defined above),-(CH_Two)_n
-CO_TwoR³²(N and R³²Is as defined above. ),
− (CH_Two)_n-CONR³³R³⁴(N, R³³And R³⁴Is
It is as defined above. ),-(CH_Two)_m-OR³⁵(M and
And R³⁵Is as defined above. ) Or-(CH_Two)_m-N
R³⁷R³⁸(M, R³⁷And R³⁸Is as defined above. )
Represents (F^Four) Together with the nitrogen atom, pyrrolidine,
Zepan, morpholine, thiazoline, piperidine-2-o
, Piperidin-4-one, thiamorpholine, carbon number 1
Piperazines optionally substituted at the 4-position with alkyl groups
Even if the 4-position is substituted with an alkoxy group having 1 to 3 carbon atoms.
Good piperidine, 4-hydroxypiperidine, or 1
Or substituted by two alkyl groups having 1 to 3 carbon atoms
Piperidine substituted at the 4-position with a good amino group (these
, Pyrrolidine, azepane, morpholine, thiazo
Phosphorus, piperidin-2-one, piperidin-4-one,
Thiamorpholine, C1-C3 alkyl group at 4-position
Piperazine which may be exchanged, alkoxy having 1 to 3 carbon atoms
Piperidine, 4-hydroxy optionally substituted at the 4-position with a group
Sipiperidine, and 1 or 2 carbon atoms having 1 to 3 carbon atoms.
Substituted at the 4-position with an amino group which may be substituted with a alkyl group
Piperidine may be substituted with one or two methyl
Good. ). Isoxazole derivatives represented by
Or the pharmaceutically acceptable salt thereof.
medicine. 10. The formula: embedded image[Where G^Two, R⁴⁹And R⁵⁰Is the meaning in claim 9.
Synonymous with righteousness. Formula: = C (NR⁶¹R⁶²) NR⁶³R⁶⁴Is the following
(1^Three), (2^Three) Or (3)^ThreeA). (1^Three) R⁶³And R⁶⁴Both represent a hydrogen atom. R⁶¹
And R⁶²Is the following (a^Five), (B)^Five) Or (c)^Five)
It is as follows. (A^Five) Independently a hydrogen atom or an alkyl having 1 to 3 carbon atoms
Represents a hydroxyl group. (B^FiveOne represents a hydrogen atom and the other represents-(CH_Two)_n−
CO_TwoR³²(N and R ³²Is the same as the meaning in claim 1.
Righteous. ),-(CH_Two)_m-OR⁶⁵(M is 2 or 3
Represents R⁶⁵Is a hydrogen atom, an alkyl having 1 to 3 carbon atoms
Group, 2-hydroxyethyl or 3-hydroxypropyl
Represents ) Or-(CH_Two)_m-NR⁶⁶R ⁶⁷(M is before
Synonymous with R⁶⁶And R⁶⁷Is independently a hydrogen atom
Or an alkyl group having 1 to 3 carbon atoms, or R⁶⁶
And R⁶⁷Together with the nitrogen atom,
, Piperidine, morpholine or N-methylpiperazine
(In these, pyrrolidine, piperidine, morpho
Phosphorus and N-methylpiperazine are available in one or two
It may be substituted with chill. ). ). (C^Five) Together with the nitrogen atom, pyrrolidine,
Peridine, morpholine or N-methylpiperazine (this
In these, pyrrolidine, piperidine, morpholine and
And N-methylpiperazine are one or two methyl
It may be replaced. ). (2^ThreeFormula: = C (NR⁶¹R⁶²) NR⁶³R⁶⁴Has the formula:(R⁶⁸Is an alkyl group having 1 to 3 carbon atoms, 2-hydroxy
Represents ethyl or 3-hydroxypropyl. )
Represents a group. (3^Three) R⁶¹And R⁶²Together with the nitrogen atom
Represents morpholine, and R⁶³And R⁶⁴Become together
To give amino-morpholin-4-yl-methylene
You. Isoxazole derivative represented by the formula
The medicament according to claim 1, comprising a salt acceptable in the above. 11. The medicament according to claim 1, comprising an isoxazole derivative selected from the following compounds or a pharmaceutically acceptable salt thereof. ({3- [1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylimino}-
Morpholin-4-yl-methyl) -amine [{3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylimino}-
(4-Methyl-piperazin-1-yl) -methyl] -amine N- {3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-yl} -N'-
(2-morpholin-4-yl-ethyl) -guanidine ({3- [1- (2-fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-ylimino} -morpholine-4- Yl-methyl) -amine [{3- [1- (2-fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-ylimino}-(4-methyl-piperazin-1-yl) −
Methyl] -amine N- {3- [1- (2-fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-yl} -N '-(2-morpholin-4-yl- Ethyl)-
Guanidine ({3- [1- (2'-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylimino}-
Morpholin-4-yl-methyl) -amine [{3- [1- (2'-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylimino}-
(4-Methyl-piperazin-1-yl) -methyl] -amine N- {3- [1- (2'-fluoro-biphenyl-4-)
Yl) -ethyl] -isoxazol-5-yl {-N '
-(2-morpholin-4-yl-ethyl) -guanidine ({3- [1- (2'-fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-ylimino} -morpholine- 4-yl-methyl) -amine [{3- [1- (2'-fluoro-biphenyl-4-yl) -1-methyl-ethyl] -isoxazol-5-ylimino}-(4-methyl-piperazine-1 -Il)-
Methyl] -amine N- {3- [1- (2'-fluoro-biphenyl-4-
Yl) -1-methyl-ethyl] -isoxazole-5
Yl @ -N '-(2-morpholin-4-yl-ethyl)
-Guanidine (3- {1- [5- (amino-morpholin-4-yl-
Methyleneamino) -isoxazol-3-yl] -ethyl} -phenyl) -phenyl-methanone [3- (1- {5- [amino- (4-methyl-piperazin-1-yl) -methyleneamino] -isoxazole-
3-yl {-ethyl) -phenyl] -phenyl-methanone N- {3- [1- (3-benzoyl-phenyl) -ethyl] -isoxazol-5-yl} -N '-(2-morpholin-4- Yl-ethyl) -guanidine (3- {1- [5- (amino-morpholin-4-yl-
Methyleneamino) -isoxazol-3-yl] -1-
Methyl-ethyl} -phenyl) -phenyl-methanone [3- (1- {5- [amino- (4-methyl-piperazin-1-yl) -methyleneamino] -isoxazole-
3-yl} -1-methyl-ethyl) -phenyl] -phenyl-methanone N- {3- [1- (3-benzoyl-phenyl) -1-]
Methyl-ethyl] -isoxazol-5-yl {-N ′
-(2-morpholin-4-yl-ethyl) -guanidine 12. The medicament according to any one of claims 1 to 11, which is a therapeutic or prophylactic agent for an autoimmune disease. 13. The medicament according to any one of claims 1 to 11, which is a therapeutic or prophylactic agent for an inflammatory disease. 14. The medicament according to any one of claims 1 to 11, which is an antirheumatic agent. 15. The medicament according to any one of claims 1 to 11, which is an anti-inflammatory agent.